US008758816B2

(12) United States Patent (10) Patent No.: US 8,758,816 B2 Fuge et al. (45) Date of Patent: Jun. 24, 2014

(54) COMPOSITIONS COMPRISING 4,061,768 A 12, 1977 Gorvin AZELASTINE AND METHODS OF USE 4,077.407 A 3, 1978 Theeuwes et al. 4,091,108 A 5, 1978 Batchelor et al. THEREOF 4,094.968 A 6, 1978 Hodson et al. 4,226,848 A 10/1980 Nagai et al. (75) Inventors: Dennis Fuge. Somerset, NJ (US); John 4,235,236 A 11/1980 Theeuwes Higson, Plymouth Meeting, PA (US); 4,254,129 A 3, 1981 Carr et al. Bryan A. Roecklein, Somerset, NJ (US); 4,313,931 A 2f1982 Walther et al. 4,430,343 A 2, 1984 Iemura et al. Gul Balwani, West Windsor, NJ (US); 4,435,440 A 3/1984 Hough et al. Alexander D. D'Addio, Piscataway, NJ 4,449,983 A 5/1984 Cortese et al. (US) 4,455,143 A 6, 1984 Theeuwes et al. (73) Assignee: Meda Pharmaceuticals Inc., Somerset, (Continued) NJ (US) FOREIGN PATENT DOCUMENTS

(*) Notice: Subject to any disclaimer, the term of this AU 37674/72 7/1973 patent is extended or adjusted under 35 DE 1046 625 12, 1958 U.S.C. 154(b) by 498 days. (Continued) (21) Appl. No.: 12/569,548 OTHER PUBLICATIONS (22) Filed: Sep. 29, 2009 Cheng et al., PNAS, vol. 23, No. 17, 6682-6687.2 (Apr. 25, 2006).* (65) Prior Publication Data (Continued) US 2010/O152147 A1 Jun. 17, 2010 Primary Examiner — Michael G. Hartley Related U.S. Application Data Assistant Examiner — Robert Cabral (63) Continuation-in-part of application No. 1 1/486,454, (74) Attorney, Agent, or Firm — Sterne, Kessler, Goldstein filed on Jul. 14, 2006, now abandoned, which is a & FOX PL.L.C. continuation-in-part of application No. 1 1/284,109, filed on Nov. 22, 2005, now Pat. No. 8,071,073. (57) ABSTRACT (60) Provisional application No. 60/630,274, filed on Nov. The present invention provides pharmaceutical compositions 24, 2004. comprising azelastine, or a pharmaceutically acceptable salt or ester thereof including aZelastine hydrochloride, and (51) Int. Cl. optionally one or more additional active agents. Preferred B65D 35/00 (2006.01) Such compositions further comprise one or more pharmaceu A6 IK9/00 (2006.01) tically acceptable carriers or excipients that reduce the (52) U.S. Cl. amount of post-nasal drip, and/or that minimize or mask the USPC ...... 424/467; 222/92: 222/93; 222/94; unpleasant bitter taste associated with post-nasal drip, of the 222/95; 222/206: 424/400 compositions into the oral cavity, upon intranasal or ocular (58) Field of Classification Search administration of the compositions. Especially effective USPC ...... 222/92,93, 94, 95, 206 excipients used in the compositions of the present invention See application file for complete search history. are hypromellose as a viscosity modifier and Sucralose as a taste-masking agent. The invention also generally relates to (56) References Cited pharmaceutical compositions comprising one or more active U.S. PATENT DOCUMENTS pharmaceutical ingredients, such as azelastine orpharmaceu tically acceptable salts or esters thereof including azelastine 158,564 A 1, 1875 Barnes hydrochloride, particularly wherein the compositions are 2,119,643 A 6, 1938 Mendl 2,136,940 A 11, 1938 Ehbrecht provided in unit dosage form. In certain embodiments, the 2.457,024 A 12/1948 Arp invention provides Such unit dosage pharmaceutical compo 2,822,314 A 2f1958 Ferlauto et al. sitions comprising azelastine hydrochloride formulated for 2.925,417 A 2, 1960 Elslager et al. use as nasal sprays and/or ocular solutions or drops. The 2,995,308 A 8, 1961 Ashkenaz invention also provides methods of treating or preventing 3,017.411 A 1/1962 Engelbrecht et al. 3,144,485. A 8, 1964 Bennet al. certain disorders, or symptomatic relief therefrom, by admin 3,173,876 A 3, 1965 ZObrist istering the compositions of the invention to a patient, e.g., for 3,267,586 A 8, 1966 Molstedt et al. the symptomatic relief of a variety of allergic and non-allergic 3,541,005 A 11, 1970 Strathmann et al. conditions, particularly conjunctivitis, sinusitis, rhinitis and 3,541,006 A 11, 1970 Bixler et al. rhinosinusitis. The compositions and methods of the present 3,546,142 A 12/1970 Michaels et al. 3,753,988 A 8/1973 Rodway et al. invention provide significant value in terms of patient accept 3,813,384 A 5/1974 Vogelsang et al. ability, convenience, and compliance. 3,845,052 A 10, 1974 Stachel et al. 3,854,770 A 12/1974 Grise et al. 3,878,217 A 4, 1975 Carr et al. 141 Claims, 10 Drawing Sheets US 8,758,816 B2 Page 2

(56) References Cited 6,380,046 B1 4/2002 Yamazaki 6,382.205 B1 5, 2002 Weinstein et al. U.S. PATENT DOCUMENTS 6,391,340 B1 5/2002 Malmqvist et al. 6,402,055 B1 6/2002 Jaeger et al. 4.495,170 A 1/1985 Beyts et al. 6,497.373 B2 12/2002 Jaeger et al. 4,501,893 A 2/1985 Findlay et al. 6,552,024 B1 4/2003 Chen et al. 4,570,630 A 2f1986 Elliott et al. 6,576,677 B1 6/2003 Ukai et al. 4,602,099 A 7, 1986 Parker 6,596.298 B2 7/2003 Leung et al. 4,621,094. A 1 1/1986 Findlay et al. 6,599.913 B 72003 Johnson et al. 4,628,055 A 12/1986 Sherlock 6,610,271 B2 8/2003 Wermeling 4.7.04.285 A 11, 1987 Alderman 6,615,826 B1 9, 2003 Gabrio et al. 4,704,387 A 1/1987 Engeletal. 6,620,438 B2 9/2003 Pairet et al. 4,728,509 A 3, 1988 Shimizu et al. 6,641,658 B1 1 1/2003 Dubey 4,738,984 A 4, 1988 Parker 6,646,121 B2 11/2003 El Kabbani et al. 4749,700 A 6/1988 Wenig 6,649,602 B1 1 1/2003 Yanni 4,751.294 A 6, 1988 Jackson 6,652,901 B2 11/2003 Ishii 4.769.369 A 9, 1988 Thomas et al. 6,681,768 B2 1/2004 Haaije de Boer et al. 4.755,754. A 1/1989 Sawaki et al. 6,696,042 B2 2/2004 Pairet et al. 4810716 A 3, 1989 Connor et al. 6,715.486 B2 4/2004 Gieschen et al. 4,811,731 A 3, 1989 Newell et al. 6,723,348 B2 4/2004 Faham et al. 4,829,064 A 5, 1989 Sunshine et al. 6,726,124 B2 4/2004 Jaeger et al. 4,829,088 A 5, 1989 Doullakas 6,779,520 B2 8/2004 Genova et al. 4,835,249 A 5/1989 Gallagher et al. 6,806,256 B2 10/2004 Ulrich et al. 4,841,047 A 6/1989 Engel et al. 6,809, 198 B2 10/2004 El Kabbani et al. 4,868,175 A 9/1989 Engle 6,911,453 B2 6/2005 Hofmeister et al. 4,871,733. A 10/1989 Sunshine et al. 6,918,547 B2 7/2005 Jaeger et al. 4,918,182 A 4, 1990 Jackson et al. 7,022,687 B1 4/2006 Szelenyl et al. 4,927,646 A 5, 1990 Jenner et al. 7,135,495 B2 11/2006 Torisu et al. 4,971,797 A 1 1/1990 Cherukuri et al. 8,071,073 B2 12/2011 Dang et al. 4,975.426 A * 12/1990 Sunshine et al...... 514f159 2001/0025.040 Al 9, 2001 Poppe et al. 5,035,237 A 7, 1991 Newell et al. 2001/005.3775 A1 12/2001 Seidel et al. 5,086.050 A 2f1992 Hettcheet al. 2002/0006440 A1 1/2002 Cherukuri ...... 424/465 5.10.814 A 5/1992 Engel et al. 2002/0009418 A1 1/2002 Steiner et al. 5,164,194. A * 1 1/1992 Hettche ...... 424/489 2002fOO37297 A1 3/2002 Crespo et al. 5,223,493 A 6, 1993 Boltralik 2002fOO61281 A1 5, 2002 Osbakken et al. 5,232,919 A 8, 1993 Scheffler et al. 2002/0076382 A1 6/2002 Kaplanet al. 5.271946 A 12, 1993 Hettche 2002/01472O1 A1 10, 2002 Chen et al. 538054 A 1/1995 Beyts et al. 2002/01871.88 A1 12/2002 Cherukuri 5.384.311 A 1/1995 Antenucci et al. 2003, OO13675 A1 1/2003 Yeadon et al. 5.420,120 A 5, 1995 Boltralik 2003, OO32600 A1 2/2003 Ulrich et al. 5,464,838 A 1 1/1995 Kutscher et al. 2003/0059511 A1 3/2003 Ishii 5,497,944 A 3, 1996 Weston et al. 2003.01.13377 A1 6/2003 Dobrozsi et al. 5,565,160 A * 10/1996 Makuuchi et al...... 264/485 2003/0161879 A1 8/2003 Ohmorietal. 5,621,005 A 4, 1997 Gowan, Jr. 2003/0215503 A1 11/2003 Havir et al. 5,654,316 A 8, 1997 Carruthers et al. 2004.0053902 A1 3, 2004 Smith 5,658,919 A 8/1997 Ratnarajetal. 2004/0097.474 A1 5/2004 Cagle et al. 5,662.271 A 9, 1997 Weston et al. 2004/O105928 A1 6/2004 Ishii 5688960 A 11/1997 Shankar 2004/01 15133 A1 6/2004 Wermeling et al. 5,69363 A 1/1997 McCormicket al. 2004/0136918 A1 7/2004 Garrett et al. 5,696.267 A 2, 1997 Reichardetail 2004/014 1925 A1 7/2004 Bosch et al. 5,719.156 A 2f1998 Shue et al. 2004/0149774 A1* 8/2004 Strong ...... 222,94 5,783,579 A 7, 1998 McCormick 2004/0204399 A1 10, 2004 Osbakken et al. 5,789,422 A 8, 1998 Reichard et al. 2004/0208830 A1 10/2004 Chaudry 5,795.894. A 8, 1998 Shue et al. 2004/0235807 A1 11/2004 Weinrich et al. 5.798.359 A 8, 1998 Shue et al. 2004/0242624 A1 12/2004 Ahari et al. 5,804,587 A 9/1998 Cupps et al. 2004/0242638 A1 12/2004 Yanni et al. 5.830,490 A 11/1998 Weinstein et al. 2004/0247648 A1 12/2004 Fadden et al. 5.840379 A 1/1998 Narodyloet al. 2004/0253307 Al 12/2004 Hague et al. 5,859,003 A 1/1999 Hettche et al. 2004/0265372 A1 12/2004 Wynn et al. 5,881,719 A 3/1999 Gottenauer et al. 2005/0059639 A1 3/2005 Wei 5,897.858 A 4/1999 Haslwanter et al. 2005/O121027 A1 6/2005 Nilsson et al. 5,901.882. A 5/1999 Siegel. 222/131 2005, 0121032 A1 6/2005 Nilsson et al. 5.941241 A 8, 1999 Weinstein et al. 2005, 01234.86 A1 6/2005 Nilsson et al. 5947.118 A 9, 1999 Hochrainer et al. 2005, 0147672 A1 7, 2005 Ohmori et al. 5.964.416 A 10/1999 Jaeger et al. 2005. O148562 A1 7, 2005 Pairet et al. 5.998.403 A 12/1999 Hettcheet al. 2005. O15394.6 A1 7/2005 Hirsch et al. 6,017909. A 1/2000 Hettche et al. 2005/0196355 A1 9/2005 Georgiades et al. 6,017,963 A 1/2000 Alfonos et al. 2005/01963.57 A1 9/2005 Georgiades et al. 6,071.498 A 6/2000 Narodylo et al. 2005/0196358 A1 9/2005 Georgiades et al. 6,149,941 A 11/2000 Schwarz et al. 2005/0266031 A1 12/2005 Dickerson et al. 6,165,512. A 12/2000 Mezaache et al. 2005/028.1772 A1 12/2005 Bromley et al. 6,241,969 B1 6/2001 Saidi et al. 2006.0025391 A1 2/2006 Lulla et al. 6,245,353 B1 6/2001 Tritthart et al. 2006/01 10331 A1 5/2006 Dang et al. 6,260,549 B1 7/2001 Sosiak 2006/0263350 A1 11, 2006 Lane 6,270,790 B1 8/2001 Robinson et al. 2007/0020330 A1 1/2007 Dang et al. 6,294,153 B1 9/2001 Modi 2007/0202050 A1* 8/2007 Berry et al...... 424/45 6,297.227 B1 10/2001 Johnson 2007/0274925 A1* 11/2007 Chaudry ...... 424/45 6,319,513 B1 1 1/2001 Dobrozsi 2009, 0291143 A1 11/2009 Lulla et al. 6,328,034 B1 12/2001 Eisele et al. 20090318397 A1 12/2009 Lulla et al. US 8,758,816 B2 Page 3

(56) References Cited Chand, N., et al., “Inhibition of Allergic Histamine Release by Azelastine and Selected Antiallergic Drugs from Rabbit U.S. PATENT DOCUMENTS Leukocytes.” Int. Arch. Allergy Appl. Immunol. 77:451-455, Karger, Switzerland (1985). 2010, O152147 A1 6/2010 Fuge et al. Chand, N., et al., “Inhibition of acute lunganaphylaxis by aerosolized 2010/0331289 A1 12/2010 Lulla et al. aZelastine in guinea pigs sensitized by three different procedures.” 2012, 0083479 A1 4/2012 Dang et al. Ann. Allergy 58:344-349, American College of Allergists, United 2012fO149690 A1 6/2012 Dang et al. States (1987). Chien, Y.W. and Chang, S., “Intranasal Drug Delivery for Systemic FOREIGN PATENT DOCUMENTS Medications.” Crit. Rev. Ther: Drug Carrier Syst. 4:67-194, CRC Press, United Kingdom (1987). DE 2164058 7/1972 DE 2 114884 10, 1972 Corrado, O.J., et al., “Histamine and allergen induced changes in DE 35 30 793 A1 3, 1986 nasal airways resistance measured by anterior rhinomanometry: DE 36 34.942 A1 5, 1987 reproducibility of the technique and the effect of topically adminis DE 1994 7234 A1 4/2001 tered antihistaminic and anti-allergic drugs.” Br: J. Clin. Pharmacol. EP O 164593 A1 12, 1985 24:283-292, Blackwell Scientific Laboratories, United Kingdom EP O 164593 B1 12, 1985 (1987). EP O 174464 A2 3, 1986 Day, Nigel, “13: Aqueous Nasal Dosage Forms,” in Pharmaceutical EP O 222 191 A1 5, 1987 Preformulation and Formulation, Gibson, Mark, ed., CRC Press, EP 0289 939 A1 11, 1988 Boca Raton, FL., pp. 491-513 (2002). EP O 316639 A2 5, 1989 Diamantis, W., et al., “In Vivo and InVitro H. Antagonist Properties EP O 174464 B1 1, 1990 of Azelastine.” Pharmacologist 23: 149 (198), American Society for EP O 222 191 B1 1, 1991 EP O 780 127 A1 6, 1997 Pharmacology and Experimental Therapeutics, Inc., United States EP O 903 151 A1 3, 1999 (1981). FR 2816507 A1 5, 2002 Diamantis, W., et al., “Inhibition of Release of SRS-A and Its Antago GB 1377231 12/1974 nism by AZelastine (A), an H. Antagonist-Antiallergic Agent. Phar WO WO 97/O1337 1, 1997 macologist 24:200 (574), American Society for Pharmacology and WO WO97. 46243 12/1997 Experimental Therapeutics, Inc., United States (1982). WO WO98,48839 11, 1998 Dolovich, J., et al., “Control of the hypersecretion of vasomotor WO WOO1,26658 A2 4/2001 rhinitis by topical ipratropium bromide.” J. Allergy Clin. Immunol. WO WOO1, 52818 A1 T 2001 80:274–278, Mosby, United States (1987). WO WO O2/O56876 A2 T 2002 Duarte, C., et al., “Treatment of Severe Seasonal Rhinoconjunctivitis WO WO O2,083.036 A2 10, 2002 WO WO 03/04977O A1 6, 2003 by a Combination of Azelastine Nasal Spray and Eye Drops: A WO WOO3,105.856 A1 12/2003 Double-Blind, Double-Placebo Study,” J. Investig. Allergol. Clin. WO WO 2004/O19955 A1 3, 2004 Immunol. 11:34-40, Hogrefe & Huber, United States (2001). WO WO 2004f1 12771 A1 12/2004 Duzman, E., et al., “Topically Applied Oxymetazoline: Ocular WO WO 2005/027839 A2 3, 2005 Vasoconstrictive Activity, Pharmacokinetics, and Metabolism.” WO WO 2005/03O331 A1 4/2005 Arch. Ophthalmol. 101:1122-1126, American Medical Association, United States (1983). OTHER PUBLICATIONS Eli Lilly & Co. v. Aradigm Corp., 376 P.3d 1352, United States (Fed. Cir. 2004). Ansel, H.C. “Chapter 11—Ophthalmic Preparations,” and “Chapter Feinberg, G. and Stokes T.C., "Application of Histamine-Induced 12—Ear, Nose, and Topical Oral Formulations,” in Introduction to Conjuncitivitis to the Assessment of a Topical Antihistamine, Pharmaceutical Dosage Forms, Lea & Febiger, Philadelphia, PA. Levocabastine.” Int. Arch. Allergy Appl. Immunol. 82:537-538, pp. 333-349 (1976). Karger, Switzerland (1987). Banov, C.H. and Lieberman, Phil, “Efficacy of azelastine nasal spray Feinberg, S.M., “Drugs in Allergy.” Trans. Amer: Acad of in the treatment of vasomotor (perennial nonallergic) rhinitis.” Ann. Opthalmol. & Otolaryngol. 124:283-286, Douglas Printing Com Allergy Asthma. Immunol. 86:28-35, American College of Allergy, pany, United States (1950). Asthma, and Immunology, United States (2001). Feinberg, S.M. “Antihistamine Therapy. Experimental and Clinical Barkman, R., et al., “Preservatives in Eye Drops.” ACTA Correlation.” Annals of the New York Acadmey of Sciences 50: 1186 Ophthamologica 47:461-475, Munksgaard, Denmark (1969). 1201, New York Academy of Sciences, United States (1950). Bende, M. and Pipkorn, U. “Topical levocabastine, a selective H1 File, R. R. and Patton, T.F., “Topically Applied Pilocarpine: Human antagonist, in seasonal allergic rhinoconjunctivitis. Allergy 42.512 Pupillary Response as a Function of Drop Size.” Arch. Ophthal. 515, Munksgaard, Denmark (1987). 98: 112-115, American Medical Association, United States (1980). Bentley, A.J. and Jackson, R.T., "Changes in the Patency of the Upper Fraki, J.E., et al., “Contact Allergy to Various Components of Topical Nasal Passage Induced by Histamine and Antihistamines.” The Preparations for Treatment of External Otitis.” Acta Otolaryngol. Laryngoscope. LXXX: 1859-1870, Lippincott Wilkins & Williams, 100:414-418. Taylor & Francis, United Kingdom (1985). United States (1970). Gibson, M., "12: Ophthalmic Dosage Forms,” in Pharmaceutical Berger, W.E., et al., “Double-blind trials of azelastine nasal spray Preformulation and Formualation, Gibson, Mark, ed., CRC Press, monotherapy versus combination therapy with loratadine tablets and Boca Raton, FL., pp. 459-489 (2002). beclomethasone nasal spray in patients with seasonal allergic Giede-Tuch, C., et al., “AZelastine eye-drops in seasonal allergic rhinitis.” Ann. Allergy Asthma Immunol. 82:535-541, American Col conjunctivitis or rhinoconjunctivitis.” Allergy 53:857-862, lege of Allergy, Asthma, and Immunology, United States (1999). Munksgaard (1998). Blue, J.A., “Current Concepts of Allergy of the Eye.” Annals of Golden, S.J. and Craig, T.J., “Efficacy and safety of azelastine nasal Allergy 33:267-273, American College of Allergy and Immunology, spray for the treatment of allergic rhinitis.J. Am. Osteopath. Assoc. United States (1974). 99:S7-S12, American Osteopathic Association, United States (1999). Burstein, N.L., “The Effects of Topical Drugs and Preservatives on Hamilton, L.H., “Effect of Topical Decongestants on Nasal Airway the Tears and Corneal Epithelium in Dry Eye.” Trans. Opthalmol. Resistance.” Curr: Ther: Res. Clin. Exp. 24:261-268. Therapeutic Soc. U.K. 104:402-409. The Ophthalmological Societies of the Research Press, Inc., United States (1978). United Kingdom, United Kingdom (1985). Havas, T.E., et al., “The Effects of combined H and H histamine Busse, W.W., et al., “Corticosteroid-sparing Effect of Azelastine in antagonists on alterations in nasal airflow resistance induced by the Management of Bronchial Asthma.” Am J. Respir: Crit. Care Med. topical histamine provocation.” J. Allergy Clin. Immunol. 78:856 153:122-127. American Thoracic Society, United States (1996). 860, Mosby, United States (1986). US 8,758,816 B2 Page 4

(56) References Cited dipropionate as acqueous nasal spray or pressurized aerosol. J. Allergy Clin. Immunol. 77:858-864, Mosby, United States (1986). OTHER PUBLICATIONS Pearlman, D.S., “Antihistamines: Pharmacology and Clinical Use.” Drugs 12:258-273, ADIS Press, New Zealand (1976). Hermens, W.A. and Merkus, F.W., “The Influence of Drugs on Nasal Pécoud, A., et al., “Effect of a New Selective H. Receptor Antagonist Ciliary Movement.” Pharm. Res. 4:445-449, Plenum Publishers, (Levocabastine) in a Nasal and Conjuctival Provocation Test.” Int. United States (1987). Arch. Allergy Appl. Immunol. 82:541-543, Karger, Switzerland Horak. F., et al., “AZelastine in Pollen-Induced Allergic Rhinitis, A (1987). Pharmacodynamic Study of Onset of Action and Efficacy.” Clin. Physicians' Desk Reference, 33rd ed., Huff, Barbara and Kelly, Drug Investig. 7:34-40, Adis International Ltd., New Zealand (1994). International Search Report for International Application No. PCT/ Gwynned L., eds., Medical Economics Company, Oradell, N.J., pp. US05/42362, United States Patent and Trademark Office, United 570-572,873, 892, 1512, 1515, and 1851 (1979). States, mailed May 4, 2006. Physicians' Desk Reference, 1st ed., Huff, Barbara and Kelly, Kassem, A.A., et al., “Formulation and Stabilization of Antazoline Gwynned L., eds. Medical Economics Company, Oradell, N.J., pp. Hydrochloride Nasal Drops.” Bulletin of the Faculty of Pharmacy 502, 503, 506, 522, 539, 553, 616, 637, 638, 646, 654, and 655 XV:161-175, Cairo University Press, Egypt (1976). (1980). Keeney, E.I., “Medical Progress: Histamine and the Antihistamine Physicians' Desk Reference, 59th ed., Murray, Lori, ed., Thomson Drugs.” Calif Med. 72:377-389, California Medical Association, PDR, Montvale, N.J., pp. 1973-1975 (2005). United States (1950). Pipkorn, U., et al., “A Double-Blind Evaluation of Topical Kersten, R.C., “Ophthalmic Drugs.” Prim. Care 9:743-756, Levocabastine, a New Specific H. Antagonist in Patients with Aller Saunders, United States (1982). gic Conjuctivitis.” Allergy 40:491-496, Blackwell Munksgaard, Ger Kimberly-Clark Corp. v. The Proctor & Gamble Distributing Co., many (1985). Inc., 973 F.2d 911, 23 U.S.P.Q.2d 1921, United States (Fed. Cir. Portmann, D., et al., English language abstract of "Acceptability of 1992). local treatment of allergic rhinitis with a combination of a corticoid Kirkegaard, J., et al., “Effect of the H. Antihistamine (beclomethasone) and an antihistaminic (aZelastine). Rev. Laryngol. Chlorpheniramine Maleate on Histamine-Induced Symptoms in the Otol. Rhinol. (Bord.) 121:273-9, Revue De Laryngologie, France Human Conjuctiva.” Allergy 37:203-208, Blackwell Munksgaard, (2000). Denmark (1982). Reader, M.J., “Influence of Isotonic Agents on the Stability of Kirkegaard, J., et al., “Inhibition of Histamine-Induced Nasal Symp Thimerosal in Ophthalmic Formulations.” J. Pharm. Sci. 73:840 toms by the H. Antihistamine Chlorphenitamine Maleate: Demon 841, American Pharmaceutical Association, United States (1984). stration of Topical Effect.” Br: J. Dis. Chest 77: 113-121, Balliere Reich, I., et al., “Tonicity, Osmoticity, Osmolality and Osmolarity.” Tindall and Cassell, United Kingdom (1983). in Remington. The Science and Practice of Pharmacy, 20th edition, Kubo, N., et al., “Antimuscarinic Effects of Antihistamines: Quanti Gennaro, Alfonso R. et al., eds. Lippincott Williams and Wilkins, tative Evaluation by Receptor-Binding Assay.” Jpn. J. Pharmacol. Philadelphia, PA. pp. 246-262 (2000). 43:277-282, Japanese Pharmacological Society, Japan (1987). Saito.Y., “Recent Trends in Aerosol Therapy for Allergic Rhinitis.” Z. Lancer, J.M., et al., “A comparison by rhinomanometry of Erk: Atmungsorgane 166:25-29, Johann Ambrosius Barth, Germany beclomethasone and terfenadine in the treatment of seasonal (1986). rhinitis.” J. Laryngol. Otol. 101:350-354. Headley Brothers Ltd., Secher, C., et al., “Significance of H and H receptors in the human United Kingdom (1987). nose: rationale for topical use of combined antihistamine prepara Lam, S.W., et al., “Determination of Thimerosal in Opthalmic Solu tions.” J. Allergy Clin. Immunol. 70:211-218, Mosby, United States tions by Radial Compression Separation HPLC,” J. Parenter: Sci. (1982). Technol. 35:262-265. Parenteral Drug Association, United States Shin, M.-H... et al., “The effect of azelastine on the early allergic (1981). response.” Clin. Exp. All 22:289-295, Blackwell Scientific Publica Lenhard, G. et al., “Double-blind, Randomised, Placebo-controlled tions, United Kingdom (1992). Study of Two Concentrations of Azelastine Eye Drops in Seasonal Tasaka, K. and Akagi, M., “Anti-allergic Properties of a New Hista Allergic Conjunctivitis or Rhinoconjunctivitis.” Curr: Med. Res. mine Antagonist, 4-(p-Chlorobenzyl)-2-N-Methyl Opin. 14:21-28, LibraPharm. Ltd., United Kingdom (1997). perhydroazepinyl-(4)-1-(2H)-phthalazinone Hydrochloride Lieberman, P. “Management of allergic rhinitis with a combination (AZelastine).” Arzneimittel Forschung. Drug Research 29:488-493, antihistaminefanti-inflammatory agent.” J. Allergy Clin. Immunol. Editio Cantor, Germany (1979). 103:S400-404, Mosby, United States (1999). Tatsumi, K., et al., “Studies on Metabolic Fate of a New Antiallergic McNeely, W. and Wiseman, L.R., “Intranasal AZelastine: A Review Agent, AZelastine (4-(p-Chlorobenzyl)-2-N- of its Efficacy in the Management of Allergic Rhinitis.” Drugs 56:91 Methylperhydroazepinyl-(4)-1-(2H)-Phthalazinone Hydrochlo 114, Adis International, Ltd., New Zealand (1998). ride).” Japan. J. Pharmacol. 30:37-48, The Japanese Pharmacologi Meltzer, E.O. and Schatz, M., “Pharmacotherapy of Rhinitis—1987 cal Society, Japan (1980). and Beyond.” Immunol. Allergy Clin. North Am. 7:57-91, W.B. Tatsumi, K., et al., “Metabolism of an Antiallergic Agent, AZelastine Saunders, United States (1987). (4-(p-Chlorobenzyl)-2N-Methylperhydroazepinyl-(4)-1-(2H)- Naclerio, R.M., et al., “In Vivo Model for the Evaluation of Topical Phthalazinone Hydrochloride) in Rats and Guinea Pigs.” Hiroshima Antiallergic Medications.” Arch. Otolaryngol. 110:25-27, American J. Med. Sci. 33:669-678, Hiroshima University School of Medicine, Medical Association, United States (1984). Japan (1984). Newsom-Smith, G., et al., “A placebo controlled study comparing the Togias, A. G. et al., “Demonstration of Inhibition of Mediator efficacy of intranasal azelastine and beclomethasone in the treatment Release from Human Mast Cells by AZatadine Base” J. Am. Med. of seasonal allergic rhinitis.” Eur: Arch. Otorhinolaryngol. 254:236 Assoc. 255.225-229, American Medical Association, United States 241. Springer-Verlag, Germany (1997). (1986). Okuda, M., et al., “Effect of E-0659 for Nasal Allergy.” Oto-Rhino vande Donk, H.J., et al., “The effects of nasal drops on the ciliary beat Laryngology Tokyo 23:441-461, Tokyo, Jibinkokagaku Kyoshitsu, frequency of chicken embryo tracheas.” Rhinology 19:215-230, Tokyo Jikei Ika Daigaku, Japan (1980). International Rhinologic Society, Netherlands (1981). Okuda, M., et al., English language abstract for Okuda, M., et al., van de Donk, H.J., et al., “The effects of drugs on ciliary motility: III. “Effect of E-0659 for Nasal Allergy.” Oto-Rhino-Laryngology Tokyo Local anaesthetics and anti-allergic drugs.” Int. J. Pharm. 12:77-85, 23:441-461, Tokyo, Jibinkokagaku Kyoshitsu, Tokyo Jikei Ika Elsevier Biomedical Press, Netherlands (1982). Daigaku, Japan (1980) (listed on accompanying PTO/SB/08B as Vanden Bussche, G., “Levocabastine Hydrochloride.” Drugs Future document NPL49). 11:841-843, J R Prous S.A. Publishers, United States (1986). Orgel, H. A., et al., "Clinical, rhinomanometric, and cytologic evalu Wang, D., et al., “Effect of Topical Applications of Budesonide and ation of seasonal allergic rhinitis treated with beclomethasone Azelastine on Nasal Symptoms, Eosinophil Count and Mediator US 8,758,816 B2 Page 5

(56) References Cited Meltzer, E.O., et al., “Efficacy of azelastine in perennial allergic rhinitis: Clinical and rhinomanometric evaluation.” J. Allergy Clin. OTHER PUBLICATIONS Immunol. 82:447-455. The C.V. Mosby Company, United States (1988). Release in Atopic Patients after Nasal Allergen Challenge during the Mirimanoff, A. and Paley, A., “Controle physiologique des gouttes Pollen Season.” Int. Arch. Allergy Immunol. 1.14:185-192, S. Karger, nasales Sur la mucueuse du cobaye. Effet toxicue temporaire et Switzerland (1997). permanent.” Pharm. Acta Helvetiae 41:25-38, City-Druck AG, Ger Wasicko, M.J., et al., “Nasal and Pharyngeal Resistance after Topical many (1966). Mucosal Vasoconstriction in Normal Humans.” Am. Rev. Respir: Dis. Morén, F. “Chap. 10. Aerosol dosage forms and formulations,” in: 144: 1048-1052, American Lung Association, United States (1991). Aerosols in Medicine Principles Diagnosis and Therapy, Morén, F. Weeke, E.R., “Epidemiology of Hay Fever and Perennial Allergic et al., eds., Elsevier, New York, NY. pp. 261-287 (1985). Rhinitis.” Monogr: Allergy 21:1-20, Karger, Switzerland (1987). Mygind, N. "Chap 1. Upper airway: structure, function and therapy.” Weiler, J.M., et al., “Multicenter, double-blind, multiple-dose, paral in: Aerosols in Medicine Principles, Diagnosis and Therapy, Morén, lel groups efficacy and safety trial of azelastine, chlorpheniramine, F., et al., eds. Elsevier, New York, NY. pp. 1-20 (1985). and placebo in the treatment of spring allergic rhinitis. J. Allergy Naclerio, R.M., “The effect of antihistamines on the immediate aller Clin. Immunol. 82:801-11, Mosby, United States (1998). gic response: A comparative review.” Otolaryngol. Head Neck Surg. Young, T., et al., “Nasal obstruction as a risk factor for sleep-disor 108:723-730, Mosby, United States (1993). dered breathing.” J. Allergy Clin. Immunol. 99:S757-62, Mosby, Newman, S.P. and Clarke, S.W. “Chap. 11. Aerosols in therapy,” in: United States (1997). Aerosols in Medicine. Principles, Diagnosis and Therapy, Morén, F. Dialog File 351. Accession No. 4564452, Derwent WPI English et al., eds., Elsevier, New York, NY. pp. 289-312 (1985). language abstract for EP 289939 A1 (listed on accompanying PTO/ Rafferty, P. et al., “The in vivo potency and selectivity of azelastine SB/08A as document FP2) (1988). as an H histamine-receptor antagonist in human airways and skin.” Dialog File 351. Accession No. 4782022, Derwent WPI English J. Allergy Clin. Immunol. 82:1113-1118. The C.V. Mosby Company, language abstract for EP 316639 A2 (listed on accompanying PTO/ United States (1988). SB/08A as document FP3) (1994). Schlumpf, R., “3.5.5. Sterilitat und Konservierung waBriger Dialog File 351. Accession No. 12914778, Derwent WPI English Augentropfen.” in: Ophthalmika. Pharmakologie, Biopharmazie und language abstract for FR 2816 507 A1 (listed on accompanying Galenik der Augenarzneimittel, Dolder, R., et al., eds., Wis PTO/SB/08A as document FP10) (2002). senschaftlicje Verlagsgesellschaft mbH. Stuttgart, Gemany, pp. 392 Letter from Apotex to MedPointe Pharmaceuticals, “Re: Apotex 415 (1983). Azelastine Hydrochloride Nasal Spray (hereinafter Apotex Togias, A., et al., “The effect of a topical tricyclic antihistamine on the Azelastine product), pp. 1-24, dated Jan. 24, 2006. response of the nasal mucosa to challenge with cold, dry air and Answer of Apotex Corp. to Plaintiffs Amended Complaint, Affirma histamine.” J. Allergy Clin. Immunol. 79:599–604. The C.V. Mosby tive Defenses and Couterclaims in MedPointe Healthcare Inc. v. Company, United States (1987). "Allergische Rhinits—eine Crux medicorm.” Z. Allg. Med. 57: 1939 Apotex Inc. and Apotex Corp., C.A. 06-164 (SLR), Electronically 1940, Hippokrates Verlag GmbH, Germany (1981). mailed on Apr. 14, 2006. Andersen, N.H., et al., “Treatment of hay fever with sodium Aberer, W. and Tappeiner, G., “Allergy to Topically-applied Antihis cromoglycate, hyposensitization, or a combination.” Allergy 42:343 tamines—Discrepancy Between Literature and Practice.” Wiener 351, Munksgaard, Denmark (1987). klin. Wochen. 100:763-765, Springer-Verlag, Germany (1988). Asta Pharma Aktiennesellschaft, “Comparison of efficacy and toler Breuninger, H., “Nosedrops and Eardrops.” HNO 19:65-68, ability of azelastine nasal spray, azelastine tablets and astemizole in Springer-Verlag, Germany (1971). the treatment of seasonal allergic rhinitis.” Asta Pharma Report, Chand, N., et al., “Effect of Aerosolized Azelastine on Acute Lung Project No. A-05610, Asta Pharma Aktiennesellschaft, 5 pages Anaphylaxis in Guinea Pigs (GP) Sensitized by Two Different Pro (1990). cedures.” Pharmacologist 27:162, Abstract No. 76, American Soci Asta-Werke Aktiengesellschaft Chemische Fabrik, "Löslichkeit von ety for Pharmacology and Experimental Therapeutics, United States Azelastin und Azelastinsalzen.” Asia-Werke Report, Report No. UB (1985). 61.83, Asta-Werke Aktiengesellschaft Chemische Fabrik, 10 pages Chand, N., et al., “Inhibition of IgE-mediated allergic histamine (1983). release from rat peritoneal mast cells by azelastine and selected Chand, N., et al., “Modulation of in vitro anaphylaxis of guinea-pig antiallergic drugs.” Agents & Actions 16:318-322, Birkhäuser, Ger isolated tracheal segments by azelastine, inhibitors of arachidonic many (1985). acid metabolism and selected antiallergic drugs.” Br. J. Pharmac. Dolder, B.V.R. and Triemli, S., “7. Arzneiformen Zur Anwendung an 87:443-448, The Macmillan Press Ltd., United Kingdom (1986). Auge, OhrundNase.” in: Pharmazeutische Technoalogie, Sucker, H., Etter, J.C., et al., "Le controle des gouttes nasales: action de dif et al., eds. Georg Thieme Verlag, Stuttgart, Germany, pp. 693-729 ferentes solutions Sur la muqueuse du cobaye et Sur celle de (1978). l'homme.' Schweiz. Med. Wochenschr: 94: 1531-1534, EMH Swiss Dolovich, M.B., et al., “Aerosols in diagnosis: ventilation, airway Medical Publishers, Switzerland (1964). penetrance, airway reactivity, epithelial permeability and mucocili Fukuda, T., et al., “Influence of 1-(2-Ethoxyethyl)-2-(4-methyl-1- ary transport.” Aerosols in Medicine Principles, Diagnosis and homopiperazinyl)benzimidazole Difumarate (KB-2413), a New Therapy, Morén, F., et al., eds. Elsevier, New York, NY. pp. 225-259 Antiallergic, on Ciliary Movement.” Arzneim.-Forsch. 34:816-818, (1985). Editio Cantor, Germany (1984). Etter, J.C., et al., "Le controle des gouttes nasales: action de dif Handbook of Nonprescription Drugs, 7" Ed., American Pharmaceu ferentes solutions Sur la muqueuse du cobaye et Sur celle de tical Association, Washington, DC, pp. 166-169 and 428-430 (1982). l'homme.' Schweiz. Med. Wochenschr: 94: 1531-1534, EMH Swiss Kemp, J.P. et al., “A dose-response study of the bronchodilator action Medical Publishers, United States (1964). of azelastine in asthma.” J. Allerg. Clin. Immunol. 7.9:893-899. The Fickweiler, E., "Biopharmazie der Oto-Rhino-Laryngologica.” Die C.V. Mosby Company, United States (1987). Pharmazie 38:274–278, Govi-Verlag Pharmazautischer Verlag, Ger Kranz, O., ed., Vademecum, 12" Ed., Editio Cantor Aulendorf, Ger many (1983). many, pp. 174-181 (1981). Grumbach, P.E., et al., “Remarques Sur le controle physiologique des Magnussen, H., “The Inhibitory Effect of Azelastine and Ketotifen on gouttes nasales.” Schweiz. Med. Wochenschr: 96:358-360, EMH Histamine-induced Bronchoconstriction in Asthmatic Patients.” Swiss Medical Publishers, United States (1966). Chest 91:855-858, American College of Chest Physicians, United Lippold, B.C., ed., “I. Arzneformen Zur Anwendung in der Nase,” in: States (1987). Biopharmazie, Wissenschaftliche Verlagsgesellschaft mbH. Stut Mirimanoff, A. and Paley, A., “Controle physiologique des gouttes tgart, Germany, pp. 142-145 (1984). nasales Sur la mucueuse du cobaye. Effet toxicue temporaire et US 8,758,816 B2 Page 6

(56) References Cited Office Action for U.S. Appl. No. 10/518,016, Lulla, A., et al., filed Jul. 6, 2005, mailed on Jan. 23, 2009. OTHER PUBLICATIONS Office Action for U.S. Appl. No. 10/518,016, Lulla, A., et al., filed Jul. 6, 2005, mailed on Oct. 17, 2008. permanent.” Pharm. Acta Helvet. 41:25-38, Schweizerische Office Action for U.S. Appl. No. 1 1/284.109, Dang, P.G., et al., filed Apotheker-Verein. The Netherlands (1966). Nov. 22, 2005, mailed on Feb. 27, 2009. Morrison, W.W., ed., “Formulary: Prescriptions for Medications to Bielory, L., et al., “Treating the Ocular Component of Allergic be Used by Patients.” Diseases of the Ear; Nose & Throat, 2" Ed., Rhinoconjunctivitis and Related Eye Disorders.” Medscape Gen. Appleton-Century-Crofts, Inc., New York, pp. 699-707 (1948). Med. 9; 15 pages, available online at http://www.medscape.com/ Ollier, S., et al., “The effect of single and multiple dose therapy with viewarticle/560750, Medscape, United States (Aug. 2007). aZelastine on the immediate asthmatic response to allergen provoca Brain, J.D., et al., “Chap. 5. Mechanisms of aerosol deposition and tion testing.” J. Allergy Clin. Immunol. 78:358-364. The C.V. Mosby clearance,” in: Aerosols in Medicine Principles, Diagnosis and Company, United States (1986). Therapy, Morén, F., et al., eds. Elsevier, New York, NY. pp. 123-147. Pivonka, J., et al., “Determination of Azelastine and 198-199, 207-209 (1985). Desmethylazelastine in Human Plasma by High-Performance Liquid Chand, N., et al., “Is Airway Hyperactivity in Asthma. Due to Hista Chromatography.” J. Chromat. 420:89-98. Elsevier Science Publish mine H-Receptor Deficiency?” Med. Hypoth. 6: 1105-1112, ers B.V., The Netherlands (1987). Churchill Livingstone, United States (1980). Sauer P.-H., “Rhinomanometrische Kontrollen des Chand, N., et al., “Inhibition of Calcium Ionophore (A23187)-Stimu Nasenwiderstandes.” Die Med. Welt. 34:1319-1324, Schattauer, Ger lated Histamine Release from Rat Peritoneal Mast Cells by many (1983). Azelastine: Implications for Its Mode of Action.” Eur: J. Pharm. Schaffer, N. and Seidmon, E.E., “The Intranasal Use of 96:227-233, Elsevier Science Publishers B.V., Netherlands (1983). Prophenpyridamine Maleate and Chlorpropenpyridamine Maleate in Chand, N., et al., “Inhibition of allergic and non-allergic histamine Allergic Rhinitis.” Ann. Allergy 10:194-196, The American College Secretion from rat peritoneal mast cells by calcium antagonists.” Br: of Allergists, United States (1952). J. Pharmac. 83:899-902, Macmillan Press Ltd., United Kingdom Su, X.Y. and Po, A.L.W. “The effect of some commercially available (1984). antihistamine and decongestant intra-nasal formulations on ciliary Chand, N., et al., “Inhibition of Passive Cutaneous Anaphylaxis beat frequency.” J. Clin. Pharm. Therap. 18:219-222, Blackwell Sci (PCA) by Azelastine: Dissociation of Its Antiallergic Activities from entific Publications, United Kingdom (1993). Antihistaminic and Antiserotonin Properties.” Int. J. Wanner, A., “Effects of Methylxanthines on Airway Mucociliary Immunopharmac. 7:833-838, Pergamon Press, United Kingdom Function.” Am. J. Med. 79:16-21. Technical Publishing, United States (1985). (1985). Yu, C.D., et al., “Cascade Impactor Method for the Droplet Size Chand, N., et al., “Inhibition of Leukotriene (SRS-A)-Mediated Characterization of a Metered-Dose Nasal Spray.” J. Pharm. Sci. Acute Lung Anaphylaxis by Azelastine in Guinea Pigs.” Allergy 73:344-348. The American Pharmaceutical Association, United 41:473–478, Munksgaard International Publishers, Denmark (1986). States (1984). Chien, Y.W., ed., “2. Histamine and Antihistamines' in: Transnasal German Patent Application No. 34 33 776.8, applicant Asta-Werke Systemic Medications, Elsevier, Netherlands, pp. 80-81 (1985). Aktiengesellschaft Chemische Fabrik, filed Sep. 14, 1984. Cirillo, V.J., et al., “Pharmacology and Therapeutic Use of Antihis Unverified English language translation of German Patent Applica tamines.” Am. J. Hosp. Pharm. 33:1200-1207, American Society of tion No. 34 33 776.8, applicant Asta-Werke Aktiengesellschaft Hospital Pharmacists, United States (1976). Chemische Fabrik, conducted on Jan. 14, 2008. Deardorff, D.I., "Chap. 83. Ophthalmic Solutions,”, in: Remington's German Patent Application No. 3539 873.6, applicant Asta-Werke Pharmaceutical Sciences, 14" Ed., Hoover, J.E., et al., eds., Mack Aktiengesellschaft Chemische Fabrik, filed Nov. 11, 1985. Publishing Company, Easton, PA, pp. 1545-1577 (1970). Unverified English language translation of German Patent Applica Druce, H.M. “Allergic and Nonallergic Rhinitis.” in Allergy, Prin tion No. 35 39 873.6, applicant Asta-Werke Aktiengesellschaft ciples & Practice, vol. II. Mosby, St. Louis, MO, pp. 1005 and 1014 Chemische Fabrik, conducted on Apr. 19, 2007. (1998). STNEasy, Chemical Abstracts Service. Accession No. 1961:38.125, Fields, D.A.S., et al., “Inhibition by azelastine of nonallergic hista unverified English language abstract of DE 1 046 625 (listed on mine release from rat peritoneal mast cells.”.J. Allergy Clin. Immunol. accompanying PTO/SB/08A as document FP20) (1958). 73:400-403, The C.V. Mosby Company, United States (1984). Dialog File 351. Accession No. 498209, WPI unverified English Fokkens, W.J., et al., “Once daily fluticasone furoate nasal spray is language abstract of DE 2 114884 (listed on accompanying PTO/ effective in seasonal allergic rhinitis caused by grass pollen. Allergy SB/08A as document FP21) (1971). 62: 1078-1084, Blackwell Munksgaard, Denmark (2007). Dialog File 351. Accession No. 3637108, WPI unverified English Gale A.E., et al., “Intranasal topical flunisolide therapy in children language abstract of EPO 174464 A2 and B1 (listed on accompany with seasonal allergic rhinitis.” Clin. Allergy 10:527-533, Blackwell ing PTO/SB/08A as documents. FP23 and FP28 respectively) and of Scientific Publications, United Kingdom (1980). DE 3530793 Al (listed on accompanying PTO/SB/08A as document Hill, D., et al., “Beclomethasone Dipropionate Aerosol in the Treat FP24) (1986). ment of Children with Severe Perennial Rhinitis.' Med. J. Austr. Dialog File 351. Accession No. 4037878, WPI unverified English 2:603-604, Australian Medical Association, Australia (1978). language abstract of EP 0 222 191 A1 and B1 (listed on accompany Hoover, J.E., "Chap. 78. Classification.” in: Remington's Pharma ing PTO/SB/08A as documents. FP26 and FP29 respectively) and of ceutical Sciences, 14' Ed., Hoover, J.E., et al., eds., Mack Publishing DE 3634942A1 (listed on accompanying PTO/SB/08A as document Company, Easton, PA, pp. 1461-1462 (1970). FP25) (1987). Kimura, E.T., “Effects of Chemical on Ciliated Tracheal Epithe Wilson, C.O., et al., “Recent Antihistamine Developments: The lium.” A.M.A. Arch. Otolaryngol. 69:674-686, American Medical “Dual-Acting” Antihistamines,” in Wilson and Gisvold's Textbook of Association, United States (1959). Organic Medicinal and Pharmaceutical Chemistry. Edition. I 1. Knothe, V.J. and Aschoff, E., "Experimentelle Untersuchungen Zum Block, J.H., and Beale Jr., J.M., eds., Lippincott Williams & Wilkins, Effekt einiger schleimhantabschwellender Nasentropfen.” Das Baltimore, MD, p. 717 (Jan. 2004). Deutsche Gesundheit. 24:2384-2388, VEBVerlag Volk and Gesund International Search Report for International Application No. PCT/ heit, Germany (1969). GB03/02557, mailed on Sep. 17, 2003, European Patent Office, Lancaster, R., “Topical or Systemic Therapy?,” Prescribers'.J. 23:47 Rijswijk, Netherlands. 53 HMSO (1983). Dialog File 351. Accession No. 11047925, Derwent WIP English Ledford, D.K., “Rhinitis.” in: Allergic Diseases, Diagnosis and language abstract for DE 1994 7234 A1 (cited as document FP30) Treatment, 2" Ed., Lieberman, P., and Anderson, J.A., eds., Humana (2001). Press, Totowa, NJ, pp. 159-182 (2000). US 8,758,816 B2 Page 7

(56) References Cited The Washington Manual Allergy, Asthma and Immunology Subspe cialty Consult, Lippincott Williams & Wilkins, pp. 148-149 (2003). OTHER PUBLICATIONS “Allergic Rhinitis-Prevention.” WebMD Medical Reference, accessed at: http://www.webmd.com/allergies/tcfallergic-rhinitis Lieberman, P., “Antihistamines,” in: Allergic Diseases, Diagnosis and Treatment, 2" Ed., Lieberman, P., and Anderson, J.A., eds. prevention (cited in an Office Action dated Nov. 18, 2001 in parent Humana Press, Totowa, NJ, pp. 323-335 (2000). U.S. Appl. No. 1 1/486,454, filed Jul. 14, 2006). Pernarowski, M.. “Chap. 80. Solutions, Emulsions, and Suspen Office Action mailed on Sep. 9, 2010 in U.S. Appl. No. 1 1/486,454. sions,”, in: Remington's Pharmaceutical Sciences, 14" Ed., Hoover, inventors Dang et al., filed Jul. 14, 2006. J.E., et al., eds., Mack Publishing Company, Easton, PA, pp. 1478 Office Action mailed on Feb. 17, 2010 in U.S. Appl. No. 1 1/486,454, 1500 (1970). inventors Dang et al., filed Jul. 14, 2006. Sciarra, J.J., “Chap. 90. Aerosols,” in: Remington's Pharmaceutical Office Action mailed on Aug. 31, 2009 in U.S. Appl. No. 1 1/486,454. Sciences, 14' Ed., Hoover, J.E., et al., eds. Mack Publishing Com inventors Dang et al., filed Jul. 14, 2006. pany, Easton, PA, pp. 1729-1753 (1970). Office Action mailed on Nov. 18, 2008 in U.S. Appl. No. 1 1/486,454. Simons, F.E. "Chap. 100. New Medications for rhinitis,” in: Asthma inventors Dang et al., filed Jul. 14, 2006. and Rhinitis, Busse, W.W. and Holgate, S.T., eds., Blackwell Scien tific Publications, Boston, MA, pp. 1325-1336 (1995). Office Action mailed on Jan. 26, 2009 in U.S. Appl. No. 1 1/284, 109, Simons, F.E.R., “Antihistamines,” in: Allergy; Principles & Practice, inventors Dang et al., filed Nov. 22, 2005. vol. II, Mosby, St. Louis, MO, pp. 612-637 (1998). Office Action mailed on Apr. 29, 2011 in U.S. Appl. No. 1 1/486,454. Swift, D.L., “Chap. 3, Aerosol characterization and generation.” in: inventors Dang et al., filed Jul. 14, 2006. Aerosols in Medicine, Principles, Diagnosis and Therapy, Morén, F. "Combination of azelastine and steroids,' inventors Lulla, A. et al., et al., eds., Elsevier, New York, NY. pp. 53-76 (1985). U.S. Appl. No. 12/879,515, filed Sep. 10, 2010. Swinyard, E.A. and Harvey, S.C., Chap. 64. "Histamine and Antihis Pre-Grant Opposition Brief filed Feb. 2, 2010 by Cipla Limited tamines.” in: Remington's Pharmaceutical Sciences. 14' Ed., against Indian Patent Application No. 2092/KOLNP 2007. Hoover, J.E., et al., eds., Mack Publishing Company, Easton, PA, pp. Office Action mailed Apr. 29, 2011 in U.S. Appl. No. 1 1/486,454. 1142-1153 (1970). United States Pharmacopeia, The National Formulary, 21 Revision, inventors Dang et al., filed Jul. 14, 2006. United States Pharmacopeial Convention, Inc., Rockville, MD, pp. Office Action mailed on Jul. 21, 2011 in U.S. Appl. No. 1 1/284.109, 1329, 1333-1343, 1635, 1639, 1655, 1657-1660 (1985). inventors Dang et al., filed Nov. 22, 2005. Weiler, J.M. and Meltzer, E.O., “AZelastine nasal spray as adjunctive Office Action mailed Sep. 8, 2010 in U.S. Appl. No. 1 1/284.109, therapy to azelastine tablets in the management of seasonal allergic inventors Dang et al. filed Nov. 22, 2005. rhinitis.” Ann. Allergy Asthma Immunol. 79:327-332, American Col Office Action mailed Feb. 23, 2011 in U.S. Appl. No. 1 1/284, 109, lege of Allergy, Asthma & Immunology, United States (1997). inventors Dang et al. filed Nov. 22, 2005. Zechal, H.-J., “Pharmacological and Toxicological Properties of Office Action mailed Sep. 30, 2010 in U.S. Appl. No. 12,508,393, Azelastine, a Novel Antiallergic Agent.” Arzeim.-Forsch./Drug Res. inventors Lulla et al., filed Jul. 23, 2009. 31: 1184-1193, Editio Cantor, Germany (1981). Zopf, L.C. and Blaug, S.M.. “Chap. 85. Medicated Applications,” in: Office Action mailed Sep. 30, 2010 in U.S. Appl. No. 12/508,388, Remington's Pharmaceutical Sciences, 14th Ed., Hoover, J.E., et al., inventors Lulla et al., filed Jul. 23, 2009. eds., Mack Publishing Company, Easton, PA, pp. 1594-1625 (1970). Bernstein, J.A. et al., “Double-blind, placebo-controlled trial of Ciprandi, G. et al., “Adhesion Molecules Modulation: A new target reformulated azelastine nasal spray in patients with seasonal allergic for rhinitis treatment,” in: Passali, D., Ed., Pediatric rhinitis.” Am. J. Rhinol. Allergy 23: 512-517. Oceanside Publications, Otorhinolaryngology. An Update, Kugler Publications, pp. 157-161 Inc. (2009). (1998). Schmidt, B.M.W et al., “The New Topical Steroid Ciclesonide Is Office Action mailed Sep. 14, 2009 in U.S. Appl. No. 1 1/284,109, Effective in the Treatment of Allergic Rhinitis.” J. Clin. Pharm. 39: Dang, P.G., et al., filed Nov. 22, 2005. 1062-1069, American College of Clinical Pharmacology (1999). Office Action mailed Feb. 3, 2010 in U.S. Appl. No. 1 1/284,109, LaForce, C. et al., “Safety and efficacy of azelastine nasal spray Dang, P.G., et al., filed Nov. 22, 2005. (Astelin NS) for seasonal allergic rhinitis: a 4-week comparative Office Action mailed Apr. 28, 2010 in U.S. Appl. No. 10/518,016, Lulla, A., et al., filed Jul. 6, 2005. multicenter trial.” Annals of Allergy, Asthma, and Immunology 76: Gray, H., “Anatomy of the Human Body,” 20th ed., Lewis, W., ed., 181-188, Elsevier (1996). Lea & Febiger, Philadelphia, PA (1918), http://www.bartleby.com/ Office Action mailed on Jun. 27, 2012 in U.S. Appl. No. 13/284.836, 1077 (cited in an Office Action dated Feb. 17, 2010, in parent U.S. inventors Dang et al., filed Oct. 28, 2011. Appl. No. 1 1/486,454, filed Jul. 14, 2006). Storms, W.W. “Treatment of seasonal allergic rhinitis with Allen, L., et al., “Ansel's Pharmaceutical Dosage Forms and Drug fluticasone propionate aqueous nasal spray: review of comparator Delivery Systems.” Lippincott Williams & Wilkins, 7th ed., pp. 93-98 studies.” Allergy 50 (Supplement 23): 25-29, John Wiley & Sons, (1999). Belgium (1995). “Drug Facts and Comparisons.” 1994 ed., Wolters Kluwer Co., pp. 2278. * cited by examiner U.S. Patent

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SSNLu euleSeguOuy effueuo UeeW US 8,758,816 B2 1. 2 COMPOSITIONS COMPRISING crystalline powder with a strong bitter taste. The chemical AZELASTINE AND METHODS OF USE name for azelastine hydrochloride is (+)-1-(2H)-phthalazi THEREOF none, 4-(4-chlorophenyl)methyl-2-(hexahydro-1-methyl 1H-azepin-4-yl)-, mono-hydrochloride and its molecular for CROSS REFERENCE TO RELATED mula is CHCINO.HC1. Other salt forms suitable for use APPLICATIONS in pharmaceutical compositions include azelastine embonate, which is reduced in bitterness compared to azelastine HCl The present application is a continuation-in-part of U.S. (see U.S. Pat. No. 5.232,919 the disclosure of which is incor application Ser. No. 1 1/486,454, filed Jul. 14, 2006, now porated herein by reference), but which may also be less abandoned, which is a continuation-in-part of U.S. applica 10 effective than azelastine HC1. tion Ser. No. 1 1/284,109, filed Nov. 22, 2005, now, U.S. Pat. Research has shown that aZelastine and its physiologically No. 8,071,073 which claims the benefit of the filing date of acceptable salt forms exhibit beneficial effects when the cor U.S. Provisional Patent Application No. 60/630,274, filed responding formulations are applied directly onto the nasal Nov. 24, 2004, the disclosures of all of which are incorporated mucosa and/or the conjunctival sac of the eye (see U.S. Pat. herein by reference in their entireties. 15 No. 5,164,194). Elimination of symptoms or noticeable relief has thus been achieved in allergic rhinitis (seasonal and/or BACKGROUND OF THE INVENTION nonseasonal), vasomotor rhinitis and allergic conjunctivitis. Despite its effectiveness, azelastine hydrochloride pos 1. Field of the Invention sesses a strong bitter taste. This bitter taste is so intense that it The present invention is in the fields of pharmaceuticals, was found to be unpleasant even at a dilution of 1x10” (see formulations chemistry and pharmacology. The invention U.S. Pat. No. 5,164,194). The bitter taste was not thought to generally relates to compositions comprising aZelastine or be a problem in intranasal delivery of azelastine hydrochlo pharmaceutically acceptable salts or esters thereof, including ride (see id.). However, subsequent clinical studies have aZelastine hydrochloride. In certain embodiments, the inven shown that the bitter taste of azelastine hydrochloride is, tion provides pharmaceutical compositions comprising 25 indeed, an undesired element as a portion of the medication aZelastine hydrochloride formulated for use as nasal sprays usually drips down into the pharynx after intranasal admin and/or ocular Solutions or drops, as well as dosage formula istration leading to an unpleasant and undesired taste experi tions for oral and pulmonary delivery. The invention also ence by the patient. For example, MedPointe Pharmaceuti relates to pharmaceutical compositions comprising one or cals, Inc. (Somerset, N.J.) has reported in the ASTELINR) more active pharmaceutical ingredients, including antihista 30 product label insert that in clinical studies, the bitter taste mines such as azelastine orpharmaceutically acceptable salts adverse event occurred statistically more often in patients or esters thereof, for example, azelastine hydrochloride, par treated with ASTELINR brand Nasal Spray (containing 0.10% ticularly wherein the compositions are provided in unit dos w/v azelastine hydrochloride) versus vehicle placebo (19.7% age form. In certain embodiments, the invention provides vs. 0.6%). Likewise, the fluid formed by a combination of an Such unit dosage pharmaceutical compositions comprising 35 ocularly administered medication, and induced tears secreted antihistamines such as azelastine hydrochloride formulated by the lachrymal glands, drains via the nasolachrymal duct for use as nasal sprays and/or ocular orotic Solutions or drops. into the nose and ultimately down the pharynx (see Day, N., The invention also relates to methods of use of such compo “Ophthalmic Dosage Forms, in: Pharmaceutical Preformu sitions in treating, alleviating or preventing symptoms asso lation and Formulation, Buffalo Grove, Ill.: Interpharm Press ciated with a variety of allergic and non-allergic conditions, 40 (2002)). Such post-nasal drip caused by the ocular adminis particularly conjunctivitis and rhinitis. tration of compositions comprising azelastine hydrochloride 2. Related Art therefore can also induce a bitter and unpleasant taste expe AZelastine is a second-generation H1 antagonistantihista rience by the patient. Ukai et al. (U.S. Pat. No. 6,576,677) mine which is used for its anti-allergic, anti-asthmatic and disclose the use of polyvinylpyrrolidone and/or copolyvidone antihistamine properties. AZelastine is a phthalazinone 45 to mask the taste of bitter medicaments, including azelastine. derivative having the following structural formula: Although the current conventional systems used for appli cation of nasal or ocular pharmaceutical formulations have been shown to be clinically efficacious, they can suffer from (I) relatively low efficiency levels in delivering pharmaceutical C 50 containing Solutions to the nasal mucosa or conjunctiva of a patient, thereby wasting a Substantial portion of the pharma ceutical formulations and Substantially increasing drug deliv ery costs. The low efficiency of current conventional delivery systems can also require patients to devote relatively long 55 time periods or high Volume of application of the formula tions to receive an effective dose of the active pharmaceutical ingredient, which can lead to decreased patient compliance. Moreover, the use of preservatives in pharmaceutical formu N-CH lations, often problematic for nasal or ocular medications due 60 to the stinging of the nose or eye associated with the preser Vative, is nonetheless typically required so as to reduce or avoid bacterial contamination in multi-use conventional con tainers currently used for storage and application of nasal and ocular pharmaceutical formulations. Azelastine can be produced in a variety of salt forms. The 65 There remains a need for atherapeutically effective dose of form most frequently used in pharmaceuticals is azelastine aZelastine hydrochloride, particularly for nasal, ocular, or hydrochloride, which occurs as a white, almost odorless, pulmonary delivery, which possesses a more desired taste US 8,758,816 B2 3 4 and/or has a reduced ability to drip down into the pharynx of a variety of routes, including but not limited to intranasal, after intranasal or ocular administration, thus improving ocular, oral, buccal, Sublingual administration and the like. patient acceptability and compliance. Accordingly, there is In additional embodiments, the invention provides the also a need for new and improved methods and devices for the intranasal or ocular pharmaceutical compositions described storage and delivery of pharmaceutical compositions, such as above, which may further comprise one or more agents that those comprising antihistamines including azelastine hydro reduce or prevent postnasal drip of the compositions into the chloride, particularly for nasal, ocular, otic or topical delivery, pharynx upon intranasal or ocular administration of the com which will reduce administration costs, increase patient com positions. Certain Such compositions may comprise, for pliance, enhance overall effectiveness of the therapy and example, one or more Viscosity-increasing agents that reduce or eliminate the need for including preservatives in the 10 increase the viscosity of the azelastine-containing composi formulations. tion. Suitable viscosity-increasing agents for use in accor dance with this aspect of the invention include, but are not BRIEF SUMMARY OF THE INVENTION limited to, polyvinylpyrrolidones (PVP) (preferably having a molecular weight of about 10,000 to about 360,000, as well as The present invention provides compositions, particularly 15 mixtures containing one or more grades or molecular weight stable pharmaceutical compositions, comprising azelastine of PVP), cellulose derivatives (including, but not limited to, and/or one or more pharmacologically acceptable salts or hydroxyethyl cellulose, carboxymethyl cellulose or its salts, esters thereof, particularly azelastine hydrochloride, in unit hypromellose, and the like), carrageenan, guar gum, algi dosage configuration. In certain embodiments, the pharma nates, carbomers, polyethylene glycols, polyvinyl alcohol, ceutical compositions comprise one or more pharmaceuti Xanthan gum, and the like. In certain preferred embodiments, cally acceptable carriers or excipients, particularly one or hypromellose is used as a viscosity-increasing agent in the more Such carriers or excipients that are useful informulating nasal or ocular formulations provided by the present inven the composition into a form suitable for delivery to a variety tion. of locations in or on the body, including intranasal, intraocu Certain compositions of the invention may further com lar, intraotic and skin (topical) application. In particular 25 prise one or more additional components or agents, including embodiments, the pharmaceutical compositions comprise one or more solvents, one or more preservatives, one or more one or more pharmaceutically acceptable carriers or excipi stabilizers, one or more solubility-improving agents, one or ents, particularly one or more Such carriers or excipients that more isotonicity agents, one or more buffers or buffering are useful informulating the composition into a form Suitable agents, one or more synthetic, semi-synthetic or natural bio for intranasal delivery, e.g., via aerosol or spray approaches, 30 adhesives, and the like. or for ophthalmic delivery, e.g., via ocular drops, or for pull The invention also provides methods of treating or prevent monary delivery, e.g., via a suitable device in a unit dosage ing a variety of allergy-related and/or vasomotor-related con configuration. ditions, or symptoms thereof, including allergic rhinitis, In certain additional embodiments, the invention provides vasomotor rhinitis, allergic conjunctivitis and the like. pharmaceutical compositions comprising (or consisting 35 According to this aspect of the invention, the compositions essentially of) Suitable concentrations of azelastine, or a phar may be administered to the patient via any Suitable mode of maceutically acceptable salt or ester thereof (such as azelas administration, including intranasal, ocular, oral, buccal, Sub tine hydrochloride (HCl)) to provide a therapeutically effec lingual, pulmonary or the like. Suitably, the compositions are tive dose of azelastine, or a pharmaceutically acceptable salt administered directly to the nasal mucosa (i.e., intranasally, orester thereof, and one or more pharmaceutically acceptable 40 e.g., in the form of a nasal spray or drops) or to the conjunc carriers or excipients, wherein at least one of the pharmaceu tival sac of the eye (i.e., ocularly, e.g., in the form of ocular tically acceptable carriers or excipients is a taste-masking drops). agent that masks the bitter taste associated with azelastine or The present invention also provides oral dosage pharma its salts or esters such that the bitter taste experienced by a ceutical compositions comprising (or consisting essentially patient, upon administration of the pharmaceutical composi 45 of) a therapeutically effective dose of azelastine, or a phar tion to the patient, is reduced or eliminated, thus enhancing maceutically acceptable salt or ester thereof, at a concentra the organoleptic acceptance of the composition when applied tion of from about 0.05% to about 5.0% by weight, or to to the nasal, ocular, oral or pharyngeal mucosa. In preferred provide about 0.5 mg to about 10 mg per dose, and one or Such embodiments, the taste-masking agent is selected from more pharmaceutically acceptable carriers or excipients, the group consisting of Sucralose, thaumatin (e.g., Talin R.) 50 wherein at least one of the pharmaceutically acceptable car Sucrose, saccharin (including the salt forms: Sodium, cal riers or excipients is a taste masking agent, e.g., Sucralose. In cium, etc.), fructose, dextrose, corn syrup, aspartame, certain such embodiments, the amount of azelastine, or a acesulfame-K, Xylitol, Sorbitol, erythritol, ammonium gly pharmaceutically acceptable salt thereof (e.g., azelastine cyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, HCl) is in the range of about 0.05 mg to about 10 mg. Suitably camphor, and natural or artificial flavors or flavoring agents 55 the concentration of sucralose is about 0.05% to about 0.15% (for example menthol, mints, Vanilla, orange, etc.), or com by weight. Exemplary forms of oral dosage compositions binations of two or more of Such agents. Particularly pre include, but are not limited to, liquid solutions, Suspensions, ferred Such embodiments provide Such pharmaceutical com tablets, capsules, chewable tablets, orally disintegrating tab positions in which the taste-masking agent is Sucralose, at a lets, effervescent compositions and orally dissolving/con suitable concentration, for example, from about 0.001% to 60 sumable films. 1%, preferably from about 0.01% to about 0.5%, more pref The present invention also provides pharmaceutical com erably from about 0.02% to about 0.2%, or most preferably positions comprising (or consisting essentially of) atherapeu from about 0.05% to about 0.15%, of the total composition. tically effective dose of azelastine, or a pharmaceutically Additional Such embodiments may further comprise one or acceptable salt or ester thereof, at a concentration of from more additional flavoring agents, such as menthol, mints, 65 about 0.05% to about 5.0% by weight, and one or more Vanilla, orange, etc. The compositions of the present inven pharmaceutically acceptable carriers or excipients, wherein tion preferably can be formulated for administration via any at least one of the pharmaceutically acceptable carriers or US 8,758,816 B2 5 6 excipients is Sucralose, and wherein the pharmaceutical com nedcromil Sodium), anti-viral agents (such as abacavir, acy position further comprises one or more additional active clovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, agents. Suitable additional active agents for use in Such com atriplaboceprevir, cidofovir, combivir, darunavir delavirdine, positions include, but are not limited to, antihistamines (such didanosine, docosanol, edoxudine, efavirenz, emitricitabine, ascetirizine, fexofenadine, olopatadine, terfenadine andlora enfuVirtide, entecavir, famciclovir, fomivirsen, foSam tadine), Steroids (such as fluoromethalone, fluticaSone, prenavir, foScarnet, foSfonet, ganciclovir, ibacitabine, immu mometasone, triamcinolone, betamethasone, flunisolide, novir, idoxuridine, imiquimod, indinavir, inosine, integrase budesonide, beclomethasone, budesonide, rimexolone, inhibitor, lamivudine, lopinavir, loviride, maraviroc, moroxy loteprednol (e.g., loteprednoletabonate), beloxil, prednisone dine, nelfinavir, nevirapine nexavir, oseltamivir, peginter and dexamethasone) or pharmaceutically acceptable salt, 10 feron alfa-2a, penciclovir, peramivir, pleconaril, podophyllo esters or derivatives thereof, leukotriene antagonists (such as toxin, raltegravir, ribavirin, rimantadine, ritonavir, albuterol Sulfate, aminophylline, amoxicillin, amplicillin, saquinavir, stavudine, tenofovir, tipranavir, trifluridine, triz astemizole, attenuated tubercle bacillus, azithromycin, ivir, tromantadine, truvada, Valaciclovir, Valganciclovir, bacampicillin, beclomethasone dipropionate, budesonide, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir and bupropion hydrochloride, cefaclor, cefadroxil, cefixime, cef 15 Zidovudine), antiseptics (Such as iodine, chlorhexidine prozil, cefuroxime axetil, cephalexin, ciprofloxacin hydro acetate, sodium hypochlorite and calcium hydroxide), neuro chloride, clarithromycin, clindamycin, cloxacillin, doxycy kinin antagonists (such as oXimes, hydrazones, piperidines, cline, erythromycin, ethambutol, fenoterol hydrobromide, piperazines, aryl alkyl amines, hydrazones, nitroalkanes, fluconazole, flunisolide, fluticasone propionate, fluticaSone amides, is oxazolines, quinolines, isoquinolines, azanorbor furoate, formoterol fumarate, gatifloxacin, influenza virus names, naphthyridines and benzodiazepines), 5-lipoxygenase vaccine, ipratropium bromide, isoniazid, isoproterenol inhibitors (such as Zileuton, docebenone, piripost and hydrochloride, itraconazole, ketoconazole, ketotifen, levof tenidap) and triamcinolone or triamcinolone derivatives. loxacin, minocycline, montelukast, moxifloxacin, nedocro Suitably the amount of Sucralose in Such compositions is mil sodium, nicotine, nystatin, ofloxacin, orciprenaline, osel about 0.05% to about 0.15% by weight. The pharmaceutical tamivir, Oseltamivir Sulfate, Oxtriphylline, penicillin, 25 compositions can also comprise combinations of azelastine pirbuterol acetate, pivampicillin, pneumococcal conjugate and multiple additional active agents, for example, azelastine, vaccine, pneumococcal polysaccharide vaccine, prednisone, one or more steroids and one or more decongestants; or pyrazinamide, rifampin, Salbutamol, Salmeterol Xinafoate, aZelastine, one or more steroids and one or more leukotriene Sodium cromoglycate, terbutaline Sulfate, terfenadine, theo antagonists. Such combination compositions can also further phylline, triamcinolone acetonide, Zafirlukast and Zan 30 comprise Sucralose and/or other additional carriers or excipi amivir), decongestants (such as pseudoephedrine, phenyle entS. phedrine, phenylephrine, phenylpropanolamine, In another embodiment, the present invention provides oxymetazoline, propylhexedrine, Xylometazoline, epineph Sustained release pharmaceutical compositions for oral deliv rine, ephedrine, desoxyephedrine, naphazoline, and tetrahy ery comprising (or consisting essentially of) a therapeutically drozoline), expectorants (such as guaifenesin, sodium cro 35 effective dose of azelastine, or a pharmaceutically acceptable moglycate, codeine phosphate, and isoproternol salt or ester thereof, and one or more pharmaceutically hydrochloride), anti-fungal agents (such as amphotericin B, acceptable carriers or excipients, wherein at least one of the nystatin, fluconazole, ketoconazole, terbinafine, itracona pharmaceutically acceptable carriers or excipients is sucral Zole, imidazole, triazole, ciclopirox, clotrimazole, and ose, and wherein the azelastine, or the pharmaceutically miconazole), non-steroidal anti-inflammatory agents (such as 40 acceptable salt or ester thereof, is: 1) coated with one or more ibuprofen, diclofenac, aceclofenac, naproxen, etodolac, flur Sustained release components; 2) bound to a cation biprofen, fenoprofen, ketoprofen, suprofen, fenbufen, flupro exchanger; 3) reacted with one or more osmotically active fen, tolmetin Sodium, oxaprozin, Zomepirac, Sulindac Substances and coated with a semi-permeable membrane and indomethacin, piroXicam, mefenamic acid, nabumetone, a hole is bored into the membrane; or 4) embedded in, or is meclofenamate Sodium, diflunisal, flufenisal, piroxicam, 45 bound to, one or more substances selected from of the group ketorolac, Sudoxicam and isoxicam), non-steroidal immuno consisting of digestible fats, indigestible fats, polymers and philin-dependent immunosuppressants (such as cyclospo Swelling agents. Suitably, the amount of azelastine in Such rine, tacrolimus, ascomycin, pimecrolimus, rapamycin, sustained release compositions is about 0.05% to about everolimus, and other agents that inhibit calcineurin), COX-2 10.0% by weight and the amount of sucralose in such sus inhibitors (such as rofecoxib, celecoxib, Valdecoxib, lumira 50 tained release compositions is about 0.05% to about 0.15% by coxib, meloxicam, and nimeSulide), anti-infective agents weight. In certain Such embodiments, the amount of azelas (such as penicillin, beta lactam antibiotics, cephalosporins, tine or salt thereof (e.g., azelastine HCl) is about 0.5 mg to macrollides, ketolides, Sulfonamides, quinolones, aminogly about 10 mg. cosides, cefuroxime, Vancomycin, amoxicillin, gentamicin In another embodiment, the present invention provides and lineZolid), mucolytic agents (such as acetylcysteine and 55 liquid pharmaceutical compositions for ocular administra dornase alpha), anticholinergic agents (such as mivacurium, tion, comprising (or consisting essentially of) a therapeuti atracurium, fazadinium, rocuronium, Vecuronium, doxacu cally effective dose of azelastine, or a pharmaceutically rium, metocurine, pancuronium, pipecuronium, gallamine, acceptable salt or ester thereof, and one or more pharmaceu hexafluoronium, suxamethonium, Succinylcholine, decame tically acceptable carriers or excipients, wherein at least one thonium, atropine, Scopolamine, hyoscyamine, benzatropine, 60 of the pharmaceutically acceptable carriers or excipients is trihexyphenidyl, biperiden, glycopyrrolate, ipratropium, Sucralose, wherein the composition is free, or Substantially pirenzepine, telenzepine, tiotropium, darifenacin, Vedaclid free of preservatives, and wherein the composition is pro ine, tropicamide, cyclopentolate, dicycloverine, tolterodine, vided in a single unit-dose container or multi-dose container. oxybutynin, homatropine, orphenadrine, diphenhydramine, Suitably, the amount of azelastine in Such liquid, unit-dose or hemicholinium-3, Vesamicol, pralidoxime, obidoxime, 65 multi-dose pharmaceutical compositions is about 0.05% to oxitropium, alcuronium, dimethyltubocurarine, tubocurarine about 0.15% by weight and the amount of sucralose in such and ipratropium), mast cell stabilizers (such as cromolyn and liquid, unit-dose pharmaceutical compositions is about US 8,758,816 B2 7 8 0.05% to about 0.15% by weight. Suitable single unit-dose The present invention also provides methods of treating containers or multi-dose containers include, but are not lim Snoring in an animal, comprising administering to the animal ited to, high density polyethylene containers, for example, atherapeutically effective dose of azelastine, or a pharmaceu high density polyethylene containers produced using a blow tically acceptable salt or ester thereof, and one or more phar fill-seal manufacturing technique with a volume capacity of 5 maceutically acceptable carriers or excipients, wherein at about 1 mL. least one of the pharmaceutically acceptable carriers or In another embodiment, the present invention provides excipients is Sucralose. The amount of azelastine in Such liquid pharmaceutical compositions for nasal administration, compositions suitably is about 0.05% to about 0.15% by comprising (or consisting essentially of) a therapeutically weight, and the amount of Sucralose in Such compositions is 10 suitably about 0.05% to about 0.15% (e.g., 0.05%, 0.10% or effective dose of azelastine, or a pharmaceutically acceptable 0.15%) by weight. salt or ester thereof, and one or more pharmaceutically The present invention also provides methods of treating or acceptable carriers or excipients, wherein at least one of the preventing allergic rhinitis, non-allergic vasomotor rhinitis or pharmaceutically acceptable carriers or excipients is Sucral allergic conjunctivitis in an animal. Such as a human, Suffer ose, wherein the composition is free, or substantially free of 15 ing from or predisposed thereto, comprising administering to preservatives, and wherein the composition is provided in said animal a pharmaceutical composition comprising an either a single unit-dose container or multi-dose container. effective amount aZelastine and a taste-masking amount of Suitably, the amount of azelastine in Such liquid, unit-dose or sucralose, thereby avoiding the bitter taste associated with the multi-dose pharmaceutical compositions is about 0.05% to aZelastine. about 0.15% by weight and the amount of sucralose in such In suitable embodiments, the present invention provides liquid, unit-dose or multi-dose pharmaceutical compositions pharmaceutical compositions comprising (or consisting is about 0.05% to about 0.15% (e.g., 0.05%, 0.10% or 0.15%) essentially of) the following: by weight. Suitable single unit-dose containers or multi-dose About 0.05% to about 0.15% (w/v) azelastine hydrochlo containers include, but are not limited to, high density poly ride; and about 0.01% to about 1.0% (w/v) steroid selected ethylene containers, for example, high density polyethylene 25 from the group consisting of fluticasone, mometaSone, dex containers produced using a blow-fill-seal manufacturing amethasone beloxil, loteprednol (e.g., loteprednol eta technique with a Volume capacity of about 1 mL. bonate), budesonide and triamcinolone, or a pharmaceuti The present invention also provides inhalable powderphar cally acceptable salt, ester or derivative thereof (e.g., maceutical compositions comprising (or consisting essen fluticasone propionate, fluticasone dipropionate, fluticaSone tially of), a therapeutically effective dose of azelastine, or a 30 furoate, fluticasone maleate, fluticasone Valerate, and the pharmaceutically acceptable salt or ester thereof, and one or like). more pharmaceutically acceptable carriers or excipients, About 0.05% to about 0.15% (w/v) azelastine hydrochlo wherein the azelastine is in the form of micronized particles ride; about 0.01% to about 1.0% (w/v) steroid selected from and wherein at least one of the pharmaceutically acceptable the group consisting of fluticaSone (e.g., fluticaSone propi carriers or excipients is Sucralose, for example, micronized 35 onate, fluticasone dipropionate, fluticasone furoate, flutica particles of sucralose. Suitable such inhalable powder phar Sone maleate, fluticaSone Valerate, and the like), mometa maceutical compositions comprise micronized particles of Sone, dexamethasone beloxil, loteprednol (e.g., loteprednol aZelastine with an average particle size of about 1 um to about etabonate), budesonide and triamcinolone; and about 0.1% to 5um, and micronized particles of Sucralose with an average about 0.15% (w/v) sucralose. particle size of about 1 um to about 20 lum. Such inhalable 40 About 0.1% (w/v) azelastine hydrochloride; about 0.01% powderpharmaceutical compositions of the present invention to about 1.0% (w/v) steroid selected from the group consist can beformulated for pulmonary delivery using, for example, ing of fluticasone (e.g., fluticasone propionate, fluticaSone a dry powder inhaler. Suitably, the amount of azelastine in dipropionate, fluticaSone furoate, fluticasone maleate, fluti Such inhalable powder pharmaceutical compositions is about casone Valerate, and the like), mometasone, dexamethasone 0.1% to about 20.0% by weight and the amount of sucralose 45 beloxil, loteprednol (e.g., loteprednoletabonate), budesonide in Such inhalable powder pharmaceutical compositions is and triamcinolone; and about 0.1% (w/v) sucralose. about 0.05% to about 20.0% by weight. About 0.1% (w/v) azelastine hydrochloride; about 0.01% The present invention also provides inhalable spray phar to about 1.0% (w/v) steroid selected from the group consist maceutical compositions comprising (or consisting essen ing of fluticasone (e.g., fluticasone propionate, fluticaSone tially of), a suitable concentration to provide atherapeutically 50 dipropionate, fluticaSone furoate, fluticasone maleate, fluti effective dose of azelastine, or a pharmaceutically acceptable casone Valerate, and the like), mometasone, dexamethasone salt or ester thereof, and one or more pharmaceutically beloxil, loteprednol (e.g., loteprednoletabonate), budesonide acceptable carrier, stabilizer or excipient, wherein the azelas and triamcinolone; and about 0.15% (w/v) sucralose. tine is in a solution form and wherein at least one of the About 0.15% (w/v) azelastine hydrochloride; about 0.01% pharmaceutically acceptable carriers or excipients is Sucral 55 to about 1.0% (w/v) steroid selected from the group consist ose dissolved in the solution. Such inhalable spray pharma ing of fluticasone (e.g., fluticasone propionate, fluticaSone ceutical compositions when used with a suitable device pro dipropionate, fluticaSone furoate, fluticasone maleate, fluti vide a fine spray of the components (including active and casone Valerate, and the like), mometasone, dexamethasone non-active components) having an average particle size of beloxil, loteprednol (e.g., loteprednoletabonate), budesonide about 1 um to about 5um. Such inhalable spray pharmaceu 60 and triamcinolone; and about 0.1% (w/v) sucralose. tical compositions of the present invention can be formulated About 0.15% (w/v) azelastine hydrochloride; about 0.01% for pulmonary delivery using, for example, a suitable device to about 1.0% (w/v) steroid selected from the group consist or inhaler. Suitably the amount of azelastine in such inhalable ing of fluticasone (e.g., fluticasone propionate, fluticaSone spray pharmaceutical compositions is about 0.1% to about dipropionate, fluticaSone furoate, fluticasone maleate, fluti 10% by weight and the amount of sucralose in such inhalable 65 casone Valerate, and the like), mometasone, dexamethasone spray pharmaceutical compositions is about 0.05% to about beloxil, loteprednol (e.g., loteprednoletabonate), budesonide 0.15% (e.g., 0.05%, 0.10% or 0.15%) by weight. and triamcinolone; and about 0.15% (w/v) sucralose. US 8,758,816 B2 9 10 About 0.05% to about 0.15% (w/v) azelastine hydrochlo About 0.05% to about 0.15% (w/v) azelastine hydrochlo ride; and about 0.1% to about 5.0% (w/v) montelukast. ride; about 0.01% to about 1.0% (w/v) steroid selected from About 0.05% to about 0.15% (w/v) azelastine hydrochlo the group consisting of fluticaSone (e.g., fluticaSone propi ride; about 0.1% to about 5.0% (w/v) montelukast; and about onate, fluticasone dipropionate, fluticasone furoate, flutica 0.1% to about 0.15% (w/v) sucralose. Sone maleate, fluticaSone Valerate, and the like), mometa About 0.1% (w/v) azelastine hydrochloride; about 0.1% to Sone, dexamethasone beloxil, loteprednol (e.g., loteprednol about 5.0% (w/v) montelukast; and about 0.1% (w/v) sucral etabonate), budesonide, and triamcinolone; and about 0.1% OS. to about 1.0% (w/v) decongestant selected from the group About 0.1% (w/v) azelastine hydrochloride; about 0.1% to consisting of pseudoephedrine and phenylephrine. 10 About 0.05% to about 0.15% (w/v) azelastine hydrochlo about 5.0% (w/v) montelukast; and about 0.15% (w/v) sucral ride; about 0.01% to about 1.0% (w/v) steroid selected from OS. the group consisting of fluticaSone (e.g., fluticaSone propi About 0.15% (w/v) azelastine hydrochloride; about 0.1% onate, fluticasone dipropionate, fluticasone furoate, flutica to about 5.0% (w/v) montelukast; and about 0.1% (w/v) Sucralose. Sone maleate, fluticaSone Valerate, and the like), mometa 15 Sone, dexamethasone beloxil, loteprednol (e.g., loteprednol About 0.15% (w/v) azelastine hydrochloride; about 0.1% etabonate), budesonide, and triamcinolone; about 0.1% to to about 5.0% (w/v) montelukast; and about 0.15% (w/v) about 1.0% (w/v) decongestant selected from the group con Sucralose. sisting of pseudoephedrine and phenylephrine; and about About 0.05% to about 0.15% (w/v) azelastine hydrochlo 0.1% to about 0.15% (w/v) sucralose. ride; and about 0.1% to about 1.0% (w/v) decongestant About 0.1% (w/v) azelastine hydrochloride; about 0.01% selected from the group consisting of pseudoephedrine and to about 1.0% (w/v) steroid selected from the group consist phenylephrine. ing of fluticasone (e.g., fluticasone propionate, fluticaSone About 0.05% to about 0.15% (w/v) azelastine hydrochlo dipropionate, fluticaSone furoate, fluticasone maleate, fluti ride; about 0.1% to about 1.0% (w/v) decongestant selected casone Valerate, and the like), mometasone, dexamethasone from the group consisting of pseudoephedrine and phenyle 25 beloxil, loteprednol (e.g., loteprednol etabonate), budes phrine; and about 0.1% to about 0.15% (w/v) sucralose. onide, and triamcinolone; about 0.1% to about 1.0% (w/v) About 0.1% (w/v) azelastine hydrochloride; about 0.1% to decongestant selected from the group consisting of pseu about 1.0% (w/v) decongestant selected from the group con doephedrine and phenylephrine; and about 0.1% (w/v) sisting of pseudoephedrine and phenylephrine; and about Sucralose. 0.1% (w/v) sucralose. 30 About 0.1% (w/v) azelastine hydrochloride; about 0.01% About 0.1% (w/v) azelastine hydrochloride; about 0.1% to to about 1.0% (w/v) steroid selected from the group consist about 1.0% (w/v) decongestant selected from the group con ing of fluticasone (e.g., fluticasone propionate, fluticasone sisting of pseudoephedrine and phenylephrine; and about dipropionate, fluticaSone furoate, fluticasone maleate, fluti 0.15% (w/v) sucralose. casone Valerate, and the like), mometasone, dexamethasone About 0.15% (w/v) azelastine hydrochloride; about 0.1% 35 beloxil, loteprednol (e.g., loteprednol etabonate), budes to about 1.0% (w/v) decongestant selected from the group onide, and triamcinolone; about 0.1% to about 1.0% (w/v) consisting of pseudoephedrine and phenylephrine; and about decongestant selected from the group consisting of pseu 0.1% (w/v) sucralose. doephedrine and phenylephrine; and about 0.15% (w/v) About 0.15% (w/v) azelastine hydrochloride; about 0.1% Sucralose. to about 1.0% (w/v) decongestant selected from the group 40 About 0.15% (w/v) azelastine hydrochloride; about 0.01% consisting of pseudoephedrine and phenylephrine; and about to about 1.0% (w/v) steroid selected from the group consist 0.15% (w/v) sucralose. ing of fluticasone (e.g., fluticasone propionate, fluticaSone About 0.05% to about 0.15% (w/v) azelastine hydrochlo dipropionate, fluticaSone furoate, fluticasone maleate, fluti ride; and about 0.1% to about 10.0% (w/v) NSAID selected casone Valerate, and the like), mometasone, dexamethasone from the group consisting of ibuprofen, diclofenac, ace 45 beloxil, loteprednol (e.g., loteprednol etabonate), budes clofenac and naproxen. onide, and triamcinolone; about 0.1% to about 1.0% (w/v) About 0.05% to about 0.15% (w/v) azelastine hydrochlo decongestant selected from the group consisting of pseu ride; about 0.1% to about 10.0% (w/v) NSAID selected from doephedrine and phenylephrine; and about 0.1% (w/v) the group consisting of ibuprofen, diclofenac, aceclofenac Sucralose. and naproxen; and about 0.1% to about 0.15% (w/v) sucral 50 About 0.15% (w/v) azelastine hydrochloride; about 0.01% OS. to about 1.0% (w/v) steroid selected from the group consist About 0.1% (w/v) azelastine hydrochloride; about 0.1% to ing of fluticasone (e.g., fluticasone propionate, fluticaSone about 10.0% (w/v) NSAID selected from the group consisting dipropionate, fluticaSone furoate, fluticasone maleate, fluti of ibuprofen, diclofenac, aceclofenac and naproxen; and casone Valerate, and the like), mometasone, dexamethasone about 0.1% (w/v) sucralose. 55 beloxil, loteprednol (e.g., loteprednol etabonate), budes About 0.1% (w/v) azelastine hydrochloride; about 0.1% to onide, and triamcinolone; about 0.1% to about 1.0% (w/v) about 10.0% (w/v) NSAID selected from the group consisting decongestant selected from the group consisting of pseu of ibuprofen, diclofenac, aceclofenac and naproxen; and doephedrine and phenylephrine; and about 0.15% (w/v) about 0.15% (w/v) sucralose. Sucralose. About 0.15% (w/v) azelastine hydrochloride; about 0.1% 60 About 0.05% to about 0.15% (w/v) azelastine hydrochlo to about 10.0% (w/v) NSAID selected from the group con ride; about 0.01% to about 1.0% (w/v) steroid selected from sisting of ibuprofen, diclofenac, aceclofenac and naproxen; the group consisting of fluticaSone (e.g., fluticaSone propi and about 0.1% (w/v) sucralose. onate, fluticasone dipropionate, fluticasone furoate, flutica About 0.15% (w/v) azelastine hydrochloride; about 0.1% Sone maleate, fluticaSone Valerate, and the like), mometa to about 10.0% (w/v) NSAID selected from the group con 65 Sone, dexamethasone beloxil, loteprednol (e.g., loteprednol sisting of ibuprofen, diclofenac, aceclofenac and naproxen; etabonate), budesonide, and triamcinolone; and about 0.1% and about 0.15% (w/v) sucralose. to about 5.0% (w/v) montelukast. US 8,758,816 B2 11 12 About 0.05% to about 0.15% (w/v) azelastine hydrochlo Sufficient amount of an isotonicity agent to yield an osmola ride; about 0.01% to about 1.0% (w/v) steroid selected from lity of about 220 mosmol/kg to about 350 mosmol/kg; and QS the group consisting of fluticaSone (e.g., fluticaSone propi Water. onate, fluticasone dipropionate, fluticasone furoate, flutica About 0.05% to about 0.15% (w/v) azelastine hydrochlo Sone maleate, fluticaSone Valerate, and the like), mometa ride; about 0.1% to about 1% (w/v) decongestant selected Sone, dexamethasone beloxil, loteprednol (e.g., loteprednol from the group consisting of pseudoephedrine and phenyle etabonate), budesonide, and triamcinolone; about 0.1% to phrine; about 0.001% to about 5.00% (w/v) of a water-soluble about 5.0% (w/v) montelukast; and about 0.1% to about polymer; about 0.01% to about 0.1% (w/v) disodium edetate; 0.15% (w/v) sucralose. about 0.001% to about 0.5% (w/v) benzalkonium chloride: About 0.1% (w/v) azelastine hydrochloride; about 0.01% 10 about 0.1% to about 0.15% sucralose; a sufficient amount of to about 1.0% (w/v) steroid selected from the group consist a pharmaceutically acceptable buffer to maintain the pH of ing of fluticasone (e.g., fluticasone propionate, fluticaSone the composition within a range of from about 4.5 to about 7.4: dipropionate, fluticaSone furoate, fluticasone maleate, fluti a Sufficient amount of an isotonicity agent to yield an osmo casone Valerate, and the like), mometasone, dexamethasone lality of about 220 mosmol/kg to about 350 mosmol/kg; and beloxil, loteprednol (e.g., loteprednol etabonate), budes 15 QS water. onide, and triamcinolone; about 0.1% to about 5.0% (w/v) About 0.05% to about 0.15% (w/v) azelastine hydrochlo montelukast; and about 0.1% (w/v) sucralose. ride; about 0.1% to about 10% (w/v) NSAID selected from About 0.1% (w/v) azelastine hydrochloride; about 0.01% the group consisting of ibuprofen, diclofenac, aceclofenac to about 1.0% (w/v) steroid selected from the group consist and naproxen; about 0.001% to about 5.00% (w/v) of a water ing of fluticasone (e.g., fluticasone propionate, fluticaSone soluble polymer; about 0.01% to about 0.1% (w/v) disodium dipropionate, fluticaSone furoate, fluticasone maleate, fluti edetate; about 0.001% to about 0.5% (w/v) benzalkonium casone Valerate, and the like), mometasone, dexamethasone chloride; about 0.1% to about 0.15% sucralose; a sufficient beloxil, loteprednol (e.g., loteprednol etabonate), budes amount of a pharmaceutically acceptable buffer to maintain onide, and triamcinolone; about 0.1% to about 5.0% (w/v) the pH of the composition within a range of from about 4.5 to montelukast; and about 0.15% (w/v) sucralose. 25 about 7.4, a Sufficient amount of an isotonicity agent to yield About 0.15% (w/v) azelastine hydrochloride; about 0.01% an osmolality of about 220 mosmol/kg to about 350 mosmol/ to about 1.0% (w/v) steroid selected from the group consist kg; and QS water. ing of fluticasone (e.g., fluticasone propionate, fluticaSone About 0.05% to about 0.15% (w/v) azelastine hydrochlo dipropionate, fluticaSone furoate, fluticasone maleate, fluti ride; about 0.01% to about 1% (w/v) steroid selected from the casone Valerate, and the like), mometasone, dexamethasone 30 group consisting of fluticasone (e.g., fluticaSone propionate, beloxil, loteprednol (e.g., loteprednol etabonate), budes fluticasone dipropionate, fluticaSone furoate, fluticaSone onide, and triamcinolone; about 0.1% to about 5.0% (w/v) maleate, fluticasone valerate, and the like), mometasone, dex montelukast; and about 0.1% (w/v) sucralose. amethasone beloxil, loteprednol (e.g., loteprednol eta About 0.15% (w/v) azelastine hydrochloride; about 0.1% bonate), budesonide and triamcinolone; about 0.1% to about to about 1.0% (w/v) steroid selected from the group consist 35 1% (w/v) decongestant selected from the group consisting of ing of fluticasone (e.g., fluticasone propionate, fluticaSone pseudoephedrine and phenylephrine; about 0.001% to about dipropionate, fluticaSone furoate, fluticasone maleate, fluti 5.00% (w/v) of a water-soluble polymer; about 0.01% to casone Valerate, and the like), mometasone, dexamethasone about 2% of a suspending agent; about 0.01% to about 0.2% beloxil, loteprednol (e.g., loteprednol etabonate), budes ofa wetting agent; about 0.01% to about 0.1% (w/v) disodium onide, and triamcinolone; about 0.1% to about 5.0% (w/v) 40 edetate; about 0.001% to about 0.5% (w/v) of a preservative montelukast; and about 0.15% (w/v) sucralose. such as benzalkonium chloride and/or phenylethyl alcohol; About 0.05% to about 0.15% (w/v) azelastine hydrochlo about 0.1% to about 0.15% sucralose; a sufficient amount of ride; about 0.01% to about 1% (w/v) steroid selected from the a pharmaceutically acceptable buffer to maintain the pH of group consisting of fluticasone (e.g., fluticasone propionate, the composition within a range of from about 4.5 to about 7.4: fluticasone dipropionate, fluticaSone furoate, fluticaSone 45 a Sufficient amount of an isotonicity agent to yield an osmo maleate, fluticaSone Valerate, and the like), mometasone, dex lality of about 220 mosmol/kg to about 350 mosmol/kg; and amethasone beloxil, loteprednol (e.g., loteprednol eta QS water. bonate), budesonide, and triamcinolone; about 0.001% to About 0.05% to about 0.15% (w/v) azelastine hydrochlo about 5.00% (w/v) of a water-soluble polymer; about 0.01% ride; about 0.01% to about 1% (w/v) steroid selected from the to about 2% of a suspending agent; about 0.01% to about 50 group consisting of fluticasone (e.g., fluticaSone propionate, 0.2% of a wetting agent; about 0.01% to about 0.1% (w/v) fluticasone dipropionate, fluticaSone furoate, fluticaSone disodium edetate; about 0.001% to about 0.5% (w/v) of a maleate, fluticaSone Valerate, and the like), mometaSone, dex preservative such as benzalkonium chloride and/or phenethyl amethasone beloxil, loteprednol (e.g., loteprednol eta alcohol; about 0.1% to about 0.15% sucralose; a sufficient bonate), budesonide and triamcinolone; about 0.1% to about amount of a pharmaceutically acceptable buffer to maintain 55 1% (w/v) montelukast; about 0.001% to about 5.00% (w/v) of the pH of the composition within a range of from about 4.5 to a water-soluble polymer; about 0.01% to about 2% of a sus about 7.4, a Sufficient amount of an isotonicity agent to yield pending agent; about 0.01% to about 0.2% of a wetting agent; an osmolality of about 220 mosmol/kg to about 350 mosmol/ about 0.01% to about 0.1% (w/v) disodium edetate; about kg; and QS water. 0.001% to about 0.5% (w/v) of a preservative such as benza About 0.05% to about 0.15% (w/v) azelastine hydrochlo 60 lkonium chloride and/or phenylethyl alcohol; about 0.1% to ride; about 0.1% to about 5% (w/v) montelukast; about about 0.15% sucralose; a sufficient amount of a pharmaceu 0.001% to about 5.00% (w/v) of a water-soluble polymer; tically acceptable buffer to maintain the pH of the composi about 0.01% to about 0.1% (w/v) disodium edetate; about tion within a range of from about 4.5 to about 7.4; a sufficient 0.001% to about 0.5% (w/v) benzalkonium chloride; about amount of an isotonicity agent to yield an osmolality of about 0.1% to about 0.15% sucralose; a sufficient amount of a 65 220 mosmol/kg to about 350 mosmol/kg; and QS water. pharmaceutically acceptable buffer to maintain the pH of the In another embodiment, the present invention provides composition within a range of from about 4.5 to about 7.4, a methods of treating or preventing a physical disorder in an US 8,758,816 B2 13 14 animal Suffering from or predisposed thereto, comprising polymers include polyethylene, particularly medium-density administering to said animal an effective amount of any one polyethylene (MDPE) (or branched polyethylene) or high of the pharmaceutical compositions described herein. Suit density polyethylene (HDPE) (or linear, polyethylene). In ably the animal is a human, and the physical disorder is more particular embodiments, wherein the unit dose con selected from the group consisting of allergic rhinitis, non tainer is made of high density polyethylene (HDPE) and allergic vasomotor rhinitis and allergic conjunctivitis. wherein the single unit dosage of the pharmaceutical compo In an additional embodiment, the present invention pro sition has a volume of less than about 0.6 ml, and wherein the vides methods of treating or preventing allergic rhinitis, non Squeezable chamber has a Volume of less than about or equal allergic vasomotor rhinitis or allergic conjunctivitis in an to about 1.0 ml. Preferred such embodiments include the use animal (e.g., a mammal Such as a human) Suffering from or 10 of unit dosage container systems wherein the Volume of the predisposed thereto, comprising co-administering to the ani unit dosage of the pharmaceutical composition within the mal an effective amount of azelastine or a saltorester thereof container is about 0.1 ml to about 1.0 ml (suitably about 0.1 and an effective amount of one or more steroids. Suitably, the ml, about 0.15 ml, about 0.2 ml, about 0.21 ml, about 0.22 ml, azelastine is azelastine HC1. Examples of steroids for co about 0.23 ml, about 0.24 ml, about 0.25 ml, about 0.3 ml, administration include, but are not limited to, fluorometha 15 about 0.35 ml, about 0.4 ml, about 0.45 ml, about 0.5 ml, lone, fluticasone (e.g., fluticasone propionate, fluticaSone about 0.55 ml, about 0.6 ml, about 0.65 ml, about 0.7 ml, dipropionate, fluticaSone furoate, fluticasone maleate, fluti about 0.75 ml, about 0.8 ml, about 0.85 ml, about 0.9 ml, casone Valerate, and the like), mometaSone, triamcinolone, about 0.95 ml or about 1.0 ml), more preferably about 0.1 ml betamethasone, flunisolide, budesonide, beclomethasone, to about 0.5 ml (suitably about 0.1 ml, about 0.15 ml, about budesonide, rimexolone, beloxil, prednisone, loteprednol 0.2 ml, about 0.21 ml, about 0.22 ml, about 0.23 ml, about (e.g., loteprednoletabonate), (e.g., loteprednol (e.g., lotepre 0.24 ml, about 0.25 ml, about 0.3 ml, about 0.35 ml, about 0.4 dinoletabonate) etabonate) and dexamethasone, and pharma ml, about 0.45 ml or about 0.5 ml), and the volume of the ceutically acceptable esters, salts, conjugates and otherforms squeezable chamber is about 0.5 ml to about 1.0 ml. of such steroids. Suitably, the co-administration will com In additional embodiments, the invention provides such prise co-administration of azelastine and fluticasone (e.g., 25 unit dose configurations wherein the unit dosage container fluticasone propionate, fluticaSone dipropionate, fluticaSone further comprises an extension attached to the squeezable furoate, fluticasone maleate, fluticasone Valerate, and the chamber having opposed first and second Surfaces wherein like). In certain such embodiments, the azelastine (or salt or identification can be located on at least one of the first and ester thereof) and the steroid are contained togetherina single second Surfaces. Such identification can be engraved, e.g., in pharmaceutical composition, for example, a single pharma 30 writing, on the container extension and may be used to iden ceutical composition comprising azelastine (or a salt or ester tify the contents of the unit dosage container (e.g., providing thereof) and a steroid. In other embodiments, the azelastine the identity and/or volume of the pharmaceutical composition (or a salt or ester thereof) is contained in one composition, contained therein, the manufacturing lot or control number of e.g., a pharmaceutical composition comprising azelastine (or the pharmaceutical composition contained therein, the expi a salt or ester thereof) and the steroid is contained in a differ 35 ration date of the pharmaceutical composition contained ent composition, e.g., a pharmaceutical composition com therein, etc.). prising a steroid. In one such embodiment, the pharmaceutical formulation In Suitable embodiments, the co-administration comprises contained within the unit dosage container is a composition administering azelastine and one or more steroids (or com described herein, such as a pharmaceutical composition that position(s) comprising the agents separately or both agents 40 comprises at least one antihistamine, such as, but not limited together) at the same time. In further embodiments, the co to, azelastine or a pharmaceutically acceptable salt thereof administration comprises administeringaZelastine and one or (such as azelastine hydrochloride), as well as other antihista more steroids (or composition(s) comprising the agents sepa mines, such as cetirizine, fexofenadine, olopatadine, terfena rately or both agents together) within less than about 30 dine and loratadine, or pharmaceutically acceptable salts minutes of each other, less than about 20 minutes of each 45 thereof, and optionally one or more additional active pharma other, or less than about 15 minutes of each other. If admin ceutical ingredients, one or more pharmaceutically accept istered separately (e.g., in separate compositions), the azelas able carriers or diluents, one or more taste-masking agents, tine and the one or more steroids can be co-administered in and/or one or more preservatives, and the like. any order. Suitably, the azelastine (or a salt or ester thereof) In additional embodiments, the present invention provides and the one or more steroids are co-administered to the nasal 50 compositions of matter comprising a plurality of unit dosage passage. containers, each of the individual unit dosage containers com In certain additional embodiments, the invention provides prising a single unit dosage of a pharmaceutical composition, a unit dosage composition of matter, comprising: (a) a single Such as one of the pharmaceutical compositions described unit dosage of a pharmaceutical composition; and (b) a unit herein, wherein each unit dosage container comprises: (a) a dosage container comprising: (i) a squeezable chamber hold 55 Squeezable chamber holding the single unit dosage and hav ing the single unit dosage of the composition and having an ing an opening wherein the single unit dosage exits the open opening wherein the single unit dosage exits the opening ing when the Squeezable chamber is squeezed; and (b) a when the Squeezable chamber is squeezed; and (ii) a closure closure mechanism removably attached to the opening of the mechanism removably attached to the opening of the squeez Squeezable chamber. In certain Such embodiments, the unit able chamber. In certain embodiments, the unit dosage con 60 dose container is made of a Suitable polymer, including but tainer is made of a moldable polymer. not limited to, polyethylene, polypropylene (PP), polystyrene In Such embodiments, Suitable polymers include, but are (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene not limited to, polyethylene, polypropylene (PP), polystyrene terephthalate (PET), polycarbonate (PC), polyoxymethylene (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene (POM), polysulfon (PSF), polyethersulfon (PES), polyacry terephthalate (PET), polycarbonate (PC), polyoxymethylene 65 late (PAR), and polyamid (PA). In certain embodiments, the (POM), polysulfon (PSF), polyethersulfon (PES), polyacry unit dose container is made of polyethylene, particularly late (PAR), and polyamid (PA). In certain embodiments, medium-density polyethylene (MDPE) (or branched poly US 8,758,816 B2 15 16 ethylene) or high density polyethylene (HDPE) (or linear Sucralose, Sorbitol, Xylitol, lactitol, mannitol, menthol, and polyethylene). In certain such embodiments, the unit dose the like). According to one such aspect of the invention, Such container is made of HDPE. In more particular embodiments, formulations are contained in unit dose configuration in the the unit dose container is made of HDPE and the single unit absence of preservatives; however, in other aspects, one or dosage of the pharmaceutical composition has a Volume of 5 more preservatives such as benzalkonium chloride may be less than about 0.6 ml, and the squeezable chamber has a included within the formulation. volume of less than or equal to about 1.0 ml. Preferred such In certain additional aspects, the invention provides meth embodiments include the use of a plurality of unit dosage ods of treating or preventing a physical disorder, condition or containers wherein the volume of the unit dosage of the symptom thereof, in a patient by administering to the eye, pharmaceutical composition within each of the individual 10 nose, ear, skin, etc. of a patient a unit dosage form of a containers in the plurality of containers is about 0.1 ml to pharmaceutical composition of the invention comprising an about 0.5 ml (suitably about 0.1 ml, about 0.15 ml, about 0.2 effective amount of one or more active pharmaceutical ingre ml, about 0.21 ml, about 0.22 ml, about 0.23 ml, about 0.24 dients in a unit dosage form. Suitably, the methods comprise ml, about 0.25 ml, about 0.3 ml, about 0.35 ml, about 0.4 ml, providing a unit dosage form comprising a unit dosage con about 0.45 ml or about 0.5 ml), and the volume of each of the 15 tainer made of high density polyethylene, the unit dosage squeezable chambers is about 0.5 ml to about 1.0 ml. form having a volume of less than about 0.6 ml and said In certain Such embodiments, the invention provides an dosage container having a Volume of less than or equal to assembly comprising such a plurality of unit dosage contain about 1.0 ml. Suitably the unit dose form contains one or more ers wherein at least two of the unit dosage containers are antihistamines (e.g. azelastine HCl) or pharmaceutically removably attached to one another. In particular embodi acceptable salts thereof, and optionally one or more addi ments the unit dosage containers in the form of a plurality of tional active pharmaceutical ingredients such as those containers corresponding to the prescribed dosage regime, described herein. The unit dosage form is then administered e.g., two, three, five or 10 containers are removably attached to the Subject, and the unit dosage container is then discarded. to one another. The plurality of unit dosage containers are In certain Such aspects, the physical disorder, condition or separated from one another by a removably attached perfo 25 symptom thereoftreatable or preventable by such methods of ration, demarcation, or similar marking thereof. In certain the invention includes, but is not limited to, allergic or non embodiments, the perforation facilitates removal of a single allergic nasal, ocular or skin conditions treatable or prevent unit dose container from the plurality of unit dosage contain able using the pharmaceutical compositions of the present ers. Certain embodiments according to this aspect of the invention (preferably in unit dose configuration). Such as invention may further comprise a container (e.g., a box, blis 30 allergic reactions to plant or insect allergens, environmental terpackage, foil package, etc.) comprising one or more of the allergens, allergic and non-allergic ocular conditions (e.g., pluralities of containers that comprise the pharmaceutical hay fever conjunctivitis, perennial allergic conjunctivitis, formulation, in a package or kit format. In additional embodi giant papillary conjunctivitis (including that associated with ments, the plurality of containers, for example in a package or the use of contact lenses), allergic and non-allergic nasal kit format, may further comprise instructions for use of the 35 conditions (e.g., allergic rhinitis (including seasonal allergic unit dosage containers by the end user. rhinitis and perennial allergic rhinitis), non-allergic rhinitis, Non-limiting exemplary unit dosage forms of the present sinusitis, rhino-sinusitis and the like) non-allergic noninfec compositions comprise formulations comprising an antihis tious conjunctivitis, Vernal keratoconjunctivitis or atopic tamine (including H. H. H. and H antagonists). Such as keratoconjunctivitis) and irritant dermatitis, as well as other aZelastine or a pharmaceutically acceptable salt thereof Such 40 related or similar disorders. Other physical conditions, disor as azelastine hydrochloride. In other embodiments, the for ders or symptoms thereofsuitably treated or prevented using mulations comprise two or more active pharmaceutical ingre the pharmaceutical compositions of the present invention dients, one of which may be an antihistamine Such as azelas (preferably in unit dose configuration) include, but are not tine hydrochloride and the other of which may be a second limited to, nasal and ocular conditions associated with the active pharmaceutical ingredient including, but not limited to, 45 common cold; nasal, ocular or skin conditions resulting from one or more additional antihistamines (including H. H. H. a reaction to insect bites; postoperative ocular inflammation; and H receptor antagonists such cetirizine, fexofenadine, acute anterior uveitis; allergic blepharitis; keratitis (such as olopatadine, terfenadine and loratadine, or pharmaceutically herpes Zoster or Superficial punctate keratitis), uticaria and acceptable salts thereof), one or more steroids (e.g., one or the like; as well as otic conditions such as otitis media, tinni more safe steroids), one or more leukotriene antagonists, one 50 tus, Eustachian tube constriction or blockage, and the like. In or more prostaglandin D2 receptor antagonists, one or more another embodiment, the pharmaceutical compositions of the decongestants, one or more anti-fungal agents, triamcinolone present invention (preferably in unit dose configuration) can and triamcinolone derivatives, one or more non-steroidal be used to treat or prevent motion sickness. In another immunophilin-dependent immunosuppressants (NSIDIs), embodiment, the pharmaceutical compositions of the present one or more anti-inflammatory agents, one or more non 55 invention (preferably in unit dose configuration) can be used steroidal anti-inflammatory agents (NSAIDs), one or more to treat or prevent Snoring. COX-2 inhibitors, one or more anti-infective agents, one or Other features and advantages of the invention will be more mucolytic agents, one or more anticholinergic agents, apparent from the following detailed description, and from one or more mast cell stabilizers, one or more antibiotics, one the claims. The disclosed materials, methods, and examples or more non-antibiotic anti-microbial agents, one or more 60 are for illustrative purposes only and are not intended to be anti-viral agents, one or more antiseptics, one or more neu limiting. Skilled artisans will appreciate that methods and rokinin antagonists, platelet activating factor (PAF) and one materials similar or equivalent to those described herein can or more 5-lipoxygenase (5-LO) inhibitors. In additional be used to practice the invention. embodiments, the pharmaceutical compositions may com Unless otherwise defined, all technical and scientific terms prise one or more additional reagents, such as one or more 65 used herein have the meaning commonly understood by one pharmaceutically acceptable carriers, excipients, buffers, skilled in the art to which this invention belongs. All publi salts, isotonicity agents, or taste-masking agents (such as cations, patent applications, patents, and other references US 8,758,816 B2 17 18 mentioned herein are incorporated by reference in their one or more buffers or buffering agents, one or more bioad entirety. In case of conflict, the present specification, includ hesives, one or more Suspending agents (e.g., microcrystal ing definitions, will control. line cellulose, Sodium carboxy methyl cellulose, hypromel lose carbopol and the like), one or more Surfactants or wetting BRIEF DESCRIPTION OF THE agents and/or one or more isotonicity agents. To reduce or DRAWINGS/FIGURES eliminate the bitter taste associated with azelastine (or a salt or ester thereof. Such as azelastine hydrochloride), the com FIG. 1 shows the effects on the total nasal symptom score positions of the present invention further comprise one or resulting from the co-administration of azelastine HCl and more stable taste-masking, flavoring, or Sweetening agents, fluticasone propionate. 10 ora combination of such agents. To reduce the post-nasal drip FIG.2 shows the mean improvement in severity score from of the compositions of the present invention for intranasal or baseline for the symptom of runny nose, resulting from the ocular administration, the compositions of the present inven co-administration of azelastine HCl and fluticasone propi tion may further comprise one or more stable viscosity-in Onate. creasing agents, one or more stable bioadhesive agents, and/ FIG.3 shows the mean improvement in severity score from 15 or a combination of Viscosity-increasing agents and baseline for the symptom of itchy nose, resulting from the bioadhesive agents. In other embodiments, the pharmaceuti co-administration of azelastine HCl and fluticasone propi cal compositions can comprise one or more additional active Onate. agents, such as those described herein, in addition to azelas FIG. 4 shows the mean improvement in severity score from tine, including, but not limited to, additional antihistamines baseline for the symptom of Sneezing, resulting from the (including H. H. and H receptor antagonists), Steroids (e.g., co-administration of azelastine HCl and fluticasone propi safe steroids), leukotriene antagonists, prostaglandin D2 Onate. receptor antagonists, decongestants, anti-fungal agents, tri FIG.5 shows the mean improvement in severity score from amcinolone and triamcinolone derivatives, non-steroidal baseline for the symptom of congestion, resulting from the immunophilin-dependent immunosuppressants (NSIDIs), co-administration of azelastine HCl and fluticasone propi 25 anti-inflammatory agents, non-steroidal anti-inflammatory Onate. agents (NSAIDs), COX-2 inhibitors, anti-infective agents, FIG. 6 shows the cumulative improvement in total nasal mucolytic agents, anticholinergic agents, mast cell stabiliz symptom score versus baseline, resulting from the co-admin ers, non-antibiotic anti-microbial agents, anti-viral agents, istration of azelastine HCl and fluticaSone propionate. antiseptics, neurokinin antagonists, platelet activating factor FIG. 7 shows a schematic of an exemplary unit dosage 30 (PAF) and 5-lipoxygenase (5-LO) inhibitors. container used in accordance with the invention. In certain embodiments, the pharmaceutical compositions FIG. 8 shows a plurality of unit dosage containers used in comprise one or more pharmaceutically carriers or excipi accordance with the invention. ents, particularly one or more Such carriers or excipients that FIG. 9 is a line plot of the mean change from baseline in are useful informulating the composition into a form Suitable total nasal symptom score (TNSS) (a.m. and p.m. combined) 35 for delivery intranasally via aerosol or spray approaches, or over a 14 day period, in the intent-to-treat population. for delivery ocularly via drops. In related embodiments, the (A A A) Azelastine; (ee e) Fluticasone; and invention provides such pharmaceutical compositions in (FFF) Azelastine + Fluticasone. which at least one of the carriers or excipients is a taste FIG. 10 is a line plot of the mean change from baseline in masking agent, such as Sucralose, and other compositions in 40 which at least one of the carriers or excipients is a viscosity total nasal symptom score (TNSS) (a.m. and p.m. combined) increasing agent, Such as hypromellose. In certain preferred over a 14 day period, in the per-protocol population. embodiments, the pharmaceutical compositions provided by (A A A) Azelastine; (? - ?) Fluticasone; and the invention comprise at least one taste-masking agent Such (FFF) Azelastine + Fluticasone. as Sucralose, and at least one viscosity-increasing agent Such 45 as hypromellose. The compositions of the invention are par DETAILED DESCRIPTION OF THE INVENTION ticularly useful in treating or preventing the symptoms asso ciated with a variety of conditions such as allergic rhinitis Overview (seasonal and/or perennial), non-allergic rhinitis, vasomotor rhinitis, rhinosinusitis, allergic conjunctivitis, allergic and As used herein when referring to any numerical value, the 50 non-allergic ear conditions (including otitis media, tinnitus, term “about’ means a value falling within a range that is Eustachian tube constriction or blockage, and the like) and +10% of the stated value. For example, “about 50° C.” other physical disorders as described elsewhere herein and as encompasses a range of temperatures from 45° C. to 55° C. will be apparent to the ordinarily skilled artisan. inclusive; similarly, “about 100 mM encompasses a range of The present invention provides compositions, particularly concentrations from 90 mM to 110 mM, inclusive. 55 pharmaceutical compositions, comprising one or more active As used herein, the articles “a,” “an and "one” mean “at pharmaceutical ingredients in a pharmaceutically acceptable least one' or “one or more of the object to which they refer, form, preferably in unit dose configuration. By “unit dose unless otherwise specified or made clear by the context in configuration' as used herein is meant that the pharmaceuti which they appear herein. cal formulation is contained within a container which is The present invention provides compositions, particularly 60 designed to deliver an effective single dosage of the pharma pharmaceutical compositions, comprising azelastine and/or ceutical formulation to an area of a patient’s body that is to be one or more of its pharmacologically acceptable salts or treated with the formulation, and to then be discarded and not esters thereof, particularly azelastine hydrochloride. Pre reused. The present invention also provides compositions of ferred such compositions of the invention comprise azelastine matter comprising a container (e.g., a unit dose container) hydrochloride as the active ingredient, and may further com 65 comprising one or more pharmaceutical ingredients. prise one or more additional components. Such as one or more Single dose, disposable, containers for dispensing pharma Solvents, one or more preservatives, one or more stabilizers, ceutically active agents to the nose and eyes have been dis US 8,758,816 B2 19 20 closed (see, e.g., U.S. Pat. Nos. 7,185,790, 6,619,516 and lated at a higher concentration of azelastine (or salt thereof) 4,469.254), including dispensers comprising integrated can be delivered at a smaller Volume to provide a given dosage nozzles and removable caps (see, e.g., U.S. Pat. No. 6,666, ofazelastine (or salt thereof), thus minimizing the possibility 359). However, for unit dose containers utilizing small vol of postnasal drip of the solution into the pharynx which leads ume vessels (e.g., about 1 mL containers containing about 0.1 5 to an unpleasant taste sensation by the person to whom the to about 0.7 mL of solution) in general, more pliable materi aZelastine-containing nasal spray is administered. als, such as low density (high pressure) polyethylene that In certain embodiments, the compositions of the invention were easily Squeezed were required, thus allowing for dis may be formulated into forms for oral administration, includ pensing of the solution (see, e.g., U.S. Pat. No. 3,197,120). ing Solid dosage forms or liquid dosage forms. In alternative Prior to the present invention, the use of high density poly 10 embodiments, the compositions of the invention may be for ethylene in Small Volume, unit dose containers had not been mulated into forms for direct administration to the mucosa, developed. including the nasal mucosa (i.e., intranasal administration), Compositions and Modes of Administration ocular tissue or conjunctival sac (i.e., ocular administration), In certain embodiments, the invention provides composi buccal mucosa (i.e., buccal administration) or oral mucosa tions, particularly pharmaceutical compositions, comprising 15 under the tongue (i.e., Sublingual administration). (or consisting essentially of) a therapeutically or pharmaco Solid dosage forms for oral administration include cap logically effective amount ofazelastine or a pharmaceutically Sules, tablets, pills, powders, particles and granules. In Such acceptable salt or ester thereof and one or more pharmaceu Solid dosage forms, the active compound(s) (e.g., antihista tically acceptable carriers or excipients. Particularly pre mines such as azelastine) are mixed with at least one phar ferred for use in the compositions of the invention is azelas maceutically acceptable excipient or carrier Such as (a) fillers tine hydrochloride (see U.S. Pat. Nos. 3,813,384, 4,704,387 or extenders such as starches, lactose, Sucrose, glucose, man and 5,164,194, the disclosures of which are incorporated nitol, dicalcium phosphate and microcrystalline cellulose; (b) herein by reference in their entireties). By “pharmaceutically binders such as sodium carboxymethylcellulose, alginates, acceptable carrier or excipient' is meant a non-toxic solid, gelatin, polyvinylpyrrolidone, and acacia; (c) disintegrating semisolid or liquid filler, diluent, encapsulating material or 25 agents Such as agar-agar, calcium carbonate, potato or tapioca formulation auxiliary of any type. starch, alginic acid, certain silicates, sodium carboxymethyl The compositions of the present invention can be admin cellulose, pregelatinized Starch and sodium starch glycolate; istered to a patient via any suitable mode of administration, (d) lubricants such as calcium Stearate, magnesium Stearate, including oral, intranasal, ocular, buccal, Sublingual, pulmo Stearic acid, Solid polyethylene glycols, Sodium lauryl Sulfate, nary or the like. In certain embodiments, the compositions are 30 and mixtures thereof, and/or (e) glidants such as talc, silicon administered directly to the nasal mucosa (i.e., intranasally, dioxide and starch. In the case of capsules, tablets and pills, e.g., in the form of a nasal spray or drops) or to the conjunc the dosage form may also comprise buffering agents. Solid tival sac of the eye (i.e., ocularly, e.g., in the form of ocular compositions of a similar type may also be employed as fillers drops) or to the ear canal (i.e., otically, for example, in the in Soft and hard filled gelatin capsules using Such excipients form of ear drops, solution, spray, wash, cream or ointment). 35 as lactose or milk Sugar as well as high molecular weight In alternative embodiments, the compositions are adminis polyethylene glycols, oils and the like. The Solid dosage tered topically to the buccal or Sublingual cavity or intrapul forms of tablets, dragees, capsules, pills, and granules can be monarily, or topically to the skin in the form of drops, spray, prepared with coatings, which may in themselves provide ointment, etc. Regardless of their mode of administration, the taste-masking, and shells such as enteric coatings and other compositions provided by the present invention Suitably com 40 coatings that are well known in the pharmaceutical formulat prise from about 0.0001% to about 1.0%, and more suitably ing art. The Solid dosage forms also may optionally contain from about 0.005% to about 0.5% or most suitably from about opacifying, coloring and/or flavoring agents, and can also be 0.05% to about 0.15% (e.g., about 0.05%, about 0.06%, about formulated Such that they release the active azelastine ingre 0.07%, about 0.08%, about 0.09%, about 0.10%, about dient(s) only, or preferentially, in a certain part of the intesti 0.11%, about 0.12%, about 0.13%, about 0.14% or about 45 nal tract, optionally in a delayed manner (see U.S. Pat. No. 0.15%), of antihistamine (e.g., H. H. H. and/or H antihis 5,271.946, the disclosure of which is incorporated herein by tamines as disclosed herein) based on the weight of the active reference in its entirety). Examples of embedding composi ingredient. For example, azelastine-containing compositions tions which can be used include polymeric Substances and provided by the present invention suitably comprise from waxes. The active compounds can also be in micro-encapsu about 0.0001% to about 1.0%, and more suitably from about 50 lated form, if appropriate, with one or more of the above 0.005% to about 0.5% or most suitably from about 0.05% to mentioned excipients. about 0.15% (e.g., about 0.05%, about 0.06%, about 0.07%, Liquid dosage forms for nasal, ocular or oral administra about 0.08%, about 0.09%, about 0.10%, about 0.11%, about tion include pharmaceutically acceptable emulsions, solu 0.12%, about 0.13%, about 0.14% or about 0.15%), of pure tions, Suspensions, syrups and elixirs. In addition to the active aZelastine Salt (e.g., azelastine HCl) based on weight (calcu 55 pharmaceutical ingredient(s). Such as the antihistamine com lated as the free azelastine base) as the active ingredient. The pound(s) (e.g., H. H. H. and/or H antagonists, such as percentage of active pharmaceutical ingredient (e.g., antihis aZelastine compound(s)), the liquid dosage forms may con tamines such as azelastine) in a given composition of the tain inert diluents and/or solvents commonly used in the art. invention is calculated as a percentage of the weight of the Water is the solvent of choice for the formulations of the composition for Solid dosage forms (i.e., weight/weight) or as 60 invention; however, combinations of water with other physi a percentage of the Volume of the composition for Solution or ologically acceptable solvents as required are also satisfac liquid dosage forms (i.e., weight/volume). The amount of a tory for use. Other solvents, solubilizing agents and emulsi given salt form of azelastine (e.g., azelastine hydrochloride) fiers suitable for use in place of, or in addition to, water to be included in a given composition of the invention is include but are not limited to saturated aliphatic mono- and calculated so that the composition contains the amount of 65 polyvalent alcohols which contain 2-6 carbonatoms (includ pure azelastine noted above. In certain compositions of the ing, but not limited to, ethanol, 1.2-propylene glycol, Sorbitol, invention, e.g., nasal spray formulations, a solution formu and glycerine), polyglycols such as polyethylene glycols, and US 8,758,816 B2 21 22 surfactants/emulsifiers like the fatty acid esters of sorbitan, and Osmolarity,” in: Remington. The Science and Practice of and mixtures thereof. Oils, in particular, cottonseed, peanut, Pharmacy, 20" Edition, Lippincott Williams and Wilkins, or corn oils, may also be added to the compositions. The Philadelphia, Pa. (2000)). combination of the additional Solvents in the aqueous solu It is desirable that the compositions of the present invention tion should preferably not exceed about 15% (w/v) of the total that are to be administered in liquid form (including intrana composition. Besides inert diluents, the oral compositions sally, orally or ocularly applied formulations) have a pH of can also include adjuvants such as wetting agents, emulsify about 4.5 to about 7.4, and preferably have a pH of about 5.5 ing and Suspending agents (e.g., microcrystalline cellulose, to 7.1, for physiological reasons. Accordingly, in additional Sodium carboxymethyl cellulose, hypromellose, carbopol embodiments, the compositions of the invention may further 10 comprise one or more buffering agents or combinations and the like), Surfactants, Sweetening, flavoring, and perfum thereof, that are used to adjust and/or maintain the composi ing agents, including those described in further detail herein tions into the desired pH range. Adjustment of pH or buffering below. Liquid dosage forms that provide the active ingredient agents that are suitable for use in the compositions of the in Suspension may comprise, in addition to the active azelas invention include, but are not limited to, citric acid, sodium tine compound(s), one or more Suspending agents such as 15 citrate, sodium phosphate (dibasic, heptahydrate form), and microcrystalline cellulose, magnesium aluminum silicate, boric acid or equivalent conventional buffers, or combina bentonite, agar-agar, hypromellose, sodium carboxymethyl tions thereof. The appropriate amounts of buffers and buffer cellulose, carbopol/carbomer, pectin, acacia, tragacanth or ing agents, or combinations thereof, that are to be used in the their mixtures. compositions of the invention are readily determined by those Certain liquid compositions of the invention may further of ordinary skill without undue experimentation, particularly comprise one or more preservatives and/or one or more sta in view of the guidance contained herein and in standard bilizers. Preservatives that are suitable for use in the compo formularies such as the United States Pharmacopoeia, Rem sitions of the invention include, but are not limited to, edetic ington. The Science and Practice of Pharmacy, and the like, acid and their alkali salts such as disodium EDTA (also the disclosures of which are incorporated herein by reference referred to as “disodium edetate' or “the disodium salt of 25 in their entireties. edetic acid) and calcium EDTA (also referred to as “calcium As noted above, azelastine salts, particularly azelastine edetate'), benzyl alcohol, methylparaben, propylparaben, hydrochloride, have a strong bitter taste when the compounds butylparaben, chlorobutanol, phenylethyl alcohol, benzalko or compositions comprising them are administered intrana nium chloride, thimerosal, propylene glycol, Sorbic acid, and Sally, ocularly, or orally. Thus, in certain embodiments, the benzoic acid derivatives. The preservatives should be used at 30 liquid formulations of the invention, particularly those that a concentration of from about 0.001% to about 0.5% (w/v) in are to be administered intranasally, ocularly, or orally, pref the final composition. The combination of benzalkonium erably further comprise one or more taste-masking agents, chloride, used at a concentration of from about 0.001% to one or more flavoring agents, and/or one or more Sweetening about 0.5% or preferably from about 0.005% to about 0.1% agents, or a combination of Such agents. Non-limiting (w/v), and edetic acid (as a disodium salt), used at a concen 35 examples of such substances include sucralose (about 0.001 tration of from about 0.005% to about 0.1% (w/v), are the to about 1%), sucrose (about 0.5 to about 10%), saccharin preferred preservative/stabilizer combination used in the (including the salt forms: sodium, calcium, etc.) (about 0.01 compositions of the present invention. Certain compositions to about 2%), fructose (about 0.5 to about 10%), dextrose of the invention may further comprise one or more solubility (about 0.5 to about 10%), corn syrup (about 0.5 to about enhancing agents that are used to improve the solubility of the 40 10%), aspartame (about 0.01 to about 2%), acesulfame-K aZelastine compound used as an active ingredient. Solubility (about 0.01 to about 2%), xylitol (about 0.1 to about 10%), enhancing agents that are suitable for use in the compositions sorbitol (about 0.1 to about 10%), erythritol (about 0.1 to of the invention include, but are not limited to, polyvinylpyr about 10%), ammonium glycyrrhizinate (about 0.01 to about rolidone (preferably grades 25, 30, 60, or 90), poloxamer, 4%), thaumatin (TalinTM) (about 0.01 to about 2%), neotame polysorbate 80, sorbitan monooleate 80, and polyethylene 45 (about 0.01 to about 2%) mannitol (about 0.5 to about 5%), glycols (molecular weights of 200 to 600). menthol (about 0.01 to about 0.5%), eucalyptus oil (about Certain compositions of the invention may further com 0.01 to about 0.5%), camphor (about 0.01 to about 0.5%), prise one or more solubility-enhancing agents that are used to natural and/or artificial flavors such as Artificial Custard improve the solubility of the azelastine compound used as an Cream Flavor #36184 from International Flavors and Fra active ingredient. Solubility-enhancing agents that are Suit 50 grances, Inc. (New York, N.Y.) (about 0.01 to about 1.0%), able for use in the compositions of the invention include, but and the like. Sucralose, an intense Sweetener marketed for are not limited to, polyvinylpyrrolidone (preferably grades food and beverage use as SPLENDAR) by McNeil Nutrition 25, 30, 60, or 90), poloxamer, polysorbate 80, sorbitan als LLP (Fort Washington, Pa.), is especially effective as a monooleate 80, and polyethylene glycols (molecular weights Sweetening and taste-masking agent in the compositions of of 200 to 600). 55 the present invention, particularly when used at concentra Certain compositions of the invention may further com tions of from about 0.001% to about 1%, preferably at con prise one or more agents that are used to render the compo centrations of from about 0.01% to about 0.5%, and more sition isotonic, particularly in those compositions in which preferably at concentrations of from about 0.02% to about water is used as a solvent. Such agents are particularly useful 0.2%, and most preferably from about 0.05% to about 0.15% in compositions formulated for nasal or ocular application, 60 (e.g., about 0.05%, about 0.06%, about 0.07%, about 0.08%, since they adjust the osmotic pressure of the formulations to about 0.09%, about 0.10%, about 0.11%, about 0.12%, about the same osmotic pressure as nasal or ocular secretions. 0.13%, about 0.14%, or about 0.15%), of the total composi Agents that are suitable for Such a use in the compositions of tion. Sucralose has been shown to be useful as a taste modi the invention include, but are not limited to, sodium chloride, fying agent in oral delivery of certain pharmaceutical com Sorbitol, propylene glycol, dextrose, Sucrose, and glycerine, 65 positions, for example in Sore throat spray products (see U.S. and other isotonicity agents that are known in the art (see, e.g., Pat. No. 6,319.513), oral suspensions (see U.S. Pat. Nos. Reich et al., “Chapter 18: Tonicity, Osmoticity, Osmolality 5,658,919 and 5,621,005), solid dosage forms (see U.S. Pat. US 8,758,816 B2 23 24 No. 6,149,941), quick melt dosage forms (see U.S. Pat. No. unit dose containers are described herein. Polymers suitable 6,165.512) and mucosal delivery (see U.S. Pat. No. 6,552, for use according to this aspect of the invention include, but 024), but has notheretofore been shown to be useful in intra are not limited to, polyethylene, polypropylene (PP), poly nasally or ocularly applied compositions such as those of the styrene (PS), nylon (Ny), polyvinyl chloride (PVC), polyeth present invention. Additional Such compositions of the inven ylene terephthalate (PET), polycarbonate (PC), polyoxym tion may comprise one or more additional taste-masking or ethylene (POM), polysulfon (PSF), polyethersulfon (PES), flavoring agents such as those described herein, for example polyacrylate (PAR), and polyamide (PA). In certain embodi menthol at a concentration of from about 0.01% to about 1%, ments, polymers include polyethylene, particularly medium preferably at a concentration of from about 0.05% to about density polyethylene (MDPE) (or branched polyethylene) or 0.1%. Suitable compositions of the invention include, for 10 high density polyethylene (HDPE) (or linear polyethylene). example, about 0.1%-0.15% azelastine and about 0.05%- A particularly preferred polymer for use with azelastine 0.15% sucralose, for example, about 0.1% azelastine and containing pharmaceutical formulations is HDPE, since as about 0.05%-0.15% sucralose, or about 0.125%-0.15% discussed hereinbelow, it has been found that azelastine (and azelastine and about 0.05%-0.15% sucralose, or about 0.10% salts or esters thereof) has a high degree of undesirable leach azelastine and about 0.15% sucralose, or about 0.15%azelas 15 ability into containers manufactured of other polymers, tine and about 0.15% sucralose. including polyethylenes having lower densities than HDPE. As noted above, intranasal or ocular application of azelas Compositions Comprising Additional Active Agents tine-containing compositions, particularly those containing In addition to azelastine (e.g., aZelastine HCl) and the aZelastine hydrochloride, is often complicated by the postna various excipients, taste masking agents, viscosity-increasing sal drip of the composition into the pharynx following intra agents and the like disclosed herein, the pharmaceutical com nasal or ocular administration. Such postnasal drip can induce positions of the invention can further comprise (or consist a very bitter and unpleasant taste experience by the patient. essentially of) one or more additional active agents, such as Thus, to avoid, reduce or minimize such issues arising from those disclosed throughout U.S. Patent Publication No. 2005/ postnasal drip, certain compositions of the present invention 0.148562, the disclosure of which is herein incorporated by may alternatively or further comprise one or more water 25 reference in its entirety. Exemplary additional active agents soluble viscosity-increasing agents. Such agents are prefer include, but are not limited to, additional antihistamines (in ably used at the concentration of about 0.01% to about 5.0% cluding H. H. and H receptor antagonists), Steroids (e.g., (w/v), in order to typically produce a viscosity of the final safe steroids), leukotriene antagonists, prostaglandin D2 solution between about 2 and about 300 centipoise. Use of receptor antagonists, decongestants, expectorants, anti-fun Such viscosity-increasing agents extends the mucocilliary 30 gal agents, triamcinolone and triamcinolone derivatives, non clearance time, increases retention in the nasal cavity, and steroidal immunophilin-dependent immunosuppressants reduces post nasal drip, of intranasally applied compositions (NSIDIs), anti-inflammatory agents, non-steroidal anti-in (see U.S. Pat. No. 5,897.858, the disclosure of which is incor flammatory agents (NSAIDs), COX-2 inhibitors, anti-infec porated herein by reference in its entirety) such as those of the tive agents, mucolytic agents, anticholinergic agents, mast present invention. Viscosity-increasing agents that are Suit 35 cell stabilizers, non-antibiotic anti-microbial agents, anti-vi able for use in accordance with the present invention include, ral agents, antiseptics, neurokinin antagonists, platelet acti but are not limited to, polyvinylpyrrolidones, cellulose vating factor (PAF) and 5-lipoxygenase (5-LO) inhibitors. derivatives including, but not limited to, hydroxyethyl cellu Examples of antihistamines in addition to azelastine (e.g., lose, carboxymethyl cellulose or its salts, hypromellose, car H receptor antagonists) Suitable for inclusion in the present rageenan, guar gum, alginates, carbomers, polyethylene gly 40 compositions include, but are not limited to, acrivastine, cols, polyvinyl alcohol, and Xanthan gum. Particularly cyclizine, carebastine, cyproheptadine, carbinoxamine, preferred is hypromellose, at a concentration of about 0.001% doxylamine, dimethindene, ebastine, epinastine, efletirizine, to about 5.00%, preferably at a concentration of about 0.01% ketotifen, levocabastine, mizolastine, meduitazine, to about 1%, more preferably at a concentration of about 0.1% mianserin, noberastine, meclizine, norastemizole, olopata to about 0.5%, and most preferably at a concentration of about 45 dine, picumast, tripelenamine, temelastine, trimeprazine, 0.1% to about 0.3%. triprolidine, bromopheniramine, chlorpheniramine, dexchlo The compositions of the present invention that are pro rpheniramine, triprolidine, clemastine, diphenhydramine, vided in solution form may be preserved, aseptically manu diphenylpyraline, tripelennamine, hydroxy Zine, methdila factured and/or sterilized, for example, by filtration through a Zine, promethazine, trimeprazine, azatadine, cyproheptadine, bacterial-retaining filter. 50 antazoline, pheniramine, pyrilamine, astemizole, terfena In exemplary embodiments, the compositions of matter dine, loratadine, cetirizine, levocetirizine, fexofenadine, des comprise a container (e.g., a unit dose container) comprising carboethoxyloratadine, desloratadine, dimenhydrinate and aZelastine and/or one or more pharmacologically acceptable hydroxy Zine. salts or esters thereof, particularly azelastine hydrochloride. Examples of H receptor antagonists suitable for inclusion Suitable compositions of matter comprise a unit dose con 55 in the present compositions include, but are not limited to, tainer comprising azelastine hydrochloride, and may further thioperamide, impromidine, burimamide, clobempropit, comprise one or more additional components, such as one or impentamine, mifetidine, clozapine, S-sopromidine, R-So more solvents, one or more preservatives, one or more stabi promidine and ciproxifam. lizers, one or more buffers or buffering agents, one or more Examples of leukotriene antagonists (e.g., leukotriene D4 bioadhesives, one or more Suspending agents (e.g., microc 60 antagonists) Suitable for inclusion in the present composi rystalline cellulose, Sodium carboxymethyl cellulose, tions include, but are not limited to, albuterol sulfate, amino hypromellose carbopol and the like), one or more Surfactants phylline, amoxicillin, amplicillin, astemizole, attenuated or wetting agents and/or one or more isotonicity agents. tubercle bacillus, azithromycin, bacampicillin, beclometha In exemplary embodiments, the compositions of matter Sone dipropionate, budesonide, bupropion hydrochloride, comprise a unit dose container of a moldable polymer, Such as 65 cefaclor, cefadroxil, cefixime, cefprozil, cefuroxime axetil, a plastic, into which leaching of the pharmaceutical ingredi cephalexin, ciprofloxacin hydrochloride, clarithromycin, ent is limited to an acceptable amount over time. Exemplary clindamycin, cloxacillin, doxycycline, erythromycin, etham US 8,758,816 B2 25 26 butol, fenoterol hydrobromide, fluconazole, flunisolide, flu their entireties, and otheresters, salts, conjugates, derivatives ticasone propionate, formoterol fumarate, gatifloxacin, influ and analogs of such steroids that will be familiar to one of enza virus vaccine, ipratropium bromide, isoniazid, ordinary skill in the art. isoproterenol hydrochloride, itraconazole, ketoconazole, Examples of anti-infective agents suitable for inclusion in ketotifen, levofloxacin, minocycline, montelukast (e.g., mon the present compositions include, but are not limited to, peni telukast Sodium), moxifloxacin, nedocromil Sodium, nico cillins and other beta lactamantibiotics, cephalosporins, mac tine, nystatin, ofloxacin, orciprenaline, oseltamivir, Oselta rolides, ketolides, Sulfonamides, quinolones (including halo mivir sulfate, oxtriphylline, penicillin, pirbuterol acetate, quinolones Such as fluoroquinolones, including pivampicillin, pneumococcal conjugate vaccine, pneumo ciprofloxacin), aminoglycosides, and lineZolid. coccal polysaccharide vaccine, prednisone, pyrazinamide, 10 Examples of non-antibiotic antimicrobials suitable for inclusion in the present compositions include, but are not rifampin, salbutamol, Salmeterol Xinafoate, sodium cro limited to, taurolidine. moglycate (cromolyn Sodium), terbutaline Sulfate, terfena Examples of mast cell stabilizers suitable for inclusion in dine, theophylline, triamcinolone acetonide, Zafirlukast and the present compositions include, but are not limited to, cro Zanamivir. 15 molyn and nederomil sodium. Examples of decongestants suitable for inclusion in the Examples of mucolytic agents Suitable for inclusion in the present compositions include, but are not limited to, pseu present compositions include, but are not limited to, acetyl doephedrine, phenylephedrine, phenylephrine, phenylpro cysteine and dornase alpha. panolamine, oxymetazoline, propylhexedrine, Xylometazo Examples of antibiotic agents Suitable for inclusion in the line, epinephrine, ephedrine, desoxyephedrine, naphazoline, present compositions include, but are not limited to, and tetrahydrozoline. cefuroxime, Vancomycin, amoxicillin and gentamicin. Examples of expectorants suitable for inclusion in the Examples of antiseptics suitable for inclusion in the present compositions include, but are not limited to, guaifen present compositions include, but are not limited to, iodine, esin, codeine phosphate, and isoproternol hydrochloride. chlorhexidine acetate, Sodium hypochlorite, and calcium Examples of anti-fungal agents suitable for inclusion in the 25 hydroxide. present compositions include, but are not limited to, ampho Examples of anticholinergics Suitable for inclusion in the tericin B, nystatin, fluconazole, ketoconazole, terbinafine, present compositions include, but are not limited to, mivacu itraconazole, imidazole, triazole, ciclopirox, clotrimazole, rium, atracurium, faZadinium, rocuronium, Vecuronium, and miconazole. doxacurium, metocurine, pancuronium, pipecuronium, gal 30 lamine, hexafluoronium, suxamethonium, Succinylcholine, Examples of NSAIDs suitable for inclusion in the present decamethonium, atropine, Scopolamine, hyoscyamine, ben compositions include, but are not limited to, ibuprofen, ace Zatropine, trihexyphenidyl, biperiden, glycopyrrolate, iprat clofenac, diclofenac, naproxen, etodolac, flurbiprofen, feno ropium, pirenzepine, telenZepine, tiotropium, darifenacin, profen, ketoprofen, Suprofen, fenbufen, fluprofen, tolmetin Vedaclidine, tropicamide, cyclopentolate, dicycloverine, Sodium, oxaprozin, Zomepirac, Sulindac, indomethacin, 35 tolterodine, oxybutynin, homatropine, orphenadrine, diphen piroXicam, mefenamic acid, nabumetone, meclofenamate hydramine, hemicholinium-3, Vesamicol, pralidoxime, obi Sodium, diflunisal, flufenisal, piroXicam, ketorolac, Sudoxi doXime, oxitropium, alcuronium, dimethyltubocurarine, tub cam and isoxicam. ocurarine and ipratropium. By “non-steroidal immunophilin-dependent immunosup Examples of prostaglandin D2 receptor antagonists Suit pressant’ or “NsIDI is meant any non-steroidal agent that 40 able for inclusion in the present compositions include, but are decreases proinflammatory cytokine production or secretion, not limited to, non-steroidal anti-inflammatories (NSAIDs), binds an immunophilin, or causes a down regulation of the COX-2 inhibitors, bicyclic amino (indole) derivatives (see, proinflammatory reaction. Ns|DIs suitable for inclusion in e.g., U.S. Pat. Nos. 6,693.203 and 6,498,190, the disclosures the present compositions include, but are not limited to, cal of which are incorporated by reference herein in their entire cineurin inhibitors, such as cyclosporine, tacrolimus, asco 45 ties), thiazoles (see, e.g., U.S. Patent Publication No. 2009/ mycin, pimecrolimus, as well as other agents (peptides, pep 0221604, the disclosure of which is incorporated herein by tide fragments, chemically modified peptides, or peptide reference in its entirety), and the like. mimetics) that inhibit the phosphatase activity of calcineurin. Examples of anti-viral agents suitable for inclusion in the NSIDIs also include rapamycin (sirolimus) and everolimus, present compositions include, but are not limited to, abacavir, which bind to an FK506-binding protein, FKBP-12, and 50 acyclovir, adefovir, amantadine, amprenavir, arbidol, ataza block antigen-induced proliferation of white blood cells and navir, atripla boceprevir, cidofovir, combivir, darunavir cytokine secretion. delavirdine, didanosine, docosanol, edoxudine, efavirenz, Examples of COX-2 inhibitors suitable for inclusion in the emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, present compositions include, but are not limited to, rofe fosamprenavir, foScarnet, foSfonet, ganciclovir, ibacitabine, coxib, celecoxib, Valdecoxib, lumiracoxib, meloxicam, and 55 immunovir, idoxuridine, imiquimod, indinavir, inosine, inte nimeSulide. grase inhibitor, lamivudine, lopinavir, loviride, maraviroc. Examples of steroids suitable for inclusion in the present moroxydine, nelfinavir, nevirapine, nexavir, oseltamivir, compositions include but are not limited to, fluoromethalone, peginterferon alfa-2a, penciclovir, peramivir, pleconaril. fluticasone (e.g., fluticasone propionate, fluticasone dipropi podophyllotoxin, raltegravir, ribavirin, rimantadine, onate, fluticaSone furoate, fluticasone maleate, fluticaSone 60 ritonavir, saquinavir, stavudine, tenofovir, tipranavir, trifluri Valerate, and the like), mometaSone, triamcinolone, dine, trizivir, tromantadine, truvada, Valaciclovir, Valganci betamethasone, flunisolide, budesonide, beclomethasone, clovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zan budesonide, rimexolone, beloxil, prednisone, loteprednol amivir and Zidovudine. (e.g., loteprednoletabonate) (e.g., loteprednol (e.g., lotepre Examples of neurokinin antagonists Suitable for inclusion dinoletabonate) etabonate), dexamethasone and its analogues 65 in the present compositions include, but are not limited to, (e.g., dexamethasone beloxil) described in U.S. Pat. Nos. oXimes, hydrazones, piperidines, piperazines, aryl alkyl 5,223,493 and 5,420,120, incorporated herein by reference in amines, hydrazones, nitroalkanes, amides, isoxazolines, US 8,758,816 B2 27 28 quinolines, isoquinolines, azanorbornanes, naphthyridines, weight (e.g., about 0.01%, about 0.02%, about 0.03%, about and benzodiazepines, such as those disclosed in U.S. Pat. 0.04%, about 0.05%, about 0.06%, about 0.07%, about Nos. 5,798,359; 5,795,894; 5,789,422:5,783,579; 5,719,156; 0.08%, about 0.09%, or about 0.1% by weight). Preferred 5,696,267:5,691.362; 5,688,960; 5,654.316, incorporated by steroids for use in the formulations of the present invention reference herein in their entireties. 5 are “safe steroids.” As used herein, the term "safe steroid' Examples of 5-lipoxygenase (5-LO) inhibitors suitable for means a steroid which treats eosinophil and neurotrophil inclusion in the present compositions include, but are not associated inflammation, reduces papillae formation, and limited to, Zileuton, docebenone, piripost and tenidap. which is effective in treating inflammation, without causing a The concentrations, absolute amounts and relative clinically significant elevation in intraocular pressure (TOP). amounts (i.e., relative to the concentration or absolute amount 10 Exemplary safe steroids that can be used in the various for of azelastine or a salt thereof, e.g. azelastine HCl) of the mulations of the present invention, particularly for delivery additional one or more active agents will be familiar to one of using nasal spray or ocular drop delivery systems include, but ordinary skill in the art. For example, the amounts of addi are not limited to, any glucocorticoid which meets the safe tional active agents (e.g., one or more steroid(s), leukotriene steroid definition, including but not limited to, fluorometha antagonist(s), anithistamine(s), decongestant(s), NSAIDs, 15 lone, fluticaSone (and its conjugates, salts, esters, analogues etc), can be present in any amount, for example about 0.01% or deriviates, e.g., fluticaSone propionate, fluticaSone furoate, to about 99% (e.g., about 0.01%, about 0.1%, about 1%, about fluticasone maleate, fluticaSone Valerate, and the like), rimex 10%, about 20%, about 30%, about 40%, about 50%, about olone, loteprednol (e.g., loteprednoletabonate), dexametha 60%, about 70%, about 80%, or about 90%). sone beloxil and its analogues described in U.S. Pat. Nos. In one embodiment, the present invention provides com 5,223,493 and 5,420,120, the disclosures of which are incor positions of matter comprising a container (e.g., a unit dose porated by reference herein in their entireties. Additional container) comprising one or more pharmaceutical ingredi 'safe steroids' and methods for determining appropriate ents, including one or more antihistamines, such as an H. H. amounts of such agents for inclusion in the present composi H and H antihistamines disclosed herein one or more Ste tions are disclosed in U.S. Pat. No. 6,649,602, the disclosure roids (e.g., safe steroids), one or more leukotriene antago 25 of which is incorporated by reference herein in its entirety. nists, one or more prostaglandin D2 receptor antagonists, Exemplary compositions of the present invention comprising decongestants, one or more anti-fungal agents, one or more azelastine and a safe steroid comprise about 0.1%-0.15% non-steroidal immunophilin-dependent immunosuppres azelastine, about 0.01%-0.1% of a safe steroid, and optionally sants (NSIDIs), one or more anti-inflammatory agents, non about 0.05%-0.15% Sucralose. steroidal anti-inflammatory agents (NSAIDs), one or more 30 In one embodiment, the present invention provides phar COX-2 inhibitors, one or more anti-infective agents, muco maceutical compositions comprising (or consisting essen lytic agents, one or more anticholinergic agents, one or more tially of) an effective amount of azelastine (suitably azelas mast cell stabilizers, one or more non-antibiotic anti-micro tine hydrochloride) along with an effective amount of bial agents, one or more anti-viral agents, one or more anti fluticasone, Suitably fluticasone propionate, fluticaSone septics, one or more neurokinin antagonists, platelet activat 35 furoate, fluticasone maleate, fluticasone Valerate, and the like. ing factor (PAF) and/or one or more 5-lipoxygenase (5-LO) In certain Suitable embodiments, such compositions further inhibitors. comprise one or more additional ingredients, such as one or In one embodiment, the pharmaceutical compositions more excipients, one or more taste-masking agents and/or one comprise (or consisting essentially of) an effective amount of or more viscosity-increasing agents. Such compositions can aZelastine (Suitably aZelastine hydrochloride) along with an 40 be formulated as intranasal or ocular Suspensions or solu effective amount of one or more steroids. Exemplary steroids tions, with a pH of about 6.0 to 8.0. In other embodiments, the include those discussed throughout. In certain Suitable compositions can be formulated as oral (e.g., tablets or cap embodiments, the compositions further comprise one or more Sules) or topical delivery formulations, such as those dis additional ingredients, such as one or more excipients, one or closed throughout. While the amount of azelastine can be more taste-masking agents and/or one or more viscosity 45 varied and adjusted appropriately by the ordinarily skilled increasing agents. Such compositions can be formulated as artisan, it is Suitably contained in the intranasal or ocular intranasal or ocular Suspensions or solutions, with a pH of formulations in an amount of about 0.0001% to about 1.0% about 6.0 to 8.0. In other embodiments, the compositions can by weight, and more suitably from about 0.005% to about be formulated as oral (e.g., tablets or capsules) or topical 0.5% or most suitably from about 0.05% to about 0.15% (e.g., delivery formulations, such as those disclosed throughout. 50 0.05%, 0.06%, 0.07%, 0.08%, 0.09%. 0.10%, 0.11%, 0.12%, While the amount of azelastine can be varied and adjusted 0.13%, 0.14%, 0.15%), of pure azelastine (calculated as the appropriately by the ordinarily skilled artisan, it is suitably free azelastine base). The amount of fluticasone, suitably contained in the intranasal or ocular formulations in an fluticasone propionate, fluticasone furoate, fluticaSone male amount of about 0.0001% to about 1.0% by weight, and more ate, fluticasone Valerate, and the like, present in the various suitably from about 0.005% to about 0.5% or most suitably 55 formulations can be varied and adjusted appropriately by the from about 0.05% to about 0.15% (e.g., 0.05%, 0.06%, ordinarily skilled artisan, and can be present in any amount, 0.07%, 0.08%, 0.09%. 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, for example about 0.01% to about 99% (e.g., about 0.01%. 0.15%), of pure azelastine (calculated as the free azelastine about 0.1%, about 1%, about 10%, about 20%, about 30%, base). The amount of steroid(s) present in the various formu about 40%, about 50%, about 60%, about 70%, about 80%, or lations can be varied and adjusted appropriately by the ordi 60 about 90%). Suitably the amount of fluticasone, suitably flu narily skilled artisan, and can be present in any amount, for ticasone propionate, fluticaSone dipropionate or fluticasone example about 0.01% to about 99% (e.g., about 0.01%, about fuorate is about 0.01% to about 1.5% by weight, more suit 0.1%, about 1%, about 10%, about 20%, about 30%, about ably about 0.01% to about 1.0% by weight, or even more 40%, about 50%, about 60%, about 70%, about 80%, or about suitably about 0.05% to about 0.1% by weight (e.g., about 90%). Suitably the amount of steroid is about 0.01% to about 65 0.01%, about 0.02%, about 0.03%, about 0.04%, about 1.5% by weight, more suitably about 0.01% to about 1.0% by 0.05%, about 0.06%, about 0.07%, about 0.08%, about weight, or even more suitably about 0.05% to about 0.1% by 0.09%, or about 0.1% by weight). US 8,758,816 B2 29 30 In another embodiment, the present invention provides In an additional embodiment, the pharmaceutical compo pharmaceutical compositions comprising (or consisting sitions comprise (or consist essentially of) an effective essentially of) an effective amount of one or more antihista amount of one or more antihistamines (such as those mines (including H. H. H. and H antagonistic antihista described herein, including H1, H3 and H4 antagonistic anti mines as disclosed herein) along with an effective amount of 5 histamines) along with an effective amount of one or more loteprednol (e.g., loteprednol etabonate), Suitably lotepred additional anti-allergic and/or one or more anti-asthmatic nol (e.g., loteprednoletabonate) etabonate (see e.g., U.S. Pat. agents. Exemplary anti-allergics and anti-asthmatics include No. 7,022.687, the disclosure of which is incorporated herein those discussed herein, including, but not limited to, H. by reference in its entirety) In certain suitable embodiments, receptor antagonists, H receptor antagonists and leukotriene 10 antagonists (e.g., leukotriene D4 antagonists). In Suitable Such compositions further comprise one or more additional Such embodiments, the compositions further comprise one or ingredients, such as one or more excipients, one or more more additional ingredients, such as one or more excipients, taste-masking agents and/or one or more viscosity-increasing one or more taste-masking agents and/or one or more viscos agents. Such compositions can be formulated as intranasal or ity-increasing agents. Such compositions can be formulated ocular suspensions or solutions, with a pH of about 6.0 to 8.0. 15 as intranasal or ocular Suspensions or Solutions, with a pH of In other embodiments, the compositions can beformulated as about 6.0 to 8.0. In other embodiments, the compositions can oral (e.g., tablets or capsules) or topical delivery formula be formulated for oral or pulmonary delivery, such as those tions, such as those disclosed throughout. While the amount described herein. While the amount of azelastine can be var of azelastine can be varied and adjusted appropriately by the ied and adjusted appropriately by the ordinarily skilled arti ordinarily skilled artisan, it is Suitably contained in the intra san, it is suitably contained in the intranasal or ocular formu nasal or ocular formulations in an amount of about 0.0001% lations in an amount of about 0.0001% to about 1.0% by to about 1.0% by weight, and more suitably from about weight, and more suitably from about 0.005% to about 0.5% 0.005% to about 0.5% or most suitably from about 0.05% to or most suitably from about 0.05% to about 0.15% (e.g., about 0.15% (e.g., 0.05%, 0.06%, 0.07%, 0.08%, 0.09%. about 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%), of pureazelas 25 0.12%, 0.13%, 0.14%, 0.15%), of pure azelastine (calculated tine (calculated as the free azelastine base). The amount of as the free azelastine base). The amount of one or more loteprednol (e.g., loteprednol etabonate), Suitably lotepred additional anti-allergic and/or anti-asthmatics present in the nol (e.g., loteprednol etabonate) etabonate, present in the various formulations can be varied and adjusted appropriately various formulations can be varied and adjusted appropriately by the ordinarily skilled artisan and can be present in any by the ordinarily skilled artisan, and can be present in any 30 amount, for example about 0.01% to about 99% (e.g., about amount, for example about 0.01% to about 99% (e.g., about 0.01%, about 0.1%, about 1%, about 10%, about 20%, about 0.01%, about 0.1%, about 1%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%). Suitably the amount of these additional 80%, or about 90%). Suitably the amount ofloteprednol (e.g., compounds will be in an amount of about 0.01% to about 10% loteprednol etabonate), Suitably loteprednol (e.g., lotepred 35 by weight, or more suitably in an amount of about 0.1% to nol etabonate) etabonate, is about 0.01% to about 1.5% by about 5.0% by weight. In addition, the compositions can also weight, more suitably about 0.01% to about 1.0% by weight, comprise sucralose at about 0.05%-0.15%. or even more suitably about 0.05% to about 0.1% by weight Suitable compositions of the present invention comprise (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, (or consistessentially of), for example (percentages ofazelas about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 40 tine refer to weight percentages of azelastine HC1 or other 0.09%, or about 0.1% by weight). suitable salt): In another embodiment, the pharmaceutical compositions About 0.05% azelastine and about 0.05% sucralose; comprise (or consistessentially of) an effective amount of one About 0.05% azelastine and about 0.1% sucralose; or more antihistamines (such as those described herein, About 0.05% azelastine and about 0.15% sucralose; including H. H. H. and H antagonistic antihistamines) 45 About 0.1% azelastine and about 0.05% sucralose; along with an effective amount of one or more steroids, and About 0.1% azelastine and about 0.1% sucralose; also an effective amount of one or more decongestants. In About 0.1% azelastine and about 0.15% sucralose; Suitable Such embodiments, the compositions further com About 0.125% azelastine and about 0.05% sucralose; prise one or more additional ingredients, such as one or more About 0.125% azelastine and about 0.1% sucralose; excipients, one or more taste-masking agents and/or one or 50 About 0.125% azelastine and about 0.15% sucralose; more viscosity-increasing agents. Such compositions can be About 0.15% azelastine and about 0.05% sucralose; formulated as intranasal or ocular Suspensions or Solutions, About 0.15% azelastine and about 0.1% sucralose; with a pH of about 6.0 to 8.0. In other embodiments, the About 0.15% azelastine and about 0.15% sucralose; compositions can be formulated as oral or topical delivery About 0.05% azelastine and about 0.01% steroid: formulations, such as those disclosed throughout. The appro 55 About 0.1% azelastine and about 0.01% steroid: priate amounts of azelastine, steroid and decongestant can be About 0.125% azelastine and about 0.01% steroid; readily determined by those or ordinary skill in the art. Suit About 0.15% azelastine and about 0.01% steroid: ably, the amount of steroid and azelastine used will be in the About 0.05% azelastine and about 0.05% steroid; ranges disclosed herein. The amount of decongestant can be About 0.1% azelastine and about 0.05% steroid: present in any amount, for example about 0.01% to about 60 About 0.125% azelastine and about 0.05% steroid; 99% (e.g., about 0.01%, about 0.1%, about 1%, about 10%, About 0.15% azelastine and about 0.05% steroid: about 20%, about 30%, about 40%, about 50%, about 60%, About 0.05% azelastine and about 0.1% steroid: about 70%, about 80%, or about 90%). Suitably the amount of About 0.1% azelastine and about 0.1% steroid; decongestant is about 0.05% to about 1.5% by weight, or About 0.125% azelastine and about 0.1% steroid: more suitably in an amount of about 0.1% to about 1.0% by 65 About 0.15% azelastine and about 0.1% steroid: weight. In addition, the compositions can also comprise About 0.05% azelastine, about 0.01% steroid and about Sucralose at about 0.05%-0.15%. 0.05% sucralose; US 8,758,816 B2 31 32 About 0.1% azelastine, about 0.01% steroid and about About 0.125% azelastine, about 0.1% steroid and about 0.05% sucralose; 0.15% sucralose; About 0.125% azelastine, about 0.01% steroid and about About 0.15% azelastine, about 0.1% steroid and about 0.05% sucralose; 0.15% sucralose; About 0.15% azelastine, about 0.01% steroid and about About 0.05% azelastine and about 0.01% fluticasone (e.g., 0.05% sucralose; fluticasone propionate, fluticaSone dipropionate or flutica About 0.05% azelastine, about 0.05% steroid and about Sone furoate), mometaSone, dexamethasone beloxil, lotepre 0.05% sucralose; dinol (e.g., loteprednoletabonate), budesonide, or triamcino About 0.1% azelastine, about 0.05% steroid and about lone; 10 About 0.1% azelastine and about 0.01% fluticasone (e.g., 0.05% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.125% azelastine, about 0.05% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.05% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% steroid and about loteprednol etabonate), budesonide, or triamcinolone; 0.05% sucralose; 15 About 0.125% azelastine and about 0.01% fluticasone About 0.05% azelastine, about 0.1% steroid and about (e.g., fluticaSone propionate, fluticaSone dipropionate, fluti 0.05% sucralose; casone furoate, fluticaSone maleate, fluticasone Valerate, and About 0.1% azelastine, about 0.1% steroid and about the like), mometasone, dexamethasone beloxil, loteprednol 0.05% sucralose; (e.g., loteprednoletabonate), budesonide, or triamcinolone; About 0.125% azelastine, about 0.1% steroid and about About 0.15% azelastine and about 0.01% fluticasone (e.g., 0.05% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.15% azelastine, about 0.1% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.05% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% steroid and about loteprednol etabonate), budesonide, or triamcinolone; 0.1% sucralose; 25 About 0.05% azelastine and about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.01% steroid and about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.1% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.01% steroid and about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% sucralose; loteprednol etabonate), budesonide, or triamcinolone; About 0.15% azelastine, about 0.01% steroid and about 30 About 0.1% azelastine and about 0.05% fluticasone (e.g., 0.1% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.05% azelastine, about 0.05% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.1% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% steroid and about loteprednol etabonate), budesonide, or triamcinolone; 0.1% sucralose; 35 About 0.125% azelastine and about 0.05% fluticasone About 0.125% azelastine, about 0.05% steroid and about (e.g., fluticaSone propionate, fluticaSone dipropionate, fluti 0.1% sucralose; casone furoate, fluticaSone maleate, fluticasone Valerate, and About 0.15% azelastine, about 0.05% steroid and about the like), mometasone, dexamethasone beloxil, loteprednol 0.1% sucralose; (e.g., loteprednoletabonate), budesonide, or triamcinolone; About 0.05% azelastine, about 0.1% steroid and about 40 About 0.15% azelastine and about 0.05% fluticasone (e.g., 0.1% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine, about 0.1% steroid and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% steroid and about loteprednol etabonate), budesonide, or triamcinolone; 0.1% sucralose; 45 About 0.05% azelastine and about 0.1% fluticasone (e.g., About 0.15% azelastine, about 0.1% steroid and about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.1% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05% azelastine, about 0.01% steroid and about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone; About 0.1% azelastine, about 0.01% steroid and about 50 About 0.1% azelastine and about 0.1% fluticasone (e.g., 0.15% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.125% azelastine, about 0.01% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% steroid and about loteprednol etabonate), budesonide, or triamcinolone; 0.15% sucralose; 55 About 0.125% azelastine and about 0.1% fluticasone (e.g., About 0.05% azelastine, about 0.05% steroid and about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.05% steroid and about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone; About 0.125% azelastine, about 0.05% steroid and about 60 About 0.15% azelastine and about 0.1% fluticasone (e.g., 0.15% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.15% azelastine, about 0.05% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.1% steroid and about loteprednol etabonate), budesonide, or triamcinolone; 0.15% sucralose; 65 About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.1% steroid and about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the US 8,758,816 B2 33 34 like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.05% sucralose; about 0.15% sucralose; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.05% sucralose; about 0.05% sucralose; About 0.125% azelastine, about 0.01% fluticasone (e.g., 10 About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and 15 loteprednol etabonate), budesonide, or triamcinolone and about 0.05% sucralose; about 0.05% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.05% sucralose; about 0.05% sucralose; About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 25 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.1% sucralose; about 0.05% sucralose; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone 30 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.1% sucralose; about 0.1% sucralose; About 0.125% azelastine, about 0.01% fluticasone (e.g., 35 About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.1% sucralose; 40 about 0.1% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and 45 loteprednol etabonate), budesonide, or triamcinolone and about 0.1% sucralose; about 0.1% sucralose; About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.15% sucralose; about 0.1% sucralose; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 55 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.15% sucralose; about 0.15% sucralose; About 0.125% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone 60 ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.15% sucralose; about 0.15% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., 65 About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the US 8,758,816 B2 35 36 like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.15% sucralose; about 0.15% sucralose; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.15% sucralose; about 0.15% sucralose; 10 About 0.15% azelastine, about 0.1% fluticasone (e.g., flu About 0.05%azelastine, about 0.1% fluticasone (e.g., flu ticasone propionate, fluticaSone dipropionate, fluticasone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and 15 about 0.15% sucralose; about 0.05% sucralose; About 0.05% azelastine and about 0.1% leukotriene About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti antagonist; casone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine and about 0.1% leukotriene antago furoate, fluticasone maleate, fluticasone Valerate, and the nist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine and about 0.1% leukotriene loteprednol etabonate), budesonide, or triamcinolone and antagonist; about 0.05% sucralose; About 0.15% azelastine and about 0.1% leukotriene About 0.125% azelastine, about 0.1% fluticasone (e.g., antagonist; fluticasone propionate, fluticaSone dipropionate, fluticaSone About 0.05% azelastine and about 0.5% leukotriene furoate, fluticasone maleate, fluticasone Valerate, and the 25 antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine and about 0.5% leukotriene antago loteprednol etabonate), budesonide, or triamcinolone and nist; about 0.05% sucralose; About 0.125% azelastine and about 0.5% leukotriene About 0.15% azelastine, about 0.1% fluticasone (e.g., flu antagonist; ticasone propionate, fluticaSone dipropionate, fluticasone 30 About 0.15% azelastine and about 0.5% leukotriene furoate, fluticasone maleate, fluticasone Valerate, and the antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine and about 5.0% leukotriene loteprednol etabonate), budesonide, or triamcinolone and antagonist; about 0.05% sucralose; About 0.1% azelastine and about 5.0% leukotriene antago About 0.05%azelastine, about 0.1% fluticasone (e.g., flu 35 nist; ticasone propionate, fluticaSone dipropionate, fluticasone About 0.125% azelastine and about 5.0% leukotriene furoate, fluticasone maleate, fluticasone Valerate, and the antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine and about 5.0% leukotriene loteprednol etabonate), budesonide, or triamcinolone and antagonist; about 0.1% sucralose; 40 About 0.05% azelastine, about 0.1% leukotriene antago About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti nist and about 0.05% sucralose; casone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine, about 0.1% leukotriene antagonist furoate, fluticasone maleate, fluticasone Valerate, and the and about 0.05% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% leukotriene antago loteprednol etabonate), budesonide, or triamcinolone and 45 nist and about 0.05% sucralose; about 0.1% sucralose; About 0.15% azelastine, about 0.1% leukotriene antago About 0.125% azelastine, about 0.1% fluticasone (e.g., nist and about 0.05% sucralose; fluticasone propionate, fluticaSone dipropionate, fluticaSone About 0.05% azelastine, about 0.1% leukotriene antago furoate, fluticasone maleate, fluticasone Valerate, and the nist and about 0.1% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 About 0.1% azelastine, about 0.1% leukotriene antagonist loteprednol etabonate), budesonide, or triamcinolone and and about 0.1% sucralose; about 0.1% sucralose; About 0.125% azelastine, about 0.1% leukotriene antago About 0.15% azelastine, about 0.1% fluticasone (e.g., flu nist and about 0.1% sucralose; ticasone propionate, fluticaSone dipropionate, fluticasone About 0.15% azelastine, about 0.1% leukotriene antago furoate, fluticasone maleate, fluticasone Valerate, and the 55 nist and about 0.1% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.1% leukotriene antago loteprednol etabonate), budesonide, or triamcinolone and nist and about 0.15% sucralose; about 0.1% sucralose; About 0.1% azelastine, about 0.1% leukotriene antagonist About 0.05%azelastine, about 0.1% fluticasone (e.g., flu and about 0.15% sucralose; ticasone propionate, fluticaSone dipropionate, fluticasone 60 About 0.125% azelastine, about 0.1% leukotriene antago furoate, fluticasone maleate, fluticasone Valerate, and the nist and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% leukotriene antago loteprednol etabonate), budesonide, or triamcinolone and nist and about 0.15% sucralose; about 0.15% sucralose; About 0.05% azelastine, about 0.5% leukotriene antago About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 65 nist and about 0.05% sucralose; casone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine, about 0.5% leukotriene antagonist furoate, fluticasone maleate, fluticasone Valerate, and the and about 0.05% sucralose; US 8,758,816 B2 37 38 About 0.125% azelastine, about 0.5% leukotriene antago About 0.1% azelastine, about 0.1% montelukastandabout nist and about 0.05% sucralose; 0.1% sucralose; About 0.15% azelastine, about 0.5% leukotriene antago About 0.125% azelastine, about 0.1% montelukast and nist and about 0.05% sucralose; about 0.1% sucralose; About 0.05% azelastine, about 0.5% leukotriene antago About 0.15% azelastine, about 0.1% montelukast and nist and about 0.1% sucralose; about 0.1% sucralose; About 0.1% azelastine, about 0.5% leukotriene antagonist About 0.05% azelastine, about 0.1% montelukast and and about 0.1% sucralose; about 0.15% sucralose; About 0.125% azelastine, about 0.5% leukotriene antago About 0.1% azelastine, about 0.1% montelukastandabout 10 0.15% sucralose; nist and about 0.1% sucralose; About 0.125% azelastine, about 0.1% montelukast and About 0.15% azelastine, about 0.5% leukotriene antago about 0.15% sucralose; nist and about 0.1% sucralose; About 0.15% azelastine, about 0.1% montelukast and About 0.05% azelastine, about 0.5% leukotriene antago about 0.15% sucralose; nist and about 0.15% sucralose; 15 About 0.05% azelastine, about 0.5% montelukast and About 0.1% azelastine, about 0.5% leukotriene antagonist about 0.05% sucralose; and about 0.15% sucralose; About 0.1% azelastine, about 0.5% montelukastandabout About 0.125% azelastine, about 0.5% leukotriene antago 0.05% sucralose; nist and about 0.15% sucralose; About 0.125% azelastine, about 0.5% montelukast and About 0.15% azelastine, about 0.5% leukotriene antago about 0.05% sucralose; nist and about 0.15% sucralose; About 0.15% azelastine, about 0.5% montelukast and About 0.05% azelastine, about 5.0% leukotriene antago about 0.05% sucralose; nist and about 0.05% sucralose; About 0.05% azelastine, about 0.5% montelukast and About 0.1% azelastine, about 5.0% leukotriene antagonist about 0.1% sucralose; and about 0.05% sucralose; 25 About 0.1% azelastine, about 0.5% montelukastandabout About 0.125% azelastine, about 5.0% leukotriene antago 0.1% sucralose; nist and about 0.05% sucralose; About 0.125% azelastine, about 0.5% montelukast and About 0.15% azelastine, about 5.0% leukotriene antago about 0.1% sucralose; nist and about 0.05% sucralose; About 0.15% azelastine, about 0.5% montelukast and About 0.05% azelastine, about 5.0% leukotriene antago 30 about 0.1% sucralose; nist and about 0.1% sucralose; About 0.05% azelastine, about 0.5% montelukast and About 0.1% azelastine, about 5.0% leukotriene antagonist about 0.15% sucralose; and about 0.1% sucralose; About 0.1% azelastine, about 0.5% montelukastandabout About 0.125% azelastine, about 5.0% leukotriene antago 0.15% sucralose; nist and about 0.1% sucralose; 35 About 0.125% azelastine, about 0.5% montelukast and About 0.15% azelastine, about 5.0% leukotriene antago about 0.15% sucralose; nist and about 0.1% sucralose; About 0.15% azelastine, about 0.5% montelukast and About 0.05% azelastine, about 5.0% leukotriene antago about 0.15% sucralose; nist and about 0.15% sucralose; About 0.05% azelastine, about 5.0% montelukast and About 0.1% azelastine, about 5.0% leukotriene antagonist 40 about 0.05% sucralose; and about 0.15% sucralose; About 0.1% azelastine, about 5.0% montelukastandabout About 0.125% azelastine, about 5.0% leukotriene antago 0.05% sucralose; nist and about 0.15% sucralose; About 0.125% azelastine, about 5.0% montelukast and About 0.15% azelastine, about 5.0% leukotriene antago about 0.05% sucralose; nist and about 0.15% sucralose; 45 About 0.15% azelastine, about 5.0% montelukast and About 0.05% azelastine and about 0.1% montelukast; about 0.05% sucralose; About 0.1% azelastine and about 0.1% montelukast; About 0.05% azelastine, about 5.0% montelukast and About 0.125% azelastine and about 0.1% montelukast; about 0.1% sucralose; About 0.15% azelastine and about 0.1% montelukast; About 0.1% azelastine, about 5.0% montelukastandabout About 0.05% azelastine and about 0.5% montelukast; 50 0.1% sucralose; About 0.1% azelastine and about 0.5% montelukast; About 0.125% azelastine, about 5.0% montelukast and About 0.125% azelastine and about 0.5% montelukast; about 0.1% sucralose; About 0.15% azelastine and about 0.5% montelukast; About 0.15% azelastine, about 5.0% montelukast and About 0.05% azelastine and about 5.0% montelukast; about 0.1% sucralose; About 0.1% azelastine and about 5.0% montelukast; 55 About 0.05% azelastine, about 5.0% montelukast and About 0.125% azelastine and about 5.0% montelukast; about 0.15% sucralose; About 0.15% azelastine and about 5.0% montelukast; About 0.1% azelastine, about 5.0% montelukastandabout About 0.05% azelastine, about 0.1% montelukast and 0.15% sucralose; about 0.05% sucralose; About 0.125% azelastine, about 5.0% montelukast and About 0.1% azelastine, about 0.1% montelukastandabout 60 about 0.15% sucralose; 0.05% sucralose; About 0.15% azelastine, about 5.0% montelukast and About 0.125% azelastine, about 0.1% montelukast and about 0.15% sucralose; about 0.05% sucralose; About 0.05% azelastine and about 0.1% decongestant; About 0.15% azelastine, about 0.1% montelukast and About 0.1% azelastine and about 0.1% decongestant; about 0.05% sucralose; 65 About 0.125% azelastine and about 0.1% decongestant; About 0.05% azelastine, about 0.1% montelukast and About 0.15% azelastine and about 0.1% decongestant; about 0.1% sucralose; About 0.05% azelastine and about 0.5% decongestant; US 8,758,816 B2 39 40 About 0.1% azelastine and about 0.5% decongestant; About 0.125% azelastine, about 1.0% decongestant and About 0.125% azelastine and about 0.5% decongestant; about 0.1% sucralose; About 0.15% azelastine and about 0.5% decongestant; About 0.15% azelastine, about 1.0% decongestant and About 0.05% azelastine and about 1.0% decongestant; about 0.1% sucralose; About 0.1% azelastine and about 1.0% decongestant; 5 About 0.05% azelastine, about 1.0% decongestant and About 0.125% azelastine and about 1.0% decongestant; about 0.15% sucralose; About 0.15% azelastine and about 1.0% decongestant; About 0.1% azelastine, about 1.0% decongestant and About 0.05% azelastine, about 0.1% decongestant and about 0.15% sucralose; about 0.05% sucralose; About 0.125% azelastine, about 1.0% decongestant and About 0.1% azelastine, about 0.1% decongestant and 10 about 0.15% sucralose; about 0.05% sucralose; About 0.15% azelastine, about 1.0% decongestant and About 0.125% azelastine, about 0.1% decongestant and about 0.15% sucralose; about 0.05% sucralose; About 0.05% azelastine and about 0.1% pseudoephedrine About 0.15% azelastine, about 0.1% decongestant and or phenylephrine; about 0.05% sucralose; 15 About 0.05% azelastine, about 0.1% decongestant and About 0.1% azelastine and about 0.1% pseudoephedrine or about 0.1% sucralose; phenylephrine; About 0.1% azelastine, about 0.1% decongestant and About 0.125% azelastine and about 0.1% pseudoephedrine about 0.1% sucralose; or phenylephrine; About 0.125% azelastine, about 0.1% decongestant and About 0.15% azelastine and about 0.1% pseudoephedrine about 0.1% sucralose; or phenylephrine; About 0.15% azelastine, about 0.1% decongestant and About 0.05% azelastine and about 0.5% pseudoephedrine about 0.1% sucralose; or phenylephrine; About 0.05% azelastine, about 0.1% decongestant and About 0.1% azelastine and about 0.5% pseudoephedrine or about 0.15% sucralose; 25 phenylephrine; About 0.1% azelastine, about 0.1% decongestant and About 0.125% azelastine and about 0.5% pseudoephedrine about 0.15% sucralose; or phenylephrine; About 0.125% azelastine, about 0.1% decongestant and About 0.15% azelastine and about 0.5% pseudoephedrine about 0.15% sucralose; or phenylephrine; About 0.15% azelastine, about 0.1% decongestant and 30 About 0.05% azelastine and about 1.0% pseudoephedrine about 0.15% sucralose; or phenylephrine; About 0.05% azelastine, about 0.5% decongestant and About 0.1%azelastine and about 1.0%pseudoephedrine or about 0.05% sucralose; phenylephrine; About 0.1% azelastine, about 0.5% decongestant and About 0.125% azelastine and about 1.0% pseudoephedrine about 0.05% sucralose; 35 or phenylephrine; About 0.125% azelastine, about 0.5% decongestant and About 0.15% azelastine and about 1.0% pseudoephedrine about 0.05% sucralose; or phenylephrine; About 0.15% azelastine, about 0.5% decongestant and About 0.05% azelastine, about 0.1% pseudoephedrine or about 0.05% sucralose; phenylephrine and about 0.05% sucralose; About 0.05% azelastine, about 0.5% decongestant and 40 About 0.1% azelastine, about 0.1% pseudoephedrine or about 0.1% sucralose; phenylephrine and about 0.05% sucralose; About 0.1% azelastine, about 0.5% decongestant and About 0.125% azelastine, about 0.1% pseudoephedrine or about 0.1% sucralose; phenylephrine and about 0.05% sucralose; About 0.125% azelastine, about 0.5% decongestant and About 0.15% azelastine, about 0.1% pseudoephedrine or about 0.1% sucralose; 45 phenylephrine and about 0.05% sucralose; About 0.15% azelastine, about 0.5% decongestant and About 0.05% azelastine, about 0.1% pseudoephedrine or about 0.1% sucralose; phenylephrine and about 0.1% sucralose; About 0.05% azelastine, about 0.5% decongestant and About 0.1% azelastine, about 0.1% pseudoephedrine or about 0.15% sucralose; phenylephrine and about 0.1% sucralose; About 0.1% azelastine, about 0.5% decongestant and 50 About 0.125% azelastine, about 0.1% pseudoephedrine or about 0.15% sucralose; phenylephrine and about 0.1% sucralose; About 0.125% azelastine, about 0.5% decongestant and About 0.15% azelastine, about 0.1% pseudoephedrine or about 0.15% sucralose; phenylephrine and about 0.1% sucralose; About 0.15% azelastine, about 0.5% decongestant and About 0.05% azelastine, about 0.1% pseudoephedrine or about 0.15% sucralose; 55 phenylephrine and about 0.15% sucralose; About 0.05% azelastine, about 1.0% decongestant and About 0.1% azelastine, about 0.1% pseudoephedrine or about 0.05% sucralose; phenylephrine and about 0.15% sucralose; About 0.1% azelastine, about 1.0% decongestant and About 0.125% azelastine, about 0.1% pseudoephedrine or about 0.05% sucralose; phenylephrine and about 0.15% sucralose; About 0.125% azelastine, about 1.0% decongestant and 60 About 0.15% azelastine, about 0.1% pseudoephedrine or about 0.05% sucralose; phenylephrine and about 0.15% sucralose; About 0.15% azelastine, about 1.0% decongestant and About 0.05% azelastine, about 0.5% pseudoephedrine or about 0.05% sucralose; phenylephrine and about 0.05% sucralose; About 0.05% azelastine, about 1.0% decongestant and About 0.1% azelastine, about 0.5% pseudoephedrine or about 0.1% sucralose; 65 phenylephrine and about 0.05% sucralose; About 0.1% azelastine, about 1.0% decongestant and About 0.125% azelastine, about 0.5% pseudoephedrine or about 0.1% sucralose; phenylephrine and about 0.05% sucralose; US 8,758,816 B2 41 42 About 0.15% azelastine, about 0.5% pseudoephedrine or About 0.125% azelastine, about 0.1% NSAID and about phenylephrine and about 0.05% sucralose; 0.1% sucralose; About 0.05% azelastine, about 0.5% pseudoephedrine or About 0.15% azelastine, about 0.1% NSAID and about phenylephrine or phenylephrine and about 0.1% sucralose; 0.1% sucralose; About 0.1% azelastine, about 0.5% pseudoephedrine or 5 About 0.05% azelastine, about 0.1% NSAID and about phenylephrine or phenylephrine and about 0.1% sucralose; 0.15% sucralose; About 0.125% azelastine, about 0.5% pseudoephedrine or About 0.1% azelastine, about 0.1% NSAID and about phenylephrine and about 0.1% sucralose; 0.15% sucralose; About 0.15% azelastine, about 0.5% pseudoephedrine or About 0.125% azelastine, about 0.1% NSAID and about phenylephrine and about 0.1% sucralose; 10 0.15% sucralose; About 0.05% azelastine, about 0.5% pseudoephedrine or About 0.15% azelastine, about 0.1% NSAID and about phenylephrine and about 0.15% sucralose; 0.15% sucralose; About 0.1% azelastine, about 0.5% pseudoephedrine or About 0.05% azelastine, about 0.5% NSAID and about phenylephrine and about 0.15% sucralose; 15 0.05% sucralose; About 0.125% azelastine, about 0.5% pseudoephedrine or About 0.1% azelastine, about 0.5% NSAID and about phenylephrine and about 0.15% sucralose; 0.05% sucralose; About 0.15% azelastine, about 0.5% pseudoephedrine or About 0.125% azelastine, about 0.5% NSAID and about phenylephrine and about 0.15% sucralose; 0.05% sucralose; About 0.05% azelastine, about 1.0% pseudoephedrine or About 0.15% azelastine, about 0.5% NSAID and about phenylephrine and about 0.05% sucralose; 0.05% sucralose; About 0.1% azelastine, about 1.0% pseudoephedrine or About 0.05% azelastine, about 0.5% NSAID and about phenylephrine and about 0.05% sucralose; 0.1% sucralose; About 0.125% azelastine, about 1.0% pseudoephedrine or About 0.1% azelastine, about 0.5% NSAID and about phenylephrine and about 0.05% sucralose; 25 0.1% sucralose; About 0.15% azelastine, about 1.0% pseudoephedrine or About 0.125% azelastine, about 0.5% NSAID and about phenylephrine and about 0.05% sucralose; 0.1% sucralose; About 0.05% azelastine, about 1.0% pseudoephedrine or About 0.15% azelastine, about 0.5% NSAID and about phenylephrine and about 0.1% sucralose; 0.1% sucralose; About 0.1% azelastine, about 1.0% pseudoephedrine or 30 About 0.05% azelastine, about 0.5% NSAID and about phenylephrine and about 0.1% sucralose; 0.15% sucralose; About 0.125% azelastine, about 1.0% pseudoephedrine or About 0.1% azelastine, about 0.5% NSAID and about phenylephrine and about 0.1% sucralose; 0.15% sucralose; About 0.15% azelastine, about 1.0% pseudoephedrine or About 0.125% azelastine, about 0.5% NSAID and about phenylephrine and about 0.1% sucralose; 35 0.15% sucralose; About 0.05% azelastine, about 1.0% pseudoephedrine or About 0.15% azelastine, about 0.5% NSAID and about phenylephrine and about 0.15% sucralose; 0.15% sucralose; About 0.1% azelastine, about 1.0% pseudoephedrine or About 0.05% azelastine, about 10.0% NSAID and about phenylephrine and about 0.15% sucralose; 0.05% sucralose; About 0.125% azelastine, about 1.0% pseudoephedrine or 40 About 0.1% azelastine, about 10.0% NSAID and about phenylephrine and about 0.15% sucralose; 0.05% sucralose; About 0.15% azelastine, about 1.0% pseudoephedrine or About 0.125% azelastine, about 10.0% NSAID and about phenylephrine and about 0.15% sucralose; 0.05% sucralose; About 0.05% azelastine and about 0.1% NSAID: About 0.15% azelastine, about 1.0% NSAID and about About 0.1% azelastine and about 0.1% NSAID: 45 0.05% sucralose; About 0.125% azelastine and about 0.1% NSAID: About 0.05% azelastine, about 10.0% NSAID and about About 0.15% azelastine and about 0.1% NSAID: 0.1% sucralose; About 0.05% azelastine and about 0.5% NSAID: About 0.1% azelastine, about 10.0% NSAID and about About 0.1% azelastine and about 0.5% NSAID: 0.1% sucralose; About 0.125% azelastine and about 0.5% NSAID: 50 About 0.125% azelastine, about 10.0% NSAID and about About 0.15% azelastine and about 0.5% NSAID: 0.1% sucralose; About 0.05% azelastine and about 10.0% NSAID: About 0.15% azelastine, about 10.0% NSAID and about About 0.1% azelastine and about 10.0% NSAID: 0.1% sucralose; About 0.125% azelastine and about 10.0% NSAID; About 0.05% azelastine, about 10.0% NSAID and about About 0.15% azelastine and about 10.0% NSAID: 55 0.15% sucralose; About 0.05% azelastine, about 0.1% NSAID and about About 0.1% azelastine, about 10.0% NSAID and about 0.05% sucralose; 0.15% sucralose; About 0.1% azelastine, about 0.1% NSAID and about About 0.125% azelastine, about 10.0% NSAID and about 0.05% sucralose; 0.15% sucralose; About 0.125% azelastine, about 0.1% NSAID and about 60 About 0.15% azelastine, about 10.0% NSAID and about 0.05% sucralose; 0.15% sucralose; About 0.15% azelastine, about 0.1% NSAID and about About 0.05% azelastine and about 0.1% ibuprofen, 0.05% sucralose; diclofenac, aceclofenac or naproxen; About 0.05% azelastine, about 0.1% NSAID and about About 0.1% azelastine and about 0.1% ibuprofen, 0.1% sucralose; 65 diclofenac, aceclofenac or naproxen; About 0.1% azelastine, about 0.1% NSAID and about About 0.125% azelastine and about 0.1% ibuprofen, 0.1% sucralose; diclofenac, aceclofenac or naproxen; US 8,758,816 B2 43 44 About 0.15% azelastine and about 0.1% ibuprofen, About 0.125% azelastine, about 0.5% ibuprofen, diclofenac, aceclofenac or naproxen; diclofenac, aceclofenac or naproxen and about 0.1% Sucral About 0.05% azelastine and about 0.5% ibuprofen, oSe; diclofenac, aceclofenac or naproxen; About 0.15% azelastine, about 0.5% ibuprofen, About 0.1% azelastine and about 0.5% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.1% Sucral diclofenac, aceclofenac or naproxen; oSe; About 0.125% azelastine and about 0.5% ibuprofen, About 0.05% azelastine, about 0.5% ibuprofen, diclofenac, aceclofenac or naproxen; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.15% azelastine and about 0.5% ibuprofen, oSe; 10 About 0.1% azelastine, about 0.5% ibuprofen, diclofenac, diclofenac, aceclofenac or naproxen; aceclofenac or naproxen and about 0.15% Sucralose; About 0.05% azelastine and about 10.0% ibuprofen, About 0.125% azelastine, about 0.5% ibuprofen, diclofenac, aceclofenac or naproxen; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.1% azelastine and about 10.0% ibuprofen, oSe; diclofenac, aceclofenac or naproxen; 15 About 0.15% azelastine, about 0.5% ibuprofen, About 0.125% azelastine and about 10.0% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.15% sucral diclofenac, aceclofenac or naproxen; oSe; About 0.15% azelastine and about 10.0% ibuprofen, About 0.05% azelastine, about 10.0% ibuprofen, diclofenac, aceclofenac or naproxen; diclofenac, aceclofenac or naproxen and about 0.05% sucral About 0.05% azelastine, about 0.1% ibuprofen, oSe; diclofenac, aceclofenac or naproxen and about 0.05% sucral About 0.1% azelastine, about 10.0% ibuprofen, oSe; diclofenac, aceclofenac or naproxen and about 0.05% sucral About 0.1% azelastine, about 0.1% ibuprofen, diclofenac, oSe; aceclofenac or naproxen and about 0.05% sucralose; About 0.125% azelastine, about 10.0% ibuprofen, About 0.125% azelastine, about 0.1% ibuprofen, 25 diclofenac, aceclofenac or naproxen and about 0.05% sucral diclofenac, aceclofenac or naproxen and about 0.05% sucral oSe; oSe; About 0.15% azelastine, about 10.0% ibuprofen, About 0.15% azelastine, about 0.1% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.05% sucral diclofenac, aceclofenac or naproxen and about 0.05% sucral oSe; oSe; 30 About 0.05% azelastine, about 10.0% ibuprofen, About 0.05% azelastine, about 0.1% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.1% Sucral diclofenac, aceclofenac or naproxen and about 0.1% sucral OSe: oSe; About 0.1% azelastine, about 10.0% ibuprofen, About 0.1% azelastine, about 0.1% ibuprofen, diclofenac, diclofenac, aceclofenac or naproxen and about 0.1% Sucral aceclofenac or naproxen and about 0.1% Sucralose; 35 oSe; About 0.125% azelastine, about 0.1% ibuprofen, About 0.125% azelastine, about 10.0% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.1% Sucral diclofenac, aceclofenac or naproxen and about 0.1% Sucral oSe; oSe; About 0.15% azelastine, about 0.1% ibuprofen, About 0.15% azelastine, about 10.0% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.1% Sucral 40 diclofenac, aceclofenac or naproxen and about 0.1% Sucral oSe; oSe; About 0.05% azelastine, about 0.1% ibuprofen, About 0.05% azelastine, about 10.0% ibuprofen, diclofenac, aceclofenac or naproxen and about 0.15% sucral diclofenac, aceclofenac or naproxen and about 0.15% sucral oSe; oSe; About 0.1% azelastine, about 0.1% ibuprofen, diclofenac, 45 About 0.1% azelastine, about 10.0% ibuprofen, aceclofenac or naproxen and about 0.15% Sucralose; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.125% azelastine, about 0.1% ibuprofen, oSe; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.125% azelastine, about 10.0% ibuprofen, oSe; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.15% azelastine, about 0.1% ibuprofen, 50 oSe; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.15% azelastine, about 10.0% ibuprofen, oSe; diclofenac, aceclofenac or naproxen and about 0.15% sucral About 0.05% azelastine, about 0.5% ibuprofen, oSe; diclofenac, aceclofenac or naproxen and about 0.05% sucral About 0.05% azelastine, about 0.01% steroid and about oSe; 55 0.1% decongestant; About 0.1% azelastine, about 0.5% ibuprofen, diclofenac, About 0.1% azelastine, about 0.01% steroid and about aceclofenac or naproxen and about 0.05% sucralose; 0.1% decongestant; About 0.125% azelastine, about 0.5% ibuprofen, About 0.125% azelastine, about 0.01% steroid and about diclofenac, aceclofenac or naproxen and about 0.05% sucral 0.1% decongestant; oSe; 60 About 0.15% azelastine, about 0.01% steroid and about About 0.15% azelastine, about 0.5% ibuprofen and about 0.1% decongestant; 0.05% sucralose; About 0.05% azelastine, about 0.05% steroid and about About 0.05% azelastine, about 0.5% ibuprofen, 0.1% decongestant; diclofenac, aceclofenac or naproxen and about 0.1% Sucral About 0.1% azelastine, about 0.05% steroid and about oSe; 65 0.1% decongestant; About 0.1% azelastine, about 0.5% ibuprofen, diclofenac, About 0.125% azelastine, about 0.05% steroid and about aceclofenac or naproxen and about 0.1% Sucralose; 0.1% decongestant; US 8,758,816 B2 45 46 About 0.15% azelastine, about 0.05% steroid and about About 0.05% azelastine, about 0.05% steroid, about 0.1% 0.1% decongestant; decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.1% steroid and about About 0.1% azelastine, about 0.05% steroid, about 0.1% 0.1% decongestant; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.1% steroid and about 0.1% About 0.125% azelastine, about 0.05% steroid, about 0.1% decongestant; decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.1% steroid and about About 0.15% azelastine, about 0.05% steroid, about 0.1% 0.1% decongestant; decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.1% steroid and about About 0.05% azelastine, about 0.1% steroid, about 0.1% 0.1% decongestant; 10 decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.01% steroid and about About 0.1% azelastine, about 0.1% steroid, about 0.1% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.01% steroid and about About 0.125% azelastine, about 0.1% steroid, about 0.1% 0.5% decongestant; 15 decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.01% steroid and about About 0.15% azelastine, about 0.1% steroid, about 0.1% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.01% steroid and about About 0.05% azelastine, about 0.01% steroid, about 0.5% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.05% steroid and about About 0.1% azelastine, about 0.01% steroid, about 0.5% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.05% steroid and about About 0.125% azelastine, about 0.01% steroid, about 0.5% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.05% steroid and about About 0.15% azelastine, about 0.01% steroid, about 0.5% 0.5% decongestant; 25 decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.05% steroid and about About 0.05% azelastine, about 0.05% steroid, about 0.5% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.1% steroid and about About 0.1% azelastine, about 0.05% steroid, about 0.5% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.1% steroid and about 0.5% 30 About 0.125% azelastine, about 0.05% steroid, about 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.1% steroid and about About 0.15% azelastine, about 0.05% steroid, about 0.5% 0.5% decongestant; decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.1% steroid and about About 0.05% azelastine, about 0.1% steroid, about 0.5% 0.5% decongestant; 35 decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.01% steroid and about About 0.1% azelastine, about 0.1% steroid, about 0.5% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.01% steroid and about About 0.125% azelastine, about 0.1% steroid, about 0.5% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.01% steroid and about 40 About 0.15% azelastine, about 0.1% steroid, about 0.5% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.01% steroid and about About 0.05% azelastine, about 0.01% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.05% steroid and about About 0.1% azelastine, about 0.01% steroid, about 1.0% 1.0% decongestant; 45 decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.05% steroid and about About 0.125% azelastine, about 0.01% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.05% steroid and about About 0.15% azelastine, about 0.01% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.05% steroid and about 50 About 0.05% azelastine, about 0.05% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.1% steroid and about About 0.1% azelastine, about 0.05% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.1% steroid and about 1.0% About 0.125% azelastine, about 0.05% steroid, about 1.0% decongestant; 55 decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.1% steroid and about About 0.15% azelastine, about 0.05% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.1% steroid and about About 0.05% azelastine, about 0.1% steroid, about 1.0% 1.0% decongestant; decongestant and about 0.05% sucralose; About 0.05% azelastine, about 0.01% steroid, about 0.1% 60 About 0.1% azelastine, about 0.1% steroid, about 1.0% decongestant and about 0.05% sucralose; decongestant and about 0.05% sucralose; About 0.1% azelastine, about 0.01% steroid, about 0.1% About 0.125% azelastine, about 0.1% steroid, about 1.0% decongestant and about 0.05% sucralose; decongestant and about 0.05% sucralose; About 0.125% azelastine, about 0.01% steroid, about 0.1% About 0.15% azelastine, about 0.1% steroid, about 1.0% decongestant and about 0.05% sucralose; 65 decongestant and about 0.05% sucralose; About 0.15% azelastine, about 0.01% steroid, about 0.1% About 0.05% azelastine, about 0.01% steroid, about 0.1% decongestant and about 0.05% sucralose; decongestant and about 0.1% Sucralose; US 8,758,816 B2 47 48 About 0.1% azelastine, about 0.01% steroid, about 0.1% About 0.125% azelastine, about 0.1% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.1% Sucralose; About 0.125% azelastine, about 0.01% steroid, about 0.1% About 0.15% azelastine, about 0.1% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.1% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 0.1% About 0.05% azelastine, about 0.01% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.05% steroid, about 0.1% About 0.1% azelastine, about 0.01% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.05% steroid, about 0.1% About 0.125% azelastine, about 0.01% steroid, about 0.1% decongestant and about 0.1% Sucralose; 10 decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.05% steroid, about 0.1% About 0.15% azelastine, about 0.01% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.05% steroid, about 0.1% About 0.05% azelastine, about 0.05% steroid, about 0.1% decongestant and about 0.1% Sucralose; 15 decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.1% steroid, about 0.1% About 0.1% azelastine, about 0.05% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.1% steroid, about 0.1% About 0.125% azelastine, about 0.05% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.1% steroid, about 0.1% About 0.15% azelastine, about 0.05% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.1% steroid, about 0.1% About 0.05% azelastine, about 0.1% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.01% steroid, about 0.5% About 0.1% azelastine, about 0.1% steroid, about 0.1% decongestant and about 0.1% Sucralose; 25 decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.01% steroid, about 0.5% About 0.125% azelastine, about 0.1% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.01% steroid, about 0.5% About 0.15% azelastine, about 0.1% steroid, about 0.1% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 0.5% 30 About 0.05% azelastine, about 0.01% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.05% steroid, about 0.5% About 0.1% azelastine, about 0.01% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.05% steroid, about 0.5% About 0.125% azelastine, about 0.01% steroid, about 0.5% decongestant and about 0.1% Sucralose; 35 decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.05% steroid, about 0.5% About 0.15% azelastine, about 0.01% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.05% steroid, about 0.5% About 0.05% azelastine, about 0.05% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.1% steroid, about 0.5% 40 About 0.1% azelastine, about 0.05% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.1% steroid, about 0.5% About 0.125% azelastine, about 0.05% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.1% steroid, about 0.5% About 0.15% azelastine, about 0.05% steroid, about 0.5% decongestant and about 0.1% Sucralose; 45 decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.1% steroid, about 0.5% About 0.05% azelastine, about 0.1% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.01% steroid, about 1.0% About 0.1% azelastine, about 0.1% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.01% steroid, about 1.0% 50 About 0.125% azelastine, about 0.1% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.01% steroid, about 1.0% About 0.15% azelastine, about 0.1% steroid, about 0.5% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 1.0% About 0.05% azelastine, about 0.01% steroid, about 1.0% decongestant and about 0.1% Sucralose; 55 decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.05% steroid, about 1.0% About 0.1% azelastine, about 0.01% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.05% steroid, about 1.0% About 0.125% azelastine, about 0.01% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.05% steroid, about 1.0% 60 About 0.15% azelastine, about 0.01% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.15% azelastine, about 0.05% steroid, about 1.0% About 0.05% azelastine, about 0.05% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; About 0.05% azelastine, about 0.1% steroid, about 1.0% About 0.1% azelastine, about 0.05% steroid, about 1.0% decongestant and about 0.1% Sucralose; 65 decongestant and about 0.15% Sucralose; About 0.1% azelastine, about 0.1% steroid, about 1.0% About 0.125% azelastine, about 0.05% steroid, about 1.0% decongestant and about 0.1% Sucralose; decongestant and about 0.15% Sucralose; US 8,758,816 B2 49 50 About 0.15% azelastine, about 0.05% steroid, about 1.0% like), mometasone, dexamethasone beloxil, loteprednol (e.g., decongestant and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.05% azelastine, about 0.1% steroid, about 1.0% about 0.1% pseudoephedrine or phenylephrine; decongestant and about 0.15% Sucralose; About 0.125% azelastine, about 0.1% fluticasone (e.g., About 0.1% azelastine, about 0.1% steroid, about 1.0% fluticasone propionate, fluticasone dipropionate, fluticaSone decongestant and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.1% steroid, about 1.0% like), mometasone, dexamethasone beloxil, loteprednol (e.g., decongestant and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.15% azelastine, about 0.1% steroid, about 1.0% about 0.1% pseudoephedrine or phenylephrine; decongestant and about 0.15% Sucralose; 10 About 0.15% azelastine, about 0.1% fluticasone (e.g., flu About 0.05% azelastine, about 0.01% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticaSone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and 15 about 0.1% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu fluticasone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.125% azelastine, about 0.01% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticaSone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.125% azelastine, about 0.01% fluticasone (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticasone dipropionate, fluticaSone fluticasone propionate, fluticaSone dipropionate, fluticaSone 30 furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., 35 fluticasone propionate, fluticasone dipropionate, fluticaSone fluticasone propionate, fluticaSone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; 40 About 0.05% azelastine, about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and 45 about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.125% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticaSone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticasone dipropionate, fluticaSone fluticasone propionate, fluticaSone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the 55 like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.05%azelastine, about 0.1% fluticasone (e.g., flu fluticasone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone 60 furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% pseudoephedrine or phenylephrine; about 0.1% pseudoephedrine or phenylephrine; About 0.05% azelastine, about 0.1% fluticasone (e.g., flu About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 65 ticasone propionate, fluticaSone dipropionate, fluticasone casone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 51 52 loteprednol etabonate), budesonide, or triamcinolone and like), mometasone, dexamethasone beloxil, loteprednol (e.g., about 0.5% pseudoephedrine or phenylephrine; loteprednol etabonate), budesonide, or triamcinolone and About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti about 1.0% pseudoephedrine or phenylephrine; casone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti furoate, fluticasone maleate, fluticasone Valerate, and the casone propionate, fluticasone dipropionate, fluticaSone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone and like), mometasone, dexamethasone beloxil, loteprednol (e.g., about 0.5% pseudoephedrine or phenylephrine; loteprednol etabonate), budesonide, or triamcinolone and About 0.125% azelastine, about 0.1% fluticasone (e.g., about 1.0% pseudoephedrine or phenylephrine; fluticasone propionate, fluticaSone dipropionate, fluticaSone 10 About 0.125% azelastine, about 0.1% fluticasone (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the fluticasone propionate, fluticasone dipropionate, fluticaSone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone and like), mometasone, dexamethasone beloxil, loteprednol (e.g., about 0.5% pseudoephedrine or phenylephrine; loteprednol etabonate), budesonide, or triamcinolone and About 0.15% azelastine, about 0.1% fluticasone (e.g., flu 15 about 1.0% pseudoephedrine or phenylephrine; ticasone propionate, fluticaSone dipropionate, fluticasone About 0.15% azelastine, about 0.1% fluticasone (e.g., flu furoate, fluticasone maleate, fluticasone Valerate, and the ticasone propionate, fluticaSone dipropionate, fluticasone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone and like), mometasone, dexamethasone beloxil, loteprednol (e.g., about 0.5% pseudoephedrine or phenylephrine; loteprednol etabonate), budesonide, or triamcinolone and About 0.05% azelastine, about 0.01% fluticasone (e.g., about 1.0% pseudoephedrine or phenylephrine; fluticasone propionate, fluticaSone dipropionate, fluticaSone About 0.05% azelastine, about 0.01% fluticasone (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the fluticasone propionate, fluticasone dipropionate, fluticaSone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone and 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., about 1.0% pseudoephedrine or phenylephrine; loteprednol etabonate), budesonide, or triamcinolone, about About 0.1% azelastine, about 0.01% fluticasone (e.g., flu 0.1% pseudoephedrine or phenylephrine and about 0.05% ticasone propionate, fluticaSone dipropionate, fluticasone Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.01% fluticasone (e.g., flu like), mometasone, dexamethasone beloxil, loteprednol (e.g., 30 ticasone propionate, fluticaSone dipropionate, fluticasone loteprednol etabonate), budesonide, or triamcinolone and furoate, fluticasone maleate, fluticasone Valerate, and the about 1.0% pseudoephedrine or phenylephrine: like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the 35 Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone and fluticasone propionate, fluticasone dipropionate, fluticaSone about 1.0% pseudoephedrine or phenylephrine; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.01% fluticasone, like), mometasone, dexamethasone beloxil, loteprednol (e.g., mometasone, dexamethasone beloxil, loteprednol (e.g., 40 loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone and 0.1% pseudoephedrine or phenylephrine and about 0.05% about 1.0% pseudoephedrine or phenylephrine; Sucralose; About 0.05% azelastine, about 0.05% fluticasone (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 45 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone, about about 1.0% pseudoephedrine or phenylephrine; 0.1% pseudoephedrine or phenylephrine and about 0.05% About 0.1% azelastine, about 0.05% fluticasone, mometa Sucralose; Sone, dexamethasone beloxil, loteprednol (e.g., loteprednol 50 About 0.05% azelastine, about 0.05% fluticasone (e.g., etabonate), budesonide, or triamcinolone and about 1.0% fluticasone propionate, fluticasone dipropionate, fluticaSone pseudoephedrine or phenylephrine; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.05% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 55 0.1% pseudoephedrine or phenylephrine and about 0.05% like), mometasone, dexamethasone beloxil, loteprednol (e.g., Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.1% azelastine, about 0.05% fluticasone (e.g., flu about 1.0% pseudoephedrine or phenylephrine; ticasone propionate, fluticaSone dipropionate, fluticasone About 0.15% azelastine, about 0.05% fluticasone (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the fluticasone propionate, fluticaSone dipropionate, fluticaSone 60 like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% pseudoephedrine or phenylephrine and about 0.05% loteprednol etabonate), budesonide, or triamcinolone and Sucralose; about 1.0% pseudoephedrine or phenylephrine; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.05%azelastine, about 0.1% fluticasone (e.g., flu 65 fluticasone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 53 54 loteprednol etabonate), budesonide, or triamcinolone, about About 0.05% azelastine, about 0.05% fluticasone (e.g., 0.1% pseudoephedrine or phenylephrine and about 0.05% fluticasone propionate, fluticasone dipropionate, fluticaSone Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.05% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 0.5% pseudoephedrine or phenylephrine and about 0.05% like), mometasone, dexamethasone beloxil, loteprednol (e.g., Sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.1% azelastine, about 0.05% fluticasone (e.g., flu 0.1% pseudoephedrine or phenylephrine and about 0.05% ticasone propionate, fluticaSone dipropionate, fluticasone 10 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05%azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 15 About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about 30 ticasone propionate, fluticaSone dipropionate, fluticasone 0.1% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the 35 Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., 40 loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.05% 45 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 About 0.15% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 55 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 60 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about 65 ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 55 56 loteprednol etabonate), budesonide, or triamcinolone, about About 0.15% azelastine, about 0.1% fluticasone (e.g., flu 1.0% pseudoephedrine or phenylephrine and about 0.05% ticasone propionate, fluticaSone dipropionate, fluticasone Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.01% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 1.0% pseudoephedrine or phenylephrine and about 0.05% like), mometasone, dexamethasone beloxil, loteprednol (e.g., Sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.05% azelastine, about 0.01% fluticasone (e.g., 1.0% pseudoephedrine or phenylephrine and about 0.05% fluticasone propionate, fluticasone dipropionate, fluticaSone 10 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 15 About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 30 fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the 35 Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., 40 loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.05% 45 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05%azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 55 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 60 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about 65 ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.05% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 57 58 loteprednol etabonate), budesonide, or triamcinolone, about About 0.125% azelastine, about 0.05% fluticasone (e.g., 0.1% pseudoephedrine or phenylephrine and about 0.1% fluticasone propionate, fluticasone dipropionate, fluticaSone Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti like), mometasone, dexamethasone beloxil, loteprednol (e.g., casone propionate, fluticasone dipropionate, fluticaSone 5 loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 0.5% pseudoephedrine or phenylephrine or phenylephrine like), mometasone, dexamethasone beloxil, loteprednol (e.g., and about 0.1% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.15% azelastine, about 0.50% fluticasone (e.g., 0.1% pseudoephedrine or phenylephrine and about 0.1% fluticasone propionate, fluticasone dipropionate, fluticaSone 10 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 15 About 0.05% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 30 fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine or phenylephrine furoate, fluticasone maleate, fluticasone Valerate, and the 35 and about 0.1% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., 40 loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine or phenylephrine 45 furoate, fluticasone maleate, fluticasone Valerate, and the and about 0.1% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 55 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 60 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 65 fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 59 60 loteprednol etabonate), budesonide, or triamcinolone, about About 0.1% azelastine, about 0.01% fluticasone (e.g., flu 1.0% pseudoephedrine or phenylephrine and about 0.1% ticasone propionate, fluticaSone dipropionate, fluticasone Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05% azelastine, about 0.05% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone 5 loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 0.1% pseudoephedrine or phenylephrine and about 0.15% like), mometasone, dexamethasone beloxil, loteprednol (e.g., Sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.125% azelastine, about 0.01% fluticasone (e.g., 1.0% pseudoephedrine or phenylephrine and about 0.1% fluticasone propionate, fluticasone dipropionate, fluticaSone 10 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 15 About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about 30 ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05%azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the 35 Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 40 loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.1% 45 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 About 0.05% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 55 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 60 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 65 fluticasone propionate, fluticasone dipropionate, fluticaSone 0.1% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 61 62 loteprednol etabonate), budesonide, or triamcinolone, about About 0.05% azelastine, about 0.1% fluticasone (e.g., flu 0.1% pseudoephedrine or phenylephrine and about 0.15% ticasone propionate, fluticaSone dipropionate, fluticasone Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.1% fluticasone (e.g., flu like), mometasone, dexamethasone beloxil, loteprednol (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 0.5% pseudoephedrine or phenylephrine and about 0.15% like), mometasone, dexamethasone beloxil, loteprednol (e.g., Sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 0.1% pseudoephedrine or phenylephrine and about 0.15% casone propionate, fluticasone dipropionate, fluticaSone 10 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 15 About 0.125% azelastine, about 0.1% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 30 fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the 35 Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., 40 loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% 45 furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 1.0% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 55 1.0% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; 60 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticaSone dipropionate, fluticaSone 1.0% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about 65 ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% pseudoephedrine or phenylephrine and about 0.15% furoate, fluticasone maleate, fluticasone Valerate, and the Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 63 64 loteprednol etabonate), budesonide, or triamcinolone, about About 0.15% azelastine, about 0.1% steroid and about 1.0% pseudoephedrine or phenylephrine and about 0.15% 0.1% leukotriene antagonist; Sucralose; About 0.05% azelastine, about 0.01% steroid and about About 0.125% azelastine, about 0.05% fluticasone (e.g., 0.5% leukotriene antagonist; fluticasone propionate, fluticaSone dipropionate, fluticaSone About 0.1% azelastine, about 0.01% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.5% leukotriene antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% steroid and about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% leukotriene antagonist; 1.0% pseudoephedrine or phenylephrine and about 0.15% About 0.15% azelastine, about 0.01% steroid and about Sucralose; 10 About 0.15% azelastine, about 0.05% fluticasone (e.g., 0.5% leukotriene antagonist; fluticasone propionate, fluticaSone dipropionate, fluticaSone About 0.05% azelastine, about 0.05% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.5% leukotriene antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% steroid and about loteprednol etabonate), budesonide, or triamcinolone, about 15 0.5% leukotriene antagonist; 1.0% pseudoephedrine or phenylephrine and about 0.15% About 0.125% azelastine, about 0.05% steroid and about Sucralose; 0.5% leukotriene antagonist; About 0.05%azelastine, about 0.1% fluticasone (e.g., flu About 0.15% azelastine, about 0.05% steroid and about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% leukotriene antagonist; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05% azelastine, about 0.1% steroid and about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.5% leukotriene antagonist; loteprednol etabonate), budesonide, or triamcinolone, about About 0.1% azelastine, about 0.1% steroid and about 0.5% 1.0% pseudoephedrine or phenylephrine and about 0.15% leukotriene antagonist; Sucralose; About 0.125% azelastine, about 0.1% steroid and about About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 25 0.5% leukotriene antagonist; casone propionate, fluticasone dipropionate, fluticaSone About 0.15% azelastine, about 0.1% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 0.5% leukotriene antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.01% steroid and about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% leukotriene antagonist; 1.0% pseudoephedrine or phenylephrine and about 0.15% 30 About 0.1% azelastine, about 0.01% steroid and about Sucralose; 5.0% leukotriene antagonist; About 0.125% azelastine, about 0.1% fluticasone (e.g., About 0.125% azelastine, about 0.01% steroid and about fluticasone propionate, fluticaSone dipropionate, fluticaSone 5.0% leukotriene antagonist; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.01% steroid and about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 35 5.0% leukotriene antagonist; loteprednol etabonate), budesonide, or triamcinolone, about About 0.05% azelastine, about 0.05% steroid and about 1.0% pseudoephedrine or phenylephrine and about 0.15% 5.0% leukotriene antagonist; Sucralose; About 0.1% azelastine, about 0.05% steroid and about About 0.15% azelastine, about 0.1% fluticasone (e.g., flu 5.0% leukotriene antagonist; ticasone propionate, fluticaSone dipropionate, fluticasone 40 About 0.125% azelastine, about 0.05% steroid and about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% leukotriene antagonist; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.05% steroid and about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% leukotriene antagonist; 1.0% pseudoephedrine or phenylephrine and about 0.15% About 0.05% azelastine, about 0.1% steroid and about Sucralose; 45 5.0% leukotriene antagonist; About 0.05% azelastine, about 0.01% steroid and about About 0.1% azelastine, about 0.1% steroid and about 5.0% 0.1% leukotriene antagonist; leukotriene antagonist; About 0.1% azelastine, about 0.01% steroid and about About 0.125% azelastine, about 0.1% steroid and about 0.1% leukotriene antagonist; 5.0% leukotriene antagonist; About 0.125% azelastine, about 0.01% steroid and about 50 About 0.15% azelastine, about 0.1% steroid and about 0.1% leukotriene antagonist; 5.0% leukotriene antagonist; About 0.15% azelastine, about 0.01% steroid and about About 0.05% azelastine, about 0.01% steroid, about 0.1% 0.1% leukotriene antagonist; leukotriene antagonist and about 0.05% sucralose; About 0.05% azelastine, about 0.05% steroid and about About 0.1% azelastine, about 0.01% steroid, about 0.1% 0.1% leukotriene antagonist; 55 leukotriene antagonist and about 0.05% sucralose; About 0.1% azelastine, about 0.05% steroid and about About 0.125% azelastine, about 0.01% steroid, about 0.1% 0.1% leukotriene antagonist; leukotriene antagonist and about 0.05% sucralose; About 0.125% azelastine, about 0.05% steroid and about About 0.15% azelastine, about 0.01% steroid, about 0.1% 0.1% leukotriene antagonist; leukotriene antagonist and about 0.05% sucralose; About 0.15% azelastine, about 0.05% steroid and about 60 About 0.05% azelastine, about 0.05% steroid, about 0.1% 0.1% leukotriene antagonist; leukotriene antagonist and about 0.05% sucralose; About 0.05% azelastine, about 0.1% steroid and about About 0.1% azelastine, about 0.05% steroid, about 0.1% 0.1% leukotriene antagonist; leukotriene antagonist and about 0.05% sucralose; About 0.1% azelastine, about 0.1% steroid and about 0.1% About 0.125% azelastine, about 0.05% steroid, about 0.1% leukotriene antagonist; 65 leukotriene antagonist and about 0.05% sucralose; About 0.125% azelastine, about 0.1% steroid and about About 0.15% azelastine, about 0.05% steroid, about 0.1% 0.1% leukotriene antagonist; leukotriene antagonist and about 0.05% sucralose; US 8,758,816 B2 65 66 About 0.05% azelastine, about 0.1% steroid, about 0.1% About 0.1% azelastine, about 0.05% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.1% steroid, about 0.1% About 0.125% azelastine, about 0.05% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.1% steroid, about 0.1% About 0.15% azelastine, about 0.05% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.1% steroid, about 0.1% About 0.05% azelastine, about 0.1% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.01% steroid, about 0.5% About 0.1% azelastine, about 0.1% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; 10 leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.01% steroid, about 0.5% About 0.125% azelastine, about 0.1% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.01% steroid, about 0.5% About 0.15% azelastine, about 0.1% steroid, about 0.1% leukotriene antagonist and about 0.05% sucralose; 15 leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 0.5% About 0.05% azelastine, about 0.01% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.05% steroid, about 0.5% About 0.1% azelastine, about 0.01% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.05% steroid, about 0.5% About 0.125% azelastine, about 0.01% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.05% steroid, about 0.5% About 0.15% azelastine, about 0.01% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.05% steroid, about 0.5% About 0.05% azelastine, about 0.05% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; 25 leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.1% steroid, about 0.5% About 0.1% azelastine, about 0.05% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.1% steroid, about 0.5% About 0.125% azelastine, about 0.05% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.1% steroid, about 0.5% 30 About 0.15% azelastine, about 0.05% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.1% steroid, about 0.5% About 0.05% azelastine, about 0.1% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.01% steroid, about 5.0% About 0.1% azelastine, about 0.1% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; 35 leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.01% steroid, about 5.0% About 0.125% azelastine, about 0.1% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.01% steroid, about 5.0% About 0.15% azelastine, about 0.1% steroid, about 0.5% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 5.0% 40 About 0.05% azelastine, about 0.01% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.05% steroid, about 5.0% About 0.1% azelastine, about 0.01% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.05% steroid, about 5.0% About 0.125% azelastine, about 0.01% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; 45 leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.05% steroid, about 5.0% About 0.15% azelastine, about 0.01% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.05% steroid, about 5.0% About 0.05% azelastine, about 0.05% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.1% steroid, about 5.0% 50 About 0.1% azelastine, about 0.05% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.1% steroid, about 5.0% About 0.125% azelastine, about 0.05% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.1% steroid, about 5.0% About 0.15% azelastine, about 0.05% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; 55 leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.1% steroid, about 5.0% About 0.05% azelastine, about 0.1% steroid, about 5.0% leukotriene antagonist and about 0.05% sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.05% azelastine, about 0.01% steroid, about 0.1% About 0.1% azelastine, about 0.1% steroid, about 5.0% leukotriene antagonist and about 0.1% Sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.1% azelastine, about 0.01% steroid, about 0.1% 60 About 0.125% azelastine, about 0.1% steroid, about 5.0% leukotriene antagonist and about 0.1% Sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.125% azelastine, about 0.01% steroid, about 0.1% About 0.15% azelastine, about 0.1% steroid, about 5.0% leukotriene antagonist and about 0.1% Sucralose; leukotriene antagonist and about 0.1% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 0.1% About 0.05% azelastine, about 0.01% steroid, about 0.1% leukotriene antagonist and about 0.1% Sucralose; 65 leukotriene antagonist and about 0.15% Sucralose; About 0.05% azelastine, about 0.05% steroid, about 0.1% About 0.1% azelastine, about 0.01% steroid, about 0.1% leukotriene antagonist and about 0.1% Sucralose; leukotriene antagonist and about 0.15% Sucralose; US 8,758,816 B2 67 68 About 0.125% azelastine, about 0.01% steroid, about 0.1% About 0.15% azelastine, about 0.1% steroid, about 5.0% leukotriene antagonist and about 0.15% Sucralose; leukotriene antagonist and about 0.15% Sucralose; About 0.15% azelastine, about 0.01% steroid, about 0.1% About 0.05% azelastine, about 0.01% fluticasone (e.g., leukotriene antagonist and about 0.15% Sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.05% azelastine, about 0.05% steroid, about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the leukotriene antagonist and about 0.15% Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% steroid, about 0.1% loteprednol etabonate), budesonide, or triamcinolone and leukotriene antagonist and about 0.15% Sucralose; about 0.1% montelukast; About 0.125% azelastine, about 0.05% steroid, about 0.1% About 0.1% azelastine, about 0.01% fluticasone (e.g., flu leukotriene antagonist and about 0.15% Sucralose; 10 ticasone propionate, fluticaSone dipropionate, fluticasone About 0.15% azelastine, about 0.05% steroid, about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the leukotriene antagonist and about 0.15% Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.1% steroid, about 0.1% loteprednol etabonate), budesonide, or triamcinolone and leukotriene antagonist and about 0.15% Sucralose; 15 about 0.1% montelukast; About 0.1% azelastine, about 0.1% steroid, about 0.1% About 0.125% azelastine, about 0.01% fluticasone (e.g., leukotriene antagonist and about 0.15% Sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.125% azelastine, about 0.1% steroid, about 0.1% furoate, fluticasone maleate, fluticasone Valerate, and the leukotriene antagonist and about 0.15% Sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.1% steroid, about 0.1% loteprednol etabonate), budesonide, or triamcinolone and leukotriene antagonist and about 0.15% Sucralose; about 0.1% montelukast; About 0.05% azelastine, about 0.01% steroid, about 0.5% About 0.15% azelastine, about 0.01% fluticasone (e.g., leukotriene antagonist and about 0.15% Sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine, about 0.01% steroid, about 0.5% furoate, fluticasone maleate, fluticasone Valerate, and the leukotriene antagonist and about 0.15% Sucralose; 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.01% steroid, about 0.5% loteprednol etabonate), budesonide, or triamcinolone and leukotriene antagonist and about 0.15% Sucralose; about 0.1% montelukast; About 0.15% azelastine, about 0.01% steroid, about 0.5% About 0.05% azelastine, about 0.05% fluticasone (e.g., leukotriene antagonist and about 0.15% Sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.05% azelastine, about 0.05% steroid, about 0.5% 30 leukotriene antagonist and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.05% steroid, about 0.5% like), mometasone, dexamethasone beloxil, loteprednol (e.g., leukotriene antagonist and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.125% azelastine, about 0.05% steroid, about 0.5% about 0.1% montelukast; leukotriene antagonist and about 0.15% Sucralose; 35 About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.15% azelastine, about 0.05% steroid, about 0.5% ticasone propionate, fluticaSone dipropionate, fluticasone leukotriene antagonist and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05% azelastine, about 0.1% steroid, about 0.5% like), mometasone, dexamethasone beloxil, loteprednol (e.g., leukotriene antagonist and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.1% azelastine, about 0.1% steroid, about 0.5% 40 about 0.1% montelukast; leukotriene antagonist and about 0.15% Sucralose; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.1% steroid, about 0.5% fluticasone propionate, fluticasone dipropionate, fluticaSone leukotriene antagonist and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.1% steroid, about 0.5% like), mometasone, dexamethasone beloxil, loteprednol (e.g., leukotriene antagonist and about 0.15% Sucralose; 45 loteprednol etabonate), budesonide, or triamcinolone and About 0.05% azelastine, about 0.01% steroid, about 5.0% about 0.1% montelukast; leukotriene antagonist and about 0.15% Sucralose; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.01% steroid, about 5.0% fluticasone propionate, fluticasone dipropionate, fluticaSone leukotriene antagonist and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.01% steroid, about 5.0% 50 like), mometasone, dexamethasone beloxil, loteprednol (e.g., leukotriene antagonist and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.15% azelastine, about 0.01% steroid, about 5.0% about 0.1% montelukast; leukotriene antagonist and about 0.15% Sucralose; About 0.05% azelastine, about 0.1% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% steroid, about 5.0% ticasone propionate, fluticaSone dipropionate, fluticasone leukotriene antagonist and about 0.15% Sucralose; 55 furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.05% steroid, about 5.0% like), mometasone, dexamethasone beloxil, loteprednol (e.g., leukotriene antagonist and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.125% azelastine, about 0.05% steroid, about 5.0% about 0.1% montelukast; leukotriene antagonist and about 0.15% Sucralose; About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti About 0.15% azelastine, about 0.05% steroid, about 5.0% 60 casone propionate, fluticasone dipropionate, fluticaSone leukotriene antagonist and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05% azelastine, about 0.1% steroid, about 5.0% like), mometasone, dexamethasone beloxil, loteprednol (e.g., leukotriene antagonist and about 0.15% Sucralose; loteprednol etabonate), budesonide, or triamcinolone and About 0.1% azelastine, about 0.1% steroid, about 5.0% about 0.1% montelukast; leukotriene antagonist and about 0.15% Sucralose; 65 About 0.125% azelastine, about 0.1% fluticasone (e.g., About 0.125% azelastine, about 0.1% steroid, about 5.0% fluticasone propionate, fluticasone dipropionate, fluticaSone leukotriene antagonist and about 0.15% Sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the US 8,758,816 B2 69 70 like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.1% montelukast; about 0.5% montelukast; About 0.15% azelastine, about 0.1% fluticasone (e.g., flu About 0.125% azelastine, about 0.1% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.1% montelukast; about 0.5% montelukast; About 0.05% azelastine, about 0.01% fluticasone (e.g., 10 About 0.15% azelastine, about 0.1% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and 15 loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 0.5% montelukast; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.05% azelastine, about 0.01% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.125% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the 25 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone 30 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.05% azelastine, about 0.05% fluticasone (e.g., 35 About 0.15% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; 40 about 5.0% montelukast; About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and 45 loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 50 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 55 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.05%azelastine, about 0.1% fluticasone (e.g., flu About 0.15% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone 60 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone and about 0.5% montelukast; about 5.0% montelukast; About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 65 About 0.05% azelastine, about 0.1% fluticasone (e.g., flu casone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the US 8,758,816 B2 71 72 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone and 0.1% montelukast and about 0.05% sucralose; about 5.0% montelukast; About 0.05% azelastine, about 0.1% fluticasone (e.g., flu About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti ticasone propionate, fluticaSone dipropionate, fluticasone casone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone and 0.1% montelukast and about 0.05% sucralose; about 5.0% montelukast; About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti About 0.125% azelastine, about 0.1% fluticasone (e.g., 10 fluticasone propionate, fluticaSone dipropionate, fluticaSone casone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone, about about 5.0% montelukast; 15 0.1% montelukast and about 0.05% sucralose; About 0.15% azelastine, about 0.1% fluticasone (e.g., flu About 0.125% azelastine, about 0.1% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone and loteprednol etabonate), budesonide, or triamcinolone, about about 5.0% montelukast; 0.1% montelukast and about 0.05% sucralose; About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 0.1% montelukast and about 0.05% sucralose; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.05% azelastine, about 0.01% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 30 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 0.5% montelukast and about 0.05% sucralose; About 0.125% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone 35 ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 0.5% montelukast and about 0.05% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., 40 About 0.125% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 45 0.5% montelukast and about 0.05% sucralose; About 0.05% azelastine, about 0.05% fluticasone (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 50 loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 0.5% montelukast and about 0.05% sucralose; About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 55 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 0.5% montelukast and about 0.05% sucralose; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the 60 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.05% sucralose; 0.5% montelukast and about 0.05% sucralose; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone 65 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 73 74 loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.05% sucralose; 5.0% montelukast and about 0.05% sucralose; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.05% sucralose; 5.0% montelukast and about 0.05% sucralose; About 0.05%azelastine, about 0.1% fluticasone (e.g., flu About 0.15% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone 10 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.05% sucralose; 15 5.0% montelukast and about 0.05% sucralose; About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti About 0.05% azelastine, about 0.1% fluticasone (e.g., flu casone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.05% sucralose; 5.0% montelukast and about 0.05% sucralose; About 0.125% azelastine, about 0.1% fluticasone (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti fluticasone propionate, fluticaSone dipropionate, fluticaSone casone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.05% sucralose; 5.0% montelukast and about 0.05% sucralose; About 0.15% azelastine, about 0.1% fluticasone (e.g., flu About 0.125% azelastine, about 0.1% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 30 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.05% sucralose; 5.0% montelukast and about 0.05% sucralose; About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone 35 ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.05% sucralose; 5.0% montelukast and about 0.05% sucralose; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu 40 About 0.05% azelastine, about 0.01% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.05% sucralose; 45 0.1% montelukast and about 0.1% sucralose; About 0.125% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 50 loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.05% sucralose; 0.1% montelukast and about 0.1% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 55 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.05% sucralose; 0.1% montelukast and about 0.1% sucralose; About 0.05% azelastine, about 0.05% fluticasone (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the 60 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.05% sucralose; 0.1% montelukast and about 0.1% sucralose; About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone 65 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 75 76 loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone 10 ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 15 0.5% montelukast and about 0.1% sucralose; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.05%azelastine, about 0.1% fluticasone (e.g., flu About 0.15% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti About 0.05% azelastine, about 0.1% fluticasone (e.g., flu casone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the 30 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.125% azelastine, about 0.1% fluticasone (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti fluticasone propionate, fluticaSone dipropionate, fluticaSone 35 casone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.15% azelastine, about 0.1% fluticasone (e.g., flu 40 About 0.125% azelastine, about 0.1% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.1% montelukast and about 0.1% sucralose; 45 0.5% montelukast and about 0.1% sucralose; About 0.05% azelastine, about 0.01% fluticasone (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 50 loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.1% sucralose; 0.5% montelukast and about 0.1% sucralose; About 0.1% azelastine, about 0.01% fluticasone (e.g., flu About 0.05% azelastine, about 0.01% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 55 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.1% sucralose; 5.0% montelukast and about 0.1% sucralose; About 0.125% azelastine, about 0.01% fluticasone (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the 60 furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 0.5% montelukast and about 0.1% sucralose; 5.0% montelukast and about 0.1% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone 65 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 77 78 loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.1% sucralose; 0.1% montelukast and about 0.15% sucralose; About 0.15% azelastine, about 0.01% fluticasone (e.g., About 0.125% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.1% sucralose; 0.1% montelukast and about 0.15% sucralose; About 0.05% azelastine, about 0.05% fluticasone (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone 10 fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.1% sucralose; 15 0.1% montelukast and about 0.15% sucralose; About 0.1% azelastine, about 0.05% fluticasone (e.g., flu About 0.05% azelastine, about 0.05% fluticasone (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticasone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.1% sucralose; 0.1% montelukast and about 0.15% sucralose; About 0.125% azelastine, about 0.05% fluticasone (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu fluticasone propionate, fluticaSone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.1% sucralose; 0.1% montelukast and about 0.15% sucralose; About 0.15% azelastine, about 0.05% fluticasone (e.g., About 0.125% azelastine, about 0.05% fluticasone, fluticasone propionate, fluticaSone dipropionate, fluticaSone mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the 30 loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% montelukast and about 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.15% azelastine, about 0.05% fluticasone (e.g., 5.0% montelukast and about 0.1% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.05%azelastine, about 0.1% fluticasone (e.g., flu furoate, fluticasone maleate, fluticasone Valerate, and the ticasone propionate, fluticaSone dipropionate, fluticasone 35 like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% montelukast and about 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.05% azelastine, about 0.1% fluticasone (e.g., flu 5.0% montelukast and about 0.1% sucralose; ticasone propionate, fluticaSone dipropionate, fluticasone About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 40 furoate, fluticasone maleate, fluticasone Valerate, and the casone propionate, fluticasone dipropionate, fluticaSone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% montelukast and about 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti 5.0% montelukast and about 0.1% sucralose; 45 casone propionate, fluticasone dipropionate, fluticaSone About 0.125% azelastine, about 0.1% fluticasone (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the fluticasone propionate, fluticaSone dipropionate, fluticaSone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% montelukast and about 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about 50 About 0.125% azelastine, about 0.1% fluticasone (e.g., 5.0% montelukast and about 0.1% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.15% azelastine, about 0.1% fluticasone (e.g., flu furoate, fluticasone maleate, fluticasone Valerate, and the ticasone propionate, fluticaSone dipropionate, fluticasone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 55 0.1% montelukast and about 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.15% azelastine, about 0.1% fluticasone (e.g., flu 5.0% montelukast and about 0.1% sucralose; ticasone propionate, fluticaSone dipropionate, fluticasone About 0.05% azelastine, about 0.01% fluticasone (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the fluticasone propionate, fluticaSone dipropionate, fluticaSone like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the 60 loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.1% montelukast and about 0.15% sucralose; loteprednol etabonate), budesonide, or triamcinolone, about About 0.05% azelastine, about 0.01% fluticasone (e.g., 0.1% montelukast and about 0.15% sucralose; fluticasone propionate, fluticasone dipropionate, fluticaSone About 0.1% azelastine, about 0.01% fluticasone (e.g., flu furoate, fluticasone maleate, fluticasone Valerate, and the ticasone propionate, fluticaSone dipropionate, fluticasone 65 like), mometasone, dexamethasone beloxil, loteprednol (e.g., furoate, fluticasone maleate, fluticasone Valerate, and the loteprednol etabonate), budesonide, or triamcinolone, about like), mometasone, dexamethasone beloxil, loteprednol (e.g., 0.5% montelukast and about 0.15% sucralose; US 8,758,816 B2 79 80 About 0.1% azelastine, about 0.01% fluticasone (e.g., flu like), mometasone, dexamethasone beloxil, loteprednol (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.01% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.01% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 10 About 0.125% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.01% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 15 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.15% azelastine, about 0.01% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05% azelastine, about 0.05% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.05% fluticasone (e.g., flu 25 like), mometasone, dexamethasone beloxil, loteprednol (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.05% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% montelukast and about 0.15% sucralose; 30 furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.05% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticasone dipropionate, fluticasone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.125% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about 35 fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.15% azelastine, about 0.05% fluticasone (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., fluticasone propionate, fluticaSone dipropionate, fluticaSone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., 40 About 0.15% azelastine, about 0.05% fluticasone (e.g., loteprednol etabonate), budesonide, or triamcinolone, about fluticasone propionate, fluticasone dipropionate, fluticaSone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.05%azelastine, about 0.1% fluticasone (e.g., flu like), mometasone, dexamethasone beloxil, loteprednol (e.g., ticasone propionate, fluticaSone dipropionate, fluticasone loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 45 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.05% azelastine, about 0.1% fluticasone (e.g., flu loteprednol etabonate), budesonide, or triamcinolone, about ticasone propionate, fluticaSone dipropionate, fluticasone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti like), mometasone, dexamethasone beloxil, loteprednol (e.g., casone propionate, fluticasone dipropionate, fluticaSone 50 loteprednol etabonate), budesonide, or triamcinolone, about furoate, fluticasone maleate, fluticasone Valerate, and the 5.0% montelukast and about 0.15% sucralose; like), mometasone, dexamethasone beloxil, loteprednol (e.g., About 0.1% azelastine, about 0.1% fluticasone (e.g., fluti loteprednol etabonate), budesonide, or triamcinolone, about casone propionate, fluticasone dipropionate, fluticaSone 0.5% montelukast and about 0.15% sucralose; furoate, fluticasone maleate, fluticasone Valerate, and the About 0.125% azelastine, about 0.1% fluticasone, 55 like), mometasone, dexamethasone beloxil, loteprednol (e.g., mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.15% sucralose; 0.5% montelukast and about 0.15% sucralose; About 0.125% azelastine, about 0.1% fluticasone (e.g., About 0.15% azelastine, about 0.1% fluticasone (e.g., flu fluticasone propionate, fluticasone dipropionate, fluticaSone ticasone propionate, fluticaSone dipropionate, fluticasone 60 furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., like), mometasone, dexamethasone beloxil, loteprednol (e.g., loteprednol etabonate), budesonide, or triamcinolone, about loteprednol etabonate), budesonide, or triamcinolone, about 5.0% montelukast and about 0.15% sucralose; 0.5% montelukast and about 0.15% sucralose; About 0.15% azelastine, about 0.1% fluticasone (e.g., flu About 0.05% azelastine, about 0.01% fluticasone (e.g., 65 ticasone propionate, fluticaSone dipropionate, fluticasone fluticasone propionate, fluticaSone dipropionate, fluticaSone furoate, fluticasone maleate, fluticasone Valerate, and the furoate, fluticasone maleate, fluticasone Valerate, and the like), mometasone, dexamethasone beloxil, loteprednol (e.g., US 8,758,816 B2 81 82 loteprednol etabonate), budesonide, or triamcinolone, about (e.g., magnesium Stearate), and flow agents (e.g., colloidal 5.0% montelukast and about 0.15% sucralose. silicon dioxide, such as Cab-O-Sil M5(R) available from Cabot Other suitable compositions of the invention include, for Corporation, Kokomo, Ind.). example, about 0.1%-0.15% azelastine and about 0.05%- Suitable amounts of Sweetener (e.g., Sucralose) used in the 0.15% sucralose, for example, about 0.1% azelastine and 5 chewable formulations, will be familiar to, and can be readily about 0.05%-0.15% sucralose, or about 0.125%-0.15% determined by, those skilled in the art. In certain embodi azelastine and about 0.05%-0.15% sucralose, or about 0.10% ments, the Sweetener is present in an amount from about azelastine and about 0.15% sucralose, or about 0.15%azelas 0.05% to about 5.0% (e.g., about 0.05%, about 0.1%, about tine and about 0.15% sucralose. Additional compositions of 0.125%, about 0.15%, about 0.2%, about 0.3%, about 0.4%, the invention include, for example, about 0.1%-0.15%azelas 10 about 0.5%, about 0.6%, about 0.7%, about 0.8%, about tine, about 0.05%-0.15% sucralose and about 0.1%-10% sor 0.9%, about 1%, about 1.25% about 1.5%, about 1.75%, bitol, for example, about 0.1% azelastine, about 0.05%- about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, 0.15% sucralose and about 0.1%-10% sorbitol, or about about 3.25%, about 3.5%, about 3.75%, about 4%, about 0.125%-0.15% azelastine, about 0.05%-0.15% sucralose and 15 4.25%, about 4.5%, about 4.75% or about 5%). Those or about 0.1%-10% sorbitol, or about 0.10% azelastine, about ordinary skill in the art will appreciate that the amount of 0.15% sucralose and about 0.1%-10% sorbitol, or about Sweetener may vary depending on the strength of the particu 0.15% azelastine, about 0.15% sucralose and about 0.1%- lar sweetener used and the levels approved by the regulatory 10% sorbitol. authorities for use in pharmaceutical products. Chewable and/or Orally Dissolving Formulations Suitable cyclodextrins for use in the chewable formula Chewable Formulations tions of the present invention include C, B, or Y cyclodextrins, In addition to the Solid dosage forms disclosed throughout, or an alkylated or hydroxyalkylated derivatives thereof, such the present invention also provides chewable oral formula as heptakis (2,6-di-O-methyl)-f-cyclodextrin (DIMEB), ran tions. In certain such embodiments, the formulations will domly methylated B-cyclodextrin (RAMEB), and hydrox comprise (or consist essentially of) an effective amount of 25 ypropyl B-cyclodextrin (HPBCD). A suitable cyclodextrin is aZelastine (e.g., azelastine HCl) along with Suitable excipi B-cyclodextrin (available from Cerestar USA, Inc., Ham ents that allow the formulations to be chewed by the patient. mond, Ind. or from Roquette America, Inc., Keokuk. IA under In additional embodiments, the formulations can further the trade name KleptoseTM). If desired, the complex of the comprise one or more taste-masking or Sweetening agents, active Substance with cyclodextrin can be prepared in Such as those described herein. In one embodiment, Sucralose advance, for example, by malaxating or granulating the is used in the chewable formulations. Additional active azelastine and any additional active substance(s) and the agents, such as those described herein, can also optionally be cyclodextrin in the presence of water, or by preparing an added to the chewable formulations. The amounts of azelas aqueous solution containing the azelastine and any additional tine, other optional active agents (e.g., Steroids, deconges 35 active Substance(s) and the cyclodextrin in the desired molar tants, leukotriene antagonists, and combinations thereof), and ratio. Alternatively, the azelastine and any additional active Sweetening agents (e.g., Sucralose) in the chewable formula Substance(s) and the cyclodextrin can be simply mixed with tions of the present invention are readily determinable by other excipients and adjuvants. The molar ratio of the azelas those of ordinary skill in the art, and include those amounts tine and any additional active Substance(s) to cyclodextrin is and combinations described herein. For example, the chew 40 suitably from about 1.0:1.0 to about 4.0:1.0. able formulations of the present invention comprise (or con A typical manufacturing process for making either a single sist essentially of) about 0.05% to about 5% azelastine, layer or bi-layer chewable tablet generally involves blending optionally about 0.01% to about 10% other active agent(s) (or of the desired ingredients to form a uniform distribution of the more as required), and about 0.05% to about 0.15% sucralose. aZelastine (and any other active agent(s)), excipients (e.g., Such chewable formulations are especially useful in patient 45 colorants and flavoring agents as well as others). If desired, an populations where compliance is an issue. Such as children, inclusion complex of the azelastine and any other active agent the elderly, and patients who may have difficulty swallowing (s) and cyclodextrin (e.g., B-cyclodextrin) may be formed or using spray/inhalable formulations. prior to blending into the mixture by malaxating the azelas The formulations may also contain colorants to improve tine and any other active agent(s) and cyclodextrin in the the appearance of the chewable formulations, especially since 50 presence of water in a planetary mixer for about 20 minutes. an attractive coloration imparted by a colorant may improve The mixture is then dried in a drying oven. After drying, the patient compliance. The relative amounts of the colorants complex is mixed with any color/flavoring blend. The blend is selected will vary depending upon the particular hue of the then compressed into a single layer or bi-layer tablet using individual colorants and the resultant color desired. standard methods well-known to those skilled in the art (e.g., Any standard pharmaceutically acceptable excipient can 55 Kilian T-100 tablet press or Courtoy 292/43 rotary bi-layer be used in the chewable tablet formulations which provides press). The colorants and flavoring agents may be added to adequate compression Such as diluents (e.g., mannitol. Xyli both layers to form a uniform presentation of the tablet. tol, maltitol, lactitol, Sorbitol, lactose. Sucrose, and compress Methods for preparation of chewable tablets and various ible sugars such as DiPacR) (dextrinized sucrose), available components for use in the tablets can be found throughout the from Austin Products Inc. (Holmdel, N.J.), binders, disinte 60 detailed description section and the Examples of U.S. Patent grants, splitting or Swelling agents (e.g., polyvinyl polypyr Publication No. 2003/0215503, the disclosure of which is rolidone, croScarmellose sodium (e.g., Ac-Di-Sol available incorporated by reference herein for all purposes. Additional from FMC BioPolymer, Philadelphia, Pa.), starches and chewable/orally dissolving tablets, and methods for their derivatives, cellulose and derivatives, microcrystalline cellu manufacture, are disclosed in U.S. Patent Publication No. loses, such as AviceITM PH 101 or AviceITM CE-15 (a micro 65 2004/0265372 and U.S. Pat. No. 6,270,790, the disclosures of crystalline modified with guar gum), both available from each of which are incorporated by reference herein for all FMC BioPolymer, (Philadelphia, Pa.), lubricating agents purposes. US 8,758,816 B2 83 84 Orally Disintegrating Tablets acid, sodium Stearyl fumarate, micronised polyoxyethyleneg In another embodiment, the present invention provides lycol (micronised Macrogol 6000), leukine, sodium benzoate orally disintegrating/orodispersible tablets, such as those dis and mixtures thereof. The amount of lubricant generally is closed in U.S. Pat. No. 6,723,348, the disclosure of which is from about 0 to about 3%, e.g., from about 1 to about 2% by incorporated herein by reference in its entirety for all pur weight, based on the weight of the tablet. The lubricant can be poses. The orally disintegrating/orodispersible tablets Suit dispersed within the mixture of excipients, or according to ably disintegrate in the buccal cavity upon contact with saliva one embodiment, sprayed over the outer surface of the tablet. forming an easy-to-Swallow Suspension. Such tablets com Thus, according to one embodiment of the disintegrating prise (or consist essentially of) aZelastine (e.g., azelastine tablets of the invention, the lubricant is in powderform and is, HCl), and optionally, one or more additional active agents 10 (such as those described herein), in the form of coated gran at least in part, disposed on the Surface of the tablets. ules, and a mixture of excipients comprising at least one The permeabilising agent allows the creation of a hydro disintegrating agent, a soluble diluent agent, a lubricant and philic network which facilitates the penetration of saliva and optionally a Swelling agent, an antistatic (fluid flow) agent, a hence assists the disintegration of the tablet. Suitable perme permeabilising agent, taste-masking agents/sweeteners, fla 15 abilising agent include, but are not limited to, silica with a Voring agents and colors. In certain Such embodiments, the high affinity for aqueous solvents, such as colloidal silica disintegrating/orodispersible tablets comprise the taste (AerosilTM), precipitated silica (SyloidTMFP244), maltodex masking agent Sucralose. The amounts of azelastine, other trins, B-cyclodextrins and mixtures thereof. The amount of optional active agents (e.g., Steroids, decongestants, leukot permeabilising agent Suitably is between about 0 and about riene antagonists, and combinations thereof), and Sweetening 5%, e.g., from about 0.5 to about 2% by weight, based on the agents (e.g., Sucralose) in the orally disintegrating tablet for weight of the tablet. mulations of the present invention are readily determinable A Swelling agent can be incorporated in the mixture of by those of ordinary skill in the art, and include those amounts excipients. Suitable Swelling agents include, but are not lim and combinations described herein. For example, the orally ited to, starch, modified starch or microcrystalline cellulose. disintegrating tablet formulations of the present invention 25 An antistatic agent can also be incorporated as a flow aid. comprise about 0.1% to about 0.15% azelastine, optionally Suitable antistatic agents include, but are not limited to, about 0.01% to about 10% other active agent(s) (or more as micronised or non-micronised talc, fumed silica (Aerosil TM required), and about 0.05% to about 0.15% sucralose. R972), colloidal silica (AerosilTM 200), precipitated silica In Suitable embodiments, the particles/granules of azelas (SyloidTMFP 244), and mixtures thereof. tine (and any other optional active agents) have a particle size 30 According to one such embodiment of the invention, the such that about 100% of the particles have an average size of granules of azelastine or one of its pharmaceutically accept less than about 50 Lum. In suitable such embodiments, azelas tine (and any other optional active agents) are present as able salts (and optionally, one or more additional active coated granules. agents such as those described herein) are characterized in In one embodiment, the disintegrating tablets according to 35 that the granules are coated and comprise microcrystals of the invention comprise coated granules of azelastine (and aZelastine or one of its pharmaceutically acceptable salts optionally, one or more additional active agents) or one of its (e.g., azelastine HCl). Sucralose, at least one binder, and pharmaceutically acceptable salts (such as azelastine HCl), a optionally a diluent agent, an antistatic agent, and a coloring taste-masking agent Such as Sucralose, and a mixture of agent. Furthermore, the granulation excipients can also excipients, the ratio of the mixture of excipients to the coated 40 include disintegrating agents and/or surfactants. granules suitably is about 0.4:1 to about 9:1, more suitable Suitable binders include, but are not limited to, cellulosic about 1.5:1 to about 5:1, or about 2 to 3 parts by weight, the polymers, such as ethylcellulose, hydroxypropylcellulose mixture of excipients suitably comprising: at least one disin and hydroxypropylmethyl cellulose, acrylic polymers. Such tegrating agent, a soluble diluent agent, a lubricant, and as insoluble acrylateammoniomethacrylate copolymer, poly optionally a permeabilising agent, a Swelling agent, an anti 45 acrylate or polymethacrylic copolymer, povidones, copovi static agent, flavoring agents and one or more coloring agents. dones, polyvinylalcohols, alginic acid, Sodium alginate, In Suitable embodiments, the disintegrating agent is starch, pregelatinized starch, Sucrose and its derivatives, guar selected from the group consisting of croScarmellose, avail gum, polyethylene glycol, for example an acrylic polymer, able as e.g. Ac-di-solTM, crospovidone available as e.g. Kol such as EudragitTM E100, and mixtures thereof. lidon CLTM, sodium starch glycolate and mixtures thereof. 50 Optionally, in order to enhance the granulation of the According to one embodiment of the invention, the soluble aZelastine (and one or more additional active agents) or one of diluent is a polyol having less than 13 carbonatoms and being its pharmaceutically acceptable salts, a diluent agent can be either in the form of a directly compressible product with an used. Suitable diluent agents include, but are not limited to, average particle size of about 100 to 500 um, or in the form of microcrystalline cellulose, Sucrose, dicalcium phosphate, a powder with an average particle size of less than about 100 55 starches, lactose and polyols of less than 13 carbon atoms, um, this polyol suitably being selected from the group con Such as mannitol. Xylitol, Sorbitol, maltitol, pharmaceutically sisting of mannitol. Xylitol, Sorbitol and maltitol. The propor acceptable amino acids, Such as glycin, and their mixtures. tion of disintegrating agent Suitably is from about 3 to about In one embodiment, a granule of azelastine or one of its 15% by weight, e.g., about 5 to about 15% by weight, and in pharmaceutically acceptable salts (as well as any additional the case of a mixture, each disintegrating agent being present 60 active agents, such as those described herein), can be in the between about 1 and about 10% by weight, e.g., about 5 to form of a core of granulated microcrystals of azelastine, about 10% by weight, and the proportion of soluble diluent coated with at least one layer comprising azelastine. Such a agent being about 30 to about 90% by weight, e.g., about 40 coated core is characterized in that the core and the layer to about 60% by weight, based in each case on the weight of comprise each from 70% to 95%, preferably 80% to 95% by the tablet. 65 weight of azelastine, or one of the pharmaceutically accept Suitable lubricants for use in the disintegrating tablets able salts thereof, the balance to 100% being formed with at include, but are not limited to, magnesium Stearate, Stearic least one binder and optionally Sucralose, and that the coated US 8,758,816 B2 85 86 core is Suitably a sphere. See e.g., French patent application Effervescent Formulations FR 00 14803, the disclosure of which is incorporated by In another embodiment, the present invention provides a reference herein. Solid, effervescent, rapidly dissolving dosage form of azelas In one embodiment of the invention, the granules can com tine for oral administration, such as disclosed in U.S. Pat. No. 6.245,353, the disclosure of which is incorporated by refer prise (or consist essentially of): from about 10% to about ence herein in its entirety. In such an embodiment, the effer 95%, e.g., from about 50% to about 70% of azelastine or a Vescent formulation comprise (or consist essentially of) (a) pharmaceutically acceptable salt thereof (e.g., azelastine aZelastine or a pharmaceutically acceptable salt thereof (e.g., HCl) and optionally one or more additional active agents, aZelastine HCl), and optionally one or more additional active such as those described herein, at most about 20% by weight agents such as those disclosed herein, (b) an effervescent base of the binder, relative to the weight of azelastine, or one of the 10 comprising at least one of (i) at least one of (1) an organic pharmaceutically acceptable salts thereof, at most about 5%, edible acid and (2) a salt thereof, (ii) at least one of an alkali suitably about 2% by weight of the antistatic agent, relative to metal and an alkaline earth metal carbonate and bicarbonate, the weight of said granules, suitably about 0.05% to about 5% and (c) optionally a pharmaceutically acceptable auxiliary ingredient. In certain suitable embodiments, the effervescent Sucralose and optionally a diluent agent for the balance to 15 formulations further comprise one or more taste-masking 100%. agents. Such as Sucralose, and/or other taste-masking agents The granules can also be coated with a coating composition described herein. The amounts of azelastine, other optional comprising at least one coating polymer selected from the active agents (e.g., steroids, decongestants, leukotriene group consisting of cellulosic polymers, acrylic polymers and antagonists, and combinations thereof), and Sweetening their mixtures. Among the cellulosic polymers, ethylcellu agents (e.g., Sucralose) in the effervescent formulations of the lose, hydroxypropylcellulose (HPC) and hydroxypropylm present invention are readily determinable by those of ordi ethylcellulose (HPMC), can be used. Among the acrylic poly nary skill in the art, and include those amounts and combina mers, insoluble acrylate ammonio-methacrylate copolymer tions described herein. For example, the effervescent formu (EudragitTM RL100 or RS100 or EudragitTM RL30D or lations of the present invention comprise about 0.1% to about RS30D), polyacrylate (EudragitTM NE30D), or methacrylic 25 0.15% azelastine, optionally about 0.01% to about 10% other copolymers (e.g., EudragitTM L100-55 EudragitTM L30D, active agent(s) (or more if required), and about 0.05% to EudragitTM E100 and EudragitTM EPO) can be used, alone, in about 0.15% sucralose. combination, or in admixture with pH-dependent polymers. A solution or Suspension of azelastine or salt thereof is EudragitTM E100 or a mixture of EudragitTM EPO and formed by adding water to the soluble or dispersible efferves EudragitTMNE30D are suitably used. In one embodiment, the 30 cent tablets or soluble granules, with evolution of CO gas. The resulting effervescent Solution or Suspension can be binder and the coating polymer are the same polymer. ingested very easily, even by patients who have difficulties Optionally, permeabilising agents, plasticizers, soluble Swallowing. The rapidly disintegrating tablet can also be agents, disintegrating agents and Surfactants, can be added as administered so that it directly disintegrates in the mouth. A coating additives. Suitable plasticizers include, but are not 35 rapid release of the active ingredient is of particular impor limited to, triacetine, triethylacetate, triethylcitrate tance here, to ensure a rapid onset of action. (EudraflexTM) ethylphthalate, or mixtures thereof. The plas Effervescent agents capable of releasing CO2, which can ticizer is used in proportions of at most about 30%, preferably be used in the present invention, include alkali metal carbon 10% by weight of the coating polymers. Suitable soluble ates or alkali metal bicarbonates, such as Sodium carbonate or agents include polyols having less than 13 carbon atoms. 40 sodium bicarbonate. Agents for inducing CO release which Surfactants may be an anionic, nonionic, cationic, Zwitteri are Suitably employed are edible organic acids, or their acidic onic or amphoteric Surfactant. Suitable disintegrating agents salts, which are present in solid form and which can be for include, but are not limited to, croscarmellose, available as mulated with the azelastine active ingredient and the other e.g. Ac-di-solTM, crospovidone available as e.g. Kollidon auxiliary ingredients (as well as any other active agents) to CLTM, and mixtures thereof. 45 provide granules or tablets, without premature evolution of Suitably, the coated granules according to the present CO. Edible organic acids which can be so used include for invention have a particle size distribution between about 150 example, tartaric acid, malic acid, fumaric acid, adipic acid, um and about 500 um, more suitably between about 150 um Succinic acid, ascorbic acid, maleic acid or citric acid. Phar and about 425um, such that at least 50%, more suitably at maceutically acceptable acidic salts include, for example, least 70% of the granules have a particle size ranging between 50 salts of polybasic acids which are present in Solid form and in about 150 and about 425 um, and less than 15% of the gran which at least one acid function is still present, such as ules have a particle size less than about 150 Lum. Sodium dihydrogen or disodium hydrogen phosphate or In one embodiment, the coated granules according to the monosodium or disodium citrate. invention comprise: from about 10% to about 95%, prefer In one embodiment, the present invention provides effer ably about 40 to about 75% of granules of azelastine or one of 55 Vescent aZelastine formulations including the formulations its pharmaceutically acceptable salts, Suitably azelastine HCl and compositions described herein, having an effervescent and optionally one or more optional additional active agents, base comprising (a) a mixture of calcium carbonate with an such as those disclosed herein, sucralose from about 0.05% to organic edible acid; (b) a mixture of calcium carbonate, about 5%, from about 5 to about 90%, suitably about 10 to Sodium carbonate, sodium bicarbonate and an organic edible about 70% and even more suitably from about 25 to about 60 acid; or (c) a mixture of sodium bicarbonates, sodium car 55% of a coating polymer, such as EudragitTM E100, the bonate and an organic edible acid. percentages being expressed by weight relative to the weight The soluble or dispersible effervescentazelastine tablets or of the granules of azelastine, or one of its pharmaceutically the soluble granules Suitably comprise (or consisting essen acceptable salts, from about 0 to about 10% of a permeabi tially of) from about 0.5 mg to about 10 mgazelastine (or salt lising agent. Such as colloidal silica, the percentages being 65 thereof, e.g., azelastine HCl) and from about 50 mg to about expressed by weight relative to the weight of the coating 5000 mg, suitably from about 500 mg to about 3000 mg of an polymer. effervescent base, optionally, along with other active agents US 8,758,816 B2 87 88 (such as those described herein) and excipients, including be prepared by chemically treating starches to produce, for taste-masking agents such as Sucralose, Suitably at about example, acid treatment starches, enzyme treatment starches, 0.05% to about 5%. oxidized Starches, cross-bonding starches, and other starch The effervescent base suitably comprises from about 100 derivatives. Starches suitable for modification to produce mg to about 500 mg calcium ions as, for example, calcium 5 modified starches may be obtained from natural products carbonate, and from about 20 mg to about 1500 mg citric acid Such as corn, potatoes, tapioca as well as genetically modified and/or its salts. In another embodiment, the effervescent base forms of the same Such as high amylose and waxy corn as well comprises from about 50 mg to about 2000 mg sodium bicar as Sorghum varieties. bonate, from about 20 mg to about 200 mg of sodium carbon Examples of modified starches for use in the practice of the ate and from about 20 mg to about 1500 mg citric acid and/or 10 present invention include, but are not limited to, modified from about 20 mg to about 500 mg tartaric acid. corn starches, modified tapioca Starches, acid and enzyme An additional suitable composition of the effervescent hydrolyzed corn and/or potato starches, hypochlorite-oxi base comprises from about 50 mg to about 500 mg sodium dized Starches, acid-thinned starches, ethylated Starches, bicarbonate, from about 20 mg to about 100 mg sodium cross-bonded Starches, hydroxypropylated tapioca starches, carbonate, and from about 50 mg to about 750 mg calcium 15 hydroxypropylated corn starches, pregelatinized modified carbonate and from about 100 mg to about 1500 mg of citric starches, and the like. Preferred modified starches are acid. selected from pregelatinized modified corn starches and The soluble/dispersible tablets can be prepared by known pregelatinized modified tapioca Starches. processes for preparing effervescent bases, such as those Representative examples of commercially available modi disclosed in U.S. Pat. No. 6,245,353, the disclosure of which 20 fied starches useful in the present invention include PURE is incorporated herein by reference in its entirety. COTETM modified starches such as PURE-COTETM B793 (a Orally Dissolving/Consumable Films pregelatinized modified corn starch) and PURE-COTETM Another embodiment of the present invention is directed to B795 (a pregelatinized modified corn starch), for example, a physiologically acceptable film that is particularly well available from Grain Processing Corporation, 1600 Oregon adapted to dissolve in the oral cavity of a warm-blooded 25 Street, Muscatine, Iowa 52761-1494 USA. animal including humans, and adhere to the mucosa of the In one Such embodiment of the present invention, the modi oral cavity, to allow delivery of azelastine or a salt thereof, fied starch is present in amounts ranging from about 1% to e.g., azelastine HCl, and optionally one or more additional about 90% by weight, in another embodiment about 10% to active agents such as those described herein. Such physi about 90% by weight, and in yet another embodiment from ologically acceptable films suitable for use in accordance 30 about 35% to about 80% by weight of the film. with this aspect of the present invention are disclosed in U.S. Modified starch may be included in the film alone or Patent Application No. 2004/0247648, the disclosure of optionally in combination with an additional water soluble which is incorporated herein by reference in its entirety. film forming polymers such as those selected from, for In one Such embodiment of the present invention, an orally example, pullulan, hydroxypropylmethylcellulose, hydroxy dissolving/consumable film comprises a modified Starch, 35 ethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrroli aZelastine or a salt thereof, e.g., azelastine HCl, and option done, carboxymethyl cellulose, polyvinyl alcohol, Sodium ally, one or more additional active agents such as those alginate, polyethylene glycol, tragacanth gum, guar gum, described herein, Suitably, one or more taste-masking agents, acacia gum, arabic gum, polyacrylic acid, methylmethacry Such as Sucralose, and optionally, at least one water soluble late copolymers, carboxyvinyl polymers, amylose, high amy polymer. The amounts of azelastine, other optional active 40 lose starch, hydroxypropylated high amylose starch, pectin, agents (e.g., Steroids, decongestants, leukotriene antagonists, dextrin, chitin, chitosan, levan, elsinan, collagen, gelatin, and combinations thereof), and Sweetening agents (e.g., Zein, gluten, soy protein isolate, whey protein isolate, casein Sucralose) in the orally dissolving/consumable film formula and combinations thereof. A preferred water soluble polymer tions of the present invention are readily determinable by is pullulan. The amount of the water soluble polymer typi those of ordinary skill in the art, and include those amounts 45 cally is up to about 99% by weight, suitably up to about 80% and combinations described herein. For example, the orally by weight, more suitably up to about 50% by weight, and dissolving/consumable film formulations of the present most suitably up to about 40% by weight of the film. invention comprise about 0.5 mg to about 10 mgaZelastine, Sustained Release Formulations optionally about 0.5 mg to about 10 mg other active agent(s), In another embodiment, the present invention provides and about 0.05% to about 0.15% sucralose. 50 Sustained release azelastine formulations, such as the formu The consumable films of the present invention may com lations and compositions described herein, which also com prise one or more of the following ingredients: water, antimi prise a taste-masking agent, such as Sucralose. In additional crobial agents, additional film forming agents or water embodiment, Such Sustained release formulations of the soluble polymers, plasticizing agents, flavorings, Sulfur pre present invention can further comprise one or more additional cipitating agents, saliva stimulating agents, cooling agents, 55 active agents, such as those described herein. Surfactants, stabilizing agents, emulsifying agents, thicken Methods for preparing Sustained release tablets, capsules, ing agents, binding agents, coloring agents, triglycerides, caplets, pellets and the like, as well as excipients for use in the polyethylene oxides, propylene glycols, additional taste Sustained release formulations of the present invention, are masking agents or Sweeteners, fragrances, preservatives and well known in the art, and can be found, for example, through the like, as described in U.S. Pat. No. 6,596,298, the disclo- 60 out the detailed description section and the Examples of U.S. sure of which is incorporated by reference herein in its Pat. No. 5.271,946, the disclosure of which is incorporated entirety. herein by reference in its entirety for all purposes. In one such embodiment, the consumable films of the As discussed in U.S. Pat. No. 5.271,946, the sustained present invention include a modified starch. The modified release formulations of the present invention can be obtained starches used in accordance with the present invention can be 65 as follows: prepared by mechanically, chemically or thermally modify 1. Through binding of azelastine or a pharmaceutically ing unmodified Starches. For example, modified Starches may acceptable salt thereof (e.g., azelastine HCl), and optionally US 8,758,816 B2 89 90 one or more additional active agents such as those described Semi-permeable materials which can be used as polymers herein, to physiologically acceptable cation exchangers. The for osmosis and reverse osmosis are, for example: cellulose following may, for example, be used as Such cation exchang acylate, cellulose diacylate, cellulose triacylate, cellulose ers: acrylic and methacrylic resins with exchangeable pro acetate, cellulose diacetate, cellulose triacetate, B-glucan tons, acid groups: COO e.g. AmberliteTM IRP-64 Polysty acetate, acetaldehyde dimethyl acetate, cellulose acetate rene resins with exchangeable Na', acid groups: SO, e.g. ethylcarbamate, polyamide, polyurethane, Sulphonated poly AmberliteTMIRP-69. styrene, cellulose acetate phthalate, cellulose acetate methyl 2. Coating of active ingredient particles, granulate orpellet carbamate, cellulose acetate Succinate, cellulose acetate dim grains or azelastine-containing tablets with coatings of the ethylamino acetate, cellulose acetate chloracetate, cellulose 10 dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cel following Substances, or mixtures of the following Sub lulose dipentanate, cellulose acetate Valerate, cellulose stances: hydroxypropylmethyl cellulose phthalate- or acetate acetate-p-toluene Sulphonate, cellulose acetate butyrate, Succinate; cellulose-, starch-, as well as polyvinyl acetate ethyl cellulose, selectively permeable polymers which are phthalate; carboxymethyl cellulose; hypromellose; carbopol formed by joint precipitation of a polycation and a polyanion starch acetate; cellulose acetate; polyvinyl acetate; methyl 15 as disclosed in U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541, cellulose phthalate, methylcellulose Succinate, methyl cellu 005, 3,541,006 and 3,546,142, the disclosures of which are lose phthalate succinate as well as methyl cellulose phthalic incorporated by reference herein in their entireties. Coatings acid half ester; Zein; ethyl cellulose as well as ethyl cellulose of this type in semi-permeable membranes may for example Succinate; shellac, gluten; ethylcarboxyethyl cellulose; also be effected according to U.S. Pat. Nos. 4,455,143 and ethacrylate-maleic acid anhydride copolymer; maleic acid 4,449,983, the disclosures of which are incorporated by ref anhydride vinyl methyl ether copolymer; sterol maleic acid erence herein. copolymerizate, 2-ethylhexylacrylate maleic acid anhydride; The proportion of osmotically active substance can be from crotonic acid vinyl acetate copolymer; glutaminic acid/ about 10 to about 800 parts by weight, suitably about 20 to glutaminic acid ester copolymer; carboxymethylethyl cellu about 600, and more suitably about 50 to about 400 parts by lose glycerin mono-octanoate; cellulose acetate Succinate; 25 weight, based on 1 part by weight of azelastine. The amount polyarginin; fats, oils, waxes, fatty alcohols; anionic poly of coating Substances applied is such that the semi-permeable merizates of methacrylic acid and methacrylic acid esters membrane is about 50 to about 500 suitably about 100 to (EudragitTML, EudragitTMS); copolymerizates of acrylic and about 300 um thick. methacrylic acid esters with a low ammonium group 4. Embedding of or binding azelastine (or salt thereof) (EudragitTMRS) content, as well as copolymers of acrylic and 30 and/or any other optional additional active agent(s) to the methacrylic acid esters and trimethyl ammonium methacry following Substances or mixtures of these Substances: late (EudragitTMRL), copolymerizates of acrylic acid ethyl Digestible fats, such as triglycerides of saturated fatty and methacrylic acid methyl esters 70:30 (EudragitTMNE 30 acids, CHO to CHO, and mixtures thereof, peanut oil D), copolymerizates of acrylic acid, methacrylic acid as well and hydrated peanut oil, castor oil and hydrated castor oil, as their esters (ratio of the free carboxyl groups to the ester 35 olive oil, sesame oil, cottonseed oil and hydrogenated cotton groups for example 1:1) (EudragitTML 30 D). seed oil, corn oil, wheat germ oil, Sunflower seed oil, cod liver Such Sustained release formulations may also contain con oil, mixtures of mono-, di- and triesters of palmitic and Stearic ventional softeners (e.g. dibutyl sebacate, citric and tartaric acid with glycerine, glycerine trioleate, diglycol Stearate, acid esters, glycerin and glycerin esters, phthalic acid esters Stearic acid. and similar Substances). It also is possible to add water 40 Indigestible fats or fat-like Substances, for example esters soluble Substances such as polyethylene glycols, polyvi of aliphatic Saturated or unsaturated fatty acids (2 to 22 car nylpyrrolidone, copolymerizates of polyvinylpyrrolidone bonatoms, in particular 10 to 18 carbonatoms) with monova and polyvinyl acetate, hydroxypropyl cellulose, hydroxypro lent aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, pylmethyl cellulose. The addition of solids such as talcum beeswax, fatty alcohols (straight chain or branched) of chain and/or magnesium Stearate to the coating is also possible. 45 length CH-OH to CoHOH, in particular C2H5OH to Organic acids (such as for example citric acid, tartaric acid, C2H8OH. maleic, fumaric, ascorbic acid) may also be incorporated into Polymers such as polyvinyl alcohol, polyvinyl chloride, the pellet grains, granulate grains or tablets. polyacrylic acid (CarbopolTM); anionic polymerizates of 3. Coating of pressed disks, tablets, granulates containing methacrylic acid and methacrylic acid esters (EudragitTML, the azelastine or salt thereof, and optionally one or more 50 EudragitTMS), acrylic and methacrylic acid ester copolymer additional active agents such as those described herein, and izates with trimethyl ammonium methacrylate (EudragitTM one or more osmotically active Substances, (e.g. mannitol, RL, EudragitTM RS). Sorbitol and the like) with a semi-permeable membrane, e.g. Copolymerizates of ethyl acrylates and methyl methacry of 70 to 90 weight% of cellulose acetate and hydroxypropy lates (EudragitTMNE 30 D), as well as of acrylic acid, meth lmethyl cellulose or hypromellose (30 to 10 weight%). 55 acrylic acid as well as esters thereof (ratio of free carboxyl Other osmotically active substances that can be used groups to ester groups 1:1) (EudragitTML 30 D), polyethyl include organic and inorganic compounds or Soluble Sub ene, polyglycolic acid, polyhydroxybutyric acid, polylactic stances which generate an osmotic pressure gradient as com acid, copolymers of lactic acid and glycolic acid (manufac pared to the outer liquid via the semi-permeable wall. turer: Boehringer Ingelheim), copolymers of lactic acid and Osmotically active agents or osmotically active compounds 60 ethylene oxide, copolymers of glycolic acid and ethylene include magnesium Sulfate, magnesium chloride, sodium oxide, copolymers of lactic acid and hydroxybutyric acid, chloride, lithium chloride, potassium sulfate, potassium hydroxypropylmethyl cellulose-phthalate or -acetate Succi hydrogen phosphate, urea, saccharose and the like. Other nate; cellulose acetate phthalate, starch acetate phthalate as osmotically active agents are disclosed in U.S. Pat. Nos. well as polyvinyl acetate phthalate; carboxymethyl cellulose; 3,854,770, 4,077.407 and 4,235,236, the disclosures of each 65 methylcellulose phthalate. -Succinate, -phthalate Succinate, of which are incorporated herein by reference in their entire methyl cellulosephthalic acid halfester; Zein; ethyl cellulose; ties. shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate US 8,758,816 B2 91 92 maleic acid anhydride copolymer; maleic acid anhydride Unit Dosage Forms vinyl methyl ether copolymer; styrene maleic acid copoly In additional embodiments, the present invention provides merizate; 2-ethylhexyl acrylate maleic acid anhydride; cro compositions of matter comprising a unit dosage (e.g., single tonic acid vinyl acetate copolymer, glutaminic acid/ unit dosage) of a pharmaceutical composition and a unit dosage container. In Suitable Such embodiments, the pharma glutaminic acid ester copolymer; carboxymethyl cellulose ceutical composition comprises one or more antihistamines, glycerine mono-octanoate; cellulose acetate Succinate; pol including H. H. H. and H antihistamines as described yarginine; cross-linked alginate; cross-linked gelatin. herein, for example, azelastine and salts thereof. Such as Swelling agents such as methyl cellulose, hydroxypropyl azelastine HC1. Suitably, the unit dosage (unit dose, unit cellulose, hydroxypropyl methyl cellulose (Pharmacoat, dosage, single unit dose and single unit dosage are used Methocel E (propylene glycol ether of methyl cellulose)). 10 interchangeably herein) container will comprise a low Vol alginic acid and their salts (Na, Ca Salt, also mixtures of ume, e.g., the Volume of the unit dosage container will Suit Sodium alginate and calcium salts such as CaFIPO), starch, ably be less than about 5 ml, suitably less than about 4 ml, less carboxymethyl starch, carboxymethyl cellulose and their thanabout 3 ml, less than about 2 ml, less than about 1 ml, less salts (e.g. Na Salts), galacto mannan, gum arabic, karaya than about 0.9 ml, less than about 0.8 ml, less than about 0.7 15 ml, less than about 0.6 ml, less than about 0.5 ml, less than rubber, ghatti gum, agar-agar, carrageen, Xanthan rubber, about 0.4 ml, less than about 0.3 ml, less than about 0.2 ml or guar rubber and its derivatives, carob bean flour, propylene less than about 0.1 ml. For example, the unit dosage container glycol alginate, pectin, tragacanth. can comprise a volume of about 0.05 ml to about 1 ml, about The amounts of azelastine or salt thereof, and optionally 0.1 ml to about 1 ml, about 0.1 ml to about 0.9 ml, about 0.1 one or more additional active agents such as those described ml to about 0.8 ml, about 0.1 ml to about 0.7 ml, about 0.1 ml herein, in the formulations of the invention are about 0.1 mg to about 0.6 ml, about 0.1 ml to about 0.5 ml, about 0.1 ml to to about 50 mg, suitably about 0.2 mg to about 30 mg, and about 0.4 ml, about 0.1 ml to about 0.4 ml, about 0.1 ml to more suitably about 0.5 mg to about 20 mg of azelastine. about 0.3 ml, or about 0.1 ml to about 0.2 ml. Exemplary Suitable exemplary Sustained release components are: materials that can be used to prepare unit dose container are a) Cation exchangers: Sodium poly(styrene, divinylbenze 25 described herein or otherwise known in the art, and include ne)sulphonate (e.g. AmberliteTM IRP 69). Suitably 3 to 10 high density polyethylene. In further embodiments, the unit parts of AmberliteTMIRP69 are for example used per 1 part of dosage pharmaceutical composition can further comprise one aZelastine (base). or more additional active agents, one or more diluents, one or b) Coating substances: Hydroxypropylmethyl cellulose more carriers, one or more taste-masking, etc., as described phthalate, suitably at 1.5 to 3 parts of hydroxypropyl methyl 30 herein. cellulose phthalate 55 are used per 1 part of azelastine. Ethyl The pharmaceutical compositions described herein may be cellulose, suitably 0.1 to 1 part of ethylcellulose are used per stored, and/or delivered for administration to a patient, for 1 part of azelastine. Eudragit resins, for example EudragitTM example in a unit dosage container. For example, the unit RS 0.01 to 0.1 part of EudragitTM RS per 1 part of azelastine. dosage container may have a dimensional configuration simi c) Semi-permeable layers with osmotically acting active 35 lar to those disclosed in U.S. Pat. Nos. 7,185,790, 6,666,359, Substance containing core and outlet openings: Coating with 6,619,516 and 4,469.254. In particular embodiments, the unit 100 to 300 um thick layer of 82% cellulose acetate and 18% dosage container may have a configuration of unit dosage hydroxypropyl methyl cellulose. container 100, as shown in FIGS. 7-8. Unit dosage container d) Embedding Substances: Hydrocolloids e.g. hydroxypro 100 may have a squeezable chamber 102, a closure mecha pyl methyl cellulose: 2 to 10 parts of hydrocolloid per 1 part 40 nism 104, and an extension 106. The portion of the squeez ofazelastine. EudragitTMRS: 10 to 15 parts of EudragitTM RS able chamber 102 that is compressable is indicated by hatch per 1 part of azelastine. Glycerineditripalmito Stearate (e.g. marks. Precirol Ato 5) 1 to 10 parts of Precirol Ato 5 per 1 part of For ease of description, the container of the invention will aZelastine. be described in a normal (upright) operating position and The requisite release of azelastine (and optionally, any 45 terms such as upper, lower, horizontal, etc., will be used with additional active agents) of 0.05 to 5 mg per hour suitably reference to this position. It will be understood, however, that occurs within the desired range through the parameters the container may be manufactured, stored, transported, used, described herein. Should it be desired to achieve a specific and sold in an orientation other than the position described release rate within this range it is possible, for example, to herein. proceed as follows: 50 In certain embodiments, the Squeezable chamber may be 1. The preparation of the coating or embedding of the bulbous or flat or substantially flat in shape, having a first active Substance in the described manner. Surface and a second Surface, which may hold a single unit 2. Testing of the release of active Substance from the dosage dosage of any of the pharmaceutical compositions described form using 0.1 NHCl (2 hours) and phosphate buffer pH 6.8 herein. In certain preferred embodiments, the squeezable (Subsequently) as release medium. 55 chamber is flat in shape, as such a geometry renders the 3.a) Should too much substance be released: Increase of Squeezable chamberless structurally strong thanasqueezable the proportion of the Sustained release component and/or chamber of bulbous shape; this reduced structural strength reduction of the proportion of water-soluble auxiliary sub and flat shape provides excellent squeezability to the chamber stances. Reduction of the proportion of osmotically active while at the same time providing an integral unit dose vial. Substance. 60 The squeezable chamber may have a main body with a neck b) Should too little substance be released: Reduction of the at one end leading to an opening through which the single unit proportion of the Sustained release component and/or dosage may exit the unit dosage container when Squeezable increase of the proportion of water soluble auxiliary sub chamber is squeezed. The squeezable chamber has a first stances. Increase of the proportion of osmotically active Sub Surface and a second Surface that may have ridges extending Stance. 65 therefrom to facilitate gripping the Squeezable chamber. In In one embodiment, a release rate of about 0.05 mg of certain embodiments, where the first and second Surfaces and aZelastine per hour can be achieved. are long flat Smooth surfaces which impart Squeezability but US 8,758,816 B2 93 94 which at the same time could be slippery between the fingers, width of about 5 mm to about 20 mm, for example, about 12.9 the integral ridges provide good anti-slip features and control mm, and a thickness of about 1 mm to about 10 mm, for points for the person delivering the medication. The neck of example, about 2.5 mm. In one embodiment, the unit dosage the sqeezable chamber allows for the user to more accurately container may have a length of about 50 mm to about 100mm, position the tip of the dosage form, for example, near or into for example, about 85.5 mm when the closure mechanism is the eyelid area or ear canal. attached and may have a length of about 50 mm to about 100 The squeezable chamber may be sized to have an internal mm, for example, about 74.9 mm, when the closure mecha volume of less than or equal to about 1.0 ml, suitably about nism is removed. These measurements are merely exemplary 0.5 ml to about 1.0 ml. The squeezable chamber may have a and may be varied as needed. Suitable alternative embodi length of about 20 mm to about 40 mm, for example, about 10 ments employing other container measurements will be 32.9 mm; a width of about 5 mm to about 20 mm, suitably readily apparent to one of ordinary skill in the relevant arts in about 12.2 mm; and a thickness at its thickest point of about view of the present disclosure, drawings and claims. 3 mm to about 10 mm, suitably, about 6.6 mm. The opening The material for the unit dosage container may be a mold may have a diameter of about 1 mm to about 5 mm, for able polymer, such as a plastic, that the pharmaceutical com example, about 1.7 mm. These measurements are merely 15 position will not leach into upon storage therein. Polymers exemplary and may be varied as needed by the ordinarily Suitable for use according to this aspect of the invention skilled artisan. include, but are not limited to, polyethylene, polypropylene In suitable such embodiments of the invention, the single (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride unit dosage of a pharmaceutical composition held in the (PVC), polyethylene terephthalate (PET), polycarbonate Squeezable chamber may have a Volume in a range of from (PC), polyoxymethylene (POM), polysulfon (PSF), poly about 0.1 ml to about 0.6 ml. In more suitable embodiments, ethersulfon (PES), polyacrylate (PAR), and polyamid (PA). the Volume of the single unit dosage may be about 0.1 ml, In certain embodiments, polymers include polyethylene, par about 0.15 ml, about 0.2 ml, about 0.21 ml, about 0.22 ml, ticularly medium-density polyethylene (MDPE) (or about 0.23 ml, about 0.24 ml, about 0.25 ml, about 0.3 ml, branched polyethylene) or high density polyethylene (HDPE) about 0.35 ml, about 0.4 ml, about 0.45 ml, about 0.5 ml, 25 (or linear, polyethylene). A particularly preferred polymer for about 0.55 ml or about 0.6 ml. In certain such preferred use with azelastine-containing pharmaceutical formulations embodiments, the Volume of the single unit dosage enables is HDPE. In general, high-density polyethylene has a specific the patient to dose all the affected eyes, ears, nostrils or other gravity in the range of about 0.94 to about 0.965; medium parts of the body with one vial or dosage unit, and then discard density polyethylene has a specific gravity in the range of the unit dosage container, additional Volumes Suitable for 30 about 0.925 to about 0.94; and low-density polyethylene has Such a purpose will be readily apparent to those of ordinary a specific gravity in the range of about 0.91 to about 0.925. skill in the art. In suitable embodiments, the volume of phar As the unit dosage container holds a single unit dosage, it maceutical composition that is provided in a droplet form to is important that the pharmaceutical composition not the patient via the unit dose forms of the present invention is degrade, dissipate or dissolve by leaching into the material of one the order of about 0.01 to about 0.05 ml, suitably about 35 the unit dosage container to an unacceptable extent, as Such 0.02, about 0.03, about 0.035, about 0.04 or about 0.05 ml. would minimize the effectiveness of the pharmaceutical com The closure mechanism may be removably attached to the position. It has unexpectedly been found that a low-volume opening of the Squeezable chamber. The closure mechanism (e.g., less than about 1 ml), Squeezable container can be made may be a twist-off or pull-off top. In one such embodiment, according to the present invention which overcomes the prob the closure mechanism is molded as part of the unit dosage 40 lems of pharmaceutical compositions leaching into unit dose container and when the closure mechanism is twisted or containers. Specifically, the problems of antihistamines, pulled by the end-user, it breaks away from the unit dosage more specifically azelastine and azelastine HCl, leaching into container revealing the opening to the Squeezable chamber. In lower-density polyethylene unit dose containers (e.g., low this embodiment, the closure mechanism is notable to reseal density and medium density PE) has been overcome by pre the opening after use. 45 paring a low-volume unit dose container of HDPE. In contrast The extension may be attached to the squeezable chamber to lower-density PE unit dose containers, HDPE unit dose on a side opposite opening. The extension may be a solid flat containers reduce, Substantially reduce, or eliminate leaching panel that is sealed from an interior of Squeezable chamber. of azelastine into the material of the container. In further The extension may have a first Surface and a second Surface, embodiments, a coating or layer (for example a coating of wherein identification can be located on one or both of first 50 HDPE or other suitably material) can be disposed on the Surface and second Surface. The identification may include, inside of the unit dose container so as to minimize leaching of but is not limited to, the name of the pharmaceutical compo the pharmaceutical composition into the material of the con sition held in Squeezable chamber, the ingredients of the tainer. pharmaceutical composition, the expiration date of the phar The container of this aspect of the present invention may be maceutical composition, the name and address of the manu 55 fabricated and assembled with conventional molding appara facturer of the pharmaceutical composition, a tracking or lot tus that will provide a container having the structural and number, or combinations thereof. The identification may, for functional specifications described herein. example, be written, engraved (e.g., using heat, laser or In certain Such embodiments, the components of unit dos mechanical engraving), tattooed or otherwise placed on first age container may be molded. For example, the squeezable and/or second Surface, or may, for example, be located on a 60 chamber and extension may be molded in two halves through portion of extension which, in certain embodiments, may be compression or injection molding and then fused or otherwise referred to in the art as an “engraving section.” In further joined together around the periphery. embodiments, the identification may be provided on a label or In Such embodiments, the unit dosage containers prepared other item which can then be attached (e.g., via adhesive) to and used in accordance with the present invention can be extension on the first and/or second Surface. 65 fabricated by any suitable blow molding technique. The con In one embodiment, the extension may have a length of tainers preferably are fabricated in a two stage operation by about 30 mm to about 50 mm, for example, about 42.0 mm; a blow molding preforms, which are themselves injection or US 8,758,816 B2 95 96 compression molded. The containers alternatively can be The unit dosage container of the present invention is formed in a single stage injection stretchblow molding opera adapted for both cold-fill and hot-fill applications. In hot-fill tion, or in an injection extrusion blow molding operation in applications, in which the container is filled with hot liquid which the finish is injection molded and a tube is extruded product and then capped, an internal vacuum develops as the from the finish and blow molded to form the container body. product cools. The squeezable chamber may distort under the In molding operations of these types, the container finish vacuum pressure within the container. The squeezable cham typically is injection or compression molded to its final con ber may assume an oval geometry, or a triangular geometry figuration and is of relatively rigid construction, while the with the corners of the triangle being randomly located at container body is blow molded after the finish is formed. The longitudinally extending channels. However, the fingers of a container also can be formed in an extrusion blow molding 10 user will still naturally nestle along the Squeezable chamber, operation. Other container molding operations familiar to so that the container can be readily Squeezed to dispense those of ordinary skill in the art can also be employed. product. Thus, the ergonomic wrap-around grip design of the Alternatively, the Squeezable chamber and extension may squeezable chamber is maintained in both hot-fill and cold be molded as a single unit wherein the squeezable chamber is fill applications. formed utilizing a modified blow molding process in which 15 The unit dosage container design, in addition to functional the container is formed by blow molding, the pharmaceutical convenience, incorporates several other desirable features. formulation is filled or introduced into the newly formed The body itself is designed to empty readily without signifi container, and the container is sealed and ejected from the cant hold up. The unit dosage container is produced which manufacturing device Such a manufacturing process is fre retains the pharmaceutical composition until Squeezed and quently referred to in the art as a “blow-fill-seal' process, and can be held in a horizontal or inverted position without drip will be familiar to those of ordinary skill in the art. ping. That is, the opening, after removal of the break off tab, Whether the container is molded as separate halves that are is specifically dimensioned in its diameter to allow retention then sealed, or as a single unit, the closure mechanism may be of aqueous-based products until Squeezed. separately molded and then fused to neck to seal opening of The surfaces of the container body are contoured to allow Squeezable chamber. 25 the contents to be readily expelled without “hold-up' which The squeezable chamber may be molded such that the wall contrasts to a prior art stand up squeeze bottle in which the thickness of the Squeezable chamber enables Squeezable contents will typically flow out by gravity should the bottle be chamber to be easily Squeezed to dispense the pharmaceutical inadvertently knocked over or inverted. composition out opening. The Squeezable chamber may be After removing the break off tab, the liquid is dispensed molded so that application of a compressive force to the 30 from the container preferably in an upright position by press Squeezable chamber may substantially flatten the squeezable ing or Squeezing the main chamber, for example, between chamber thus facilitating the complete discharge of the phar thumb and forefinger, thus compressing the air trapped in the maceutical composition. The pharmaceutical composition main chamber of the container and causing the liquid in the can be dispensed as a drop (or drops), a stream, a spray, a mist measuring chamber to be sprayed out from the container in a or other suitable method of dispensing. The wall thickness of 35 fine stream. All of the contents may be discharged at one time the squeezable chamber may be from about 0.2 mm to about or only a portion may be discharged by controlling the com 7 mm, suitably about 0.4mm to about 0.5 mm. Suitably, when pressive force applied. HDPE is utilized as the material for squeezable chamber, the After removing the break off tab, the unit dosage container polymer will have a compressive strength in the range of used in accordance with this aspect of the present invention about 2.7 to about 3.6*10 psi, a flexural yield strength of 40 permits the administration of a precisely measured Volume of about 1.0*10 psi, and a flexural modulus of about 1.0 to pharmaceutical composition in the unit dosage container by about 2.6*10 psi. dispensing only the pharmaceutical composition contained in A plurality of unit dosage containers may be molded the squeezable chamber. An opening is thus provided through together as an assembly. Each of the unit dosage containers which can be administered precisely measured Successive are removably attached to assembly and may be broken away 45 amounts of pharmaceutical composition in a drop formatorin from assembly by pulling, twisting or otherwise breaking a thin, finely divided stream, with the unit dosage container assembly. Each of the unit dosage containers in assembly may and the head of the patient both in a normal upright position. also hold the same pharmaceutical composition or a different Another advantage is that, in the case of simultaneous treat pharmaceutical composition from the other unit dosage con ment of the nose and eyes, a sterile solution can always be tainers in assembly. For example, the unit dosage containers 50 used for the eyes by opening a new container each time. This may hold pharmaceutical composition A and unit dosage is not possible with conventional pipette bottles presently in containers may hold pharmaceutical composition B. Assem use since they are not adapted for single use. For application bly may be packaged in a containeralong with instructions for to the eyes, ears and other parts of the body, it is also possible administering the single unit dosages. to administer the pharmaceutical composition contents of the In certain embodiments, the unit dose container is filled 55 chamber in the form of drops instead of measured dosages by with liquid product after fabrication and a dispensing closure pointing the measuring chamber downwardly instead of is applied to the unit dosage container. To dispense the phar upwardly when administering the contents. Besides the maceutical composition from the squeezable chamber the advantage of greater hygiene, in the case of the treatment of a sides of chamber are gripped by a user, and the squeezable cold, the container according to the present invention is also chamber is deformed or squeezed radially inwardly to 60 more pleasant to use than the manipulation with the known increase the pressure within the container and thereby dis containers or dropping pipettes. pense product through the dispensing closure. The squeez In still further embodiments, the unit dosage forms dis able chamber in accordance with the present invention is closed herein can be used in combination with various nebu specifically contoured for maximizing the dispensing of liq lizers or other particle dispersion devices. For example, drug uid from the container. When the squeezable chamber is 65 delivery devices such as disclosed in U.S. Pat. No. 7.231.919, grasped by a user, the fingers of the users hand naturally can be used in combination with the unit dosage forms. In nestle along the squeezable chamber. Such embodiments, the pharmaceutical composition (e.g., an US 8,758,816 B2 97 98 antihistamine Such as azelastine hydrochloride) contained in facturing technique with a volume capacity of about 1 mL. the unit dosage forms of the present invention can be placed suitably less than about 0.5 ml, as described in detail herein. into the particle dispersion devices, and then nebulized for As the unit-dose formulations of the present invention are delivery to the patient's nasal passage. Suitably opened, used (i.e., the pharmaceutical composition is The compositions of the present invention that are pro administered/delivered to the eye, nose, ear, mouth, skin, vided in solution form may optionally contain a preservative, etc.), and then discarded, preservatives are an optional com and/or may be aseptically manufactured and/or sterilized for ponent of such formulations. The ability to provide sealed example by filtration through a bacterial-retaining filter. In unit dose formulations limits or reduces the ability of bacteria certain aspects of the invention, the formulations are asepti to grow in the formulations. In addition, the use of single cally manufactured and/or sterilized and are then sealed 10 unit-dose containers eliminates the concern of contamination within unit dose containers using the “blow-fill-seal for the user (or other outside sources), as once the unit-dose approach described elsewhere herein. container is opened and a single dose of the present formula Liquid Dosage Forms Free of Preservatives tions or compositions is delivered, the container is discarded. While preservatives are useful in limiting concerns related The use of single unit-dose containers eliminates the con to chemical degradation or bacterial growth in the liquid 15 cern of contamination for the user (or other outside sources), formulations of the present invention, the presence of these as once the unit-dose container is opened and a single dose of preservatives can themselves cause stinging or irritation, the present formulations or compositions is delivered, the especially when administered to the oral or nasal mucosa, or container is discarded. to ocular tissue or the conjunctival sac. Therefore, in order to The preservative-free formulations of the present invention reduce this irritation, in one embodiment, the liquid dosage can also be used with multi-dose containers, such as, high forms disclosed herein, e.g., liquid dosage forms for nasal, density polyethylene bottles with a volume capacity of about ocular or oral administration, Such as pharmaceutically 10 mL fitted with a spray pump specifically designed for use acceptable emulsions, solutions, Suspensions, syrups and with preservative free formulations. elixirs, can be prepared free, or substantially free, of preser Formulations For Pulmonary Delivery vatives. As used herein the phrase “free, or substantially free, 25 In further embodiments, the present invention provides of preservatives' means that the liquid formulations contain formulations and compositions for pulmonary delivery of less than about 0.0001% (weight/volume) of a preservative, aZelastine or a salt thereof, and optionally, one or more addi more suitably less than about 0.00001% (weight/volume) of a tional active agents, such as those described herein. For preservative, and most Suitably, no preservative. example, inhalable preparations comprising azelastine or a In order to maintain the integrity of the liquid formulations, 30 salt thereof (e.g., azelastine HCl), and optionally, one or more and specifically, to protect them from bacterial contamination additional active agents such as those described herein, can be transferred from the patient or external environment, the produced. delivery systems useful for applying the various liquid for Inhalable preparations include inhalable powders, propel mulations can be appropriately engineered to limit bacteria lant-containing metering aerosols or propellant-free inhal from entering the solutions. For example, in order to limit the 35 able solutions. Inhalable powders according to the invention introduction of bacteria or particulates that may come from containing azelastine or a salt thereof, and optionally one or the user of a nasal spray (e.g. from the nasal passage), the more additional active ingredients including those described spray bottle can be fitted with a filter or other device to limit herein, may comprise the active ingredients on their own, or or prevent the introduction of such bacteria into the bottle a mixture of the active ingredients with physiologically and/or formulation. This filter can form part of the spray or 40 acceptable excipients. In certain such embodiments, the dropper nozzle, or can be located within the structure of the inhalable formulas comprise the compositions of the present spray or dropper bottle itself. The filter allows the various invention in an inhalable form. Within the scope of the present liquid formulations of the present invention to pass through invention, the term propellant-free inhalable solutions also the filter to the patient, but limits bacteria or particulates from includes concentrates or sterile inhalable solutions ready for the patient or the external environment from entering the 45 use. The preparations according to the invention may com nozzle and bottle. Suitable filters are known in the art and are prise azelastine or a salt thereof and optionally one or more commercially available from well-known sources, and additional active ingredients including those described include microporous filtration membranes made from poly herein, in one formulation, or in two or more separate formu mers, such as, but not limited to, poly(etherSulfone), poly lations. (vinylidene fluoride), mixed cellulose esters, and poly(tet 50 Physiologically acceptable excipients that may be used to rafluoroethylene). In general, the pore size of Such prepare the inhalable powders according to the present inven membranes are on the order of less than about 0.5 microns, tion include, but are not limited to, monosaccharides (e.g., more suitably less than about 0.3 microns and most suitably glucose or arabinose), disaccharides (e.g., lactose, saccha less than or equal to about 0.22 microns. Use of Such mem rose, maltose), oligo- and polysaccharides (e.g., dextran), brane filters eliminate the need for preservatives in the various 55 polyalcohols (e.g., Sorbitol, mannitol. Xylitol), salts (e.g., liquid formulations of the present invention when utilized in Sodium chloride, calcium carbonate) or mixtures of these nasal spray or ocular drop delivery systems. excipients with one another. Suitably, mono- or disaccharides The preservative free liquid formulations and composi are used, for example, lactose or glucose in the form of their tions of the present invention can also be provided in single hydrates. Lactose and lactose monohydrate represent exem unit-dose containers. Such containers are acceptable to 60 plary excipients. Excipients for use in the inhalable prepara deliver the therapeutic dose of azelastine (or salt or ester tions can have an average particle size of up to about 250 um, thereof, including azelastine hydrochloride) and optionally suitably between about 10 um and about 150 um, most suit one or more additional active agents (such as those described ably between about 15um and about 80 Lum. In certain such herein) to the eyes, nose or mouth. In certain Such embodi embodiments, finer excipient fractions can be added with an ments of the invention, the compositions can be effectively 65 average particle size of about 1 um to about 9 um. These finer contained in a package comprising a high density polyethyl excipients are also selected from the group of possible excipi ene (HDPE) container produced using a blow-fill-seal manu ents disclosed throughout. Finally, in order to prepare the US 8,758,816 B2 99 100 inhalable powders according to the present invention, micro gases may be used on their own or in mixtures thereof. Par nised active ingredients (e.g., aZelastine and optionally one or ticularly Suitable propellant gases are halogenated alkane more additional agents described throughout), Suitably with derivatives selected from TG 134a and TG227. an average particle size of about 0.5um to about 10 Jum, more The propellant-driven inhalation aerosols according to the suitably from about 1 um to about 5 um, are added to the present invention may also contain other ingredients such as excipient mixture. Processes for producing the inhalable co-solvents, stabilizers, Surfactants, antioxidants, lubricants powders according to the present invention by grinding and and pH adjusters. All of these ingredients, and Suitable com micronizing and by finally mixing the ingredients together mercial sources thereof, are well known in the art. are routine and well known to those of ordinary skill in the art. The inhalation aerosols containing propellant gas accord The inhalable powders according to the present invention can 10 ing to the present invention may contain up to about 5 wt % of be prepared and administered either in the form of a single active Substances (or more ifrequired). Aerosols according to powder mixture which contains azelastine or a salt thereof the invention contain, for example, about 0.002 wt.% to about and optionally one or more additional active agents such as 5 wt.%, about 0.01 wt.% to about 3 wt.%, about 0.015 wt.% those described herein, or in the form of separate inhalable to about 2 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.5 powders, in which one powder contains only azelastine or a 15 wt.% to about 2 wt.%, or about 0.5 wt.% to about 1 wt.% of salt thereof, and another powder contains one or more addi active Substances (e.g. azelastine or a salt thereof and option tional active agents such as those described herein. Methods ally one or more additional active agents such as those for preparing the inhalable powders of the present invention, described herein). as well as devices for their delivery, are disclosed in U.S. Pat. In embodiments where the active Substance(s) are present Nos. 6,696,042 and 6,620,438: U.S. Published Patent Appli in dispersed form, the particles of active Substance(s) Suitably cation Nos. 2002/0009418, 2005/0121032, 2005/0121027 have an average particle size of up to about 10 suitably from and 2005/0123486, the disclosures of each of which are about 0.1 um to about 5 more suitably from about 1 um to incorporated herein by reference in their entireties. about 5 Lim. The inhalable powders according to the present invention Propellant-driven inhalation aerosols according to certain may be administered using inhalers well known in the art. 25 Such embodiments of the present invention may be adminis Inhalable powders according to the present invention which tered using inhalers known in the art (e.g., MDIs: metered contain a physiologically acceptable excipient in addition to dose inhalers, see e.g., U.S. Pat. Nos. 6,380,046, 6,615,826 the active agents may be administered, for example, by means and 6,260,549, the disclosures of each of which are incorpo of inhalers which deliver a single dose from a Supply using a rated herein by reference in their entireties). Accordingly, in measuring chamber as described in U.S. Pat. No. 4,570,630, 30 another aspect, the present invention provides pharmaceuti or by other means as described in U.S. Pat. Nos. 5,035.237 cal compositions in the form of propellant-driven aerosols and 4,811,731, the disclosures of which are incorporated by combined with one or more inhalers suitable for administer reference herein in their entireties. The inhalable powders of ing these aerosols. In addition, the present invention provides the present invention can also be administered by dry powder inhalers which are characterized in that they contain the pro inhalers (DPIs) or pre-metered DPIs (see e.g., U.S. Pat. Nos. 35 pellant gas-containing aerosols described throughout. The 6,779,520, 6,715,486 and 6,328,034, the disclosures of each present invention also provides cartridges which are fitted of which are incorporated herein by reference in their entire with a suitable valve and can be used in a suitable inhaler and ties). Suitably, the inhalable powders according to the present which contain one or more of the propellant gas-containing invention which contain physiologically acceptable excipi inhalation aerosols described throughout. Suitable cartridges ents in addition to the active agents are packed into capsules 40 and methods of filling these cartridges with the inhalable (to produce so-called inhalettes) which are used in inhalers as aerosols containing propellant gas according to the invention described, for example, in U.S. Pat. No. 5,947,118, the dis are known in the art. closure of which is incorporated herein by reference in its In another embodiment, the present invention provides entirety. An additional DPI that can be used with the powder propellant-free inhalable formulations, such as Solutions and formulations of the present invention is the Novalizer R by 45 Suspensions, comprising (or consisting essentially of) azelas Sofotec (Bad Homburg, Germany). A description of this DPI, tine or a salt thereof and optionally one or more additional as well as methods to formulate powders for use in it, are active agents such as those described herein. Suitable solvents disclosed in U.S. Pat. Nos. 5,840,279; 5,881,719; 6,071.498: for use in Such embodiments include aqueous and alcoholic and 6,681,768, the disclosures of which are incorporated Solvents, Suitably an ethanolic Solution. The Solvents may be herein by reference in their entireties. 50 water on its own or a mixture of water and ethanol. The According to another embodiment of the present invention, relative proportion of ethanol compared with water suitably is inhalation aerosols containing propellant gas comprising (or up to about 70 percent by volume, more suitably up to about consisting essentially of) azelastine or a salt thereof and 60 percent by volume, or up to about 30 percent by volume. optionally, one or more additional active ingredients such as The remainder of the volume is made up of water. The solu those described herein, dissolved in a propellant gas or in 55 tions or Suspensions containing azelastine or a salt thereof dispersed form, can be produced. AZelastine or a salt thereof, and optionally one or more additional active agents, such as and one or more optional active ingredients, such as those those described herein, separately or together, are adjusted to disclosed herein, may be present in separate formulations or a pH of 2 to 7, using suitable acids or bases. The pH may be in a single preparation, in which all active ingredients are each adjusted using acids selected from inorganic or organic acids. dissolved, each dispersed, or one or more active components 60 Examples of Suitable inorganic acids include hydrochloric are dissolved and any others are dispersed. The propellant acid, hydrobromic acid, nitric acid, Sulfuric acid and phos gases which may be used to prepare the inhalation aerosols phoric acid. Examples of suitable organic acids include ascor according to the invention are known in the art. Suitable bic acid, citric acid, malic acid, tartaric acid, maleic acid, propellant gases include, but are not limited to, hydrocarbons Succinic acid, fumaric acid, acetic acid, formic acid, propi Such as n-propane, n-butane or isobutane and halohydrocar 65 onic acid, etc. Exemplary inorganic acids include hydrochlo bons such as fluorinated derivatives of methane, ethane, pro ric and sulfuric acids. It is also possible to use the acids which pane, butane, cyclopropane or cyclobutane. The propellant have already formed an acid addition salt with one or more of US 8,758,816 B2 101 102 the active Substances. Exemplary organic acids include ascor able formulations, such as solutions or Suspensions, as bic acid, fumaric acid and citric acid. If desired, mixtures of described herein, combined with a device suitable for admin the above acids may be used, particularly in the case of acids istering Such formulations. which have other properties in addition to their acidifying The propellant-free inhalable formulations, e.g., Solutions qualities, e.g., as flavorings, antioxidants or complexing or Suspensions, according to the present invention may take agents, such as citric acid or ascorbic acid, for example. the form of concentrates or sterile inhalable solutions or sus Hydrochloric acid can be used to adjust the pH. pensions ready for use. Formulations ready for use may be Co-solvents and/or other excipients may be added to the produced from the concentrates, for example, by the addition propellant-free inhalable formulations of the present inven of isotonic saline solutions. Sterile formulations ready for use 10 may be administered using energy-operated fixed or portable tion. Suitable co-solvents are those which contain hydroxyl nebulizers which produce inhalable aerosols by means of groups or other polar groups, e.g., alcohols—such as isopro ultrasound or compressed air by the Venturi principle or other pyl alcohol, glycols—such as propylene glycol, polyethylene principles. glycol, polypropylene glycol, glycol ether, glycerol, poly The present invention also provides fine particle dosages of oxyethylene alcohols and polyoxyethylene fatty acid esters. 15 aZelastine or a salt thereof (e.g., azelastine HCl) and option The terms excipients and additives in this context denote any ally one or more additional active agents such as those pharmacologically acceptable Substance which is not an described herein. A delivered fine particle dose (FPD) of active substance but which can be formulated with the active aZelastine or a salt thereof (e.g., azelastine HCl) administered Substance or Substances in the pharmacologically suitable by inhalation herein is not limited, and may generally be in a solvent in order to improve the qualitative properties of the range from about 1 to about 50 ug, including about 5, 10, 15, active substance formulation. Suitably, these substances have 20, 30 and 40 ug. The correct metered dose loaded into an no pharmacological effect or, in connection with the desired inhaler to be used for the purpose of administration can be therapy, no appreciable or at least no undesirable pharmaco adjusted for predicted losses such as retention and more or logical effect. The excipients and additives include, for less efficient de-aggregation of the inhaled dose. example, Surfactants such as Soy lecithin, oleic acid, Sorbitan 25 Excipient particles having a physical median particle size esters, such as polysorbates, polyvinylpyrrolidone, other sta larger than about 25um and having a very narrow particle size bilizers, complexing agents, antioxidants and/or preserva distribution with generally less than 5% of the particles by tives which prolong the shelf life of the finished pharmaceu mass being below 10 um generally show good flow proper tical formulation, flavorings, vitamins and/or other additives ties, and are suitable for use in mixtures together with azelas known in the art. The additives also include pharmacologi 30 tine or a salt thereof (e.g. azelastine HCl) and optionally one or more additional active agents, such as those described cally acceptable salts such as sodium chloride as isotonic herein. For inhalation purposes, carrier particles having a agents. mass median particle size in a range from about 10 to about Exemplary excipients include antioxidants such as ascor 250 umare typically selected, including about 30, 50, 70, 100, bic acid, Vitamin A, vitamin E, tocopherols and similar vita 35 130, 160, 190, and 220 Lum. The median particle size chosen mins and provitamins occurring in the human body. within this range depends on many factors, e.g. type of carrier Preservatives may be used to protect the inhalable formu substance, degree of powderflowability to be attained, type of lations disclosed herein from contamination with pathogens. inhaler and ease of de-aggregation during inhalation of the Suitable preservatives are those which are known in the art, resulting medicament. Commercial grades of Respitos are particularly cetyl pyridinium chloride, benzalkonium chlo 40 available (lactose monohydrate from DMV of several defined ride or benzoic acid or benzoates such as sodium benzoate in particle size distributions up to 400 um) suitable as particular the concentration known from the prior art. The preservatives excipients to be used in formulations containing azelastine, mentioned above are Suitably present in concentrations of up e.g. grade SV003. Uniform homogeneous azelastine powder to about 50 mg/100 ml, more suitably between about 5 and formulations having a physical median particle size down to about 20 mg/100 ml. Alternatively, the inhalable formulations 45 about 10 um can also provide good flow properties when the can be prepared without preservatives, for example, in unit particles have been modified to have a very smooth surface, dose forms, such as described herein. thereby improving the flow properties of the formulation. The propellant-free inhalable formulations according to A practical lower limit for volumetric dose forming for the present invention can be administered using inhalers of such inhalable powderformulations is in a range of about 0.5 the kind which are capable of nebulizing a small amount of a 50 to 1 mg. Smaller doses can be difficult to produce and still liquid formulation in the therapeutic dose within a few sec maintain a low relative standard deviation between doses in onds to produce anaerosol Suitable for therapeutic inhalation. the order of 10%. Typically, though, dose masses range from Suitable inhalers are those in which a quantity of less than about 1 to 10 mg. about 100 uL, less than about 50 uL, or between about 10 ul Suitable excipients for inclusion in the azelastine powder and about 30 uL of active substance solution can be nebulized 55 formulations include, but are not limited to, monosaccha in one spray action to forman aerosol with an average particle rides, disaccharides, polylactides, oligo- and polysaccha size of less than about 20 um, suitably less than about 10um, rides, polyalcohols, polymers, salts or mixtures from these in such a way that the inhalable part of the aerosol corre groups, e.g. glucose, arabinose, lactose, lactose monohy sponds to the therapeutically effective quantity. drate, lactose anhydrous (i.e., no crystalline water present in Suitable apparatuses for propellant-free delivery of a 60 lactose molecule), saccharose, maltose, dextran, Sorbitol, metered quantity of a liquid pharmaceutical composition mannitol. Xylitol, Sodium chloride and calcium carbonate. according to the present invention are described for example Excipients for use with azelastine or a salt thereof (e.g., in U.S. Pat. Nos. 5,497,944; 5,662,271; 5,964,416; 6,402, azelastine HCl) and optionally one or more additional active 055; 6,497,373; 6,726,124; and 6,918,547, the disclosures of agents, such as those described herein, generally are selected which are incorporated herein by reference in their entireties. 65 from among excipients which have good moisture qualities in In another embodiment, the present invention provides phar the sense that the substance will not adversely affect the active maceutical formulations in the form of propellant-free inhal agent fine particle dose (FPD) for the shelf life of the product US 8,758,816 B2 103 104 regardless of normal changes in ambient conditions during respiratory tract, including asthma and chronic obstructive storage. Suitable “dry” excipients are well known in the art pulmonary disease (COPD), and complications thereof such and include those disclosed herein. For example, lactose can as pulmonary hypertension, as well as allergic and non-aller be selected as a dry excipient, or lactose monohydrate can be gic rhinitis. In addition, the inhalable formulations according used in a formulation with azelastine or a salt thereof (and to the present invention may be used to treat cystic fibrosis optionally one or more additional active agents, such as those and allergic alveolitis (Farmer's Lung). described herein). Lactose has the inherent property of having The present invention also provides inhalable spray phar a low and constant water sorption isotherm. Excipients hav maceutical compositions comprising (or consisting essen ing a similar or lower sorption isotherm can also be used. tially of), a suitable concentration to provide atherapeutically As discussed throughout, and in a further aspect of the 10 effective dose of azelastine, or a pharmaceutically acceptable present invention, azelastine or a salt thereof (e.g. azelastine salt or ester thereof, and one or more pharmaceutically HCl) may be mixed or formulated with one or more additional acceptable carrier, stabilizer or excipient, wherein the azelas active agents such as those described herein in the dry powder tine is in a solution form and wherein at least one of the or other inhalable formulations. The present invention also pharmaceutically acceptable carriers or excipients is sucral encompasses the use of azelastine or a salt thereof where a 15 ose dissolved in the solution. Such inhalable spray pharma combination of azelastine or a salt thereof with other agents, ceutical compositions when used with a suitable device pro Such as those described herein, constitute a formulation from vide a fine spray of the components (including active and which metered doses are then produced, filled and sealed into non-active components) having an average particle size of dry, moisture-tight, high barrier seal containers intended for about 1 um to about 5um. Such inhalable spray pharmaceu insertion into a DPI to be administered according to a par tical compositions of the present invention can be formulated ticular dosing regime or as needed by the user. Suitable addi for pulmonary delivery using, for example, a suitable device tional active agents include those disclosed throughout, for or inhaler. Suitably the amount of azelastine in such inhalable example, inhaled steroids: e.g., budesonide, fluticaSone (e.g., spray pharmaceutical compositions is about 0.1% to about fluticasone propionate, fluticaSone dipropionate, fluticaSone 10% by weight and the amount of sucralose in such inhalable fuorate, fluticasone maleate, fluticasone Valerate, and the 25 spray pharmaceutical compositions is about 0.05% to about like), rofileponide, mometasone, and/or ciclesonide; NSAIDs, 0.15% by weight, though other suitable amounts will readily e.g., ibuprofen; leukotriene antagonists, e.g., montelukast; be determined by the ordinarily skilled artisan. additional antihistamines, e.g., epinastine, cetirizine, fex Clinical Indications ofenadine, olopatadine, levocabastine, loratadine, mizolas The compositions provided by the present invention are tine, ketotifene, emedastine, dirnetindene, clemastine, bami 30 useful in methods for the treatment of a variety of physical pine, ceXchlorpheniramine, pheniramine, doxylamine, disorders in animals (particularly mammals including chlorphenoxamine, dimenhydrinate, diphenhydramine, humans) that are predisposed to or suffering from a physical promethazine, ebastine, desloratidine and/or meclozine; disorder that may be delayed, prevented, cured or otherwise beta-mimetics: e.g., formoterol, salmeterol, salbutamol and/ treated by the administration of azelastine or a pharmaceuti or terbutalinsulphate; PDE IV inhibitors: e.g., 3',5'-cyclic 35 cally acceptable salt or ester thereof. Thus, in additional nucleotide phosphodiesterases and derivates; adenosine A2a embodiments, the invention provides methods of treating or receptor agonists: e.g., Ribofuranosylvanamide derivates, preventing Such physical disorders, comprising administer and/or substances described in U.S. Published Patent Appli ing an effective amount of one or more of the compositions of cation No. 2003/013.675, the disclosure of which is incorpo the invention to an animal (particularly a mammal, including rated by reference herein in its entirety. 40 a human) that is predisposed to or Suffering from Such a A sealed, dry, high barrier container can be loaded with a physical disorder. As used herein, an animal that is "predis powderform azelastine or a salt thereof (e.g., azelastine HCl) posed to a physical disorder is defined as an animal that does and optionally one or more additional active agents, such as not exhibit a plurality of overt physical symptoms of the those described herein, in the form of a blister and may disorder but that is genetically, physiologically or otherwise comprise a flat dose bed or a formed cavity in aluminum foil 45 at risk for developing the disorder. In Such situations, the or a molded cavity in a polymer material, using a high barrier compositions of the present invention may thus be used pro seal foil against ingress of moisture, e.g. of aluminum or a phylactically as chemopreventive agents for Such disorders. combination of aluminum and polymer materials. The sealed, Suitably, the invention provides methods of treating or dry, high barrier container may form a part of an inhaler preventing a physical disorder, condition or symptom thereof, device or it may form a part of a separate item intended for 50 in a patient by administering to the eye, nose, ear, skin, etc. of insertion into an inhaler device for administration of pre a patient a unit dosage form of a pharmaceutical composition metered doses. of the invention comprising an effective amount of one or The inhalable pharmaceutical formulations of the present more active pharmaceutical ingredients. Suitably, the meth invention that comprise (or consist essentially of) azelastine ods comprise providing a unit dosage form comprising a unit or a salt thereof (e.g., azelastine HCl) and a suitable steroid 55 dosage container made of high density polyethylene, the unit (e.g., a safe steroid) are Suitably formulated as azelastine: dosage form having a Volume of less than about 0.6 ml and the steroid in ratios by weight ranging from about 1:300 to about dosage container having a Volume of less than about 1.0 ml. 50:1, and more suitably from about 1:250 to about 40:1. In Suitably the unit dose form contains one or more antihista exemplary formulations which contain azelastine or a salt mines (e.g. azelastine HCl) or pharmaceutically acceptable thereof (e.g., azelastine HCl) and a steroid selected from 60 salts thereof. The unit dosage form is then administered to the among budesonide, fluticasone, mometasone, and Subject, and the unit dosage container is then discarded. It ciclesonide, the weight ratio of azelastine (or salt thereof): should be understood that “discarded simply means that the steroid are suitably in the range of about 1:150 to about 30:1. unit dosage container is not used for any Subsequent dosings. and more suitably from about 1:50 to 20:1. According to the invention, a mammal (preferably a The inhalable formulations of the present invention are 65 human) that is predisposed to or suffering from a physical especially suitable for the treatment of inflammatory (includ disorder may be treated by administering to the animal an ing allergic) or obstructive diseases of the upper or lower effective dose of one or more of the pharmaceutical compo US 8,758,816 B2 105 106 sitions of the present invention. Physical disorders treatable patient, the total daily usage of the compositions of the with the compositions and methods of the present invention present invention will be decided or recommended by the include, but are not limited to, any physical disorder that is attending physician, pharmacist or other medical practitioner characterized by one or more symptoms such allergic rhinitis/ within the scope of Sound medical judgment. rhinosinusitis, vasomotor rhinitis, and/or allergic conjunc The intranasal formulations of this invention are most tivitis, inflammatory or obstructive diseases of the upper or effective when proper product design is utilized. The pre lower respiratory tract, including asthma and chronic obstruc ferred product design includes a composition of the invention tive pulmonary diseases (COPD), and complications thereof contained within a delivery system, such as a bottle and a Such as pulmonary hypertension, cystic fibrosis and allergic pump, for nasal delivery of the formulation in a mist of spray alveolitis (Farmer's Lung), as well as non-allergic rhinitis or 10 droplets to coat the mucosa of the nasal cavity upon admin conjunctivitis, or allergic or nonallergic skin conditions. istration. Preferred pumps for use in such products of the Examples of such allergic nasal, ocular, ear or skin conditions invention are metered multi-dose pumps; however, single treatable or preventable using the pharmaceutical composi unit-dose containers are also acceptable to deliver the thera tions of the present invention (preferably in unit dose con peutic dose of azelastine (or salt or ester thereof, including figuration) include, but are not limited to, allergic reactions to 15 azelastine hydrochloride) to the nasal cavity. The selection of plant or insect allergens, environmental allergens, allergic the pump is based on the desired dosefspray Volume and spray ocular conditions (e.g., hay fever conjunctivitis, perennial pattern appropriate for local delivery to the nasal mucosa. In allergic conjunctivitis, giant papillary conjunctivitis (includ certain Such embodiments of the invention, the compositions ing that associated with the use of contact lenses), nonallergic can be effectively contained in a package comprising a high noninfectious conjunctivitis, Vernal keratoconjunctivitis or density polyethylene bottle fitted with a screw cap, and are atopic keratoconjunctivitis) and irritant dermatitis, uticaria, delivered by a metered-dose spray pump designed for intra and the like, as well as otic conditions such as otitis media, nasal application in volumes of 0.07 to 0.15 ml such as the tinnitus, Eustachian tube constriction or blockage, and the VP3/140 18/415 or the VP3/140F 18/415 Spigot 522 pumps like. The compositions of the invention are also useful in designed by Valois Pharm, Marly le Roi, France. In addition, treating or preventing the symptoms of Such disorders, and 25 the intranasal formulations can be provided in a unit dose thereby provide symptomatic relief to patients suffering from form, such as described herein. or predisposed to such disorders. The ocular formulations of this invention are also most Other physical conditions or disorders suitably treated or effective when proper product design is utilized. The pre prevented using the pharmaceutical compositions of the ferred product design includes a composition of the invention present invention (preferably in unit dose configuration) 30 contained within a delivery system, such as a bottle and a include, but are not limited to, nasal and ocular conditions dropper, for ocular delivery of the formulation to coat the associated with the common cold; nasal, ocular or skin con conjunctival sac of the eyes upon administration. Preferred ditions resulting from a reaction to insect bites; postoperative packages for use in Such products of the invention are multi ocular inflammation; acute anterior uveitis; dermatituS/ dose; however, single unit-dose containers are also accept keratisis; allergic blepharitis; keratitis (such as herpes Zoster 35 able to deliver the therapeutic dose of azelastine (or salt or or Superficial punctate keratitis), and the like; otic conditions ester thereof, including azelastine hydrochloride) to the eyes. Such as uticaria and the like, as well as otitis media, tinnitus, In certain such embodiments of the invention, the composi Eustachian tube constriction or blockage, and the like. In tions can be effectively contained in a package comprising a another embodiment, the pharmaceutical compositions of the high density polyethylene bottle (HDPE) in volume capacity present invention (preferably in unit dose configuration) can 40 of 10 mL fitted with a low density polyethylene dropper and be used to treat or prevent motion sickness, such as that secured with a HDPE cap closure. In addition, the ocular associated with travel by boat, airplane, automobile, etc., formulations can be provided in a unit dose form, such as wherein the composition is administered to (or self-adminis described herein. tered by) a person Susceptible to motion sickness at least Suitable compositions of the present invention include about 15-30 minutes prior to beginning such travel. 45 about 0.1%, about 0.125% or about 0.15% azelastine, and The compositions of the invention are also useful in treat about 0.05%-0.15% sucralose. Described below are non-lim ing or preventing the symptoms of Such disorders, and iting examples of the compositions of the present invention, thereby provide symptomatic relief to patients suffering from comprising 0.05%, 0.1% or 0.15% azelastine hydrochloride, or predisposed to such disorders. 0.1% to 0.3% of hypromellose as a thickener, 0.05% to 0.15% Dosing 50 of sucralose as a Sweetening and taste-masking agent, and/or As noted above, by the invention, a composition compris 0.05% menthol as a taste-masking/flavoring agent. Suitable ing an effective amount of azelastine or a pharmaceutically Such compositions can also comprise one or more additional acceptable salt or ester thereof (e.g., azelastine HCl), and active agents such as those described herein at the various optionally, one or more additional active agents such as those concentrations and amounts described herein. These compo described herein, can be administered to a patient to provide 55 sitions are well-tolerated despite the intense bitterness con symptomatic relief from a variety of disorders, including tributed by the presence of azelastine hydrochloride. Thus, allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, as use of Such compositions of the invention provide symptom well as the various other disorders disclosed throughout and atic relief from allergic rhinitis, vasomotor rhinitis, or allergic known in the art. One of ordinary skill will appreciate that the conjunctivitis, while significantly improving patient accept amount or concentration of azelastine (or saltorester thereof, 60 ability and compliance. including azelastine hydrochloride) that constitutes “an Treatment of Snoring effective amount of azelastine can be determined empiri The present invention also provides a method for treating cally. Non-limiting examples of effective amounts of azelas Snoring that in Some cases eliminates Snoring entirely, and in tine (or salt or ester thereof, including azelastine hydrochlo other cases reduces the intensity and frequency of Snoring. ride) for use in the pharmaceutical compositions of the 65 The treatment comprises administering a prescribed dosage present invention include those described in detail herein. It in one or more doses per day of azelastine or a physiologically also will be understood that, when administered to a human acceptable salt thereof along with a taste-masking agent. The US 8,758,816 B2 107 108 aZelastine is Suitably topically applied to the nasal passage, tions, otherwise weight/weight). Preferred preservatives generally in the form of a nasal spray or in other delivery among the quaternary ammonium compounds are alkylben forms described herein. AZelastine is administered in an Zyl dimethyl ammonium chloride and mixtures thereof, for amount effective to inhibit Snoring and may be administered example the compounds generally known as “benzalkonium once or more than once a day. In a Suitable embodiment, at 5 chloride. least one dose is administered prior to bedtime. Published Such formulations of the present invention for treatment of International Patent Application No. WO 02/056876, the dis Snoring (solutions, Suspensions as well as oily solutions or closure of which is incorporated by reference herein in its Suspensions, ointments, emulsions, creams, gels, dosage entirety, describes compositions and methods for treatment of aerosols) can contain about 0.0005 to about 2, preferably Snoring that can be used in the practice of the present inven 10 about 0.001 to about 1, or about 0.003 to about 0.5% (weight/ tion. weight) of azelastine (related to the free azelastine base). In one embodiment, the present invention provides a sterile Should azelastine be present as a salt, the amounts should be and stable aqueous Solution of azelastine or one or more of its recalculated as necessary to give the amounts of azelastine, in salts (e.g., azelastine HCl), along with one or more taste the free acid form shown above. In the case of powders, the masking agents and optionally one or more additional active 15 concentration of azelastine base generally is about 0.0005 to agents such as those described herein, which can be used in about 2 percent by weight relative to the solid carrier sub the form of drops, ointments, creams, gels, insufflatable pow StanceS. ders or, in a suitable embodiment, in the form of a spray In the case of Solutions, the dosage per nostril is, for (preferably a nasal spray). The spray can beformed by the use example, 0.01 to 0.2 ml, in particular 0.05 to 0.15 ml. Such a of a conventional spray-squeeze bottle or a pump vaporizer. dosage should be applied once to several times, preferably 1 In addition, it is also possible to use compressed gas aerosols. to 5 times daily (optionally also hourly). For example, 0.03 to 3 mg of azelastine base can be released Suitable acid components for azelastine salts are, for per individual actuation. example, hydrophilic acids (HCl, HBr), sulfuric acid, phos In certain such embodiments, the formulations of the phoric acids), nitric acid, organic mono-, di- or tricarboxylic present invention for use in treating Snoring comprise one or 25 acids of aliphatic, alicyclic, aromatic or heterocyclic organic more taste-masking agents, one or more flavoring agents, acids (embonic acid, citric acid, tartaric acid), aliphatic and and/or one or more Sweetening agents, or a combination of aromatic Sulfonic acids (for example camphorsulfonic acid). Such agents. Non-limiting examples of Such substances It is also suitable to add buffer substances such as citric include those described herein. For example, sucralose is acid/sodium hydrogensulphateborate buffer, phosphates (so especially effective as a Sweetening and taste-masking agent 30 dium hydrogenorthophosphate, disodiumhydrogenphos in the compositions of the present invention for use in treat phate), tromethamol or equivalent conventional buffers in ment of snoring, particularly when used at concentrations of order, for example, to adjust the formulation to a pH value of from about 0.001% to about 1%, suitably at concentrations of 6 to 7.5, preferably 6.5 to 7.1. from about 0.01% to about 0.5%, and more suitably at con In one embodiment, snoring is treated by use of a 0.1% or centrations of from about 0.02% to about 0.2%, and most 35 a 0.15% aqueous solution of azelastine hydrochloride, suit suitably from about 0.05% to about 0.15%, of the total com ably as a nasal spray. The spray is metered to deliver about position. 137 lug of azelastine hydrochloride (equivalent to 125 ug of Solvents which may be used for such formulations include, aZelastine base). but are not limited to, water, Saturated aliphatic mono and In addition to aZelastine, the compositions useful for treat polyvalent alcohols which contain 2-3 carbon atoms (for 40 ing Snoring can also optionally contain one or more additional example ethanol. Isopropanol. 1,2-propylene glycol, glycer active agents such as those described herein. In addition, the ine), liquid polyglycols (molecular weight 200 to 600). The compositions for treating Snoring can also further comprise solvent used is suitably water or mixtures of water with other one more sedatives or sleeping aids to help assist the user in physiologically acceptable solvents (for example those men falling asleep. Suitable sedatives and sleep aids include, but tioned above). Suitably, the amount of the latter solvent in the 45 are not limited to, melatonin (N-acetyl-5-methox aqueous mixture should not exceed 15% by weight. ytryptamine), a melatonin agonist, GABA (gamma-amino Such solutions or formulations suitably can contain preser butyric acid), other antihistamines (for example, benocten Vatives and stabilizers, as well as other excipients disclosed and olopatadine), benzodiazepines (for example, midazolam, herein. Suitable excipients include, for example: ethylene diazepam), diazepines, phenobarbiturates, diphenhy diamine tetra-acetic acid (eidetic acid) and their alkali Salts 50 dramines or methiazoles. Other suitable sleep aids include (for example dialkali salts such as disodium salt, calcium salt, plant extracts such as: Valeriana officinalis, Lavandula calcium-sodium salt), lower alkyl p-hydroxybenzoates, chlo angustifolia, Humulus lupulus, passiflora incarnate, Ocimum rohexidine (for example in the form of the acetate or glucon basilicum, Nardostachysjatanamsi, Hypericum perforatum, ate), phenyl mercury borate. Furthermore, it is possible, for Corydalis cava, Daliva militiorrhiza, Cyperipedium pubes example, to use sodium-(2-ethylmercurithio)-benzoate gen 55 cens, Cymbopogon flexuosus, Melissa officinalis, Monarda erally known as “thimerosal” which may be present in an didymia, Citrus aurantii, Psicidia piscioula, and the like. amount of 0.001 to 0.05, preferably from 0.005 to 0.02, for Co-Administration of Azelastine and Steroid example 0.01% (weight/volume in liquid formulations, oth In a further embodiment, the present invention provides erwise weight/weight). Other suitable preservatives are: phar methods of treating a variety of disorders, including allergic maceutically useful quaternary ammonium compounds, for 60 rhinitis, vasomotor rhinitis, allergic conjunctivitis, as well as example cetylpyridinium chloride, tetradecyltrimethyl the various other disorders disclosed throughout and known ammonium bromide, generally known as 'cetrimide.” ben in the art, by co-administering azelastine (or a pharmaceuti Zyldimethyl-2-[2-(p-(1,1,3,3-tetramethyl-butyl)phenoxy cally acceptable salt thereof, e.g., aZelastine HCl) and one or ethoxy-ammonium chloride, generally known as “benzetho more steroids. Suitably, azelastine or a pharmaceutically nium chloride' and myristyl-:-picolinium chloride. Each of 65 acceptable Saltoresterthereof (e.g., azelastine HCl) is admin these compounds may be used in a concentration of 0.002 to istered in the form of a nasal spray, although additional deliv 0.05, for example 0.02% (weight/volume in liquid formula ery routes and formulations as described throughout can also US 8,758,816 B2 109 110 be used (e.g., oral, ocular, inhalation, etc.). As described each other, within less than about 16 minutes of each other, throughout, compositions for administration of azelastine via within less than about 17 minutes of each other, within less the nasal route (as well as other routes described throughout) than about 18 minutes of each other, withinless than about 19 can further comprise one or more excipients, for example, a minutes of each other, within less than about 20 minutes of taste-masking agent such as Sucralose, as well as one or more each other, within less than about 25 minutes of each other, additional active agents selected from those described herein within less than about 30 minutes of each other, within less or otherwise known in the art, for example a decongestant. than about 35 minutes of each other, withinless than about 40 Examples of steroids Suitable for co-administration in Such minutes of each other, within less than about 45 minutes of embodiments of the present invention include, but are not each other, within less than about 50 minutes of each other, limited to, fluoromethalone, fluticasone (and its conjugates, 10 withinless than about 55 minutes of each other, or within less esters, variants, salts, derivatives and the like, e.g., fluticaSone than about 60 minutes of each other. propionate sold under the brand name FLONASE(R) by In certain embodiments, azelastine or a pharmaceutically GlaxoSmithKline, Research Triangle Park, N.C., fluticasone acceptable salt or ester thereof (e.g., aZelastine HCl) and one dipropionate, fluticaSone fuorate, fluticasone maleate, fluti or more steroids are administered at the same time using a casone Valerate, and the like), mometaSone, triamcinolone, 15 spray or dispensing device that allows for administration of betamethasone, flunisolide, beclomethasone, budesonide, both active agents from separated storage containers at the rimexolone, beloxil, prednisone, loteprednol (e.g., lotepred same time. For example, a device comprising two reservoirs, nol etabonate), dexamethasone and its analogues (e.g., dex one of which contains azelastine or a pharmaceutically amethasone beloxil) described in U.S. Pat. Nos. 5,223,493 acceptable salt or ester thereof (e.g., azelastine HCl) in a and 5,420,120, incorporated herein by reference in their suitable spray formulation, the other of which comprises one entireties, as well as other steroids described throughout. or more steroids, also in a suitable spray formulation. By Preferred steroids for use in the formulations of the present activating the spray or dispensing devise, a dose from each invention are “safe steroids.” As used herein, the term "safe reservoir, i.e., an azelastine dose and a steroid dose, are steroid' means a steroid which treats eosinophil and neu administered to the nasal passage of the patient at the same rotrophil associated inflammation, reduces papillae forma 25 time. A device in which each separate reservoir can be dis tion, and which is effective in treating inflammation, without pensed at different times is also envisioned. The dosage and causing a clinically significant elevation in intraocular pres volume of spray from each reservoir can also be controlled sure (IOP). Exemplary safe steroids that can be used in the and modified as required depending upon the agent being various formulations of the present invention, particularly for delivered. Additional devices and methods are envisioned for delivery using nasal spray or ocular drop delivery systems 30 other modes of administration, e.g., for pulmonary delivery include, but are not limited to, any glucocorticoid which via inhalation as described hereinabove, for example using meets the safe steroid definition, including but not limited to, dry powder inhalers (DPIs) or pre-metered DPIs. fluoromethalone, fluticaSone (and its conjugates, esters, vari In a further embodiment, co-administration comprises ants, salts, derivatives and the like, e.g., fluticasone propi administering azelastine or a pharmaceutically acceptable onate sold under the brand name FLONASER by Glaxo 35 salt or ester thereof (e.g., azelastine HCl) from a first spray or SmithKline, Research Triangle Park, N.C., fluticasone dispensing device, and then administering one or more Ste dipropionate, fluticaSone fuorate, fluticasone maleate, fluti roids from a second spray or dispensing device (the devices casone Valerate, and the like), rimexolone, loteprednol (e.g., can be attached or joined to one another, or they can be loteprednol etabonate), dexamethasone beloxil and its ana completely separate dispensing devices) within the time peri logues described in U.S. Pat. Nos. 5.223,493 and 5,420,120. 40 ods set forth herein. For example, azelastine or a pharmaceu Additional “safe steroids' and methods for determining tically acceptable salt or ester thereof (e.g. azelastine HCl) appropriate amounts of Such agents for inclusion in the can be administered by spraying a dose (or one or more sprays present compositions are disclosed in U.S. Pat. No. 6,649. can be used depending on the required dose) of active agent 602, the disclosure of which is incorporated by reference into each nasal passage of the patient (or a single nasal pas herein in its entirety. 45 sage depending on the required dose). The dose amount is As used herein, the term “co-administration” refers to determined by the configuration of the spray device and the administering azelastine or a pharmaceutically acceptable concentration of the agent in the spray formulation. Then, salt or ester thereof (e.g., azelastine HCl) by any mode of within the time periods set forth throughout, (e.g., within less administration (e.g., intranasally, orally, ocularly, via inhala than about 1 minute, less than about 5 minutes, less than about tion, etc.) and one or more steroids also by any mode of 50 10 minutes, less than about 15 minutes, less than about 20 administration (e.g., intranasally, orally, ocularly, via inhala minutes, etc.) a dose of steroid is provided to the patient by tion, etc.) simultaneously, i.e., at the same time, or within a spraying each nasal passage with a steroid in a nasal spray suitable time period of one another. More suitably, azelastine formulation (or a single nasal passage depending on the and one or more Steroids are administered in the form of a required dose). Suitably, two sprays each of azelastine or a nasal spray formulation within less than about 1 minute of 55 pharmaceutically acceptable Saltorester thereof (e.g., azelas each other (and can be administered at the same time), or tine HCl) and a steroid in nasal spray formulations are given within less than about 2 minutes of each other, within less to each nasal passage, though in Suitable embodiments, a than about 3 minutes of each other, within less than about 4 single or multiple sprays can be administered to one or both minutes of each other, within less than about 5 minutes of nasal passages. In further embodiments, doses of additional each other, within less than about 6 minutes of each other, 60 steroids and/or other agents can be co-administered before or within less than about 7 minutes of each other, within less after the administration of azelastine and a first steroid. Simi than about 8 minutes of each other, within less than about 9 lar sequential co-administration of these active ingredients minutes of each other, within less than about 10 minutes of via other modes of administration, e.g., via inhalation for each other, within less than about 11 minutes of each other, pulmonary delivery as described elsewhere herein, is also within less than about 12 minutes of each other, within less 65 contemplated by the present invention. than about 13 minutes of each other, withinless than about 14 The present invention also encompasses the co-adminis minutes of each other, within less than about 15 minutes of tration of azelastine and one or more steroids, where the US 8,758,816 B2 111 112 steroids, or both the steroids and azelastine, are administered pared to azelastine or steroid administration alone, in Symp via a route other than via nasal spray. For example, azelastine toms such as runny nose, itchy nose, Sneezing, congestion and (or a salt or ester thereof, e.g. azelastine HCl) can be admin total nasal symptom score. (See Example 13). Specifically, it istered via nasal spray, and one or more steroids administered has now been found that the co-administration of azelastine or via oral, inhalation, injection, or other Suitable route. Alter a pharmaceutically acceptable salt or ester thereof (e.g., natively, aZelastine (or a salt or ester thereof, e.g. azelastine azelastine HCl) and one or moresteroids unexpectedly results HCl) can be administered via pulmonary delivery (e.g., via in better therapeutic benefit to patients to whom the agents inhalation as described elsewhere herein), and one or more have been co-administered than would be expected, in that the steroids can be administered via nasal, oral, inhalation, injec effect on the symptoms of allergic rhinitis, non-allergic vaso tion or other Suitable route. In yet another non-limiting 10 motor rhinitis or allergic conjunctivitis, of the two agents approach, azelastine (or a salt or ester thereof, e.g. azelastine co-administered (whether in the same composition or in sepa HCl) can be administered ocularly, and one or more steroids rate compositions) is significantly greater than the effects of can be administered via nasal, oral, inhalation, injection or either agent administered separately. other suitable route. As one of ordinary skill will be aware, It will be readily apparent to one of ordinary skill in the there are other examples of suitable modes of co-administra 15 relevant arts that other suitable modifications and adaptations tion of azelastine (or a salt or ester thereof, e.g. azelastine to the methods and applications described herein may be HCl) and a steroid, based on the description herein and that made without departing from the scope of the invention or any will be familiar to the practitioner; such other examples are embodiment thereof. It is to be understood that while the also encompassed by the present invention. invention has been described in conjunction with the detailed In a further embodiment, co-administration comprises description thereof, the foregoing description is intended to administration of azelastine (or a salt or ester thereof, e.g. illustrate and not limit the scope of the invention, which is aZelastine HCl) and one or more steroids in the same compo defined by the scope of the appended claims. Other aspects, sition. In certain such embodiments, the azelastine (or salt or advantages, and modifications are within the scope of the ester thereof) and the steroid are contained togetherina single claims. Having now described the present invention in detail, pharmaceutical composition, for example, a single pharma 25 the same will be more clearly understood by reference to the ceutical composition comprising azelastine (or a salt or ester following examples, which are included herewith for pur thereof) and a steroid (either in a solution or a suspension poses of illustration only and are not intended to be limiting of dosage form). Such compositions may take any form, particu the invention. larly those described herein that are formulated for nasal administration, pulmonary administration (e.g., via inhala 30 EXAMPLES tion), ocular administration, oral administration, injection and the like. Example 1 The amount of azelastine for co-administration can be varied and adjusted appropriately by the ordinarily skilled Azelastine Hydrochloride Nasal Solution artisan. Suitably azelastine or a pharmaceutically acceptable 35 salt or ester thereof (e.g., azelastine HCl) is contained in the In one exemplary composition of the invention, a nasal intranasal formulations for co-administration in an amount of spray formulation containing azelastine hydrochloride was about 0.0001% to about 1.0% by weight, and more suitably prepared using hypromellose as a thickener, Sorbitol as an from about 0.005% to about 0.5% or most suitably from about isotonicity agent and Sweetener, and Sucralose as both a 0.05% to about 0.20% (e.g., 0.05%, 0.06%, 0.07%, 0.08%, 40 Sweetener and a taste-masking agent. 0.09%. 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%), of pure azelastine (calculated as the free azelastine base). The amount of steroid(s) present in the formulations for co-administration can be varied and Ingredient % adjusted appropriately by the ordinarily skilled artisan. Suit 45 Azelastine Hydrochloride O.1SO ably, one or more steroids are present in any amount in the Hypromellose 2900, USP 4000 O.100 Edetate Disodium, USP O.OSO nasal formulations, for example about 0.01% to about 1.5% Sorbitol 70%, USP 6.400 (e.g., about 0.01%, about 0.05%, about 0.1%, about 0.25%, Sodium Citrate, USP, Dihydrate O.O68 about 0.5%, about 0.75%, about 1%, about 1.5%). Suitably Sucralose, NF O.1SO the amount of steroid is about 0.01% to about 1.5% by weight, 50 Benzalkonium Chloride 50% Solution, NF O.O2S more suitably about 0.01% to about 1.0% by weight, or even Water Purified or Deionized Q.S. to 100% more suitably about 0.01% to about 0.1% by weight (e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about Following preparation, the composition was filtered, and 0.05%, about 0.06%, about 0.07%, about 0.08%, about was packaged into high density polyethylene bottles fitted 0.09%, or about 0.1% by weight). Amounts, compositions 55 with a screw cap and comprising a VP3 metered-dose spray and selection of buffers, isotonicity-adjusting agents, antioxi pump designed for intranasal application in a Volume of about dants, preservatives, viscosity-increasing agents, chelating 0.14 ml (Valois). For use, one or two sprays were adminis agents, and other excipients (including taste-masking agents tered to each nostril two times per day, or as prescribed. Such as Sucralose) and other components of the formulations for use in the co-administration embodiments of the present 60 Example 2 invention are described herein and readily determinable by those of skill in the art. Azelastine Hydrochloride Nasal Solution It has been found that co-administration of azelastine or a pharmaceutically acceptable Saltorester thereof (e.g., azelas In another exemplary composition provided by the present tine HCl) and one or more steroids provides a significant 65 invention, a nasal spray formulation containing azelastine improvement in patients suffering from allergic rhinitis, non hydrochloride was prepared using hypromellose as a thick allergic vasomotor rhinitis or allergic conjunctivitis, as com ener and Sucralose and menthol as taste-masking agents: US 8,758,816 B2 113 114 -continued Ingredient % Ingredient % Azelastine Hydrochloride O.100 Benzalkonium Chloride 50%, NF O.O2S Hypromellose 2900, USP 4000 O.300 Water Purified or Deionized Q.S. to 100% Edetate Disodium, USP O.OSO Sodium Citrate, USP, Dihydrate O.O68 Sucralose, NF O.OSO Following preparation, the composition was aseptically Propylene Glycol, USP 1.895 filtered, and was packaged into high density polyethylene Menthol, USP O.OSO Benzalkonium Chloride 50%, NF O.O2S 10 bottles fitted with low density polyethylene dropper tips and Water Purified or Deionized Q.S. to 100% a high density polyethylene protective cap. The droppers were designed for delivery of approximately 0.03 mL per Following preparation, the composition was filtered, and drop. For use, one drop was instilled into each affected eye was packaged into high density polyethylene bottles fitted twice a day, or as prescribed. with a screw cap and comprising a VP3 metered-dose spray 15 pump designed for intranasal applicationina Volume of about Example 5 0.14 ml (Valois). For use, one or two sprays were adminis Sensory Descriptive Bitterness Taste Analysis of tered to each nostril two times per day, or as prescribed. Astelin Nasal Spray Example 3 To determine effectiveness of masking agents in improving the taste of Astelin RNasal Spray, a sensory evaluation of Azelastine Hydrochloride Nasal Solution various formulations was conducted. Testing was carried out via a randomized, double-blind, placebo-controlled trial to In another exemplary composition of the invention, a nasal 25 evaluate comparability between the currently FDA-approved spray formulation containing azelastine hydrochloride was Astelin R. Nasal Spray formulation and various sweetened prepared using hypromellose as a thickener, Sodium chloride aZelastine hydrochloride nasal spray formulations. The as an isotonicity agent, and Sucralose as both a Sweetener and objective of the study was to determine if a sweetened for a taste-masking agent. mulation of azelastine hydrochloride (containing 137 ug 30 azelastine HCl), that includes 0.15% sucralose as a taste masking agent, is equivalent in efficacy and safety to the currently approved formulation of Astelin(R) Nasal Spray Ingredient % (also containing 137 jug of azelastine HCl). Azelastine Hydrochloride O.100 Methodology: Hypromellose 2900, USP 4000 O.100 35 Edetate Disodium, USP O.OSO Panelists: Twelve highly trained descriptive panelists led Citric Acid Anhydrous, USP O.O44 by a panel leader. Dibasic Sodium Phosphate Heptahydrate, USP O486 Data Analysis: Data were entered into an Excel spread Sodium Chloride, USP O.687 sheet and proofed for accuracy. An analysis was conducted Sucralose, NF O.1SO Benzalkonium Chloride 50% Solution, NF O.O2S with the data using ANOVA and Duncan means separation at Water Purified or Deionized Q.S. to 100% 40 a confidence level of 95% using SPSS 13.0 for Windows. Methodology: Panelists measured the bitterness, noted other flavors perceived as well as observed the length of time Following preparation, the composition was filtered, and the bitterness lasted in the throat. was packaged into high density polyethylene bottles fitted All solutions were prepared with Milli-Q Water with a screw cap and comprising a VP3 metered-dose spray 45 Standard Solutions pump designed for intranasal applicationina Volume of about 0.05% caffeine, bitter 2 0.14 ml (Valois). For use, one or two sprays were adminis 0.08% caffeine, bitter 5 tered to each nostril about two times per day, or as prescribed. 0.11% caffeine, bitter 7.5 Example 4 Test samples were coded with random three-digit numbers. 50 Panelists scored samples on ballots individually. Samples were evaluated by panelists using a 15-point intensity scale Azelastine Hydrochloride Ocular Solution divided into 0.1 point increments with Zero indicating no measurable effect and 15 indicating an extremely strong In another exemplary composition provided by the present effect. invention, an ocular formulation containingaZelastine hydro 55 Product Identification: chloride was prepared using hypromellose as a thickener, (1) Astelin Nasal Spray Batch #1326 (two sprays) (azelas Sorbitol as an isotonicity agent, and Sucralose as a taste tine hydrochloride, 137 ugazelastine HCl per two sprays) masking agent: (2) Astelin Nasal Spray Batch #1326 (four sprays) (azelas tine hydrochloride, 137 ugazelastine HCl per two sprays) 60 (3) Astelin Nasal Spray Batch #03-33-01c (two sprays) Ingredient % (azelastine hydrochloride solution 0.1% w/v Investigational Formulation with sorbitol and high concentration of sucral Azelastine Hydrochloride O.OSO ose, 137 ugaZelastine HCl per two sprays) Hypromellose 2900, USP 4000 O.100 Edetate Disodium, USP O.OSO (4) Astelin Nasal Spray Batch #03-33-01c (four sprays) Sucralose, NF O.1SO 65 (azelastine hydrochloride solution 0.1% w/v Investigational Sorbitol Solution 70%, USP 6.667 Formulation with sorbitol and high concentration of sucral ose, 137 ugaZelastine HCl per two sprays). US 8,758,816 B2 115 116 (1) Results and Discussion The 03-33-01c samples were significantly less bitter and (A) Commercial Formulation (Standard Azelastine Hydro gave less nasal discomfort than the Commercial Formulation. chloride Commercial Formulation) The 03-33-01c samples were equally preferred due to the This sample and sample 1326 four sprays exhibited the masking Sweetness. most bitterness with nasal discomfort that fell between mild 5 and moderate. The bitterness was more intense in those who experienced more drainage. However, the bitterness dissi Example 6 pated within 30 minutes for most panelists. A couple of pan elists experienced some residual bitterness for 2 to 3 hours Preservative Free Ocular Solution for Unit Dose after testing. The nasal discomfort was predominately 10 described as tingling, cooling or slight burning. (B) Sample 1326 Four Sprays One exemplary composition provided by the present inven This sample and the Commercial Formulation displayed tion, is a liquid dosage formulation containing azelastine the most bitterness with nasal discomfort that fell between is hydrochloride prepared using hypromellose as a thickener mild and moderate. Several panelists described this sample as and Sucralose and menthol as a taste-masking agent in the similar or identical to the Commercial Formulation. As with ranges provided below: the Commercial Formulation, most panelists did not notice any bitterness after 30 minutes. (C) Sample 1326 Two Sprays 2O Ingredient % This sample was significantly less bitter than the Commer Azelastine Hydrochloride O.OSOO-1SO cial Formulation using four sprays. Additionally, the nasal Hypromellose 2900, USP 4000 O.300 discomfort was lessened and described as mild. For most, the Edetate Disodium, USP O.OSO bitterness lasted less than 30 minutes. Some panelists ques Sodium Citrate, USP, Dihydrate O.O68 Sucralose, NF O.OSO-O.1SO tioned the effectiveness of two sprays versus four sprays. 25 Propylene Glycol, USP 1.895 (D) Sample 03-33-01c Four Sprays Water Purified or Deionized Q.S. to 100% While this sample was also significantly less bitter than the Commercial Formulation using four sprays, the Sweetness was notable. Following preparation, the Solution is filtered, and pack The nasal discomfort was described as mild and similar to 30 aged into high density polyethylene containers. An approxi Sample 1326 two sprays and 03-33-01c two sprays. Most mateunit dose volume of about 0.25 mL to 1 mL is filled in the panelists described this sample as more sweet than bitter. As container which has a capacity of about 1 mL. The use of a they experienced drainage, the Sweet flavor intensified over single unit-dose container eliminates the concerns of con riding any bitterness. Both sweet and bitter flavors dissipated tamination and provides the convenience of portability. within an hour. 35 (E) Sample 03-33-01c Two Sprays Example 7 This sample exhibited the least bitterness. Although the panelists noted a slight Sweetness in this sample, it was not nearly as strong as when using four sprays. The Sweetness did Azelastine Hydrochloride Nasal Solution not override the slight bitterness as it did when using four 40 Comprising Steroid sprays. The nasal discomfort was described as mild. Most indicated no bitter or Sweet taste after 30 minutes. The bitter One exemplary composition of the invention is a nasal ness faded faster than the sweetness. As with Sample 1326 spray formulation containing azelastine hydrochloride pre two sprays, some panelists questioned the effectiveness of pared using hypromellose as a thickener, a steroid, and Sucral two sprays versus four. 45 ose as both a Sweetener and a taste-masking agent. Panelists Preferences Of the fourtest samples, 4 of 11 panelists ranked 03-33-01c two sprays as their first choice. Four panelists ranked it as their second choice. They liked the slight sweetness that Ingredient % masked the bitterness; however, several did question whether 50 Azelastine Hydrochloride O.OS-O.1SO two sprays were as effective as four. Steroid (fluticaSone, mometaSone, O.O1-2.0 Four of eleven panelists chose 03-33-01c four sprays as dexamethasone beloxil, loteprednol (e.g., their first choice with four indicating it would be their second loteprednoletabonate), budesonide, or triamcinolone) choice. Again, they preferred the sweet flavor that masked the Hypromellose 2900, USP 4000 O.100 bitterness and they felt it was effective. 55 Edetate Disodium, USP O.OSO Three of eleven panelist chose 1326 two sprays as their first Sorbitol 70%, USP 6.400 choice, with one choosing it as a second choice. Some did not Sodium Citrate, USP, Dihydrate O.O68 Sucralose, NF O.1-0.15 like the sweetness and preferred a slight bitterness. Some Benzalkonium Chloride 50% Solution, NF O.O2S questioned the effectiveness of two sprays. Water Purified or Deionized Q.S. to 100% No panelists ranked 1326 four sprays as their first choice. 60 One panelist chose it as her second choice because she did not like the sweet taste at all. Following preparation, the Solution is packaged into high (2) Conclusions density polyethylene bottles fitted with a screw cap and com The panelists recognized the Commercial Formulation and prising a VP3 metered-dose spray pump designed for intra sample 1326 four sprays as the same. 65 nasal application of about 0.14 ml (Valois). For use, one or Using two sprays of sample 1326 helped significantly with two sprays can be administered to each nostril two times per the bitterness and nasal discomfort. day, or as prescribed. US 8,758,816 B2 117 118 Example 8 pared using hypromellose as a thickener, an NSAID, and Sucralose as both a Sweetener and a taste-masking agent. Azelastine Hydrochloride Nasal Solution Comprising Leukotriene Antagonist One exemplary composition of the invention is a nasal Ingredient % spray formulation containing azelastine hydrochloride pre Azelastine Hydrochloride O.OS-O.1SO pared using hypromellose as a thickener, a leukotriene NSAID (ibuprofen, diclofenac, O. 1-1O.O antagonist, and Sucralose as both a Sweetener and a taste aceclofenac or naproxen) 10 Hypromellose 2900, USP 4000 O.100 masking agent. Edetate Disodium, USP O.OSO Sorbitol 70%, USP 6.400 Sodium Citrate, USP, Dihydrate O.O68 Optionally, Sucralose, NF O.1-0.15 Benzalkonium Chloride 50% Solution, NF O.O2S Ingredient % Water Purified or Deionized Q.S. to 100% 15 Azelastine Hydrochloride O.OS-O.1SO Leukotriene antagonist (montelukast) O.1-5.O Hypromellose 2900, USP 4000 O.100 Following preparation, the Solution is packaged into high Edetate Disodium, USP O.OSO density polyethylene bottles fitted with a screw cap and com Sorbitol 70%, USP 6.400 prising a VP3 metered-dose spray pump designed for intra Sodium Citrate, USP, Dihydrate O.O68 Sucralose, NF O. 1-0.15 nasal application of about 0.14 ml (Valois). For use, one or Benzalkonium Chloride 50% Solution, NF O.O2S two sprays can be administered to each nostril two times per Water Purified or Deionized Q.S. to 100% day, or as prescribed. Following preparation, the Solution is packaged into high Example 11 density polyethylene bottles fitted with a screw cap and com 25 prising a VP3 metered-dose spray pump designed for intra Azelastine Hydrochloride Nasal Solution nasal application of about 0.14 ml (Valois). For use, one or Comprising Steroid and Decongestant two sprays can be administered to each nostril two times per day, or as prescribed. One exemplary composition of the invention is a nasal 30 spray formulation containing azelastine hydrochloride pre Example 9 pared using hypromellose as a thickener, a steroid, a decon gestant, and Sucralose as both a Sweetener and a taste-mask Azelastine Hydrochloride Nasal Solution ing agent. Comprising Decongestant 35 One exemplary composition of the invention is a nasal spray formulation containing azelastine hydrochloride pre Ingredient % pared using hypromellose as a thickener, a decongestant, and Azelastine Hydrochloride O.OS-O.1SO Sucralose as both a Sweetener and a taste-masking agent. Steroid (fluticaSone, mometaSone, O.O1-2.0 40 dexamethasone beloxil, loteprednol (e.g., loteprednoletabonate), budesonide, or triamcinolone) Decongestant (pseudoephedrine or 0.1-1.0 Ingredient % phenylephrine) Hypromellose 2900, USP 4000 O.100 Azelastine Hydrochloride O.OS-O.1SO 45 Edetate Disodium, USP O.OSO Decongestant (pseudoephedrine or 0.1-2.0 Sorbitol 70%, USP 6.400 phenylephrine) Sodium Citrate, USP, Dihydrate O.O68 Hypromellose 2900, USP 4000 O.100 Optionally, Sucralose, NF O.1-0.15 Edetate Disodium, USP O.OSO Benzalkonium Chloride 50% Solution, NF O.O2S Sorbitol 70%, USP 6.400 Water Purified or Deionized Q.S. to 100% Sodium Citrate, USP, Dihydrate O.O68 Optionally, Sucralose, NF O. 1-0.15 50 Benzalkonium Chloride 50% Solution, NF O.O2S Following preparation, the composition is packaged into Water Purified or Deionized Q.S. to 100% high density polyethylene bottles fitted with a screw cap and comprising a VP3 metered-dose spray pump designed for Following preparation, the Solution is packaged into high intranasal application of about 0.14 ml (Valois). For use, one density polyethylene bottles fitted with a screw cap and com 55 or two sprays can be administered to each nostril two times prising a VP3 metered-dose spray pump designed for intra per day, or as prescribed. nasal application of about 0.14 ml (Valois). For use, one or two sprays can be administered to each nostril two times per Example 12 day, or as prescribed. 60 Azelastine Hydrochloride Nasal Solution Example 10 Comprising Steroid and Leukotriene antagonist Azelastine Hydrochloride Nasal Solution One exemplary composition of the invention is a nasal Comprising NSAID spray formulation containing azelastine hydrochloride pre 65 pared using hypromellose as a thickener, Steroid, a leukot One exemplary composition of the invention is a nasal riene antagonist, and Sucralose as both a Sweetener and a spray formulation containing azelastine hydrochloride pre taste-masking agent. US 8,758,816 B2 119 120 a taste-masking agent, such as Sucralose, in the pharmaceu tical formulations (whetherformulations of each agent alone, Ingredient % or a single formulation containing both agents) is highly Azelastine Hydrochloride O.OS-O.1SO desired, to enhance patient compliance and thereby maximize Steroid (fluticaSone, mometaSone, O.O1-2.O therapeutic benefit. dexamethasone beloxil, loteprednol (e.g., The results of the clinical trial are summarized and pre loteprednoletabonate), budesonide, or sented in Appendix A hereinbelow and in FIGS. 1-6. FIG. 1 triamcinolone) shows the effect on the total nasal symptom score (TNSS) for Leukotriene antagonist (montelukast) O.1-5.O Hypromellose 2900, USP 4000 O.100 all three treatment groups. The co-administration of (aZelas Edetate Disodium, USP O.OSO 10 tine hydrochloride (HCl)) and (fluticasone propionate) dem Sorbitol 70%, USP 6.400 onstrated a reduction in the TNSS versus either agent alone. Sodium Citrate, USP, Dihydrate O.O68 FIGS. 2-5 show the mean improvement in severity score (0-3 Optionally, Sucralose, NF O. 1-0.15 scale) from baseline for the symptoms of runny nose, itchy Benzalkonium Chloride 50% Solution, NF O.O2S nose, Sneezing and congestion, respectively. In all cases, the Water Purified or Deionized Q.S. to 100% co-administration of (azelastine hydrochloride (HCl)) and 15 (fluticasone propionate) demonstrated a reduction in the Following preparation, the Solution is packaged into high severity of the symptom versus either agent alone. FIG. 6 density polyethylene bottles fitted with a screw cap and com shows the cumulative improvement in TNSS versus baseline prising a VP3 metered-dose spray pump designed for intra using area under the curve (AUC) units, indicating a greater than 40% improvement in TNSS versus either active agent nasal application of about 0.14 ml (Valois). For use, one or alone. Taken together, these results demonstrate that a signifi two sprays can be administered to each nostril two times per cant and unexpected therapeutic benefit is obtained by co day, or as prescribed. administration of azelastine HCl and fluticasone propionate, beyond the response that was expected based on therapeutic Example 13 results observed by administration of either agent alone. 25 A number of studies have examined the additive benefit of Co-Administration of Azelastine Hydrochloride and combining a nasal steroid with an oral antihistamine or a Fluticasone Propionate leukotriene antagonist in rhinitis (Juniper et al., J. Allergy Clin. Immunol. 83(3):627-633 (1989); Ratner et al., J. Fam. A two-week, randomized, double-blind study, which Pract. 47(2):118-125 (1998); Simpson, R. J. Ann. Allergy evaluated the effects of the co-administration of ASTELINR) 73(6):497-502 (1994); Backhouse et al., J. Int. Med. Res. 30 14(1):35-41 (1986); Juniper et al., CMAJ 156(8): 1123-1131 (azelastine hydrochloride (HCl)) and FLONASE(R) (flutica (1997); Barnes et al., Clin. Exp. Allergy 36(5):676-684 (May sone propionate) compared to either product alone in patients 2006); Di Lorenzo et al., Clin. Exp. Allergy 34(2):259-67 with seasonal allergic rhinitis (SAR) was conducted during (2004)). The majority of these studies showed that the com the 2006 Texas mountain cedar season. After a 5-day placebo bination of an oral rhinitis agent with a nasal Steroid was no lead-in period, 151 patients with moderate-to-severe allergic 35 better, with respect to improvement in Symptoms and total rhinitis symptoms were randomized to either: (1) (49 total symptom scores, than the nasal steroid alone; a few of the patients) ASTELINR) (azelastine hydrochloride (HCl)) plus studies demonstrated only minimal improvement. For placebo Saline nasal spray 2 sprays per nostril, 15 minutes example, in a study examining the administration of flutica apart, twice daily (AM & PM); (2) (50 total patients) FLO Sone propionate and loratadine alone or in combination, no NASER (fluticasone propionate) plus placebo saline nasal 40 incremental benefit was observed in TNSS (itchy nose, sneez spray, 2 sprays per nostril, 15 minutes apart, once daily (AM) ing, runny nose, nasal congestion) or Rhinitis Quality of Life and two sessions of placebo Saline nasal spray, 2 sprays per Questionnaire (ROLO) when comparing the combination of nostril, 15 minutes apart (PM); or (3) (52 total patients) the these agents versus fluticasone propionate alone (Ratner et co-administration of ASTELINR) (azelastine hydrochloride al., J. Fam. Pract. 47(2):118-125 (1998)). In another study, the (HCl)) 2 sprays per nostril plus FLONASER (fluticasone 45 addition of levocetirizine to fluticasone propionate did not propionate) 2 sprays per nostril (AM), 15 minutes apart, and provide incremental relief in TNSS, ROLO or peak nasal inspiratory flow relative to results with fluticasone propionate ASTELINR) (azelastine hydrochloride (HCl)) 2 sprays per alone (Barnes et al., Clin. Exp. Allergy 36(5):676-684 (May nostrill plus placebo Saline nasal spray, 15 minutes apart, (PM) 2006)). In a study examining the effects of administration of for a 2-week double-blind treatment period. fluticasone propionate alone versus co-administration of flu The primary efficacy variable was the change from base 50 ticasone with cetirizine or montelukast, no incremental line in the Total Nasal Symptom Score (TNSS), which com improvement in TNSS was observed with the combination of prised Sneezing, itchy nose, runny nose, and nasal congestion fluticasone and cetirizine versus fluticasone alone; similarly, (individual symptoms scores were assigned a value between there was no incremental benefit in TNSS with the combina 0 and 3, where 0-no symptoms and 3-severe symptoms). tion of fluticaSone and montelukast versus fluticaSone alone This study was not statistically designed to assess the differ 55 (Di Lorenzo et al., Clin. Exp. Allergy 34(2):259-67 (2004)). ences between ASTELINR) and FLONASE(R). In contrast, as shown above, in the present studies adminis The most common adverse events (AEs) were bitter taste tration of ASTELINR) brand azelastine HCl nasal spray in (8.2% in ASTELINR) (azelastine hydrochloride (HCl)) combination with fluticasone propionate demonstrated a group, 2.0% in FLONASER (fluticasone propionate) group, magnitude of response that is both clinically meaningful and 13.5% in co-administration group) and headache (4.1% in 60 statistically Superior to the individual components. ASTELINR) (azelastine hydrochloride (HCl)) group, 4.0% in FLONASER (fluticasone propionate) group, 5.8% in co-ad Example 14 ministration group). No other AE was reported by more than one patient in any treatment group. There were no discontinu Unit Dose Azelastine Hydrochloride Ocular Solution ations due to AEs. The significantly higher bitter taste AE 65 score for the co-administration group versus that seen in the In one exemplary composition provided by the present groups receiving either agent alone indicates that inclusion of invention, a unit dose ocular formulation containing azelas US 8,758,816 B2 121 122 tine hydrochloride was prepared using hypromellose as a and optionally using one or more taste-masking agents (e.g., thickener, Sorbitol as an isotonicity agent, and including Sucralose and/or menthol), but without the inclusion of any Sucralose as a taste-masking agent: preservative:

Ingredient % (w/v) Ingredient % Azelastine Hydrochloride O.OSO Azelastine Hydrochloride O.OSOO-1SO Hypromellose 2900, USP 4000 O.100 Hypromellose 2900, USP 4000 O.300 Edetate Disodium, USP O.OSO 10 Edetate Disodium, USP O.OSO Sucralose, NF O.1SO Sodium Citrate, USP, Dihydrate O.O68 Sorbitol Solution 70%, USP 6.667 Sucralose, NF O.OSO-O.1SO Benzalkonium Chloride 50%, NF O.O2S Sorbitol Solution 70%, USP 6.667 Water Purified or Deionized Q.S. to 100% Propylene Glycol, USP 1.895 Water Purified or Deionized Q.S. to 100% 15 Following preparation, the composition was aseptically Following preparation, the solution was filtered, and pack filtered, and was packaged using a “blow-fill-seal' packaging aged into high density polyethylene containers. Such compo approach into high density polyethylene (HDPE) containers sitions are particularly amenable for use in the unit dose such as those depicted in FIGS. 7-8, at a volume of approxi configurations provided by the present invention since upon mately 0.24 ml per container into the unit dosage containers single use the container and any residual pharmaceutical that had a Volume of approximately 1 ml. composition contained therein is discarded. Thus, in this The thickness of the walls of the container were optimized exemplary embodiment, an approximate unit dose Volume of So as to allow Squeezability to ensure delivery of the appro about 0.25 ml to about 0.5 ml was filled into each low volume priate amount of the formulation. HDPE container using the “blow-fill-seal approach described in Example 14 herein. For use, one drop was For use, one drop was instilled into each affected eye twice 25 instilled into each affected eye twice a day, or as prescribed. a day, or as prescribed. Following a single use (defined as Following a single use (defined as application of the appro application of the appropriate number of drops into each eye priate number of drops into each eye from a single unit dose from a single unit dose container), the container was dis container), the container was discarded Such that for the next carded Such that for the next application, a new unit dose application, a new unit dose container was used. The use of a container was used. Thus, two separate single unit dose con 30 single unit-dose container eliminates the concerns of con tainers were used per day per patient, one for the first dosing tamination (which is particularly important for preservative and one for the second dosing. free compositions such as those described in this Example), and provides the convenience of portability; both of these Example 15 aspects have been found to improve patient compliance with 35 prescribing regimens in the treatment of allergic ocular con Preservative Free Ocular Solution for Unit Dose ditions such as allergic conjunctivitis associated with sea Sonal, vasomotor or perennial allergies. Another exemplary composition provided by the present invention is a liquid dosage formulation containing azelastine hydrochloride prepared using hypromellose as a thickener APPENDIX A

MedPoints Pharmaceuticals MP 428 Program: PATDISP. SAS 14.1.1 Patient Disposition All Randomized Patients (Page 1 of 1) Azelastine + Azelastine FluticaSone FluticaSone Total All Randomized Patients (N) 49 50 52 151 Number of Patients Who Completed Study N (%) 49 (100.0) 48 (96.0) 50 (96.2) 147 (97.4) Number of Patients Who Discontinued Study N (%) 0 (0.0) 2 (4.0) 2 (3.8) 4 (2.6) Primary Reason for Discontinuation From Study N (%) Adverse Event 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Treatment Failure 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) Non-Compliance 0 (0.0) 0 (0.0) 2 (3.8) 2 (1.3) Patient Withdrew Consent 0 (0.0) 1 (2.0) 0 (0.0) 1 (0.7) Lost to Follow-Up 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Administrative Problems 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Other 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Safety Population N (%) 49 (100.0) 50 (100.0) 52 (100.0) 151 (100.0) Intent-to-Treat Population N (%) 49 (100.0) 50 (100.0) 52 (100.0) 151 (100.0) Per-Protocol Population N (%) 49 (100.0) 47 (94.0) 48 (92.3) 144 (95.4) Safety Population includes all randomized patients who took at least one dose of the study drug. Intent-to-Treat Population (ITT) includes all patients who were randomized and had at least one postbaseline observation. Per-Protocol Population includes all patients who completed the 2-week treatment period per protocol. Note: all percentages are based on all randomized patients shown in the same column, Reference: 16.2.1 US 8,758,816 B2 123 124

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.1 Patient Demographics and Baseline Characteristics Intent-to-Treat Population (Page 1 of 4)

Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151)

Age (Years) N 49 50 52 151 Mean 38.4 37.4 36.0 37.2 Standard Deviation 15.36 14.78 14.75 14.89 Median 36.0 37.5 36.5 37.0 Min-Max 12-73 12-72 13-70 12-73 12 to <18 N(%) 3 (6.1) 6 (12.0) 5 (9.6) 14 (9.3) 18 to <65 N(%) 42 (85.7) 43 (86.0) 45 (86.5) 130 (86.1) 65 or older N(%) 4 (8.2) 1 (2.0) 2 (3.8) 7 (4.6) Sex N(%) Male 22 (44.9) 15 (30.0) 19 (36.5) 56 (37.1) Female 27 (55.1) 35 (70.0) 33 (63.5) 95 (62.9) Race N(%) Asian or Pacific Islander 0 (0.0) 3 (6.0) 1 (1.9) 4 (2.6) Hispanic or Latino 7 (14.3) 13 (26.0) 8 (15.4) 28 (18.5) Black or African American 5 (10.2) 2 (4.0) 2 (3.8) 9 (6.0) American Indian or 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Alaska Native White or Caucasian 36 (73.5) 32 (64.0) 41 (78.8) 109 (72.2) Other 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7)

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.1 Patient Demographics and Baseline Characteristics Intent-to-Treat Population (Page 2 of 4)

Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151)

Height (in) N 49 50 52 151 Mean 65.9 65.2 65.7 65.6 Standard Deviation 4.45 4.22 4.33 4.32 Median 6S.O 6S.O 6S.O 6S.O Min-Max S6-74 56-78 58-79 56-79 Height (in) N 3 6 5 14 (Age 12 to <18 Years) Mean 59.7 63.2 63.2 62.4 Standard Deviation 1.53 4.45 4.06 3.91 Median 6O.O 63.5 61.O 61.0 Min-Max 58-61 56-69 59-68 56-69 Height (in) N 46 44 47 137 (Ages 18 Years) Mean 66.3 65.5 66.O 65.9 Standard Deviation 4.28 4.17 4.32 4.24 Median 6S.O 6S.O 6S.O 6S.O Min-Max S6-74 56-78 58-79 56-79

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.1 Patient Demographics and Baseline Characteristics Intent-to-Treat Population (Page 3 of 4)

Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151)

Weight (1b) N 49 50 52 151 Mean 1812 172.9 173.8 175.9 Standard Deviation 47.09 40.42 51.05 46.30 Median 1740 168.5 162.5 169.0 Min-Max 98-284 85-269 99-303 85-303 Weight (1b) N 3 6 5 14 (Age 12 to <18 Years) Mean 104.7 136.3 128.1 126.6 Standard Deviation 7.02 46.66 21.20 33.75 Median 104.O 122.5 121.4 118.0 Min-Max 98-112 85-199 108-163 85-199 US 8,758,816 B2 125 126 -continued

Weight (1b) N 46 44 47 137 (Ages 18 Years) Mean 1862 177.9 1786 18O.9 Standard Deviation 44.12 37.37 SO.99 4449 Median 177.8 169.5 1690 1710 Min-Max 102-284 117-269 99-303 99-303

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.1 Patient Demographics and Baseline Characteristics Intent-to-Treat Population (Page 4 of 4)

Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151)

Total Score N 49 50 52 151 Mean 19.6 19.5 19.5 19.5 Standard Deviation 2.11 2.74 2.97 2.62 Median 19.7 19.4 19.5 19.7 Min-Max 15-24 14-24 13-24 13-24 Duration of Texas Mountain N 49 50 52 151 Cedar Allergy (Years) Mean 19.2 15.7 16.2 17.0 Standard Deviation 13.32 9.69 9.15 10.87 Median 16.0 14.O 13.5 14.O Min-Max 3-SO 3-51 4-40 3-51

Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. References: 16.2.4.1 and 16.2.6.1

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.2 Patient Demographics and Baseline Characteristics Per-Protocol Population (Page 1 of 4) Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 47) (N = 48) (N = 144) Age (Years) N 49 47 48 144 Mean 38.4 35.9 35.8 36.7 Standard Deviation 15.36 13.89 15.09 14.75 Median 36.0 37.0 36.0 36.0 Min-Max 12-73 12-61 13-70 12-73 12 to <18 N(%) 3 (6.1) 6 (12.8) 5 (10.4) 14 (9.7) 18 to <65 N(%) 42 (85.7) 41 (87.2) 41 (85.4) 124 (86.1) 65 or older N(%) 4 (8.2) O (0.0) 2 (4.2) 6 (4.2) Sex N(%) Male 22 (44.9) 15 (31.9) 19 (39.6) 56 (38.9) Female 27 (55.1) 32 (68.1) 29 (60.4) 88 (61.1) Race N(%) Asian or Pacific Islander 0 (0.0) 3 (6.4) 1 (2.1) 4 (2.8) Hispanic or Latino 7 (14.3) 13 (27.7) 6 (12.5) 26 (18.1) Black or African American 5 (10.2) 2 (4.3) 2 (4.2) 9 (6.3) American Indian or 0 (0.0) O (0.0) 0 (0.0) 0 (0.0) Alaska Native White or Caucasian 36 (73.5) 29 (61.7) 39 (81.3) 104 (72.2) Other 1 (2.0) O (0.0) 0 (0.0) 1 (0.7) MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.2 Patient Demographics and Baseline Characteristics Per-Protocol Population (Page 2 of 4) Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 47) (N = 48) (N = 144) Height (in) N 49 47 48 144 Mean 65.9 65.1 65.9 65.6 Standard Deviation 4.45 4.33 4.28 4.34 Median 6S.O 6S.O 65.2 6S.O Min-Max S6-74 56-78 59-79 56-79 US 8,758,816 B2 127 128 -continued Height (in) N 3 6 5 14 (Age 12 to <18 Years) Mean 59.7 63.2 63.2 624 Standard Deviation 1.53 4.45 4.06 3.91 Median 6O.O 63.5 61.O 61.O Min-Max 58-61 56-69 59-68 56-69 Height (in) N 46 41 43 130 (Ages 18 Years) Mean 66.3 65.4 66.2 66.O Standard Deviation 4.28 4.30 4.25 4.26 Median 6S.O 6S.O 65.4 6S.O Min-Max S6-74 56-78 60-79 56-79

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.2 Patient Demographics and Baseline Characteristics Per-Protocol Population (Page 3 of 4) Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 47) (N = 48) (N = 144) Weight (1b) N 49 47 48 144 Mean 1812 173.4 1740 176.3 Standard Deviation 47.09 40.95 50.53 46.21 Median 1740 169.0 162.5 169.5 Min-Max 98-284 85-269 108-303 85-303 Weight (1b) N 3 6 5 14 (Age 12 to <18 Years) Mean 104.7 136.3 128.1 126.6 Standard Deviation 7.02 46.66 21.20 33.75 Median 104.O 122.5 121.4 118.0 Min-Max 98-112 85-199 108-163 85-199 Weight (1b) N 46 41 43 130 (Ages 18 Years) Mean 1862 178.9 1793 1816 Standard Deviation 44.12 37.68 S.O.34 44.23 Median 177.8 17O.O 1690 172.5 Min-Max 102-284 117-269 115-303 102-303

MedPointe Pharmaceuticals MP 428 Program: DEMOG. SAS 14.1.2.2 Patient Demographics and Baseline Characteristics Per-Protocol Population (Page 4 of 4) Azelastine + Azelastine FluticaSone FluticaSone Total Demographics Category/Statistics (N = 49) (N = 47) (N = 48) (N = 144)

Total Score N 49 47 48 144 Mean 19.6 19.5 19.3 19.5 Standard Deviation 2.11 2.74 2.97 2.62 Median 19.7 19.2 18.8 19.5 Min-Max 15-24 14-24 13-24 13-24 Duration of Texas Mountain N 49 47 48 144 Cedar Allergy (Years) Mean 19.2 14.5 16.5 16.8 Standard Deviation 13.32 8.14 9.38 10.65 Median 16.O 14.0 14.0 14.0 Min-Max 3-SO 3-36 4-40 3-SO Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. References: 16.2.4.1 and 16.2.6.1

MedPointe Pharmaceuticals MP 428 Program: RHINITIS. SAS 14.1.3 Rhinitis Diagnosis Screening Results Intent-to-Treat Population (Page 1 of 6) Azelastine + Azelastine FluticaSone FluticaSone Total Background Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151) Current Age (Years) N 45 44 47 136 Mean 4O.S 40.6 38.3 39.8 Standard Deviation 14.24 12.58 13.65 13:46 Median 42.O 39.0 38.0 39.0 Min-Max 18-73 18-72 18-70 18-73 US 8,758,816 B2 129 130 -continued Age of Symptoms Onset (Years) N 45 44 47 136 Mean 21.3 23.6 20.4 21.7 Standard Deviation 13.51 1214 12.58 12.73 Median 17.0 23.5 2O.O 19.0 Min-Max 3-57 1-SO 1-51 1-57 Parental History of Allergy N(%) N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 23 (46.9) 15 (30.0) 21 (40.4) 59 (39.1) No 11 (22.4) 9 (18.0) 13 (25.0) 33 (21.9) Don't Know 11 (22.4) 20 (40.0) 13 (25.0) 44 (29.1) Parent History of Asthma N(%) N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 6 (12.2) 4 (8.0) 9 (17.3) 19 (12.6) No 30 (61.2) 30 (60.0) 34 (65.4) 94 (62.3) Don't Know 9 (184) 10 (20.0) 4 (7.7) 23 (15.2) MedPointe Pharmaceuticals MP 428 Program: RHINITIS. SAS 14.1.3 Rhinitis Diagnosis Screening Results Intent-to-Treat Population (Page 2 of 6) Azelastine + Azelastine FluticaSone FluticaSone Total Background Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151) Symptoms Experienced N(%) N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) (All symptoms that apply) Sneezing 43 (87.8) 39 (78.0) 46 (88.5) 128 (84.8) Stuffy Nose 41 (83.7) 43 (86.0) 47 (90.4) 131 (86.8) Runny Nose 42 (85.7) 39 (78.0) 45 (86.5) 126 (83.4) Postnasal Drainage 41 (83.7) 40 (80.0) 42 (80.8) 123 (81.5) Itchy watery Eyes 42 (85.7) 42 (84.0) 43 (82.7) 127 (84.1) Ear Plugging 27 (55.1) 26 (52.0) 26 (50.0) 79 (52.3) Sinus Pressure 37 (75.5) 35 (70.0) 39 (75.0) 111 (73.5) MedPointe Pharmaceuticals MP 428 Program: RHINITIS. SAS 14.1.3 Rhinitis Diagnosis Screening Results Intent-to-Treat Population (Page 3 of 6) Azelastine + Azelastine FluticaSone FluticaSone Total Allergic Triggers N(%) Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151) Cat or Cat Hair N 45 (91.8) 44 (88.0) 47 (90.4) 36 (90.1) Yes 16 (32.7) 17 (34.0) 27 (51.9) 60 (39.7) No 20 (40.8) 13 (26.0) 15 (28.8) 48 (31.8) Don't Know 9 (184) 14 (28.0) 5 (9.6) 28 (18.5) Dog or Dog Hair N 45 (91.8) 44 (88.0) 47 (90.4) 36 (90.1) Yes 12 (24.5) 11 (22.0) 15 (28.8) 38 (25.2) No 30 (61.2) 27 (54.0) 27 (51.9) 84 (55.6) Don't Know 3 (6.1) 6 (12.0) 5 (9.6) 14 (9.3) Other Furry Animals N 45 (91.8) 44 (88.0) 47 (90.4) 36 (90.1) Yes 6 (12.2) 9 (18.0) 13 (25.0) 28 (18.5) No 22 (44.9) 21 (42.0) 22 (42.3) 65 (43.0) Don't Know 17 (34.7) 14 (28.0) 12 (23.1) 43 (28.5) Symptoms During Spring N 45 (91.8) 44 (88.0) 47 (90.4) 36 (90.1) Summer, or Fall Yes 39 (79.6) 38 (76.0) 39 (75.0) 16 (76.8) No 5 (10.2) 3 (6.0) 6 (11.5) 14 (9.3) Don't Know 1 (2.0) 3 (6.0) 2 (3.8) 6 (4.0) Any Allergic Triggers N 45 (91.8) 44 (88.0) 47 (90.4) 36 (90.1) Yes 42 (85.7) 41 (82.0) 44 (84.6) 27 (84.1) No 3 (6.1) 3 (6.0) 3 (5.8) 9 (6.0) Don't Know 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

MedPointe Pharmaceuticals MP 428 Program: RHINITIS. SAS 14.1.3 Rhinitis Diagnosis Screening Results Intent-to-Treat Population (Page 4 of 6)

Azelastine + Azelastine FluticaSone FluticaSone Total Non-allergic Triggers N(%) Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151) Temperature or Humidity Changes N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 30 (61.2) 29 (58.0) 33 (63.5) 92 (60.9) No 7 (14.3) 9 (18.0) 5 (9.6) 21 (13.9) Don't Know 8 (16.3) 6 (12.0) 9 (17.3) 23 (15.2) US 8,758,816 B2 131 132 -continued Smoke N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 25 (51.0) 22 (44.0) 27 (51.9) 74 (49.0) No 14 (28.6) 18 (36.0) 16 (30.8) 48 (31.8) Don't Know 6 (12.2) 4 (8.0) 4 (7.7) 14 (9.3) Perfumes or Fragrances N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 24 (49.0) 24 (48.0) 19 (36.5) 67 (44.4) No 19 (38.8) 16 (32.0) 22 (42.3) 57 (37.7) Don't Know 2 (4.1) 4 (8.0) 6 (11.5) 12 (7.9) Incense or Candles N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 13 (26.5) 22 (44.0) 12 (23.1) 47 (31.1) No 28 (57.1) 18 (36.0) 29 (55.8) 75 (49.7) Don't Know 4 (8.2) 4 (8.0) 6 (11.5) 14 (9.3) Household Cleaning Products N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 16 (32.7) 20 (40.0) 18 (34.6) 54 (35.8) No 23 (46.9) 22 (44.0) 24 (46.2) 69 (45.7) Don't Know 6 (12.2) 2 (4.0) 5 (9.6) 13 (8.6)

MedPointe Pharmaceuticals MP 428 Program: RHINITIS. SAS 14.1.3 Rhinitis Diagnosis Screening Results Intent-to-Treat Population (Page 5 of 6)

Azelastine + Azelastine FluticaSone FluticaSone Total Non-allergic Triggers N(%) Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151)

Any Non-allergic Triggers N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) Yes 42 (85.7) 39 (78.0) 39 (75.0) 120 (79.5) No 3 (6.1) 5 (10.0) 7 (13.5) 15 (9.9) Don't Know 0 (0.0) 0 (0.0) 1 (1.9) 1 (0.7)

MedPointe Pharmaceuticals MP 428 Program: RHINITIS. SAS 14.1.3 Rhinitis Diagnosis Screening Results Intent-to-Treat Population (Page 6 of 6)

Azelastine + Drugs That Symptoms Responded Azelastine FluticaSone FluticaSone Total Well in the Past N(%) Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151)

Non-Sedating Antihistamines N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) No Effect 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) Small Effect 10 (20.4) 7 (14.0) 10 (19.2) 27 (17.9) Moderate Effect 18 (36.7) 19 (38.0) 21 (40.4) 58 (38.4) Big Effect 9 (184) 11 (22.0) 9 (17.3) 29 (19.2) Don't Know 7 (14.3) 7 (14.0) 7 (13.5) 21 (13.9) Nasal Corticosteriods N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) No Effect 1 (2.0) 0 (0.0) 0 (0.0) 1 (0.7) Small Effect 5 (10.2) 1 (2.0) 6 (11.5) 12 (7.9) Moderate Effect 11 (22.4) 18 (36.0) 21 (40.4) 50 (33.1) Big Effect 9 (184) 7 (14.0) 8 (15.4) 24 (15.9) Don't Know 19 (38.8) 18 (36.0) 12 (23.1) 49 (32.5) Nasal Antihistamines N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) No Effect 1 (2.0) 2 (4.0) 0 (0.0) 3 (2.0) Small Effect 2 (4.1) 1 (2.0) 2 (3.8) 5 (3.3) Moderate Effect 9 (184) 12 (24.0) 13 (25.0) 34 (22.5) Big Effect 2 (4.1) 2 (4.0) 2 (3.8) 6 (4.0) Don't Know 31 (63.3) 27 (54.0) 30 (57.7) 88 (58.3) The Best Response From Any N 45 (91.8) 44 (88.0) 47 (90.4) 136 (90.1) of These Drugs No Effect 2 (4.1) 0 (0.0) 0 (0.0) 2 (1.3) Small Effect 8 (16.3) 2 (4.0) 8 (15.4) 18 (11.9) Moderate Effect 16 (32.7) 23 (46.0) 22 (42.3) 61 (40.4) Big Effect 15 (30.6) 15 (30.0) 13 (25.0) 43 (28.5) Don't Know 4 (8.2) 4 (8.0) 4 (7.7) 12 (7.9)

Reference: 16.2.4.3 US 8,758,816 B2 133 134

MedPointe Pharmaceuticals MP 428 Program: DUREXPO.SAS 14.1.4. Duration of Exposure and Compliance With Study Drugs Intent-to-Treat Population (Page 1 of 1)

Azelastine + Azelastine FluticaSone FluticaSone Total Category/Statistics (N = 49) (N = 50) (N = 52) (N = 151) Duration of Exposure (Days) N 49 50 52 151 Mean 14.6 14.1 14.3 14.3 Standard Deviation O.84 240 1.82 1.81 Median 1S.O 14.0 1S.O 1S.O Min-Max 12-16 1-18 6-19 1-19 Total Number of Doses Taken N 49 50 52 151 Mean 42.8 40.9 41.3 41.6 Standard Deviation 2.82 6.8O 6.13 5.57 Median 44.0 42.O 42.O 42.O Min-Max 30-47 3-51 1O-47 3-51 Number of Patients With 49 (100.0) 50 (100.0) 49 (94.2) 148 (98.0) e80% Compliance N(%) Each patient recieved 3 bottles of medication at each treatment visit. Two bottles were for AM dosing and the 3 bottle is for PM dosing. The patients were instructed to administer 2 sprays per nostril from each bottle once daily (3 doses total each day) at the specified time period (AM or PM) with a 15-30 minute wait between dosings from the two AM bottles, References: 16.2.5.1 and 16.2.6.1

MedPointe Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.1.1 AUC of Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 1 of 1)

Variable Standard ANOVA Time Point Treatment Na Mean LS Mean Deviation Minimum Median Maximum Source p-value TNSS (Am and PM Combined) Baseline Azelastine (A) 49 1960 1966 2.113 15.3 1970 24.0 Treatment 0.957 FluticasOne (F) 49 19.53 19.56 2.771 13.7 19.17 24.0 Azelastine + 52 1948 19.51 2.967 13.1 1945 24.0 Fluticasone (A + F) Change from Baseline in TNSS (AM and PM Combined) AUC Azelastine 49 6038 -59.72 54.570 -184.5 -56.OO 37.7 A wSA - F O.007 Fluticasone 49 6453 -65.00 S8.166 -231.3 -5113 49.7 F wSA - F O.O24 Azelastine + 52 -92.21 -92.85 70.981 -261.5 -94.SO Sf.8 Treatment O.O15 Fluticasone Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model for change. p-value for between treatment group comparison, except Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariant. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. Area-under-the-curve of change from baseline in TNSS from Day 1 to Day 14 with the change onlay 1 setto 0. The last-observation-carried-forward method was applied for missing TNSS scores proir to calculating the AUC. Reference: 16.2.6.1

MedPointe Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.1.2 AUC of Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 1 of 1)

Variable Standard ANOVA Time Point Treatment Na Mean LS Mean Deviation Minimum Median Maximum Source p-value TNSS (AM and PM Combined) Baseline Azelastine (A) 49 1960 1966 2.113 15.3 19.70 24.O Treatment FluticasOne (F) 47 19.52 1961 2.740 13.7 19.17 24.O Azelastine + 48 19.27 1940 2.973 13.1 18.8O 24.O Fluticasone (A + F) US 8,758,816 B2 135 136 -continued

Change from Baseline in TNSS (AM and PM Combined)

AUCe Azelastine 49 - 60.38 -59.23 54.570 -184.5 -56.00 37.7 A wSA - F Fluticasone 47 -65.66 -65.38 58.782 -231.3 -51.13 49.7 F wSA - F Azelastine + 48 -92.91 -94.O3 69.530 -261.5 -100.42 57.8 Treatment Fluticasone

Total number of per-protocol patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model for change. p-value for between treatment group comparison, except Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as covariant. For Baseline, the p-value was based on a ANOVA model containing treatment group and site as fixed effects. Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. Area-under-the-curve of change from baseline in TNSS from Day 1 to Day 14 with the change on Day 1 set to 0. The last-observation-carried-forward method was applied for missing TNSS scores proir to calculating the AUC. Reference: 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.1 Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 1 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

AM and PM Combined TNSS

Baseline Azelastine (A) 49 19.60 1966 2.113 5.3 19.70 24.0 Treatment O.958 FluticasOne (F) 50 19.53 19.57 2.742 3.7 19.38 24.0 Azelastine + Fluticasome 52 19.48 19.52 2.967 3.1 19.45 24.0 (A + F) Change from Baseline in AM and PM Combined TNSS

Overal/ Azelastine 49 -4.73 -4.76 4.297 -14.4 -4.24 3.1 <0.001. A wSA - F O.OO8 Fluticasone 49 -506 -5.24 4.582 -18.5 -391 3.7 <0.001 F wSA - F O.O29 Azelastine + Fluticasome 52 -7.22 -7.40 S.S86 -20.2 -7.33 4.7 <0.001 Treatment O.018 Day <0.001 Treatment * Day O.182 Day 2 Azelastine 49 -3.23 -3.10 4.33O -14.2 -2.67 4.1 <0.001. A wSA - F O.138 Fluticasone 49 -3.24 -3.12 4.331 -18.5 -2.00 2.7 <0.001 F wSA - F 0.144 Azelastine + Fluticasome 52 -4.53 -4.46 5.391 -16.1 -3.01 4.1 <0.001 Treatment O.232

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.1 Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 2 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined TNSS

Day 3 Azelastine 49 -3.28 -3.21 4.61O -16.2 -1.67 4.1 <0.001. A wSA - F O.OO9 Fluticasone 49 -4.12 -4.09 4.931 -18.5 -3.20 5.3 <0.001 F wSA - F O.O84 Azelastine + Fluticasome 52 -5.82 -5.8O 5.520 -17.1 -4.68 4.3 <0.001 Treatment O.O29 Day 4 Azelastine 49 -3.93 -3.89 S.O22 -17.2 -2.92 4.3 <0.001. A wSA - F O.OO9 Fluticasone 49 -4.53 -4.53 4.924 -18.5 -4.17 4.5 <0.001 F wSA - F O.O45 Azelastine + Fluticasome 52 -6.61 -6.62 S. 619 -17.1 -6.62 4.1 <0.001 Treatment O.O23 Day 5 Azelastine 49 -4.48 -4.46 5.225 -17.2 -367 4.2 <0.001. A wSA - F O.O14 Fluticasone 49 -516 -5.20 S.236 -18.5 -440 5.3 <0.001 F wSA - F O.O72 Azelastine + Fluticasome 52 -7.19 -7:23 6.28O -21.0 -6.85 6.1 <0.001 Treatment O.O39 US 8,758,816 B2 137 138 -continued

Day 6 Azelastine 49 -4.44 -440 S.147 -16.0 -3.7O 5.4 <0.001. A wSA - F O.OO3 Fluticasone 49 -510 -5.12 S.S24 -18.5 -4.45 5.3 <0.001 F wSA - F O.019 Azelastine + Fluticasome 52 -7.78 -7.82 6.225 -22.0 -7.99 S.1 <0.001 Treatment O.007

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.1 Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 3 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

Change from Baseline in AM and PM Combined TNSS

Day 7 Azelastine 49 -509 -5.05 S.OO6 -16.0 -4.67 5.4 <0.001. A wSA - F O.O28 Fluticasone 49 -SO2 -5.06 4.989 -18.5 -5.OO 5.5 <0.001 F wSA - F O.O28 Azelastine + Fluticasome 52 -7.42 -747 6.319 -23.0 -7.07 S.1 <0.001 Treatment O.O39 Day 8 Azelastine 49 -5.38 -5.37 5.056 -17.O -5.OO 2.4 <0.001. A wSA - F O.O15 Fluticasone 49 -4.55 -4.64 4.647 -18.5 -3.7O 3.7 <0.001 F wSA - F O.OO2 Azelastine + Fluticasome 52 -7.90 -7.98 6.O3S -21.0 -7.11 S.1 <0.001 Treatment O.OOS Day 9 Azelastine 49 -5.38 -5.36 4.799 -18.0 -3.83 2.1 <0.001. A wSA - F O.O33 Fluticasone 49 -5.08 -5.17 S.219 -18.5 -458 2.7 <0.001 F wSA - F O.O21 Azelastine + Fluticasome 52 -7.59 -7.68 6.184 -23.0 -7.15 4.1 <0.001 Treatment O.O37 Day 10 Azelastine 49 -5.36 -5.29 4.976 -15.O -533 4.0 <0.001. A wSA - F O.018 Fluticasone 49 -5.61 -5.64 5.676 -18.5 -4.83 9.2 <0.001 F wSA - F O.O39 Azelastine + Fluticasome 52 -7.94 -8.OO 6.375 -23.0 -7.14 S.1 <0.001 Treatment O.O3S

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.1 Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 4 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

Change from Baseline in AM and PM Combined TNSS

Day 11 Azelastine 49 -5.77 -5.70 5.576 -18.1 -4.70 3.8 <0.001. A wSA - F O.O21 Fluticasone 49 -5.77 -5.85 5.742 -18.5 -4.83 9.2 <0.001 F wSA - F O.O28 Azelastine + Fluticasome 52 -8.28 -8.39 6.459 -23.0 -7.72 4.3 <0.001 Treatment O.O33 Day 12 Azelastine 49 -5.54 -546 6.109 -19.0 -5.OO 4.2 <0.001. A wSA - F O.O17 Fluticasone 49 -6.08 -6.12 5.874 -18.9 -5.17 9.2 <0.001 F wSA - F O.062 Azelastine + Fluticasome 52 -8.32 -8.40 6.652 -24.0 -7.93 4.1 <0.001 Treatment O.041 Day 13 Azelastine 49 -5.70 -5.65 6.06O -19.0 -5.30 5.7 <0.001. A wSA - F O.O16 Fluticasone 49 - 6.83 -6.95 6.345 -18.9 -6.20 9.2 <0.001 F wSA - F O.176 Azelastine + Fluticasome 52 -8.48 -8.61 6.513 -24.0 -8.43 5.8 <0.001 Treatment O.OS4 Day 14 Azelastine 49 -5.62 -5.56 5.890 -19.0 -5.30 6.7 <0.001. A wSA - F O.O09 Fluticasone 49 -6.91 -7.O2 6.614 -18.5 -5.85 9.2 <0.001 F wSA - F O.145 Azelastine + Fluticasome 52 -8.69 -8.82 6.517 -23.0 -9.34 5.8 <0.001 Treatment O.O31

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient change was based on a paired t-test. p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. JOverall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1 US 8,758,816 B2 139 140

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.2 Percent Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 1 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N. Mean Mean Deviation Minimum Median Maximum p-value Source p-value

AM and PM Combined TNSS

Baseline Azelastine (A) 49 19.60 1966 2.113 15.3 19.70 24.0 Treatment O.958 FluticasOne (F) 50 19.53 19.57 2.742 13.7 19.38 24.0 Azelastine + Fluticasome 52 1948 1952 2.967 13.1 19.45 24.0 (A + F) Percent Change from Baseline in AM and PM Combined TNSS

Overal Azelastine 49 -24.47 -24.78 22.215 -71.9 -24.26 15.4 <0.001. A wSA - F O.O11 Fluticasone 49 -26.12 -27.13 24.462 -100.0 -21.93 19.9 <0.001 F wSA - F O.O3S Azelastine + Fluticasome 52 -36.94 -37.87 27.683 -86.9 -39.66 26.1 <0.001 Treatment O.O24 Day <0.001 Treatment * Day 0.155 Day 2 Azelastine 49 -1693 -1631 22.796 -70.5 - 12.31 20.8 <0.001. A wSA - F O.2O7 Fluticasone 49 -1691 - 16.35 23.714 -100.0 - 12.46 18.5 <0.001 F wSA - F O.210 Azelastine + Fluticasome 52 -22.82 -22.43 27.943 -84.7 -14.36 22.7 <0.001 Treatment O.344

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.2 Percent Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 2 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N' Mean Mean Deviation Minimum Median Maximum p-value Source p-value Percent Change from Baseline in AM and PM Combined TNSS

Day 3 Azelastine 49 -17.08 - 16.85 24.024 -76.5 -8.11 20.8 <0.001. A wSA - F O.O14 Fluticasone 49 -22.26 -22.17 26.773 -100.0 - 16.67 28.6 <0.001 F wSA - F O.151 Azelastine + Fluticasome 52 -29.65 -29.50 27.863 -94.1 -25.13 23.2 <0.001 Treatment O.O47 Day 4 Azelastine 49 -20.50 -20.41 26.044 -81.1 -14.29 21.8 <0.001. A wSA - F O.O11 Fluticasone 49 -23.67 -23.7S 25.917 -100.0 -23.60 27.3 <0.001 F wSA - F 0.055 Azelastine + Fluticasome 52 -33.92 -33.92 28.009 -85.1 -36.38 22.7 <0.001 Treatment O.O29 Day 5 Azelastine 49 -23.15 -23.2O 26.633 -81.1 -18.64 21.0 <0.001. A wSA - F O.O16 Fluticasone 49 -26.89 -27.2O 27.945 -100.0 -22.77 28.6 <0.001 F wSA - F O.O84 Azelastine + Fluticasome 52 -37.02 -37.22 31.706 -100.0 -36.34 33.8 <0.001 Treatment O.O45 Day 6 Azelastine 49 -23.13 -23.15 26.683 -80.0 -18.78 29.0 <0.001. A wSA - F O.OO3 Fluticasone 49 -26.90 -27.15 29.542 -100.0 -22.20 28.6 <0.001 F wSA - F O.O24 Azelastine + Fluticasome 52 -40.33 -40.50 31.771 -100.0 -45.75 28.3 <0.001 Treatment O.OO9

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.2 Percent Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 3 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N. Mean Mean Deviation Minimum Median Maximum p-value Source p-value Percent Change from Baseline in AM and PM Combined TNSS

Day 7 Azelastine 49 -26.52 -26.40 26.583 -84.1 -23.31 29.0 <0.001. A wSA - F O.O37 Fluticasone 49 -25.75 -26.OO 26.507 -100.0 -23.81 33.3 <0.001 F wSA - F O.O31 Azelastine + Fluticasome 52 -38.04 -38.27 31.298 -958 -41.11 28.3 <0.001 Treatment O.048 Day 8 Azelastine 49 -28.13 -28.22 26.628 -894 -23.73 11.2 <0.001. A wSA - F O.O2O Fluticasone 49 -23.38 -23.87 24.935 -100.0 -20.97 25.4 <0.001 F wSA - F O.OO2 Azelastine + Fluticasome 52 -40.61 -40.94 29.617 -100.0 -4352 28.3 <0.001 Treatment O.OOS Day 9 Azelastine 49 -27.72 -27.79 24.151 -81.8 -1935 11.1 <0.001. A wSA - F O.O38 Fluticasone 49 -25.94 -26.5O 27.382 -100.0 -23.40 18.5 <0.001 F wSA - F O.O22 Azelastine + Fluticasome 52 -38.97 -39.40 31.247 -100.0 -40.03 22.7 <0.001 Treatment O.O39 US 8,758,816 B2 141 142 -continued

Day 10 Azelastine 49 -27.81 -27.60 25.985 -77.9 -28.93 19.7 <0.001. A wSA - F O.O2S Fluticasone 49 -28.76 -28.93 30.182 -100.0 -27.10 61.6 <0.001 F wSA - F O.044 Azelastine + Fluticasome 52 -40.56 -40.78 31.425 -100.0 -40.01 28.3 <0.001 Treatment O.047

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.2.2 Percent Change from Baseline in TNSS: AM and PM Combined Intent-to-Treat Population (Page 4 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N' Mean Mean Deviation Minimum Median Maximum p-value Source p-value

Percent Change from Baseline in AM and PM Combined TNSS

Day 11 Azelastine 49 -29.42 -29.24 27.960 -90.0 -26.11 18.6 <0.001. A wSA - F O.O27 Fluticasone 49 -29.30 -29.71 30.855 -100.0 -27.71 61.6 <0.001 F wSA - F O.O33 Azelastine + Fluticasome 52 -42.09 -42.55 31.725 -958 -41.75 28.8 <0.001 Treatmen O.042 Day 12 Azelastine 49 -28.25 -27.99 31.095 -95.0 -25.86 21.0 <0.001. A wSA - F O.018 Fluticasone 49 -31.04 -31.31 31.574 -100.0 -27.78 61.6 <0.001 F wSA - F O.064 Azelastine + Fluticasome 52 -42.62 -42.96 32.096 -100.0 -43.60 22.7 <0.001 Treatmen O.044 Day 13 Azelastine 49 -29.35 -29.24 31.149 -95.0 -26.15 32.7 <0.001. A wSA - F O.O24 Fluticasone 49 -34.97 -35.63 33.815 -100.0 -30.43 61.6 <0.001 F wSA - F O.2OS Azelastine + Fluticasome 52 -43.11 -43.75 32.779 -100.0 -44.47 43.9 <0.001 Treatmen 0.077 Day 14 Azelastine 49 -28.86 -28.7O 3O499 -95.0 -25.00 38.5 <0.001. A WSA + F O.O13 Fluticasone 49 -35.00 -35.62 34.687 -100.0 -28.71 61.6 <0.001 F wSA - F O.152 Azelastine + Fluticasome 52 -44.29 -44.92 33.557 -958 -48.83 43.9 <0.001 Treatmen O.044

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient change was based on a paired t-test. p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. 'Overall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.1 Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 1 of 4) Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value AM and PM Combined TNSS

Baseline Azelastine (A) 49 19.60 1966 2.113 15.3 19.70 24.0 Treatment O.853 FluticasOne (F) 47 1952 1961 2.740 13.7 19.17 24.0 Azelastine + Fluticasome 48 19.27 1940 2.973 13.1 18.8O 24.0 (A + F) Change from Baseline in AM and PM Combined TNSS Overal/ Azelastine 49 -4.73 -4.73 4.297 -14.4 -4.24 3.1 <0.001. A wSA - F O.OO7 Fluticasone 47 -5.14 -5.24 4.633 -18.5 -391 3.7 <0.001 F wSA - F O.O3O Azelastine + Fluticasome 48 -7.28 -7.44 5.466 -20.2 -8.01 4.7 <0.001 Treatment O.O17 Day <0.001 Treatment * Day O.1SO US 8,758,816 B2 143 144 -continued

Day 2 Azelastine 49 -3.23 -3.08 4.33O -14.2 -2.67 4.1 <0.001. A wSA - F O.133 Fluticasone 47 -3.27 -3.10 4.412 -18.5 -2.00 2.7 <0.001 F wSA - F O.145 Azelastine + Fluticasome 48 -4.60 -4.48 S.326 -16.1 -3.46 4.1 <0.001 Treatment O.232

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.1 Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 2 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined TNSS

Day 3 Azelastine 49 -3.28 -3.19 4.61O -16.2 -1.67 4.1 <0.001. A wSA - F O.O09 Fluticasone 47 -4.25 -4.18 4.977 -18.5 -3.47 5.3 <0.001 F wSA - F O.102 Azelastine + Fluticasome 48 -5.96 -586 5.526 -17.1 -4.83 4.3 <0.001 Treatment O.O31 Day 4 Azelastine 49 -3.93 -3.87 S.O22 -17.2 -2.92 4.3 <0.001. A wSA - F O.O11 Fluticasone 47 -4.63 -4.61 4.961 -18.5 -4.17 4.5 <0.001 F wSA - F O.064 Azelastine + Fluticasome 48 -6.62 -6.59 S.S66 -17.1 -6.93 4.1 <0.001 Treatment O.O31 Day 5 Azelastine 49 -4.48 -4.43 5.225 -17.2 -367 4.2 <0.001. A wSA - F O.O13 Fluticasone 47 -5.23 -5.23 S.328 -18.5 -440 5.3 <0.001 F wSA - F O.074 Azelastine + Fluticasome 48 -7.27 -7.31 6.212 -21.0 -7.37 6.1 <0.001 Treatment O.O37 Day 6 Azelastine 49 -4.44 -4.38 S.147 -16.0 -3.7O 5.4 <0.001. A wSA - F O.OO2 Fluticasone 47 -512 -5.11 S. 632 -18.5 -4.45 5.3 <0.001 F wSA - F O.O15 Azelastine + Fluticasome 48 -7.91 -7.97 6.076 -22.0 -8.25 S.1 <0.001 Treatment O.OO6

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.1 Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 3 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined TNSS

Day 7 Azelastine 49 -509 -S.O1 S.OO6 -16.0 -4.67 5.4 <0.001. A wSA - F O.O2O Fluticasone 47 -4.99 -4.98 S.093 -18.5 -5.OO 5.5 <0.001 F wSA - F O.O2O Azelastine + Fluticasome 48 -7.50 -7.60 6.147 -23.0 -7.26 S.1 <0.001 Treatment O.O28 Day 8 Azelastine 49 -5.38 -5.33 5.056 -17.O -5.OO 2.4 <0.001. A wSA - F O.O12 Fluticasone 47 -4.59 -4.61 4.683 -18.5 -3.7O 3.7 <0.001 F wSA - F O.OO2 Azelastine + Fluticasome 48 -7.98 -8.05 5.859 -21.0 -7.61 S.1 <0.001 Treatment O.004 Day 9 Azelastine 49 -5.38 -5.32 4.799 -18.0 -3.83 2.1 <0.001. A wSA - F O.O3O Fluticasone 47 -518 -5.21 5.252 -18.5 -458 2.7 <0.001 F wSA - F O.O2S Azelastine + Fluticasome 48 -7.56 -769 5.978 -23.0 -7.33 4.1 <0.001 Treatment O.O39 Day 10 Azelastine 49 -5.36 -5.25 4.976 -15.O -533 4.0 <0.001. A wSA - F O.O13 Fluticasone 47 -5.74 -5.70 5.713 -18.5 -4.83 9.2 <0.001 F wSA - F O.O38 Azelastine + Fluticasome 48 -7.96 -8.10 6.172 -23.0 -7.43 S.1 <0.001 Treatment O.O29

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.1 Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 4 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined TNSS

Day 11 Azelastine 49 -5.77 -5.64 5.576 -18.1 -4.70 3.8 <0.001. A wSA - F O.O13 Fluticasone 47 -5.89 -5.89 5.775 -18.5 -4.83 9.2 <0.001 F wSA - F O.O24 Azelastine + Fluticasome 48 -8.33 -8.58 6.485 -23.0 -7.8O 4.3 <0.001 Treatment O.O23 Day 12 Azelastine 49 -5.54 -540 6.109 -19.0 -5.OO 4.2 <0.001. A wSA - F O.O13 Fluticasone 47 -6.20 -6.16 5.905 -18.9 -5.17 9.2 <0.001 F wSA - F O.061 Azelastine + Fluticasome 48 -8.31 -8.50 6.586 -24.0 -8.52 4.1 <0.001 Treatment O.O34 Day 13 Azelastine 49 -5.70 -5.59 6.06O -19.0 -5.30 5.7 <0.001. A wSA - F O.O10 Fluticasone 47 -7.01 -7.03 6.375 -18.9 -6.50 9.2 <0.001 F wSA - F 0.157 Azelastine + Fluticasome 48 -8.56 -8.81 6.570 -24.0 -8.57 5.8 <0.001 Treatment O.O37 US 8,758,816 B2 145 146 -continued

Day 14 Azelastine 49 -5.62 -SSO 5.890 -19.0 -5.30 6.7 <0.001. A wSA - F O.OO6 Fluticasone 47 -7.14 -7.15 6.638 -18.5 -6.00 9.2 <0.001 F wSA - F O.147 Azelastine + Fluticasome 48 -8.73 -8.98 6.476 -23.0 -9.68 5.8 <0.001 Treatment O.O22

Total number of per-protocol patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient change was based on a paired t-test, p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects. Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. JOverall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.2 Percent Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 1 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N' Mean Mean Deviation Minimum Median Maximum p-value Source p-value

AM and PM Combined TNSS

Baseline Azelastine (A) 49 19.60 1966 2.113 15.3 19.70 24.0 Treatment O.853 FluticasOne (F) 47 1952 1961 2.740 13.7 19.17 24.0 Azelastine + Fluticasome 48 1927 1940 2.973 13.1 18.80 24.0 (A + F) Percent Change from Baseline in AM and PM Combined TNSS Overal/ Azelastine 49 -24.47 -24.72 22:215 -71.9 -24.26 15.4 <0.001. A wSA - F O.O10 Fluticasone 47 -26.46 -27.12 24.721 -100.0 -21.93 19.9 <0.001 F wSA - F O.036 Azelastine + Fluticasome 48 -37.49 -38.14 27.305 -86.9 -42.91 26.1 <0.001 Treatment O.O24 Day <0.001 Treatment * Day O.121 Day 2 Azelastine 49 -1693 - 16.25 22.796 -70.5 - 12.31 20.8 <0.001. A wSA - F O.2O6 Fluticasone 47 -1711 - 16.38 24-182 -100.0 - 12.46 18.5 <0.001 F wSA - F O.220 Azelastine + Fluticasome 48 -23.31 -22.55 27.918 -84.7 -15.83 22.7 <0.001 Treatment 0.355

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.2 Percent Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 2 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N. Mean Mean Deviation Minimum Median Maximum p-value Source p-value Percent Change from Baseline in AM and PM Combined TNSS

Day 3 Azelastine 49 -17.08 - 16.85 24.024 -76.5 -8.11 20.8 <0.001. A wSA - F O.O15 Fluticasone 47 -22.87 -22.68. 27.056 -100.0 - 16.67 28.6 <0.001 F wSA - F O181 Azelastine + Fluticasome 48 -30.54 -29.80 28.004 -94.1 -26.52 23.2 <0.001 Treatment O.OSO Day 4 Azelastine 49 -20.50 -20.39 26.044 -81.1 -14.29 21.8 <0.001. A wSA - F O.O13 Fluticasone 47 -24.08 -24.10 26.117 -100.0 -23.60 27.3 <0.001 F wSA - F O.074 Azelastine + Fluticasome 48 -34.28 -33.89 27.955 -85.1 -36.87 22.7 <0.001 Treatment O.O39 Day 5 Azelastine 49 -23.15 -23.17 26.633 -81.1 -18.64 21.0 <0.001. A wSA - F O.O15 Fluticasone 47 -27.16 -27.42 28.408 -100.0 -22.77 28.6 <0.001 F wSA - F O.O86 Azelastine + Fluticasome 48 -37.72 -37.73 31.603 -100.0 -38.16 33.8 <0.001 Treatment O.044 US 8,758,816 B2

-continued

Day 6 Azelastine 49 -23.13 -23.16 26.683 -80.O -18.78 29.0 <0.001. A wSA - F O.OO3 Fluticasone 47 -26.95 -27.15 30.062 -100.0 -22.20 28.6 <0.001 F wSA - F O.O2O Azelastine + Fluticasome 48 -41.28 -41.37 31.333 -100.0 -46.23 28.3 <0.001 Treatment O.007

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.2 Percent Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 3 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N. Mean Mean Deviation Minimum Median Maximum p-value Source p-value

Percent Change from Baseline in AM and PM Combined TNSS

Day 7 Azelastine 49 -26.52 -26.32 26.583 -84.1 -23.31 29.0 <0.001. A wSA - F O.O29 Fluticasone 47 -25.57 -25.63 27.007 -100.0 -23.81 33.3 <0.001 F wSA - F O.O23 Azelastine + Fluticasome 48 -38.70 -38.96 30.725 -958 -42.41 28.3 <0.001 Treatment O.O37 Day 8 Azelastine 49 -28.13 -28.14 26.628 -894 -23.73 11.2 <0.001. A wSA - F O.O17 Fluticasone 47 -2343 -2368 25.045 -100.0 -20.97 25.4 <0.001 F wSA - F O.OO2 Azelastine + Fluticasome 48 -41.30 -41.38 28.967 -100.0 -44.94 28.3 <0.001 Treatment O.OOS Day 9 Azelastine 49 -27.72 -27.68 24.151 -81.8 -1935 11.1 <0.001. A wSA - F O.036 Fluticasone 47 -26.33 -26.65 27.549 -100.0 -23.40 18.5 <0.001 F wSA - F O.O24 Azelastine + Fluticasome 48 -39.14 -39.58 30.647 -100.0 -41.75 22.7 <0.001 Treatment O.043 Day 10 Azelastine 49 -27.81 -27.49 25.985 -77.9 -28.93 19.7 <0.001. A wSA - F O.O2O Fluticasone 47 -29.26 -29.19 30.406 -100.0 -27.10 61.6 <0.001 F wSA - F O.043 Azelastine + Fluticasome 48 -40.96 -41.38 30.734 -100.0 -40.26 28.3 <0.001 Treatment O.041

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.3.2 Percent Change from Baseline in TNSS: AM and PM Combined Per-Protocol Population (Page 4 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N' Mean Mean Deviation Minimum Median Maximum p-value Source p-value

Percent Change from Baseline in AM and PM Combined TNSS

Day 11 Azelastine 49 -29.42 -29.05 27.960 -90.0 -26.11 18.6 <0.001. A wSA - F O.018 Fluticasone 47 -29.69 -29.83 31,043 -100.0 -27.71 61.6 <0.001 F wSA - F O.O27 Azelastine + Fluticasome 48 -42.64 -43.56 31.959 -958 -42.32 28.8 <0.001 Treatment O.O31 Day 12 Azelastine 49 -28.25 -27.82. 31.095 -95.0 -25.86 21.0 <0.001. A wSA - F O.O14 Fluticasone 47 -31.50 -3145 31.763 -100.0 -27.78 61.6 <0.001 F wSA - F O.061 Azelastine + Fluticasome 48 -42.93 -43.59 31.937 -100.0 -46.30 22.7 <0.001 Treatment O.O38 Day 13 Azelastine 49 -29.35 -29.06 31.149 -95.0 -26.15 32.7 <0.001. A wSA - F O.O17 Fluticasone 47 -35.73 -35.99 34.040 -100.0 -30.43 61.6 <0.001 F wSA - F O.182 Azelastine + Fluticasome 48 -43.85 -44.83 33.178 -100.0 -45.75 43.9 <0.001 Treatment 0.057 Day 14 Azelastine 49 -28.86 -28.52 30.499 -95.0 -25.00 38.5 <0.001. A wSA - F O.O10 Fluticasone 47 -36.03 -36.26 34.913 -100.0 -34.31 61.6 <0.001 F wSA - F O.153 Azelastine + Fluticasome 48 -44.84 -45.84 33.645 -958 -49.84 43.9 <0.001 Treatment O.O34

Total number of per-protocol patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient percent change was based on a paired t-test. p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. JOverall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1 US 8,758,816 B2 149 150

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.1 Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 1 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

AMTNSS

Baseline Azelastine (A) 49 966 9.68 1.128 7.2 9.67 12.0 Treatment 0.725 FluticasOne (F) SO 9.79 9.81 1.369 7.2 9.78 12.0 Azelastine + Fluticasome 52 9.86 9.88 1422 6.O 9.92 12.0 (A + F) Change from Baseline in AMTNSS

Overal Azelastine 49 -2.21 -2.22 2.157 -7.3 -1.86 1.8 <0.001. A wSA - F O.OO3 Fluticasone 49 -2.57 -2.SS 2.403 -95 -2.14 2.5 <0.001 F wSA - F O.O21 Azelastine + Fluticasome 52 -3.76 -3.7O 2.891 -10.8 -367 2.3 <0.001 Treatment O.OO8 Day <0.001 Treatment * Day O.06S Day 2 Azelastine 49 -1.48 -1.46 2.322 -7.3 -1.25 2.3 <0.001. A wSA - F O.209 Fluticasone 49 -1.65 - 1.58 2.266 -95 -1.00 1.4 <0.001 F wSA - F O.308 Azelastine + Fluticasome 52 -2.17 -2.O7 2.908 -8.7 -1.25 2.7 <0.001 Treatment O4O6

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.1 Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 2 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in AMTNSS

Day 3 Azelastine 49 -1.29 -1.28 2.451 -8.0 -O.8O 2.3 <0.001. A wSA - F O.OO3 Fluticasone 49 -2.04 -2.01 2.667 -95 -150 3.0 <0.001 F wSA - F O.093 Azelastine + Fluticasome 52 -2.98 -2.92 3.193 -9.0 -2.17 3.3 <0.001 Treatment O.O11 Day 4 Azelastine 49 -1.76 -1.79 2.623 -8.3 -1.33 2.5 <0.001. A wSA - F O.OO7 Fluticasone 49 -2.41 -2.43 2.401 -95 -2.67 1.5 <0.001 F wSA - F O. 119 Azelastine + Fluticasome 52 -3.28 -3.27 3.08O -10.3 -3.08 2.3 <0.001 Treatment O.O24 Day 5 Azelastine 49 -2.23 -2.25 2.664 -8.3 -1.67 2.3 <0.001. A wSA - F O.O3O Fluticasone 49 -2.57 -2.59 2.696 -9.8 -2.00 3.0 <0.001 F wSA - F O-110 Azelastine + Fluticasome 52 -3.51 -350 3.242 -10.0 -3.25 2.7 <0.001 Treatment O.O79 Day 6 Azelastine 49 -2.01 -2.01 2.597 -9.0 -2.00 3.0 <0.001. A wSA - F O.OO1 Fluticasone 49 -2.57 -2.59 2.981 -9.8 -2.20 3.0 <0.001 F wSA - F O.O24 Azelastine + Fluticasome 52 -3.94 -3.94 3.283 -11.0 -4.00 2.3 <0.001 Treatment O.OOS

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.1 Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 3 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in AMTNSS

Day 7 Azelastine 49 -2.52 -2.52 2.SS4 -8.0 -2.20 3.0 <0.001. A wSA - F O.018 Fluticasone 49 -2.57 -2.SS 2.618 -95 -2.00 3.0 <0.001 F wSA - F O.O21 Azelastine + Fluticasome 52 -3.94 -3.90 3.444 -12.0 -3.58 2.7

Day 10 Azelastine 49 -2.27 -2.29 2.62O -8.0 -2.17 2.2 <0.001. A wSA - F O.004 Fluticasone 49 -2.73 -2.74 2.986 -95 -2.80 4.4 <0.001 F wSA - F O.O34 Azelastine + Fluticasome 52 -4.01 -3.99 3.301 -12.0 -3.7O 2.7 <0.001 Treatment O.O12

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.1 Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 4 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

Change from Baseline in AMTNSS

Day 11 Azelastine 49 -2.48 -2.53 2.898 -9.0 -2.00 2.2 <0.001. A wSA - F O.007 Fluticasone 49 -249 -2.52 3.082 -95 -2.00 4.4 <0.001 F wSA - F O.007 Azelastine + Fluticasome 52 -4.19 -4.16 3.362 -12.0 -3.63 3.3 <0.001 Treatmen O.OO8 Day 12 Azelastine 49 -2.58 -2.60 2.934 -9.0 -2.50 2.2 <0.001. A wSA - F O.O12 Fluticasone 49 -298 -2.99 3.121 -11.3 -2.75 4.4 <0.001 F wSA - F O.O59 Azelastine + Fluticasome 52 -4.17 -4.15 3.283 -12.0 -3.83 1.5 <0.001 Treatmen O.O32 Day 13 Azelastine 49 -2SO -2.55 2.992 -9.0 -1.80 3.0 <0.001. A wSA - F O.OOS Fluticasone 49 -3.32 -3.38 3.328 -10.3 -3.OO 4.4 <0.001 F wSA - F O.141 Azelastine + Fluticasome 52 -4.28 -4.29 3.215 -12.0 -4.08 3.0 <0.001 Treatmen O.O2O Day 14 Azelastine 49 -2.52 -2.56 2.982 -9.0 -2.00 3.0 <0.001. A WSA + F O.004 Fluticasone 49 -3.28 -3.33 3.348 -95 -3.OO 4.4 <0.001 P wSA - F O.103 Azelastine + Fluticasome 52 -4.34 -4.34 3.245 -12.0 -4.63 3.3 <0.001 Treatmen O.O17

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline of analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient change was based on an paired t-test. p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. 'Overall includes TNSS scores from Day 2 to Day 14. Reference 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.2 Percent Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 1 of 4) Variable Paired Time LS Standard t-test ANOVA Point Treatment N. Mean Mean Deviation Minimum Median Maximum p-value Source p-value

AMTNSS

Baseline Azelastine (A) 49 9.66 9.68 1.128 7.2 9.67 12.0 Treatment 0.725 FluticasOne (F) 50 9.79 9.81 1.369 7.2 9.78 12.0 Azelastine + Fluticasome 52 9.86 9.88 1422 6.O 9.92 12.0 (A + F) Percent Change from Baseline in AMTNSS Overal/ Azelastine 49 -23.29 -23.13. 22.865 -73.1 -19.23 18.6 <0.001. A wSA - F O.OO6 Fluticasone 49 -26.49 -26.39 25.046 -100.0 -23.89 27.4 <0.001 F wSA - F O.O3S Azelastine + Fluticasome 52 -37.53 -37.13 28.119 -90.4 -40.04 26.9 <0.001 Treatment O.O16 Day <0.001 Treatment * Day O.O45 US 8,758,816 B2 153 154 -continued

Day 2 Azelastine 49 -1579 -15.45 25.055 -78.6 - 14.29 24.1 <0.001. A wSA - F O403 Fluticasone 49 -17.21 -16.43 24.390 -100.0 -11.11 18.4 <0.001 F wSA - F O.S2O Azelastine + Fluticasome 52 -20.59 -19.66 28.925 -89.7 -13.12 28.6 <0.001 Treatment O.678

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.2 Percent Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 2 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N' Mean Mean Deviation Minimum Median Maximum p-value Source p-value Percent Change from Baseline in AMTNSS

Day 3 Azelastine 49 -13.75 - 13.37 26.139 -88.9 -7.89 24.1 <0.001. A wSA - F O.007 Fluticasone 49 -22.09 -21.72 28.857 -100.0 -14.29 33.3 <0.001 F wSA - F O.2O6 Azelastine + Fluticasome 52 -29.29 -28.86 32.070 -100.0 -23.79 38.5 <0.001 Treatment O.O2S Day 4 Azelastine 49 -1884 - 1888. 27.966 -893 - 14.89 26.3 <0.001. A wSA - F O.O11 Fluticasone 49 -25.07 -25.32 24.92O -100.0 -27.27 17.6 <0.001 F wSA - F O.168 Azelastine + Fluticasome 52 -32.82 -32.90 30.178 -91.1 -32.58 26.9 <0.001 Treatment O.040 Day 5 Azelastine 49 -23.62 -23.57 27.972 -893 - 15.79 24.1 <0.001. A wSA - F O.041 Fluticasone 49 -26.62 -26.91 28.378 -100.0 -19.23 33.3 <0.001 F wSA - F O.138 Azelastine + Fluticasome 52 -35.41 -35.63 32.170 -100.0 -33.23 28.6 <0.001 Treatment O. 106 Day 6 Azelastine 49 -21.35 -21.14 27.405 -90.0 - 16.67 33.3 <0.001. A wSA - F O.OO2 Fluticasone 49 -27.12 -27.42 31.284 -100.0 -23.81 33.3 <0.001 F wSA - F O.040 Azelastine + Fluticasome 52 -39.68 -40.06 32.703 -100.0 -40.66 26.9 <0.001 Treatment O.OO8

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.2 Percent Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 3 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N. Mean Mean Deviation Minimum Median Maximum p-value Source p-value Percent Change from Baseline in AMTNSS

Day 7 Azelastine 49 -26.58 -26.26 27.521 -80.0 -25.00 33.3 <0.001. A wSA - F O.O27 Fluticasone 49 -26.29 -26.16 27.454 -100.0 -22.22 33.3 <0.001 F wSA - F O.O26 Azelastine + Fluticasome 52 -39.62 -39.49 33.817 -100.0 -40.65 28.6 <0.001 Treatment O.036 Day 8 Azelastine 49 -27.83 -27.73 29.736 -90.0 -25.00 2O.O <0.001. A wSA - F O.O21 Fluticasone 49 -24.67 -25.01 26.795 -100.0 -19.23 33.3 <0.001 F wSA - F O.OO6 Azelastine + Fluticasome 52 -41.25 -41.56 31.878 -100.0 -43.02 26.9 <0.001 Treatment O.O12 Day 9 Azelastine 49 -26.20 -26.38 25.942 -81.8 -22.22 18.4 <0.001. A wSA - F O.O15 Fluticasone 49 -24.52 -24.94 27.327 -100.0 -21.95 33.3 <0.001 F wSA - F O.007 Azelastine + Fluticasome 52 -40.21 -40.39 31:450 -100.0 -38.98 26.9 <0.001 Treatment O.O12 Day 10 Azelastine 49 -23.81 -23.62. 28.124 -80.0 -23.64 2SO <0.001. A wSA - F O.OO8 Fluticasone 49 -28.06 -28.09 31748 -100.0 -28.36 57.9 <0.001 F wSA - F O.OS2 Azelastine + Fluticasome 52 -40.09 -40.04 32.464 -100.0 -39.49 33.3 <0.001 Treatment O.O22

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.4.2 Percent Change from Baseline in TNSS: AM Intent-to-Treat Population (Page 4 of 4)

Variable Paired Time LS Standard t-test ANOVA Point Treatment N' Mean Mean Deviation Minimum Median Maximum p-value Source p-value Percent Change from Baseline in AMTNSS

Day 11 Azelastine 49 -25.65 -25.86 29.971 -90.0 -19.40 22.0 <0.001. A wSA - F O.O16 Fluticasone 49 -25.02 -25.25 32.944 -100.0 -18.37 57.9 <0.001 F wSA - F O.O12 Azelastine + Fluticasome 52 -41.35 -41.23 32.948 -100.0 -43.25 38.5 <0.001 Treatment O.O17 Day 12 Azelastine 49 -26.72 -26.61 30.825 -90.0 -26.32 2SO <0.001. A wSA - F O.O16 Fluticasone 49 -30.49 -30.64 32.747 -100.0 -26.83 57.9 <0.001 F wSA - F O.O73 Azelastine + Fluticasome 52 -41.84 -41.89 31.114 -100.0 -38.98 15.4 <0.001 Treatment O.042 Day 13 Azelastine 49 -26.20 -26.36 31.095 -90.0 -18.37 33.3 <0.001. A wSA - F O.O11 Fluticasone 49 -34.03 -34.62. 34.647 -100.0 -28.36 57.9 <0.001 F wSA - F O.2O3 Azelastine + Fluticasome 52 -42.46 -42.77 32.117 -100.0 -43.92 SO.O <0.001 Treatment O.040 US 8,758,816 B2 155 156 -continued

Day 14 Azelastine 49 -26.44 -26.51 31.727 -90.O -2O.OO 33.3 <0.001. A wSA - F O.O10 Fluticasone 49 -33.12 -33.54 34.789 -100.0 -31.03 57.9 <0.001 F wSA - F O.126 Azelastine + Fluticasome 52 -43.30 -43.48 32.821 -100.0 -46.19 38.5 <0.001 Treatment O.O33

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient percent change was based on a paired t-test, p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. JOverall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.1 Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 1 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

PMTNSS

Baseline Azelastine (A) 49 9.94 9.97 1.126 7.3 1O.OO 12.0 Treatment O456 FluticasOne (F) SO 9.74 9.77 1436 6.5 9.63 12.0 Azelastine + Fluticasome 52 9.62 9.64 1.725 3.4 9.8O 12.0 (A + F) Change from Baseline in PMTNSS

Overal/ Azelastine 49 -2.51 -2.57 2.253 -7.1 -2.38 1.8 <0.001. A wSA - F O.O23 Fluticasone SO -2.43 -2.71 2.288 -9.0 -1.86 1.5 <0.001 F wSA - F O.042 Azelastine + Fluticasome 52 -3.46 -3.73 2.791 -9.4 -352 2.8 <0.001 Treatment O.043 Day <0.001 Treatment * Day O.S63 Day 2 Azelastine 49 -1.76 -1.65 2.490 -8.2 -1.00 2.0 <0.001. A wSA - F 0.155 Fluticasone 49 - 159 -1.54 2.465 -9.0 -1.00 2.3 <0.001 F wSA - F O.098 Azelastine + Fluticasome 52 -2.37 -2.37 2.732 -8.8 -1.67 1.4 <0.001 Treatment O.198

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.1 Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 2 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value Change from Baseline in PMTNSS

Day 3 Azelastine 49 - 1.98 -191 2.535 -8.2 -150 2.0 <0.001. A wSA - F O.O60 Fluticasone 49 -2.08 -2.08 2.560 -9.6 -1.80 2.7 <0.001 F wSA - F O.118 Azelastine + Fluticasome 52 -2.85 -2.88 2.68O -8.8 -2.63 2.4 <0.001 Treatment O.129 Day 4 Azelastine 49 -2.17 -2.09 2.774 -9.2 -2.20 2.0 <0.001. A wSA - F O.O26 Fluticasone 49 -2.12 -2.10 2.842 -9.6 -1.80 3.0 <0.001 F wSA - F O.O28 Azelastine + Fluticasome 52 -3.33 -3.35 2.886 -8.8 -3.47 3.4 <0.001 Treatment O.O37 Day 5 Azelastine 49 -2.25 -2.19 3.062 -9.2 -1.20 2.5 <0.001. A wSA - F O.O14 Fluticasone 49 -2.59 -2.61 2.675 -9.0 -2.00 2.3 <0.001 F wSA - F O.O71 Azelastine + Fluticasome 52 -3.67 -3.73 3.392 -11.0 -3.60 3.4 <0.001 Treatment O.O38 US 8,758,816 B2 157 158 -continued

Day 6 Azelastine 49 -2.43 -2.38 2.763 -9.0 -2.00 2.4 <0.001. A wSA - F O.O11 Fluticasone 49 -2.53 -2.53 2.751 -9.0 -2.00 2.3 <0.001 F wSA - F O.O22 Azelastine + Fluticasome 52 -3.85 -388 3.144 -11.0 -3.63 3.4 <0.001 Treatment O.019

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.1 Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 3 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N. Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

Change from Baseline in PMTNSS

Day 7 Azelastine 49 -2.57 -2.54 2.705 -8.4 -2.25 2.4 <0.001. A wSA - F O.074 Fluticasone 49 -2.45 -2.50 2.632 -9.0 -2.00 3.0 <0.001 F wSA - F O.064 Azelastine + Fluticasome 52 -3.48 -3.57 3.178 -11.0 -3.13 2.4 <0.001 Treatment O.107 Day 8 Azelastine 49 -2.76 -2.69 2.584 -8.5 -2.75 1.8 <0.001. A wSA - F O.O27 Fluticasone 49 -2.18 -2.24 2.575 -9.0 -2.00 4.3 <0.001 F wSA - F O.OO3 Azelastine + Fluticasome 52 -3.81 -391 3.062 -10.0 -3.43 3.4 <0.001 Treatment O.007 Day 9 Azelastine 49 -2.86 -2.78 2.675 -9.0 -2.33 1.2 <0.001. A wSA - F O.128 Fluticasone 49 -2.69 -2.73 2.852 -9.0 -2.00 3.3 <0.001 F wSA - F O.107 Azelastine + Fluticasome 52 -3.58 -367 3.226 -11.0 -350 3.4 <0.001 Treatment O.191 Day 10 Azelastine 49 -3.08 -3.01 2.812 -9.0 -3.OO 2.8 <0.001. A wSA - F O.102 Fluticasone 49 -2.88 -2.90 2.900 -9.0 -2.60 4.8 <0.001 F wSA - F OO67 Azelastine + Fluticasome 52 -3.92 -4.00 3.26S -11.0 -3.43 2.4 <0.001 Treatment O.130

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.1 Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 4 of 4)

Variable Paired Time Standard t-test ANOVA Point Treatment N' Mean LS Mean Deviation Minimum Median Maximum p-value Source p-value

Change from Baseline in PMTNSS

Day 11 Azelastine 49 -3.29 -3.20 3.122 -95 -3.33 2.4 <0.001. A wSA - F O.O99 Fluticasone 49 -3.29 -3.33 2.862 -9.7 -3.OO 4.8 <0.001 F wSA - F O.148 Azelastine + Fluticasome 52 -4.10 -4.21 3.338 -11.0 -350 1.8 <0.001 Treatmen O.195 Day 12 Azelastine 49 -2.96 -2.85 3.340 -10.0 -2.40 2.8 <0.001. A wSA - F O.O31 Fluticasone 49 -3.10 -3.13 3.029 -9.0 -3.OO 4.8 <0.001 F wSA - F O.O81 Azelastine + Fluticasome 52 -4.15 -4.26 3.553 -12.0 -3.63 3.4 <0.001 Treatmen O.O71 Day 13 Azelastine 49 -3.21 -3.11 3.248 -10.0 -3.OO 3.7 <0.001. A wSA - F O.062 Fluticasone 49 -3.51 -3.57 3.187 -9.3 -3.OO 4.8 <0.001 F wSA - F O.244 Azelastine + Fluticasome 52 -4.19 -4.32 3.505 -12.0 -3.90 2.8 <0.001 Treatmen O.167 Day 14 Azelastine 49 -3.10 -3.OO 3.142 -10.0 -2.80 3.7 <0.001. A wSA - F O.O2S Fluticasone 49 -363 -3.70 3.473 -9.3 -3.OO 4.8 <0.001 F wSA - F O.228 Azelastine + Fluticasome 52 -4.35 -4.48 3.448 -11.0 -4.10 3.8 <0.001 Treatmen O.O79

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient change was based on a paired t-test, p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. 'Overall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1 US 8,758,816 B2 159 160

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.2 Percent Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 1 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value

PMTNSS

Baseline Azelastine (A) 49 9.94 9.97 1.126 7.3 10.00 12.0 Treatment O456 FluticasOne (F) 50 9.74 9.77 1436 6.5 9.63 12.0 Azelastine + Fluticasome 52 9.62 9.64 1.725 3.4 9.8O 12.0 (A + F) Percent Change from Baseline in PMTNSS

Overal Azelastine 49 -25.39 -26.45 22:390 -70.8 -21.68 18.9 <0.001. A wSA - F O.O2O Fluticasone SO -24.98 -27.7S 24.983 -100.0 -20.34 21.9 <0.001 F wSA - F O.O37 Azelastine + Fluticasome 52 -36.18 -38.67 27.800 -86.3 -35.94 32.4 <0.001 Treatment O.O37 Day <0.001 Treatment * Day O.575 Day 2 Azelastine 49 -17.76 -17.15 24.989 -732 -10.00 2O.O <0.001. A wSA - F O.166 Fluticasone 49 -1652 - 16.05 26.828 -1OOO -11.11 2SO <0.001 F wSA - F O-110 Azelastine + Fluticasome 52 -24.74 -24.49 28.552 -89.8 - 16.15 16.3 <0.001 Treatment O.219

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.2 Percent Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 2 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N' Mean Mean Deviation mum Median Maximum p-value Source p-value Percent Change from Baseline in PMTNSS

Day 3 Azelastine 49 -20.01 -19.66 25506 -732 - 15.15 2O.O <0.001. A wSA - F O.074 Fluticasone 49 -22.28 -2222 27.434 -100.0 -20.OO 28.6 <0.001 F wSA - F O.190 Azelastine + Fluticasome 52 -29.10 -29.08 26.759 -898 -28.08 27.9 <0.001 Treatment O.178 Day 4 Azelastine 49 -21.99 -21.42 27.647 -82.1 -23.08 2O.O <0.001. A wSA - F O.O34 Fluticasone 49 -22.22 -21.91 30.751 -100.0 -20.00 37.5 <0.001 F wSA - F O.040 Azelastine + Fluticasome 52 -34.16 -34.05 30.123 -89.8 -36.04 39.5 <0.001 Treatment O.OS4 Day 5 Azelastine 49 -2250 -22.87 30.099 -82.1 -13.04 26.3 <0.001. A wSA - F O.O12 Fluticasone 49 -27.06 -2751 29.028 -1OOO -22.22 33.3 <0.001 F wSA - F O.O72 Azelastine + Fluticasome 52 -38.96 -39.10 35.621 -100.0 -41.86 39.5 <0.001 Treatment O.O3S Day 6 Azelastine 49 -24.82 -25.18 28.081 -81.8 -20.45 2SO <0.001. A wSA - F O.O11 Fluticasone 49 -26.62 -26.81 29.839 -1OOO -22.22 2SO <0.001 F wSA - F O.O22 Azelastine + Fluticasome 52 -40.94 -40.78 32.866 -100.0 -41.86 39.5 <0.001 Treatment O.019

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.2 Percent Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 3 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value Percent Change from Baseline in PMTNSS

Day 7 Azelastine 49 -26.20 -26.39 28.186 -89.4 -23.81 2SO <0.001. A wSA - F O.O85 Fluticasone 49 -25.18 -25.72 28.316 -100.0 -20.45 37.5 <0.001 F wSA - F O.066 Azelastine + Fluticasome 52 -36.25 -36.65 31.573 -91.7 -36.50 27.9 <0.001 Treatment O.117 Day 8 Azelastine 49 -28.17 -27.94 26.451 -894 -27.27 18.9 <0.001. A wSA - F O.036 Fluticasone 49 -21.91 -22.44 28.831 -100.0 -21.95 63.0 <0.001 F wSA - F O.OO2 Azelastine + Fluticasome 52 -39.45 -40.02 29.932 -100.0 -36.70 39.5 <0.001 Treatment O.OO8 Day 9 Azelastine 49 -28.91 -28.94 25.922 -81.8 -25.00 12.2 <0.001. A wSA - F O.127 Fluticasone 49 -27.18 -27.82. 30.627 -1OOO -22.22 48.1 <0.001 F wSA - F O.O86 Azelastine + Fluticasome 52 -37.64 -38.21 33.093 -100.0 -39.83 39.5 <0.001 Treatment O.167 US 8,758,816 B2 161 162 -continued

Day 10 Azelastine 49 -3129 -31.30 28.433 -886 -33.33 29.7 <0.001. A wSA - F O.109 Fluticasone 49 -29.48 -29.73 31.092 -100.0 -27.27 65.5 <0.001 F wSA - F O.063 Azelastine + Fluticasome 52 -41.03 -41.24 32.243 -100.0 -41.86 27.9 <0.001 Treatment O.129

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.5.2 Percent Change from Baseline in TNSS: PM Intent-to-Treat Population (Page 4 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value

Percent Change from Baseline in PMTNSS

Day 11 Azelastine 49 -32.77 -32.80 30.2O2 -90.0 -33.96 2SO <0.001. A wSA - F O.O84 Fluticasone 49 -33.54 -34.15 30.853 -100.0 -33.33 65.5 <0.001 F wSA - F O.128 Azelastine + Fluticasome 52 -43.12 -43.71 33.524 -100.0 -39.11 2SO <0.001 Treatment O.166 Day 12 Azelastine 49 -29.44 -29.18 32.936 -100.0 -25.00 29.7 <0.001. A wSA - F O.O27 Fluticasone 49 -31.52 -32.OO 33.300 -100.0 -31.82 65.5 <0.001 F wSA - F O.O71 Azelastine + Fluticasome 52 -43.65 -44.26 35.487 -100.0 -44.95 39.5 <0.001 Treatment O.062 Day 13 Azelastine 49 -3227 -32.19 33.2O7 -100.0 -33.33 44.0 <0.001. A wSA - F OO67 Fluticasone 49 -35.75 -36.56 34.708 -100.0 -33.33 65.5 <0.001 F wSA - F O.227 Azelastine + Fluticasome 52 -44.03 -44.83 36.109 -100.0 -43.68 38.9 <0.001 Treatment O.174 Day 14 Azelastine 49 -31.14 -31.07 31.947 -100.0 -28.57 44.0 <0.001. A wSA - F O.O28 Fluticasone 49 -36.79 -37.7O 37.211 -100.0 -33.33 65.5 <0.001 F wSA - F O.2O6 Azelastine + Fluticasome 52 -45.57 -46.50 36.136 -100.0 -44.51 52.8 <0.001 Treatment O.087

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient percent change was based on a paired t-test, p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. JOverall includes TNSS scores from Day 2 to Day 14, Reference: 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.6.1 Change from Baseline in Individual Nasal Symptom Score (AM and PM Combined): Itchy Nose Intent-to-Treat Population (Page 1 of 4) Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value AM and PM Combined Nasal Symptom Score: Itchy Nose Baseline Azelastine (A) 49 4.74 4.76 O.807 2.9 4.73 6.O Treatment O.982 FluticasOne (F) SO 4.76 4.78 1.309 O.O S.16 6.O Azelastine + Fluticasome 52 4.72 4.74 1.047 1.5 4.76 6.O (A + F) Change from Baseline in AM and PM Combined Nasal Symptom Score: Itchy Nose Overal/ Azelastine 49 -1.16 -1.14 1.358 -4.5 -O.98 1.1 <0.001. A wSA - F O.OO9 Fluticasone 49 -1.24 -1.25 1.464 -5.4 -0.95 2.2 <0.001 F wSA - F O.O23 Azelastine + Fluticasome 52 - 1.94 - 1.94 1.730 -58 -1.89 2.3 <0.001 Treatment O.O17 Day <0.001 Treatment * Day O.889 Day 2 Azelastine 49 -0.61 -0.58 1.245 -4.2 -OSO 1.8 0.001 A vs A + F O.O22 Fluticasone 49 -0.66 -0.61 1600 -5.4 -0.40 3.2 O.OO6 F wSA - F O.O27 Azelastine + Fluticasome 52 -1.28 -1.25 1.742 -5.1 -1.00 2.0 <0.001 Treatment O.O33 US 8,758,816 B2 163 164 -continued

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.6.1 Change from Baseline in Individual Nasal Symptom Score (AM and PM Combined): Itchy Nose Intent-to-Treat Population (Page 2 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined Nasal Symptom Score: Itchy Nose

Day 3 Azelastine 49 -0.84 -0.85 364 -4.2 -O.75 1.3 <0.001. A wSA - F O.O2O Fluticasone 49 -0.97 -O.99 533 -5.4 -0.67 2.2 <0.001 F wSA - F O.061 Azelastine + Fluticasome 52 -1.53 -1.55 770 -6.0 -1.38 1.9 <0.001 Treatment O.046 Day 4 Azelastine 49 -1.00 -1.01 606 -4.8 -O.73 2.2 <0.001. A wSA - F O.O3O Fluticasone 49 -0.97 -0.98 .638 -5.4 -O.90 2.3 <0.001 F wSA - F O.O24 Azelastine + Fluticasome 52 -1.69 -1.71 683 -6.0 -1.67 1.O <0.001 Treatment O.O37 Day 5 Azelastine 49 -1.10 -1.11 690 -4.8 -O.75 1.3 <0.001. A wSA - F O.O31 Fluticasone 49 -1.15 -1.16 6SO -5.4 -1.00 2.3 <0.001 F wSA - F O.042 Azelastine + Fluticasome 52 -1.86 -1.88 .998 -6.0 -1.81 1.9 <0.001 Treatment O.OS2 Day 6 Azelastine 49 -1.14 -1.14 6SO -4.8 -O.73 1.4 <0.001. A wSA - F O.019 Fluticasone 49 -1.21 -1.21 630 -5.4 -1.00 1.6 <0.001 F wSA - F O.O32 Azelastine + Fluticasome 52 - 1.94 -1.95 923 -6.0 -2.00 1.9 <0.001 Treatment O.O33

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.6.1 Change from Baseline in Individual Nasal Symptom Score (AM and PM Combined): Itchy Nose Intent-to-Treat Population (Page 3 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N' Mean Mean Deviation mum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined Nasal Symptom Score: Itchy Nose

Day 7 Azelastine 49 -1.17 -1.18 .464 -4.8 -O.90 1.3 <0.001. A wSA - F O.O09 Fluticasone 49 -1.27 -130 S8O -5.4 -1.00 2.3 <0.001 F wSA - F O.O24 Azelastine + Fluticasome 52 -2.03 -2.06 993 -6.0 -2.00 2.9 <0.001 Treatment O.O17 Day 8 Azelastine 49 -1.12 -1.15 497 -4.8 -O.83 1.4 <0.001. A wSA - F O.004 Fluticasone 49 -1.29 -1.33 643 -5.4 -1.15 3.2 <0.001 F wSA - F O.018 Azelastine + Fluticasome 52 -2.11 -2.15 2.059 -6.0 -1.95 2.9 <0.001 Treatment O.O09 Day 9 Azelastine 49 -1.27 -129 472 -5.4 -O.93 1.3 <0.001. A wSA - F O.019 Fluticasone 49 -1.35 -1.40 624 -5.4 -1.30 2.2 <0.001 F wSA - F O.040 Azelastine + Fluticasome 52 -2.05 -2.10 2.025 -6.0 -2.00 2.9 <0.001 Treatment O.O37 Day 10 Azelastine 49 -1.35 - 1.35 743 -50 -1.10 1.3 <0.001. A wSA - F O.041 Fluticasone 49 -1.19 -1.21 .817 -5.4 -1.00 3.4 <0.001 F wSA - F O.O15 Azelastine + Fluticasome 52 -2.05 -2.08 904 -6.0 -2.00 2.0 <0.001 Treatment O.O32

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.6.1 Change from Baseline in Individual Nasal Symptom Score (AM and PM Combined): Itchy Nose Intent-to-Treat Population (Page 4 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined Nasal Symptom Score: Itchy Nose

Day 11 Azelastine 49 -1.37 - 1.39 1.803 -50 -1.10 1.4 <0.001. A wSA - F O.O28 Fluticasone 49 -1.29 -1.33 1810 -5.4 -1.08 3.4 <0.001 F wSA - F O.019 Azelastine + Fluticasome 52 -2.13 -2.18 1908 -6.0 -2.12 2.9 <0.001 Treatment O.O3O Day 12 Azelastine 49 -133 -1.33 1930 -6.0 -1.00 1.3 <0.001. A wSA - F O.O17 Fluticasone 49 -1.48 -1.50 1945 -5.4 -1.17 3.4 <0.001 F wSA - F O.OS1 Azelastine + Fluticasome 52 -2.19 -2.23 1.883 -6.0 -2.23 2.0 <0.001 Treatment O.O39 Day 13 Azelastine 49 -1.43 -1.44 1.842 -5.4 -1.15 1.8 <0.001. A wSA - F O.078 Fluticasone 49 -1.62 -1.64 2.031 -6.0 -1.42 3.4 <0.001 F wSA - F O.224 Azelastine + Fluticasome 52 -2.05 -2.10 1.978 -6.0 -2.25 2.9 <0.001 Treatment O.194 US 8,758,816 B2 165 166 -continued

Day 14 Azelastine 49 -139 -1.39 1903 -6.0 -1.15 1.8 <0.001. A wSA - F O.O17 Fluticasone 49 -1.74 -1.76 2.052 -6.0 -1.57 3.4 <0.001 F wSA - F O.146 Azelastine + Fluticasome 52 -2.26 -2.30 1.946 -6.0 -2.56 2.9 <0.001 Treatment O.OS3

Total number of intent-to-treat patients with available data. LS Mean = Least-Square Mean obtained from analysis of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) model otherwise. p-value for the within-patient change was based on a paired t-test, p-value for between treatment group comparison, except Overall and Baseline, was based on an ANCOVA model containing treatment group and site as fixed effects, and baseline as a covariate. For Overall, the p-value was based on a repeated measures ANCOVA model containing study day as the within-patient effect, treatment group and site as the between-patient effects, treatment-by-study day interaction, and baseline as a covariate. For Baseline, the p-value was based on an ANOVA model containing treatment group and site as fixed effects, Mean baseline TNSS over 5-day Lead-in Period, including Day 1 AM. JOverall includes TNSS scores from Day 2 to Day 14. Reference: 16.2.6.1

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.6.2 Change from Baseline in Individual Nasal Symptom Score (AM and PM Combined): Congestion Intent-to-Treat Population (Page 1 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N' Mean Mean Deviation mum Median Maximum p-value Source p-value AM and PM Combined Nasal Symptom Score: Congestion

Baseline Azelastine (A) 49 S.48 S.48 O.S11 4.5 5.47 6.O Treatment 0.505 Fluticasone (F) 50 5.51 5.51 O.388 4.5 5.55 6.O Azelastine + Fluticasome 52 S.40 S.40 0.578 3.8 5.45 6.O (A + F) Change from Baseline in AM and PM Combined Nasal Symptom Score: Congestion

Overal/ Azelastine 49 -1.12 -1.08 1452 -SO -0.77 1.5 <0.001. A wSA - F O.019 Fluticasone 49 -1.19 -1.14 1243 -5.2 -O.99 O.9 <0.001 F wSA - F O.O3S Azelastine + Fluticasome 52 -1.70 -1.70 1349 -4.6 -1.54 1.2 <0.001 Treatment O.O34 Day <0.001 Treatment * Day O.220 Day 2 Azelastine 49 -0.78 -0.73 1386 -4.1 -0.17 1.5 <0.001. A wSA - F 0.717 Fluticasone 49 -0.65 -0.59 1.380 -5.4 -O.30 1.2 O.OO2 F wSA - F O349 Azelastine + Fluticasome 52 -0.84 -O.83 1243 -3.7 -O.88 1.9 <0.001 Treatment O641

MedPoints Pharmaceuticals MP 428 Program: REFTNSS.SAS 14.2.6.2 Change from Baseline in Individual Nasal Symptom Score (AM and PM Combined): Congestion Intent-to-Treat Population (Page 2 of 4)

Paired Variable LS Standard Mini- t-test ANOVA Time Point Treatment N. Mean Mean Deviation mum Median Maximum p-value Source p-value Change from Baseline in AM and PM Combined Nasal Symptom Score: Congestion

Day 3 Azelastine 49 -0.68 -0.62 1.701 -58 O.OO 1.5 O.OO7. A wSA - F O.O11 Fluticasone 49 -0.90 -0.81 1.457 -5.4 -0.67 1.1 <0.001 F wSA - F O.O59 Azelastine + Fluticasome 52 -1.38 -1.37 1.511 -5.4 -1.43 1.9 <0.001 Treatment O.O3O Day 4 Azelastine 49 -0.82 -0.78 1.533 -5.1 -O.92 1.5 <0.001. A wSA - F O.O10 Fluticasone 49 -1.06 -1.00 1.388 -5.2 -1.00 1.4 <0.001 F wSA - F O.O70 Azelastine + Fluticasome 52 -1.53 -153 1497 -SO -1.48 1.8 <0.001 Treatment O.O31 Day 5 Azelastine 49 -1.07 -1.02 1680 -5.1 -O.90 1.5 <0.001. A wSA - F O-110 Fluticasone 49 -1.06 -1.00 1462 -5.4 -O.83 1.1 <0.001 F wSA - F O.099 Azelastine + Fluticasome 52 -1.53 -153 1679 -5.4 -155 1.8 <0.001 Treatment O.169 Day 6 Azelastine 49 -1.09 -1.04 1771 -58 -O.92 1.5 <0.001. A wSA - F O.044 Fluticasone 49 -1.10 -1.03 1.563 -5.4 -O.83 1.1 <0.001 F wSA - F O.042 Azelastine + Fluticasome 52 -1.69 -1.69 1.569 -SO -1.57 1.8 <0.001 Treatment O.064