USOO6939559B1 (12) United States Patent (10) Patent No.: US 6,939,559 B1 Nishibe et al. (45) Date of Patent: Sep. 6, 2005 (54) PHARMACEUTICAL COMPOSITION FOR 5,474,764 A 12/1995 Patel et al. APPLICATION TO MUCOSA 5,474,768 A 12/1995 Robinson 5,733,569 A 3/1998 AZria et al. ................. 424/434 (75) Inventors: Yoshihisa Nishibe, Hino (JP); Wataru 5,869,096 A 2/1999 Barclay et al. ............. 424/468 Kinoshita, Hino (JP); Hiroyuki 5,942.242 A 8/1999 Mizushima et al. Kawabe, Tokyo (JP) 5,976,573 A * 11/1999 Kim FOREIGN PATENT DOCUMENTS (73) Assignee: Teijin Limited, Osaka (JP) CA 2107587 A1 10/1992 (*) Notice: Subject to any disclaimer, the term of this CA 1327314 A1 3/1994 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 09/446,276 OTHER PUBLICATIONS Bauer K.H. et al Pharmazeutische Technologie, George (22) PCT Filed: Apr. 21, 1999 Thieme verlag, Stuttgart, 3, p. 239, 1991.* (86) PCT No.: PCT/JP99/02126 Dictionary of Food Additivies, 1 Edition, (1994), pp. 36-37. S371 (c)(1), Dictionary of Food Additivies, 1 edition, p. 49-50 (1994), (2), (4) Date: Dec. 21, 1999 and partial translation. (87) PCT Pub. No.: WO99/53899 Textbook of Pharmacology, 2" edition, p. 319-320 (1987), and partial translation. PCT Pub. Date: Oct. 28, 1999 (Continued) (30) Foreign Application Priority Data Primary Examiner-Carlos A. Azpuru Apr. 21, 1998 (JP) ........................................... 10-110887 Apr. 21, 1998 (JP) ........................................... 10-110888 (74) Attorney, Agent, or Firm Sughrue Mion, PLLC (51) Int. Cl.................................................. A61F 13/02 (57) ABSTRACT (52) U.S. Cl. ....................................................... 424/434 The present invention provides a pharmaceutical composi (58) Field of Search .......................................... 424/434 tion for application to the mucosa to be used in drug therapy comprising a water-insoluble and/or water-low Soluble (56) References Cited Substance, a medicament, and an aqueous medium, and having an osmotic pressure of less than 290 mOsm. This U.S. PATENT DOCUMENTS composition is Superior over conventional pharmaceutical 4,271,143 A 6/1981 Schoenwald et al. compositions for application to the mucosa, due to efficient 4,613,500 A 9/1986 Suzuki et al. and high permeability to the blood at the mucosa. The 4,615,697 A 10/1986 Robinson present invention further provides a pharmaceutical compo 5,147,654 A 9/1992 Place et al. ................. 424/473 Sition for application to the mucosa comprising a hemostatic 5,179,079 A 1/1993 Hansen et al. ................. 514/4 agent and a medicament. This composition is Superior over 5,188,826 A 2/1993 Chandrasekaran et al. conventional pharmaceutical compositions for application to 5,192,535 A 3/1993 Davis et al. the mucosa, due to permeability and retentivity at the 5,200,195 A 4/1993 Dong et al. ................. 424/473 5,281,580 A 1/1994 Yamamoto et al. ........... 514/12 COS. 5,340,572 A 8/1994 Patel et al. 5,393,773. A 2/1995 Craig et al. 29 Claims, 4 Drawing Sheets Composition 1 Composition 11 Composition 2 12 Composition 12 Composition 3 13 Composition 13 2 Composition 4 14 Composition 14 Composition 5 15 Composition 15 - Composition 6 Composition 7 3 O O 50 1OO 150 2OO 250 300 Osmotic Pressure (mosm) US 6,939,559 B1 Page 2 FOREIGN PATENT DOCUMENTS ABSTRACT "Nasal absorption of propranolo from differ CA 2164624 A1 1/1995 dosage forms by rats and dogs' J Pharm Sci Dec. 1980; CA 226814.0 A1 4/1998 69(12): 1411–3. CA 2278025 A1 7/1998 ABSTRACT "Nasal absorption of testosterone in rats' J EP 496 308 A1 * 1/1991 Pharm SciSep. 1984; 73(9): 1300–1. EP O4963O8 A1 7/1991 EP O781546 A1 12/1996 ABSTRACT “The time of onset of action of Sublingual EP O 781 546 A1 12/1996 ............ A61 K/9/00 nitroglycerin in exercise-induced angina pectoris. A meth HU 209 247 B 4/1994 ......... A61K/31/685 odological study” Eur Hear JJul. 1985; 6(7): 625-30. 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WO WO 97/31626 A1 9/1997 ABSTRACT “Pharmacodynamics of acute intranasal WO WO 98/OO178 A1 1/1998 administration of Verapamil: comparison with i.v. and oral administration.” Biopharm Drug Dispos Oct.-Dec. 1985; OTHER PUBLICATIONS 6(4): 447-54. Machida Minoru, et al. “Effects of Surfactants and Protease ABSTRACT “Pharmacokinetics of hyrdomorphone after Inhibitors on Nasal Absorption of Recombinant Human intravenous, peroral and rectal administration to human Granulocyte Colony-Stimulating Factor (rhG-CSF) in subjects.” Biopharm Drug Dispos Mar.-Apr. 1988; 9(2): Rats" Biol. Pharm. Bull 17(10) 1375–1378 1994. 187-99. Nomura Hideaki, et al. “Effects of a Dosing Solution on the Nasal Absorptionof Non-glycosylated Recombinant Human ABSTRACT “Pharmacokinetics of bioavailability of Granulocyte Colony-Stimulating Factor in Rats' Biol. hydromorphone: effect of various routes of administration.” Pharm. Bull 19(10) 1490–1493 1996. Pharm Res Nov. 1988; 5(11): 718–21. 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ABSTRACT “Enhanced absorption of bumetanide from Suppositories containing weak acids in rabbits.” Biol Pharm ABSTRACT "Asthma therapy: present trends and future Bull Mar. 1993; 16(3): 263–7. prospects.” Compr Ther Mar. 1990; 16(3):12–6. ABSTRACT “Studies on the nasal absorbtion of genta ABSTRACT “Transdermal nitroglycerin systems: meth mycin.” Chung Hua Erh Pi Yen Hou Ko Tsa Chih 1994: ods for comparison.” Clin Ther May-Jun. 1991; 13(3): 29(3): 134-6. 361-7. ABSTRACT "Pharmacokinetics and endometrial effects ABSTRACT “Intranasal absorption of physostigmine and of vaginal administration of micronied progesterone in an arecoline.” J Pharm Sci Aug. 1991; 80(8):750–1. oil-based solution to postmenopausal women.” Fertil Steril Apr. ; 1996; 65(4): 860–2. ABSTRACT “A comparative evaluation of two transder ABSTRACT “Colonic mucus, Smoking and ulcerative mal nitroglycerin delivery systems: Nitro-Dur versus Trans colitis.” Ann R Coll Surg Engl Mar.; 1996; 78(2): 85–91. derm-Nitro. The Collaborative Investigation Group.” Clin ABSTRACT “Studies on the response of nitroglycerin Ther Sep.-Oct. 1991; 13(5): 545–9. oral Spray compared with Sublingual tablets for angina ABSTRACT “Pharmacokinetics and bioavailability of pectoris patients with dry mouth. A multicenter trial.” ArZ papaverine HCI following intravenous, peroral, rectal, vagi neimittelforschung Feb.; 1997; 47(2): 128–31. nal, topical and buccal adminisitration in beagle dogs.” ABSTRACT “Oral transmucosal fentanyl citrate: random Biopharm Drug Dispos Oct. 1991, 12(7): 537–46. ized, double-blinded, placebo-controlled trial for treatment International Search Report. of breakthrough pain in cancer patients.' J Natl Cancer Inst Apr. 15, 1998; 90(8): 611-6. * cited by examiner U.S. Patent Sep. 6, 2005 Sheet 1 of 4 US 6,939,559 B1 009 09Z :[:zI :£I :†7I .9I 00Z 09||00|| (uusOu)?unsseldo?ouuSO 09 Bioavailability (%) U.S. Patent Sep. 6, 2005 Sheet 2 of 4 US 6,939,559 B1 l-l 8| 6| |2 22 6I | .LI :8I .6I :IZ ...ZZ 00||Z00'Z0909€009007 eunssejaO??ouusO(uusOu) 8I Z 09 LI IZ 09 09 0#7 OZ 0|| Bioavailability (%) U.S. Patent Sep. 6, 2005 Sheet 3 of 4 US 6,939,559 B1 00?709800809Z00Z||00 (uusOuu)ºunssºudo?ouuSO 09 Bioavailability (%) U.S. Patent Sep. 6, 2005 Sheet 4 of 4 US 6,939,559 B1 C A ) US 6,939,559 B1 1 2 PHARMACEUTICAL COMPOSITION FOR (Japanese Unexamined Patent Publication (Kokai) No. 63 APPLICATION TO MUCOSA (1988)-303931), for example, provides a method of applying to the nasal cavity a growth hormone-releasing factor at the liquid form having an osmotic pressure ratio of 1 (an PHARMACEUTICAL COMPOSITION FOR 5 osmotic pressure of 290 mOsm) or lower as a method for APPLICATION TO MUCOSA enabling quick and efficient absorption of the a growth hormone-releasing factor through the nasal mucosa to the TECHNICAL FIELD blood circulation. Furthermore, Ohwaki et al. (Japanese The present invention relates to a pharmaceutical com Unexamined Patent Publication (Kokai) No.