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WO 2014/055801 Al 10 April 2014 (10.04.2014) P O P C T

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WO 2014/055801 Al 10 April 2014 (10.04.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/055801 Al 10 April 2014 (10.04.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/522 (2006.01) A61K 31/401 (2006.01) kind of national protection available): AE, AG, AL, AM, A61P 27/00 (2006.01) A61K 31/416 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/4375 (2006.01) A61K 31/44 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/52 (2006.01) A61K 31/352 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/519 (2006.01) A61K 31/473 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, A61K 31/444' (2006.01) A61K 31/4985 (2006.01) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, A61K 31/4704 (2006.01) A61K 31/506 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, A61K 31/472 (2006.01) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (21) International Application Number: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, PCT/US2013/06333 1 ZW. (22) International Filing Date: (84) Designated States (unless otherwise indicated, for every 3 October 2013 (03. 10.2013) kind of regional protection available): ARIPO (BW, GH, (25) Filing Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (26) Publication Language: English TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (30) Priority Data: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 61/710,674 5 October 2012 (05. 10.2012) US MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 61/802,074 15 March 2013 (15.03.2013) US TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventor; and (71) Applicant : HENKIN, Robert, I. [US/US]; 6601 Published: Broxburn Drive, Bethesda, MD 20817 (US). — with international search report (Art. 21(3)) (74) Agents: VAN GOOR, David, W. et al; Wilson Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA 94304-1050 (US). © 00 o o (54) Title: PHOSPHODIESTERASE INHIBITORS FOR TREATING TASTE AND SMELL DISORDERS (57) Abstract: Methods and compositions are disclosed for the treatment of taste and smell disorders. The compositions comprise phosphodiesterase inhibitors and are formulated for intranasal administration. PHOSPHODIESTERASE INHIBITORS FOR TREATING TASTE AND SMELL DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Nos. 61/710,674, filed October 5, 2012, and 61/802,074, filed March 15, 2013, each of which application is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Phosphodiesterases (PDE) are a diverse family of enzymes that hydrolyze cyclic nucleotides resulting in the modulation of intracellular levels of the second messengers cAMP and cGMP, and hence, cell function. Numerous diseases and conditions result from low levels of cyclic nucleotides. The use of PDE inhibitors to raise cellular levels of cyclic nucleotides offers the ability to prevent, treat, or ameliorate diseases, conditions or their symptoms, however, systemic administration may not achieve therapeutically effective concentrations due to unacceptable side effects or to inability to obtain therapeutic levels in clinically responsive tissues. There is a need for suitable compositions and methods of delivery to achieve medically relevant concentrations of PDE inhibitors without unacceptable side effects. The present invention addresses these unmet needs. SUMMARY OF INVENTION [0003] The inventive embodiments provided in this Summary of Invention are meant to be illustrative only and to provide an overview of selective embodiments disclosed herein. The Summary of Invention, being illustrative and selective, does not limit the scope of any claim, does not provide the entire scope of inventive embodiments disclosed or contemplated herein, and should not be construed as limiting or constraining the scope of this disclosure or any claimed inventive embodiment. [0004] In a first aspect, disclosed herein are multi-dose nasal spray devices for delivery of theophylline to a human's nasal epithelium that delivers a dosage unit in a plume upon actuation, wherein the dosage unit comprises, for example, from 10 µg to 200 µg of theophylline in a pharmaceutically acceptable carrier comprising one or more excipients; and wherein the plume is characterized by: (a) a total volume of, for example, from 25 to 200 µ and (b) a droplet size distribution characterized by one or more of the following: (i) less than 5 % of the droplets in the µιη µιη plume having a size of less than 10 , (ii) a D 10 of greater than 12.5 , wherein 10% of the µιη droplets in the plume have a size less than the D 10 , (iii) a D 0 of from 30 to 70 , wherein 50% µιη of the droplets in the plume have a size less than the D 0 , (iv) a D 0 of less than 200 , wherein 90% of the droplets in the plume have a size less than the D90, and (v) a span of from 1 to 6, (D90 wherein the span is calculated according to: - D 10 )/D50 . [0005] In some embodiments, the dosage unit comprises from 15 µg to 150 µg of theophylline. In some embodiments, the dosage unit comprises from 20 µg to 100 µg of theophylline. In some embodiments, the dosage unit comprises about 100 µg theophylline. In some embodiments, the dosage unit comprises about 75 µg theophylline. In some embodiments, the dosage unit comprises about 50 µg of theophylline. In some embodiments, the dosage unit comprises about 20 µg of theophylline. [0006] Also disclosed are multi-dose nasal spray devices for delivery of theophylline to a human's nasal epithelium that delivers a dosage unit in a plume upon actuation, wherein the dosage unit comprises, for example, from 0.17 µg/kg to 3.4 µg/kg of theophylline in a pharmaceutically acceptable carrier comprising one or more excipients; and wherein the plume is characterized by: (a) a total volume, for example, of from 25 µ to 200 µ and (b) a droplet size distribution characterized by one or more of the following: (i) less than 5% of the droplets in the µιη µιη plume having a size of less than 10 , (ii) a D 10 of greater than 12.5 , wherein 10% of the µιη 50%> droplets in the plume have a size less than the D 10 , (iii) a D 0 of from 30 to 70 , wherein of the droplets in the plume have a size less than the D o, (iv) a D 0 of less than 200 µιη, wherein 90% of the droplets in the plume have a size less than the D90, and (v) a span of from 1 to 6, o. wherein the span is calculated according to: (D90 - D 10 )/D [0007] In some embodiments, the dosage unit comprises from 0.25 µg/kg to 2.6 µg/kg of theophylline. In some embodiments, the dosage unit comprises from 0.33 µg/kg to 1.7 µg/kg of theophylline. In some embodiments, the dosage unit comprises about 1.7 µg/kg theophylline. In some embodiments, the dosage unit comprises about 1.3 µg/kg theophylline. In some embodiments, the dosage unit comprises about 0.85 µg/kg of theophylline. In some embodiments, the dosage unit comprises about 0.33 µg/kg of theophylline. [0008] In some embodiments, the dosage unit is a steroid-free dosage unit. [0009] In some embodiments, the pharmaceutically acceptable carrier has a pH that is greater than 7.0. In some embodiments, the pharmaceutically acceptable carrier has a pH that is from 7.1 to 8.5. In some embodiments, the pharmaceutically acceptable carrier has a pH that is from 7.1 to 7.4. In some embodiments, the pharmaceutically acceptable carrier has a pH that is about: 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pharmaceutically acceptable carrier has a pH that is at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, or 8.5. [0010] In some embodiments, the plume is characterized by the total volume of the plume that is from 50 to 150 µ . In some embodiments, the plume is characterized by the total volume of the plume that is from 75 to 125 µ . In some embodiments, the plume is characterized by the total volume of the plume that is from 90 µ to 110 µ . In some embodiments, the plume is characterized by the total volume of the plume that is about: 25 µ , 30 µΐ , 35 µΐ , 40 µΐ , 45 µΐ , 50 µΐ , 55 µΐ , 60 µΐ , 65 µΐ , 70 µΐ , 75 µΐ , 80 µΐ , 85 µΐ , 90 µΐ , 100 µΐ , 110 µΐ , 120 µΐ , 130 µΐ , 140 µΐ , 150 µΐ , 160 µΐ , 170 µΐ , 180 µΐ , 190 µΐ , or 200 µ .
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