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WO 2010/074753 Al (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 1 July 2010 (01.07.2010) WO 2010/074753 Al (51) International Patent Classification: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61M 11/00 (2006.01) A61P 25/20 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/US2009/006688 NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, 2 1 December 2009 (21 .12.2009) TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (30) Priority Data: ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/203,560 23 December 2008 (23.12.2008) US TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant (for all designated States except US): MAP MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, PHARMACEUTICALS, INC. [US/US]; 2400 Bayshore TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Parkway, Suite 200, Mountain View, CA 94043 (US). ML, MR, NE, SN, TD, TG). (72) Inventors (for US only): COOK, Robert, O.; 42 Scott Declarations under Rule 4.17: Dr., Hillsborough, NJ 08844 (US). ARMER, Thomas, — of inventorship (Rule 4Λ 7(iv)) A.; 19000 Tilson Avenue, Cupertino, CA 95014 (US). Published: (74) Agent: BATES, Owen; 2400 Bayshore Parkway, Suite 200, Mountain View, CA 94043 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, amendments (Rule 48.2(h)) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (54) Title: INHALATION DEVICES AND RELATED METHODS FOR ADMINISTRATION OF SEDATIVE HYPNOTIC COMPOUNDS (57) Abstract: An inhalation device for administering one or more sedatives via pulmonary delivery for treating a sleep distur- bance. INHALATION DEVICES AND RELATED METHODS FOR ADMINISTRATION OF SEDATIVE HYPNOTIC COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit of U.S. provisional application no. 61/203,560 filed 23-December 2008 entitled "Inhalation Devices and Related Methods for Administration of Sedative Hypnotic Compounds" which is hereby incorporated by reference in its entirety. FIELD [0002] Described herein are formulations and devices for inhalation administration of sedative compounds. Specifically, formulations and devices that aerosolize sedative compounds for the treatment insomnia, including sleep onset and sleep maintenance are described. Methods and kits for treating insomnia are also described. BACKGROUND [0003] Insomnia is a common sleep disturbance that affects the quantity or quality of sleep. Insomnia may be acute (one to several nights) or chronic (months to years). The symptoms of insomnia are typically described as an inability to fall asleep (sleep onset insomnia) or remain asleep (sleep maintenance insomnia). In some instances, insomnia is associated with other medical conditions, such as anxiety and depression, or with use of certain medications. According to the National Sleep Foundation's Sleep in America Poll 2005, insomnia was a concern because the effects of sleep deprivation were reported to decrease the quality of life of the individual, and in some cases, compromise the safety and normal functioning of the individual in the workplace and while driving. [0004] The current treatment of insomnia will vary depending on the etiology, nature, and severity of symptoms, and may include the use of pharmacologic agents. These agents typically are sedative compounds that include, but are not limited to: barbiturates, benzodiazepines, non-benzodiazepine sedatives (i.e. imidazopyridine class (Zolpidem), pyrazolopyrimidine class (zaleplon) and pyrrolopyrazine class (eszopiclone)), GABA A receptor agonists, antihistamines, orexin receptor agonists, phenothiazines, melatonin, and melatonin MTl and MT2 receptor agonists. As used herein, the terms "sedative", "hypnotic", "sedative hypnotic" and similar words or phrases are to be understood to be synonymous and refer to the ability to induce sleep. [0005] Currently, oral nonbenzodiazepines such as Ambien® tablets (Zolpidem tartrate) (Sanofi-Aventis, Bridgewater, NJ), Lunesta® tablets (eszoplicone) (Sepracor, Marlborough, MA), and Sonata® capsules (zaleplon) (King Pharmaceuticals, Bristol, TN). [0006] Other nonbenzodiazapine treatments, all orally administered, which may include melatonin (OTC) and the melatonin receptor MT1ZMT agonist Rozerem® tablets (ramelteon) (Takeda Pharmaceutical Co., Ltd., Osaka, Japan), are frequently prescribed for sleep disturbances. [0007] Developmental compounds include the nonbenzodiazapine GABA A agonist, Indiplon (Neurocrine, San Diego, CA) and those with novel receptor activity such as HYl 0275 which is a dual-acting H 1ZS-HT Acompound (HypnionZLilly, Lexington, MA) and almorexant, an orexin receptor antagonist (ActelionZGSK, Basel, Switzerland). These newer therapies minimize or avoid undesirable side effects typical of the GABA A agonists, such as memory impairment and dependence and abuse potential, tolerance and rebound insomnia. [0008] All of these compounds are administered orally, and therefore can take from 1-2 hours to onset of therapeutic effects. Food or alcohol intake can significantly enhance or retard the therapeutic effects or time to onset. Because of the long time to onsets, the long duration of effects and the variability with GI loading, these therapies must be administered on a specific schedule hours before retiring for a normal sleep period. Because oral bioavailability can be low, relatively high doses are required to achieve and sustain systemic circulation concentrations sufficiently high to be effective, particularly for sleep maintenance. Such high dosage levels, combined with the long half lives of elimination typical of these compounds, result in long washout periods which can prolong residual sedation into normal waking hours. [0009] Given the importance of the sedative-hypnotics in treating insomnia, an alternative to oral administration would be desirable to administer sedative hypnotics by means that would have rapid onset and could be administered just before retiring for normal sleep period. Devices for generating aerosols of sedative- hypnotic drugs for inhalation would enable rapid onset because therapeutically effective concentrations can be achieved rapidly by pulmonary administration. Additionally inhalation avoids interference from food or drink that is found with oral administration. Inhalation also bypasses first pass metabolism and results in higher bioavailability for small molecules such as the sedative-hypnotics. Therefore lower doses can be used to rapidly achieve therapeutic concentrations in systemic circulation in as fast as 2- 3 minutes. The lower doses minimize side effects and residual sedation at the end of sleep period. SUMMARY [0010] The invention described herein includes formulations, methods, inhalation devices and kits for the treatment of sleep disturbances. The devices generally include a housing, an aerosol generating mechanism, and a sedative composition. The preferred inhalation device is a pressurized metered dose inhaler (pMDI). The pMDI may be breath- actuated. [0011] The sedative compositions may include any barbiturates, benzodiazepines, non-benzodiazepine sedatives, GABA A receptor agonists, antihistamines, orexin receptor agonists, phenothiazines, melatonin, and melatonin MT1 and MT receptor agonists, 5-HT A antagonists, or combinations thereof that are useful for treating sleep disturbances. In addition to the sedative, excipients such as solvents, dispersants, preservatives, antioxidants, buffering agents, and flavoring agents may be used in the compositions. The sedative composition may be contained in pressurized metered dose inhaler (pMDI) within a pressurized reservoir fitted with a metering valve as a particle suspension or solution in a fluorocarbon propellant media. [0012] The formulations, methods, and inhalation devices may be used to treat various sleep disturbances. For example, the formulations, methods, and inhalation devices may be used to treat insomnia, including acute insomnia, chronic insomnia, sleep onset insomnia, and sleep maintenance insomnia. In some embodiments of the invention, the aerosol generated by the inhalation device is capable of rapidly initiating sleep, thus decreasing sleep latency. As used herein, the terms "rapid" or "rapidly" refer to the induction of sleep within at least about 30 minutes after administration of the sedative. In other embodiments, the aerosol of the formulation is also capable of maintaining sleep for at least about 4 hours. In another embodiment, a drug combination may be administered, where one drug provides rapid induction of sleep, and the other drug provide longer-acting sedation for sleep maintenance, but not so long as to cause residual
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