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(12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji Et Al US 20050215521A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji et al. (43) Pub. Date: Sep. 29, 2005 (54) MODAFINIL COMBINATION THERAPY FOR Publication Classification IMPROVING SLEEP QUALITY (51) Int. Cl.' .................. A61K 31/724; A61K 31/7008; (76) Inventors: Karim Lalji, Sudbury, MA (US); A61K 31/4164; A61K 31/195; Timothy J. Barberich, Concord, MA A61K 31/165 (US) (52) U.S. Cl. ............................ 514/58; 514/221; 514/389; 514/561; 514/557; 514/23; Correspondence Address: 514/618; 514/469 FOLEY HOAG, LLP PATENT GROUP, WORLD TRADE CENTER WEST (57) ABSTRACT 155 SEAPORT BLVD One aspect of the present invention relates to pharmaceutical BOSTON, MA 02110 (US) compositions comprising a compound that modulates the orexin System and a Sedative agent. In a preferred embodi (21) Appl. No.: 11/018,869 ment, the compound that modulates the orexin System is (22) Filed: Dec. 21, 2004 modafinil and the Sedative agent is eSZopiclone. The phar maceutical compositions of the invention are useful in the Related U.S. Application Data treatment of various sleep disorders. In addition, the present invention relates to a method of treating a patient Suffering (60) Provisional application No. 60/531,822, filed on Dec. from a sleep abnormality or insomnia comprising adminis 22, 2003. Provisional application No. 60/541,684, tering a therapeutically effective amount of a pharmaceutical filed on Feb. 4, 2004. composition of the invention. Patent Application Publication Sep. 29, 2005 Sheet 1 of 2 US 2005/0215521 A1 Figure 1 (RS)-Zopiclone D-Malic Acid Acetone Mixing/Heating Methanol Methanol-DCooling/Crystallizatio (S)-Zopiclone D-Malate See Methanol Filtration/Washing Mother Liquors/Washes -Ge IPC (S)-Zopiclone D-Malate Patent Application Publication Sep. 29, 2005 Sheet 2 of 2 US 2005/0215521 A1 Figure 2 (S)-Zopiclone D-Malate Water D Mixing/Heating Ethyl Acetate Water Potassium Carbonate -D -D CO, Gas Aqueous Waste Water Aqueous Waste Ethyl Acetate Polish Filtration Solid Waste Ethyl Acetate Distillation Distillate Waste -> Irc ooling/Crystallization Ethyl Acetate Wash Filtration/Washing Mother Liquors/Washes -Ge. IPC (S)-Zopiclone API US 2005/0215521 A1 Sep. 29, 2005 MODAFNIL COMBINATION THERAPY FOR frequent complaint, reported by 32% of the adult population IMPROVING SLEEP QUALITY Surveyed in the Los Angeles area (Bixler et al, Amer. Journal of Psychiatry 136:1257-1262, 1979), and 13% of the popu RELATED APPLICATIONS lation Surveyed in San Marino, Italy (Lugaresi et al., Psy 0001. This application claims the benefit of priority to chiatric Annals 17:446-453, 1987). Fully 45% of the sur U.S. Provisional Patent Application Ser. No. 60/531,822, veyed adult population of Alachua County, Florida, reported filed Dec. 22, 2003; and U.S. Provisional Patent Application trouble getting to sleep or staying asleep (Karacan et al., Ser. No. 60/541,684, filed Feb. 4, 2004. Social Science and Medicine 10:239-244, 1976). The preva BACKGROUND OF THE INVENTION lence of insomnia has also been shown to be related to the age and Sex of the individuals, being higher in older indi 0002 Sleep is controlled by two biological processes, the viduals and in females. homeostatic drive and the circadian rythym. The homestatic drive manifests itself as an increased drive for sleep. This 0006 Early treatments for insomnia commonly drive for sleep accumulates acroSS the period of WakefulneSS employed central nervous System (CNS) depressants such as (typically daytime) and dissipates across the sleep period. barbiturates. These compounds are typically long acting (on The circadian rhythm of Sleep-wake shows a biphasic curve the order of 8-50 hours) due to long terminal half-lives, and with the greatest drive for Sleep occurring between midnight have a well-known Spectrum of Side effects, including and 5 AM, and between 2 PM and 4 PM. It is believed that lethargy, confusion, depression and next day hangover major circadian influences are an alerting pulse in the effects. In addition, chronic use has been associated with a evening and in the morning. It is the interaction of these high potential for addiction involving both physical and processes which give rise to the 24-hour sleep Schedule. For psychological dependence. individuals with a usual sleep period of 11 PM to 7 AM, Sleep onset in the evening occurs primarily as a function of 0007. During the 1980s, the pharmaceutical treatment of homeostatic drive. After about four hours of sleep (at about insomnia shifted away from barbiturates and other CNS 3 AM) homeostatic drive dissipates significantly and wake depressants toward the benzodiazepine class of Sedative fulneSS begins to intrude into the sleep period. This propen hypnotic agents. This class of compounds produces a calm sity to increased WakefulneSS is further increased by the rise ing effect that results in a sleep-like State in humans and in the circadian alerting pulse at about 5 AM. animals, with a greater Safety margin than prior hypnotics. The therapeutic actions of benzodiazepines are believed to 0003. In terms of the pharmacological management of be mediated by binding to a specific receptor on benzodi insomnia, two Vulnerabilities have been recognized. The aZepine GABA complexes in the brain. As a result of this first is difficulty initially falling asleep, with the second binding, Synaptic transmission is altered at neurons contain being reawakening in the middle of the night. The formu ing the benzodiazepine GABA complex. The clinical use lations of the present invention address both of these issues fulness of different benzodiazepine hypnotics relates largely by use of a particularly short acting Sedative-hypnotic com to their pharmacokinetic differences with regard to this pound which has a single pulse at Sleep onset, and a Second binding and, in particular, to the half-lives of the parent pulse at the time of the decline in homeostatic processes and compound and its active metabolites. However, many ben rise in the circadian pulse. The increase in plasma concen Zodiazepines possess Side effects that limit their usefulness tration from the dip or T value to that of T has been in certain patient populations. These problems include Syn found to be particularly beneficial in preventing Subsequent ergy with other CNS depressants (especially alcohol), the awakening of the patient. Much like the initial plasma development of tolerance upon repeat dosing, rebound concentration pulse from time of administration to T, insomnia following discontinuation of dosing, hangover which results in the patient falling asleep, the pulse from the effects the next day and impairment of psychomotor perfor concentration at Ti to T2 has been found to be par mance and memory. Next day SleepineSS and memory ticularly beneficial for sleep maintenance. To this end, it is impairment, which can include amnesia for events occurring believed that this increase in plasma concentration is more prior to and after drug administration, is of particular con beneficial than merely maintaining a constant plasma con cern in the elderly whose cognitive functions may already be centration of the Sedative-hypnotic compound. For example, impaired by the aging process. by having the plasma concentration dip between T and T2 the patient is exposed to a lower Overall dosage, 0008 More recent treatments for insomnia have used thereby decreasing Subsequent effects, Such as unwanted non-benzodiazepine compounds, which Show an improved hangover effect. In addition, a lower plasma concentration at Side effect profile over the benzodiazepine class of Sedative T. decreases incidents of nighttime falls and/or amnesia, hypnotics. The first of these agents to be approved by the particularly in the elderly. United States Food and Drug Administration (FDA) for marketing in the United States was Ambien (Zolpidem), 0004. Many physiological functions are characterized by which is based on the imidazopyridine backbone (see U.S. diurnal rhythms, in which levels of circulating hormones, Pat. Nos. 4,382,938 and 4,460,592). In addition to Ambien, catecholamines and other compounds fluctuate during the another compound known as Sonata (Zaleplon), which is a day and/or night. Certain medical disorders, Such as insom pyrazolopyrimidine-based compound (see U.S. Pat. No. nia, are associated with abnormalities in these rhythms. The 4,626.538), was recently approved by the FDA. Other time, within a 24 hour period, of administration of drugs for non-benzodiazepine compounds and/or methods for making the prevention and treatment of Such disorders can be a or using the same have also been reported (see, e.g., U.S. critical factor in determining efficacy of the therapy. Pat. Nos. 4,794,185, 4,808,594, 4,847,256, 5,714,607, 0005. The term “insomnia" refers to the perception of 4,654,347; 5,538,977, 5,891,891). Attempts have also been inadequate or non-restful sleep by a patient. Insomnia is a disclosed to provide controlled-release dosage forms, par US 2005/0215521 A1 Sep. 29, 2005 ticularly in the context of Zolpidem and Salts thereof (See of insomnia in adults in the United States: difficulty falling WO 00/33835 and EP 1 005 863 A1). asleep, waking a lot during the night, waking up too early and not being able to get back to Sleep; and waking up 0009. Accordingly, there is a need in the art for sedative feeling unrefreshed. In the Survey, 58% of the respondents hypnotic compositions that induce and maintain Sleep as reported experiencing at least one of these Symptoms a few Single dose nocturnal formulations, but without the side nights a week or more, and 35% reported difficulties every effects associated with the longer acting hypnotics. The night or almost every night within the past year (National present invention fulfills this need and further provides other Sleep Foundation.
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