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(12) Patent Application Publication (10) Pub. No.: US 2012/0231083 A1 Carley Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0231083 A1 Carley Et Al US 2012023.1083A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0231083 A1 Carley et al. (43) Pub. Date: Sep. 13, 2012 (54) SUSTAINED RELEASE CANNABINOID Publication Classification MEDCAMENTS (51) Int. Cl. (75) Inventors: David Carley, Evanston, IL (US); A6IR 9/14 (2006.01) Kenton Fedde, Wildwood, MO A6IP II/00 (2006.01) (US); John KOLENG, Austin, TX A63L/352 (2006.01) (US); Peter LETENDRE, Lafayette, CO (US) (52) U.S. Cl. .......... 424/494; 514/454; 424/490; 424/497 (73) Assignees: The Board of Trustees of the University of Illinois, Urbana, IL (57) ABSTRACT (US); PIER PHARMACEUTICALS, The present invention provides a medicament which results in Louisville, CO (US) delivery of a therapeutic level of one or more cannabinoids during a clinically relevant therapeutic window. The thera (21) Appl. No.: 13/474,666 peutic window is a longer window than provided by an imme diate release medicament such as Marinol containing an (22) Filed: May 17, 2012 equivalent amount of the cannabinoid. Oral administration of O O the present compositions provides therapeutic dosing while Related U.S. Application Data maintaining safe, side effect sparing, levels of a cannabinoid. (63) Continuation of application No. PCT/US 10/57302, The present invention also provides methods of treating can filed on Nov. 18, 2010. nabinoid-sensitive disorders. Patent Application Publication Sep. 13, 2012 Sheet 1 of 5 US 2012/0231.083 A1 SaxxXxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX s: Y ySY 3 ES wsa reg YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYS SYYYYYYYYYYYYYYYYYYYYYYY was reg wim assists sex-sex w s t & tiratics & Eitect 3 airs Patent Application Publication Sep. 13, 2012 Sheet 2 of 5 US 2012/0231.083 A1 Ks 2 ist iaif s s s as a & Patent Application Publication Sep. 13, 2012 Sheet 3 of 5 US 2012/0231.083 A1 Figure 3 Patent Application Publication Sep. 13, 2012 Sheet 4 of 5 US 2012/0231.083 A1 Figure 4 5. 4.5 4 3.5 gs 3 E 15'' O 1 O.5 O O 2 4 6 8 10 12 mg Cannabinoid Patent Application Publication Sep. 13, 2012 Sheet 5 of 5 US 2012/0231.083 A1 Figure 5 . " . SEH) --2.5 mg - WATER --2.5 mg --5 g me 1 mg 's an 2 : 8 S 1 2 S 8 is a 2$ 38 3 TSE) --2.5 rig - IATER --2.5 stag rdrS rig re-ring US 2012/023 1083 A1 Sep. 13, 2012 SUSTAINED RELEASE CANNABINOID gressive-type asphyxia until the individual is briefly aroused MEDCAMENTS from the sleeping state, thereby restoring airway patency and thus restoring airflow. CROSS REFERENCE TO RELATED 0008. An important factor that leads to the collapse of the APPLICATIONS upper airway in OSAS is the generation of a critical subat mospheric pressure during the act of inspiration that exceeds 0001. This application is a continuation of PCT/US2010/ the ability of the airway dilator and abductor muscles to 057302, filed 10 Nov. 2010, which claims priority to U.S. maintain airway stability. Sleep plays a crucial role by reduc Provisional 61/262,523, filed 18 Nov. 2009, which are hereby ing the activity of the muscles of the upper airways including incorporated by reference in their entirety. the dilator and abductor muscles. 0009. In most individuals with OSAS the patency of the TECHNICAL FIELD airway is also compromised structurally and is therefore pre 0002 The present invention relates to cannabinoid com disposed to occlusion. In a minority of individuals the struc positions and methods of treating cannabinoid-sensitive dis tural compromise is usually due to obvious anatomic abnor orders (e.g. apnea) with cannabinoids. malities, i.e. adenotonsillar hypertrophy, retrognathia, or macroglossia. However, in the majority of individuals predis posed to OSAS, the structural abnormality is simply a subtle BACKGROUND reduction in airway size, i.e., "pharyngeal crowding.” Obesity 0003 Over the past several years, much effort has been also frequently contributes to the reduction in size seen in the devoted to the study of a discrete group of breathing disorders upper airways. The act of Snoring, which is actually a high that occur primarily during sleep with consequences that may frequency vibration of the palatal and pharyngeal soft tissues, persist throughout the waking hours, most commonly in the usually aggravates the narrowing via the production of edema form of sleepiness and/or cognitive/motor impairment, in the soft tissues. thereby manifesting itself into Substantial economic loss 0010. The recurrent episodes of nocturnal asphyxia and of (e.g., thousands of lost man-hours) or employment safety arousal from sleep that characterize OSAS lead to a series of factors (e.g., employee non-attentiveness during operation of secondary physiologic events, which in turn give rise to the heavy-machinery). Sleep-related breathing disorders are clinical complications of the syndrome. The most common characterized by repetitive reduction in breathing (hypop manifestations are neuropsychiatric and behavioral distur nea), cessation of breathing (apnea), or a continuous or Sus bances that are thought to arise from the fragmentation of tained reduction in Ventilation (hypoVentilation). sleep and loss of slow-wave sleep induced by the recurrent 0004. In general, sleep apnea is defined as an intermittent arousal responses. Nocturnal cerebral hypoxia also may play cessation of airflow at the nose and mouth during sleep. By an important role. The most pervasive manifestation is exces convention, apneas of at least 10 seconds in duration have sive daytime sleepiness, although insomnia is common in the been considered important, but in most individuals, the elderly with OSAS. OSAS is now recognized as a leading apneas are 20-30 seconds in duration and may be as long as cause of daytime sleepiness and has been implicated as an 2-3 minutes. While there is some uncertainty as to the mini important risk factor for such problems as motor vehicle mum number of apneas that should be considered clinically accidents. Other related symptoms include intellectual important, by the time most individuals come to attention of impairment, memory loss, personality disturbances, and the medical community they have at least 10 to 15 events per impotence. hour of sleep. 0011. Other major manifestations are cardiorespiratory in 0005 Sleep apneas have been classified into three types: nature and are thought to arise from the recurrent episodes of central, obstructive, and mixed. In central sleep apnea the nocturnal asphyxia. Most individuals demonstrate a cyclical neural drive to all respiratory muscles is transiently abol slowing of the heart during the apneas to 30 to 50 beats per ished. In obstructive sleep apneas, airflow ceases despite con minute, followed by tachycardia of 90 to 120 beats perminute tinuing respiratory drive because of occlusion of the oropha during the ventilatory phase. A Small number of individuals ryngeal airway. Mixed apneas, which comprise a central develop severe bradycardia with asystoles of 8 to 12 seconds apnea followed by an obstructive component, are a variant of in duration or dangerous tachyarrhythmias, including unsus obstructive sleep apnea. The most common type of apnea is tained Ventricular tachycardia. OSAS also aggravates left obstructive sleep apnea. Although airflow persists during Ventricular failure in patients with underlying heart disease. hypopneas, like apneas they are associated with reduced oxy This complication is most likely due to the combined effects gen levels in the arterial blood and/or arousals from sleep. of increased left ventricular afterload during each obstructive Apneas and hypopneas are viewed as carrying equal clinical event, secondary to increased negative intrathoracic pressure, significance. Because airflow persists, hypopneas are not recurrent nocturnal hypoxemia, and chronically elevated classified as either central or obstructive. sympathoadrenal activity. 0006 Obstructive sleep apnea syndrome (OSAS) has been 0012 Central sleep apnea is less prevalent as a syndrome identified in as many as 24% of working adult men and 9% of than OSAS, but can be identified in a wide spectrum of similar women, with peak prevalence in the sixth decade of patients with medical, neurological, and/or neuromuscular life. Habitual heavy snoring, which is an almost invariant disorders associated with diurnal alveolar hypoventilation or feature of OSAS, has been described in up to 24% of middle periodic breathing. The definitive event in central sleep apnea aged men, and 14% of similarly aged women, with even is transient abolition of central drive to the ventilatory greater prevalence in older Subjects. muscles. The resulting apnea leads to a primary sequence of 0007 Obstructive sleep apnea syndrome's definitive event events similar to those of OSAS. Several underlying mecha is the occlusion of the upper airway, frequently at the level of nisms can result in cessation of respiratory drive during sleep. the oropharynx. The resultant apnea generally leads to a pro First are defects in the metabolic respiratory control system US 2012/023 1083 A1 Sep. 13, 2012 and respiratory neuromuscular apparatus. Other central sleep one or more cannabinoids during a clinically relevant thera apnea disorders arise from transient instabilities in an other peutic window. The therapeutic window provided by present wise intact respiratory control system. medicaments is a longer window than provided by immediate 0013 Many healthy individuals demonstrate a small num release medicaments such as Marinol, containing an equiva ber of central apneas during sleep, particularly at sleep onset lent amount of the cannabinoid. The present compositions are and in REM sleep. These apneas are not associated with any especially suitable for conditions that are benefitted by thera physiological or clinical disturbance. In individuals with peutic levels for more than about 5 hours, e.g. about 6 to about clinically significant central sleep apnea, the primary 8 hours or for as long as about 8 or about 12 hours. sequence of events that characterize the disorder leads to 0018.
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