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

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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. The present compositions provide therapeutic dos prominent physiological and clinical consequences. In those ing at levels controlled to generally avoid levels typically individuals with central sleep apnea alveolar hypoVentilation associated with certain side effects. The present compositions syndrome, daytime hypercapnia and hypoxemia are usually comprise a cannabinoid partitioned in an immediate release evident and the clinical picture is dominated by a history of compartment and in a delayed release compartment. recurrent respiratory failure, polycythemia, pulmonary 0019. The present invention provides methods of treating hypertension, and right-sided heart failure. Complaints of cannabinoid-sensitive disorders. Examples of cannabinoid sleeping poorly, morning headache, and daytime fatigue and sensitive disorders are sleep apnea, anxiety, stress, headache, sleepiness are also prominent. In contrast, in individuals nausea, glaucoma, pain, arthritis, irritable bowel syndrome, whose central sleep apnea results from instability in respira ulcerative colitis, Crohn's disease, anorexia or cachexia Syn tory drive, the clinical picture is dominated by features related drome, bladder dysfunction, spasticity due to multiple scle to sleep disturbance, including recurrent nocturnal awaken rosis, Huntington's disease, and Alzheimer's disease. ings, morning fatigue, and daytime sleepiness. 0020 Optionally, the present medicaments provide oral 0014 Currently, the most common and most effective dosing of about 0.1 to about 75 mg of a cannabinoid. Option treatment, for adults with sleep apnea and other sleep-related ally, the Subject sleeps during the therapeutic window. breathing disorders, are mechanical forms of therapy that 0021 Optionally, the oral medicaments of the present deliver positive airway pressure (PAP). Under PAP treatment, invention provide a therapeutic response without causing, or an individual wears a tight-fitting plastic mask over the nose while causing only mild, side effects associated with cannab when sleeping. The mask is attached to a compressor, which inoids. Optionally, the oral medicaments of the present inven forces air into the nose creating a positive pressure within the tion, when administered to a subject immediately before a patient's airways. The principle of the method is that pressur sleep cycle, provide a therapeutic response without causing izing the airways provides a mechanical 'splinting action, (or without Substantially causing) side effects once the Sub which prevents airway collapse and therefore, obstructive ject has awoken (e.g. post treatment window). sleep apnea. Although an effective therapeutic response is 0022. In one embodiment, the invention provides a medi observed in most patients who undergo PAP treatment, many cament comprising a cannabinoid dose, an excipient, and one patients cannot tolerate the apparatus or pressure and refuse or more release modifiers present in an amount to provide, treatment. Moreover, covert monitoring studies clearly dem when administered orally, a therapeutic window which onstrate that long-term compliance with PAP treatment is extends over both an early treatment window (e.g. providing very poor. A variety of upper airway and craniofacial Surgical a Tmax of about 30 minutes to about 3 hours) and a late procedures have been attempted for treatment of OSAS. therapeutic window. Adenotonsillectomy appears to be an effective cure for OSAS 0023 The applicants also describe an invention compris in many children, but upper airway Surgery is rarely curative ing treating a subject with a low dose (e.g. about 0.1 to about in adult patients with OSAS. Surgical “success” is generally 20 mg) of a cannabinoid (e.g. THC) in an oral dosage form taken to be a 50% reduction in apnea incidence and there are that does not contain a release modifier (e.g. Marinol). no useful screening methods to identify the individuals that would benefit from the surgery versus those who would not BRIEF DESCRIPTION OF THE DRAWINGS derive a benefit. 0015 Recently, the present inventors demonstrated that (0024 FIG. 1 depicts the % of subjects with a 75% reduc intraperitoneal injection of THC at 10 mg/kg in a rat model of tion in AHI versus duration of reduction: the effect of THC sleep apnea reduced breathing cessation during non-REM dose. (“NREM) sleep as described in US 2004/0127572. What is 0025 FIG. 2 depicts dose and time dependent effects of needed in the art is a convenient oral medicament in an THC on apnea Suppression. amount that reduces apnea. 0026 FIG.3 depicts AHI in sleep apnea patients during a 0016. Also needed is an oral dosage that is effective yet target treatment window. minimizes undesirable effects (e.g. of inducing psychotropic 0027 FIG. 4 depicts the relationship of Cmax (ng/ml) and responses). Also needed is a medicament that provides thera cannabinoid amount (mg) for an immediate release compart peutic efficacy for a period of time roughly equivalent to a ment (Marinol formulation). typical human sleep period (e.g. about 6 to 8 hours) and that (0028 FIG.5 depicts plasma profiles depicted in US 2009/ doesn’t require repeated dosage through that period. Also O181080 of a THC formulation. needed is an oral medicament that allows the Subject to wake from sleep without residual side effects that negatively impact DETAILED DESCRIPTION OF THE INVENTION wakefulness and alertness without other known affects such as an overly-stimulated appetite. 0029. As used here, the following definitions and abbre viations apply. SUMMARY OF THE INVENTION 0030 AHI means apnea-hypopnea index, which is 0017. The present invention provides new compositions calculated by dividing the number of apnea and hypop (medicaments) that result in delivery of a therapeutic level of nea events by the number of hours of sleep. The AHI US 2012/023 1083 A1 Sep. 13, 2012

index generally quantifies the overall severity of sleep tion of the tablet (i.e. the release of the drug in this apnea including sleep disruptions and desaturations. portion is not delayed by a release modifier). Similarly, Typically, an AHI of 5-15 is considered mild, 15-30 is in this example, the delayed release compartment is the moderate, and above 30 is severe. portion of the tablet towards the interior, where the 0031 “AUC” (area-under-the-curve) is the overall release modification (or release modifier) is the func amount of THC (or metabolite thereof) in the blood tional result of the location within the dosage form. stream or plasma after a dose. AUC can be calculated by 0.038. “Examplary” (or “e.g. or “by example’) means a collecting multiple blood samples over a period of time, non-limiting example. graphing the drug concentrations, and calculating the 0039) “Extended therapeutic window' means a thera drug as the area under this drug concentration curve. peutic window which extends over both an early treat AUC can be expressed in units of amount of THCxtime/ ment window and a late treatment window 0039“Imme Volume (e.g. ngxhr/ml). diate release dosage compartment” (or “IR”) means a 0032 “Cnax” means the maximum plasma concentra dosage compartment that does not contain a release tion of THC (or a metabolite thereof) during an interval modifier in a release modifying amount. In one embodi of time. ment, the immediate release dosage compartment is the 0033 "Cannabinoid-sensitive disorder” means a disor portion of a dosage form that releases greater than 75% der that, when a cannabinoid or a cannabinoid receptor of the cannabinoid contained in the portion within 60 modulator is administered, modulates a pathophysi minutes, or greater than 50% within 30 minutes in an in ologic pathway that ameliorates the disorder or clini vitro dissolution assay (e.g. a dissolution assay cally relevant symptoms thereof. Relevant pathophysi described in Example 10). Typically, an immediate ologic pathways can be desirably modulated by present release compartment releases the cannabinoid in an in medicaments. For example, administration may modu vitro dissolution assay at a rate of at least 50% of a late the pathways of acid (e.g. GABA, glutamate), Marinol formulation, e.g. about 50% to 150% of a monoamine (e.g. histamine, dopamine, serotonin, nora Marinol formulation. drenaline) purine (e.g. adenosine, ADP, ATP), peptide 0040 “Marinol’ means a gel capsule medicament of (e.g. Somatostatin, neuropeptide Y, neurokinin, chole dronabinol as it generally is formulated and available cystokinin), Vanilloid, prostanoid, opiod and/or other under the trademark MARINOLOR). Where reference is neurotransmitters. Accordingly, cannabinoid-sensitive made to Marinol at a concentration that is not commer disorders include disorders mediated by or sensitive to cially available, it is meant to refer to a medicament neurotransmitter action. formulated similarly to other strengths of MARINOLR), 0034). “C. (or trough) is the lowest concentration of i.e. containing dronabinol, gelatin, glycerin, and sesame THC (or a metabolite thereof) in the plasma (following oil. the Cmax) within a defined treatment window. 0041) “Release modifiers’ means a pharmaceutically 0035) “Delayed release” (or “DR) means release of a acceptable ingredient or ingredients that act indepen cannabinoid in a manner Such that release of the cannab dently or in concert to cause the delayed release of a inoid in vivo is delayed in comparison to the release cannabionoid from a medicament or dosage compart from an immediate release compartment (e.g. a Marinol ment and/or that slow or delay the absorption of the formulation). In vivo release can be estimated from an in cannabionoid in the gut. vitro release assay appropriate for the formulation (e.g. 0.042 "Substantially similar, as it relates to a refer as set forth in Example 10). Examples of medicament enced quantifiable parameter (e.g. THC plasma level, types which display delayed release include extended Cmax, Tmax, or therapeutic response) means that the release, Sustained release, continuous release, timed release, and pulsatile release (e.g. timed release or subject parameter is from about 50% to about 200% of instant release plus timed release). the referenced parameter, or from about 75% to about 0036 “Delayed release dosage compartment' is a dos 150%, or about 80% to about 120%. age compartment comprising a release-modifying 0.043 “Therapeutic window' means a period of time amount of a release modifier. In one embodiment, the during which a therapeutically effective level of drug is release of a cannabinoid partitioned in a delayed release maintained. compartment is delayed by about any of 100%, 150%, 0044 "Treatment window' means the period of time 200%, 300%, 400%, 500%. 600%, 700%, or 800%, beginning at the time of administration (i.e. T) of the compared to an immediate release medicament such as drug composition and ending at a defined time. The Marinol in an in vitro dissolution assay (e.g. Example treatment window can be further divided into sub-peri 10). ods, such as “early treatment window' (e.g. T-T or 0037 “Dosage compartment’ means a discrete layer, T-Ts) or “late treatment window (e.g. Ta-Tsior sphere, fraction or formulation encompassing a cannab T-Ts). The units of Subscript of “T”, where not inoid. In one embodiment, the delayed release compart stated, are "hours' (for example, T-T). ment may be dispersed in or co-localized to a component 0045 “THC' means a cannabinoid of the present inven of the immediate release compartment. It should further tion (as described below). be understood that in some dosage forms, the immediate 0046 “Therapeutic efficiency' means the ratio of thera release dosage compartment(s) and the delayed release peutic response to side effects (i.e. any treatment-related dosage compartment(s) are distinguished by their loca effects that are notatherapeutic response). 0047 “Thera tion within the dosage form. By way of example, in the peutic response' means any response that can be con monolithic matrix tablets of Example 17—e.g. a matrix, sidered to representa reduction in the signs or symptoms the immediate release compartment is the outside por of a medical condition. For apnea, a therapeutic US 2012/023 1083 A1 Sep. 13, 2012

response is, for example, a reduction in apnea-hypopnea taught in the National Institute on Drug Abuse Research index, Snoring, oxygen desaturation of the arterial blood, Monograph Series 79, “Structure-Activity Relationships of or sleep disruption. the Cannabinoids. 0047. “Tmax’ means the time between the administra 0056. In certain embodiments of the present invention, the tion of the medicament and the time that a maximum cannabinoid can be Delta-9-tetrahydrocannabinol, also plasma level (Cmax) of the referenced cannabinoid (or known as dronabinol. Dronabinol is naturally-occurring and has been extracted from Cannabis sativa L. (marijuana). It has metabolite) is achieved. also been produced chemically as described in U.S. Pat. No. 0.048 Present Medicaments for Cannabinoid Sensitive 3.668,224. Dronabinol is a light-yellow resinous oil that is Disorders Sticky at room temperature, but hardens upon refrigeration. It 0049. The present medicaments are surprisingly effective turns to a flowable liquid when heated at higher temperatures. for treating certain cannabinoid sensitive disorders. Technical Dronabinol is insoluble in water and typically formulated in features include providing, when administered to certain Sub sesame oil. It has a pKa of 10.6 and an octanol-waterpartition jects: (1) a therapeutic window which begins within about 30 coefficient: 6,000:1 at pH 7. Dronabinol is available in natural minutes or about 1 hour or about 2 hours of administration (extracted from plant) and synthetic forms. On the other hand, (e.g. as shown by Example 3); (2) a therapeutic window that synthetic dronabinol may be utilized and may be synthesized is about 1 to about 10 hours longer than the therapeutic using the starting materials: Olivetol and p-2.8-menthadien window of an immediate release dosage (e.g. as shown in 2-ol (PMD). Example 5); and (3) plasma levels that do not elevate into a 0057 The term “dronabinol is further meant to encom level where reduced therapeutic efficacy and/or deleterious pass naturally occurring dronabinol, synthetically derived side effects are produced (e.g. as shown in Example 3, it has dronabinol, and synthetically modified dronabinol starting been Surprisingly discovered that certain patients with can with a molecule obtained from a natural Source for example, nabinoid-sensitive disorders exhibit a non-monotonic dose United States Patent Application Publication 2005/0171361, response of the inverted U type). hereby incorporated by reference in its entirety, describes a Cannabinoids method of extracting delta-9-THC acid from the plant mate 0050 rial by chromatography and then synthetically converting it to 0051. The compositions of the present invention provide dronabinol. one or more cannabinoids in a medicament that can deliver to a subject a desired target PK profile, where the PK profile 0.058 Structural features of the present cannabinoids, and achieves a therapeutic level of a cannabinoid during a thera structure-function relationships are well-known in the art and peutic window. Cannabinoids of the present invention are any taught, for example, by Rao Rapaka and Alexandros Makriy member of a group of Substances that are structurally related annis in "Structure-Activity Relationships of the Cannab to tetrahydrocannabinol and that bind to a cannabinoid recep inoids, NIDA Research Monograph 79 (1987). tor such as CB1 or CB2 or both (THC). The cannabinoid can 0059 PK Profile be a naturally occurring compound (e.g. present in Can 0060 Compositions of the present invention comprise nabis), a compound metabolized by a plant or animal, or a cannabinoids in an amount of about 0.1 mg to about 75 mg. synthetic derivative. 0061 These doses in the compositions of the present 0052. The cannabinoid may be included in its free form, or invention are formulated to provide PK profiles that unex in the form of a salt; an acid addition salt of an ester; an amide; pectedly result in therapeutically effective levels of a cannab an enantiomer, an isomer, a tautomer, a prodrug; a derivative inoid during a desired therapeutic window. Among the useful of an active agent of the present invention; different isomeric PK profiles of the present invention are the following (where forms (for example, enantiomers and diastereoisomers), both the medicament of the present invention is administered at in pure form and in admixture, including racemic mixtures; To): enol forms. 0062 PK Profile 1: A present THC medicament is orally 0053. The cannabinoids of the present invention are fur administered resulting in (a) a THC plasma concentration of ther meant to encompass natural cannabinoids, natural can 50% to 200% from T through Twhen compared to the THC nabinoids that have been purified or modified, and syntheti plasma concentration from T through T attained by orally cally derived cannabinoids, for example, United States Patent administering a comparator of /2 of the THC dose in a Application Publication 2005/0266.108, hereby incorporated Marinol capsule at T and (b) a THC plasma concentration of by reference in its entirety, describes a method of purifying 50% to 200% from Ts through Ts when compared to the cannabinoids obtained from plant material. plasma concentration from Ts through Ts attained by orally 0054 The cannabinoids of the present invention can be administering a comparator of twice the THC dose in a any of 9-tetrahydrocannabinol, 8-tetrahydrocannabinol, (+)- Marinol capsule at To. 1,1-dimethylheptyl analog of 7-hydroxy-delta-6-tetrahydro 0063 PK Profile 2: A present THC medicament is orally cannabinol, 3-(5'-cyano-1", 1'-dimethylpentyl)-1-(4-N-mor administered resulting in a THC plasma concentration of pholinobutyryloxy) delta 8-tetrahydrocannabinol 50% to 200% from T through T, when compared to the hydrochloride, dexanabinol, nabilone, levonantradol, or plasma concentration attained by orally administering a com N-(2-hydroxyethyl)hexadecanoamide. The cannabinoids of parator of /2 of the THC dose in a Marinol capsule at T and the present invention can be any of the non-psychotropic /2 of the THC dose in a Marinol capsule at T. cannabinoid 3-dimethylnepty 11 carboxylic acid homologine 0064 PK Profile 3: A present THC medicament is orally 8, delta-8-tetrahydrocannabinol. (J. Med. Chem. 35, 3135, administered resulting in a THC plasma concentration greater 1992). than about 150% from T through T, when compared to the 0055. The cannabinoids of the present invention can fur plasma concentration attained by orally administering /2 of ther be any of the active metabolites, derivatives, or analogs as the THC dose amount in a Marinol capsule. at T. US 2012/023 1083 A1 Sep. 13, 2012

0065. PK Profile 4: A present THC medicament is orally greater than (e.g. about 150% or more of) those seen during a administered resulting in a THC plasma concentration at T. late treatment window (e.g. between Tand TsorT. and that is greater than about 75% when compared to the plasma T) after orally administering the reference Marinol cap level at Tattained by orally administering /2 of the THC dose Sule. in a Marinol capsule. 0075 PK Profile 14: The PK profile of PK Profile 12 0066 PK Profile 5: A present THC medicament is orally where the plasma levels are greater than (e.g. about 150% or administered resulting in a THC AUC of 8.64-11.52 ngxhr/ more of) those seen during a mid-treatment window (e.g. ml, a Cmax between 0.4 ng/ml and 4.5 ng/ml; and a Tmax between T. and Ts) after orally administering the refer between 0.5 and 3.5 hours, optionally between 0.5 and 1.5 ence Marinol capsule. hours. 0.076 PK Profile 15: The PK profile of PK Profile 12 0067 PK Profile 6: A present THC medicament is orally where the plasma levels are substantially similar to (e.g. 50%- administered resulting in a THC plasma concentration during 200%) of those seen during an early treatment window after an early-treatment window (e.g. during To-Ta) and a orally administering the reference Marinol capsule. maximum THC plasma concentration (Cmax) that is Substan 0.077 PK Profile 16: The PK profile of PK Profile 12 tially similar to that provided by an immediate release form where the plasma levels and/or an AUC during a mid treat (e.g. a single Marinol capsule containing about /2 the dose). ment window (e.g. between T and Ts or at Ta) are 0068. PK Profile 7: A present THC medicament is orally greater than about 75% of those seen during an early treat administered resulting in a THCTmax substantially similar to ment window (e.g. between T2 and Tai or at Ts) after the Tmax of an orally administered immediate release orally administering the reference Marinol capsule. Marinol capsule containing about/2 the dose. Optionally, the 0078 PK Profile 17: The PK profile of PK Profile 12 PK profile provides a Tmax during an early treatment window where the plasma levels and/or an AUC during a treatment (e.g. from T12-T1st T2-Ti, or at about Tin). window (e.g. between T. and T) are substantially similar 0069. PK Profile 8: A present THC medicament is orally to (e.g. 50%-200% of) to those observed when two Marinol administered resulting in a plasma cannabinoid level (or capsules containing about/2 the THC dose are orally admin therapeutic response) during a late-treatment window (e.g. istered in Succession; e.g. one at To and one at T. during T-Ts) substantially similar to that produced when 0079 PK Profile 18: The PK profile of PK Profile 12 two Marinol capsules containing about /2 the dose are orally where the plasma levels and/or an AUC during a late treat administered in succession (e.g. one at To and one at about ment window (e.g. between Tai and TsorT. and Ts) are Tah). less than those observed when two Marinol capsules contain 0070 PK Profile 9: A present THC medicament is orally ing about/2 the THC dose are orally administered in succes administered resulting in a THC plasma level during a late Sion; i.e. one at To and one at Ts). treatment window (e.g. during T-Ts) substantially simi 0080 PK Profile 19: The PK profile of PK Profile 12 lar to that produced during an early-treatment window (e.g. where the plasma levels and/or an AUC during a late treat during T-T) by a Marinol capsule containing about /2 ment window (e.g. between Tai and TsorT. and Ts) are the dose. Optionally, the plasma level and/or AUC during the Substantially similar to and optionally less than (e.g. about late-treatment window is substantially similar to that pro 30%-100% of) those observed when two Marinol capsules duced during the early-treatment window by the Marinol containing about /2 the THC dose are orally administered in capsule. Succession; i.e. one at To and one at T. (0071 PKProfile 10: A present THC medicament is orally I0081 PK Profile 20: The PK profile of any one of PK administered resulting in a plasma THC level during a late Profile 1-19 where the plasma levels and/or an AUC during a treatment window (e.g. during Ta-Ts. Such as during Tai late treatment window (e.g. between Tand Tor Tand Ts, Ts-T, and/or T-T7) that is greater than that T.) are substantially similar to plasma levels and/or an AUC produced during a mid-treatment window (e.g. during T between Tsi and To. T. Such as hours T-Ts and/or Tsu-T) by a Marinol 0082 Medicaments capsule containing about /2 the dose. Optionally, the plasma I0083. With the teachings provided herein, one skilled in leveland/or AUC during the late-treatment window is greater the art can now provide a medicament that, when orally than that produced during the mid-treatment window by the administered to a Subject, produces a therapeutic response Marinol capsule. over a desired therapeutic window (e.g. extending over both 0072 PK Profile 11: A present THC medicament is orally an early treatment window and a late treatment window). In administered resulting in an AUC during a treatment window Some embodiments, the formulations minimize the total (e.g. during To-Ts) which is about 3-4 times greater than amount of drug administered, thus significantly decreasing that of a Marinol capsule containing about /2 the dose. side effects and increasing the therapeutic efficiency. Optionally, the Cmax is substantially similar to that of the I0084. The medicaments of the present invention comprise Marinol capsule. Optionally, the Tmax is less than about T. a cannabinoid partitioned between an immediate release (e.g. from about Tost-Ts. Such as about T). compartment and a delayed release compartment. The por 0073 PK Profile 12: A present THC medicament is orally tion of the cannabinoid in the immediate release compartment administered resulting in plasma levels and/or an AUC during can be about any of the following percents (%): 10-75, 10-50, an early treatment window (e.g. during To-T) which are 20-50, 25-75, 40-60, 35-75, or 40-80. substantially similar to (e.g. 50%-200% of) those produced I0085. The compositions of the present invention comprise when a reference Marinol capsule containing /2 the THC a cannabinoid and one or more excipients (e.g. release modi dose is orally administered. fiers) in appropriate amounts to provide a desired PK profile 0074 PK Profile 13: The PK profile of PK Profile 12, (e.g. any of PK profiles 1-20). The component(s) of the com where the plasma levels and/or an AUC during a late treat positions may be in any form, e.g. liquid, Solid, and semi ment window (e.g. between Tand TsorT. and Ts) are Solid components. The medicament can be formulated to US 2012/023 1083 A1 Sep. 13, 2012 provide any desired release properties, for example, immedi provide an immediate therapeutic response (e.g. during an ate release, pulsatile release, extended release, delayed early-treatment window) and one or more release modifiers in release, controlled-release, continuous release, prolonged an effective amount to provide an extended therapeutic win release, timed release, and combinations thereof (e.g. imme dow (e.g. providing a therapeutic response during a late diate release--controlled-release, immediate release+delayed treatment window). release, etc.). 0093. A medicament of the present invention comprises I0086. The appropriate selection and amount of excipients one or more dosage compartments. is often influenced by the selection and amount (or fraction of 0094. A dosage compartment of the present invention can the total dose) of cannabinoid(s) associated (e.g. com be a delayed release dosage compartment or an immediate pounded) with the excipients in a component (e.g. micropar release dosage compartment. ticle) of the dosage (and vice versa). With the teachings pro 0.095 Optionally the delayed release dosage compartment vided herein, one skilled in the art can now formulate comprises a liquid delayed release component (e.g. a delayed medicaments which contain an excipient and release modifi release aqueous or semi-aqueous component or syrup). ers in an effective amount to provide both an immediate (or 0096 Optionally the delayed release dosage compartment early) effect and an extended (or late) effect. For example, in comprises a Solid delayed release component (e.g. an osmotic one embodiment an immediate effect (or a Substantial portion component, or a lyophilized or dried solid component thereof) is provided while the sustained effect (or a substan selected from a lipid component, a glass Sugar component, a tial portion thereof) is provided by one or more Sustained (e.g. guest-host component, or a co-precipitate component), or a extended or delayed) release modifiers. The skilled artisan semi-solid delayed release component (e.g. a semi-solid will, of course, recognize that Sustained effects (e.g. late SEDDS component). Optionally, the solid delayed release plasma levels) may be influenced by an immediate release dosage component or semi-solid delayed release dosage com component in a dosage, for example, due to residual levels of ponent is a component coated or complexed with a delayed the immediately released drug. However, with the teachings release layer or compound, for example to provide a timed provided herein, one skilled in the art can adjust the release release compartment. properties of one or more release components (e.g. by varying 0097. Optionally, the delayed release dosage compart the amount of drug therein or the relative amounts or types of ment comprises a Solid component, for example, a lyo release modifiers therein). philized or dried, solid component selected from: a solid fat I0087. The desired PK profiles can be achieved by the component, a glass Sugar component, a guest-host compo skilled artisan, in many cases, without performing clinical nent, and a co-precipitate component; wherein the Solid com studies. For example, useful guidance is provided by the ponent has been coated or otherwise compounded with a United States Food and Drug Administration (FDA) in the delayed (e.g. timed) release layer or delayed release modifier. guidance document entitled “Extended Release Oral Medi 0098. Optionally, a medicament comprises more than two caments: Development, Evaluation and Application of In or more compartments (e.g. 3, 4, 5, or 6 compartments). Such Vitro/In Vivo Correlation. as timed-release compartments having different times of can 0088. The medicaments of the present invention can be nabinoid release. Optionally, the medicament comprises an made with different polymorphic forms (e.g. salts, crystalline immediate release compartment and a plurality of delayed forms, hydrates, esters, and Solvates), each with physico (e.g. timed) release compartments. Optionally, the plurality chemical properties affecting drug delivery (e.g. absorption). of delayed release compartments includes one or two or more Selection of the release modifiers is done with consideration delayed release compartments (e.g. 2, 3, or 4, with different of the THC form. A number of such forms are well known in release times) and/or one or more extended release compart the art. mentS. 0089 For example, in one embodiment of the invention, 0099 Liquid Dosage Compartments the cannabinoid form used in the formulation is a cannabinoid 0100. In one embodiment, a dosage compartment of the ester or salts thereof (e.g. a polar ester Such as an ester of a present composition is a liquid or predominantly liquid (a terminal carboxylic acid). Esterified forms of THC are liquid) dosage compartment. Any formulation useful for oily described, for example, in U.S. Pat. No. 4,933,368, U.S. Pat. or lipophilic compounds may be used. For example, the com No. 5,389,375 and U.S. Pat. No. 6,008,383. Other useful ponent may be in the form of an aqueous or non-aqueous polar esters are the hemi-ester of malonic acid and the alani liquid, an oil or other lipophilic medium, an emulsion, a nate esterofalanine. It has been reported, e.g., in U.S. Pat. No. syrup, and the like. Optionally, a liquid compartment is 5,508,051 and U.S. Pat. No. 5,389,375, that salts of the ter encapsulated (e.g. a hard gel or soft gel). Optionally, the minal carboxylic acid group of the ester, for example, the compartment is coated with a delayed (e.g. extended, Sus N-methylglutamine salt as well as the Sodium and potassium tained, or timed) release coating. The skilled artisan will salts are also useful. readily appreciate that the liquid dosage compartments taught 0090. In another example, the cannabinoid form used in herein are amenable to delayed release or immediate release the formulation is in crystalline form. Optionally, the cannab compartments, depending on, for example, the appropriate inoid form is crystalline trans-(+/-)-THC. Examples of such selection and amount of excipients. crystalline forms are described, for example, in US 2007/ 0101. Optionally, the liquid dosage compartment of the OO72939. present invention comprises an aqueous or semi-aqueous liq 0091. A medicament of the present invention can option uid component comprising a cannabinoid and organic co ally provide atherapeutic window which extends over both an Solvents (e.g. ethanol, propylene glycol and polyethylene early treatment window and a late treatment window. glycol). Optionally, the composition further comprises a 0092. One embodiment of the present invention provides a buffer. An example of such a component is described in US medicament comprising a compartment comprising a can 2009/0181080. For example, optionally a component con nabinoid and one or more excipients in an effective amount to tains from 15% to about 65% ethanol, from about 10% to US 2012/023 1083 A1 Sep. 13, 2012

about 60% buffered aqueous solution, from about 0.1 to about 100H. Optionally, the oil component is a mixture of oils or 25% propylene glycol and from about 1% to about 25% complex mixture (as described above), for example, as with polyethylene glycol. Optionally, the component is buffered to lecithin. Optionally, the lecithin comprises a mixture of phos a pH of about 6.5 to 7.5 (e.g. 7). Such an aqueous or semi pholipids, for example, phosphatidylcholine (e.g. 13-18%); aqueous liquid component may be formulated for tailored phosphatidylethonolamine (e.g. 10-15%); phosphatidyinosi (e.g. delayed) release. For example, FIG. 5 (reproduced from tol (e.g. 10-15%); and phosphatidic acid (e.g. 5-12%). Vita FIG. 6 of US 2009/0181080) shows the profile of several min E (tocopherol) can also be used in the oil component. delayed release components that may be incorporated into a Optionally, the oil-based carrier is sesame oil. Optionally, the present dosage (e.g. by formulating with an immediate oil component (e.g. sesame oil) contains an effective amount release component taught herein and/or varying the drug of an anti-oxidant selected from the group consisting of sesa amount and/or selection or relative amounts of excipients in min, Sesamol, Sesamolin, lecithin and any combination of the the component). In one embodiment, the liquid aqueous or foregoing (either already present in the (unpurified) Sesame semi-aqueous compartment is formulated as an immediate oil or added to purified sesame oil. Examples of components release compartment. In another embodiment, the liquid described above are described in WO 2006/063109. In one aqueous or semi-aqueous compartment is formulated as a embodiment, the liquid lipophilic compartment is formulated delayed release compartment. as an immediate release compartment. In another embodi ment, the liquid lipophilic compartment is formulated as a 0102 Optionally, the liquid dosage compartment of the delayed release compartment. present invention comprises a lipophilic medium (sometimes referred to simply as an ‘oil’) liquid component comprising a 0103 Optionally, the liquid dosage compartment of the cannabinoid and a lipophilic medium, for example, an oil or present invention is a SEDDS dosage compartment compris oil-based carrier. Optionally, the oil comprises one or more ing a cannabinoid, an oily medium, and at least one Surfac triglycerides (e.g. a triglyceride component). Optionally, the tant. An example of Such a SEDDS dosage compartment is oil comprises one or more phospholipids (e.g. a phospholip described in US 2007/0104741. The oily medium may com ids component). Optionally, the oil comprises one or more prise, for example, triglycerides and/or mixed glycerides and/ triglycerides and one or more phospholipids. Optionally, the or free fatty acids containing medium and/or long chain Satu oil comprises a mixture of two or more of phospholipids, rated, mono-unsaturated, and/or poly-unsaturated free fatty glycolipids, triglycerides, sterols, Small quantities of fatty acids. The Surfactant promotes self-emulsification, which, for acids, carbohydrates and sphingolipids, such as a complex example, promotes targeted chylomicron delivery and opti mixture thereof (e.g. lecithin). Optionally, the oil comprises mal availability to a mammalian intestinal lumen. The dosage an antioxidant oil. Such oil-based carriers are readily avail compartment may, for example, include co-solvents, anti able from commercial sources. Examples of suitable oils or oxidants, viscosity modifying agents, cytochrome P450 oil-based carriers (e.g. triglyceride carriers) include, but are metabolic inhibitors, and P-GP efflux inhibitors, for tailored not limited to, Aceituno oil, Almond oil, Arachis oil, Babassu (e.g. delayed) release rates. Optionally, the SEDDS compo oil, Blackcurrant seed oil, Borage oil, Buffalo ground oil, nent is a Type I, II, or III SEDDS. Type I formulations contain Candlenut oil, Canola oil, Lipex 108 (Abitec), Castor oil, an oily medium (e.g. triglycerides and/or mixed glycerides Chinese vegetable tallow oil, Cocoa butter, Coconut oil and/or medium/long chain Saturated, mono-unsaturated, and Pureco 76 (Abitec), Coffee seed oil, Corn oil, Cottonseed oil, poly-unsaturated free fatty acids); whereas the oily medium Crambe oil, Cuphea species oil. Evening primrose oil, Grape may also be polyfunctional with potential Surfactant charac seed oil, Groundnut oil, Hemp seed oil, Illipe butter, Kapok teristics to promote self-emulsification. Type II contains an seed oil, Linseed oil, Menhaden oil, Mowrah butter, Mustard oily medium (e.g. triglycerides and/or mixed glycerides and/ seed oil, Oiticica oil, Olive oil, Palm oil, Palm kernel oil, or medium/long chain Saturated, mono-unsaturated, and Peanut oil, Poppy seed oil, Rapeseed oil, Rice bran oil, Saf poly-unsaturated free fatty acids) and at least one surfactant flower oil, Sal fat, Sesame oil, Shark liver oil, Sheanut oil, component to promote self-emulsification. Type III contains Soybean oil, Stillingia oil, Sunflower oil, Tall oil, Tea seed oil, an oily medium (e.g. triglycerides and/or mixed glycerides Tobacco seed oil, Tung oil (China wood oil), Ucuhuba, Ver and/or medium/long chain Saturated, mono-unsaturated, and nonia oil. Wheat germ oil, mixtures of any of the foregoing, poly-unsaturated free fatty acids) and at least one surfactant and the like. Fractionated triglycerides, modified triglycer component to promote self-emulsification, and at least one ides, synthetic triglycerides, and mixtures of triglycerides are hydrophilic cosolvent. Optionally, the SEDDS compartment also within the scope of the invention. Other examples of oils, is coated with a release modifying coating (e.g. timed, for example, triglycerides, include vegetable oils, fish oils, extended, or delayed). In one embodiment, the liquid SEDDS animal fats, hydrogenated vegetable oils, partially hydroge compartment is formulated as an immediate release compart nated vegetable oils, medium and long-chain triglycerides, ment. In another embodiment, the liquid SEDDS compart and structured triglycerides. Optionally, the vegetable oil is ment is formulated as a delayed release compartment. Soybean oil, olive oil, cotton seed oil, peanut oil, Sesame oil 0104 Optionally, the liquid dosage compartment is com and castor oil, with sesame oil and castor oil optionally being bined with another compartment in a multi-phase dosage preferred. Examples of useful phospholipids include: Pho form. For example, the liquid dosage compartment can be sal(R) 50 PG: Phosal(R) 53MCT: Phosal(R) 75SA, Phospholi provided as an immediate release compartment and com pon R 80; Phospholipon(R) 80H; Phospholipon(R) 85G: Phos bined with a solid dosage compartment formulated for pholipon R 90G: Phospholipon(R) 90H; and Phospholipon(R) delayed release. Examples of useful multi-phase dosage 90NG. Examplary phospholipids suitable for dermal medi forms are described in U.S. Pat. No. 7,670,612. caments include: Phosal(R) 50 PG: Phosal(R) 50SA; Phosal(R) 0105 Semi-Solid Dosage Compartments 53MCT: Phosal R75SA; Phospholipon R 80; Phospholipon(R) 0106. In one embodiment, a dosage compartment of the 80H; Phospholipon R 85G: Phospholipon R90NG: Phospho present composition is a semi-solid dosage compartment. lipon R 90G: Phospholipon R 90H; and Phospholipon(R) Any formulation useful for oily or lipophilic compounds may US 2012/023 1083 A1 Sep. 13, 2012

be used. For example, the compartment may be in the form of able from commercial sources. Examples of suitable oils or self-emulsifying drug delivery system (SEDDS), or a lipo oil-based carriers (e.g. triglyceride carriers) include, but are philic medium compartment. Optionally, the semi-solid com not limited to, Aceituno oil, Almond oil, Arachis oil, Babassu partment is encapsulated (e.g. a hard gel or softgel). Option oil, Blackcurrant seed oil, Borage oil, Buffalo ground oil, ally, the compartment is coated with a release modifying Candlenut oil, Canola oil, Lipex 108 (Abitec), Castor oil, coating (e.g. timed release coating). Chinese vegetable tallow oil, Cocoa butter, Coconut oil 0107 Optionally, the dosage compartment is a semi-solid Pureco 76 (Abitec), Coffee seed oil, Corn oil, Cottonseed oil, SEDDS dosage compartment comprising a cannabinoid, an Crambe oil, Cuphea species oil. Evening primrose oil, Grape oily medium, at least one surfactant, and a semi-solid inducer seed oil, Groundnut oil, Hemp seed oil, Illipe butter, Kapok (e.g. an amphiphilic/non-amphiphilic solute such as ascorbyl seed oil, Linseed oil, Menhaden oil, Mowrah butter, Mustard palmitate). Such a SEDDS component is described, for seed oil, Oiticica oil, Olive oil, Palm oil, Palm kernel oil, example, in US 2007/0104741. The oily medium may com Peanut oil, Poppy seed oil, Rapeseed oil, Rice bran oil, Saf prise, for example, triglycerides and/or mixed glycerides and/ flower oil, Sal fat, Sesame oil, Shark liver oil, Sheanut oil, or free fatty acids containing medium and/or long chain Satu Soybean oil, Stillingia oil, Sunflower oil, Tall oil, Tea seed oil, rated, mono-unsaturated, and/or poly-unsaturated free fatty Tobacco seed oil, Tung oil (China wood oil), Ucuhuba, Ver acids. The Surfactant promotes self-emulsification, which, for nonia oil. Wheat germ oil, mixtures of any of the foregoing, example, promotes targeted chylomicron delivery and opti and the like. Fractionated triglycerides, modified triglycer mal availability to a mammalian intestinal lumen. The ides, synthetic triglycerides, and mixtures of triglycerides are amphiphilic/non-amphiphilic Solute promotes prolonged dis also within the scope of the invention. Other examples of oils, Solution profiles (e.g. for delayed release). The component for example, triglycerides, include vegetable oils, fish oils, may, for example, include co-solvents, anti-oxidants, viscos animal fats, hydrogenated vegetable oils, partially hydroge ity modifying agents, cytochrome P450 metabolic inhibitors, nated vegetable oils, medium and long-chain triglycerides, P-GP efflux inhibitors, and finally amphiphilic/non-am and structured triglycerides. Optionally, the vegetable oil is phiphilic solutes to induce semi-solid formation for tailored Soybean oil, olive oil, cotton seed oil, peanut oil, Sesame oil (e.g. delayed) release rates. For example, an isotropic semi and castor oil, with sesame oil and castor oil optionally being Solid or waxy Solid phase may be prepared by dissolving a preferred. Examples of useful phospholipids include: Pho high concentration of ascorbyl palmitate (or other sal(R) 50 PG: Phosal(R) 53MCT: Phosal(R) 75SA, Phospholi amphiphilic/non-amphiphilic solutes) in an oily liquid state. pon R 80; Phospholipon(R) 80H; Phospholipon(R) 85G: Phos Upon administration as an isotropic semi-solid phase and pholipon R 90G: Phospholipon R 90H; and Phospholipon(R) upon initial dilution in the gastric region of a mammal, the 90NG. Examplary phospholipids suitable for dermal medi contents immediately form a solid dispersion or coarse col caments include: Phosal(R) 50 PG: Phosal(R) 50SA; Phosal(R) loidal dispersion for protection against acid catalyzed degra 53MCT: Phosal R75SA; Phospholipon R 80; Phospholipon(R) dation of cannabinoids. Optionally, the SEDDS component is 80H; Phospholipon R 85G: Phospholipon R90NG: Phospho a Type I, II, or III SEDDS. Type I formulations contain an oily lipon R 90G: Phospholipon R 90H; and Phospholipon(R) medium (e.g. triglycerides and/or mixed glycerides and/or 100H. Optionally, the oil component is a mixture of oils or medium/long chain Saturated, mono-unsaturated, and poly complex mixture (as described above), for example, as with unsaturated free fatty acids); whereas the oily medium may lecithin. Optionally, the lecithin comprises a mixture of phos also be polyfunctional with potential Surfactant characteris pholipids, for example, phosphatidylcholine (e.g. 13-18%); tics to promote self-emulsification. Type II contains an oily phosphatidylethonolamine (e.g. 10-15%); phosphatidyinosi medium (e.g. triglycerides and/or mixed glycerides and/or tol (e.g. 10-15%); and phosphatidic acid (e.g. 5-12%). Vita medium/long chain Saturated, mono-unsaturated, and poly min E (tocopherol) can also be used in the oil component. unsaturated free fatty acids) and at least one surfactant com Optionally, the oil-based carrier is sesame oil. Optionally, the ponent to promote self-emulsification. Type III contains an oil component (e.g. sesame oil) contains an effective amount oily medium (e.g. triglycerides and/or mixed glycerides and/ of an anti-oxidant selected from the group consisting of sesa or medium/long chain Saturated, mono-unsaturated, and min, Sesamol, Sesamolin, lecithin and any combination of the poly-unsaturated free fatty acids) and at least one surfactant foregoing (either already present in the (unpurified) Sesame component to promote self-emulsification, and at least one oil or added to purified sesame oil. In one embodiment, the hydrophilic cosolvent. Optionally, the SEDDS compartment semi-solid oil compartment is formulated as an immediate is coated with a release modifying coating (e.g. delayed release compartment. In another embodiment, the semi-solid release coating or timed-release coating). oil compartment is formulated as a delayed release compart 0108 Optionally, the semi-solid dosage compartment of ment. Examples of compartments described above are the present invention comprises a lipophilic (sometimes described in WO 2006/063109. referred to simply as ‘oil’) semi-solid component comprising 0109 Solid Dosage Compartments a cannabinoid and a lipophilic medium, for example, an oil or 0110. In one embodiment, a dosage compartment of the oil-based carrier. Optionally, the oil comprises one or more present invention is a Solid dosage compartment. Any formu triglycerides (e.g. a triglyceride component). Optionally, the lation useful for oily or lipophilic compounds may be used. oil comprises one or more phospholipids (e.g. a phospholip For example, the dosage compartment may be a solid lipid ids component). Optionally, the oil comprises one or more dosage compartment, a solid dosage compartment produced triglycerides and one or more phospholipids. Optionally, the from an aqueous mixture or emulsion, a Solid dosage com oil comprises a mixture of two or more of phospholipids, partment produced by extrusion (e.g. hot melt extrusion), or a glycolipids, triglycerides, sterols, Small quantities of fatty Solid emulsion that is, for example, dried. Other Solid dosage acids, carbohydrates and sphingolipids, such as a complex compartments include osmotic particles. Optionally, a solid mixture thereof (e.g. Lecithin). Optionally, the oil comprises dosage compartment (e.g. powdered, spray dried, or freeze an antioxidant oil. Such oil-based carriers are readily avail dried forms) is formed into a tablet, pill, microsphere, and the US 2012/023 1083 A1 Sep. 13, 2012

like. Optionally, a solid dosage compartment is coated or release compartment. In another embodiment, the Solid co otherwise compounded with pharmaceutically acceptable precipitate compartment is formulated as a delayed release materials and/or excipients known in the art to provide a compartment. cannabinoid component affording delayed release (e.g. 0114 Optionally, the Solid dosage compartment is a Sugar delayed release modifiers or timed-release coating). glass compartment Sugar comprising, a cannabinoid, and a 0111 Optionally, the solid dosage compartment is a solid glass of a Sugar, a Sugar alcohol, a mixture of Sugars or a lipid dosage compartment comprising a cannabinoid, a Solid mixture of Sugar alcohols. An example of Such a dosage fat and one or more phospholipids, for example, as described compartment is described in US 2003/0229027. Optionally, in WO9736577. The dosage compartment may be prepared the cannabinoid is incorporated in the Sugar glass as a mono molecular encapsulation without formation of a guest-host by dissolving the cannabinoid together with lipid components complex. The solid dosage compartment may, for example, comprising at least one solid fat and at least one phospholipid be prepared by a) dissolving the cannabinoid compound in an in a suitable organic solvent; evaporating the solvent to dry organic solvent that is soluble in water and dissolving the ness; hydrating the dry solid lipid mixture with an aqueous Sugar, Sugar alcohol, mixture of Sugars or mixture of Sugar phase, with mechanical shaking, to obtain a lipid dispersion alcohols in water; b) mixing the dissolved cannabonoid com in water; homogenizing the resultant lipid dispersion, Such as pound and the dissolved Sugar, Sugar alcohol, mixture of by high-pressure homogenization, to reduce the particle size Sugars or mixture of Sugar alcohols to obtain a Sufficiently to the Submicron range; and drying the Submicron dispersion. stable mixture; and c) drying the mixture by freeze drying, Alternatively, the dosage compartment may be prepared by spray drying, vacuum drying, or Super critical drying. The directly drying the lipid mixture that is dissolved in the dissolution rate of the cannabinoid may be tailored by organic solvent. For example, the Solid lipid mixture formu manipulating the dissolution rate of the Sugar glass, for lations can be spray dried or freeze-dried to obtain dry com example, to produce delayed release. In one embodiment, the positions suitable for the preparation of Solid-dosage com Solid Sugar glass compartment is formulated as an immediate partments, such as hard gelatin capsules or tablets. These release compartment. In another embodiment, the Solid Sugar Solid dosage compartments may, for example, further com glass compartment is formulated as a delayed release com prise cryoprotectants, antioxidants, free flowing imparting partment. agents, Surface active materials and/or emulsifiers. In one 0115 Optionally, the solid dosage compartment is a hot embodiment, the Solid lipid compartment is formulated as an melt extrudate. An examplary method of making a solid hot immediate release compartment. In another embodiment, the melt extrudate comprises mixing a cannabinoid and a carrier Solid lipid compartment is formulated as a delayed release by a rotating screw through the heated barrel of an extruder compartment. and pressing the melt through a die into a product of uniform 0112 Optionally, the solid dosage compartment is a solu shape. Useful carriers include polymers known in the art as bilizing compartment comprises a solubilizing agent (e.g. extrudate carriers. For example, the carrier can be a hydro host such as a cyclodextrin) and the cannabinoid. An example phobic and/or hydrophilic fusible carrier or diluent (e.g. with of such a dosage compartment is described in WO9932.107. a melting point from 35°C. 150°C.). As another example, the The Solid dosage compartment may be produced from an carrier can be a high molecular weight poly(ethylene oxide). aqueous mixture or emulsion. The solubilizing action of for As another example, the carrier can comprise a polymer example, cyclodextrins, is caused by the formation of So matrix comprising a thermoplastic polymer or lipophilic car called inclusion complexes or guest-host complexes, which rier. Optionally, the carrier further comprises a plasticizer. may then be dried (e.g. freeze dried) to produce a powder Optionally, the carrier further comprises a delayed release material and optionally mixed with a microsphere (e.g. Swell modifier. Optionally, the polymers used in the extrusion pro ing starch microsphere). Other microspheres that may be used cess function as thermal binders, drug stabilizers, drug solu in the present compositions include those made from chito bilizers and/or drug release controlling excipients with no san, polyvinylpyrrolidone, alginate, polycarbophil, pectin, compressibility requirements. Examples of useful polymer hyaluronic acid (and esters thereof), agar agarose, dextran, carriers include vinyl polymers (polyvinylpyrrolidone albumin, ovalbumin, collagen, and casein. In one embodi PVP), PVP-vinyl acetate PVP-VA), poly(ethylene oxide) ment, the solid solubilizing compartment is formulated as an (PEO), Eudragit (acrylates), PE glycol (PEG) and cellulose immediate release compartment. In another embodiment, the derivatives (hydroxypropylcellulose HPC), hydroxypropyl Solid solubilizing compartment is formulated as a delayed methylcellulose HPMC, HPMC acetate succinate HPM release compartment. CAS), cellulose acetate ICA and CA-phthalate CAPI). 0113 Optionally, the solid dosage compartment is a co Other examples of useful hot melt extrusion carriers or meth precipitate compartment comprising a co-precipitate of a can ods are described in U.S. Pat. No. 6,488,963 B1, US nabinoid, a tocopherol polyethyleneglycol succinate (TPGS) 20100047340, US 20080274194, U.S. Pat. No. 6,375,963, or equivalent; and a dispersion adjuvant in an amount Suffi U.S. Pat. No. 7,771,632, U.S. Pat. No. 6,743,442, and U.S. cient to assist in dispersing the lipophilic Substance in the Pat. No. 5,849.240. In one embodiment, the hot melt extru Succinate. An example of Such a dosage compartment is date compartment is formulated as an immediate release described for a cannabinoid in U.S. Pat. No. 5,891,469. The compartment. In another embodiment, the hot melt extrudate dosage compartment may be produced, for example, by co compartment is formulated as a delayed release compartment melting TPGS and the cannabinoid at 40.degree.-60.degree. (e.g. Sustained release or timed release). C.; adding a dispersion adjuvant to the melted mixture with 0116. Optionally, the solid dosage compartment is an agitation; adding a fumed silica to the mixture with agitation; osmotic compartment comprising an osmotic dosage com and drying the resultant mixture at 100.degree. C. to yield a partment comprising a layered core (e.g. single layer or dry powder co-precipitate. In one embodiment, the Solid co bilayer core) comprising a cannabinoid and an expandable precipitate compartment is formulated as an immediate polymer; a semipermeable membrane Surrounding the core; US 2012/023 1083 A1 Sep. 13, 2012

and a passageway disposed in the semipermeable membrane immediate release compartment. In another embodiment, the for tailored (e.g. delayed) release of the cannabinoid. Option crystalline compartment is formulated as a delayed release ally, the core is a multilayer (e.g. bilayer) comprising first compartment (e.g. Sustained release or timed release). layer comprising the cannabinoid and excipient (e.g. low 0118 Optionally, the solid dosage compartment is a molecular weight polymers) and a second layer comprising delayed release compartment comprising a gastroretentive an osmopolymer. An example of such a dosage compartment compartment. Gastroretentive compartments can comprise, is described in WO 2008/024490. Optionally, the second for example, a water-swellable polymer that swells upon layer further comprises an osmoagent. Optionally, the one or imbibition of water to a size that is large enough to promote more outer layers also comprise a cannabinoid to provide a retention of the dosage form in the stomach, and provides more immediate release in addition to the tailored release. controlled delivery of the cannabinoid (e.g. by diffusion). Useful osmopolymers include high molecular weight poly Examples of useful gastroretentive compartments are oxyethylene oxides or the derivatives thereof. Other useful described in WO 03/035029 A1, U.S. Pat. No. 6,635,280 B2, osmopolymers include hydrogels such as Carbopol.R acidic U.S. Pat. No. 6,340,475 B2, U.S. Pat. No. 6,488,962 B1, and carboxy polymers, a polymer of acrylic acid crosslinked with PCT WO 2007/0521. 25 A2. a polyallyl Sucrose, also known as carboxypolymethylene 0119 Optionally, the solid dosage compartment is com and carboxyvinyl polymer having a molecular weight of 250, bined with another compartment in a multi-phase dosage 000 to 4,000,000; Cyanamer R polyacrylamides; cross-linked form. For example, the Solid dosage compartment can be water Swellable indene-maleic anhydride hydrogel polymers; provided as a delayed release compartment and combined Good-rite R polyacrylic acid having a molecular weight of with a liquid dosage compartment formulated for immediate 80,000 to 200,000; PolyoxR polyethylene oxide polymers release. Examples of useful multi-phase dosage forms are having a molecular weight of 100,000 to 5,000,000 and described in U.S. Pat. No. 7,670,612. higher, starch graft copolymers: Aqua-KeepS(R) acrylate poly I0120 Delayed Release Coatings mer polysaccharides composed of condensed glucose units I0121. As described herein, medicaments of the present Such as diester cross-linked polyglucan, and the like. Useful invention may include a delayed release compartment. While oSmoagents include Soluble salts of inorganic acids, such as any delayed release compartment is useful in the present magnesium chloride or Sulphate, lithium, Sodium or potas invention, one embodiment provides a dosage compartment, sium chloride; soluble salts of organic acids, such as sodium wherein the compartment comprises a delayed release coat or potassium acetate, magnesium Succinate, sodium ben ing (e.g. Sustained, extended or pulsatile release coating). For Zoate, sodium citrate, sodium ascorbate; carbohydrates, such example, one or more pulsatile release coatings can be pro as arabinose, ribose, Xylose, glucose, fructose, galactose, vided to deliver a burst of cannabinoid release at one or more mannose, Sucrose, maltose, lactose, raffinose; hydroSoluble predetermined time intervals (e.g. a burst at a time between aminoacids, Such as glycine, leukine, alanine, methionine; about 1 and 5 hrs, 2 and 4 hrs, or 2.5-3.5 hrs, such as a burst organic polymeric osmoagents, such as sodium carboxym at 2 hrs, 2.5 hrs, 3 hrs, 3.5 hrs, or 4 hrs). ethylcellulose, hydroxypropylmethylcellulose, hydroxyeth 0.122 Any dosage compartment taught herein may com ylmethylcellulose, polyvinylpirrolidone, polyoxyethylene prise a delayed release coating in order to provide a delayed oxide, carbomers and polyacrylamides. Examples of useful release compartment. For example, an otherwise immediate osmotic dosage layers and components are described in U.S. release compartment (e.g. an immediate release liquid soft Pat. No. 6,919,373, U.S. Pat. No. 6,930,129, U.S. Pat. No. gel or hard gel) may be converted into a delayed release 5,264,446, U.S. Pat. No. 5,674,895, U.S. Pat. No. 5,840,754, compartment by coating the compartment with a delayed US 2010/0143472, U.S. Pat. No. 4,327,725, U.S. Pat. No. release coating (i.e. a delayed release modifier coating). Addi 4,111,202, and WO 2008/024490. tionally or alternatively, a delayed release compartment of the 0117 Optionally, the solid dosage compartment com invention (e.g. a delayed release liquid soft gel or hard gel) prises a crystalline cannabinoid form. Optionally, the crystal may be coated in order to further modify its release proper line form is a mixture of cannabinoid enantiomers. Option ties. The coated compartment may be a solid compartment, ally, the crystalline form is a mixture of trans-(-)-THC and liquid compartment, or semi-solid compartment. trans-(+)-THC (e.g. dronabinol and its (+) enantiomer). I0123. By way of example, the delayed release coating may Optionally, the mixture is a racemic mixture. Examples of be a continuous coat which encapsulates the compartment as such crystalline forms are described in US 2007/0072939. It a whole (e.g. Surrounding an entire tablet compartment, hard is interesting to note that US 2007/0072939 describes the gel compartment or microparticles compartment as a whole). trans-(-) entantiomer (dronabinol) as the more potent of the As an alternative example, the delayed release coating may be two, and that the activity of the trans-(+) enantiomer is only a discontinuous coating, and coat the compartment by indi about 1% compared to the trans-(-)-enantiomer. This, how vidually encapsulating components of the compartment (e.g. ever, has not been shown for sleep related disorders taught by Surrounding individual microparticles, hard gels, or tablets herein (e.g. apnea) or the activity associated with treatment. which make up the compartment). For example, a discontinu When formulating a medicament comprising a mixture of ous delayed release coating is optionally useful when one trans-(-)-THC and trans-(+)-THC, one embodiment provides compartment (e.g. solid microparticles) is mixed with that only trans-(-)-THC (e.g. dronabinol) is considered for another compartment (e.g. an immediate release liquid com PK profile evaluation and drug dose or dosage amount. In partment) because it further segregates the compartments (in alternative embodiment, both the trans-(-)-THC and trans the medicament and/or once ingested). (+)-THC are considered, but values for the trans-(+)-THC 0.124. Any release modifying coating (e.g. extended, pull enantiomer are multiplied by a coefficient of about 1% to satire, or delayed) may be used to encapsulate a compartment about 10% (e.g. multiplied by coefficient of about 1% to taught herein. Examples of such are well known in the art. As correct for its hypothetically reduced activity). In one an illustrative embodiment, the coating may comprise a embodiment, the crystalline compartment is formulated as an hydrophobic release modifier, for example, an alkylcellulose US 2012/023 1083 A1 Sep. 13, 2012

(e.g. ethylcellulose), an acrylic polymer, mixture thereof, and ful for preparing pH-dependent coatings which may be used the like. Optionally, the delayed release coating is applied in in accordance with the present invention. For example, there the form of an organic or aqueous Solution or dispersion. are a family of copolymers synthesized from diethylamino Optionally, the delayed release coating comprises a plasti ethyl methacrylate and other neutral methacrylic esters, also cizer, or other excipient, Such as optional excipients taught known as methacrylic acid copolymer or polymeric meth herein. Optionally, the delayed release (e.g. pulsatile release) acrylates, commercially available as Eudragit(R) from Evonik. coating is pH dependent. Optionally, the delayed release coat There are several different types of Eudragit(R). For example, ing is a water Swellable Sustained release coating. Optionally, Eudragit E is an example of a methacrylic acid copolymer the delayed release coating is low permeability coating or a which Swells and dissolves in acidic media. Eudragit L is a high permeability coating, such as those described herein. methacrylic acid copolymer which does not swell at about Optionally, the delayed release coating is a low melting point pH-5.7 and is soluble at about pH>6. Eudragit S does not hydrophobic material (e.g. wax). swell at about pH-6.5 and is soluble at about pH>7. Eudragit 0.125. A non-limiting example of a useful alkylcellulosic RL and Eudragit RS are water swellable, and the amount of polymer is ethylcellulose, although the artisan will appreciate water absorbed by these polymers is pH-dependent, however, that other cellulose and/or alkylcellulose polymers may be medicaments coated with Eudragit RL and RS may be pH readily employed, singly or in any combination, as all or part independent. of a delayed release coating according to the invention. One I0129. Optionally, a useful acrylic delayed release coating commercially-available aqueous dispersion of ethylcellulose comprises a copolymer of acrylic and methacrylic esters with is Aquacoat(R) (FMC Corp., Philadelphia, Pa., U.S.A.). Aqua a low content of quaternary ammonium groups, for example, coat(R) is prepared by dissolving the ethylcellulose in a water having a molar ratio of ammonium groups to the remaining immiscible organic solvent and then emulsifying the same in neutral (meth)acrylic esters of 1:20 to 1:40, such as 1:20 or water in the presence of a surfactant and a stabilizer. After 1:40. Optionally, a useful acrylic delayed release coating homogenization to generate Submicron droplets, the organic comprises a mixture of two acrylic resin lacquers, e.g. those Solvent is evaporated under vacuum to form a pseudolatex. commercially available from Evonik under the Tradenames Prior to using the same as a coating, one may intimately mix Eudragit R. RL30D and Eudragit R RS30D, respectively. the Aquacoat(R) with a Suitable plasticizer. Another aqueous Eudragit R. RL30D and Eudragit R RS30D are copolymers of dispersion of ethylcellulose is commercially available as acrylic and methacrylic esters with a low content of quater Surelease R (Colorcon, Inc., West Point, Pa., U.S.A.). This nary ammonium groups, the molar ratio of ammonium groups product is prepared by incorporating plasticizer into the dis to the remaining neutral (meth)acrylic esters being 1:20 in persion during the manufacturing process. A hot melt of a Eudragit R. RL30D and 1:40 in Eudragit R RS30D. The mean polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic molecular weight is about 150,000. The code designations acid) is prepared as a homogeneous mixture, which is then RL (high permeability) and RS (low permeability) refer to the diluted with an alkaline solution to obtain an aqueous disper permeability properties of these agents. Eudragit(R) RL/RS sion which can be applied directly onto Substrates. mixtures are insoluble in water and in digestive fluids. How 0126 Examples of useful acrylic polymers include acrylic ever, coatings formed from the same are Swellable and per acid and methacrylic acid copolymers, methyl methacrylate meable in aqueous solutions and digestive fluids. The copolymers, ethoxyethyl methacrylates, cynaoethyl meth Eudragit(R) RL/RS dispersions of the present invention may acrylate, poly(acrylic acid), poly(methacrylic acid), meth be mixed together in any desired ratio in order to ultimately acrylic acid alkylamide copolymer, poly(methyl methacry obtain a delayed-release formulation having a desirable pro late), polymethacrylate, poly(methyl methacrylate) file. Optional delayed-release formulations may be obtained, copolymer, polyacrylamide, aminoalkyl methacrylate for instance, from a retardant coating derived from 100% copolymer, poly(methacrylic acid anhydride), and glycidyl Eudragit RRL, 50% Eudragit R. RL:50% Eudragit R RS, and methacrylate copolymers. 10% Eudragit R. RL:Eudragit R 90% RS. Of course, one 0127 Optionally, a delayed release acrylic polymer is skilled in the art will recognize that other acrylic polymers comprised of one or more ammonio methacrylate copoly may also be used, such as, for example, Eudragit R.L. mers. Ammonio methacrylate copolymers are well known in 0.130. In one embodiment, a delayed release coating com the art, and are described, for example, as fully polymerized prises a plasticizer. For example, where the coating is pro copolymers of acrylic and methacrylic acid esters with a low duced with an aqueous dispersion of a hydrophobic delayed content of quaternary ammonium groups. In order to tailor a release material, an effective amount of a plasticizer is option dissolution profile, one may, for example, incorporate two or ally provided to further improve the physical properties of the more ammonio methacrylate copolymers having differing release modifying coating. For example, because ethylcellu physical properties, such as different molar ratios of the qua lose has a relatively high glass transition temperature and ternary ammonium groups to the neutral (meth)acrylic esters. does not form flexible films under normal coating conditions, 0128. In one embodiment, the delayed release coating is one may incorporate a plasticizer into an ethylcellulose pH dependent. Optionally, the pH dependent delayed release release coating (or other alkylcellulose or other delayed coating is a pulsatile release coating to deliver a burst of release coating) before using the same as a coating material. cannabinoid release at a predetermined time (e.g. upon enter Generally, the amount of plasticizer included in a coating ing the gut). Optionally, the pH dependent delayed release Solution is based on the concentration of a film-former, e.g., coating is a water-Swellable coating. Optionally, the amount most often from about 1 to about 50 percent by weight of the of water absorbed by the coating is pH-dependent. Option film-former. Concentration of the plasticizer, may be deter ally, the delayed release coating does not Swell at about mined based on routine experimentation with the particular pH-5.7 and is soluble at about pH>6. Optionally, the delayed coating Solution and method of application. Examples of release coating does not swell at about pH-6.5 and is soluble suitable plasticizers for ethylcellulose and the like include at about pH>7. Methacrylic acid ester-type polymers are use dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl US 2012/023 1083 A1 Sep. 13, 2012

citrate, and triacetin, although it is possible that other plasti cium and sodium Stearates, Stearic acid, talc, waxes, cizers (such as acetylated monoglycerides, phthalate esters, Stearowet, boric acid, sodium benzoate, sodium acetate, castor oil, etc.) may be used. Examples of suitable plasticizers Sodium chloride, DL-leucine, polyethylene glycols, sodium for the acrylic polymers of the present invention include, but oleate, or Sodium lauryl Sulfate, and the like. are not limited to citric acid esters such as triethyl citrate, 0.142 (h) Wetting agents such as oleic acid, glyceryl tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene monostearate, Sorbitan monooleate, Sorbitan monolaurate, glycol. Other plasticizers which have proved to be suitable for triethanolamine oleate, polyoxyethylene Sorbitan enhancing the elasticity of the films formed from acrylic films monooleate, polyoxyethylene Sorbitan monolaurate, Sodium such as Eudragit(R) RL/RS lacquer solutions include polyeth oleate, or Sodium lauryl Sulfate, and the like. ylene glycols, propylene glycol, diethyl phthalate, castor oil, 0.143 (i) Diluents such lactose, starch, mannitol, sorbitol, and triacetin. Optionally, triethyl citrate is used as a plasti dextrose, microcrystalline cellulose, dibasic calcium phos cizer for the aqueous dispersions of ethyl cellulose of the phate. Sucrose-based diluents, confectioner's Sugar, monoba present invention. sic calcium sulfate monohydrate, calcium Sulfate dihydrate, 0131. In one embodiment, a delayed release coating com calcium lactate trihydrate, dextrates, inositol, hydrolyzed prises a small amount of talc. This may, for example, reduce cereal Solids, amylose, powdered cellulose, calcium carbon the tendency of the aqueous dispersion of a hydrophobic ate, glycine, or bentonite, and the like. delayed release coating to Stick during processing, and may 0144 () Anti-adherents or glidants such as talc, corn additionally act as a polishing agent. starch, DL-leucine, sodium lauryl Sulfate, and magnesium, 0.132. Other examples of useful delayed release coatings calcium, or Sodium Stearates, and the like. and useful dosage forms which comprise delayed release 0145 (k) Pharmaceutically compatible carriers compris coatings are described in U.S. Pat. No. 7,670.612. ing acacia, gelatin, colloidal silicon dioxide, calcium glyc 0133) Optional Excipients erophosphate, calcium lactate, maltodextrin, glycerine, mag 0134 Component and/or composition properties, for nesium silicate, sodium caseinate, Soy lecithin, Sodium example, bulk stability, dissolution and other release proper chloride, tricalcium phosphate, dipotassium phosphate, ties of composition components (e.g. solid, liquid, or semi Sodium Stearoyl lactylate, carrageenan, monoglyceride, dig Solid dosage compartments) may be manipulated by choosing lyceride, or pregelatinized Starch, and the like. an appropriate excipient, amount thereof, or formulation method using such. Non-limiting examples of pharmaceuti 0146 (1) delayed release modifiers (e.g. selected from cal excipients include: optional excipients) Such as delayed release coatings, 0135 (a) Binders such as acacia, alginic acid and salts extended release coatings, and extended release components thereof, cellulose derivatives, methylcellulose, hydroxyethyl which are complexed with a cannabinoid component. cellulose, hydroxypropyl cellulose, magnesium aluminum 0147 Combinations silicate, polyethylene glycol, gums, polysaccharide acids, 0.148. The present medicaments can optionally be com bentonites, hydroxypropyl methylcellulose, gelatin, polyvi bined with one or more additional therapeutic agents. Option nylpyrrolidone, polyvinylpyrrolidone/viny-I acetate copoly ally, the one or more additional therapeutic agents can be mer, crospovidone, povidone, polymethacrylates, hydrox provided as immediate release agents, delayed release agents, ypropylmethylcellulose, hydroxypropylcellulose, starch, or a combination thereof. pregelatinized starch, ethylcellulose, tragacanth, dextrin, 014.9 The present medicaments can optionally be com microcrystalline cellulose, Sucrose, or glucose, and the like. bined with therapeutic agents useful in the treatment of a 0136 (b) Disintegration agents such as starches, pregela cannabinoid-sensitive disorder. For example, the one or more tinized corn starch, pregelatinized starch, celluloses, cross additional therapeutic agents are optionally therapeutic linked carboxymethylcellulose, crospovidone, cross-linked agents useful in the treatment of cannabinoid-sensitive disor polyvinylpyrrolidone, a calcium, a sodium alginate complex, der selected from: apnea, seizures, a neurological disorder, a clays, alginates, gums, or Sodium starch glycolate, and any pain disorder, an appetite or wasting disorder, nausea, Vom disintegration agents used in tablet preparations. iting, a sleep disorder, a breathing disorder, or a sleep-related 0.137 (c) Filling agents such as lactose, calcium carbon breathing disorder. ate, calcium phosphate, dibasic calcium phosphate, calcium 0150. Optionally, the present medicaments are combined Sulfate, microcrystalline cellulose, cellulose powder, dex with one or more anti-apnea therapeutic agents, for example, trose, dextrates, dextran, starches, pregelatinized starch, any of serotonin reuptake inhibitors, serotonin receptor Sucrose, Xylitol, lactitol, mannitol, Sorbitol, Sodium chloride, antagonists, serotonin receptor (e.g. Subtype 1) agonists, polyethylene glycol, and the like. serotonin agonists, noradrenalin reuptake inhibitors, com 0138 (d) Surfactants such as sodium lauryl sulfate, sorbi bined serotonin/noradrenalin reuptake inhibitors, glutamate tan monooleate, polyoxyethylene Sorbitan monooleate, receptor antagonists, glutamate antagonists, inhibitors of polysorbates, poloxamers, bile salts, glyceryl monostearate, glutamate release, glycine antagonists, GABA receptor ago PluronicTM line (BASF), and the like. nists, calcitonin gene-related peptide (CGRP) receptor 0139 (e) pH correcting agents (buffers) such as citric acid, antagonists or release inhibitors, adenosine, adenosine ana Succinic acid, fumaric acid, malic acid, tartaric acid, maleic logs and nucleoside (e.g. adenosine) uptake blockers or acid, glutaric acid, their alkaline salts, sodium bicarbonate reuptake inhibitors, opioid antagonists, Vanilloid receptor and sodium carbonate and the like. ligands, pilocarpine compounds, sodium proton pump inhibi 0140 (f) Stabilizers such as any antioxidation agents, tors, ubidecarenones, antihistimines, prostaglandins, pros buffers, or acids, and the like, can also be utilized. tanoid receptor antagonists, inhibitors of prostanoid synthe 0141 (g) Lubricants such as magnesium Stearate, calcium sis, modulators of CRTH2, COX-2 and/or FAAH, antitussive hydroxide, talc, sodium Stearyl fumarate, hydrogenated veg agents, compounds that stimulate the central nervous system, etable oil, Stearic acid, glyceryl behenate, magnesium, cal agents that prolong the action of endocannabimimetics, US 2012/023 1083 A1 Sep. 13, 2012

inhibitors of endocannabinoid membrane transport, inhibi tories, nandrolone, antidepressants, atypical antipsychotics tors of cannabinoid metabolism, and cannabinoid degradative Such as olanzapine, dexamethasone, prednisolone and meth enzyme antagonists. ylprednisolone. 0151 Optionally, the present medicaments are combined 0156 Optionally, the present medicaments are combined with one or more anti-apnea therapeutic agents or combina with one or more anti-glaucoma therapeutic agents, e.g., fish tions of apneatherapeutic agents disclosed in any of U.S. Pat. oil and omega 3 fatty acids, bilberries, vitamin E. cannab inoids, carnitine, coenzyme Q10, curcurmin, Salvia miltior No. 6,331,536, U.S. Pat. No. 6,555,564, U.S. Pat. No. 6,727, rhiza, dark chocolate, erythropoietin, folic acid, Ginkgo 242, U.S. Pat. No. 7,160,898, U.S. Pat. No. 6,974,814, U.S. biloba, Ginseng, L-glutathione, grape seed extract, green tea, Pat. No. 7,705,039, US20060241164, US20070123517, magnesium, melatonin, methylcobalamin, N-acetyl-L cys US20080200367, US20080261922, US20090005357, teine, pycnogenols, resveratrol, quercetin and salt, magne US20090221658, US20100137251, EP1066036, sium, ginkgo, salt and fludrocortisone. EP1372638, EP1572202, EP1868602, JP20100591.95, 0157 Optionally, the present medicaments are combined WO/1999/043319, WO/2000/051590, WO/2002/080903, with one or more anti-emetics, e.g., serotonin receptor WO/2004/041272, WO/2006/113448, WO/2006/133197, antagonist, dopamine antagonist, NK1 receptor antagonist, WO/2007/047372, WO/2007/047575, WO/2007/047576, antihistamine, benzodiazepine, anticholinergic, or steroid WO/2007/047577, which disclose useful examples of the Such as dexamethasone. anti-apnea therapeutic agents and/or other anti-apnea thera 0158 Optionally, the present medicaments are combined peutic agents. with one or more additional therapeutic agents selected from: 0152 Optionally, the present medicaments are combined antihistamines, antimicrobial agents, fungistatic agents, ger with one or more anti-convulsants, for example, anti-convul micidal agents, hormones, antipyretic agents, antidiabetic sants of any of the following types: aldehydes, aromatic agents, bronchodilators, antidiarrheal agents, antiarrhythmic allylic alcohols, barbiturates, benzodiazepines, bromides, agents, coronary dilation agents, glycosides, spasmolytics, carbamates, carboxamides, fatty acids, fructose derivatives, antihypertensive agents, antidepressants, antianxiety agents, gaba analogs, hydantoins, oxazolidinediones, propionates, antipsychotic agents, other psychotherapeutic agents, Ste pyrimidinediones, pyrrolidines, Succinimides, Sulfonamides, roids, corticosteroids, analgesics, cold medications, vitamins, triazines, ureas, and valproylamides (amide derivatives of sedatives, hypnotics, contraceptives, nonsteroidal anti-in valproate). flammatory drugs, blood glucose lowering agents, choles 0153. Optionally, the present medicaments are combined terollowering agents, anticonvulsantagents, otherantiepilep with one or more analgesics, for example, any of NSAIDs tic agents, immunomodulators, anticholinergics, (e.g. ibuprofen), paracetamol, COX-1 inhibitors, COX-2 sympatholytics, sympathomimetics, vasodilatory agents, inhibitors, COX-3 inhibitors, opioids (e.g. hydrocodone or anticoagulants, antiarrhythmics, prostaglandins having vari oxycodone), morphinomimetics, flupirtine, tricyclic antide ous pharmacologic activities, diuretics, sleep aids, antihista pressants (e.g. amitriptyline), tetracyclic antidepressants, minic agents, antineoplastic agents, oncolytic agents, antian anticonvulsants (e.g. carbamazepine, gabapentin, or pregaba drogens, antimalarial agents, and antileprosy agents. lin), anticholinergics, antispasmodics, K+ channel openers, 0159. The present medicaments can optionally be com NMDA receptor antagonists (e.g., dextromethorphan, ket bined with one or more SSRIs, e.g., fluoxetine, paroxetine, amine, and amantadine), Steroids, anti-inflammatories, non fluvoxamine, Sertraline, citalopram, norfluoxetine, r(-) flu narcotic analgesic (e.g. tramadol), NK1 receptor antagonists oxetine, S(+) fluoxetine, demethylsertraline, demethylcitalo (e.g., ezlopitant and SR-14033, SSR-241585), CCK receptor pram, Venlafaxine, milnacipran, Sibutramine, nefazodone, antagonists (e.g., loxiglumide), NK3 receptor antagonists R-hydroxynefazodone, (-)Venlafaxine, and (+) Venlafaxine. (e.g., talnetant, osanetant SR-142801, SSR-241585), norepi 0160 The present medicaments can optionally be com nephrine-serotonin reuptake inhibitors (NSRI; e.g., milnacip bined with one or more serotonin receptor antagonists, e.g., ran), Vanilloid receptoragonists and antagonists, cannabinoid the free base form or a quaternized form of Zatosetron, tro receptor agonists (e.g. arvanil), sialorphin, inhibitors of pisetron, dolasetron, hydrodolasetron, mescaline, Oxetorone, neprilysin, CCK receptor agonists (e.g., caerulein), SSRIs homochlorcyclizine, perlapine, ondansetron (GR38032F), (e.g. fluoxetine, paroxetine, or Sertraline), serotonin receptor ketanserin, loxapine, olanzapine, chlorpromazine, haloperi agonists, serotonin receptor antagonists, triptans (e.g. dol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, Sumatriptan), GABA analogs (e.g. GABApentin or pre-gaba (-) cisapride, (+) norcisapride, (-) norcisapride, desmethy lin), muscle relaxants, alpha-adrenergic, PDEV inhibitors, lolanzapine, 2-hydroxymethylolanzapine, 1-(2-fluorophe PDEVII inhibitors, and glycine antagonists. nyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dim 0154 Optionally, the present medicaments are combined ethylaminoethyl)-oxime, risperidone, cyproheptadine, with one or more anxiolytic or anti-anxiety therapeutic clozapine, methysergide, granisetron, mianserin, ritanserin, agents, for example, any of benzodiazepines, buspirone, tri cinanserin, LY-53,857, metergoline, LY-278,584, methio cyclic antidepressants, SSRIs, monoamine oxidase inhibi thepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ tors, antipsychotic agents, antihistamines (e.g. Atarax or Vis 205,557,3-tropanyl-indole-3-carboxylate, 3-tropanyl-in taril), barbiturates (e.g. phenobarbital), and beta-blockers dole-3-carboxylate methiodide, and other serotonin receptor (e.g. propranolol), and propanediols (e.g. meprobamate). antagonists and their quaternized forms or one of its pharma 0155 Optionally, the present medicaments are combined ceutically acceptable salts. with one or more anti-wasting therapeutic agents or appetite 0.161 The present medicaments can optionally be com stimulants, for example, any of tricyclic antidepressants, bined with one or more serotonin receptor agonists, e.g., tetracyclic antidepressants, cyproheptadine, buclizine, mege 8-OH-DPAT, Sumatriptan, L694247 (2-5-3-(4-methylsul strol, ginger. EPA (fish oil), erthythropoietin, thalidomide, phonylamino)benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-3yl ghrelin, interferon, melatonin, non-steroidal anti-inflamma ethanamine), buspirone, alnitidan, Zalospirone, ipsapirone, US 2012/023 1083 A1 Sep. 13, 2012 gepirone, Zolmitriptan, risatiriptan, 311 C90, C.-Me-5-HT, SC51089, L-798, 106, prostanoid receptor antisense oligo BW723C86 (1-5(2-thienylmethoxy)-1H-3-indolylpropan nucleotides, ONO-8713, ONO-AE829, ONO-AE2-227, 2-amine hydrochloride), and MCPP (m-chlorophenylpipera SC51322, ZD-6416, ONO-3144, ONO-3708, ONO-NT-12, Zine). SC-236, SC-299, SC-51234A, SKF-104493, SKF-105561, 0162 The present medicaments can optionally be com SKF-105809, SKF-106978, SKF-86002, SQ-28852, CGP bined with one or more C. 2 adrenergic receptor antagonists, 47969A, CGS-11776, FR-122047, L-64.0035, L-651392, e.g., phenoxybenzamine, phentolamine, tolazoline, tera L-651896, L-655240, L-657925, L-657926, L-745296, Zosine, doxazosin, trimaZosin, yohimbine, indoramin, L-745337, L-746483, L-761066, L-768277, PD-138387, ARC239, and prazosin. WY-48090, S-5751, BWA868C, ramatroban, Ifetroban, 0163 The present medicaments can optionally be com SQ-29548, ICI-192605, S-1452, FCE-27262, ONO-8809, bined with one or more noradrenalin reuptake inhibitors, e.g. ONO-NT-126, CBS-1108, L-636499, diphloretin phosphate, desipramine, nortriptyline, reboxetine, nisoxetine, atomoxet polyphloretin phosphate, BM-613, BM-500, BM-519, ine, or LYI 39603 (tomoxetine). BM-567, BM-573, ONO-3708, seratrodast, GW627368 and 0164. The present medicaments can optionally be com taprostene, YM-158, YM-26734, YM-57158, Z-335, bined with one or more antitussive agents, e.g., RSD931, ZD-9583, 6-N-(2-benzyloxy-5-bromobenzyl)-N-ethy FK888, CP99994, SR48968, codeine, SR1428O1, laminolpyridazine-3-carboxylic acid, 6-N-(5-bromo-2-(2- SB235375, nociceptin/orphanin FQ, 15-HPETE, NADA, methylprop-2-en-1-yloxy) benzyl)-N-ethylaminopy anandamide, lidocaine, benzonatate, mexiletine, NS1619, ridazine-3-carboxylic acid (disclosed in Example 15 of furosemide, Zafirlukast, HOE 140, dihydrocodone, oxyc International Patent Publication No. WO97/00864), N-pro odone, BW443C noscapine, dextromethorphan, SKF 10047. panesulphonyl-6-N-(5-bromo-2-(cyclopropylmethoxy) baclofen, diphenhydramine, caramiphen, glaucine, cilomi benzyl)-N-ethylaminolpyridazine-3-carboxamide (disclosed last, RO-64-6198, NKP608, levchromkalim, BRL55834, in Example 14 of International Patent Publication No. WO icatibant, Suplatast tosilate, epinastine, levodropropizine, and 97/00863), N-(3,5-dimethylisoxazol-4-ylsulphonyl)-6-N- other antitussive agents {Trends in Pharm Sci 25: 569-576, (5-chloro-2-(2-methylpropoxy)benzyl-N-ethylaminopy 2004; BrJ Pharmacol 1 17:853-858, 1996). ridazine-3-carboxamide (disclosed as compound number 1 in 0.165. The present medicaments can optionally be com Example 8 of International Patent Publication No. WO bined with one or more CCK receptor antagonists, e.g. CCK 97/00863), 6-N-(5-bromo-2-(cyclopropylmethoxy) ben A receptor antagonist, a CCKB receptor antagonists, or an Zyl)-N-ethylaminolpyridazine-3-carboxylic acid (disclosed antagonist exhibits activity against both CCKA and CCKB in Example 3 of International Patent Publication No. receptors. Examplary antagonists which exhibit activity 97/00863), and the like. toward both CCKA and CCKB receptors include benzotript 0.168. The present medicaments can optionally be com and proglumide. Examplary CCK A receptor antagonists bined with one or more CGRP receptor antagonists, e.g., include L-364,718 (devazepide); loxiglumide; dexloxiglu BIBN4096BS, SB-(+)-273779, CGRPs, Compound 1 (4- mide; lorglumide:L-lorglumide: D-lorglumide; PD-140,548; (2-oxo-2,3-dihydro-benzoimidazol-1-y-piperidine-1-car TP-680; T-0632: A-67396; A-70276: A-71134 and SR 27897. boxylic acid 1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2- Examplary CCKB receptor antagonists include CR2945: (4-phenyl-piperazin-1-yl)-ethyl-amide), and other CGRP YMO22; itriglumide: L-740,093: L-365,260; L-156,586: receptor antagonists (see, Arulmani et ah, 2004, Eur J Phar LY-262691;ureidoacetamides (e.g., RP69758, RP 72540, RP macol 500:315-330 for review) 73870); tetronothiodin; peptide analogs (CI-1015 and 0169. The present medicaments can optionally be com CI-988); YF476; A-63387 and GV150013X. Other exam bined with one or more opioids, e.g. buprenorphine, butor plary CCK receptor antagonists include, but are not limited phanol, codeine, fentanyl, hydrocodone, hydromorphone, to, A-647 18: A-65186; spiroglumide: CR-2345; CR-2767; methadone, morphine, oxycodone, or propoxyphene. CR2622; tarazepide: L-365,260: L-708.474; L-368,730; 0170 The present medicaments can optionally be com L-369.466; L-736,380: FK-480; FR175985; FR193108; bined with one or more glutamate antagonists, e.g. NMDA FR196979; FR202893, FR208418; FR2084.19; CP212,454; antagonists, AMPA antagonists, or kainate receptor antago CP310,713; GV191869X; GV 1991 14X; RPR101 1367; nists. Examplary glutamate receptor antagonists include S-0509; DA-3934; D51-9927; LY-202769; CCK-8; CCK-4; D-AP5 (D(-)-2-amino-5-phosphonopentanoate), CGS19755 CAM1189; PD-135,666; CAM 1481; PD-140,547: PD-140, (4-phosphonomethyl-2-piperidine carboxylic acid), 723; PD-149,164: JB93182: AG-041 R: SR-27,897 (lini CGP37849 (D.L-(E)-2-amino-4-methylphosphono-3-pen tript); KSG-504; and 2-NAP. tanoic acid), LY233053 (cis-(+)-4-(2H-tetrazol-5-yl)methyl 0166 The present medicaments can optionally be com piperidine-2-carboxylic acid), AIDA (1-aminoindan-1.5 bined with one or more NSAIDs, e.g., aspirin, choline and (RS)-dicarboxylic acid), (S)-(+)-CBPG ((s)-(+)-2-(3'- magnesium salicylates, choline salicylate, celecoxib, carboxy-bicyclo(1.1.1.)pentyl)glycine), CPCCOEt diclofenac potassium, diclofenac sodium, diclofenac sodium (cyclopropan(b)chromen-la-carboxylate), EGLU ((S)-(C)- with misoprostol, diflunisal, etodolac, fenoprofen calcium, ethylglutamate), LY307452 (2s.4s-2-amino-4-(4,4-diphenyl flurbiprofen, ibuprofen, indomethacin, ketoprofen, magne but-1-yl)pentan-1,5-dioc acid) LY341495 (2s-2-amino-2- sium salicylate, meclofenamate sodium, mefenamic acid, (1S,2S-2-carboxy-cyclopropan-1-yl)-3-(Xanth-9-yl) meloxicam, nabumetone, naproxen, naproxen Sodium, propanoic acid), PCCG-4 (2s, 1s.2s.3R)-2-(2-carboxy-3- oxaprozin, piroXicam, rofecoxib, Salsalate, sodium salicylate, phenylcyclopropyl)glycine), 4-CPG Sulindac, tolmetin Sodium, or Valdecoxib. (4-carboxyphenylglycine), memantine, and amantadine. 0167. The present medicaments can optionally be com 0171 The present medicaments can optionally be com bined with one or more prostanoid receptor antagonists, e.g., bined with one or more NMDA antagonist, e.g., L-glutamate AH-6809, ONO-8711 and ONO-8713, L-161,982 (4), derivatives, tetrahydroquinoline, imidazoloquinoxalinone, AH-23848 (4), ONO-AE3-208 (4), SC19220, ONO-8711, isatine, fused cycloalkylquinoxalinediones, quinoxaline, US 2012/023 1083 A1 Sep. 13, 2012 spermine, a 4-hydroxy-3-nitro-1,2-dihydroquinolon-2-one oXo-1,2,3,4-tetrahydroquinoline derivative, a 3-phospho derivative, an indole derivative, a benzo-thiadiazine dioxide nopiperidine and p-pyrrolidine derivative, a benzothieno derivative, an indeno(1.2-b)pyrazin-3-one or corresponding (2,3-B)-pyrazine-2,3-(1H4H)-dione, a spiro dibenzosuber 2,3-dione, a quinoline derivative, an ethyl (phenylcarbamoyl) ane derivative, a benzomorphan derivative, a preparation of ethenyl)dichloroindole carboxylate, a thienopyrazine 2,3-di 3,4-disubstituted 2-isoxazoline(s) and isoxazoles(s), a 3-in one derivative, a 2-(2,3-dicarboxycyclopropyl) glycine, a dolylthio-acetate derivative, an arginine-derived nitric oxide 2-amino-3-substituted phenyl propionic acid derivative, biosynthesis inhibitor, a dicyclic amine derivative, a 1-carboxyalkylquinoxaline-2.3(1H.4H) dione derivative, a spiroisoindole derivative, an imidazo(1.2-A)-pyridinylalkyl thienyl-glycine derivative, a benzo-fused azacyclic com compound, a 1,2,3,4-tetrahydro-9H-pyrido indole or ben pounds, an indole derivatives, a tricyclic quinoxaline-diene Zothiophene derivative, an indole-2,3-dione-3-oxime deriva derivative, a 3-hydroxy anthranilic acid and salts, a decahy tive, a 1-aryl-2-(aminomethyl)cyclopropanecarboxamide droisoquinoline compound, a tri- or terta-Substituted guani derivative, a 4-phosphono-2-amino-alkenoic acid derivative, dine derivatives, a D- or L-tryptophan derivative, a tetrazolyl a naphthopyran derivative, a beta-ketone, a beta Oxime or beta (alkyl)-cyclohexykaminoacid derivative, al hydrazine phosphonate, atopaquinone aminoacid, kynurenic octahydrophenanthrene derivative, a benzomorphan com acidora derivative, a quinoline- or thienopyridine-carboxylic pound, a piperazinyl or piperidinyl-alkyl Substituted isox acid derivative, a 10.5 (imino-methano)-10,11-dihydro-5H azole derivative, a decahydroisoquinoline-3-carboxylic ester dibenzo(A.D)cyclohept ene or a derivative, a bicyclic amino or amide preparation, a compounds based on Conantokin-G hydroxamate derivative, an indole-2-carboxylic acid deriva peptide, a 3-heterocyclykalkyl-benzopyran-2-one derivative, tive, a Substituted adamantane derivative, a a phosphono-alkyl imidazo-pyrimidine carboxylic acid benzobicycloalkane derivative, a 2,4-disubstituted-1,2,3,4- derivative, amantidine, memantine, rimantidine, a histogra tetrahydro-quinoline derivative, a dihydro-alkyl-substituted nin peptide or analogue, a nitrobenzoic acid derivative, e.g. (immunomethano)-5H-dibenzo-cycloheptene, an aryl cyclo 44(2-methoxycarbonyl-4-nitrophenyl)methyl)piperazine hexylamine, an N-Substd. benzobicycloalkane amine, an iso carboxylic acid, a diamine derivative with selective sigma quinoline phosphonate derivative, an N,N'-disubstd.-guani receptor affinity, remacemide (2-amino-N-(1,2-diphenyl-1- dine compound, a phosphonopropenyl piperidine carboxylic methylethyl)acetamide), a phosphono-alkylidene- or acid compound, (2R,3S,4S)-alpha-carboxycyclo-propyl-gly phosphono-alkoxyimino-piperidine acid, a benzothiadiazine cine, a pyrrolidine derivative, a dihydroxy-fused heterocyclyl carboxylic acid derivative, a dihydro-benzothiadiazine diox quinoxaline derivative, a hydrogenated derivative of MK801 ide carboxylic acid derivative, a 4-hydroxy 2 (H) pyrrolone and analogues, a 5-substd. 10,11-dihydro 5H-dibenzo (A.D) derivative, a quinoxaline derivative, a tetrahydro-imidazo cycloheptene 5,10-imine, an 11-Exo-hydroxy MK 801 prepa (1,2-a) pyrimidines or its salt, a alpha-amino acid, a 4-hy ration including electrochemical cyclisation step to form droxy-pyrrolo 1,2-bipyridazin-2(1H)-one derivative, a nitro 5,10-imine bridge in 5-methyl 5-oxyamino 5H-dibenzo quinolone derivative, a 3-aryl-substd 201H)quinolone, a (A.D) cycloheptene, a tetrahydro-isoquinoline or 2-benza 2(1H)-quinolone, a phosphonic acid quinoline-2-carboxylic Zepine derivative, an N-3-phenylpropionyl-substd. Spermine acid derivative, its per hydro quinoline derivative or salt, a or related polyamine derivative, a 4a-amino-fluorene com benzimidazole(s) carrying 2 acidic groups, an N,N'-disubsti pound or a heterocyclic analogue, a cyclooctane-imine tuted guanidine derivative, a tricyclic quinoxaline dione, a derivative, a R-3-amino-1-hydroxy pyrrolidin-2-one or 2-(2,3-dicarboxycyclopropyl) glycine stereoisomer, preg methionine hydroxamate, a 10,11-dihydro-5H-dibenzo-cy nenolone Sulphate or one of its derivative, an isatine deriva clohepten-5,10-imine compound, a polyhydro-10,11-dihy tive, a 3-amino-indolyl-derivative, 2-phenyl-1,3-propanediol dro-5H-benzo(a,d)cyclohepten-5,10 imine derivative, a dicarbamate (felbamate), a benzomorphan derivative, a dihy 4-oxo-1,4-dihydroquinoline compound with 2-acidic groups, drothienopyridine derivative, an enantiomer of (aminophe a heterocyclykalkene-phosphonic acid compound, a nyl)-heteroaryl ethylamine, a pyridazine-dione derivative, a phosphono gp-containing pyridine 2-carboxylic acid, an 2H-1-benzopyran-2-one compound, a 4-Sulphonylamino alpha-amino-alpha-(3-alkylphenyl)alkyl ethanoic acid, its quinoline derivative, a R(plusy3-amino-1-hydroxy-pyrroli esters or amides, a 10,11-dihydro-5H-dibenzo-AD-cyclo dine-2-one, a 2-carboxy indole, a Substd. imino-methano hepten-5,10-imine compound, a phosphorus containing dibenzo (A.D) cycloheptene derivative, an indole-hydrazone, unsaturated amino acid or its salts, a 5 Substd.-1-, 11-dihy a piperazine derivative, a 4,6-disubstituted tryptophan and dro-5H-dibenzo-cyclohepten-5,10-imine or analogue, a het kynurenine derivative, a fluorenamine compound, a diketo erocyclic phosphonic acid derivative or its salt, a Substituted pyrido pyrazine derivative or its salts, a 2-amino-3,4-dioxo 4-(aminocarbonyl-amino)quinoline derivative, a tricyclic 1-cyclobutene derivative, a 2-acyl-amido derivative of 3,4- quinoxaline derivative, a butyryltyrosine spermine or one of dihydro-3-oxo-quinoxaline, a benzimidazole phosphono its analogue, a tri- or tetra-Substituted guanidine, a quinox aminoacid derivative, a quinoxaline phosphono-aminoacid alinylalkyl-aminoalkane phosphonic acid derivative, a derivative, a piperazine, piperidine or pyrrolidone derivative, 2-(aminophenyl)-3-(2-carboxy-indol-3-ylypropenoic acid ist salts and isomeric forms including stercoisomers, 6 4-hy derivative, a 6-piperidinylpropiony-2(3H)-benzoxazolone droxy-2(1H)-quinolinone derivative, ist salts and prodrugs, a derivative, 6-(3-4-(4-fluorobenzyl)piperidin-1-yl)propio fused pyrazine derivative, a 2-phenyl or 2-thienyl-(2)-piperi nyl)-3H-benzoxazol-2-one or one of its salts, an imidazol, dine derivative, a 3-amido or 3-sulphamido-indolyl deriva 2-alpyridine compound, a tetrahydroquinoline derivative or tive, a 3-aryl-4-hydroxy-2-(1H)-quinolone derivative, a one of its salts, a 2-methyl-5.8-substituted 2,3,4,5-tetra- or 2-heterocyclyk2-hydroxy-ethylamine derivative, a 1-aryl-2- 2.3A4a,5.9b-hexahydro-1H-pyrido4.3-bindole, a 3-ami aminomethylpyrrolidine, its optical isomers and acid-addin. noindolyl compound, a 6-pyrrolyl-quinoxaline-2,3-dione salts, a 4.6-dihalo indole2-carboxylic acid derivative, a cyclic derivative, an imidazoly(mercaptoalkyl)-quinoxaline-dione aminohydroxamate derivative, a tetracyclic amine derivative, compound, a 3-amidoindolyl derivative, a heterocyclyl-imi a 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivative, a 2,4-di dazolo-quinoxalinone compound, a naphthyl-substituted US 2012/023 1083 A1 Sep. 13, 2012 alpha-amino acid derivative, a 5-heteroaryl-2,3-quinoxaline noalkyl-cyclopropane N.N-diethyl carboxamide compound, dione derivative, a quinoxaline derivative, a 5H, 1 OH-imidazo a dexanabinol derivative, a substituted chroman derivative, a indeno 4-pyrazinone derivative, a hydroxy-(aryl-substituted Sulphonamide quinazoline-2-4-dione compound, a 6- and phenyl)-quinolone compound, an imidazo indolo pyrazinone 8-aza-, and 6,8-diaza-1,4-dihydro-quinoxaline-2,3-dione derivative, a (phenyl-amino)-(m) ethylypyridine derivative, derivative, a substituted quinoline derivative, a tetrazolylalkyl a tetrahydro-isoquinoline derivative, a 4-substituted piperi cyclohexylaminoalkanoic acid, a tricyclic indole 2-carboxy dine analogue, a 2-substituted piperidine derivative, a tri- or lic acid derivative, a 6-substd-7H-imidazo-8-pyrazinone tetra-substituted guanidine derivative, a 3-Hydroxy-4-imida derivative, a quinoxaline dione derivative or one of its radio Zolidinone, a 3-aminoquinoxalin-2-one derivative, rapamy labelled compounds, a tricyclic pyridaZinopyridine deriva cin or a derivative e.g. 1,3-Diels Alder adduct with phenyl tive, an N-substituted heterocyclylidenemethyl-indole car triazoline-dione, 1-amino-1-cyclobutanecarboxylic acid, a boxylic acid derivative, a 3-aza-8-substituted-bicyclo(3.3.0) thiamorphinan derivative, a pyrido4.3-bindole derivative, octane-2-carboxylic acid derivative, an ethano-heterocyclo 4-phenyl carbamoyl methylene tetrahydro quinoline-2-car isoquinolinium salt, a phenyl alkanolamine derivative, a boxylic acid or a derivative thereof (3R,4SY3-(4-(4-fluo dihydrobenzothiadiazinedioxide carboxylic acid derivative, a rophenyl)-4-hydroxy-piperidin-1-yl)-chroman-4,7-dio a methyl-butenylmethyl(hydroxy-propyl)carbazoledione, an phenol derivative, an indeno-pyrazin-4-one, a 2,3-dioxo-1.2. imidazo pyrazinone derivative, an imidazo-(1,2-a)pyrazine 4.5-tetrahydro-quinoxalinyl derivative, a 45-bridged qui 4-one, a benzazepine-dione derivative, disulfuram, a noxalinedione or quinolone, (1S,2S)-1-(4-hydroxyphenyl)2- 3-(indo 13-yl)-propenoic acid derivative, a 1,2,3,4-tetrahy (4-hydroxy 4-phenyl piperidin-1-yl) I-propanol methane dro-quinoline-2,3,4-trione-3 or 4-oxime compound, a pep Sulphonate trihydrate, a 4-Sulphanimide-quinoline derivative, tide antagonist at NMDA receptors, a 2-amino-2-phenyl a methanobenzocyclodecen-13-amine compound, a deriva (alkylyacetic acid derivative, 6-halo-tryptophan or a 4-halo tives of pregnenolone Sulphate, a quinoxalinyl-(alkane,alk kynurenine, a 6-tetrazolyl or isoxazoly-decahydro ene, or alkyne)-phosphonic acid or one of ist esters, a diary isoquinoline-3-carboxylic acid derivative, an an lalkylamine related to spider and wasp venom toxins, a imidazolylbenzene or salts thereof. piperazine R-alpha-carboxylic acid derivative, an imidazo 0172. The present medicaments can optionally be com indeno-pyrazin-4-one derivative, a pyridazino-quinoline bined with one or more AMPA antagonists, e.g., L-glutamate derivative, a 1-substituted, or 1,3-di-substituted, 1,3-diaryl derivatives, amino alkanoic acid derivatives, C.-amino-3-hy guanidine compound, an aza-cycloalkykfused quinoxaline droxy-5-methyl-4-isoxazolepropionate derivatives, acetyl dione, a 3-substd, 2-carboxy-indole derivative or intermedi aminophenyl-dihydro-methyl-methyl-dioxolobenzodiaz ate, a (2R)- N-trityl-4-oxo-5-(dimethyl phosphono)-nor epine, acid amide derivatives, amino-phenyl-acetic acid, 2.3- Valinate ester, a kynurenic acid derivative, an indole benzodiazepin-4-one, alkoxy-phenyl-benzodiazepine, carboxylic acid derivative, a 6-(tetrazolyl or isoxazolyl amino- or desamino 2,3-benzodiazepine, benzothiadiazine, decahydroisoquinoline-3-carboxylic acid derivative, a phe C-carboline-3-carboxylic acid, fused cycloalkylduinoxa nyl- or pyridinyl-thieno-pyridinone derivative, a fused linediones, decahydroisoquinoline, 4-hydroxypyrrolone, cycloalkylquinoxaline-dione derivative, a pyridazino-quino 4-hydroxy-pyrrolo-pyridaZinone, imidazo-pyrazinone, imi line derivative, a 1-Alpha-amino-3-biphenyl-propanoic acid dazolo-quinoxalinone, indeno-pyrazine-carboxylic acid, derivative, a 3-(Indo)-3-yl)propenoic acid derivative, a spiro indeno-pyrazinone, indoloneOXime, indolo-pyrazinone, isat heterocycle-midazo-indeno-pyrazine-4-one derivative, a ine, isatinoXime, oxadiazole, phenyl-aZolophthalazine, phe 2-heterocyclyk3-indolylpropenoic acid derivative, a piperidi nylpyridaZino-indole-1,4-dione, quinoline, quinolinone, qui noalkylheterocyclic ketone or alcohol compound, a pyrrolyl noxaline, quinoxalinedione, quinazolinone, quinolone, tetrahydro-benzoquinoxaline-dione derivative, a 7-imida nitroquinolone, and Sulphamate derivatives. Zolyl or dialkylamino, tetrahydroquinoxaline dione 0173 The present medicaments can optionally be com compound, a dibenzocycloheptene, a quinoxaline derivative, bined with one or more kainate receptor antagonists, e.g., an aryl-thio-quinoxaline derivative, a heterocyclic Substd. L-glutamate derivatives, kainic acid derivatives, acid amide imidazolo-quinoxaline derivative, a 1,4-dihydro-quinoxa derivatives, aminoalkanoic acid derivatives, aminophenyl(a- line-2,3-dione derivative, an oxa- or thia-aliphatically lkyl)acetic acid derivatives, fused cycloalkylquinoxalinedi bridged quinoxaline derivative, an aza-aliphatically bridged ones, quinoxalinedione, imidazolo-quinoxalinone, isatine, quinoxaline-2,3-dione compound, a 3-amido- or 3-sulpha phenylaZolophthalazine, pyridothiazines, 4-phosphonoalkyl mido-indole compound, a 3,5-disubstd. phenyl-naphthalene quinolinone, quinolinone, quinazoline, quinazolinedione, derivative, an imidazo (1.2-a)indeno (1.2-e) pyrazine-2-car boxylic acid derivative, a 3-phenyl-fused ring pyridine-dione quinoxalinedione, and Sulphamate derivatives. derivative, a 2-phenyl-pyridaZino-indole-dione derivative, a 0.174. The present medicaments can optionally be com 4,6-disubstd. kynurenine compound, a phosphono derivative bined with one or more inhibitors of glutamate release, e.g., of imidazol-2-alpyrimidine-2-carboxamide, a tetrahydro lamotrigine, BW 1003C87, riluzole, isoguvacine, muscimol, quinoxaline-dione derivative with N-(alkyl)carbonyl-amino THIP piperidine-4-Sulphonic acid, flunitrazepam, Zolpidem, orureido group, a tryptophan derivative, a hetero-aliphatic or abecarnil, ZK93423, L-baclofen, CGP27492, piracetam, pro hetero-araliphatic Substd. quinolone derivative, an imidazo gabide, and CGP35024. pyridine dicarboxylic acid derivative, a composition contain 0.175. The present medicaments can optionally be com ing pyrazolo-quinoline derivatives, an ethanodihydrobenzo bined with one or more glutamate reuptake promoters, e.g. quinolizinium salt, an OXopyridinylquinoxaline derivative, an Zonisamide. indeno-triazolo-pyrazin-4-one derivative, an imidazo-in 0176 The present medicaments can optionally be com deno-pyrazinone derivative, an imidazo-indeno-pyrazin-4- bined with one or more combined serotonin/noradrenaline one derivative, an imidazol-2-alpyrazine-4-one derivative, a reuptake inhibitors, e.g., Venlafaxine, milnacipran, dulloxet 5H-indeno-pyrazine-2,3-dione derivative, a phenyl-ami ine, pregabalin, LY248686, and Strattera. US 2012/023 1083 A1 Sep. 13, 2012 17

0177. The present medicaments can optionally be com bined with one or more tricyclic antidepressants, e.g., ami TABLE 1-continued triptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosul Examplary Medicanents epin/dothiepin, doxepin, imipramine, imipraminoxide, % of lofepramine, melitracen, metapramine, nitroxazepine, cannabinoid nortriptyline, noxiptiline, pipofezine, propizepine, protrip formu- Total in the IR Dosage lation Cannabinoid IR. Dosage Compart- DR Dosage tyline, and quinupramine. i amount (mg) compartment ment Compartment 0.178 The present medicaments can optionally be com 7 2.5 25, 40, oi DR compartment bined with one or more tetracylic antidepressants, e.g., ami 50, 60, 75, rom Example 10 triptyline, amitriptylinoxide, butriptyline, clomipramine, and 80 demexiptiline, desipramine, dibenzepin, dimetacrine, dosul 8 5 25, 40, oi DR compartment epin/dothiepin, doxepin, imipramine, imipraminoxide, 50, 60, 75, rom Example 10 and 80 lofepramine, melitracen, metapramine, nitroxazepine, 9 10 25, 40, oi DR compartment nortriptyline, noxiptiline, pipofezine, propizepine, protrip 50, 60, 75, rom Example 10 tyline, or quinupramine. and 80 O 2O 25, 40, oi DR compartment 0179 The present medicaments can optionally be com 50, 60, 75, rom Example 10 bined with one or more dopamine antagonist, e.g., domperi and 80 done, droperidol, haloperidol, chlorpromazine, promethaZ 1 1 25, 40, oi oil or aqueous ine, prochlorperazine, alizapride, or prochlorperazine. 50, 60, 75, iduid-fille and 80 capsule(s) with 0180. The present medicaments can optionally be com DR coating bined with one or more nk1 receptor antagonists, e.g., aprepi 2 2.5 25, 40, oi oil or aqueous tant or casopitant. 50, 60, 75, iduid-fille and 80 capsule(s) with 0181. The present medicaments can optionally be com DR coating bined with one or more antihistamine, e.g., cyclizine, diphen 3 5 25, 40, oi oil or aqueous hydramine dimenhydrinate, meclizine, promethazine, or 50, 60, 75, iduid-fille and 80 capsule(s) with hydroxy Zine. DR coating 0182. The present medicaments can optionally be com 4 10 25, 40, oi oil or aqueous 50, 60, 75, iduid-fille bined with one or more benzodiazepines, e.g., midazolam or and 80 capsule(s) with lorazepam. DR coating 0183 The present medicaments can optionally be com 5 2O 25, 40, oi oil or aqueous bined with one or more anticholinergics, e.g., hyoscine. 50, 60, 75, iduid-fille and 80 capsule(s) with 0184 The present medicaments can optionally be com DR coating bined with one or more or steroids, e.g., dexamethasone. 6 1 25, 40, oi dried solid with 50, 60, 75, DR coating 0185 Examplary Medicaments and 80 0186 By way of example, any of the formulations set forth 7 2.5 25, 40, oi dried solid with in Table 1 can usefully be prepared to provide the PK profile 50, 60, 75, DR coating and 80 of any of PK Profile 1 through PK Profile 19. 8 5 25, 40, oi dried solid with 50, 60, 75, DR coating TABLE 1. and 80 9 10 25, 40, oi dried solid with Examplary Medicanents 50, 60, 75, DR coating and 80 % of 2O 2O 25, 40, oi dried solid with cannabinoid 50, 60, 75, DR coating formu- Total in the IR Dosage and 80 lation Cannabinoid IR. Dosage Compart DR Dosage 21 1 25, 40, crystalline crystalline form i amount (mg) compartment ment Compartment 50, 60, 75, form with DR coating and 80 1 1 25, 40, oi SEDDSDR 22 2.5 25, 40, crystalline crystalline form 50, 60, 75, 50, 60, 75, form with DR coating 8 8O and 80 25, 40, oi SEDDSDR 23 5 25, 40, crystalline crystalline form 50, 60, 75, 50, 60, 75, form with DR coating 8 8O and 80 25, 40, oi SEDDSDR 24 10 25, 40, crystalline crystalline form 50, 60, 75, 50, 60, 75, form with DR coating 8 8O and 80 25, 40, oi SEDDSDR 25 2O 25, 40, crystalline crystalline form 50, 60, 75, 50, 60, 75, form with DR coating 8 8O and 80 25, 40, oi SEDDSDR 26 1 25, 40, SEDDSIR SEDDSDR 50, 60, 75, 50, 60, 75, 8 8O and 80 25, 40, oi DR compartment 27 2.5 25, 40, SEDDSIR SEDDSDR 50, 60, 75, from Example 10 50, 60, 75, 8 8O and 80 US 2012/023 1083 A1 Sep. 13, 2012 18

TABLE 1-continued TABLE 1-continued Examplary Medicaments Examplary Medicanents % of % of cannabinoid cannabinoid formu- Total in the IR Dosage formu- Total in the IR Dosage lation Cannabinoid IR. Dosage Compart- DR Dosage lation Cannabinoid IR. Dosage Compart- DR Dosage i amount (mg) compartment ment Compartment i amount (mg) compartment ment Compartment 28 5 25, 40, SEDDSIR SEDDSDR 50 2O 25, 40, oi osmotic 50, 60, 75, 50, 60, 75, and 80 and 80 29 10 25, 40, SEDDSIR SEDDSDR 51 1 25, 40, 8(OUS osmotic 50, 60, 75, 50, 60, 75, liquid and 80 and 80 30 2O 25, 40, SEDDSIR SEDDSDR 52 2.5 25, 40, 8(OUS osmotic 50, 60, 75, 50, 60, 75, liquid and 80 and 80 31 1 25, 40, crystalline DR compartment 53 5 25, 40, 8(OUS osmotic 50, 60, 75, form from Example 10 50, 60, 75, liquid and 80 and 80 32 2.5 25, 40, crystalline DR compartment S4 10 25, 40, 8(OUS osmotic 50, 60, 75, form from Example 10 50, 60, 75, liquid and 80 and 80 33 5 25, 40, crystalline DR compartment 55 2O 25, 40, 8(OUS osmotic 50, 60, 75, form from Example 10 50, 60, 75, liquid and 80 and 80 34 10 25, 40, crystalline DR compartment 56 1 25, 40, Adsorbate Adsorbate soli 50, 60, 75, form from Example 10 50, 60, 75, solid coated with a DR and 80 and 80 Coating 35 2O 25, 40, crystalline DR compartment 57 2.5 25, 40, Adsorbate Adsorbate soli 50, 60, 75, form from Example 10 50, 60, 75, solid coated with a DR and 80 and 80 Coating 36 1 25, 40, oi crystalline form 58 5 25, 40, Adsorbate Adsorbate soli 50, 60, 75, with DR coating 50, 60, 75, solid coated with a DR and 80 and 80 Coating 37 2.5 25, 40, oi crystalline form 59 10 25, 40, Adsorbate Adsorbate soli 50, 60, 75, with DR coating 50, 60, 75, solid coated with a DR and 80 and 80 Coating 38 5 25, 40, oi crystalline form 60 2O 25, 40, Adsorbate Adsorbate soli 50, 60, 75, with DR coating 50, 60, 75, solid coated with a DR and 80 and 80 Coating 39 10 25, 40, oi crystalline form 61 1 25, 40, Complexation Complexation 50, 60, 75, with DR coating 50, 60, 75, Solid solid coated with and 80 and 80 a DR coating 40 2O 25, 40, oi crystalline form 62 2.5 25, 40, Complexation Complexation 50, 60, 75, with DR coating 50, 60, 75, Solid solid coated with and 80 and 80 a DR coating 41 1 25, 40, 8(OUS solid with DR 63 5 25, 40, Complexation Complexation 50, 60, 75, liquid coating 50, 60, 75, Solid solid coated with and 80 and 80 a DR coating 42 2.5 25, 40, 8(OUS solid with DR 64 10 25, 40, Complexation Complexation 50, 60, 75, liquid coating 50, 60, 75, Solid solid coated with and 80 and 80 a DR coating 43 5 25, 40, 8(OUS solid with DR 65 2O 25, 40, Complexation Complexation 50, 60, 75, liquid coating 50, 60, 75, Solid solid coated with and 80 and 80 a DR coating 44 10 25, 40, 8(OUS solid with DR 66 1 25, 40, Adsorbate Adsorbate soli 50, 60, 75, liquid coating 50, 60, 75, solid in a DR matrix and 80 and 80 45 2O 25, 40, 8(OUS solid with DR 67 2.5 25, 40, Adsorbate Adsorbate soli 50, 60, 75, liquid coating 50, 60, 75, solid in a DR matrix and 80 and 80 46 1 25, 40, oi osmotic 68 5 25, 40, Adsorbate Adsorbate soli 50, 60, 75, 50, 60, 75, solid in a DR matrix and 80 and 80 47 2.5 25, 40, oi osmotic 69 10 25, 40, Adsorbate Adsorbate soli 50, 60, 75, 50, 60, 75, solid in a DR matrix and 80 and 80 48 5 25, 40, oi osmotic 70 2O 25, 40, Adsorbate Adsorbate soli 50, 60, 75, 50, 60, 75, solid in a DR matrix and 80 and 80 49 10 25, 40, oi osmotic 71 1 25, 40, Complexation Complexation 50, 60, 75, 50, 60, 75, Solid solid in a DR and 80 and 80 matrix US 2012/023 1083 A1 Sep. 13, 2012 19

present medicaments containing a cannabinoid in the full TABLE 1-continued range of about 0.1 mg to about 75 mg. 0194 In one embodiment, the invention provides a Examplary Medicaments method of treating apnea comprising administering less than % of about 20 mg of cannabinoid during a therapeutic window cannabinoid taught herein. formu- Total in the IR Dosage lation Cannabinoid IR. Dosage Compart- DR Dosage (0195 Titration i amount (mg) compartment ment Compartment 0196. The skilled artisan will recognize (with the teach ings of this invention) that "optimal dosing of an individual 72 2.5 25, 40, Complexation Complexation is determined by evaluating, among other factors, efficacy 50, 60, 75, Solid solid in a DR and 80 matrix and safety (i.e. the “therapeutic profile'). Through inventor 73 5 25, 40, Complexation Complexation insight, it is apparent that Subjects with certain cannabinoid 50, 60, 75, Solid solid in a DR sensitive disorders may demonstrate an increased-respon and 80 matrix siveness to medicaments of the present invention upon an 74 10 25, 40, Complexation Complexation 50, 60, 75, Solid solid in a DR extended treatment period (e.g. about one week or longer, or and 80 matrix about 2 weeks or longer, or about one month or longer, or 75 2O 25, 40, Complexation Complexation about six months or longer). Taken together, in one embodi 50, 60, 75, Solid solid in a DR ment, the present invention is a titration kit and titration and 80 matrix 76 methods for determining optimal dose. 77 0.197 Subjects are initially administered a low dose of the 78 medicament for a treatment period. At the completion of the 79 treatment period, the dose in the medicament is increased or 81 the number of medicament units is increased (a "step-up') for 82 an additional treatment period. This “escalation' cycle can be repeated multiple times until 1) optimal clinical benefit is achieved, 2) clinically relevant side effects become apparent, 0187. In one embodiment, a medicament comprises a for or 3) until the maximum dose generally considered safe is mulation comprising components set forth in Table 1, except administered. that the total cannabinoid amount is +/-50% (e.g. +/-30% or (0198 Optionally, treatment-related side effects (or trial +/-20%) of that listed in Table 1. related adverse events) are evaluated during treatment peri 0188 Therapeutic Window ods. Relevant evaluations include mental alertness, emotional 0189 Medicaments of the present invention provide a health, quality of life, sleepiness, etc. therapeutic window that is a longer window than provided by 0199 Optionally, a clinically-relevant metric(s) of the dis an immediate release medicament (e.g. as compared to a order or condition being treated is assessed during each treat Marinol capsule containing an equivalent amount of the can ment period. Methods are readily known for quantifying or nabinoid). Examples of useful therapeutic windows provided assessing apnea, pain, spasms, etc. by the present medicaments are about 4 to about 12 hours. 0200 Optionally, an initial “low dose' THC medicament Optionally, useful therapeutic windows provided here are of the present invention can contain about any mg amounts of about 6 to about 10 hours, about 6 to about 9 hours, about 6 to a cannabinoid, e.g. 0.1, 0.5, 1, 2, 5, 10, 20, or 50 (mg). about 8 hours, about 7 to about 8 hours, or about 7 to about 9 0201 Optionally, a treatment period for each dose is about hours. 1 to about 10 days or about 5 to about 10 days, or longer than 0190. Optionally, within an hour or two following the end 10 days. of the therapeutic window, the plasma levels are reduced 0202 A typical step-up dose increase is any percent of below a level that can result in undesired side effects such as about 10, 20, 25, 33, 50, 100, 200, or 400(%). impeded cognitive and/or psychomotor performance, tachy 0203 As a result of the titration study, an empirically cardia, hypotension, or impaired learning and memory. determined dose that is well tolerated (minimal or no signifi (0191 Dosing cant side effects) and optimally effective is selected. This 0.192 Compositions of the present invention comprise selected dose is administered for another period (e.g. 1 or cannabinoids in an amount of about 0.1 mg to about 75 mg or more days or more than 1 week or more than 1 month. optionally about any of the following amounts (in mg): 0.5 to 0204 Optionally, the subject is administered a “step 50, 0.5 to 25, 0.5 to 20, 0.5 to 10, 1 to 15, 1 to 5, 1 to 2.5, 2.5 down lower dose medicament (e.g. about 50% to about 75% to 50, 2.5 to 20. or about 20% to about 50% of the previous dose). A clinically 0193 The unexpected results from the clinical studies relevant metric of efficacy and side effects are assessed. If reported here teach useful doses for populations and for indi therapeutic efficacy is not diminished (over the previous viduals. However, the skilled artisan will readily recognize dose), the Subject can optionally be administered a dose with from these studies that the therapeutic level and side-effect a further reduction (i.e. a second or Subsequent step-down). producing levels of plasma THC can vary within individuals. 0205. In one embodiment, the subject has sleep apnea and For example, while a 10 mg THC medicament of the present is administered a 0.1 or 0.5 mg THC medicament of the invention typically will provide a side-effect sparing efficacy present invention (e.g. 0.5, 1, 1.5, or 2 hrs before anticipated for an extended treatment window, certain individuals will sleep time) for a treatment period. During this treatment have a higher threshold for both therapeutic efficacy and for period, overnight PSG is optionally performed. If the patient side effects. The same is true for certain individuals who will tolerates this dose (e.g. minimal treatment related side have a lower threshold for efficacy and for side effects. There effects), a step-up dose is administered daily for another fore, there is a remarkable and unexpected utility of the treatment period. Therapeutic profile is assessed, and a Sub US 2012/023 1083 A1 Sep. 13, 2012 20 sequent escalation is performed until clinically-relevant side effects are observed or maximal safe dose is administered. TABLE 3-continued 0206. A step-down titration is optionally performed and evaluated. Dronabinol Side Effects Associated with Co-administration of 0207. In one embodiment of the present invention, a kit is Other Drugs provided that contains an appropriate number of one or more Drug Side effects doses of a medicament (otherwise of the same formulation). Fluoxetine A 21 yio female with depression and bulimia The kit optionally contains patient instructions. Optionally, receiving 20 mg/day fluoxetine X 4 wks the doses are in a device that compartmentalizes the daily became hypomanic after Smoking marijuana; doses (e.g. a blisterpack). symptoms resolved after 4 days Antipyrine, barbiturates Decreased clearance of these agents, 0208 Safety presumably via competitive inhibition of 0209 Unexpectedly, it has been discovered that oral metabolism administration exemplary present medicaments maintains a Theophylline Increased theophylline metabolism reported therapeutic window while not resulting in a plasma levels at with Smoking of marijuana; effect any time throughout the treatment window (sleep period) that increase the likelihood of side effects. Such side effect-spar 0211 Utility ing medicaments avoid one or more of the effects shown in 0212. The present methods and medicaments are useful Table 2. for treating cannabinoid-sensitive disorders. 0210 Unexpectedly, it has been discovered that oral 0213. The present methods and medicaments are espe administration of examplary present medicaments maintains cially useful for treatingapnea. Optionally, the apnea is any of a therapeutic window (sleep period) while not resulting in a obstructive sleep apnea syndrome, obstructive sleep apnea/ plasma levels at any time throughout the treatment window hypopnea syndrome, upper airway resistance syndrome, that increase the likelihood of side effects associated with apnea of prematurity, congenital central hypoVentilation syn co-administration of other prescription or over the counter drome, obesity hypoVentilation syndrome, central sleep medicines such as shown in Table 3. apnea syndrome, Cheyne-Stokes respiration, and Snoring. Unexpectedly, the present compositions are useful to reduce TABLE 2 episodes of apnea, Snoring, and sleep disruption, for example as demonstrated by oximetry, or polysomnogram (“PSG”), or Dronabinol Side Effects self assessment. Side Effects 0214. In one embodiment, the administered dose and/or Cardiovascular: Conjunctivitis*, hypotension*., medicament comprises 1 mg to 75 mg (e.g. 2.5 mg to 20 mg). tachycardia, hypotension 0215. At least some of the pharmacological effects of THC Digestive: Diarrhea, fecal incontinence. are exerted through the cannabinoid pathway, by interaction Musculoskeletal: Myalgias. Nervous system: Depression, nightmares, with cannabinoid receptors such as CB1 and/or CB2. Can speech difficulties, tinnitus. nabinoid receptors are found predominantly at nerve termi impeded cognitive and/or nals where they have a role in retrograde regulation of syn psychomotor performance, or aptic function and interact with at least acid (e.g. GABA, impaired learning and memory Skin and Flushing. glutamate), monoamine (e.g. histamine, dopamine, seroto Appendages: nin, noradrenaline) purine (e.g. adenosine, ADP, ATP), pep Special senses: Vision difficulties. tide (e.g. Somatostatin, neuropeptide Y, neurokinin, cholecys tokinin), Vanilloid, prostanoid, opiod and/or other pathways. Incidence of events 0.3% to 1% For example, THCs such as delta-9-tetrahydrocannabinol act as agonists at CB1 and CB2 receptors, mimicking the effects of the naturally occurring endocannabinoids, which modulate TABLE 3 the effects of neurotransmitters. Without being bound by Dronabinol Side Effects Associated with Co-administration of theory, the inventors believe that the methods and medica Other Drugs ments of the present invention exert pharmacological action through modulation of one or more of these pathways. Drug Side effects Indeed, the cannabinoid receptors are concentrated in regions Amphetamines, cocaine, Additive hypertension, tachycardia, possibly of the brain that control functions associated with certain other sympathomimetic cardiotoxicity agents pharmacological effects of cannabinoid modulation (see Atropine, Scopolamine, other anticholinergic agents, Additive or Table 4). antihistamines, Super-additive tachycardia, drowsiness Amitriptyline, amoxapine, Additive tachycardia, hypertension, TABLE 4 desipramine, other tricyclic drowsiness antidepressants Brain Regions in Which Cannabinoid Receptors Are Abundant Barbiturates, benzo Additive drowsiness and CNS depression diazepines, ethanol, Examplary Functions lithium, opioids, Brain Region Associated with Region buspirone, antihistamines, muscle relaxants, other Basal ganglia Movement control CNS depressants Substantia nigra pars Movement control Disulfiram A reversible hypomanic reaction was reported reticulata in a 28 yo man who Smoked marijuana; Entopeduncular nucleus Movement control confirmed by dechallenge and rechallenge Globus pallidus Movement control US 2012/023 1083 A1 Sep. 13, 2012 21

0221. In one embodiment, the present methods and medi TABLE 4-continued caments are useful for treating a mood disorder. Optionally, the movement disorder is a depressive disorder, a bipolar Brain Regions in Which Cannabinoid Receptors Are Abundant disorders, or anxiety. Examplary Functions 0222. In one embodiment, the present methods and medi Brain Region Associated with Region caments are useful for treating pain. Optionally, the pain is Putamen Movement control neurological pain or nociceptive pain. Optionally, the pain is Cerebellum Body movement coordination Hippocampus Learning and memory, stress associated with a movement disorder, a headache, a spasm Cerebral cortex, especially Higher cognitive functions disorder, arthritis, dystonia, peripheral pain, or muscle ach cingulate, ing. For example, treatable pain can be associated with any frontal, and parietal regions Higher cognitive functions disorder Such as fibromyalgia or multiple Sclerosis. Nucleus accumbens Reward center Hypothalamus Body housekeeping functions 0223 Pain that is treatable by the present medicament (body temperature regulation, salt includes pain associated with any of the infections caused by and water balance, reproductive herpes simplex virus type 1 and type 2 and herpes Zoster. function) Amygdala Emotional response, fear 0224 Headaches that are treatable by the present medica Spinal cord Peripheral sensation, including pain ment include any vascular headache, e.g., migraines, cluster Brain stem Sleep and arousal, temperature headache, toxic headache, and headache caused by elevated regulation, motor control blood pressure. Central gray Analgesia 0225 Headaches that are treatable by the present medica Nucleus of the solitary tract Visceral sensation, nausea and ment also include tension headaches, postcoital headaches, vomiting exertional headaches, trigeminal neuralgia, atypical trigemi nal neuralgia, type 2 trigeminal neuralgia, trigeminal auto 0216 Based upon the insight of the inventors, the present nomic cephalalgias, hortons neuralgia, and histamine head methods and medicaments are Surprisingly effective in treat aches, and headaches secondary to head or neck trauma. ing disorders associated with the above-mentioned pathways, 0226. In one embodiment, the present methods and medi brain regions, or pharmacological effects, and other cannab caments are used for appetite stimulation or to treat wasting inoid-sensitive disorders. Accordingly, the invention pro and/or depressed appetite. Optionally the wasting and/or vides a method for treating a cannabinoid-sensitive disorder depressed appetite is associated with HIV. chemotherapy, in a subject comprising administering to the Subject a medi anorexia, or Alzheimer's disease. cament taught herein. Optionally, the cannabinoid-sensitive 0227. In one embodiment, the present methods and medi disorder is a neurological disorder, pain, an appetite or wast caments are useful for treating glaucoma. ing disorder, nausea, vomiting, a seizure disorder, a sleep 0228. In one embodiment, the present methods and medi disorder, breathing disorder, or a sleep-related breathing dis caments are useful for treating nausea and/or vomiting. order. Optionally, the method further comprises administer Optionally, the nausea and/or vomiting is associated with ing an additional therapeutic agent for treating the disorder. viral/microbial illness, HIV/AIDS, cancer, chemotherapy, Optionally, an additional therapeutic agent is included in the radiation exposure, postoperative recovery, pregnancy, medicament. Optionally, the additional therapeutic agent is motion, or poisoning. administered sequentially with the medicament. 0229. In one embodiment, the present methods and medi 0217. In one embodiment, the present methods and medi caments are useful for treating a Subject with a disorder caments are useful for treating a neurological disorder. selected from: anorexia, alcohol use disorders, cancer, amyo Optionally, the neurological disorder is of the brain, spinal trophic lateral Sclerosis, glioblastoma multiforme, glioma, cord, peripheral nerves, or muscles. Optionally, the neuro increased intraocular pressure, glaucoma, inflammatory logical disorder is a neurodegenerative disease, a neurologi bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, cal pain, a movement disorder, or a mood disorder. systemic lupus erythematosus, inflammation, peripheral neu 0218. In one embodiment, the present methods and medi ropathic pain, neuropathic pain associated with post-herpetic caments are useful for treating a neurodegenerative disease. neuralgia, diabetic neuropathy, shingles, burns, actinic kera Optionally, the neurodegenerative disease is multiple Sclero tosis, oral cavity Sores and ulcers, post-episiotomy pain, pso sis, Huntington's disease, or Alzheimer's disease. riasis, pruritis, contact dermatitis, eczema, bullous dermatitis 0219. In one embodiment, the present methods and medi herpetiformis, exfoliative dermatitis, mycosis fungoides, caments are useful for treating a neurological pain. Option pemphigus, severe erythema multiforme (e.g., Stevens ally, the neurological pain is a central or peripheral neurologi Johnson syndrome), seborrheic dermatitis, ankylosing cal pain. Optionally, the neurological pain is chronic pain. spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chon Optionally, the neurological pain is associated with fibromy drocalcinosis, joint pain secondary to dysmenorrhea, fibro algia, multiple Sclerosis, spinal cord injury, or stroke. myalgia, musculoskeletal pain, neuropathic-postoperative 0220. In one embodiment, the present methods and medi complications, polymyositis, acute nonspecific tenosynovi caments are useful for treating a movement disorder. Option tis, bursitis, epicondylitis, post-traumatic osteoarthritis, Syno ally, the movement disorder is caused by abnormalities in the Vitis,juvenile rheumatoid arthritis, major depressive disorder, basal ganglia. Optionally, the movement disorder is a spasm depression, brain cancer, asthma, lung cancer, chronic disorder, muscle spasticity, seizure disorder, chorea, Hun obstructive pulmonary disease, opioid dependence, muscle tington's disease, dystonia, basal ganglia movement disorder, tension, posttraumatic stress disorder, and bipolar disorder. Parkinson's disease, Tourette's syndrome, dyskinesia, 0230. The citations provided herein are hereby incorpo bradykinesia, or epilepsy. rated by reference for the cited subject matter. US 2012/023 1083 A1 Sep. 13, 2012 22

EXAMPLES TABLE 5 Example 1 Arousal Index (Arousals/Hour of Sleep Treatment of Apnea with Marinol Parameter 2.5 mg 10 mg Number of Subjects 17 8 0231. The goal of the clinical trial was to evaluate oral Number of Observations 23 8 dosing of THC in sleep apnea patients. One objective was to Mean Change with -4.8 -2.5 assess low doses of cannabinoids for treatment of apnea. treatment vs Placebo Another objective was to evaluate the therapeutic window of Significance vs Placebo O49 0.79 oral cannabinoid in the treatment of sleep-related disorders Such as apnea. Example 2 0232. The trial comprised a single-center, randomized, double-blind, placebo-controlled dose escalation study of Marinol for Apnea; Comparing Early and Late Treat dronabinol in 22 patients with OSAS. The study began with a ment Windows 7-day baseline/PAP-washout period, with polysomnography 0239. The study from Example 1 was further analyzed (PSG) performed on the final night. Subjects meeting inclu with respect to Arousal Index during the early treatment win sion/exclusion criteria were randomized to either placebo dow (i.e., T-T) and the late treatment window (i.e., Ts-Ts). (N=5) or dronabinol (N=17) treatment. 0233. The study drug (active or placebo) was taken 30 min TABLE 6 before bed for 21 days. Overnight PSG was performed on Arousal Index. Early and Late Treatment Window treatment nights 7, 14 and 21. The initial nightly dose was 2.5 mg and was escalated, as tolerated, to 5 mg on day 8 and to 10 2.5 mg 10 mg mg on day 15 of treatment. A blood sample was drawn imme 1 Half of Night diately after each PSG for assay of the study drug and prin cipal metabolites. Number of Subjects 17 8 Number of 23 8 0234 Sleep/activity/drug logs were maintained daily Observations throughout the study. A Stanford Sleepiness Scale (SSS) was Mean Change with -20.0 -21.9 completed every 2 waking hours for the final two days of each treatment vs Placebo Significance vs Placebo OO67 O.11 7-day baseline or treatment period. 2d Half of Night 0235. The analysis of efficacy endpoints was performed using the Efficacy Evaluable population, defined as: all sub Number of Subjects 17 8 Number of 23 8 jects completing a baseline PSG who received at least one Observations dose of study medication, who did not miss more than 3 doses Mean Change with O6 S.O during, and who completed the PSG ending the first 7-day Treatment vs Placebo treatment period. Safety/tolerability analyses were per Significance vs Placebo O.93 O.S6 formed using the All-Treated population, comprising all Sub jects who received at least one dose of study medication. All efficacy endpoints were assessed as the change from baseline Example 3 measurement of the same parameter. For example, efficacy Marinol for Apnea: 75% Reduction Analysis for AHI was examined by subtracting (for each subject) the 0240. The study from Example 1 was further analyzed AHI measured during PSG at the end of the baseline period with respect to the percentage of Subjects demonstrating a from the AHI measured at the end of the relevant treatment 75% reduction in the AHI for 2-, 4-, 6-, and 8-hour consecu period (in both active and placebo groups). Thus a decrease in tive intervals. As shown in FIG. 1, a dose of 2.5 mg (line with AHI with treatment is represented by a negative value for square data points) resulted in greater than 60% of the sub AAHI (change from baseline). jects showing a 275% reduction (versus baseline) in AHI for at least 2 consecutive hours. In contrast, a dose of 10 mg (line 0236 Results for Arousal Index (arousals per hour of with diamond data points) resulted in fewer than 30% of the sleep) are shown in Table 5. Surprisingly, these data demon subjects showing a 2-hour reduction in AHI of 275%. This strate that oral cannabinoids provide a therapeutic benefit to same phenomenon was seen with respect to a four-hour sleep continuity in apnea patients, even in reduced amounts. response interval. Thus, for a 2 and 4 hour treatment window, For example, these data Support treatment by administering 2.5 mg of Marinol was more effective in these patients than a oral doses of less than 70 mg. 60 mg. or even less than 50 mg. 10 mg dose. In contrast to the expected sigmoidal dose such as 0.1, 0.5, 1.0, or 2.5 mg-20 mg doses. response curve that typifies most drug therapies, THC effect 0237 Surprisingly, these data also demonstrate that sleep on cannabinoid-sensitive disorders such as apnea is consis apnea may be treated with orally administered cannabinoids tent with a non-monotonic response of the inverted U. Thus, without causing (or without Substantially causing) side a Superior medicament of the present invention produces a effects associated with certain cannabinoids and/or without threshold plasma THC concentration but does not reach the causing (or without Substantially causing) side effects once decreasing response portion of the dose curve. the Subject has awoken (e.g. post treatment window). Example 4 0238. These results, and those of the subsequent Examples, also Support the applicants invention of methods Marinol for Apnea: Dose and Time Dependence of treating sleep apnea with a reduced dose (e.g. about 0.1- 0241 The study from Example 1 was further analyzed for about 20 mg) of an immediate release cannabinoid. efficacy and dose response of THC with respect to AHI during US 2012/023 1083 A1 Sep. 13, 2012

early (To-T) and late (Ts-Ts) treatment windows. In the pharmacokinetic parameters include one or more of plasma results are shown in FIG. 2; the early treatment window is concentration and AUC (at various times). indicated by stippled bars and the late treatment window is indicated by solid bars. Example 7 0242. The orally administered instant release cannabinoid Oral Dosing Comparator 1 provided remarkable efficacy during the early treatment win dow. Consistent with Example 3, these results further unex 0250) An oral dosing “comparator” is provided by orally pectedly show that 2.5 mg of Marinol was superior to 10 mg administering an immediate release dosage of cannabinoid which was Superior to 5 mg. In contrast, in the late treatment (e.g. MARINOLR softgel). window, 10 mg of Marinol was Superior to 2.5 mg and 5 mg. 0251. The therapeutic response is assessed. AHI is Furthermore, based on the immediate but transient therapeu improved in Subjects receiving 1 to 75 mg. For Subjects tic effect of the immediate release doses, additional therapeu receiving lower doses of THC (e.g. 5 mg-20 mg), the AHI tic efficacy can be provided by adding a delayed-release com revealed a period of therapeutic efficacy following a latency ponent to an immediate release component. Thus, these data period. The therapeutic window does not consistently extend indicate that a Surprising therapeutic benefit is provided by through the seventh or eighth hour of sleep. medicaments of the present invention, for example, a medi cament which provides a PK profile of PK Profile 1 or any of Example 8 PK Profile 2 through PK Profile 19. Oral Dosing Comparator 2 Example 5 0252) A second oral dosing comparator is provided by the method of Example 6, where a first immediate release dosage Marinol for Apnea: Establishing the Therapeutic of cannabinoid (e.g. 2.5 mg MARINOLR softgel) to a sleep Window apnea patient 30 minutes before bed at T. The patient is allowed to fall asleep and at a predetermined time, the subject 0243 The apnea-hypopnea index (AHI) during a treat is briefly woken to receive a second immediate release dosage ment window was calculated for two examplary patients of MARINOLR soft gel (e.g. at T) and allowed to return to (“JB' and “SM) for hours T-T (RDI1-2), T-T (RDI1-2), sleep. T-T (RDI1-2), and T-Ts (RDI1-2). The patients had each 0253) The therapeutic response is assessed. AHI is taken a single 2.5 mg dose of Marinol 30 minutes before bed. improved in Subjects receiving 1 to 75 mg. For Subjects The results, as shown in FIG.3, are of the baseline (lines with receiving lower doses of THC (e.g. 5 mg-20 mg), the AHI diamond data points) and the treatment (lines without sym reveals a period of therapeutic efficacy following a latency bols). A single 2.5 mg immediate release dose of cannabinoid period. The therapeutic window generally extends through (Marinol) provided a significant therapeutic effect during an the seventh or eighth hour of sleep. early treatment window but provided a reduced therapeutic effect during a late treatment window. These data are consis Example 9 tent with the arousal index data presented in Table 6. 0244 Based on the immediate but transient therapeutic Predictable Plasma Levels effect of the immediate release dosage, these results Support 0254 FIG. 4 depicts the relationship of Cmax (ng/ml) and the formulation for a combined immediate and delayed-re cannabinoid amount (mg) for an immediate release dosage lease medicament. compartment (Marinol formulation). As can be seen from 0245. These results further support the superior therapeu FIG. 4, given the drug dose, plasma levels such as Cmax are tic efficacy of the PK profiles and present medicaments for predictable from an immediate release dosage compartment. apnea patients throughout a normal sleeping period. Example 10 Example 6 In-Vitro Dissolution Assays Oral Dosing 0255. The rate of extraction of a drug such as a cannab inoid from a medicament is a key contributor to the resulting 0246 For the purpose of comparing oral medicaments PK profile. One method of tailoring a medicament to a desired (i.e., providing a comparator), a medicament is orally admin PK profile involves the use of an in-vitro dissolution assay istered to one or more Subjects. The various factors affecting that mimics or approximates the conditions experienced by ADME (absorption, distribution, metabolism, and excretion) the drug in the GI tract. This assay can be used to predict the of the drug are standardized. For example, the patient is rate and/or efficiency of drug extraction after administration. optionally a fasted patient and optionally falls asleep within 0256 Any dissolution assay is useful when tailoring the one of 15 minutes or 30 minutes of laying down for bed. The PK profile of a medicament. Various assays are known, for same Subjects are used for comparing different medicaments example, USP Apparatus 1 (basket), 2 (paddle), 3 (recipricat (after providing an appropriate wash-out period). ing cylinder), and 4 (flow-through cell). In these assays, a 0247 Plasma levels of the drug (e.g. THC) and metabo medicament is placed in an appropriate medium (or media) lites thereof (e.g. 11-OH-THC) are taken at regular intervals and the medicament is evaluated by sampling the medium (or (e.g. every 30 minutes) during a treatment window (e.g. from media) periodically and determining the fraction or percent of To to Ts). drug dissolved or released at each sampling time. 0248. Therapeutic responses are recorded throughout the 0257 An examplary dissolution method follows. Using entire treatment window. USP Apparatus II (paddles) evaluate the medicament for 2 0249. Therapeutic responses are correlated with pharma hours in 750 mL of 0.1 NHC1. Operate the rotation speed at cokinetic parameters of the drug or metabolites thereof. The 50-75 RPM in medium held at 37 C. At two hours add 125 mL US 2012/023 1083 A1 Sep. 13, 2012 24 of previously heated 0.2M Sodium Phosphate Tribasic and adjust the pH to 6.0 with 2N HC1 or 2N NaOH. Evaluate the TABLE 7 medicament in this medium for 2 hours (total time 2 to 4 hours). At 4 hours, add an additional 125 mL of previously Pellet in Capsule (IR+DR) heated 0.2MSodium Phosphate Tribasic and adjust pH to 6.8 10 mg Dronabinol (or other THC) Capsule to 7.4 with 2N HC1 or 2N NaOH. Evaluate the drug from 4 to No. Ingredient mg capsule % Wiw 6 hours in this final medium. Note that a surfactant or solvent may be necessary in order to obtain appropriate sink condi mmediate Release Pellets/Compartment tions. 1 Dronabinol 2.5 1.16 Sodium Lauryl Sulfate 2.5 1.16 3 Neusilin US2 (Magnesium 2O.O 9.30 Example 11 Aluminometasilicate) Medicament: Immediate Release (IR) plus Delayed 4 Avicel PH101 (Microcrystalline 2S.O 11.63 Release (DR) Compartments Cellulose) SubTota SO.O 23.3 0258. A medicament is provided comprising a delayed Delayed Release Pellets/Compartment release compartment and an immediate release compartment. 5 Dronabinol 7.5 3.49 By example, the delayed release compartment is an aqueous 6 Sodium Lauryl Sulfate 7.5 3.49 or semi-aqueous liquid compartment comprising: 7 Neusilin US2 (Magnesium 6O.O 27.91 0259 a) cannabinoid (e.g. 9-THC)— from about 2 to Aluminometasilicate) 8 Avicel PH101 (Microcrystalline 75.0 34.88 about 10 mg/ml (e.g. about 5 mg/ml); Cellulose) 0260 b) ethanol from 15% to about 65% (e.g. about 9 Ethylcellulose (Aquacoat ECD30% 11.4 5.30 45%); wiw dispersion) 0261 c) propylene glycol from about 0.1 to about 25% 10 Dibutyl Sebecate 3.6 1.67 (e.g. about 5%); SubTota 16S.O 76.7 0262 d) polyethylene glycol from about 1% to about 25% (e.g. about 10%); Total Capsule Fill Weight 21S.O 1OOO 0263 e) buffered (e.g. pH 7) aqueous solution (e.g. phos phate buffer) from about 10% to about 60% (e.g. about (0272. Manufacturing Process for Dronabinol 10% w/w 37%); and Pellets. These pellets represent an immediate release com 0264 f) a viscosity modifier (e.g. hydroxypropyl cellu partment when uncoated and a delayed release compartment lose) in a viscosity modifying amount (e.g. about 0.3%). when coated. Mixtures of the two in a capsule shell provide 0265 Based on the profile data shown in FIG.5 for such a for a combination of immediate- and delayed-release com delayed release compartment (reproduced from FIG. 6 of US partments. The ratio of the two pellets types allows for varia 2009/0181080), a medicament of the present invention is tion in weighting of the dose fraction between the two com produced by combining the delayed release compartment partments. This example uses a 2.5 mg dose in the immediate with one or more additional compartments (e.g. an immediate release compartment and a 7.5 mg dose in the delayed release release compartment) to provide a PK profile of at least one of compartment. PK Profile 1 through PK Profile 19. (0273 A) Dissolve Dronabinol (1+5) in Ethanol (200 0266. With the teaching here, the skilled artisan can now proof) in a suitable tank and mixer. modify this type of formulation to meet the target PK profile. 0274 B) Disperse Sodium Lauryl Sulfate (2+6) into For example, the following modification approaches are use (A). Continue to mix. ful: 0275 C) Charge Neusilin (3+7) to a high shear granu 0267 Adjust drug to release modifier ratio lator. 0268 Adjust concentration of viscosity modifier (typi 0276 D) While mixing the Neusilin, add the dispersion cally increasing the concentration slows release) from (B). Mix until (B) is suitably dispersed. 0269. Adjust the grade of the viscosity modifier (using 0277 E). Transfer the wet contents of the high shear a higher molecular weight polymer typically slows granulator to a tray dryer. release) (0278 F) Dry at 50 C (+/-10 C) to remove the Ethanol. 0270. Use different viscosity modifiers (separate mate (0279 G) Collect the dried material from the trays and rial or combinations of materials) pass through a No. 20 mesh screen to deagglomerate. 0280 H) Charge the Dronabinol-Loaded Neusilin (G) Example 12 to a high shear granulator. 0281 I) Charge the required quantity of Avicel PH101 Medicament: Plurality of Pellets, Continuous (4+8) to the high shear granulator. Release 0282 J) Mix the contents in the high shear granulator 0271. A medicament is provided comprising a delayed for 5 minutes. release compartment and an immediate release compartment 0283 K) While mixing, add sufficient purified water to contained within the same dose unit. By example, the imme Wet maSS. diate release compartment is a plurality of Solid pellets (or 0284 L) Transfer the wet mass (K) to a suitable cold microspheres) and the delayed release compartment is a plu mass extruder fitted with a dome screen of suitable size rality of Solid pellets comprising a delayed release modifier (e.g. 0.8 mm-1.2 mm). coating. 0285 M) Extrude the wet mass to collect strands. US 2012/023 1083 A1 Sep. 13, 2012 25

0286 N) Load the collected strands (M) into a compartment is a Solid matrix layer comprising release modi marumerizer. Operate the marumerizer to produce pel fying agents. The medicament provided in this Example is a lets. solid, adsorbate to facilitate solids handling of dronabinol and 0287 O) Extrude/marumerize the entire wet mass (K) incorporation into the Solid phase immediate- and delayed from the high shear granulator. release compartments. The delayed-release compartment (0288 P) Transfer the wet pellets (O) to a fluid bed or releases portions of the dronabinol dose over time in a con tray dryer and dry. tinuous manner. (0289 Q) Collect the dried pellets (P) from the dryer into a Suitable container. TABLE 8 0290 R) Using screens, collect pellets that pass through a No. 18 mesh screen but are retained on a No. 30 mesh Bilayer/Matrix Tablet SCC. 10 mg Dronabinol (or other THC) Tablet 0291 Dronabinol DR Pellets 0292 S) Prepare the required quantity of Ethylcellulose No. Ingredient mg tablet % Wiw Coating Dispersion by adding the Dibutyl Sebecate to Immediate Release Layer/Compartment Aquacoat in a suitable tank with mixer. 1 Dronabinol 2.5 O.61 0293 T) Stir the Aquacoat/Dibutyl Sebecate dispersion 2 Sodium Lauryl Sulfate 2.5 O.61 for not less than 30 minutes. 3 Fujicalin (Dicalcium Phosphate Anhydrous) SO.O 12.14 4 Prosolv SMCC 90HD (Silicified 39.5 9.59 0294 U) Add sufficient purified water to dilute (T) to a Microcrystalline Cellulose) 20% w/w dispersion. Mix the dispersion continuously. 5 Croscarmellose Sodium S.O 1.21 0295 V) Charge the required quantity of Dronabinol 6 Magnesium Stearate O.S O.12 10% w/w Pellets (18-30 mesh) to a fluid bedcoater with bottom spray and a Wurster column insert. SubTotal 1OOO 24.27 0296 W) Apply a 10% weight gain of Ethylcellulose Delayed Release Layer/Compartment Coating Dispersion (U) to the fluidized pellets. 7 Dronabinol 7.5 1.82 0297 X) Allow the pellets to dry in the fluid bed coater 8 Sodium Lauryl Sulfate 7.5 1.82 for 15 to 30 minutes after the completion of coating. 9 Fujicalin (Dicalcium Phosphate Anhydrous) 1SO.O 36.41 10 Prosolv SMCC 90HD (Silicified 42.O 10.19 0298 Y) Collect the Dronabinol DR Pellets from the Microcrystalline Cellulose) fluid bed coater. 11 Methocel K4M Premium DC (Hypromellose 90.0 21.84 0299 Encapsulation Type 2208) 0300 Z) Using a suitable encapsulator, fill suitably sized 12 Colloidal Silicon Dioxide 1.5 O.36 two piece hard capsule shells with 50 mg of Dronabinol IR 13 Magnesium Stearate 1.5 O.36 10% w/w Pellets (18-30 mesh) and 165mg of Dronabinol DR SubTotal 3OO.O 72.82 Pellets. Outer Trade Dress Coating (Non release modifying) 0301 Modifications. 0302. With the teaching here, the skilled artisan can now 14 Opadry Colored Coating System - PVA 12.0 2.91 modify this type of formulation to meet the target PK profile. Based For example, the following modification approaches are use Total Tablet Weight 412.O 1OOOO ful: 0303 Adjust drug to surfactant ratio 0304. Use different surfactants 0312 Manufacturing Process for Dronabinol Loading 0305 Adjust weight gain of ethylcellulose coating onto Fujicalin (Adsorbate Formation) (typically higher weight gains decrease drug release) 0313 A) Dissolve Dronabinol (1+7) in Ethanol (200 (0306 Use a film modifier (e.g. the addition of proof) in a suitable tank with a mixer. hypromellose in an ethylcellulose film increases diffu 0314 B) Disperse Sodium Lauryl Sulfate (2+8) into sion or can change the rate of release by making it more (A). Continue to mix. hydrophilic) 0315 C) Charge Fujicalin (3+9) to a high shear granu 0307 Adjust the quantity or types offilm additives such lator. as the plasticizer 0316 D) While mixing the Fujicalin, add the dispersion 0308 Use a different film forming polymer from (B). Mix until (B) is suitably dispersed. 0309 Use combinations of different polymers (can add 0317 E). Transfer the wet contents of the high shear enteric polymers to ethylcellulose to increase diffusion granulator to a tray dryer. as the pH of the GI tract increases) 0310. Use post coating drying/curing to affect film 0318 F) Dry at 50 C (+/-10 C) to remove the Ethanol. properties 0319 G) Collect the dried material from the trays and pass through a No. 20 mesh screen to deagglomerate. Example 13 0320 H) Store in an HPDE drum double lined with PE bags and desiccants as required. Bilayer/Matrix Tablet 0321) Immediate Release Layer Blend/Compartment. The 0311. A medicament is provided comprising a delayed prepared powder blend provides immediate release of the release compartment and an immediate release compartment dronabinol from the compressed tablet. contained with the same dose unit. By example, the immedi 0322 I) Charge the required quantity of the Dronab ate release compartment is a distinct solid matrix layer with inol-Loaded Fujicalin (H) into a tumble blender after out release modifying excipients and the delayed release passing through a No. 20 mesh screen. US 2012/023 1083 A1 Sep. 13, 2012 26

0323 J) Charge the required quantity of Prosolv (4) to 0347 Modifications. the tumble blender after passing through a No. 20 mesh 0348 With the teaching here, the skilled artisan can now SCC. modify this type of formulation to meet the target PK profile. 0324 K) Close the blender and blend for 15 minutes. For example, the following modification approaches are use 0325 L) Open the blender and charge the required ful: quantity of CroScarmellose Sodium (5) after passing 0349 Adjust the ratio of the rate controlling matrix through a No. 20 mesh screen. excipient (typically increasing concentration slows release) 0326 M) Close the blender and blend for 5 minutes. 0350 Adjust the grade or type of matrix excipient (typi 0327 N) Open the blender and charge the required cally increasing molecular weight of the polymer slows quantity of Magnesium Stearate (6) after passing release) through a No. 20 mesh screen. 0351. Use different types of rate controlling matrix 0328 O) Close the blender and blend for 2 minutes. excipients (polymers, waxes, etc.) 0329 P) Collect the IR Layer Blend (O) from the 0352. Adjust the geometry of the tablet (tablet shapes blender into an HDPE drum double lined with PE bags the minimize their surface area to volume ratio slow and desiccants as required. drug release) 0330 Delayed Release Layer Blend/Compartment. The 0353 Adjust tablet properties (adjusting the porosity of prepared powder blend provides for a delayed release of the tablet by making them harder (less porous) or softer dronabinol from the compressed tablet using Methocel as a (more porous) affects release rate) rate modifying excipient. 0354 Use post compression curing to affect release 0331 Q) Charge the required quantity of the Dronab (e.g. can heat tablets prepared with a wax to modify inol-Loaded Fujicalin (H) into a tumble blender after release) passing through a No. 20 mesh screen. 0355 Can apply a release modifying coating over the 0332 R) Charge the required quantity of Prosolv (10) entire dosage form to add additional options and Methocel (11) to the tumble blender after passing through a No. 20 mesh screen. Example 14 0333 S) Close the blender and blend for 15 minutes. Medicament: 2 Pulse, Enteric Coating 0334 T) Open the blender and charge the required 0356. A medicament is provided comprising a delayed quantity of Colloidal Silicon Dioxide (12) after passing release compartment and an immediate release compartment through a No. 20 mesh screen. contained within the same dose unit. By example, the imme 0335 U) Close the blender and blend for 5 minutes. diate release compartment is a plurality of Solid pellets (or 0336 V) Open the blender and charge the required microspheres) and the delayed release compartment is a plu quantity of Magnesium Stearate (13) after passing rality of Solid pellets comprising a delayed release modifier through a No. 20 mesh screen. (pH dependent, enteric coating). The medicament provided in 0337 W) Close the blender and blend for 2 minutes. this example is a solid, adsorbate to facilitate Solids handling 0338 X) Collect the DR Layer Blend (W) from the of dronabinol and incorporation into a solid phase immediate blender into an HDPE drum double lined with PE bags and delayed-release compartment. The delayed-release com and desiccants as required. partment releases the entire dose of the dronabinol when the 0339 Tablet Compression. As instructed below, the imme pH of the gastrointestinal tract is sufficiently alkaline (e.g. diate release compartment comprises 25% of the total dose pH>5.5) to dissolve the coating. Since the coating is insoluble (e.g. 2.5 mg), and the delayed release compartment comprises in acidic conditions, the delayed release compartment is 75% of the total dose (e.g. 7.5 mg). The combination of the released in the small intestine unlike the immediate release two layers provides for both distinct IR and DR compart compartment which releases in the stomach. ments in a tablet. 0340 Y) Using a dual/bi-layer tablet press, compress TABLE 9 tablets containing 100 mg of the IR Layer Blend/Com Pellet in Capsule - (IR + DR) partment and 300 mg of the DR Layer Blend/Compart 10 mg Dronabinol (or other THC) Capsule ment. No. Ingredient mg capsule % wiw (0341 Z) Collect the Dronabinol 10 mg Tablets into HDPE drums lined with PE bags and desiccants as Immediate Release Pellets/Compartment required. 1 Dronabinol 2.5 1.12 0342 Tablet Coating (Non-release modifying trade dress) 2 Sodium Lauryl Sulfate 2.5 1.12 0343 A.A) Prepare the Opadry Coating System as an 3 Neusilin US2 (Magnesium 2O.O 8.99 Aluminometasilicate) 18% w/w dispersion in water using a suitable tank and 4 Avicel PH101 (Microcrystalline Cellulose) 2SO 11.24 mixer. 0344 AB) Load the Dronabinol 10 mg Tablets (Z) into SubTotal SO.O 22.47 a suitable tablet coater. Delayed Release Enteric Coated Pellets/Compartment 0345 AC) Apply a 3% weight gain of the Opadry Coat 5 Dronabinol 7.5 3.37 ing dispersion to the tablets. 6 Sodium Lauryl Sulfate 7.5 3.37 7 Neusilin US2 (Magnesium 6O.O 26.97 (0346 AD) Collect the coated tablets from the tablet Aluminometasilicate) coater into HDPE drums lined with PE bags and desic 8 Avicel PH101 (Microcrystalline Cellulose) 75.0 33.71 cants as required. US 2012/023 1083 A1 Sep. 13, 2012 27

0376 Dronabinol DR Pellets TABLE 9-continued 0377 S) Prepare the required quantity of Methacrylic Acid Copolymer Coating Dispersion by adding the Tri Pellet in Capsule - (IR+DR) ethyl Citrate to Eudragit L30D-55 in a suitable tank with 10 mg Dronabinol (or other THC) Capsule mixer. No. Ingredient mg capsule % wiw 0378. T) Stir the Eudragit/Triethyl Citrate dispersion for not less than 30 minutes. 9 Methacrylic Acid Copolymer, Type C 13.2 5.93 (Eudragit L3OD-55 30% w/w dispersion) 0379 U) Disperse the required quantity of talc in suffi 10 Triethyl Citrate 2.7 1.21 cient purified water to provide a final solids content of 11 Talc 6.6 2.97 the coating Suspension at 15% W/w. 0380 V) Combine the Eudragit/Triethyl Citrate disper SubTotal 172.5 77.53 sion and the talc/water dispersion. Mix the dispersion Total Capsule Fill Weight 222.5 1OOO continuously. 0381 W) Charge the required quantity of Dronabinol 10% w/w Pellets (18-30 mesh) to a fluid bedcoater with 0357 Manufacturing Process for Dronabinol 10% w/w bottom spray and a Wurster column insert. Pellets. These pellets represent an immediate release com 0382 X) Apply a 15% weight gain of Methacrylic Acid partment when uncoated and a delayed release compartment Coating Dispersion (W) to the fluidized pellets. when coated. Mixtures of the two in a capsule shell provide 0383 Y) Allow the pellets to dry in the fluid bed coater for a combination of immediate- and delayed-release com for 15 to 30 minutes after the completion of coating. partments. The ratio of the two pellets types allows for varia 0384 Z) Collect the Dronabinol DR Pellets from the tion in weighting of the dose fraction between the two com fluid bed coater. partments. This example uses a 2.5 mg dose in the immediate (0385 Encapsulation release compartment and a 7.5 mg dose in the delayed release 0386 AA) Using a suitable encapsulator, fill suitably compartment. sized two piece hard capsule shells with 50 mg of Dron 0358 A) Dissolve Dronabinol (1+5) in Ethanol (200 abinol IR 10% w/w Pellets (18-30 mesh) and 172.5 mg proof) in a suitable tank and mixer. of Dronabinol DR Pellets. 0359 B) Disperse Sodium Lauryl Sulfate (2+6) into (0387 Modifications. (A). Continue to mix. (0388 With the teaching here, the skilled artisan can now 0360 C) Charge Neusilin (3+7) to a high shear granu modify this type of formulation to meet the target PK profile. lator. For example, the following modification approaches are use 0361 D) While mixing the Neusilin, add the dispersion ful: from (B). Mix until (B) is suitably dispersed. 0389 For enteric coatings, increasing coating weight 0362 E) Transfer the wet contents of the high shear gain can be used to blunt release granulator to a tray dryer. 0390 Use different polymers or polymer grades to adjust trigger points (i.e. Eudragit L30D-55/L100-55 is 0363 F) Dry at 50 C (+/-10 C) to remove the Ethanol. meant to release at pH>5.5, Eudragit L100 at pH>6, 0364 G) Collect the dried material from the trays and Eudragit FS30D at pH>7.2, Eudragit S100 at pH>7.4 pass through a No. 20 mesh screen to deagglomerate. while HPMCAS-L at pH>5.5, HPMCAS-M at pH>6.0, 0365 H) Charge the Dronabinol-Loaded Neusilin (G) and HPMCAS-H at pH>6.8). Eudragit is based on meth to a high shear granulator. acrylic acid while HPMCAS is based upon hypromel 0366 I) Charge the required quantity of Avicel PH101 lose acetate Succinate. Other enterics include cellulose (4+8) to the high shear granulator. acetate phthalate, polyvinyl acetate phthalate, shellac, 0367 J) Mix the contents in the high shear granulator and others. for 5 minutes. 0391) Use release modifiers in enteric films to modify 0368 K) While mixing, add sufficient purified water to release further Wet maSS. 0392 Use alternative film additives (e.g. alternative 0369 L) Transfer the wet mass (K) to a suitable cold plasticizer and glidants) mass extruder fitted with a dome screen of suitable size (e.g. 0.8 mm-1.2 mm). Example 15 0370 M) Extrude the wet mass to collect strands. Medicament: 3 Pulse, Enteric Coating 0371 N) Load the collected strands (M) into a marumerizer. Operate the marumerizer to produce pel 0393 A medicament is provided comprising 2 delayed lets. release compartments and an immediate release compartment within the same dose unit. By example, the immediate release 0372 O) Extrude/marumerize the entire wet mass (K) compartment contains solid pellets (or microspheres) and the from the high shear granulator. delayed release compartments each have solid pellets com 0373) P) Transfer the wet pellets (O) to a fluid bed or prising different delayed release modifier (pH dependent, tray dryer and dry. enteric) coatings. The medicament provided in this example 0374 Q) Collect the dried pellets (P) from the fluid bed is a solid, adsorbate to facilitate solids handling of dronabinol dryer into a Suitable container. and incorporation into a solid phase immediate- and delayed 0375 R) Using screens, collect pellets that pass through release compartment. a No. 18 mesh screen but are retained on a No. 30 mesh 0394. Upon administration, the IR compartment releases SCC. the dronabinol and the DR. compartment releases its dose of US 2012/023 1083 A1 Sep. 13, 2012 28 dronabinol when the pH of the gastrointestinal tract is suffi 0399. D) While mixing the Neusilin, add the dispersion ciently alkaline (e.g. pH>5.5 and pH>7.2) to dissolve the from (B). Mix until (B) is suitably dispersed. different coatings (e.g. DR1 and DR2, respectively). Since 04.00 E) Transfer the wet contents of the high shear the coatings are insoluble in acidic conditions, the delayed granulator to a tray dryer. release compartments release in the upperportion of the Small 04.01 F) Dry at 50 C (+/-10 C) to remove the Ethanol. intestine and in the lower portion of the small intestine/large 0402 G) Collect the dried material from the trays and intestine, respectively, unlike the immediate release compart pass through a No. 20 mesh screen to deagglomerate. ment which releases in the stomach. 0403 H) Charge the Dronabinol-Loaded Neusilin (G) to a high shear granulator. TABLE 10 0404 I) Charge the required quantity of Avicel PH101 Pellet in Capsule - (IR + DR1 + DR2) (4+8-F15) to the high shear granulator. 10 mg Dronabinol (or other THC) Capsule 04.05 J) Mix the contents in the high shear granulator for 5 minutes. No. Ingredient mg capsule % wiw 0406 K) While mixing, add sufficient purified water to Immediate Release Pellets/Compartment Wet maSS.

1 Dronabinol 2.5 1.12 0407 L). Transfer the wet mass (K) to a suitable cold 2 Sodium Lauryl Sulfate 2.5 1.12 mass extruder fitted with a dome screen of suitable size 3 Neusilin US2 (Magnesium 2O.O 8.99 (e.g. 0.8 mm-1.2 mm). Aluminometasilicate) 0408 M) Extrude the wet mass to collect strands. 4 Avicel PH101 (Microcrystalline Cellulose) 2S.O 11.24 04.09 N) Load the collected strands (M) into a SubTotal SO.O 22.5 marumerizer. Operate the marumerizer to produce pel Delayed Release Enteric Coated Pellets/Compartment (DR1) lets. 5 Dronabinol S.O 2.25 0410 O) Extrude/marumerize the entire wet mass (K) 6 Sodium Lauryl Sulfate S.O 2.25 from the high shear granulator. 7 Neusilin US2 (Magnesium 40.O 17.98 0411 P) Transfer the wet pellets (O) to a fluid bed or Aluminometasilicate) 8 Avicel PH101 (Microcrystalline Cellulose) SO.O 22.47 tray dryer and dry. 9 Methacrylic Acid Copolymer, Type C 8.8 3.96 0412 Q) Collect the dried pellets (P) from the fluid bed (Eudragit L3OD-55 30% w/w dispersion) dryer into a suitable container. 10 Triethyl Citrate 1.8 O.81 0413 R) Using screens, collect pellets that pass through 11 Talc 4.4 1.98 a No. 18 mesh screen but are retained on a No. 30 mesh SubTotal 115.0 51.7 SCC. Delayed Release Enteric Coated Pellets/Compartment (DR2) 0414 Dronabinol DR1 Pellets 12 Dronabinol 2.5 1.12 0415 S) Prepare the required quantity of Methacrylic 13 Sodium Lauryl Sulfate 2.5 1.12 Acid Copolymer Coating Dispersion by adding the Tri 14 Neusilin US2 (Magnesium 2O.O 8.99 ethyl Citrate to Eudragit L30D-55 in a suitable tank with Aluminometasilicate) mixer. 15 Avicel PH101 (Microcrystalline Cellulose) 2S.O 11.24 16 Eudragit FS3OD (30% w/w dispersion) 7.0 3.15 0416 T) Stir the Eudragit/Triethyl Citrate dispersion 17 Triethyl Citrate O.2 O.09 for not less than 30 minutes. 18 Glycerol Monostearate O.3 O.13 0417 U) Disperse the required quantity of talc in suffi SubTotal 57.5 25.8 cient purified water to provide a final solids content of the coating Suspension at 15% W/w. Total Capsule Fill Weight 222.5 1OOO 0418 V) Combine the Eudragit/Triethyl Citrate disper sion and the talc/water dispersion. Mix the dispersion 0395. Manufacturing Process for Dronabinol 10% w/w continuously. Pellets. These pellets represent an immediate release com 0419 W) Charge the required quantity of Dronabinol partment when uncoated and delayed release compartments 10% w/w Pellets (18-30 mesh) to a fluid bedcoater with when coated with different enteric polymers. Mixtures of the bottom spray and a Wurster column insert. three in a capsule shell provide for a combination of imme 0420 X) Apply a 15% weight gain of Methacrylic Acid diate-(IR) and delayed-release compartments (DR1 and Coating Dispersion (W) to the fluidized pellets. DR2). The ratio of the three pellets types allows for variation 0421. Y) Allow the pellets to dry in the fluid bed coater in weighting of the dose fraction between the two main com for 15 to 30 minutes after the completion of coating. partments (e.g. IR and DR) with further refinement in the DR 0422 Z) Collect the Dronabinol DR1 Pellets from the compartment (e.g. DR1 and DR2). This example uses a 2.5 fluid bed coater. mg dose in the immediate release compartment and a 7.5 mg 0423 Dronabinol DR2Pellets dose in the delayed release compartment (5.0 mg dose in DR1 0424 AA) Prepare the required quantity of Eudragit and 2.5 mg dose in DR2). FS30D Coating Dispersion. 0396 A) Dissolve Dronabinol (1+5+12) in Ethanol 0425 BB) Combine the required quantity of purified (200 proof) in a suitable tank and mixer. water (sufficient to provide a final solids content of 20% 0397 B) Disperse Sodium Lauryl Sulfate (2+6+13) into W/w), triethylcitrate, and glycerol monostearate. (A). Continue to mix. 0426 CC) Heat the water/triethyl citrate/glycerol 0398 C) Charge Neusilin (3+7+14) to a high shear monostearate dispersion to 50 C-60C. Use a high shear granulator. homogenizer to mix. US 2012/023 1083 A1 Sep. 13, 2012 29

0427 DD) Allow dispersion (CC) to cool to <30 C with mixing then combine with required quantity of Eudragit TABLE 11-continued FS30D. Mix throughout coating. 0428 EE) Charge the required quantity of Dronabinol Two Pulsef Coated Soft Gels 10% w/w Pellets (18-30 mesh) to a fluid bedcoater with 10 mg Dronabinol Capsules bottom spray and a Wurster column insert. g100 g Coating 0429 FF) Apply a 15% weight gain of Eudragit FS30D No. Ingredient Suspension Coating Dispersion (EE) to the fluidized pellets. 4 Triethyl Citrate 1.8 0430 GG) Allow the pellets to dry in the fluid bed 5 Talc 4.4 coater for 15 to 30 minutes after the completion of coat 6 Purified Water 64.4 1ng. 0431 HH) Collect the Dronabinol DR2Pellets from the 0439 Preparation of Coating Suspension for the DR Com fluid bed coater. ponent 0432 Encapsulation 0440 A) Combine Eudragit L30D-55 (3) and Triethyl 0433 II) Using a suitable encapsulator, fill suitably Citrate (4). Stir for at least 30 minutes. sized two piece hard capsule shells with 50 mg of Dron 0441 B) In a separate container, disperse the Talc (5) abinol IR 10% w/w Pellets (18-30 mesh), 115 mg of into sufficient Purified Water (6) to provide a final solids Dronabinol DR1 Pellets, and 57.5 mg of Dronabinol content of 15% in the coating dispersion with a high DR2Pellets. shear homogenizer. 0434 Modifications. 0442 C) Pour the Purified Water/Talc Dispersion into 0435 With the teaching here, the skilled artisan can now the Eudragit/Triethyl Citrate Dispersion with stirring. modify this type of formulation to meet the target PK profile. 0443 D) Make sufficient coating suspension for the For example, the following modification approaches are use target batch size. 0444 Coating of Substrate ful: 0445 E) Charge the required quantity of Marinol Cap 0436 The modifications set forth in Example 14 Sule 5 mg (2) into a perforated pan coating machine. 0437 Combine an IR pellet with an enteric coated pellet 0446 F) Apply the Coating Suspension to a target and a delayed release pellet like in Example 12 weight gain of 10%. 0447 Preparation of Final Medicament Example 16 0448 G) In a suitably sized two piece hard capsule, shell combine one immediate release capsule unit (1) Medicament: Two Pulse Enteric Coating and one DR enteric coated capsule unit (F). 0449 H) Close the capsule shell. 0438 A medicament is provided comprising a delayed 0450 Modifications. release compartment and a separate immediate release com 0451. With the teaching here, the skilled artisan can now partment contained within the same dose unit or package. By modify this type of formulation to meet the target PK profile. example, the immediate release compartment is liquid com For example, the following modification approaches are use partment and the delayed release compartment is a liquid ful: compartment comprising a delayed release modifier (pH 0452 Varying the properties of the starting substrate as dependent, enteric) coating. The delayed-release compart set forth in Example 11. ment in this example is prepared by coating a liquid compart 0453 Adjust coatings as set forth in Example 12 and ment with an enteric polymer. The delayed-release compart Example 14. ment releases the entire dose of the dronabinol when the pH of 0454 Combine with other DR components as set forth the gastrointestinal tract is sufficiently alkaline (e.g. pH>5.5) in Example 15. to dissolve the coating. Since the coating is insoluble in acidic conditions, the delayed release compartment is released in the Example 17 Small intestine unlike the immediate release liquid compart ment which releases in the stomach. Medicament: IR/DR (Monolithic/Matrix Tablet, Continuous) TABLE 11 0455. Here, a medicament is provided comprising a Two Pulsef Coated Soft Gels delayed release compartment and an immediate release com 10 mg Dronabino Capsules partment contained within the same dose unit. This example g/100g Coating also illustrates a contiguous release dosage form of the No. Ingredient Suspension present invention. 0456. The release modification here, in part, is due to Immediate Release Capsule Unit Compartment spatial localization of the cannabinoid within the dosage 1 Marinol Capsule 5 mg (NDC 0051-0022-21) form. Thus, the IR compartment is localized to the perimeter Enteric Coated Capsule Unit Delayed-Release Compartment (and immediate Sub-perimeter or periphery) of the dosage Substrate form and the DR compartment is localized within or interior to the dosage form. The drug in the IR compartment is not 2 Marinol Capsule 5 mg (NDC 0051-0022-21) Enteric Coating substantially buried within the release modifying matrix The 3 Methacrylic Acid Copolymer, Type C 29.4 total dose contained with the medicament is continuously (Eudragit L3OD-55 30% w/w dispersion) released. This is another example of a solid adsorbate type dosage form of the present invention. US 2012/023 1083 A1 Sep. 13, 2012 30

0478 R) Load the Dronabinol 10 mg Tablets (P) into a TABLE 12 suitable tablet coater. 0479. S) Apply a 3% weight gain of the Opadry Coating Monolithic/Matrix Tablet (IR/DR) 10 mg Dronabinol (or other THC) Tablet dispersion to the tablets. 0480 T) Collect the coated tablets from the tablet coater No. Ingredient mg tablet % wiw into HDPE drums lined with PE bags and desiccants as Core Matrix Tablet (IR/DR Compartment) required. 0481 Modifications. 1 Dronabinol 1O.O 2.43 2 Sodium Lauryl Sulfate 1O.O 2.43 0482. With the teaching here, the skilled artisan can now 3 Fujicalin (Dicalcium Phosphate Anhydrous) 2OO.O 48.54 modify this type of formulation to meet the target PK profile. 4 Prosolv SMCC 90HD (Silicified 98.0 23.79 For example, the following modification approaches are use Microcrystalline Cellulose) ful: 5 Methocel K4M Premium DC (Hypromellose 8O.O 1942 Type 2208) 0483 Adjust ratio of drug to excipients 6 Magnesium Stearate 2.0 O49 0484 Adjust ratio of rate controlling excipients to non rate controlling excipients SubTotal 400.O 97.1 0485 Adjust properties of rate controlling excipients Outer Trade Dress Coating (Non release modifying) (e.g. molecular weight for polymers) 7 Opadry Colored Coating System - PVA 12.0 2.91 0486 Combine rate controlling excipients (e.g. Based Hypromellose Type 2208 15,000 cps grade with 100, Total Tablet Weight 412.O 1OOO 000 cps grade, etc.) 0487 Change rate controlling excipients (e.g. different polymers, different type of material Such as a wax) 0457. Manufacturing Process for Dronabinol Loading 0488. Manipulate porosity of tablet (e.g. make it harder onto Fujicalin (Adsorbate Formation) or softer) 0458 A) Dissolve Dronabinol (1) in Ethanol (200 0489. Manipulate tablet geometry proof) in a suitable tank with a mixer. 0459 B) Disperse Sodium Lauryl Sulfate (2) into (A). 0490 Apply an outer release modifying coating Continue to mix. 0491. Make adsorbate using a material that further 0460 C) Charge Fujicalin (3) to a high shear granulator. manipulates release of drug substance 0461 D) While mixing the Fujicalin, add the dispersion from (B). Mix until (B) is suitably dispersed. Example 18 0462 E) Transfer the wet contents of the high shear Medicament: IR/DR (Monolithic, Coated Tablet, granulator to a tray dryer. Continuous) 0463 F) Dry at 50 C (+/-10 C) to remove the Ethanol. 0464 G) Collect the dried material from the trays and 0492. A medicament is provided comprising a delayed pass through a No. 20 mesh screen to deagglomerate. release compartment and an immediate release compartment 0465 H) Store in an HPDE drum double lined with PE contained within the same dose unit. The IR and DR com bags and desiccants as required. partments are spatially oriented within a "continuous release' 0466 Core Matrix Tablets (IR/DR Compartment) tablet as was also illustrated in Example 17. 0467 I) Charge the required quantity of the Dronab 0493. This medicament is another example of a solid, inol-Loaded Fujicalin (H) into a tumble blender after adsorbate-type and of a coated DR compartment type dosage passing through a No. 20 mesh screen. form. 0468 J) Charge the required quantity of Prosolv (4) and Methocel (5) to the tumble blender after passing through TABLE 13 a No. 20 mesh screen. 0469 K) Close the blender and blend for 15 minutes. Monolithic? Coated Tablet 0470 L) Open the blender and charge the required 10 mg Dronabinol (or other THC) Tablet quantity of Magnesium Stearate (6) after passing No. Ingredient mg tablet %w/w through a No. 20 mesh screen. 0471 M) Close the blender and blend for 2 minutes. Core Tablet 0472. N) Collect the Powder Blend (M) from the 1 Dronabinol 1O.O 2.49 2 Sodium Lauryl Sulfate 1O.O 2.49 blender into an HDPE drum double lined with PE bags 3 Fujicalin (Dicalcium Phosphate Anhydrous) 2OO.O 49.85 and desiccants as required. 4 Prosolv SMCC 90HD (Silicified 98.3 24.50 0473] Tablet Compression Microcrystalline Cellulose) 0474 O) Using a tablet press, compress tablet matrix 5 Hydropropyl Cellulose (Klucel LF) 2O.O 4.99 cores at a target tablet weight of 400 mg. 6 Magnesium Stearate 1.7 O.42 0475 P) Collect the Dronabinol 10 mg Tablets into Controlled Release Coating (IR/DR Compartment) HDPE drums lined with PE bags and desiccants as 7 Ammonio Methacrylate Copolymer, Type A 7.5 1.87 required. (Eudragit RL30D 30% Dispersion) 8 Ammonio Methacrylate Copolymer, Type B 22.5 S.61 0476 Tablet Coating (Non-Release Modifying Trade (Eudragit RS30D 30% Dispersion) Dress) 9 Triethyl Citrate 6.O 1...SO 0477 Q) Prepare the Opadry Coating System as an 18% 10 Talc 1S.O 3.74 W/w dispersion in water using a suitable tank and mixer. US 2012/023 1083 A1 Sep. 13, 2012

0518 U) Charge the required quantity of Dronabinol 10 TABLE 13-continued mg tablet cores to a suitable tablet pan coater. 0519 V.) Apply a 15% weight gain of Ammonio Meth Monolithic? Coated Tablet 10 mg Dronabinol (or other THC) Tablet acrylate Copolymer Coating Dispersion (T) to the tablet COCS. No. Ingredient mg tablet %w/w 0520 W) Allow the coated tablets to dry in the tablet coater for an additional period of time before applying Outer Trade Dress Coating (Non release modifying) the Outer Trade Dress Coating. 11 Opadry Colored Coating System - PVA 10.2 2.54 0521 Tablet Coating (Non-release modifying trade dress) Based 0522 X) Prepare the Opadry Coating System as an 18% Total Tablet Weight 4012 1OOO W/w dispersion in water using a suitable tank and mixer. 0523 Y) Apply a 3% weight gain of the Opadry Coating 0494. Manufacturing Process: Dronabinol Loading onto to the Controlled Release coated tablets (W). 0524 Z) Collect the coated tablets from the tablet coater Fujicalin (Adsorbate Formation) into HDPE drums lined with PE bags and desiccants as 0495 A) Dissolve Dronabinol (1) in Ethanol (200 required. proof) in a suitable tank with a mixer. 0496 B) Disperse Sodium Lauryl Sulfate (2) into (A). 0525 Modifications. Continue to mix. 0526 With the teaching here, the skilled artisan can now 0497 C) Charge Fujicalin (3) to a high shear granulator. modify this type of formulation to meet the target PK profile. 0498 D) While mixing the Fujicalin, add the dispersion For example, the following modification approaches are use from (B). Mix until (B) is suitably dispersed. ful: 0499 E) Transfer the wet contents of the high shear 0527 Manipulate the coating as set forth in Example 12 granulator to a tray dryer. 0528. Alter properties of core tablet to provide for an (0500 F) Dry at 50 C (+/-10 C) to remove the Ethanol. osmotic 0501 G) Collect the dried material from the trays and pass through a No. 20 mesh screen to deagglomerate. Example 19 (0502. H) Store in an HPDE drum double lined with PE bags and desiccants as required. Medicament: IR/DR (Monolithic/Matrix Tablet, 0503 Blend for Compression Continuous) 0504 I) Charge the required quantity of the Dronab inol-Loaded Fujicalin (H) into a tumble blender after 0529. A medicament is provided comprising a delayed passing through a No. 20 mesh screen. release compartment and an immediate release compartment 0505 J) Charge the required quantity of Prosolv (4) and contained within the same dose unit. The IR and DR com Hydroxypropyl cellulose (5) to the tumble blender after partments are spatially oriented within a "continuous release' passing through a No. 20 mesh screen. tablet as was also illustrated in Example 17 and Example 18. (0506 K) Close the blender and blend for 15 minutes. 0530. The medicament provided in this Example 19 is a 0507 L) Open the blender and charge the required Solid, co-precipitate type formulation where the co-precipi quantity of Magnesium Stearate (6) after passing tate facilitates solids handling of dronabinol and incorpora through a No. 20 mesh screen. tion into a solid medicament (e.g. tablet). (0508 M) Close the blender and blend for 2 minutes. (0509 N) Collect the Powder Blend (M) from the TABLE 1.4 blender into an HDPE drum double lined with PE bags Monolithic Matrix Tablet and desiccants as required. 10 mg Dronabinol (or other THC) Tablet 0510 Core Tablet Compression 0511 O) Using a tablet press, compress tablet cores at a No. Ingredient mg tablet % wiw target tablet weight of 340 mg. Core Matrix Tablet (IR/DR Compartment) 0512 P) Collect the Dronabinol 10 mg Tablets into 1 Dronabinol 1O.O 2.72 HDPE drums lined with PE bags and desiccants as 2 Polyvinyl Caprolactam-PolyvinylAcetate- 90.0 24.46 required. Polyethylene Glycol Graft Copolymer (Soluplus) 0513 Controlled Release Coating (IR/DR Compartment) 3 Lactose Monohydrate 7O.O 1903 0514 Q) Prepare the required quantity of Ammonio 4 Microcrystalline Cellulose 7O.O 1903 Methacrylate Copolymer Coating Dispersion by adding 5 PolyvinylAcetate/Polyvinylpyrrollidone 11O.O 29.90 (Kollidon SR) the Triethyl Citrate to a mixture of Eudragit RL30D and 6 Colloidal Silicon Dioxide 3.6 O.98 Eudragit RL30D in a suitable tank with mixer. 7 Magnesium Stearate 3.6 O.98 0515 R) Stir the Eudragit/Triethyl Citrate dispersion SubTotal 357.2 97.1 for not less than 30 minutes. Outer Trade Dress Coating (Non release modifying) 0516 S) Disperse the required quantity of talc in suffi 7 Opadry Colored Coating System - PVA 10.7 2.91 cient purified water to provide a final solids content of Based the coating Suspension at 15% W/w. 0517. T) Combine the Eudragit/Triethyl Citrate disper Total Tablet Weight 367.9 1OOO sion and the talc/water dispersion. Mix the dispersion continuously. US 2012/023 1083 A1 Sep. 13, 2012 32

0531 Manufacturing Process: Spray Drying Dronabinol with SoluPlus (Coprecipitate Formation) TABLE 1.5 0532 A) Dissolve Dronabinol (1) and Soluplus (2) in Ethanol (200 proof) in a suitable tank with a mixer. Pellet in Capsules (IR/DR) 0533 B) Spray dry the dronabinol/Soluplus solution. 10 mg Dronabinol (or other THC) Capsule 0534 C) Collect the spray dried powder and dry in a No. Ingredient mg capsule % wiw vacuum oven at approximately 30 C to remove residual Core Matrix Pellets (IR/DR Compartment) ethanol. 0535 Roller Compaction 1 Dronabinol 1O.O 4.OO 2 Cellulose Acetate Butyrate (CAB 381-0.5) 177.5 71.OO 0536. D) Blend Spray Dried Dronabinol (C) with Lac 3 Triacetin 12.5 S.OO tose Monohydrate (3), Microcrystalline Cellulose (4), 4 Low Substituted Hydroxypropyl Cellulose SO.O 2O.OO and Kollidon SR (5) in a tumble mixer for 25 minutes. 0537 E). Add one-half of the required quantity of each Target Fill Weight 2SO.O 1OOO colloidal silicon dioxide (6) and magnesium Stearate (7) and continue blending in the tumble mixer for 5 minutes. 0555. Manufacturing Process: Melt Extrusion with Cellu 0538 F) Roller compact the powder blend (E) and pass lose Acetate Butyrate (Coprecipitate Formation) the compacted ribbons through a suitable mill (i.e. 0556 A) Dissolve Dronabinol (1) and Triacetin (3) in Comil, Fitzmill, or oscillating granulator) to form gran Ethanol (200 proof) in a suitable tank with a mixer. ules. 0557 B) Using a melt extruder (ie twin screw with 0539 Core Matrix Tablets (IR/DR Compartment) liquid feed addition port and vent station), prepare the (0540 G) Collect the milled granulate (F) and blend with dronabinol matrix pellets. the remaining quantity of colloidal silicon dioxide (6) 0558 C) Meter the cellulose acetate butyrate (2) and and magnesium Stearate (7) in a tumble mixer for 5 low Substituted hydroxypropyl cellulose (4) using loss minutes. in weight feeders into the extruder. 0541 H) Using a tablet press, compress tablet cores at a 0559 D) Meter the dronabinol/triacetin/ethanol solu target tablet weight of 357.2 mg. tion into the extruder downstream of the powder feed (0542 I) Collect the Dronabinol 10 mg Tablets into and upstream of the vent station. HDPE drums lined with PE bags and desiccants as 0560 E) Extrude molten mixture using heat and screw required. shear through a rod die. 0543 Tablet Coating (Non-release modifying trade dress) 0561 F) Process the cylindrical extrudate into pellets 0544 J) Prepare the Opadry Coating System as an 18% using a rotary cutter. W/w dispersion in water using a suitable tank and mixer. 0562 G) Collect the pellets. 0545 K) Load the Dronabinol 10 mg Tablets (I) into a 0563 H). Using a suitable encapsulator, fill suitably suitable tablet coater. sized two piece hard capsule shells with 250 mg of melt 0546 L) Apply a 3% weight gain of the Opadry Coating extruded pellets. dispersion to the tablets. 0564) Modifications. 0565 With the teaching here, the skilled artisan can now (0547 M) Collect the coated tablets from the tablet modify this type of formulation to meet the target PK profile. coater into HDPE drums lined with PE bags and desic For example, the following modification approaches are use cants as required. ful: 0548 Modifications. 0566. Adjust ratio of drug to excipients 0549. With the teaching here, the skilled artisan can now modify this type of formulation to meet the target PK profile. 0567 Adjust ratio of non-rate controlling excipients to For example, the following modification approaches are use rate controlling excipients ful: 0568. Use different polymers or polymer grades 0550 Use different materials to prepare coprecipiate 0569. Use different processing aids (e.g. different plas (e.g. Sugar alcohols to make a glass, etc.) ticizers if needed) 0570. Use different fillers to manipulate release 0551. Manipulate the matrix as set forth in Example 17 0571 Vary pellet size to modify release (smaller pellets 0552. Use enteric polymers to make matrix tablets typically release faster) 0572 Can compress pellets into a tablet to create a Example 20 singular dosage unit like in Example 17 and Example 19 Medicament-Pellet Type, Continuous Release-Type Example 21 0553 A medicament is provided comprising a delayed release compartment and an immediate release compartment Medicament: Monolithic/Matrix Tablet, Continuous contained within the same plurality of pellets in the dose unit. 0573 This is another example of the present medicaments The IR and DR compartments are spatially oriented within a of the monolithic/matrix-type. The dosage unit is designed to “continuous release” tablet as was also illustrated in Example swell in the stomach after ingestion and be retained for suf 17. Example 18, and Example 19. ficient quantity of time while continuously releasing the dose. 0554. The medicament provided in this Example is a solid, This is another example where the IR and DR compartments coprecipitate to facilitate solids handling of dronabinol and can be defined spatially. This is also another example of a incorporation into a plurality of pellets. useful “solid adsorbate” type dosage form. US 2012/023 1083 A1 Sep. 13, 2012

0597 T) Collect the coated tablets from the tablet coater TABLE 16 into HDPE drums lined with PE bags and desiccants as required. Monolithic/Matrix Tablet (IR/DR) - Gastroretentive 0598. Modifications. 10 mg Dronabinol (or other THC) Tablet 0599. With the teaching here, the skilled artisan can now No. Ingredient mg tablet % wiw modify this type of formulation to meet the target PK profile. For example, the following modification approaches are use Core Matrix Tablet (IR/DR Compartment) ful: 1 Dronabinol 1O.O 1.63 0600 See adjustments to matrix tablets as set forth in 2 Sodium Lauryl Sulfate 1O.O 1.63 Example 17 3 Fujicalin (Dicalcium Phosphate Anhydrous) 2OO.O 32.68 4 Polyethylene Oxide (Polyox N-6OK) 7O.O 11.44 0601 Add materials to make dosage form float (i.e. 5 Polyethylene Oxide (Polyox N-80) 3O4.O 49.67 disintegrants, effervescent salts) 6 Magnesium Stearate 6.O O.98 0602 Adjust tablet size and shape SubTotal 600.O 98.0 Outer Trade Dress Coating (Non release modifying) Example 22 7 Opadry Colored Coating System - PVA Based 12.0 1.96 Medicament: Monolithic/Matrix Tablet, Continuous Release Total Tablet Weight 612.O 1OOO 0603 This is another example of a monolithic/matrix-type tablet of the present invention. 0574. Manufacturing Process: Dronabinol Loading onto Fujicalin (Adsorbate Formation) TABLE 17 (0575 A) Dissolve Dronabinol (1) in Ethanol (200 proof) in a suitable tank with a mixer. Monolithic/Matrix Tablet (IR/DR) (0576 B) Disperse Sodium Lauryl Sulfate (2) into (A). 10 mg Dronabinol (or other THC) Tablet Continue to mix. 0577 C) Charge Fujicalin (3) to a high shear granulator. No. Ingredient mg tablet % wiw 0578 D) While mixing the Fujicalin, add the dispersion Core Matrix Tablet (IR/DR Compartment) from (B). Mix until (B) is suitably dispersed. 1 Dronabinol 1O.O 2.27 (0579 E) Transfer the wet contents of the high shear 2 Hydroxypropyl Beta Cyclodextrin 1SO.O 33.98 granulator to a tray dryer. 3 Lactose Monohydrate 75.0 16.99 0580 F) Dry at 50 C (+/-10 C) to remove the Ethanol. 4 Microcrystalline Cellulose 75.0 16.99 5 Hypromellose (Methocel K100M Premium 11O.O 24.92 0581 G) Collect the dried material from the trays and DC) pass through a No. 20 mesh screen to deagglomerate. 6 Colloidal Silicon Dioxide 4.3 0.97 0582 H) Store in an HPDE drum double lined with PE 7 Magnesium Stearate 4.3 0.97 bags and desiccants as required. 0583 Core Matrix Tablets (IR/DR Compartment) SubTotal 428.6 97.1 0584) I) Charge the required quantity of the Dronab Outer Trade Dress Coating (Non release modifying) inol-Loaded Fujicalin (H) into a tumble blender after 8 Opadry Colored Coating System - PVA 12.9 2.92 passing through a No. 20 mesh screen. Based 0585 J) Charge the required quantity of Polyox N-60K (4) and Polyox N-80 (5) to the tumble blender after Total Tablet Weight 441.5 1OOO passing through a No. 20 mesh screen. 0586 K) Close the blender and blend for 15 minutes. 0604 Manufacturing Process: Spray Drying Dronabinol 0587 L) Open the blender and charge the required with Cyclodextrin (Complex Formation) quantity of Magnesium Stearate (6) after passing 0605 A) Dissolve Dronabinol (1) and Hydroxypropyl through a No. 20 mesh screen. Beta Cyclodextrin (2) in Ethanol (200 proof) in a suit 0588 M) Close the blender and blend for 2 minutes. able tank with a mixer. 0589 N) Collect the Powder Blend (M) from the 0606 B) Spray dry the dronabino1/cyclodextrin solu blender into an HDPE drum double lined with PE bags tion. and desiccants as required. 0607 C) Collect the spray dried powder and dry in a 0590 Tablet Compression vacuum oven at approximately 30 C to remove residual 0591 O) Using a tablet press, compress tablet cores at a ethanol. target tablet weight of 600 mg. 0608 Roller Compaction 0592 P) Collect the Dronabinol 10 mg Tablets into 0609 D) Blend Spray Dried Dronabinol (C) with Lac HDPE drums lined with PE bags and desiccants as tose Monohydrate (3), Microcrystalline Cellulose (4), required. and Methocel (5) in a tumble mixer for 25 minutes. 0593 Tablet Coating (Non release modifying) 0610 E) Add one-half of the required quantity of each 0594 Q) Prepare the Opadry Coating System as an 18% colloidal silicon dioxide (6) and magnesium Stearate (7) W/w dispersion in water using a suitable tank and mixer. and continue blending in the tumble mixer for 5 minutes. 0595 R) Load the Dronabinol 10 mg Tablets (P) into a 0611 F) Roller compact the powder blend (E) and pass suitable tablet coater. the compacted ribbons through a suitable mill (i.e. 0596 S) Apply a 3% weight gain of the Opadry Coating Comil, Fitzmill, or oscillating granulator) to form gran dispersion to the tablets. ules. US 2012/023 1083 A1 Sep. 13, 2012 34

0612 Core Matrix Tablets (IR/DR Compartment) 0631 6) Perform the in vitro dissolution test of step (2), 0613 G) Collect the milled granulate (F) and blend with the PK modeling of step (3), and the comparison of step the remaining quantity of colloidal silicon dioxide (6) (4). Repeat as necessary to obtain a predicted (modeled) and magnesium stearate (7) in a tumble mixer for 5 pK profile that approximates the target pK profile. minutes. 0632 7) Performan in vivo PKanalysis of the final test 0614 H) Using a tablet press, compress tablet cores at a medicament on a study population that is representative target tablet weight of 428.6 mg. of the target patient population. When the target patient 0615) I) Collect the Dronabinol 10 mg Tablets into population is sleep apnea, the medicament can be HDPE drums lined with PE bags and desiccants as administered during a given window before bed (e.g. 30 required. mins), for example, as detailed in Example 1. Blood 0616) Tablet Coating (Non release modifying) samples can be obtained at regular intervals to measure 0617 J) Prepare the Opadry Coating System as an 18% cannabinoid and/or metabolite levels throughout the W/w dispersion in water using a suitable tank and mixer. window of the test subject's sleep without waking the 0618 K) Load the Dronabinol 10 mg Tablets (I) into a test subject (using, e.g. a heparin lock cannula). suitable tablet coater. 0633) 8) Compare the observed in vivo PK profile to the 0619 L)Apply a 3% weight gain of the Opadry Coating target PK profile. Modify the final test medicament as dispersion to the tablets. necessary by repeating the above steps. 0620 M) Collect the coated tablets from the tablet We claim: coater into HDPE drums lined with PE bags and desic 1. A medicament comprising a cannabinoid partitioned in cants as required. an immediate release compartment and in a delayed release 0621 Modifications. compartment wherein the cannabinoid is present in an 0622. With the teaching here, the skilled artisan can now amount of about 1 to about 75 mg and optionally wherein modify this type of formulation to meet the target PK profile. when administered to a human subject, the medicament pro For example, the following modification approaches are use vides a PK Profile of any one of PK Profiles 1-20. ful: 2. The medicament of claim 1 wherein about 25% to about 0623) Adjust complexation agent (e.g. different substi 90% of the cannabinoid is in the immediate release dosage tutions and types of cyclodextrins) compartment, optionally wherein about 25% to about 75% of 0624 Adjust the matrix tablet as set forth in Example the cannabinoid is in the immediate release dosage compart 17. ment. 3. The medicament of claim 2 wherein the delayed release Example 23 compartment is a solid dosage compartment. 4. The medicament of claim 3 wherein the solid dosage PK Profile Tailoring compartment is a lipid dosage compartment, a coprecipiate 0625. The present invention provides medicaments which compartment, an adsorbate compartment, a sugar glass com produce superior PK profiles. The medicaments of the present partment, a crystalline cannabinoid, a solubilizing compart invention can be produced using a wide variety of formulation ment, or an osmotic compartment. types and manufacturing processes and are not limited to any 5. The medicament of claim 3 wherein the solid dosage specific recipe. With the teachings provided herein, the compartment is an osmotic compartment comprising a core skilled artisan can now, without undue experimentation, pro comprising the cannabinoid and an expandable polymer; a duce medicaments which produce a desired PK profile (e.g. semipermeable membrane surrounding the core; and a pas any of PK profiles 1-19). For example, a medicament of the sageway disposed in the semipermeable membrane. present invention can be produced by: 6. The medicament of claim 2 wherein the delayed release 0626) 1) Produce one or more medicaments according dosage compartment is a semi-solid dosage compartment. to the present invention which, based upon the teaching 7. The medicament of claim 6 wherein the semi-solid dos here, is predicted to provide the target (desired) PK age compartment is a SEDDS dosage compartment. profile (the “test” medicaments'). 8. The medicament of claim 7 wherein the SEDDS dosage 0627 2) Perform an in vitro dissolution test on the test compartment comprises an oily medium, at least one surfac medicaments and an immediate release cannabinoid tant, and a semi-solid inducer. medicament (the "comparator”) with a known PK pro 9. The medicament of claim 1 wherein the immediate file, such as a Marinol capsule (e.g. as detailed in release dosage compartment is a liquid immediate release Example 10); compartment 0628 3) Based upon the results of the in vitro dissolu 10. The medicament of claim 9 wherein the liquid imme tion assay of the test medicament and the comparator diate release compartment comprises a lipophilic medium or medicament, predict the pK of the test medicament oil. using pK modeling as is generally well known by the 11. The medicament of claim 10 wherein the lipophilic skilled artisan. medium or oil is cottonseed oil, sesame oil, coconut oil or 0629 4) Compare the target PK profile with the pre peanut oil. dicted test medicament PK profile. 12. The medicament of claim 1 wherein the delayed release 0630) 5) Based upon any deviation between the target compartment is a liquid compartment, a solid compartment, profile and the predicted (modeled) test medicament PK or a semi-solid compartment and wherein the delayed release profile, modify the test medicament according to the compartment comprises a delayed release coating. teachings here to better approximate the target PK pro 13. The medicament of claim 12 wherein the delayed file (the final test medicament). release coating is a cellulosic polymer or an acrylic polymer. US 2012/023 1083 A1 Sep. 13, 2012

14. The medicament of claim 1 wherein the delayed release (c) optionally administering a third dose of the medicament compartment is a liquid or semi-solid compartment in the for a third treatment period wherein the third dose is form of a soft-gel, a hard-gel, or a plurality of microparticles. increased compared to the second dose; 15. The medicament of claim 1 wherein the delayed release compartment is a solid dosage compartment in the form of a (d) if step c is performed, optionally administering a fourth tablet or a plurality of microparticles. dose of the medicament for a fourth treatment period 16. The medicament of dosage form of claim 1 wherein the wherein the fourth dose is increased compared to the delayed release compartment is any one of the second dosage third dose; compartments of Table 1. (e) if step d is performed, optionally administering a fifth 17. The medicament of claim 1 wherein, the cannabinoid is dose of the medicament for a fifth treatment period dronabinol. wherein the fifth dose is increased compared to the 18. The medicament of claim 1 wherein the cannabinoid is fourth dose; in an amount of about 0.5 to about 25 mg. (f) if step e is performed, optionally administering a sixth 19. A method of treating a cannabinoid-sensitive disorder comprising administering to a subject in need thereof the dose of the medicament for a sixth treatment period medicament of claim 17. wherein the sixth dose is increased compared to the fifth 20. A method of establishing an optimal dose of a medica dose; and ment for a Subject with a cannabinoid-sensitive disorder com (g) if step f is performed, optionally administering a sixth prising the steps of: dose of the medicament for a sixth treatment period (a) administering a first dose of the medicament for a first wherein the sixth dose is increased compared to the fifth treatment period; dose, (b) administering a second dose of the medicament for a wherein the medicament is a medicament of claim 1. second treatment period wherein the second dose is increased compared to the first dose; c c c c c