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WO2011063164A2 - Médicaments de cannabinoïde à libération prolongée - Google Patents

Médicaments de cannabinoïde à libération prolongée Download PDF

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Publication number
WO2011063164A2
WO2011063164A2 PCT/US2010/057302 US2010057302W WO2011063164A2 WO 2011063164 A2 WO2011063164 A2 WO 2011063164A2 US 2010057302 W US2010057302 W US 2010057302W WO 2011063164 A2 WO2011063164 A2 WO 2011063164A2
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WIPO (PCT)
Prior art keywords
medicament
compartment
cannabinoid
dose
optionally
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PCT/US2010/057302
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English (en)
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WO2011063164A3 (fr
Inventor
David Carley
Peter Letendre
Kenton Fedde
John Koleng
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Steady Sleep Rx Co., Inc.
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Application filed by Steady Sleep Rx Co., Inc. filed Critical Steady Sleep Rx Co., Inc.
Publication of WO2011063164A2 publication Critical patent/WO2011063164A2/fr
Publication of WO2011063164A3 publication Critical patent/WO2011063164A3/fr
Priority to US13/474,666 priority Critical patent/US20120231083A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to cannabinoid compositions and methods of treating cannabinoid-sensitive disorders (e.g. apnea) with cannabinoids.
  • cannabinoid-sensitive disorders e.g. apnea
  • Sleep-related breathing disorders are characterized by repetitive reduction in breathing (hypopnea), cessation of breathing (apnea), or a continuous or sustained reduction in ventilation (hypoventilation).
  • sleep apnea is defined as an intermittent cessation of airflow at the nose and mouth during sleep.
  • apneas of at least 10 seconds in duration have been considered important, but in most individuals, the apneas are 20-30 seconds in duration and may be as long as 2-3 minutes. While there is some uncertainty as to the minimum number of apneas that should be considered clinically important, by the time most individuals come to attention of the medical community they have at least 10 to 15 events per hour of sleep.
  • apneas have been classified into three types: central, obstructive, and mixed.
  • central sleep apnea the neural drive to all respiratory muscles is transiently abolished.
  • obstructive sleep apneas airflow ceases despite continuing respiratory drive because of occlusion of the oropharyngeal airway.
  • Mixed apneas which comprise a central apnea followed by an obstructive component, are a variant of obstructive sleep apnea. The most common type of apnea is obstructive sleep apnea.
  • hypopneas Although airflow persists during hypopneas, like apneas they are associated with reduced oxygen levels in the arterial blood and/or arousals from sleep. Apneas and hypopneas are viewed as carrying equal clinical significance. Because airflow persists, hypopneas are not classified as either central or obstructive.
  • OSAS Obstructive sleep apnea syndrome
  • Habitual heavy snoring which is an almost invariant feature of OSAS, has been described in up to 24% of middle aged men, and 14% of similarly aged women, with even greater prevalence in older subjects.
  • Obstructive sleep apnea syndrome's definitive event is the occlusion of the upper airway, frequently at the level of the oropharynx.
  • the resultant apnea generally leads to a progressive-type asphyxia until the individual is briefly aroused from the sleeping state, thereby restoring airway patency and thus restoring airflow.
  • Central sleep apnea is less prevalent as a syndrome than OSAS, but can be identified in a wide spectrum of patients with medical, neurological, and/or
  • central sleep apnea is transient abolition of central drive to the ventilatory muscles.
  • the resulting apnea leads to a primary sequence of events similar to those of OSAS.
  • Several underlying mechanisms can result in cessation of respiratory drive during sleep. First are defects in the metabolic respiratory control system and respiratory neuromuscular apparatus. Other central sleep apnea disorders arise from transient instabilities in an otherwise intact respiratory control system.
  • Adenotonsillectomy appears to be an effective cure for OSAS in many children, but upper airway surgery is rarely curative in adult patients with OSAS.
  • Surgical "success" is generally taken to be a 50% reduction in apnea incidence and there are no useful screening methods to identify the individuals that would benefit from the surgery versus those who would not derive a benefit.
  • an oral dosage that is effective yet minimizes undesirable effects (e.g. of inducing psychotropic responses).
  • a medicament that provides therapeutic efficacy for a period of time roughly equivalent to a typical human sleep period (e.g. about 6 to 8 hours) and that doesn't require repeated dosage through that period.
  • an oral medicament that allows the subject to wake from sleep without residual side effects that negatively impact wakefulness and alertness without other known affects such as an overly-stimulated appetite.
  • the present invention provides new compositions (medicaments) that result in delivery of a therapeutic level of one or more cannabinoids during a clinically relevant therapeutic window.
  • the therapeutic window provided by present medicaments is a longer window than provided by immediate release medicaments such as Marinol, containing an equivalent amount of the cannabinoid.
  • the present compositions are especially suitable for conditions that are benefitted by therapeutic levels for more than about 5 hours, e.g. about 6 to about 8 hours or for as long as about 8 or about 12 hours.
  • the present compositions provide therapeutic dosing at levels controlled to generally avoid levels typically associated with certain side effects.
  • the present compositions comprise a cannabinoid partitioned in an immediate release compartment and in a delayed release compartment.
  • the present invention provides methods of treating cannabinoid-sensitive disorders.
  • cannabinoid-sensitive disorders are sleep apnea, anxiety, stress, headache, nausea, glaucoma, pain, arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, anorexia or cachexia syndrome, bladder dysfunction, spasticity due to multiple sclerosis, Huntington's disease, and Alzheimer's disease.
  • the present medicaments provide oral dosing of about 0.1 to about 75 mg of a cannabinoid.
  • the subject sleeps during the therapeutic window.
  • the oral medicaments of the present invention provide a
  • the oral medicaments of the present invention when administered to a subject immediately before a sleep cycle, provide a therapeutic response without causing (or without substantially causing) side effects once the subject has awoken (e.g. post treatment window).
  • the invention provides a medicament comprising a cannabinoid dose, an excipient, and one or more release modifiers present in an amount to provide, when administered orally, a therapeutic window which extends over both an early treatment window (e.g. providing a Tmax of about 30 minutes to about 3 hours) and a late therapeutic window.
  • a low dose e.g. about 0.1 to about 20 mg
  • a cannabinoid e.g. THC
  • a release modifier e.g. Marinol
  • Figure 1 depicts the % of subjects with a 75% reduction in AH I versus duration of reduction: the effect of THC dose.
  • Figure 2 depicts dose and time dependent effects of THC on apnea suppression.
  • Figure 3 depicts AH I in sleep apnea patients during a target treatment window.
  • Figure 4 depicts the relationship of Cmax (ng/ml) and cannabinoid amount (mg) for an immediate release compartment (Marinol formulation).
  • FIG. 5 depicts plasma profiles depicted in US 2009/0181080 of a THC formulation.
  • AH I means apnea-hypopnea index, which is calculated by dividing the number of apnea and hypopnea events by the number of hours of sleep.
  • the AH I index generally quantifies the overall severity of sleep apnea including sleep disruptions and desaturations. Typically, an AH I of 5-15 is considered mild, 15-30 is moderate, and above 30 is severe.
  • AUC area-under-the-curve
  • THC or metabolite thereof
  • AUC can be calculated by collecting multiple blood samples over a period of time, graphing the drug
  • AUC can be expressed in units of amount of THC x time/volume (e.g. ng x hr/ml).
  • Cmax means the maximum plasma concentration of THC (or a metabolite thereof) during an interval of time.
  • Cannabinoid-sensitive disorder means a disorder that, when a
  • cannabinoid or a cannabinoid receptor modulator is administered, modulates a pathophysiologic pathway that ameliorates the disorder or clinically relevant symptoms thereof.
  • Relevant pathophysiologic pathways can be desirably modulated by present medicaments.
  • administration may modulate the pathways of acid (e.g. GABA, glutamate), monoamine (e.g. histamine, dopamine, serotonin, noradrenaline) purine (e.g. adenosine, ADP, ATP), peptide (e.g. somatostatin, neuropeptide Y, neurokinin, cholecystokinin), vanilloid, prostanoid, opiod and/or other neurotransmitters.
  • acid e.g. GABA, glutamate
  • monoamine e.g. histamine, dopamine, serotonin, noradrenaline
  • purine e.g. adenosine, ADP, ATP
  • peptide
  • 0032 "Cmin” (or trough) is the lowest concentration of THC (or a metabolite thereof) in the plasma (following the Cmax) within a defined treatment window.
  • “Delayed release” means release of a cannabinoid in a manner such that release of the cannabinoid in vivo is delayed in comparison to the release from an immediate release compartment (e.g. a Marinol formulation). In vivo release can be estimated from an in vitro release assay appropriate for the formulation (e.g. as set forth in Example 10). Examples of medicament-types which display delayed release include extended release, sustained release, continuous release, timed-release, and pulsatile release (e.g. timed release or instant release plus timed release).
  • Delayed release dosage compartment is a dosage compartment comprising a release-modifying amount of a release modifier.
  • the release of a cannabinoid partitioned in a delayed release compartment is delayed by about any of: 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, or 800%, compared to an immediate release medicament such as Marinol in an in vitro dissolution assay (e.g. Example 10).
  • Dosage compartment means a discrete layer, sphere, fraction or formulation encompassing a cannabinoid.
  • the delayed release compartment may be dispersed in or co-localized to a component of the immediate release compartment. It should further be understood that in some dosage forms, the immediate release dosage compartment(s) and the delayed release dosage
  • the immediate release compartment is the outside portion of the tablet (i.e. the release of the drug in this portion is not delayed by a release modifier).
  • the delayed release compartment is the portion of the tablet towards the interior, where the release modification (or release modifier) is the functional result of the location within the dosage form.
  • Extended therapeutic window means a therapeutic window which extends over both an early treatment window and a late treatment window
  • immediate release dosage compartment means a dosage compartment that does not contain a release modifier in a release modifying amount.
  • the immediate release dosage compartment is the portion of a dosage form that releases greater than 75% of the cannabinoid contained in the portion within 60 minutes, or greater than 50% within 30 minutes in an in vitro dissolution assay (e.g. a dissolution assay described in Example 10).
  • an immediate release compartment releases the cannabinoid in an in vitro dissolution assay at a rate of at least 50% of a Marinol formulation, e.g. about 50% to 150% of a Marinol formulation.
  • Marinol means a gel capsule medicament of dronabinol as it generally is formulated and available under the trademark MARINOL®. Where reference is made to Marinol at a concentration that is not commercially available, it is meant to refer to a medicament formulated similarly to other strengths of MARINOL®, i.e. containing dronabinol, gelatin, glycerin, and sesame oil.
  • Release modifiers means a pharmaceutically acceptable ingredient or ingredients that act independently or in concert to cause the delayed release of a cannabionoid from a medicament or dosage compartment and/or that slow or delay the absorption of the cannabionoid in the gut.
  • substantially similar as it relates to a referenced quantifiable parameter (e.g. THC plasma level, Cmax, Tmax, or therapeutic response) means that the subject parameter is from about 50% to about 200% of the referenced parameter, or from about 75% to about 150%, or about 80% to about 120%.
  • a referenced quantifiable parameter e.g. THC plasma level, Cmax, Tmax, or therapeutic response
  • Therapeutic window means a period of time during which a
  • Treatment window means the period of time beginning at the time of administration (i.e. To) of the drug composition and ending at a defined time.
  • the treatment window can be further divided into sub-periods, such as “early treatment window” (e.g. T-
  • THC means a cannabinoid of the present invention (as described below).
  • Therapeutic efficiency means the ratio of therapeutic response to side effects (i.e. any treatment-related effects that are not a therapeutic response).
  • Therapeutic response means any response that can be considered to represent a reduction in the signs or symptoms of a medical condition.
  • a therapeutic response is, for example, a reduction in apnea-hypopnea index, snoring, oxygen desaturation of the arterial blood, or sleep disruption.
  • Tmax means the time between the administration of the medicament and the time that a maximum plasma level (Cmax) of the referenced cannabinoid (or metabolite) is achieved.
  • the present medicaments are surprisingly effective for treating certain cannabinoid sensitive disorders.
  • Technical features include providing, when
  • a therapeutic window which begins within about 30 minutes or about 1 hour or about 2 hours of administration (e.g. as shown by Example 3); (2) a therapeutic window that is about 1 to about 10 hours longer than the therapeutic window of an immediate release dosage (e.g. as shown in Example 5); and (3) plasma levels that do not elevate into a level where reduced therapeutic efficacy and/or deleterious side effects are produced (e.g. as shown in Example 3, it has been surprisingly discovered that certain patients with cannabinoid-sensitive disorders exhibit a non-monotonic dose- response of the inverted U type).
  • compositions of the present invention provide one or more cannabinoids in a medicament that can deliver to a subject a desired target PK profile, where the PK profile achieves a therapeutic level of a cannabinoid during a therapeutic window.
  • Cannabinoids of the present invention are any member of a group of substances that are structurally related to tetrahydrocannabinol and that bind to a cannabinoid receptor such as CB1 or CB2 or both (THC) .
  • the cannabinoid can be a naturally occurring compound (e.g. present in Cannabis), a compound metabolized by a plant or animal, or a synthetic derivative.
  • the cannabinoid may be included in its free form, or in the form of a salt; an acid addition salt of an ester; an amide; an enantiomer; an isomer; a tautomer; a prodrug; a derivative of an active agent of the present invention; different isomeric forms (for example, enantiomers and diastereoisomers), both in pure form and in admixture, including racemic mixtures; enol forms.
  • the cannabinoids of the present invention are further meant to encompass natural cannabinoids, natural cannabinoids that have been purified or modified, and synthetically derived cannabinoids, for example, United States Patent Application Publication 2005/0266108, hereby incorporated by reference in its entirety, describes a method of purifying cannabinoids obtained from plant material.
  • the cannabinoids of the present invention can be any of 9- tetrahydrocannabinol, 8-tetrahydrocannabinol, (+)-1 ,1 -dimethylheptyl analog of 7- hydroxy-delta-6-tetrahydrocannabinol, 3-(5'-cyano-1 ',1 '-dimethylpentyl)-1 -(4-N- morpholinobutyryloxy) delta 8-tetrahydrocannabinol hydrochloride], dexanabinol, nabilone, levonantradol, or N-(2-hydroxyethyl)hexadecanoamide.
  • the cannabinoids of the present invention can be any of the non- psychotropic cannabinoid 3-dimethylnepty 1 1 carboxylic acid homologine 8, delta-8-tetrahydrocannabinol. (J. Med. Chem. 35, 3135, 1992).
  • the cannabinoids of the present invention can further be any of the active metabolites, derivatives, or analogs as taught in the National Institute on Drug Abuse Research Monograph Series 79, "Structure-Activity Relationships of the Cannabinoids.
  • the cannabinoid can be Delta-9- tetrahydrocannabinol, also known as dronabinol.
  • Dronabinol is naturally- occurring and has been extracted from Cannabis sativa L. (marijuana). It has also been produced chemically as described in U.S. Pat. No. 3,668,224.
  • Dronabinol is a light- yellow resinous oil that is sticky at room temperature, but hardens upon refrigeration. It turns to a flowable liquid when heated at higher temperatures. Dronabinol is insoluble in water and typically formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.
  • Dronabinol is available in natural (extracted from plant) and synthetic forms.
  • synthetic dronabinol may be utilized and may be synthesized using the starting materials: Olivetol and p-2,8- menthadien-2-ol (PMD).
  • dronabinol is further meant to encompass naturally occurring dronabinol, synthetically derived dronabinol, and synthetically modified dronabinol starting with a molecule obtained from a natural source for example, United States Patent Application Publication 2005/0171361 , hereby incorporated by reference in its entirety, describes a method of extracting delta-9-THC acid from the plant material by chromatography and then synthetically converting it to dronabinol.
  • compositions of the present invention comprise cannabinoids in an amount of about 0.1 mg to about 75 mg.
  • compositions of the present invention are formulated to provide PK profiles that unexpectedly result in therapeutically effective levels of a cannabinoid during a desired therapeutic window.
  • useful PK profiles of the present invention are the following (where the medicament of the present invention is administered at To):
  • a present THC medicament is orally administered resulting in (a) a THC plasma concentration of 50% to 200% from Ti through T 4 when compared to the THC plasma concentration from Ti through T 4 attained by orally administering a comparator of 1 ⁇ 2 of the THC dose in a Marinol capsule at To and (b) a THC plasma concentration of 50% to 200% from T 5 through Ts when compared to the plasma concentration from T 5 through Ts attained by orally administering a comparator of twice the THC dose in a Marinol capsule at To.
  • PK Profile 2 A present THC medicament is orally administered resulting in a THC plasma concentration of 50% to 200% from Ti through T 7 when compared to the plasma concentration attained by orally administering a comparator of 1 ⁇ 2 of the THC dose in a Marinol capsule at To and 1 ⁇ 2 of the THC dose in a Marinol capsule at T3.
  • PK Profile 3 A present THC medicament is orally administered resulting in a THC plasma concentration greater than about 150% from T 4 through when compared to the plasma concentration attained by orally administering 1 ⁇ 2 of the THC dose amount in a Marinol capsule. at T .
  • PK Profile 4 A present THC medicament is orally administered resulting in a THC plasma concentration at T that is greater than about 75% when compared to the plasma level at T3 attained by orally administering 1 ⁇ 2 of the THC dose in a Marinol capsule.
  • a present THC medicament is orally administered resulting in a THC AUC of 8.64-1 1 .52 ng x hr/ml, a Cmax between 0.4 ng/ml and 4.5 ng/ml; and a Tmax between 0.5 and 3.5 hours, optionally between 0.5 and 1 .5 hours.
  • a present THC medicament is orally administered resulting in a THC plasma concentration during an early-treatment window (e.g. during Tohr -T 4 hr ) and a maximum THC plasma concentration (Cmax) that is substantially similar to that provided by an immediate release form (e.g. a single Marinol capsule containing about 1 ⁇ 2 the dose).
  • an immediate release form e.g. a single Marinol capsule containing about 1 ⁇ 2 the dose.
  • PK Profile 7 A present THC medicament is orally administered resulting in a THC Tmax substantially similar to the Tmax of an orally administered immediate release Marinol capsule containing about 1 ⁇ 2 the dose.
  • the PK profile provides a Tmax during an early treatment window (e.g. from Ti/2hr - i .5hr , i/2hr - sacred Or at about
  • a present THC medicament is orally administered resulting in a plasma cannabinoid level (or therapeutic response) during a late-treatment window (e.g. during T 4 r -Tshr) substantially similar to that produced when two Marinol capsules containing about 1 ⁇ 2 the dose are orally administered in succession (e.g. one at To and one at about T 3hr ).
  • a present THC medicament is orally administered resulting in a THC plasma level during a late-treatment window (e.g. during T 4 r -Tshr) substantially similar to that produced during an early-treatment window (e.g. during T hr -T hr ) by a Marinol capsule containing about 1 ⁇ 2 the dose.
  • the plasma level and/or AUC during the late-treatment window is substantially similar to that produced during the early-treatment window by the Marinol capsule.
  • a present THC medicament is orally administered resulting in a plasma THC level during a late-treatment window (e.g. during T 4 r -Tshr such as during T 4 hr-T 5 hr, T 5hr -T6hr, and/or T 6 hr -T7hr) that is greater than that produced during a mid- treatment window (e.g. during T 3h r-T 6 hr such as hours T h r-T 5h r and/or T 5hr -T6hr) by a Marinol capsule containing about 1 ⁇ 2 the dose.
  • the plasma level and/or AUC during the late-treatment window is greater than that produced during the mid-treatment window by the Marinol capsule.
  • PK Profile 1 1 A present THC medicament is orally administered resulting in an AUC during a treatment window (e.g. during Tohr -Tshr) which is about 3-4 times greater than that of a Marinol capsule containing about 1 ⁇ 2 the dose.
  • the Cmax is substantially similar to that of the Marinol capsule.
  • the Tmax is less than about T 2 h (e.g. from about T0.5h- 1.5h, such as about T-
  • a present THC medicament is orally administered resulting in plasma levels and/or an AUC during an early treatment window (e.g. during Tohr -T 4 hr) which are substantially similar to (e.g. 50%-200% of) those produced when a reference Marinol capsule containing 1 ⁇ 2 the THC dose is orally administered.
  • PK Profile 13 The PK profile of PK Profile 12, where the plasma levels and/or an AUC during a late treatment window (e.g. between T hr and T 8 hr or T hr and T 6 hr) are greater than (e.g. about 150% or more of) those seen during a late treatment window (e.g. between T hr and T 8 h r or T hr and T 6 hr) after orally administering the reference Marinol capsule.
  • a late treatment window e.g. between T hr and T 8 hr or T hr and T 6 hr
  • PK Profile 14 The PK profile of PK Profile 12 where the plasma levels are greater than (e.g. about 150% or more of) those seen during a mid-treatment window (e.g. between T 3 r and T 5 r ) after orally administering the reference Marinol capsule.
  • PK Profile 15 The PK profile of PK Profile 12 where the plasma levels are substantially similar to (e.g. 50%-200%) of those seen during an early treatment window after orally administering the reference Marinol capsule.
  • PK Profile 16 The PK profile of PK Profile 12 where the plasma levels and/or an AUC during a mid treatment window (e.g. between T 3hr and T 5hr or at T hr ) are greater than about 75% of those seen during an early treatment window (e.g. between T2hr and T 4 r Or at T 3 ) after orally administering the reference Marinol capsule.
  • a mid treatment window e.g. between T 3hr and T 5hr or at T hr
  • an early treatment window e.g. between T2hr and T 4 r Or at T 3
  • PK Profile 17 The PK profile of PK Profile 12 where the plasma levels and/or an AUC during a treatment window (e.g. between T-i r and T 7 r ) are substantially similar to (e.g. 50%-200% of) to those observed when two Marinol capsules containing about 1 ⁇ 2 the THC dose are orally administered in succession; e.g. one at To and one at T 3 r .
  • PK Profile 18 The PK profile of PK Profile 12 where the plasma levels and/or an AUC during a late treatment window (e.g. between T 4 r and Tshr or T 4 r and T6hr) are less than those observed when two Marinol capsules containing about 1 ⁇ 2 the THC dose are orally administered in succession; i.e. one at T 0 and one at T 3hr ).
  • a late treatment window e.g. between T 4 r and Tshr or T 4 r and T6hr
  • PK Profile 19 The PK profile of PK Profile 12 where the plasma levels and/or an AUC during a late treatment window (e.g. between T hr and T 8 hr or T hr and T 6 hr) are substantially similar to [and optionally less than] (e.g. about 30% - 100% of) those observed when two Marinol capsules containing about 1 ⁇ 2 the THC dose are orally administered in succession; i.e. one at T 0 and one at T 3hr .
  • a late treatment window e.g. between T hr and T 8 hr or T hr and T 6 hr
  • PK Profile 20 The PK profile of any one of PK Profile 1 - 19 where the plasma levels and/or an AUC during a late treatment window (e.g. between T 4 r and Tshr or T hr and T 6 h) are substantially similar to plasma levels and/or an AUC between T 8 hr and T-io hr-
  • a late treatment window e.g. between T 4 r and Tshr or T hr and T 6 h
  • a medicament that, when orally administered to a subject, produces a therapeutic response over a desired therapeutic window (e.g. extending over both an early treatment window and a late treatment window).
  • a desired therapeutic window e.g. extending over both an early treatment window and a late treatment window.
  • formulations minimize the total amount of drug administered, thus significantly decreasing side effects and increasing the therapeutic efficiency.
  • the medicaments of the present invention comprise a cannabinoid partitioned between an immediate release compartment and a delayed release compartment.
  • the portion of the cannabinoid in the immediate release compartment can be about any of the following per cents (%): 10 - 75, 10 - 50, 20 - 50, 25 - 75, 40 - 60, 35 - 75, or 40 - 80.
  • compositions of the present invention comprise a cannabinoid and one or more excipients (e.g. release modifiers) in appropriate amounts to provide a desired PK profile (e.g. any of PK profiles 1 -20).
  • the component(s) of the compositions may be in any form, e.g. liquid, solid, and semi-solid components.
  • the medicament can be formulated to provide any desired release properties, for example, immediate release, pulsatile release, extended release, delayed release, controlled-release, continuous release, prolonged release, timed release, and combinations thereof (e.g. immediate release + controlled-release, immediate release + delayed release, etc.).
  • excipients are often influenced by the selection and amount (or fraction of the total dose) of cannabinoid(s) associated (e.g. compounded) with the excipients in a component (e.g. microparticle) of the dosage (and vice versa).
  • cannabinoid(s) associated e.g. compounded
  • a component e.g. microparticle
  • one skilled in the art can now formulate medicaments which contain an excipient and release modifiers in an effective amount to provide both an immediate (or early) effect and an extended (or late) effect.
  • an immediate effect or a substantial portion thereof
  • sustained effect or a substantial portion thereof
  • sustained release modifiers e.g. extended or delayed
  • sustained effects may be influenced by an immediate release component in a dosage, for example, due to residual levels of the immediately released drug.
  • sustained effects e.g. late plasma levels
  • an immediate release component in a dosage for example, due to residual levels of the immediately released drug.
  • one skilled in the art can adjust the release properties of one or more release components (e.g. by varying the amount of drug therein or the relative amounts or types of release modifiers therein).
  • PK profiles can be achieved by the skilled artisan, in many cases, without performing clinical studies.
  • useful guidance is provided by the United States Food and Drug Administration (FDA) in the guidance document entitled "Extended Release Oral Medicaments: Development, Evaluation and
  • the medicaments of the present invention can be made with different polymorphic forms (e.g. salts, crystalline forms, hydrates, esters, and solvates), each with physicochemical properties affecting drug delivery (e.g. absorption). Selection of the release modifiers is done with consideration of the THC form. A number of such forms are well known in the art.
  • the cannabinoid form used in the formulation is a cannabinoid ester or salts thereof (e.g. a polar ester such as an ester of a terminal carboxylic acid).
  • a polar ester such as an ester of a terminal carboxylic acid.
  • Esterified forms of THC are described, for example, in U.S. 4,933,368, U.S. 5,389,375 and U.S. 6,008,383.
  • Other useful polar esters are the hemi-ester of malonic acid and the alaninate ester of alanine. It has been reported, e.g., in U.S. 5,508,051 and U.S. 5,389,375, that salts of the terminal carboxylic acid group of the ester, for example, the N-methyl glutamine salt as well as the sodium and potassium salts are also useful.
  • the cannabinoid form used in the formulation is in crystalline form.
  • the cannabinoid form is crystalline trans-(+/-)- THC.
  • a medicament of the present invention can optionally provide a therapeutic window which extends over both an early treatment window and a late treatment window.
  • One embodiment of the present invention provides a medicament comprising a compartment comprising a cannabinoid and one or more excipients in an effective amount to provide an immediate therapeutic response (e.g. during an early-treatment window) and one or more release modifiers in an effective amount to provide an extended therapeutic window (e.g. providing a therapeutic response during a late- treatment window).
  • a medicament of the present invention comprises one or more dosage compartments.
  • a dosage compartment of the present invention can be a delayed release dosage compartment or an immediate release dosage compartment.
  • the delayed release dosage compartment comprises a liquid delayed release component (e.g. a delayed release aqueous or semi-aqueous component or syrup).
  • a liquid delayed release component e.g. a delayed release aqueous or semi-aqueous component or syrup.
  • the delayed release dosage compartment comprises a solid delayed release component (e.g. an osmotic component, or a lyophilized or dried solid component selected from a lipid component, a glass sugar component, a guest-host component, or a co-precipitate component), or a semi-solid delayed release component (e.g. a semi-solid SEDDS component).
  • a solid delayed release component e.g. an osmotic component, or a lyophilized or dried solid component selected from a lipid component, a glass sugar component, a guest-host component, or a co-precipitate component
  • a semi-solid delayed release component e.g. a semi-solid SEDDS component
  • the solid delayed release dosage component or semi-solid delayed release dosage component is a component coated or complexed with a delayed release layer or compound, for example to provide a timed- release compartment.
  • the delayed release dosage compartment comprises a solid component, for example, a lyophilized or dried, solid component selected from: a solid fat component, a glass sugar component, a guest-host component, and a co-precipitate component; wherein the solid component has been coated or otherwise compounded with a delayed (e.g. timed) release layer or delayed release modifier.
  • a solid component for example, a lyophilized or dried, solid component selected from: a solid fat component, a glass sugar component, a guest-host component, and a co-precipitate component; wherein the solid component has been coated or otherwise compounded with a delayed (e.g. timed) release layer or delayed release modifier.
  • a medicament comprises more than two or more compartments (e.g. 3, 4, 5, or 6 compartments), such as timed-release compartments having different times of cannabinoid release.
  • the medicament comprises an immediate release compartment and a plurality of delayed (e.g. timed) release compartments.
  • the plurality of delayed release compartments includes one or two or more delayed release compartments (e.g. 2, 3, or 4, with different release times) and/or one or more extended release compartments.
  • a dosage compartment of the present composition is a liquid or predominantly liquid (a liquid) dosage compartment.
  • a liquid any formulation useful for oily or lipophilic compounds may be used.
  • the component may be in the form of an aqueous or non-aqueous liquid, an oil or other lipophilic medium, an emulsion, a syrup, and the like.
  • a liquid compartment is encapsulated (e.g. a hard gel or soft gel).
  • the compartment is coated with a delayed (e.g.
  • liquid dosage compartments taught herein are amenable to delayed release or immediate release compartments, depending on, for example, the
  • the liquid dosage compartment of the present invention comprises an aqueous or semi-aqueous liquid component comprising a cannabinoid and organic co-solvents (e.g. ethanol, propylene glycol and polyethylene glycol).
  • the composition further comprises a buffer.
  • a component contains from 15% to about 65% ethanol, from about 10% to about 60% buffered aqueous solution, from about 0.1 to about 25% propylene glycol and from about 1 % to about 25% polyethylene glycol.
  • the component is buffered to a pH of about 6.5 to 7.5 (e.g. 7).
  • Such an aqueous or semi-aqueous liquid component may be formulated for tailored (e.g.
  • the liquid aqueous or semi-aqueous compartment is formulated as an immediate release compartment. In another embodiment, the liquid aqueous or semi-aqueous compartment is formulated as a delayed release compartment.
  • the liquid dosage compartment of the present invention comprises a lipophilic medium (sometimes referred to simply as an 'oil') liquid component comprising a cannabinoid and a lipophilic medium, for example, an oil or oil-based carrier.
  • a lipophilic medium sometimes referred to simply as an 'oil'
  • the oil comprises one or more triglycerides (e.g. a triglyceride component).
  • the oil comprises one or more phospholipids (e.g. a
  • the oil comprises one or more triglycerides and one or more phospholipids.
  • the oil comprises a mixture of two or more of: phospholipids, glycolipids, triglycerides, sterols, small quantities of fatty acids, carbohydrates and sphingolipids, such as a complex mixture thereof (e.g. lecithin).
  • the oil comprises an antioxidant oil.
  • oil-based carriers are readily available from commercial sources. Examples of suitable oils or oil-based carriers (e.g.
  • triglyceride carriers include, but are not limited to, Aceituno oil, Almond oil, Arachis oil, Babassu oil, Blackcurrant seed oil, Borage oil, Buffalo ground oil, Candlenut oil, Canola oil, Lipex 108 (Abitec), Castor oil, Chinese vegetable tallow oil, Cocoa butter, coconut oil Pureco 76 (Abitec), Coffee seed oil, Corn oil, Cottonseed oil, Crambe oil, Cuphea species oil, Evening primrose oil, Grapeseed oil, Groundnut oil, Hemp seed oil, lllipe butter, Kapok seed oil, Linseed oil, Menhaden oil, Mowrah butter, Mustard seed oil, Oiticica oil, Olive oil, Palm oil, Palm kernel oil, Peanut oil, Poppy seed oil, Rapeseed oil, Rice bran oil, Safflower oil, Sal fat, Sesame oil, Shark liver oil, Shea nut oil, Soybean oil, Stillingia oil, Sunflower oil, Tall oil, Tea seed oil, To
  • Fractionated triglycerides include vegetable oils, fish oils, animal fats,
  • the vegetable oil is soybean oil, olive oil, cotton seed oil, peanut oil, sesame oil and castor oil, with sesame oil and castor oil optionally being preferred.
  • useful phospholipids include: Phosal® 50 PG; Phosal® 53MCT; Phosal® 75SA, Phospholipon® 80; Phospholipon® 80H;
  • Examplary phospholipids suitable for dermal medicaments include: Phosal® 50 PG ; Phosal® 50SA;Phosal® 53MCT; Phosal® 75SA; Phospholipon® 80;
  • the oil component is a mixture of oils or complex mixture (as described above), for example, as with lecithin.
  • the lecithin comprises a mixture of phospholipids, for example,
  • phosphatidylcholine e.g. 13 - 18%); phosphatidylethonolamine (e.g. 10 - 15%);
  • the oil-based carrier is sesame oil.
  • the oil component e.g. sesame oil
  • the oil component contains an effective amount of an anti-oxidant selected from the group consisting of sesamin, sesamol, sesamolin, lecithin and any combination of the foregoing (either already present in the (unpurified) sesame oil or added to purified sesame oil. Examples of components described above are described in WO 2006/063109.
  • the liquid lipophilic compartment is formulated as an immediate release compartment. In another embodiment, the liquid lipophilic compartment is formulated as a delayed release compartment.
  • the liquid dosage compartment of the present invention is a SEDDS dosage compartment comprising a cannabinoid, an oily medium, and at least one surfactant.
  • a SEDDS dosage compartment comprising a cannabinoid, an oily medium, and at least one surfactant.
  • the oily medium may comprise, for example, triglycerides and/or mixed glycerides and/or free fatty acids containing medium and/or long chain saturated, mono- unsaturated, and/or poly-unsaturated free fatty acids.
  • the surfactant promotes self- emulsification, which, for example, promotes targeted chylomicron delivery and optimal availability to a mammalian intestinal lumen.
  • the dosage compartment may, for example, include co-solvents, anti-oxidants, viscosity modifying agents, cytochrome P450 metabolic inhibitors, and P-GP efflux inhibitors, for tailored (e.g. delayed) release rates.
  • the SEDDS component is a Type I, II, or III SEDDS.
  • Type I formulations contain an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids); whereas the oily medium may also be polyfunctional with potential surfactant characteristics to promote self-emulsification.
  • Type II contains an oily medium (e.g.
  • Type III contains an oily medium (e.g.
  • the SEDDS compartment is coated with a release modifying coating (e.g. timed, extended, or delayed).
  • a release modifying coating e.g. timed, extended, or delayed.
  • the liquid SEDDS compartment is formulated as an immediate release compartment.
  • the liquid SEDDS compartment is formulated as a delayed release compartment.
  • the liquid dosage compartment is combined with another compartment in a multi-phase dosage form.
  • the liquid dosage is combined with another compartment in a multi-phase dosage form.
  • compartment can be provided as an immediate release compartment and combined with a solid dosage compartment formulated for delayed release.
  • solid dosage compartment formulated for delayed release. Examples of useful multi-phase dosage forms are described in US 7,670,612. Semi-Solid Dosage compartments
  • a dosage compartment of the present composition is a semi-solid dosage compartment.
  • Any formulation useful for oily or lipophilic compounds may be used.
  • the compartment may be in the form of self-emulsifying drug delivery system (SEDDS), or a lipophilic medium compartment.
  • the semi-solid compartment is encapsulated (e.g. a hard gel or soft gel).
  • the compartment is coated with a release modifying coating (e.g. timed release coating).
  • the dosage compartment is a semi-solid SEDDS dosage compartment comprising a cannabinoid, an oily medium, at least one surfactant, and a semi-solid inducer (e.g. an amphiphilic/non-amphiphilic solute such as ascorbyl palmitate).
  • a semi-solid inducer e.g. an amphiphilic/non-amphiphilic solute such as ascorbyl palmitate.
  • a SEDDS component is described, for example, in US 2007/0104741.
  • the oily medium may comprise, for example, triglycerides and/or mixed glycerides and/or free fatty acids containing medium and/or long chain saturated, mono- unsaturated, and/or poly-unsaturated free fatty acids.
  • the surfactant promotes self- emulsification, which, for example, promotes targeted chylomicron delivery and optimal availability to a mammalian intestinal lumen.
  • the amphiphilic/non-amphiphilic solute promotes prolonged dissolution profiles (e.g. for delayed release).
  • the component may, for example, include co-solvents, anti-oxidants, viscosity modifying agents, cytochrome P450 metabolic inhibitors, P-GP efflux inhibitors, and finally
  • amphiphilic/non-amphiphilic solutes to induce semi-solid formation for tailored (e.g. delayed) release rates.
  • an isotropic semi-solid or waxy solid phase may be prepared by dissolving a high concentration of ascorbyl palmitate (or other amphiphilic/non-amphiphilic solutes) in an oily liquid state.
  • the contents Upon administration as an isotropic semi-solid phase and upon initial dilution in the gastric region of a mammal, the contents immediately form a solid dispersion or coarse colloidal dispersion for protection against acid catalyzed degradation of cannabinoids.
  • the SEDDS component is a Type I, II, or III SEDDS.
  • Type I formulations contain an oily medium (e.g.
  • Type II contains an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids) and at least one surfactant component to promote self-emulsification.
  • Type III contains an oily medium (e.g.
  • the SEDDS compartment is coated with a release modifying coating (e.g. delayed release coating or timed-release coating).
  • a release modifying coating e.g. delayed release coating or timed-release coating.
  • the semi-solid dosage compartment of the present invention comprises a lipophilic (sometimes referred to simply as 'oil') semi-solid component comprising a cannabinoid and a lipophilic medium, for example, an oil or oil-based carrier.
  • the oil comprises one or more triglycerides (e.g. a triglyceride component).
  • the oil comprises one or more phospholipids (e.g. a
  • the oil comprises one or more triglycerides and one or more phospholipids.
  • the oil comprises a mixture of two or more of: phospholipids, glycolipids, triglycerides, sterols, small quantities of fatty acids, carbohydrates and sphingolipids, such as a complex mixture therof (e.g. Lecithin).
  • the oil comprises an antioxidant oil.
  • oil-based carriers are readily available from commercial sources. Examples of suitable oils or oil-based carriers (e.g.
  • triglyceride carriers include, but are not limited to, Aceituno oil, Almond oil, Arachis oil, Babassu oil, Blackcurrant seed oil, Borage oil, Buffalo ground oil, Candlenut oil, Canola oil, Lipex 108 (Abitec), Castor oil, Chinese vegetable tallow oil, Cocoa butter, coconut oil Pureco 76 (Abitec), Coffee seed oil, Corn oil, Cottonseed oil, Crambe oil, Cuphea species oil, Evening primrose oil, Grapeseed oil, Groundnut oil, Hemp seed oil, lllipe butter, Kapok seed oil, Linseed oil, Menhaden oil, Mowrah butter, Mustard seed oil, Oiticica oil, Olive oil, Palm oil, Palm kernel oil, Peanut oil, Poppy seed oil, Rapeseed oil, Rice bran oil, Safflower oil, Sal fat, Sesame oil, Shark liver oil, Shea nut oil, Soybean oil, Stillingia oil, Sunflower oil, Tall oil, Tea seed oil, To
  • Fractionated triglycerides include vegetable oils, fish oils, animal fats,
  • the vegetable oil is soybean oil, olive oil, cotton seed oil, peanut oil, sesame oil and castor oil, with sesame oil and castor oil optionally being preferred.
  • useful phospholipids include: Phosal® 50 PG; Phosal® 53MCT; Phosal® 75SA, Phospholipon® 80; Phospholipon® 80H;
  • Examplary phospholipids suitable for dermal medicaments include: Phosal® 50 PG ; Phosal® 50SA;Phosal® 53MCT; Phosal® 75SA; Phospholipon® 80;
  • the oil component is a mixture of oils or complex mixture (as described above), for example, as with lecithin.
  • the lecithin comprises a mixture of phospholipids, for example,
  • phosphatidylcholine e.g. 13 - 18%); phosphatidylethonolamine (e.g. 10 - 15%);
  • the oil-based carrier is sesame oil.
  • the oil component e.g. sesame oil
  • the oil component contains an effective amount of an anti-oxidant selected from the group consisting of sesamin, sesamol, sesamolin, lecithin and any combination of the foregoing (either already present in the (unpurified) sesame oil or added to purified sesame oil.
  • the semisolid oil compartment is formulated as an immediate release compartment.
  • the semi-solid oil compartment is formulated as a delayed release compartment. Examples of compartments described above are described in WO 2006/063109.
  • a dosage compartment of the present invention is a solid dosage compartment.
  • the dosage compartment may be a solid lipid dosage compartment, a solid dosage compartment produced from an aqueous mixture or emulsion, a solid dosage compartment produced by extrusion (e.g. hot melt extrusion), or a solid emulsion that is, for example, dried.
  • Other solid dosage compartments include osmotic particles.
  • a solid dosage compartment e.g. powdered, spray dried, or freeze dried forms
  • a solid dosage compartment is formed into a tablet, pill, microsphere, and the like.
  • a solid dosage compartment is coated or otherwise compounded with pharmaceutically acceptable materials and/or excipients known in the art to provide a cannabinoid component affording delayed release (e.g. delayed release modifiers or timed-release coating).
  • the solid dosage compartment is a solid lipid dosage compartment comprising a cannabinoid, a solid fat and one or more phospholipids, for example, as described in W09736577.
  • the dosage compartment may be prepared by dissolving the cannabinoid together with lipid components comprising at least one solid fat and at least one phospholipid in a suitable organic solvent; evaporating the solvent to dryness; hydrating the dry solid lipid mixture with an aqueous phase, with mechanical shaking, to obtain a lipid dispersion in water; homogenizing the resultant lipid dispersion, such as by high-pressure homogenization, to reduce the particle size to the submicron range; and drying the submicron dispersion.
  • the dosage compartment may be prepared by directly drying the lipid mixture that is dissolved in the organic solvent.
  • the solid lipid mixture formulations can be spray dried or freeze-dried to obtain dry compositions suitable for the preparation of solid-dosage compartments, such as hard gelatin capsules or tablets.
  • These solid dosage compartments may, for example, further comprise cryoprotectants, antioxidants, free flowing imparting agents, surface active materials and/or emulsifiers.
  • the solid lipid compartment is formulated as an immediate release compartment. In another embodiment, the solid lipid compartment is formulated as a delayed release compartment.
  • the solid dosage compartment is a solubilizing compartment comprises a solubilizing agent (e.g. host such as a cyclodextrin) and the cannabinoid.
  • a solubilizing agent e.g. host such as a cyclodextrin
  • the solid dosage compartment may be produced from an aqueous mixture or emulsion.
  • the solubilizing action of, for example, cyclodextrins is caused by the formation of so-called inclusion complexes or guest-host complexes, which may then be dried (e.g. freeze dried) to produce a powder material and optionally mixed with a microsphere (e.g. swelling starch microsphere).
  • microspheres that may be used in the present compositions include those made from chitosan, polyvinylpyrrolidone, alginate, polycarbophil, pectin, hyaluronic acid (and esters thereof), agar agarose, dextran, albumin, ovalbumin, collagen, and casein.
  • the solid solubilizing compartment is formulated as an immediate release compartment. In another embodiment, the solid solubilizing compartment is formulated as a delayed release compartment.
  • the solid dosage compartment is a co-precipitate compartment comprising a co-precipitate of a cannabinoid, a tocopherol polyethyleneglycol succinate (TPGS) or equivalent; and a dispersion adjuvant in an amount sufficient to assist in dispersing the lipophilic substance in the succinate.
  • TPGS tocopherol polyethyleneglycol succinate
  • An example of such a dosage compartment is described for a cannabinoid in US 5,891 ,469. The dosage
  • the solid co-precipitate compartment may be produced, for example, by co-melting TPGS and the cannabinoid at 40. degree. -60. degree. C; adding a dispersion adjuvant to the melted mixture with agitation; adding a fumed silica to the mixture with agitation; and drying the resultant mixture at 100. degree. C. to yield a dry powder co-precipitate.
  • the solid co-precipitate compartment is formulated as an immediate release compartment.
  • the solid co-precipitate compartment is formulated as a delayed release compartment.
  • the solid dosage compartment is a sugar glass compartment sugar comprising, a cannabinoid, and a glass of a sugar, a sugar alcohol, a mixture of sugars or a mixture of sugar alcohols.
  • a sugar glass compartment sugar comprising, a cannabinoid, and a glass of a sugar, a sugar alcohol, a mixture of sugars or a mixture of sugar alcohols.
  • the cannabinoid is incorporated in the sugar glass as a monomolecular encapsulation without formation of a guest-host complex.
  • the solid dosage compartment may, for example, be prepared by a) dissolving the cannabinoid compound in an organic solvent that is soluble in water and dissolving the sugar, sugar alcohol, mixture of sugars or mixture of sugar alcohols in water; b) mixing the dissolved cannabonoid compound and the dissolved sugar, sugar alcohol, mixture of sugars or mixture of sugar alcohols to obtain a sufficiently stable mixture; and c) drying the mixture by freeze drying, spray drying, vacuum drying, or super critical drying.
  • the dissolution rate of the cannabinoid may be tailored by manipulating the dissolution rate of the sugar glass, for example, to produce delayed release.
  • the solid sugar glass compartment is formulated as an immediate release compartment.
  • the solid sugar glass compartment is formulated as a delayed release compartment.
  • the solid dosage compartment is a hot melt extrudate.
  • An examplary method of making a solid hot melt extrudate comprises mixing a cannabinoid and a carrier by a rotating screw through the heated barrel of an extruder and pressing the melt through a die into a product of uniform shape.
  • Useful carriers include polymers known in the art as extrudate carriers.
  • the carrier can be a hydrophobic and/or hydrophilic fusible carrier or diluent (e.g. with a melting point from 35° C 150° C).
  • the carrier can be a high molecular weight poly(ethylene oxide).
  • the carrier can comprise a polymer matrix comprising a
  • thermoplastic polymer or lipophilic carrier further comprises a plasticizer.
  • the carrier further comprises a delayed release modifier.
  • the polymers used in the extrusion process function as thermal binders, drug stabilizers, drug solubilizers and/or drug release controlling excipients with no compressibility requirements.
  • useful polymer carriers include vinyl polymers (polyvinylpyrrolidone [PVP]), PVP-vinyl acetate [PVP-VA]), poly(ethylene oxide) (PEO), Eudragit (acrylates), PE glycol (PEG) and cellulose derivatives
  • hot melt extrudate compartment is formulated as an immediate release compartment.
  • hot melt extrudate compartment is formulated as a delayed release compartment (e.g. sustained release or timed release).
  • the solid dosage compartment is an osmotic compartment comprising an osmotic dosage compartment comprising a layered core (e.g. single layer or bilayer core) comprising a cannabinoid and an expandable polymer; a layered core (e.g. single layer or bilayer core) comprising a cannabinoid and an expandable polymer; a
  • semipermeable membrane surrounding the core; and a passageway disposed in the semipermeable membrane for tailored (e.g. delayed) release of the cannabinoid.
  • the core is a multilayer (e.g. bilayer) comprising first layer comprising the cannabinoid and excipient (e.g. low molecular weight polymers) and a second layer comprising an osmopolymer.
  • first layer comprising the cannabinoid and excipient (e.g. low molecular weight polymers)
  • second layer further comprises an osmoagent.
  • the one or more outer layers also comprise a cannabinoid to provide a more immediate release in addition to the tailored release.
  • Useful osmopolymers include high molecular weight polyoxyethylene oxides or the derivatives thereof. Other useful osmopolymers include hydrogels such as Carbopol.RTM. acidic carboxy polymers, a polymer of acrylic acid crosslinked with a polyallyl sucrose, also known as
  • carboxypolymethylene and carboxyvinyl polymer having a molecular weight of 250,000 to 4,000,000; Cyanamer.RTM. polyacrylamides; cross-linked water swellable indene- maleic anhydride hydrogel polymers; Good-rite.
  • RTM acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan; and the like.
  • Useful osmoagents include soluble salts of inorganic acids, such as magnesium chloride or sulphate, lithium, sodium or potassium chloride; soluble salts of organic acids, such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate; carbohydrates, such as arabinose, ribose, xylose, glucose, fructose, galactose, mannose, sucrose, maltose, lactose, raffinose; hydrosoluble aminoacids, such as glycine, leukine, alanine, methionine; organic polymeric osmoagents, such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose,
  • hydroxyethylmethylcellulose polyvinylpirrolidone
  • polyoxyethylene oxide polyoxyethylene oxide
  • carbomers and polyacrylamides examples of useful osmotic dosage layers and components are described in US 6,919,373, US 6,930,129, US 5,264,446, US 5,674,895, US 5,840,754, US 2010/0143472, US 4,327,725, US 4,1 1 1 ,202, and WO 2008/024490.
  • the solid dosage compartment comprises a crystalline cannabinoid form.
  • the crystalline form is a mixture of cannabinoid enantiomers.
  • the crystalline form is a mixture of trans-(-)-THC and trans-(+)-THC (e.g. dronabinol and its (+) enantiomer).
  • the mixture is a racemic mixture.
  • dronabinol is considered for PK profile evaluation and drug dose or dosage amount.
  • both the trans-(-)-THC and trans-(+)-THC are considered, but values for the trans-(+)- THC enantiomer are multiplied by a coefficient of about 1 % to about 10% (e.g.
  • the crystalline compartment is formulated as an immediate release compartment. In another embodiment, the crystalline compartment is formulated as a delayed release compartment (e.g. sustained release or timed release).
  • the solid dosage compartment is a delayed release compartment comprising a gastroretentive compartment.
  • Gastroretentive compartments can comprise, for example, a water-swellable polymer that swells upon imbibition of water to a size that is large enough to promote retention of the dosage form in the stomach, and provides controlled delivery of the cannabinoid (e.g. by diffusion). Examples of useful gastroretentive compartments are described in WO 03/035029 A1 , US 6,635,280 B2, US 6,340,475 B2, US 6,488,962 B1 , andPCT WO 2007/052125 A2.
  • the solid dosage compartment is combined with another compartment in a multi-phase dosage form.
  • the solid dosage compartment is combined with another compartment in a multi-phase dosage form.
  • the solid dosage compartment is combined with another compartment in a multi-phase dosage form.
  • the solid dosage is combined with another compartment in a multi-phase dosage form.
  • the solid dosage is combined with another compartment in a multi-phase dosage form.
  • compartment can be provided as a delayed release compartment and combined with a liquid dosage compartment formulated for immediate release.
  • liquid dosage compartment formulated for immediate release. Examples of useful multiphase dosage forms are described in US 7,670,612.
  • medicaments of the present invention may include a delayed release compartment. While any delayed release compartment is useful in the present invention, one embodiment provides a dosage compartment, wherein the compartment comprises a delayed release coating (e.g. sustained, extended or pulsatile release coating).
  • a delayed release coating e.g. sustained, extended or pulsatile release coating
  • one or more pulsatile release coatings can be provided to deliver a burst of cannabinoid release at one or more predetermined time intervals (e.g. a burst at a time between about 1 and 5 hrs, 2 and 4 hrs, or 2.5-3.5 hrs, such as a burst at 2 hrs, 2.5 hrs, 3 hrs, 3.5 hrs, or 4 hrs).
  • any dosage compartment taught herein may comprise a delayed release coating in order to provide a delayed release compartment.
  • an otherwise immediate release compartment e.g. an immediate release liquid soft gel or hard gel
  • a delayed release coating i.e. a delayed release modifier coating
  • a delayed release compartment of the invention e.g. a delayed release liquid soft gel or hard gel
  • the coated compartment may be a solid compartment, liquid compartment, or semi-solid compartment.
  • the delayed release coating may be a continuous coat which encapsulates the compartment as a whole (e.g. surrounding an entire tablet compartment, hard gel compartment or microparticles compartment as a whole).
  • the delayed release coating may be a discontinuous coating, and coat the compartment by individually encapsulating components of the compartment (e.g. by surrounding individual microparticles, hard gels, or tablets which make up the compartment).
  • a discontinuous delayed release coating is optionally useful when one compartment (e.g. solid microparticles) is mixed with another compartment (e.g. an immediate release liquid compartment) because it further segregates the compartments (in the medicament and/or once ingested).
  • any release modifying coating may be used to encapsulate a compartment taught herein.
  • the coating may comprise a hydrophobic release modifier, for example, an alkylcellulose (e.g. ethyl cellulose), an acrylic polymer, mixture thereof, and the like.
  • the delayed release coating is applied in the form of an organic or aqueous solution or dispersion.
  • the delayed release coating comprises a plasticizer, or other excipient, such as optional excipients taught herein.
  • the delayed release (e.g. pulsatile release) coating is pH dependent.
  • the delayed release coating is a water swellable sustained release coating.
  • the delayed release coating is low permeability coating or a high
  • the delayed release coating is a low melting point hydrophobic material (e.g. wax).
  • ethylcellulose A non-limiting example of a useful alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a delayed release coating according to the invention.
  • aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer.
  • the organic solvent is evaporated under vacuum to form a pseudolatex.
  • aqueous dispersion of ethylcellulose is commercially available as Surelease®
  • plasticizer (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
  • acrylic polymers include acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • a delayed release acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are described, for example, as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the delayed release coating is pH dependent.
  • the pH dependent delayed release coating is a pulsatile release coating to deliver a burst of cannabinoid release at a predetermined time (e.g. upon entering the gut).
  • the pH dependent delayed release coating is a water-swell able coating.
  • the amount of water absorbed by the coating is pH-dependent.
  • the delayed release coating does not swell at about pH ⁇ 5.7 and is soluble at about pH > 6.
  • the delayed release coating does not swell at about pH ⁇ 6.5 and is soluble at about pH > 7.
  • Methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention.
  • Eudragit® there are a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit® from Evonik.
  • Eudragit E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media.
  • Eudragit L is a methacrylic acid copolymer which does not swell at about pH ⁇ 5.7 and is soluble at about pH > 6.
  • Eudragit S does not swell at about pH ⁇ 6.5 and is soluble at about pH > 7.
  • Eudragit RL and Eudragit RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, medicaments coated with Eudragit RL and RS may be pH-independent.
  • a useful acrylic delayed release coating comprises a copolymer of acrylic and methacrylic esters with a low content of quaternary ammonium groups, for example, having a molar ratio of ammonium groups to the remaining neutral
  • a useful acrylic delayed release coating comprises a mixture of two acrylic resin lacquers, e.g. those commercially available from Evonik under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.
  • Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :20 in Eudragit® RL30D and 1 :40 in Eudragit® RS30D.
  • the mean molecular weight is about 150,000.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a delayed- release formulation having a desirable profile.
  • Optional delayed- release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL , 50% Eudragit® RL:50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS.
  • acrylic polymers may also be used, such as, for example, Eudragit®L.
  • a delayed release coating comprises a plasticizer.
  • a plasticizer for example, where the coating is produced with an aqueous dispersion of a hydrophobic delayed release material, an effective amount of a plasticizer is optionally provided to further improve the physical properties of the release modifying coating.
  • a plasticizer for example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, one may incorporate a plasticizer into an ethylcellulose release coating (or other alkylcellulose or other delayed release coating) before using the same as a coating material.
  • the amount of plasticizer included in a coating solution is based on the concentration of a film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former.
  • plasticizer Concentration of the plasticizer, may be determined based on routine experimentation with the particular coating solution and method of application.
  • suitable plasticizers for ethylcellulose and the like include dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, and triacetin, although it is possible that other plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
  • suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate, tributyl citrate, dibutyl phthalate, and possibly 1 ,2-propylene glycol.
  • plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • triethyl citrate is used as a plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • a delayed release coating comprises a small amount of talc. This may, for example, reduce the tendency of the aqueous dispersion of a hydrophobic delayed release coating to stick during processing, and may additionally act as a polishing agent.
  • composition components for example, bulk stability, dissolution and other release properties of composition components (e.g. solid, liquid, or semi-solid dosage compartments) may be manipulated by choosing an appropriate excipient, amount thereof, or formulation method using such.
  • excipients include:
  • Binders such as acacia, alginic acid and salts thereof, cellulose
  • magnesium aluminum silicate polyethylene glycol, gums, polysaccharide acids, bentonites, hydroxypropyl methylcellulose, gelatin, polyvinylpyrrolidone,
  • polymethacrylates hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, pregelatinized starch, ethylcellulose, tragacanth, dextrin, microcrystalline cellulose, sucrose, or glucose, and the like.
  • Disintegration agents such as starches, pregelatinized corn starch, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, cross-linked polyvinylpyrrolidone, a calcium, a sodium alginate complex, clays, alginates, gums, or sodium starch glycolate, and any disintegration agents used in tablet preparations.
  • 00128 (c) Filling agents such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, Pluronic.TM. line (BASF), and the like.
  • pH correcting agents such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, their alkaline salts, sodium bicarbonate and sodium carbonate and the like.
  • Stabilizers such as any antioxidation agents, buffers, or acids, and the like, can also be utilized.
  • Lubricants such as magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, magnesium, calcium and sodium stearates, stearic acid, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, or sodium lauryl sulfate, and the like.
  • Lubricants such as magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, magnesium, calcium and sodium stearates, stearic acid, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, or sodium la
  • Wetting agents such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, or sodium lauryl sulfate, and the like.
  • Diluents such lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, or bentonite, and the like.
  • Anti-adherents or glidants such as talc, corn starch, DL-leucine, sodium lauryl sulfate, and magnesium, calcium, or sodium stearates, and the like.
  • Pharmaceutically compatible carriers comprising acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan,
  • delayed release modifiers e.g. selected from optional excipients
  • delayed release coatings e.g. selected from optional excipients
  • extended release coatings e.g. selected from optional excipients
  • the present medicaments can optionally be combined with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents can be provided as immediate release agents, delayed release agents, or a
  • the present medicaments can optionally be combined with therapeutic agents useful in the treatment of a cannabinoid-sensitive disorder.
  • the one or more additional therapeutic agents are optionally therapeutic agents useful in the treatment of cannabinoid-sensitive disorder selected from: apnea, seizures, a neurological disorder, a pain disorder, an appetite or wasting disorder, nausea, vomiting, a sleep disorder, a breathing disorder, or a sleep-related breathing disorder.
  • the present medicaments are combined with one or more anti- apnea therapeutic agents, for example, any of: serotonin reuptake inhibitors, serotonin receptor antagonists, serotonin receptor (e.g. subtype 1 ) agonists, serotonin agonists, noradrenalin reuptake inhibitors, combined serotonin/noradrenalin reuptake inhibitors, glutamate receptor antagonists, glutamate antagonists, inhibitors of glutamate release, glycine antagonists , GABA receptor agonists, calcitonin gene-related peptide (CGRP) receptor antagonists or release inhibitors, adenosine, adenosine analogs and nucleoside (e.g.
  • adenosine uptake blockers or reuptake inhibitors opioid antagonists, vanilloid receptor ligands, pilocarpine compounds, sodium proton pump inhibitors, ubidecarenones, antihistimines, prostaglandins, prostanoid receptor antagonists , inhibitors of prostanoid synthesis, modulators of CRTH2, COX-2 and/or FAAH, antitussive agents, compounds that stimulate the central nervous system, agents that prolong the action of endocannabimimetics, inhibitors of endocannabinoid membrane transport, inhibitors of cannabinoid metabolism, and cannabinoid degradative enzyme antagonists.
  • the present medicaments are combined with one or more anti- apnea therapeutic agents or combinations of apnea therapeutic agents disclosed in any of: US6331536, US6555564, US6727242, US7160898, US6974814, US7705039, US20060241 164, US20070123517, US20080200367, US20080261922,
  • WO/2007/047372 disclose useful examples of the anti-apnea therapeutic agents and/or other anti-apnea therapeutic agents.
  • the present medicaments are combined with one or more anticonvulsants, for example, anti-convulsants of any of the following types: aldehydes, aromatic allylic alcohols, barbiturates, benzodiazepines, bromides, carbamates, carboxamides, fatty acids, fructose derivatives, gaba analogs, hydantoins,
  • anticonvulsants for example, anti-convulsants of any of the following types: aldehydes, aromatic allylic alcohols, barbiturates, benzodiazepines, bromides, carbamates, carboxamides, fatty acids, fructose derivatives, gaba analogs, hydantoins,
  • oxazolidinediones propionates, pyrimidinediones, pyrrolidines, succinimides, sulfonamides, triazines, ureas, and valproylamides (amide derivatives of valproate).
  • the present medicaments are combined with one or more analgesics, for example, any of: NSAIDs (e.g. ibuprofen), paracetamol, COX-1 inhibitors, COX-2 inhibitors, COX-3 inhibitors, opioids (e.g. hydrocodone or oxycodone), morphinomimetics, flupirtine, tricyclic antidepressants (e.g. amitriptyline), tetracyclic antidepressants, anticonvulsants (e.g.
  • NK1 receptor antagonists e.g., ezlopitant and SR- 14033, SSR-241585
  • CCK receptor antagonists e.g., loxiglumide
  • NK3 receptor antagonists e.g., talnetant, osanetant SR-142801 , SSR-241585
  • NRI norepinephrine- serotonin reuptake inhibitors
  • NRI norepinephrine- serotonin reuptake inhibitors
  • cannabinoid receptor agonists e.g., arvanil
  • sialorphin inhibitors of neprilysin
  • CCK receptor agonists e.g., caerulein
  • SSRIs e.g.
  • fluoxetine, paroxetine, or sertraline serotonin receptor agonists, serotonin receptor antagonists, triptans (e.g. sumatriptan), GABA analogs (e.g. GABApentin or pre-gabalin), muscle relaxants, alpha- adrenergic, PDEV inhibitors, PDEVII inhibitors, and glycine antagonists.
  • triptans e.g. sumatriptan
  • GABA analogs e.g. GABApentin or pre-gabalin
  • muscle relaxants alpha- adrenergic
  • PDEV inhibitors e.g. PDEV inhibitors
  • PDEVII inhibitors e.glycine antagonists.
  • the present medicaments are combined with one or more anxiolytic or anti-anxiety therapeutic agents, for example, any of: benzodiazepines, buspirone, tricyclic antidepressants, SSRIs, monoamine oxidase inhibitors,
  • antipsychotic agents e.g. Atarax or Vistaril
  • barbiturates e.g.
  • phenobarbital phenobarbital
  • beta-blockers e.g. propranolol
  • propanediols e.g.
  • the present medicaments are combined with one or more anti- wasting therapeutic agents or appetite stimulants, for example, any of: tricyclic antidepressants, tetracyclic antidepressants, cyproheptadine, buclizine, megestrol, ginger, EPA (fish oil), erthythropoietin, thalidomide, ghrelin, interferon, melatonin, non- steroidal anti-inflammatories, nandrolone, antidepressants, atypical antipsychotics such as olanzapine, dexamethasone, prednisolone and methylprednisolone.
  • anti- wasting therapeutic agents or appetite stimulants for example, any of: tricyclic antidepressants, tetracyclic antidepressants, cyproheptadine, buclizine, megestrol, ginger, EPA (fish oil), erthythropoietin, thalidomide, gh
  • the present medicaments are combined with one or more anti- glaucoma therapeutic agents, e.g., fish oil and omega 3 fatty acids, bilberries, vitamin E, cannabinoids, carnitine, coenzyme Q10, curcurmin, Salvia miltiorrhiza, dark chocolate, erythropoietin, folic acid, Ginkgo biloba, Ginseng, L-glutathione, grape seed extract, green tea, magnesium, melatonin, methylcobalamin, N-acetyl-L cysteine, pycnogenols, resveratrol, quercetin and salt, magnesium, ginkgo, salt and fludrocortisone.
  • one or more anti- glaucoma therapeutic agents e.g., fish oil and omega 3 fatty acids, bilberries, vitamin E, cannabinoids, carnitine, coenzyme Q10, curcurmin, Salvia miltiorrhiza, dark chocolate
  • the present medicaments are combined with one or more antiemetics, e.g., serotonin receptor antagonist, dopamine antagonist, NK1 receptor antagonist, antihistamine, benzodiazepine, anticholinergic, or steroid such as
  • the present medicaments are combined with one or more additional therapeutic agents selected from: antihistamines, antimicrobial agents, fungistatic agents, germicidal agents, hormones, antipyretic agents, antidiabetic agents, bronchodilators, antidiarrheal agents, antiarrhythmic agents, coronary dilation agents, glycosides, spasmolytics, antihypertensive agents, antidepressants, antianxiety agents, antipsychotic agents, other psychotherapeutic agents, steroids, corticosteroids, analgesics, cold medications, vitamins, sedatives, hypnotics, contraceptives,
  • additional therapeutic agents selected from: antihistamines, antimicrobial agents, fungistatic agents, germicidal agents, hormones, antipyretic agents, antidiabetic agents, bronchodilators, antidiarrheal agents, antiarrhythmic agents, coronary dilation agents, glycosides, spasmolytics, antihypertensive agents, antidepressants
  • nonsteroidal anti-inflammatory drugs blood glucose lowering agents, cholesterol lowering agents, anticonvulsant agents, other antiepileptic agents, immunomodulators, anticholinergics, sympatholytics, sympathomimetics, vasodilatory agents,
  • anticoagulants having various pharmacologic activities, diuretics, sleep aids, antihistaminic agents, antineoplastic agents, oncolytic agents, antiandrogens, antimalarial agents, and antileprosy agents.
  • the present medicaments can optionally be combined with one or more SSRIs, e.g., fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, norfluoxetine, r(-) fluoxetine, s(+) fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, milnacipran, sibutramine, nefazodone, R-hydroxynefazodone, (-)venlafaxine, and (+) venlafaxine.
  • SSRIs e.g., fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, norfluoxetine, r(-) fluoxetine, s(+) fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, milnacipran, sibutramine, nefazodone, R-hydroxynefazodone, (-)venlafaxine, and (+) venlafaxine.
  • the present medicaments can optionally be combined with one or more serotonin receptor antagonists, e.g., the free base form or a quaternized form of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochlorcyclizine, perlapine, ondansetron (GR38032F), ketanserin, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, (-) cisapride, (+) norcisapride, (-) norcisapride, desmethylolanzapine, 2- hydroxymethylolanzapine, 1 -(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1 -one- O -(2-dimethylaminoe
  • methysergide granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3- tropanyl-indole-3-carboxylate, 3-tropanyl-indole-3-carboxylate methiodide, and other serotonin receptor antagonists and their quaternized forms or one of its
  • the present medicaments can optionally be combined with one or more serotonin receptor agonists, e.g., 8-OH-DPAT, sumatriptan, L694247 (2-[5-[3-(4- methylsulphonylamino)benzyl-1 ,2,4-oxadiazol-5-yl ]-1 H-indol-3yl]ethanamine), buspirone, ainitidan, zaiospirone, ipsapirone, gepirone, zolmitriptan, risatriptan, 31 1 C90, a-Me-5-HT, BW723C86 (1 -[5(2-thienylmethoxy)-1 H-3-indolyl[propan-2-amine
  • serotonin receptor agonists e.g., 8-OH-DPAT, sumatriptan, L694247 (2-[5-[3-(4- methylsulphonylamino)benzyl-1 ,
  • the present medicaments can optionally be combined with one or more a 2 adrenergic receptor antagonists, e.g., phenoxybenzamine, phentolamine, tolazoline, terazosine, doxazosin, trimazosin, yohimbine, indoramin, ARC239, and prazosin.
  • a 2 adrenergic receptor antagonists e.g., phenoxybenzamine, phentolamine, tolazoline, terazosine, doxazosin, trimazosin, yohimbine, indoramin, ARC239, and prazosin.
  • the present medicaments can optionally be combined with one or more noradrenalin reuptake inhibitors, e.g. desipramine, nortriptyline, reboxetine, nisoxetine, atomoxetine, or LYI 39603 (tomoxetine).
  • noradrenalin reuptake inhibitors e.g. desipramine, nortriptyline, reboxetine, nisoxetine, atomoxetine, or LYI 39603 (tomoxetine).
  • the present medicaments can optionally be combined with one or more antitussive agents, e.g., RSD931 , FK888, CP99994, SR48968, codeine, SRI 42801 , SB235375, nociceptin/orphanin FQ, 15-HPETE, NADA, anandamide, lidocaine, benzonatate, mexiletine, NS 1619, furosemide, zafirlukast, HOE140, dihydrocodone, oxycodone, BW443C noscapine, dextromethorphan, SKF10047, baclofen,
  • antitussive agents e.g., RSD931 , FK888, CP99994, SR48968, codeine, SRI 42801 , SB235375, nociceptin/orphanin FQ, 15-HPETE, NADA, anandamide, lidocaine, benzonatate, mexiletine, NS 1619
  • the present medicaments can optionally be combined with one or more CCK receptor antagonists, e.g. CCK A receptor antagonist, a CCK B receptor antagonists, or an antagonist exhibits activity against both CCK A and CCK B receptors.
  • CCK receptor antagonists which exhibit activity toward both CCK A and CCK B receptors include benzotript and proglumide.
  • Examplary CCK A receptor antagonists include L-364,718 (devazepide); loxiglumide; dexloxiglumide; lorglumide; L-lorglumide; D-lorglumide; PD- 140,548; TP-680; T-0632; A-67396; A-70276; A-71 134 and SR 27897.
  • Examplary CCK B receptor antagonists include CR2945; YM022; it glumide; L-740,093; L-365,260; L- 156,586; LY-262691 ; ureidoacetamides (e.g., RP 69758, RP 72540, RP 73870);
  • CCK receptor antagonists include, but are not limited to, A-64718; A-65186; spiroglumide; CR-2345; CR-2767; CR2622; tarazepide; L-365,260; L-708,474; L-368,730; L-369,466; L-736,380; FK-480; FR175985; FR193108;
  • the present medicaments can optionally be combined with one or more NSAIDs, e.g., aspirin, choline and magnesium salicylates, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, magnesium salicylate, meclofenamate sodium, mefenamic acid, meloxicam,
  • NSAIDs e.g., aspirin, choline and magnesium salicylates, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen
  • nabumetone nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, or valdecoxib.
  • the present medicaments can optionally be combined with one or more prostanoid receptor antagonists, e.g., AH-6809, ONO-871 1 and ONO-8713, L-161 ,982 (4), AH-23848 (4), ONO-AE3-208 (4), SC19220, ONO-871 1 , SC51089, L-798,106, prostanoid receptor antisense oligonucleotides, ONO-8713, ONO-AE829, ONO-AE2- 227, SC51322, ZD-6416, ONO-3144, ONO-3708, ONO-NT-12, SC-236, SC-299, SC- 51234A, SKF-104493, SKF-105561 , SKF-105809, SKF-106978, SKF-86002, SQ- 28852, CGP-47969A, CGS-1 1776, FR-122047, L-640035, L-651392, L-651896, L- 655240
  • the present medicaments can optionally be combined with one or more CGRP receptor antagonists, e.g., BIBN4096BS, SB-(+)-273779, CGRP 8 -37 , Compound 1 (4-(2-oxo-2,3-dihydro- benzoimidazol-l-y A -piperidine-l-carboxylic acid [l-(3,5-dibromo- 4-hydroxy-benzyl)-2- oxo-2-(4-phenyl-piperazin-l-yl)-ethyl]-amide), and other CGRP receptor antagonists (see, Arulmani et ah, 2004, Eur J Pharmacol 500:315-330 for review)
  • the present medicaments can optionally be combined with one or more opioids, e.g. buprenorphine, butorphanol, codeine, fentanyl, hydrocodone,
  • opioids e.g. buprenorphine, butorphanol, codeine, fentanyl, hydrocodone,
  • hydromorphone methadone, morphine, oxycodone, or propoxyphene.
  • the present medicaments can optionally be combined with one or more glutamate antagonists, e.g. NMDA antagonists, AMPA antagonists, or kainate receptor antagonists.
  • Examplary glutamate receptor antagonists include D-AP5 (D(-)-2-amino-5- phosphonopentanoate), CGS19755 (4-phosphonomethyl-2-piperidine carboxylic acid), CGP37849 (D,L-(E)-2-amino-4-methylphosphono-3-pentanoic acid), LY233053 (cis-( ⁇ )- 4-(2H-tetrazol-5-yl)methyl-piperidine-2-carboxylic acid), AIDA (1 -aminoindan-1 ,5(RS)- dicarboxylic acid), (S)-(+)-CBPG ((s)-(+)-2-(3'-carboxy-bicyclo(1.1.1 .)pentyl)glycine), CPCCOEt (cycloprop
  • present medicaments can optionally be combined with one or more
  • NMDA antagonist e.g., L- glutamate derivatives, tetrahydroquinoline, imidazoloquinoxalinone, isatine, fused cycloalkylquinoxalinediones, quinoxaline, spermine, a 4-hydroxy-3-nitro-1 ,2-dihydroquinolon-2-one derivative, an indole derivative, a benzo-thiadiazine dioxide derivative, an indeno(1 ,2-b)pyrazin-3-one or corresponding 2,3-dione, a quinoline derivative, an ethyl
  • imino-methano dibenzo (A,D) cycloheptene derivative an indole-hydrazone, a piperazine derivative, a 4,6-disubstituted tryptophan and kynurenine derivative, a fluorenamine compound, a diketo-pyhdo pyrazine derivative or its salts, a 2-amino-3,4- dioxo-1 -cyclobutene derivative, a 2-acyl-amido derivative of 3,4-dihydro-3-oxo- quinoxaline, a benzimidazole phosphono-aminoacid derivative, a quinoxaline phosphono-aminoacid derivative, a piperazine, piperidine or pyrrolidone derivative, ist salts and isomeric forms including stereoisomers, a 4-hydroxy-2(1 H)-quinolinone derivative, ist salts and prodrugs, a fused pyrazine derivative,
  • a 4,6-dihalo indole2-carboxylic acid derivative a cyclic aminohydroxamate derivative, a tetracyclic amine derivative, a 2,4-dioxo-1 ,2,3,4-tetrahydroquinoline derivative, a 2,4-dioxo-1 ,2,3,4- tetrahydroquinoline derivative, a 3-phosphonopiperidine and p-pyrrolidine derivative, a benzothieno (2,3-B)-pyrazine-2,3-(1 H,4H)-dione, a spiro dibenzosuberane derivative, a benzomorphan derivative, a preparation of 3,4-disubstituted 2-isoxazoline(s) and isoxazoles(s), a 3-indolyl thio-acetate derivative, an arginine-derived nitric oxide biosynthesis inhibitor, a dicyclic amine derivative, a spiroiso
  • benzobicycloalkane amine an isoquinoline phosphonate derivative, an ⁇ , ⁇ '-disubstd.-guanidine compound, a phosphonopropenyl piperidine carboxylic acid compound, (2R,3S,4S)-alpha-carboxycyclo-propyl-glycine, a pyrrolidine derivative, a dihydroxy-fused heterocyclyl quinoxaline derivative, a hydrogenated derivative of MK801 and analogues, a 5-substd.
  • spermine or related polyamine derivative a 4a-amino-fluorene compound or a heterocyclic analogue, a cyclooctane-imine derivative, a R-3-amino-1 -hydroxy pyrrolidin-2-one or methionine hydroxamate, a 10,1 1 - dihydro-5H-dibenzo-cyclohepten-5,10-imine compound, a polyhydro-10, 1 1 -dihydro-5H- benzo(a,d)cyclohepten-5,10 imine derivative, a 4-oxo-1 ,4-dihydroquinoline compound with 2-acidic groups, a heterocyclykalkene-phosphonic acid compound, a phosphono gp-containing pyridine 2-carboxylic acid, an alpha-amino-alpha-(3-alkylphenyl)alkyl ethanoic acid, its esters or amides, a 10, 1 1 1 -dihydr
  • cycloalkylquinoxaline-dione derivative a pyridazino-quinoline derivative, a 1 -Alpha- amino-3-biphenyi-propanoic acid derivative, a 3-(lndol-3-yl) propenoic acid derivative, a spiro-heterocycle ⁇ midazo-indeno-pyrazine-4-one derivative, a 2-heterocyclyk3- indolylpropenoic acid derivative, a piperidinoalkyl heterocyclic ketone or alcohol compound, a pyrrolyl-tetrahydro-benzoquinoxaline-dione derivative, a 7-imidazolyl or dialkylamino,tetrahydroquinoxaline dione compound, a dibenzocycloheptene, a quinoxaline derivative, an aryl-thio-quinoxaline derivative, a heterocyclic substd.
  • imidazolo-quinoxaline derivative a 1 ,4-dihydro-quinoxaline-2,3-dione derivative, an oxa- or thia-aliphatically bridged quinoxaline derivative, an aza-aliphatically bridged quinoxaline-2,3-dione compound, a 3-amido- or 3-sulphamido-indole compound, a 3,5- disubstd.
  • phenyl-naphthalene derivative an imidazo (1 ,2-a)indeno (1 ,2-e) pyrazine-2- carboxylic acid derivative, a 3-phenyl-fused ring pyridine-dione derivative, a 2-phenyl- pyridazino-indole-dione derivative, a 4,6-disubstd.
  • kynurenine compound a phosphono derivative of imidazo(1 ,2-a)pyrimidine-2-carboxamide, a tetrahydro-quinoxaline-dione derivative with N-(alkyl)carbonyl-amino- or ureido group, a tryptophan derivative, a hetero-aliphatic or hetero-araliphatic substd.
  • quinolone derivative an imidazo-pyridine dicarboxylic acid derivative, a composition containing pyrazolo-quinoline derivatives, an ethanodihydrobenzoquinolizinium salt, an oxopyridinylquinoxaline derivative, an indeno- triazolo-pyrazin-4-one derivative, an imidazo-indeno-pyrazinone derivative, an imidazo- indeno-pyrazin-4-one derivative, an imidazo(1 ,2-a)pyrazine-4-one derivative, a 5H- indeno-pyrazine-2,3-dione derivative, a phenyl-aminoalkyl-cyclopropane N,N-diethyl carboxamide compound, a dexanabinol derivative, a substituted chroman derivative, a sulphonamide quinazoline-2-4-dione compound, a 6-and 8-aza-, and 6,8-diaza- 1 ,4d
  • dihydrobenzothiadiazinedioxide carboxylic acid derivative a methyl- butenylmethyl(hydroxy-propyl)carbazoledione, an imidazo pyrazinone derivative, an imidazo-(1 ,2-a)pyrazine-4-one, a benzazepine-dione derivative, disulfiram, a 3-(indol3- yl)-propenoic acid derivative, a 1 ,2,3,4-tetrahydro-quinoline-2,3,4-trione-3 or 4-oxime compound, a peptide antagonist at NMDA receptors, a 2-amino-2phenyl(alkylyacetic acid derivative, 6-halo-tryptophan or a 4-halo-kynurenine, a 6-tetrazolyl or isoxazoly- decahydro-isoquinoline-3-carboxylic acid derivative, an an imidazolylbenzene or salts thereof.
  • the present medicaments can optionally be combined with one or more AMPA antagonists, e.g., L- glutamate derivatives, amino alkanoic acid derivatives, o amino-3-hydroxy-5-methyl-4-isoxazolepropionate derivatives, acetyl-aminophenyl- dihydro-methyl-methyl-dioxolobenzodiazepi ne, acid amide derivatives, amino-phenyl- acetic acid, 2,3-benzodiazepin-4-one, alkoxy-phenyl-benzodiazepine, amino- or desamino 2,3-benzodiazepine, benzothiadiazine, a-carboline-3-carboxylic acid, fused cycloalkylquinoxalinediones, decahydroisoquinoline, 4-hydroxypyrrolone, 4-hydroxy- pyrrolo-pyridazinone, imidazo-pyrazinone, imidazolo-quinoxalinone, indeno-pyr
  • the present medicaments can optionally be combined with one or more kainate receptor antagonists, e.g., L- glutamate derivatives, kainic acid derivatives, acid amide derivatives, aminoalkanoic acid derivatives, aminophenyl(alkyl)acetic acid derivatives, fused cycloalkylquinoxalinediones, quinoxalinedione, imidazolo- quinoxalinone, isatine, phenylazolophthalazine, pyridothiazines, 4-phosphonoalkyl- quinolinone, quinolinone, quinazoline, quinazolinedione, quinoxalinedione, and sulphamate derivatives.
  • kainate receptor antagonists e.g., L- glutamate derivatives, kainic acid derivatives, acid amide derivatives, aminoalkanoic acid derivatives, aminophenyl(alkyl)acetic acid derivatives, fused cycloalkylquinoxaline
  • the present medicaments can optionally be combined with one or more inhibitors of glutamate release, e.g., lamotrigine, BW1003C87, riluzole, isoguvacine, muscimol, THIP, piperidine-4-sulphonic acid, flunitrazepam, Zolpidem, abecarnil, ZK93423, L-baclofen, CGP27492, piracetam, progabide, and CGP35024.
  • the present medicaments can optionally be combined with one or more glutamate reuptake promoters, e.g. zonisamide.
  • the present medicaments can optionally be combined with one or more combined serotonin/noradrenaline reuptake inhibitors, e.g., venlafaxine, milnacipran, duloxetine, pregabalin, LY248686, and Strattera.
  • serotonin/noradrenaline reuptake inhibitors e.g., venlafaxine, milnacipran, duloxetine, pregabalin, LY248686, and Strattera.
  • the present medicaments can optionally be combined with one or more tricyclic antidepressants, e.g., amitriptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin, imipramine, imipraminoxide, lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, and quinupramine.
  • tricyclic antidepressants e.g., amitriptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin
  • the present medicaments can optionally be combined with one or more tetracylic antidepressants, e.g., amitriptyline, amitriptylinoxide, butriptyline,
  • tetracylic antidepressants e.g., amitriptyline, amitriptylinoxide, butriptyline,
  • clomipramine demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin, imipramine, imipraminoxide, lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, or quinupramine.
  • the present medicaments can optionally be combined with one or more dopamine antagonist, e.g., domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, alizapride, or prochlorperazine.
  • dopamine antagonist e.g., domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, alizapride, or prochlorperazine.
  • the present medicaments can optionally be combined with one or more nk1 receptor antagonists, e.g., aprepitant or casopitant.
  • the present medicaments can optionally be combined with one or more antihistamine, e.g., cyclizine, diphenhydramine dimenhydrinate , meclizine,
  • one or more antihistamine e.g., cyclizine, diphenhydramine dimenhydrinate , meclizine,
  • promethazine or hydroxyzine.
  • the present medicaments can optionally be combined with one or more benzodiazepines, e.g., midazolam or lorazepam.
  • the present medicaments can optionally be combined with one or more anticholinergics, e.g., hyoscine.
  • present medicaments can optionally be combined with one or more or steroids, e.g, dexamethasone.
  • any of the formulations set forth in Table 1 can usefully be prepared to provide the PK profile of any of PK Profile 1 through PK Profile 19.
  • a medicament comprises a formulation comprising components set forth in Table 1 , except that the total cannabinoid amount is +/- 50% (e.g. +/- 30% or +/- 20%) of that listed in Table 1 .
  • Medicaments of the present invention provide a therapeutic window that is a longer window than provided by an immediate release medicament (e.g. as compared to a Marinol capsule containing an equivalent amount of the cannabinoid).
  • Examples of useful therapeutic windows provided by the present medicaments are about 4 to about 12 hours.
  • useful therapeutic windows provided here are about 6 to about 10 hours, about 6 to about 9 hours, about 6 to about 8 hours, about 7 to about 8 hours, or about 7 to about 9 hours.
  • the plasma levels are reduced below a level that can result in undesired side effects such as impeded cognitive and/or psychomotor performance, tachycardia, hypotension, or impaired learning and memory.
  • compositions of the present invention comprise cannabinoids in an amount of about 0.1 mg to about 75 mg or optionally about any of the following amounts (in mg): 0.5 to 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 to 50, 2.5 to 20.
  • medicament of the present invention typically will provide a side-effect sparing efficacy for an extended treatment window, certain individuals will have a higher threshold for both therapeutic efficacy and for side effects. The same is true for certain individuals who will have a lower threshold for efficacy and for side effects. Therefore, there is a remarkable and unexpected utility of the present medicaments containing a cannabinoid in the full range of about 0.1 mg to about 75 mg.
  • the invention provides a method of treating apnea comprising administering less than about 20 mg of cannabinoid during a therapeutic window taught herein.
  • the present invention is a titration kit and titration methods for determining optimal dose.
  • Subjects are initially administered a low dose of the medicament for a treatment period. At the completion of the treatment period, the dose in the
  • medicament is increased or the number of medicament units is increased (a "step-up") for 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, or 3) until the maximum dose generally considered safe is administered.
  • treatment-related side effects are evaluated during treatment periods.
  • Relevant evaluations include mental alertness, emotional health, quality of life, sleepiness, etc.
  • a clinically-relevant metric(s) of the disorder or condition being treated is assessed during each treatment period.
  • Methods are readily known for quantifying or assessing apnea, pain, spasms, etc.
  • an initial "low dose" THC medicament of the present invention can contain about any mg amounts of a cannabinoid, e.g. 0.1 , 0.5, 1 , 2, 5, 10, 20, or 50 (mg).
  • a treatment period for each dose is about 1 to about 10 days or about 5 to about 10 days, or longer than 10 days.
  • a typical step-up dose increase is any percent of about 10, 20, 25, 33, 50, 100, 200, or 400 (%).
  • an empirically determined dose that is well tolerated (minimal or no significant side effects) and optimally effective is selected. This selected dose is administered for another period (e.g. 1 or more days or more than 1 week or more than 1 month.
  • the subject is administered a "step down" lower dose medicament (e.g. about 50% to about 75% or about 20% to about 50% of the previous dose).
  • a “step down” lower dose medicament e.g. about 50% to about 75% or about 20% to about 50% of the previous dose.
  • a clinically relevant metric of efficacy and side effects are assessed. If therapeutic efficacy is not diminished (over the previous dose), the subject can optionally be administered a dose with a further reduction (i.e. a second or subsequent step-down).
  • the subject has sleep apnea and is administered a 0.1 or 0.5 mg THC medicament of the present invention (e.g. 0.5, 1 , 1 .5, or 2 hrs before anticipated sleep time) for a treatment period. During this treatment period, overnight PSG is optionally performed. If the patient tolerates this dose (e.g. minimal treatment related side effects), a step-up dose is administered daily for another treatment period. Therapeutic profile is assessed, and a subsequent escalation is performed until clinically-relevant side effects are observed or maximal safe dose is administered.
  • a 0.1 or 0.5 mg THC medicament of the present invention e.g. 0.5, 1 , 1 .5, or 2 hrs before anticipated sleep time
  • overnight PSG is optionally performed.
  • a step-up dose is administered daily for another treatment period. Therapeutic profile is assessed, and a subsequent escalation is performed until clinically-relevant side effects are observed or maximal safe dose is administered.
  • a step-down titration is optionally performed and evaluated.
  • a kit that contains an appropriate number of one or more doses of a medicament (otherwise of the same formulation).
  • the kit optionally contains patient instructions.
  • the doses are in a device that compartmentalizes the daily doses (e.g. a blisterpack).
  • oral administration examplary present medicaments maintains a therapeutic window while not resulting in a plasma levels at any time throughout the treatment window (sleep period) that increase the likelihood of side effects.
  • Such side effect-sparing medicaments avoid one or more of the effects shown in Table 2.
  • the present methods and medicaments are especially useful for treating apnea.
  • the apnea is any of obstructive sleep apnea syndrome, obstructive sleep apnea/hypopnea syndrome, upper airway resistance syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.
  • the present compositions are useful to reduce episodes of apnea, snoring, and sleep disruption, for example as demonstrated by oximetry, or
  • PSG polysomnogram
  • the administered dose and/or medicament comprises 1 mg to 75 mg (e.g. 2.5 mg to 20 mg).
  • Cannabinoid receptors are found predominantly at nerve terminals where they have a role in retrograde regulation of synaptic function and interact with at least acid (e.g. GABA, glutamate), monoamine (e.g. histamine, dopamine, serotonin,
  • noradrenaline noradrenaline purine (e.g. adenosine, ADP, ATP), peptide (e.g. somatostatin, neuropeptide Y, neurokinin, cholecystokinin), vanilloid, prostanoid, opiod and/or other pathways.
  • THCs such as delta-9- tetrahydrocannabinol act as agonists at CB1 and CB2 receptors, mimicking the effects of the naturally occurring
  • the invention provides a method for treating a cannabinoid-sensitive disorder in a subject comprising administering to the subject a medicament taught herein.
  • the cannabinoid-sensitive disorder is a neurological disorder, pain, an appetite or wasting disorder, nausea, vomiting, a seizure disorder, a sleep disorder, breathing disorder, or a sleep-related breathing disorder.
  • the method further comprises administering an additional therapeutic agent for treating the disorder.
  • an additional therapeutic agent is included in the medicament.
  • the additional therapeutic agent is administered sequentially with the medicament.
  • the present methods and medicaments are useful for treating a neurological disorder.
  • the neurological disorder is of the brain, spinal cord, peripheral nerves, or muscles.
  • the neurological disorder is a neurodegenerative disease, a neurological pain, a movement disorder, or a mood disorder.
  • the present methods and medicaments are useful for treating a neurodegenerative disease.
  • the neurodegenerative disease is multiple sclerosis, Huntington's disease, or Alzheimer's disease.
  • the present methods and medicaments are useful for treating a neurological pain.
  • the neurological pain is a central or peripheral neurological pain.
  • the neurological pain is chronic pain.
  • the neurological pain is associated with fibromyalgia, multiple sclerosis, spinal cord injury, or stroke.
  • the present methods and medicaments are useful for treating a movement disorder.
  • the movement disorder is caused by abnormalities in the basal ganglia.
  • the movement disorder is a spasm disorder, muscle spasticity, seizure disorder, chorea, Huntington's disease, dystonia, basal ganglia movement disorder, Parkinson's disease, Tourette's syndrome, dyskinesia, bradykinesia, or epilepsy.
  • the present methods and medicaments are useful for treating a mood disorder.
  • the movement disorder is a depressive disorder, a bipolar disorders, or anxiety.
  • the present methods and medicaments are useful for treating pain.
  • the pain is neurological pain or nociceptive pain.
  • the pain is associated with a movement disorder, a headache, a spasm disorder, arthritis, dystonia, peripheral pain, or muscle aching.
  • treatable pain can be associated with any disorder such as fibromyalgia or multiple sclerosis.
  • Pain that is treatable by the present medicament includes pain associated with any of the infections caused by herpes simplex virus type 1 and type 2 and herpes zoster.
  • Headaches that are treatable by the present medicament include any vascular headache, e.g., migraines, cluster headache, toxic headache, and headache caused by elevated blood pressure.
  • Headaches that are treatable by the present medicament also include tension headaches, postcoital headaches, exertional headaches, trigeminal neuralgia, atypical trigeminal neuralgia, type 2 trigeminal neuralgia, trigeminal autonomic cephalalgias, hortons neuralgia, and histamine headaches, and headaches secondary to head or neck trauma.
  • the present methods and medicaments are used for appetite stimulation or to treat wasting and/or depressed appetite.
  • the wasting and/or depressed appetite is associated with HIV, chemotherapy, anorexia, or Alzheimer's disease.
  • the present methods and medicaments are useful for treating glaucoma.
  • the present methods and medicaments are useful for treating nausea and/or vomiting.
  • the nausea and/or vomiting is associated with viral/microbial illness, HIV/AIDs, cancer, chemotherapy, radiation exposure, postoperative recovery, pregnancy, motion, or poisoning.
  • the present methods and medicaments are useful for treating a subject with a disorder selected from: anorexia, alcohol use disorders, cancer, amyotrophic lateral sclerosis, glioblastoma multiforme, glioma, increased intraocular pressure, glaucoma, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, inflammation, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g.
  • the goal of the clinical trial was to evaluate oral dosing of THC in sleep apnea patients.
  • One objective was to assess low doses of cannabinoids for treatment of apnea.
  • Another objective was to evaluate the therapeutic window of oral cannabinoid in the treatment of sleep-related disorders such as apnea.
  • the trial comprised a single-center, randomized, double-blind, placebo- controlled dose escalation study of dronabinol in 22 patients with OSAS.
  • the study began with a 7-day baseline/PAP-washout period, with polysomnography (PSG) performed on the final night.
  • the study drug (active or placebo) was taken 30 min before bed for 21 days. Overnight PSG was performed on 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 mg on day 15 of treatment. A blood sample was drawn immediately after each PSG for assay of the study drug and principal metabolites.
  • SSS Stanford Sleepiness Scale
  • Evaluable population defined as: all subjects completing a baseline PSG who received at least one dose of study medication, who did not miss more than 3 doses during, and who completed the PSG ending the first 7-day treatment period.
  • Safety/tolerability analyses were performed using the All-Treated population, comprising all subjects who received at least one dose of study medication.
  • All efficacy endpoints were assessed as the change from baseline measurement of the same parameter. For example, efficacy for AH I was examined by subtracting (for each subject) the AH I measured during PSG at the end of the baseline period from the AH I measured at the end of the relevant treatment period (in both active and placebo groups). Thus a decrease in AH I with treatment is represented by a negative value for ⁇ (change from baseline).
  • sleep apnea may be treated with orally administered cannabinoids without causing (or without substantially causing) side effects associated with certain cannabinoids and/or without causing (or without substantially causing) side effects once the subject has awoken (e.g. post treatment window).
  • Example 1 The study from Example 1 was further analyzed with respect to Arousal Index during the early treatment window (i.e., To - T 4 ) and the late treatment window (i.e., T 5 - T 8 ).
  • Example 1 The study from Example 1 was further analyzed with respect to the percentage of subjects demonstrating a 75% reduction in the AH I for 2-, 4-, 6-, and 8- hour consecutive intervals. As shown in Figure 1 , a dose of 2.5 mg (line with square data points) resulted in greater than 60% of the subjects showing a ⁇ 75% reduction (versus baseline) in AH I for at least 2 consecutive hours. In contrast, a dose of 10 mg (line with diamond data points) resulted in fewer than 30% of the subjects showing a 2- hour reduction in AH I of ⁇ 75%. This same phenomenon was seen with respect to a four-hour response interval. Thus, for a 2 and 4 hour treatment window, 2.5 mg of Marinol was more effective in these patients than a 10 mg dose.
  • Example 1 The study from Example 1 was further analyzed for efficacy and dose response of THC with respect to AH I during early (To - T 4 ) and late (T 5 - Ts) treatment windows. In the results are shown in Figure 2; the early treatment window is indicated by stippled bars and the late treatment window is indicated by solid bars.
  • medicaments of the present invention for example, a medicament which provides a PK profile of PK Profile 1 or any of PK Profile 2 through PK Profile 19.
  • a medicament is orally administered to one or more subjects.
  • ADME absorption, distribution, metabolism, and excretion
  • the patient is optionally a fasted patient and optionally falls asleep within one of 15 minutes or 30 minutes of laying down for bed.
  • the same subjects are used for comparing different medicaments (after providing an appropriate wash-out period).
  • Plasma levels of the drug (e.g. THC) and metabolites thereof (e.g. 1 1 -OH- THC) are taken at regular intervals (e.g. every 30 minutes) during a treatment window (e.g. from T 0 to T 8hr ).
  • Therapeutic responses are correlated with pharmacokinetic parameters of the drug or metabolites thereof.
  • the pharmacokinetic parameters include one or more of: plasma concentration and AUC (at various times).
  • An oral dosing "comparator” is provided by orally administering an immediate release dosage of cannabinoid (e.g. MARINOL® soft gel) .
  • cannabinoid e.g. MARINOL® soft gel
  • AH I is improved in subjects receiving 1 to 75 mg.
  • THC e.g. 5 mg - 20 mg
  • the AH I revealed a period of therapeutic efficacy following a latency period.
  • the therapeutic window does not consistently extend through the seventh or eighth hour of sleep.
  • a second oral dosing comparator is provided by the method of Example 6, where a first immediate release dosage of cannabinoid (e.g. 2.5 mg MARINOL® soft gel) to a sleep apnea patient 30 minutes before bed at T 0 .
  • the patient is allowed to fall asleep and at a predetermined time, the subject is briefly woken to receive a second immediate release dosage of MARINOL® soft gel (e.g. at T 3 ) and allowed to return to sleep.
  • AH I is improved in subjects receiving 1 to 75 mg.
  • THC e.g. 5 mg - 20 mg
  • the AH I reveals a period of therapeutic efficacy following a latency period.
  • the therapeutic window generally extends through the seventh or eighth hour of sleep.
  • Figure 4 depicts the relationship of Cmax (ng/ml) and cannabinoid amount (mg) for an immediate release dosage compartment (Marinol formulation). As can be seen from Figure 4, given the drug dose, plasma levels such as Cmax are predictable from an immediate release dosage compartment.
  • the rate of extraction of a drug such as a cannabinoid from a medicament is a key contributor to the resulting PK profile.
  • One method of tailoring a medicament to a desired PK profile involves the use of an in-vitro dissolution assay that mimics or approximates the conditions experienced by the drug in the Gl tract. This assay can be used to predict the rate and/or efficiency of drug extraction after administration.
  • Any dissolution assay is useful when tailoring the PK profile of a medicament.
  • Various assays are known, for example, USP Apparatus 1 (basket), 2 (paddle), 3 (recipricating cylinder), and 4 (flow-through cell).
  • a medicament is placed in an appropriate medium (or media) and the medicament is evaluated by sampling the medium (or media) periodically and determining the fraction or percent of drug dissolved or released at each sampling time.
  • a medicament comprising a delayed release compartment and an immediate release compartment.
  • the delayed release compartment is an aqueous or semi-aqueous liquid compartment comprising:
  • cannabinoid e.g. 9-THC
  • ethanol e.g. 15% to about 65% (e.g. about 45%);
  • polyethylene glycol - from about 1 % to about 25% (e.g. about 10%);
  • aqueous solution e.g. phosphate buffer
  • aqueous solution e.g. phosphate buffer
  • a viscosity modifier e.g. hydroxypropyl cellulose
  • a viscosity modifying amount e.g. about 0.3 %)
  • a medicament of the present invention is produced by combining the delayed release compartment with one or more additional compartments (e.g. an immediate release compartment) to provide a PK profile of at least one of PK Profile 1 through PK Profile 19.
  • additional compartments e.g. an immediate release compartment
  • Example 12 Plurality of Pellets, Continuous Release
  • a medicament comprising a delayed release compartment and an immediate release compartment contained within the same dose unit.
  • the immediate release compartment is a plurality of solid pellets (or microspheres)
  • the delayed release compartment is a plurality of solid pellets comprising a delayed release modifier coating.
  • Table 7 Pellet in Capsule (IR + DR)
  • a film modifier e.g. the addition of hypromellose in an ethylcellulose film increases diffusion or can change the rate of release by making it more hydrophilic
  • a medicament comprising a delayed release compartment and an immediate release compartment contained with the same dose unit.
  • the immediate release compartment is a distinct solid matrix layer without release modifying excipients and the delayed release compartment is a solid matrix layer comprising release modifying agents.
  • the medicament provided in this Example is a solid, adsorbate to facilitate solids handling of dronabinol and incorporation into the solid phase immediate- and delayed-release compartments.
  • the delayed-release compartment releases portions of the dronabinol dose over time in a continuous manner.
  • the prepared powder blend provides immediate release of the dronabinol from the compressed tablet.
  • the prepared powder blend provides for a delayed release of dronabinol from the compressed tablet using Methocel as a rate modifying excipient.
  • the delayed release compartment comprises 75% of the total dose (e.g. 7.5 mg).
  • the combination of the two layers provides for both distinct IR and DR compartments in a tablet.
  • AD Collect the coated tablets from the tablet coater into HDPE drums lined with PE bags and desiccants as required.
  • Example 14 Medicament 2 Pulse, Enteric Coating
  • a medicament comprising a delayed release compartment and an immediate release compartment contained within the same dose unit.
  • the immediate release compartment is a plurality of solid pellets (or microspheres) and the delayed release compartment is a plurality of solid pellets comprising a delayed release modifier (pH dependent, enteric coating).
  • the medicament provided in this example is a solid, adsorbate to facilitate solids handling of dronabinol and incorporation into a solid phase immediate- and delayed-release compartment.
  • the gastrointestinal tract is sufficiently alkaline (e.g. pH > 5.5) to dissolve the coating. Since the coating is insoluble in acidic conditions, the delayed release compartment is released in the small intestine unlike the immediate release compartment which releases in the stomach.
  • Methacrylic Acid Copolymer Type C (Eudragit
  • Pellets represent an immediate release compartment when uncoated and a delayed release compartment when coated. Mixtures of the two in a capsule shell provide for a combination of immediate- and delayed-release compartments. The ratio of the two pellets types allows for variation in weighting of the dose fraction between the two compartments. This example uses a 2.5 mg dose in the immediate release
  • Eudragit L30D-55/L100-55 is meant to release at pH > 5.5, Eudragit L100 at pH > 6, Eudragit FS30D at pH > 7.2, Eudragit S100 at pH > 7.4 while HPMCAS-L at pH > 5.5, HPMCAS-M at pH > 6.0, and HPMCAS-H at pH > 6.8).
  • Eudragit is based on methacrylic acid while HPMCAS is based upon hypromellose acetate succinate.
  • Other enterics include cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, and others.
  • Example 15 Medicament: 3 Pulse, Enteric Coating
  • a medicament comprising 2 delayed release compartments and an immediate release compartment within the same dose unit.
  • the immediate release compartment contains solid pellets (or microspheres) and the delayed release compartments each have solid pellets comprising different delayed release modifier (pH dependent, enteric) coatings.
  • the medicament provided in this example is a solid, adsorbate to facilitate solids handling of dronabinol and incorporation into a solid phase immediate- and delayed-release compartment.
  • the IR compartment releases the dronabinol and the DR. compartment releases its dose of dronabinol when the pH of the gastrointestinal tract is sufficiently alkaline (e.g. pH > 5.5 and pH > 7.2) to dissolve the different coatings (e.g. DR1 and DR2, respectively). Since the coatings are insoluble in acidic conditions, the delayed release compartments release in the upper portion of the small intestine and in the lower portion of the small intestine/large intestine, respectively, unlike the immediate release compartment which releases in the stomach.
  • the pH of the gastrointestinal tract is sufficiently alkaline (e.g. pH > 5.5 and pH > 7.2) to dissolve the different coatings (e.g. DR1 and DR2, respectively). Since the coatings are insoluble in acidic conditions, the delayed release compartments release in the upper portion of the small intestine and in the lower portion of the small intestine/large intestine, respectively, unlike the immediate release compartment which releases in the stomach.
  • Pellets represent an immediate release compartment when uncoated and delayed release compartments when coated with different enteric polymers.
  • Mixtures of the three in a capsule shell provide for a combination of immediate- (IR) and delayed-release compartments (DR1 and DR2).
  • the ratio of the three pellets types allows for variation in weighting of the dose fraction between the two main compartments (e.g. IR and DR) with further refinement in the DR compartment (e.g. DR1 and DR2).
  • This example uses a 2.5 mg dose in the immediate release compartment and a 7.5 mg dose in the delayed release compartment (5.0 mg dose in DR1 and 2.5 mg dose in DR2).
  • Dronabinol DR1 Pellets S) Prepare the required quantity of Methacrylic Acid Copolymer Coating Dispersion by adding the Triethyl Citrate to Eudragit L30D-55 in a suitable tank with mixer.
  • Dronabinol DR1 Pellets from the fluid bed coater.
  • BB Combine the required quantity of purified water (sufficient to provide a final solids content of 20% w/w), triethyl citrate, and glycerol monostearate.
  • Dronabinol 10% w/w Pellets (18-30 mesh) Charge the required quantity of Dronabinol 10% w/w Pellets (18-30 mesh) to a fluid bed coater with bottom spray and a Wurster column insert.
  • Example 16 Two Pulse Enteric Coating
  • a medicament comprising a delayed release compartment and a separate immediate release compartment contained within the same dose unit or package.
  • the immediate release compartment is liquid compartment and the delayed release compartment is a liquid compartment comprising a delayed release modifier (pH dependent, enteric) coating.
  • the delayed-release compartment in this example is prepared by coating a liquid compartment with an enteric polymer.
  • the delayed-release compartment releases the entire dose of the dronabinol when the pH of the gastrointestinal tract is sufficiently alkaline (e.g. pH > 5.5) to dissolve the coating. Since the coating is insoluble in acidic conditions, the delayed release compartment is released in the small intestine unlike the immediate release liquid compartment which releases in the stomach.
  • Example 12 Adjust coatings as set forth in Example 12 and Example 14. • Combine with other DR components as set forth in Example 15.
  • Example 17 Medicament IR/DR (Monolithic/Matrix Tablet, Continuous)
  • a medicament comprising a delayed release compartment and an immediate release compartment contained within the same dose unit.
  • This example also illustrates a contiguous release dosage form of the present invention.
  • the release modification here, in part, is due to spatial localization of the cannabinoid within the dosage form.
  • the IR compartment is localized to the perimeter (and immediate sub-perimeter or periphery) of the dosage form and the DR compartment is localized within or interior to the dosage form.
  • the drug in the IR compartment is not substantially buried within the release modifying matrix
  • the total dose contained with the medicament is continuously released.
  • This is another example of a solid adsorbate type dosage form of the present invention.
  • Dronabinol (1 ) Dissolve Dronabinol (1 ) in Ethanol (200 proof) in a suitable tank with a mixer.
  • T) Collect the coated tablets from the tablet coater into HDPE drums lined with PE bags and desiccants as required.
  • Rate controlling excipients e.g. molecular weight for polymers
  • Change rate controlling excipients e.g. different polymers, different type of material such as a wax
  • Example 18 Medicament IR/DR (Monolithic, Coated Tablet, Continuous)
  • a medicament comprising a delayed release compartment and an immediate release compartment contained within the same dose unit.
  • the IR and DR compartments are spatially oriented within a "continuous release" tablet as was also illustrated in Example 17.
  • This medicament is another example of a solid, adsorbate-type and of a coated DR compartment type dosage form .
  • Dronabinol (1 ) Dissolve Dronabinol (1 ) in Ethanol (200 proof) in a suitable tank with a mixer.
  • G) Collect the dried material from the trays and pass through a No. 20 mesh screen to deagglomerate.
  • H Store in an HPDE drum double lined with PE bags and desiccants as required.
  • T) Combine the Eudragit Triethyl Citrate dispersion and the talc/water dispersion. Mix the dispersion continuously.
  • U) Charge the required quantity of Dronabinol 10 mg tablet cores to a suitable tablet pan coater.

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Abstract

La présente invention concerne un médicament qui conduit à l'administration d'un niveau thérapeutique d'un ou plusieurs cannabinoïdes pendant une fenêtre thérapeutique cliniquement appropriée. La fenêtre thérapeutique est une fenêtre plus longue que celle produite par un médicament à libération immédiate tel que Marinol contenant une quantité équivalente du cannabinoïde. L'administration orale des présentes compositions permet un dosage thérapeutique en maintenant des taux sûrs, sans effet secondaire, d'un cannabinoïde. La présente invention concerne en outre des procédés de traitement de troubles sensibles aux cannabinoïdes.
PCT/US2010/057302 2009-11-18 2010-11-18 Médicaments de cannabinoïde à libération prolongée WO2011063164A2 (fr)

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EP2572731A1 (fr) * 2011-09-26 2013-03-27 Abbott GmbH & Co. KG Formulations à base de dispersions solides
WO2013018050A3 (fr) * 2011-08-01 2013-05-30 Ranbaxy Laboratories Limited Système d'administration de médicaments à libération contrôlée et dissolution améliorée pour médicaments peu solubles dans l'eau
CN103202811A (zh) * 2013-03-22 2013-07-17 中山大学 二氟尼柳固体分散体及其制备方法
WO2013147965A1 (fr) * 2012-03-28 2013-10-03 Freeman Keith Gerald Compositions médicales, procédés de préparation et d'utilisation de ces compositions, et kits comprenant ces compositions
EP2640379A4 (fr) * 2010-11-18 2014-08-13 Pier Pharmaceuticals Administration d'une faible dose de cannabinoïdes
WO2015025312A1 (fr) * 2013-08-21 2015-02-26 Cannabics Pharmaceuticals Inc Compositions combinant une libération immédiate et une libération prolongée de cannabinoïdes, leurs méthodes de fabrication et d'utilisation
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WO2016014454A1 (fr) * 2014-07-21 2016-01-28 Pharmaceutical Productions, Inc. Composition de forme galénique solide pour une administration par voie buccale ou sublinguale de cannabinoïdes
WO2016029215A1 (fr) * 2014-08-22 2016-02-25 Medipath, Inc. Compositions et procédés d'enrobages en cannabinoïdes utilisés dans l'administration de médicaments
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WO2016160542A1 (fr) * 2015-04-01 2016-10-06 India Globalization Capital, Inc. Compositions et méthodes de traitement de troubles épileptiques
WO2018165740A1 (fr) * 2017-03-16 2018-09-20 CannTab Therapeutics, Limited Formulations de cannabinoïdes sous forme de comprimés multicouches à libération modifiée
US10117891B2 (en) 2014-09-16 2018-11-06 India Globalization Capital, Inc. Cannabinoid composition for treating pain
US20180353463A1 (en) * 2011-07-11 2018-12-13 Teewinot Technologies Limited Cannabinoid Formulations
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US10596159B2 (en) 2015-08-12 2020-03-24 India Globalization Capital, Inc. Method and composition for treating cachexia and eating disorders
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US20210220278A1 (en) * 2018-07-18 2021-07-22 Glatt Gmbh Immediate release formulations of cannabinoids
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US11351152B2 (en) 2016-06-15 2022-06-07 India Globalization Capital, Inc. Method and composition for treating seizure disorders
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WO2019030762A3 (fr) * 2017-08-09 2019-03-21 Stahl Veronica Cannabis et ses dérivés pour le traitement de la douleur et de l'inflammation associées à la pulpe dentaire et de la régénération osseuse associée à des défauts osseux de la mâchoire
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US20220354821A1 (en) * 2018-03-19 2022-11-10 Emerald Health Therapeutics Canada Inc. Defined dose cannabis pod
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US20210220278A1 (en) * 2018-07-18 2021-07-22 Glatt Gmbh Immediate release formulations of cannabinoids
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WO2021151169A1 (fr) * 2020-01-31 2021-08-05 AusCann Group Holdings Ltd Composition de cannabinoïdes et procédé de fabrication
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US11654130B2 (en) 2021-01-29 2023-05-23 Curio Ip, Llc Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders
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