Compositions and dosage forms for oral delivery

Abstract

The present disclosure provides pharmaceutical compositions comprising cannabinoid for oral delivery, such as sublingual or buccal delivery, and dosage forms comprising the pharmaceutical compositions. The compositions of the present disclosure are substantially homogeneous and remain stable and single-phase upon storage. Also provided are methods of using the compositions for pain management and treatment of various diseases and conditions, including dementia, sleep disorders, dyskinesia, psychiatric disorders, and multiple sclerosis.

Description

[0001] This application is a divisional application of an invention patent application with an application date of May 10, 2019, application number 201980031628.9, and invention name “Compositions and dosage forms for oral delivery”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 670,374, filed May 11, 2018, which is hereby incorporated by reference in its entirety. Technical Field

[0004] The present disclosure relates to pharmaceutical compositions comprising cannabinoids for oral delivery, such as sublingual or buccal delivery, and dosage forms comprising the pharmaceutical compositions. The compositions of the present disclosure are homogeneous and remain stable upon storage. Methods of using the compositions for pain management and treatment of various diseases and disorders, such as dementia, sleep disorders, movement disorders, mental disorders, and multiple sclerosis, are also provided. Background Art

[0005] Cannabinoids are a diverse class of chemical compounds that act on cannabinoid receptors in cells, thereby altering neurotransmitter release in the brain. The ligands for these receptor proteins include naturally occurring endocannabinoids in animals, phytocannabinoids found in cannabis (Cannabis sativa) and some other plants, and artificially produced synthetic cannabinoids. The most famous cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), which is the main psychoactive compound in cannabis. Cannabidiol (CBD) is another major component of the plant.

[0006] The FDA-approved cannabinoid drug ingredient is (–)-trans-Δ 9 - Tetrahydrocannabinol, also known as dronabinol, is used as an appetite stimulant, antiemetic, and analgesic. Currently, dronabinol and nabilone are the only commercially available FDA-approved cannabinoid drugs. Dronabinol has the following structural formula:

[0007]

[0008] Dronabinol is a clear to amber resinous oil that is viscous at room temperature and hardens when refrigerated. Dronabinol is insoluble in water but can be formulated in oils such as sesame oil.

[0009] Dronabinol is available as a solution in soft gelatin capsules for oral administration under the trade name Commercially available. After oral administration, the gelatin dissolves, releasing the drug. Dronabinol is then absorbed during its passage through the gastrointestinal tract. It is indicated for the treatment of: 1) anorexia associated with weight loss in AIDS patients; and 2) nausea and vomiting associated with cancer chemotherapy in patients who have not responded adequately to conventional antiemetic therapy. Dronabinol is formulated with the following inactive ingredients: Sesame oil, gelatin, glycerin or glycerol, methylparaben, propylparaben and titanium dioxide in capsules sold in doses of 2.5 mg, 5 mg or 10 mg.

[0010] Dronabinol in a soft gelatin capsule formulation is very unstable at room temperature, and it is recommended that the product be stored under refrigerated (2-8°C) or cool (8-15°C) conditions ( Package Labels, Physicians Desk 2003 edition). In addition, It should be packaged in dark, airtight containers and stored in a cool environment between 8°C and 15°C (46°F and 59°F). In addition, due to absorption through the gastrointestinal tract, The dronabinol provided has low bioavailability. It has variable pharmacokinetics due to first-pass metabolism and is poorly absorbed by patients with vomiting and anorexia.

[0011] Currently, dronabinol and nabilone are the only approved cannabinoid drugs commercially available in the United States. is a sublingual spray containing dronabinol and cannabidiol in a 52:48 ratio that is also used to treat spasticity in multiple sclerosis. Manufactured by GW Pharmaceuticals and described in U.S. Patent No. 8,512,767. Same, It must also be refrigerated to maintain chemical stability. resemblance, Limitations include storage stability and poor pharmacokinetics.

[0012] Drug delivery via the oral mucosa is considered a promising alternative to the oral route. Oral spray formulations for sublingual or buccal administration have multiple advantages over solid oral dosage forms, such as enabling the drug to be absorbed directly through the mucosal surface under the tongue, which has a very rich vascular blood supply, resulting in a faster onset of action. Parmar, K. et al., 2017; 8(11): 4533-4539. In addition, oral spray formulations avoid problems associated with first-pass metabolism. Therefore, sublingual sprays may be advantageous when rapid onset and better efficacy are desired. For patients with dysphagia or vomiting and anorexia, oral sprays may have better compliance than oral ingestion forms such as tablets or capsules.

[0013] Generally speaking, when formulating sublingual sprays, technical challenges remain with stability and dosage uniformity of the composition. These challenges become even greater when the active ingredient presents stability and solubility challenges, as is the case with cannabinoids. Particularly challenging is the manufacture of a homogenous cannabinoid oral spray formulation that remains a single phase and does not separate after storage.

[0014] Therefore, there is a need for improved compositions containing cannabinoids for oral delivery via sublingual or buccal routes that are stable, well tolerated, and have enhanced activity. The compositions and methods described herein are directed to these and other objectives. Summary of the invention

[0015] Various non-limiting aspects and embodiments of the present disclosure are described below.

[0016] In one aspect, the present disclosure provides a pharmaceutical composition comprising a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, a film former, and about 49% w / w to about 61% w / w of a propellant, wherein the pharmaceutical composition is an oral liquid pharmaceutical composition, and wherein the pharmaceutical composition is substantially anhydrous. Specifically, the pharmaceutical composition of the present disclosure comprising about 49% w / w to about 61% w / w of a propellant produces a homogenous composition. In one embodiment, the pharmaceutical composition of the present disclosure is a single active pharmaceutical ingredient composition comprising a cannabinoid as a single pharmaceutical ingredient.

[0017] In some embodiments, the pharmaceutical compositions of the present disclosure are homogeneous.In one embodiment, the pharmaceutical compositions of the present disclosure remain stable when stored at about 4°C for at least two years or at room temperature (eg, about 23°C) for at least one month.

[0018] The pharmaceutical composition of the present disclosure comprises a cannabinoid or a pharmaceutically acceptable salt, solvate or derivative thereof. In one embodiment, the cannabinoid is selected from (-)-trans-Δ 9-tetrahydrocannabinol (dronabinol), cannabidiol (CBD), pharmaceutically acceptable salts, solvates or derivatives thereof, and combinations thereof. In one embodiment, the cannabinoid is (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0019] In one embodiment, the pharmaceutical composition comprises about 2% w / w to about 10% w / w of a hydrophobic solvent. In one embodiment, the pharmaceutical composition comprises a hydrophobic solvent that is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0020] In another embodiment, the pharmaceutical composition comprises an alkane solvent (e.g., C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C alkane solvent selected from pentane, hexane, heptane and combinations thereof. 12 Alkane solvents.

[0021] In one embodiment, the pharmaceutical composition comprises about 30% w / w to about 60% w / w of an alcohol-based solvent. In one embodiment, the pharmaceutical composition comprises an alcohol-based solvent selected from ethanol, isopropanol, n-propanol, and combinations thereof. In one embodiment, the alcohol-based solvent is isopropanol.

[0022] In one embodiment, the pharmaceutical composition comprises a co-solvent. In one embodiment, the pharmaceutical composition comprises about 0.5% w / w to about 5% w / w of a co-solvent. In one embodiment, the co-solvent is selected from benzyl alcohol, propylene glycol, dipropylene glycol, glycerol, dimethicone 350, dimethicone 1000, and combinations thereof. In one embodiment, the co-solvent is another alcohol-based solvent. In one embodiment, the co-solvent is benzyl alcohol. In one embodiment, the co-solvent is propylene glycol.

[0023] In one embodiment, the pharmaceutical composition comprises about 0.1% w / w to about 1% w / w of a film former. In one embodiment, the film former is a polymer selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, acrylic polymers, acrylic copolymers, methacrylate polymers, methacrylate copolymers, polyvinyl acetate, cellulose-based polymers, and cellulose-based copolymers.

[0024] In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 61% w / w of a propellant. In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 54% w / w of a propellant. In one embodiment, the propellant is a hydrofluoroalkane selected from 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), or a chlorofluorocarbon (CFC) selected from CFC 11, CFC 12 and CFC 114, and combinations thereof.

[0025] In one embodiment, a pharmaceutical composition according to the present disclosure comprises:

[0026] a. about 0.25% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0027] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0028] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0029] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., selected from benzyl alcohol and propylene glycol);

[0030] e. about 0.1% w / w to about 1% w / w of a film former (e.g., Eudragit E100);

[0031] f. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0032] In one embodiment, the pharmaceutical composition of the present disclosure further comprises a flavoring agent to impart a pleasant taste to the formulation, which may contribute to palatability. In some embodiments, the flavoring agent may be selected from, but not limited to, menthol, levomenthol, mint flavoring, and cinnamon flavoring in a solvent such as an alcohol-based solvent or an oil-based solvent.

[0033] In another aspect, the present disclosure provides a spray for oral application, the spray comprising an oral liquid composition comprising about 0.025% w / w to about 40% w / w of a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, a film former, and about 49% w / w to about 61% w / w of a propellant, wherein the composition is substantially anhydrous. In one embodiment, the spray is for buccal application. In one embodiment, the spray is for sublingual application.

[0034] In one embodiment, the spray of the present disclosure comprises a homogenous composition. In one embodiment, the spray of the present disclosure remains stable when stored at refrigerated temperature (e.g., about 2-8°C or about 4°C) for at least two years or at room temperature (e.g., about 23°C) for at least one month.

[0035] In one embodiment, the cannabinoid is (–)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the spray comprises from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0036] In one embodiment, the spray comprises a hydrophobic solvent, which is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0037] In another embodiment, the spray comprises a hydrophobic solvent, which is an alkane solvent, such as a C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0038] In one embodiment, a spray according to the present disclosure comprises:

[0039] a. about 0.25% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0040] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0041] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0042] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., selected from benzyl alcohol and propylene glycol);

[0043] e. about 0.1% w / w to about 1% w / w of a film former (e.g., Eudragit E100),

[0044] f. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0045] In one embodiment, the spray according to the present disclosure is a multi-dose spray, delivering between 20 and 200 microliters of the composition per dose. In one embodiment, the spray is contained in a metal can. In one embodiment, the metal can contains between about 10 ml and about 100 ml of the composition.

[0046] In one aspect, the present disclosure provides a pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt, solvate or derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, and about 49% w / w to about 61% w / w of a propellant, wherein the pharmaceutical composition is an oral liquid pharmaceutical composition, and wherein the pharmaceutical composition is free of a film former and is substantially anhydrous.

[0047] In one embodiment, the pharmaceutical composition of the present disclosure is homogeneous.In one embodiment, the pharmaceutical composition of the present disclosure remains stable when stored at about 4°C for at least two years or at room temperature (eg, about 23°C) for at least one month.

[0048] In one embodiment, the cannabinoid is selected from (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol), cannabidiol (CBD) or a pharmaceutically acceptable salt or derivative thereof, and combinations thereof. In one embodiment, the cannabinoid is (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0049] In one embodiment, the pharmaceutical composition comprises about 2% w / w to about 10% w / w of a hydrophobic solvent. In one embodiment, the pharmaceutical composition comprises a hydrophobic solvent that is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0050] In another embodiment, the pharmaceutical composition comprises a hydrophobic solvent, which is an alkane solvent, such as a C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0051] In one embodiment, the pharmaceutical composition comprises about 30% w / w to about 60% w / w of an alcohol-based solvent. In one embodiment, the pharmaceutical composition comprises an alcohol-based solvent selected from ethanol, isopropanol, n-propanol, and combinations thereof. In one embodiment, the alcohol-based solvent is isopropanol.

[0052] In one embodiment, the pharmaceutical composition comprises a co-solvent. In one embodiment, the pharmaceutical composition comprises about 0.5% w / w to about 5% w / w of a co-solvent. In one embodiment, the co-solvent is selected from benzyl alcohol, propylene glycol, dipropylene glycol, glycerol, dimethicone 350, dimethicone 1000, and combinations thereof. In one embodiment, the co-solvent is another alcohol-based solvent. In one embodiment, the co-solvent is benzyl alcohol. In one embodiment, the co-solvent is propylene glycol.

[0053] In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 61% w / w of a propellant. In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 54% w / w of a propellant. In one embodiment, the propellant is a hydrofluoroalkane selected from 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), or a chlorofluorocarbon selected from CFC 11, CFC 12 and CFC 114, and combinations thereof.

[0054] In one embodiment, a pharmaceutical composition according to the present disclosure comprises:

[0055] a. about 0.25% w / w to about 10% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0056] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0057] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0058] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., propylene glycol),

[0059] e. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0060] In one embodiment, the pharmaceutical composition of the present disclosure further comprises a flavoring agent.

[0061] In another aspect, the present disclosure provides a spray for oral application, the spray comprising an oral liquid composition comprising a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, and about 49% w / w to about 61% w / w of a propellant, wherein the composition is free of a film former and is substantially anhydrous. In one embodiment, the spray is for buccal application. In one embodiment, the spray is for sublingual application.

[0062] In one embodiment, the spray of the present disclosure comprises a homogenous composition. In one embodiment, the spray of the present disclosure remains stable when stored at about 4°C for at least two years or at about 23°C for at least one month.

[0063] In one embodiment, the cannabinoid is (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the spray comprises from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0064] In one embodiment, the spray comprises a hydrophobic solvent, which is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0065] In another embodiment, the spray comprises a hydrophobic solvent which is an alkane solvent (e.g., C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0066] In one embodiment, a spray according to the present disclosure is substantially anhydrous and comprises an oral liquid composition comprising:

[0067] a. about 0.25% w / w to about 10% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0068] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0069] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0070] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., propylene glycol),

[0071] e. and about 49% w / w to about 61% w / w / w of a propellant (e.g., 1,1,1,2-tetrafluoroethane).

[0072] In one embodiment, a spray according to the present disclosure is substantially anhydrous and comprises an oral liquid composition comprising:

[0073] a. about 2% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0074] b. about 2.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0075] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0076] d. about 2.0% w / w of a co-solvent (e.g., propylene glycol),

[0077] e. and about 53.8% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0078] In one embodiment, the spray according to the present disclosure is a multi-dose spray device, delivering between 20 and 200 microliters of composition per dose. In one embodiment, the spray is contained in a metal can. In one embodiment, the metal can contains between about 10ml and about 100ml of composition.

[0079] In some embodiments, the compositions and dosage forms of the present disclosure are useful for treating, alleviating, or reducing the symptoms of pain (e.g., migraine, neuropathic pain, trigeminal neuralgia), dementia (e.g., Alzheimer's disease, mild cognitive impairment), sleep disorders (e.g., sleep apnea, narcolepsy), movement disorders (e.g., Tourette syndrome, Parkinson's disease), psychiatric disorders (e.g., post-traumatic stress disorder), and multiple sclerosis (e.g., pain associated with multiple sclerosis, incontinence associated with multiple sclerosis).

[0080] In some specific embodiments, the compositions and dosage forms of the present disclosure can be used to treat migraine. In some specific embodiments, the pharmaceutical compositions of the present disclosure can be used to treat, improve or alleviate the symptoms of Alzheimer's disease. In certain embodiments, the pharmaceutical compositions of the present disclosure can be used to treat or prevent Alzheimer's disease.

[0081] In some specific embodiments, the compositions and dosage forms of the present disclosure can be used to treat spasticity (muscle stiffness / twitching) and / or symptom relief of neuropathic pain due to multiple sclerosis (MS). In certain embodiments, the compositions and dosage forms of the present disclosure can be used for analgesic treatment of cancer patients. In specific embodiments, the cancer patient is a patient who experiences pain while receiving opioid therapy.

[0082] In some specific embodiments, the compositions and dosage forms of the present disclosure can be used to treat chemotherapy-induced emesis, nausea, and / or vomiting in cancer patients, to treat HIV / AIDS-related anorexia, and / or as an appetite stimulant.

[0083] In another aspect, the present disclosure provides a method for treating, ameliorating or alleviating the symptoms of a disease, disorder or condition in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure. The diseases, disorders or conditions include pain (e.g., migraine, neuropathic pain, trigeminal neuralgia), dementia (e.g., Alzheimer's disease, mild cognitive impairment), sleep disorders (e.g., sleep apnea, narcolepsy), movement disorders (e.g., Tourette syndrome, Parkinson's disease), psychiatric disorders (e.g., post-traumatic stress disorder), and multiple sclerosis (e.g., pain associated with multiple sclerosis, incontinence associated with multiple sclerosis).

[0084] In one embodiment, the present disclosure provides a method of treating migraine in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure.

[0085] In one embodiment, the present disclosure provides a method for treating, improving or alleviating the symptoms of Alzheimer's disease in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure. A method for treating or preventing Alzheimer's disease is also provided.

[0086] In some embodiments, the compositions and dosage forms are administered at least once a day. In other embodiments, the administration is performed more than once a day, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In one embodiment, the administration is once a day. In one embodiment, the administration is twice a day.

[0087] In some embodiments, the compositions and dosage forms of the present disclosure are administered orally.

[0088] These and other aspects of the present disclosure will become apparent to those of ordinary skill in the art after reading the following detailed description of the disclosure, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 Depicted are the average amount of dronabinol (μg) recovered from the donor chamber, surface, buccal membrane, receiver fluid (RF), and buccal membrane + RF (combination of buccal membrane and receiver fluid) after the final time point (t=24 h).

[0090] Figure 2 A representative schematic diagram of the Franz cell is depicted. DETAILED DESCRIPTION

[0091] Detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments are merely illustrative of the present invention that can be embodied in various forms. In addition, each example given in conjunction with the various embodiments of the present invention is intended to be illustrative rather than limiting. Therefore, the specific structural and functional details disclosed herein should not be interpreted as limiting, but merely as a representative basis for teaching those skilled in the art to employ the present invention in various ways.

[0092] definition

[0093] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0094] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those skilled in the art after reading this disclosure.

[0095] The terms "treat" or "treatment" of a condition, disorder, or illness include: (1) preventing, delaying the development of, or reducing the incidence and / or likelihood of developing at least one clinical or subclinical symptom of a condition, disorder, or illness in a subject who may have or is susceptible to the condition, disorder, or illness but does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or illness; or (2) inhibiting the condition, disorder, or illness, i.e., arresting, reducing, or delaying the development of the disease or its recurrence or at least one clinical or subclinical symptom thereof; or (3) alleviating the disease, i.e., causing regression of the condition, disorder, or illness or at least one clinical or subclinical symptom thereof. The benefit to the subject being treated is statistically significant or at least perceptible to the patient or physician.

[0096] As used herein, "subject" or "patient" or "individual" or "animal" refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models of disease (e.g., mice, rats). In one embodiment, the subject is a human.

[0097] As used herein, the term "effective" as applied to dosage or amount refers to an amount of a compound or pharmaceutical composition sufficient to cause the desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include the amount of each ingredient that would be effective if administered alone. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition to be treated, the specific drug or drugs used, the mode of administration, and the like.

[0098] The phrase "pharmaceutically acceptable" as used in conjunction with the compositions of the present disclosure refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and generally do not produce adverse reactions when administered to mammals (e.g., humans). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by federal regulatory agencies or state governments or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more specifically in humans.

[0099] As used herein, the phrase "therapeutically effective amount" refers to an amount administered to produce the desired effect. The exact amount will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0100] Ranges may be expressed herein as from "about" or "approximately" one particular value and / or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0101] “Comprising” or “containing” or “including” means that at least the specified compound, element, particle or method step is present in the composition, article or method, but does not exclude the presence of other compounds, materials, particles or method steps, even if the other compounds, materials, particles or method steps have the same function as the specified ones.

[0102] As described in detail below, the inventors have discovered after extensive research that specific combinations of solvents, co-solvents, and propellants produce oral liquid pharmaceutical compositions containing cannabinoids that are homogeneous and stable after storage. Surprisingly, pharmaceutical compositions of the present disclosure comprising about 49% w / w to about 61% w / w of propellant produce homogeneous compositions that remain stable when stored at about 4°C for at least two years or at about 23°C for at least one month. As used herein, "stable" compositions are both physically and chemically stable, i.e., they remain homogeneous without phase separation, without significant changes in purity, and / or without significant changes in impurity profile.

[0103] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0104] cannabinoids

[0105] The term "cannabinoid" or "cannabinoid derivative" refers to any cannabinoid isolated from the cannabis plant, or a compound that interacts with cannabinoid receptors or is a synthetically produced cannabinoid mimetic and / or derivative, including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) and dodeca-E,4E,8Z,10E / Z-tetraenoic acid-isobutyramide, cannabigerol (CBG), cannabichromene, cannabichromene (CBL), cannabinol (CBV), tetrahydrocannabinol (THCV), cannabidiol (CBDV), cannabichromene (CBCV), cannabigerol (CBGV) and cannabigerol monomethyl ether (CBGM).

[0106] In some embodiments, the active pharmaceutical ingredient in the composition is tetrahydrocannabinol (THC) or a pharmaceutically acceptable salt thereof. THC exists in many isomeric forms, including (+)-trans-Δ 8 -Tetrahydrocannabinol, (-)-trans-Δ 8 -Tetrahydrocannabinol, (+)-trans-Δ 9 -tetrahydrocannabinol and (-)-trans-Δ 9 -Tetrahydrocannabinol (or dronabinol; trade name ). Scheme 1 shows the location and structure of stereoisomers of THC.

[0107] Solution 1

[0108]

[0109] (-)-trans-Δ 9 -THC (dronabinol) is the main natural component of cannabis. 9 -THC and Δ 8-THC has essentially the same pharmacological properties and its solubility is essentially the same. 8 -THC is more stable, does not oxidize to cannabinoids and is more 9 -THC has a much longer shelf life, but it is less potent in most pharmacological tests (see, e.g., Ophthalmic Res. (1992) 24:142-149). Therefore, it is necessary to include Δ 9 - Stabilized formulations of THC (dronabinol) and other active cannabinoid compounds and derivatives.

[0110] In some embodiments, the cannabinoid used in the present disclosure is (-)-trans-Δ 9 - Tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the cannabinoid used in the present disclosure is (-)-trans-Δ 8 -Tetrahydrocannabinol or a pharmaceutically acceptable salt thereof.

[0112] The cannabinoid may be present in the compositions of the present disclosure at about 0.025% w / w to about 10% w / w cannabinoid, or at about 0.025% w / w to about 5% w / w cannabinoid, or at about 0.05% to about 5%, or at about 0.1% to about 5%, or at about 0.25% w / w to about 2.5% w / w cannabinoid, or at about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5% w / w cannabinoid.

[0113] In some embodiments, the composition comprises about 0.8% w / w cannabinoid.

[0114] In some embodiments, the composition comprises about 2.0% w / w cannabinoid.

[0115] In some embodiments, a cannabinoid (e.g., (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt or solvate thereof) is the only cannabinoid compound present in the composition. In some embodiments, the composition is substantially free of other cannabinoid compounds and / or cannabinoid degradation products.

[0116] In some embodiments, the compositions are substantially free of certain cannabinoid compounds, such as CBD and / or CBG.

[0117] In some embodiments, the emulsion composition is substantially free of Δ 8-THC.

[0118] In some embodiments, cannabinoids are combined with other active pharmaceutical ingredients in the composition. Other active pharmaceutical ingredients include, for example, active pharmaceutical ingredients generally considered suitable for sublingual or buccal use (e.g., fentanyl and nitroglycerin).

[0119] Propellant

[0120] The compositions of the present disclosure include at least one propellant as a delivery vehicle. As used herein, the term "propellant" refers to any volatile short-chain hydrocarbon, hydrofluoroalkane, or chlorofluorocarbon approved by the Food and Drug Administration for use in a pressurized container to move a fluid in a dispenser.

[0121] In some embodiments, the propellant can be a hydrofluoroalkane (HFA). HFA propellants are volatile, non-toxic, non-flammable and environmentally friendly, which makes them excellent delivery vehicles for spray formulations. In some embodiments, the propellant is a hydrofluoroalkane selected from 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) and combinations thereof.

[0122] In one embodiment, the propellant is 1,1,1,2-tetrafluoroethane (HFC-134a).

[0123] In some embodiments, the propellant may be a chlorofluorocarbon (CFC) selected from the group consisting of CFC 11, CFC 12, and CFC 114, and combinations thereof.

[0124] Surprisingly, it was found that a specific range of propellants is required to produce a homogeneous (single phase) composition that is easily dispensed from a pressurized container in the form of a spray. Less than about 49% by weight of propellant may not be sufficient to ensure delivery of the composition, while greater than about 61% by weight of propellant can result in phase separation of the composition in the can (see Example 2).

[0125] In some embodiments, the compositions of the present disclosure comprise from about 49% w / w to about 61% w / w of propellant.In some embodiments, the compositions of the present disclosure comprise from about 49% w / w to about 61% w / w of 1,1,1,2-tetrafluoroethane (HFA-134a).

[0126] In some embodiments, the compositions of the present disclosure comprise from about 49% w / w to about 54% w / w of propellant.In some embodiments, the compositions of the present disclosure comprise from about 49% w / w to about 54% w / w of 1,1,1,2-tetrafluoroethane (HFA-134a).

[0127] In one embodiment, the composition of the present disclosure comprises about 49.5% w / w propellant. In one embodiment, the composition of the present disclosure comprises about 53.5% w / w propellant.

[0128] Film former

[0129] In some embodiments, the composition of the present disclosure includes at least one film former to form a film when applied externally to the oral mucosa. Film formation may be beneficial to extend the residence time of the composition in the mouth to maximize absorption in the oral cavity. Typically, most of the propellant components evaporate almost immediately, thereby concentrating the remaining preparation. The term "film former" encompasses any agent that will form a film substantially in the absence of a propellant or after the propellant and / or a portion of the solvent evaporates.

[0130] In some embodiments, the film former can be a polymer approved for oral administration. In some embodiments, the film former is a polymer selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, acrylic polymers, acrylic copolymers, methacrylate polymers, methacrylate copolymers, polyvinyl acetate, cellulose-based polymers, cellulose-based copolymers, and combinations thereof. Other suitable film formers are provided, for example, in US 8,349,297.

[0131] In one embodiment, the film former is a methacrylate copolymer, or specifically, a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate); or Eudragit E100).

[0132] In some embodiments, the compositions of the present disclosure may comprise from about 0.1% w / w to about 1% w / w of a film former, or about 0.1% w / w, or about 0.2% w / w, or about 0.3% w / w, or about 0.4% w / w, or about 0.5% w / w, or about 0.6% w / w, or about 0.7% w / w, or about 0.8% w / w, or about 0.9% w / w, or about 1.0% w / w of a film former.

[0133] In one embodiment, the composition of the present disclosure may comprise about 0.5% w / w of a film former.

[0134] In some embodiments, the compositions of the present disclosure may include about 0.1% w / w to about 1% w / w of a film former, or about 0.1% w / w, or about 0.2% w / w, or about 0.3% w / w, or about 0.4% w / w, or about 0.5% w / w, or about 0.6% w / w, or about 0.7% w / w, or about 0.8% w / w, or about 0.9% w / w, or about 1.0% w / w of a methacrylate copolymer, such as Eudragit E100.

[0135] In one embodiment, the composition of the present disclosure may include about 0.5% w / w of a methacrylate copolymer, such as Eudragit E100.

[0136] In some embodiments, the compositions of the present disclosure are free of film formers.

[0137] Hydrophobic solvents

[0138] In some embodiments, the composition comprises at least one hydrophobic solvent.Hydrophobic solvents for use in the compositions of the present disclosure encompass solvents that are immiscible or at least substantially immiscible with water.

[0139] In some embodiments, the hydrophobic solvent can be an oil-based solvent. The term "oil-based" encompasses any non-polar chemical substance that is in liquid form and is hydrophobic and lipophilic at ambient temperature and atmospheric pressure. The oil-based solvent can be of animal, plant or synthetic origin. In some embodiments, the oil-based solvent comprises vegetable oil. The non-limiting examples of suitable vegetable oils include hydrogenated vegetable oil, sesame oil, castor oil, soybean oil, olive oil, cottonseed oil and peanut oil or its combination.

[0140] In one embodiment, the composition of the present disclosure may include an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof.

[0141] In one embodiment, the oil-based solvent is sesame oil.

[0142] In some embodiments, the hydrophobic solvent may be an alkane solvent. The term "alkane solvent" encompasses any straight chain, branched chain, or cyclic saturated hydrocarbon that is in liquid form at ambient temperature and atmospheric pressure. Thus, the alkane solvent will typically be a low carbon number alkane, such as C5 to C 12 Alkanes. In some embodiments, the alkane solvent may be selected from pentane, hexane, heptane, and combinations thereof.

[0143] In some embodiments, the hydrophobic solvent may be present in the composition of the present disclosure at about 2% w / w to about 10% w / w, or about 2% w / w, or about 3% w / w, or about 4% w / w, or about 5% w / w, or about 6% w / w, or about 7% w / w, or about 8% w / w, or about 9% w / w, or about 10% w / w of the composition.

[0144] In one embodiment, the hydrophobic solvent may be present in the composition of the present disclosure at about 2% w / w of the composition. In one embodiment, the hydrophobic solvent may be present in the composition of the present disclosure at about 7% w / w of the composition.

[0145] In some embodiments, the oil-based solvent may be present in the composition of the present disclosure at about 2% w / w to about 10% w / w, or about 2% w / w, or about 3% w / w, or about 4% w / w, or about 5% w / w, or about 6% w / w, or about 7% w / w, or about 8% w / w, or about 9% w / w, or about 10% w / w of the composition.

[0146] In one embodiment, the oil-based solvent may be present in the composition of the present disclosure at about 2% w / w of the composition. In one embodiment, the oil-based solvent may be present in the composition of the present disclosure at about 7% w / w of the composition.

[0147] In some embodiments, the alkane solvent may be present in the composition of the present disclosure at about 2% w / w to about 10% w / w, or about 2% w / w, or about 3% w / w, or about 4% w / w, or about 5% w / w, or about 6% w / w, or about 7% w / w, or about 8% w / w, or about 9% w / w, or about 10% w / w of the composition.

[0148] In some embodiments, sesame oil may be present in the compositions of the present disclosure at about 2% w / w to about 10% w / w, or about 2% w / w, or about 3% w / w, or about 4% w / w, or about 5% w / w, or about 6% w / w, or about 7% w / w, or about 8% w / w, or about 9% w / w, or about 10% w / w of the composition.

[0149] In one embodiment, sesame oil may be present in the composition at about 2% w / w of the composition of the present disclosure. In one embodiment, sesame oil may be present in the composition at about 2.2% w / w of the composition of the present disclosure. In one embodiment, sesame oil may be present in the composition at about 2.17% w / w of the composition of the present disclosure.

[0150] In one embodiment, sesame oil may be present in the composition of the present disclosure at about 7% w / w of the composition. In one embodiment, sesame oil may be present in the composition of the present disclosure at about 7.2% w / w of the composition.

[0151] In some embodiments, the compositions of the present disclosure are substantially anhydrous.

[0152] Alcohol-based solvents

[0153] The compositions of the present disclosure include at least one alcohol-based solvent as a carrier. As used herein, an alcohol-based solvent is an organic solvent comprising an alcohol (-OH) group that is miscible, substantially miscible, or partially miscible with water. In some embodiments, a low carbon number alkyl group (e.g., C1-C 12 ) alcohol is used as an alcohol-based solvent in the composition of the present disclosure. In some embodiments, the suitable alcohol-based solvent is selected from ethanol, isopropanol and n-propanol.

[0154] In one embodiment, the alcohol-based solvent is isopropyl alcohol, also known as isopropanol.

[0155] In some embodiments, the alcohol-based solvent may be present in the composition of the present disclosure at about 30% w / w to about 60% w / w, or about 30% w / w to about 50% w / w, or about 30% w / w to about 45% w / w, or about 30% w / w, or about 35% w / w, or about 40% w / w, or about 45% w / w, or about 50% w / w of the composition.

[0156] In one embodiment, the alcohol-based solvent may be present in the composition of the present disclosure at about 40% w / w of the composition.

[0157] In some embodiments, isopropanol can be present in the compositions of the present disclosure at about 30% w / w to about 60% w / w, or about 30% w / w to about 50% w / w, or about 30% w / w to about 45% w / w, or about 30% w / w, or about 35% w / w, or about 40% w / w, or about 45% w / w, or about 50% w / w of the compositions.

[0158] In one embodiment, the composition of the present disclosure comprises about 40% w / w isopropyl alcohol.

[0159] Solvent

[0160] Surprisingly, it was discovered that incorporating another solvent (i.e., a co-solvent) into a cannabinoid formulation in addition to a hydrophobic solvent and an alcohol-based solvent provides a homogenous, monophasic (single-phase) formulation. As used herein, a "co-solvent" is a substance added to a composition comprising one or more primary solvents to increase the solubility of the active agent and impart other desired properties to the composition. In some embodiments, a suitable co-solvent may be selected from benzyl alcohol (BA), propylene glycol (PG), dipropylene glycol (DiPG), glycerin, dimethicone 350, dimethicone 1000, and combinations thereof. In some embodiments, a homogenous composition comprising a co-solvent in an amount of about 0.5% w / w to about 5% w / w of the formulation is provided.

[0161] In one embodiment, the co-solvent is benzyl alcohol.

[0162] In one embodiment, benzyl alcohol is incorporated into the formulation of the present invention as a co-solvent. In some embodiments, the compositions of the present disclosure may include 0.5% w / w to about 5% w / w, or about 1% w / w to about 3% w / w, or about 1.5% w / w to about 2% w / w, or about 2% w / w of benzyl alcohol.

[0163] In another embodiment, the co-solvent is propylene glycol.

[0164] In one embodiment, propylene glycol is incorporated into the formulation of the present invention as a co-solvent. In some embodiments, the compositions of the present invention may include 0.5% w / w to about 5% w / w, or about 1% w / w to about 3% w / w, or about 1.5% w / w to about 2% w / w, or about 2% w / w of propylene glycol.

[0165] In one embodiment, the pharmaceutical composition of the present disclosure further comprises a flavoring agent to impart a pleasant flavor to the formulation, which can contribute to palatability. In some embodiments, the flavoring agent can be selected from, but is not limited to, menthol, levomenthol, mint flavoring, and cinnamon flavoring in a solvent such as an alcohol-based solvent or an oil-based solvent.

[0166] Pharmaceutical compositions comprising film-forming agents

[0167] In one aspect, the present disclosure provides a pharmaceutical composition comprising a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, a film former, and about 49% w / w to about 61% w / w of a propellant, wherein the pharmaceutical composition is an oral liquid pharmaceutical composition, and wherein the pharmaceutical composition is substantially anhydrous.

[0168] In some embodiments, the pharmaceutical compositions of the present disclosure are homogeneous. In one embodiment, the pharmaceutical compositions of the present disclosure are stable when stored at refrigerated temperatures (e.g., about 2-8°C or about 4°C) for at least two years, or at room temperature (e.g., about 23°C) for at least one month.

[0169] In one embodiment, the pharmaceutical composition of the present disclosure is a single active pharmaceutical ingredient composition comprising a cannabinoid as a single pharmaceutical ingredient.

[0170] The pharmaceutical compositions of the present disclosure comprise cannabinoids or their derivatives. In one embodiment, the cannabinoids are selected from (–)-trans-Δ 9 -tetrahydrocannabinol (dronabinol), cannabidiol (CBD) or a pharmaceutically acceptable salt or derivative thereof, and combinations thereof. In one embodiment, the cannabinoid is (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0171] In one embodiment, the pharmaceutical composition comprises about 2% w / w to about 10% w / w of a hydrophobic solvent. In one embodiment, the pharmaceutical composition comprises a hydrophobic solvent that is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0172] In another embodiment, the pharmaceutical composition comprises a hydrophobic solvent, which is an alkane solvent, such as a C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0173] In one embodiment, the pharmaceutical composition comprises about 30% w / w to about 60% w / w of an alcohol-based solvent. In one embodiment, the pharmaceutical composition comprises an alcohol-based solvent selected from ethanol, isopropanol, n-propanol, and combinations thereof. In other embodiments, the solvent is isopropanol.

[0174] In one embodiment, the pharmaceutical composition comprises about 0.5% w / w to about 5% w / w of a co-solvent. In one embodiment, the co-solvent is selected from benzyl alcohol, propylene glycol, dipropylene glycol, glycerin, dimethicone 350, dimethicone 1000, and combinations thereof. In one embodiment, the co-solvent is another alcohol-based solvent. In one embodiment, the co-solvent is benzyl alcohol. In one embodiment, the co-solvent is propylene glycol.

[0175] In one embodiment, the pharmaceutical composition comprises about 0.1% w / w to about 1% w / w of a film former. In one embodiment, the film former is a polymer selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, acrylic polymers, acrylic copolymers, methacrylate polymers, methacrylate copolymers, polyvinyl acetate, cellulose-based polymers, and cellulose-based copolymers.

[0176] In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 61% w / w of a propellant. In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 54% w / w of a propellant. In one embodiment, the propellant is a hydrofluoroalkane selected from 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), or a chlorofluorocarbon selected from CFC 11, CFC 12 and CFC 114, and combinations thereof.

[0177] In one embodiment, a pharmaceutical composition according to the present disclosure is substantially anhydrous and comprises:

[0178] a. about 0.25% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0179] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0180] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0181] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., a co-solvent selected from benzyl alcohol and propylene glycol);

[0182] e. about 0.1% w / w to about 1% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0183] f. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0184] In one embodiment, a pharmaceutical composition according to the present disclosure is substantially anhydrous and comprises:

[0185] a. about 0.8% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0186] b. about 2% w / w to about 8% w / w of a hydrophobic solvent (e.g., sesame oil);

[0187] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0188] d. about 2% w / w of a cosolvent (e.g., a cosolvent selected from benzyl alcohol and propylene glycol);

[0189] e. about 0.5% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0190] f. and about 49% w / w to about 54% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0191] In one embodiment, a pharmaceutical composition according to the present disclosure is substantially anhydrous and comprises:

[0192] a. about 0.8% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0193] b. about 7.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0194] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0195] d. about 2.0% w / w of a cosolvent (e.g., benzyl alcohol);

[0196] e. about 0.5% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0197] f. and about 49.5% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0198] In another embodiment, the pharmaceutical composition according to the present disclosure is substantially anhydrous and comprises:

[0199] a. about 2.0% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0200] b. about 2.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0201] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0202] d. about 2.0% w / w of a co-solvent (e.g., propylene glycol);

[0203] e. about 0.5% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0204] f. and about 53.3% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0205] In one embodiment, the pharmaceutical composition of the present disclosure further comprises a flavoring agent.

[0206] Pharmaceutical composition without film-forming agent

[0207] In one aspect, the present disclosure provides a pharmaceutical composition comprising a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, and about 49% w / w to about 61% w / w of a propellant, wherein the pharmaceutical composition is an oral liquid pharmaceutical composition, and wherein the pharmaceutical composition is free of a film former and is substantially anhydrous.

[0208] In one embodiment, the pharmaceutical composition of the present disclosure is homogeneous. In one embodiment, the pharmaceutical composition of the present disclosure is stable when stored at refrigerated temperature (e.g., about 2-8°C or about 4°C) for at least two years, or at room temperature (e.g., about 23°C) for at least one month.

[0209] In one embodiment, the pharmaceutical composition of the present disclosure is a single active pharmaceutical ingredient composition comprising a cannabinoid as a single pharmaceutical ingredient.

[0210] In one embodiment, the cannabinoid is selected from (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol), cannabidiol (CBD) or a pharmaceutically acceptable salt or derivative thereof, and combinations thereof. In one embodiment, the cannabinoid is (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the pharmaceutical compositions of the present disclosure comprise from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0211] In one embodiment, the pharmaceutical composition comprises about 2% w / w to about 10% w / w of a hydrophobic solvent. In one embodiment, the pharmaceutical composition comprises a hydrophobic solvent that is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0212] In another embodiment, the pharmaceutical composition comprises a hydrophobic solvent, which is an alkane solvent, such as a C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0213] In one embodiment, the pharmaceutical composition comprises about 30% w / w to about 60% w / w of an alcohol-based solvent. In one embodiment, the pharmaceutical composition comprises an alcohol-based solvent selected from ethanol, isopropanol, n-propanol, and combinations thereof. In other embodiments, the solvent is isopropanol.

[0214] In one embodiment, the pharmaceutical composition comprises about 0.5% w / w to about 5% w / w of a co-solvent. In one embodiment, the co-solvent is selected from benzyl alcohol, propylene glycol, dipropylene glycol, glycerin, dimethicone 350, dimethicone 1000, and combinations thereof. In one embodiment, the co-solvent is another alcohol-based solvent. In one embodiment, the co-solvent is benzyl alcohol. In one embodiment, the co-solvent is propylene glycol.

[0215] In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 61% w / w of a propellant. In one embodiment, the pharmaceutical composition of the present disclosure comprises about 49% w / w to about 54% w / w of a propellant. In one embodiment, the propellant is a hydrofluoroalkane selected from 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), or a chlorofluorocarbon selected from CFC 11, CFC 12 and CFC 114, and combinations thereof.

[0216] In one embodiment, a pharmaceutical composition according to the present disclosure is free of film formers and is substantially anhydrous, and comprises:

[0217] a. about 0.25% w / w to about 10% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0218] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0219] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0220] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., propylene glycol),

[0221] e. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0222] In one embodiment, a pharmaceutical composition according to the present disclosure is free of film formers and is substantially anhydrous, and comprises:

[0223] a. about 2% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0224] b. about 2.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0225] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0226] d. about 2% w / w of a co-solvent (e.g., propylene glycol);

[0227] e. and about 53.8% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0228] In one embodiment, the pharmaceutical composition of the present disclosure further comprises a flavoring agent.

[0229] Spray for oral application comprising a film former

[0230] In another aspect, the present disclosure provides a spray for oral application, the spray comprising an oral liquid composition comprising about 0.025% w / w to about 40% w / w of a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, a film former, and about 49% w / w to about 61% w / w of a propellant, wherein the composition is substantially anhydrous. In one embodiment, the spray is for buccal application. In one embodiment, the spray is for sublingual application.

[0231] In one embodiment, the spray of the present disclosure comprises a homogenous composition. In one embodiment, the spray of the present disclosure remains stable when stored at refrigerated temperature (e.g., about 2-8°C or about 4°C) for at least two years or at room temperature (e.g., about 23°C) for at least one month.

[0232] In one embodiment, the cannabinoid is (-)-trans-Δ 9-tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the spray comprises from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0233] In one embodiment, the spray comprises a hydrophobic solvent, which is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0234] In another embodiment, the spray comprises a hydrophobic solvent, which is an alkane solvent (e.g., C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0235] In one embodiment, a spray according to the present disclosure is substantially anhydrous and comprises an oral liquid composition comprising:

[0236] a. about 0.25% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0237] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0238] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0239] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., a co-solvent selected from benzyl alcohol and propylene glycol);

[0240] e. about 0.1% w / w to about 1% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0241] f. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0242] In one embodiment, the spray according to the present disclosure is a multi-dose spray, delivering between 20 and 200 microliters of the composition per dose. In one embodiment, the spray is contained in a metal can. In one embodiment, the metal can contains between about 10 ml and about 100 ml of the composition.

[0243] In one embodiment, a spray according to the present disclosure is substantially anhydrous and comprises an oral liquid composition comprising:

[0244] a. about 0.8% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0245] b. about 2% w / w to about 8% w / w of a hydrophobic solvent (e.g., sesame oil);

[0246] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0247] d. about 2% w / w of a cosolvent (e.g., a cosolvent selected from benzyl alcohol and propylene glycol);

[0248] e. about 0.5% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0249] f. and about 49% w / w to about 54% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0250] In one embodiment, a spray according to the present disclosure is substantially anhydrous and comprises an oral liquid composition comprising:

[0251] a. about 0.8% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0252] b. about 7.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0253] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0254] d. about 2.0% w / w of a cosolvent (e.g., benzyl alcohol);

[0255] e. about 0.5% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0256] f. and about 49.5% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0257] In another embodiment, a spray according to the present disclosure is substantially anhydrous and comprises an oral liquid composition comprising:

[0258] a. about 2.0% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0259] b. about 2.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0260] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0261] d. about 2.0% w / w of a co-solvent (e.g., propylene glycol);

[0262] e. about 0.5% w / w of a film former (e.g., a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E100)),

[0263] f. and about 53.3% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0264] In one embodiment, the spray of the present disclosure further comprises a flavoring agent.

[0265] Spray for oral application without film former

[0266] In another aspect, the present disclosure provides a spray for oral application, the spray comprising an oral liquid composition comprising a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, and about 49% w / w to about 61% w / w of a propellant, wherein the composition is free of a film former and is substantially anhydrous. In one embodiment, the spray is for buccal application. In one embodiment, the spray is for sublingual application.

[0267] In one embodiment, the spray of the present disclosure comprises a homogenous composition. In one embodiment, the spray of the present disclosure remains stable when stored at refrigerated temperature (e.g., about 2-8°C or about 4°C) for at least two years or at room temperature (e.g., about 23°C) for at least one month.

[0268] In one embodiment, the cannabinoid is (-)-trans-Δ 9 -tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof. In one embodiment, the spray comprises from about 0.025% w / w to about 40% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 10% w / w of a cannabinoid. In one embodiment, the spray comprises from about 0.25% w / w to about 2% w / w of a cannabinoid.

[0269] In one embodiment, the spray comprises a hydrophobic solvent, which is an oil-based solvent. In one embodiment, the hydrophobic solvent is an oil-based solvent selected from sesame oil, soybean oil, hydrogenated vegetable oil and combinations thereof. In one embodiment, the oil-based solvent is sesame oil.

[0270] In another embodiment, the spray comprises a hydrophobic solvent, which is an alkane solvent (e.g., C5-C 12 In one embodiment, the hydrophobic solvent is a C5-C5 hydrocarbon selected from pentane, hexane, heptane, and combinations thereof. 12 Alkane solvents.

[0271] In one embodiment, a spray according to the present disclosure is free of film formers and is substantially anhydrous and comprises an oral liquid composition comprising:

[0272] a. about 0.25% w / w to about 10% w / w of dronabinol or a pharmaceutically acceptable salt thereof;

[0273] b. about 2% w / w to about 10% w / w of a hydrophobic solvent (e.g., sesame oil);

[0274] c. about 30% w / w to about 60% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0275] d. about 0.5% w / w to about 5% w / w of a co-solvent (e.g., propylene glycol),

[0276] e. and about 49% w / w to about 61% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0277] In one embodiment, the spray according to the present disclosure is a multi-dose spray, delivering between 20 and 200 microliters (μL) of the composition per dose. In one embodiment, the spray is contained in a metal can. In one embodiment, the metal can contains between about 10 ml and about 100 ml of the composition.

[0278] In one embodiment, a spray according to the present disclosure is free of film formers and is substantially anhydrous and comprises an oral liquid composition comprising:

[0279] a. about 2% w / w dronabinol or a pharmaceutically acceptable salt thereof;

[0280] b. about 2.2% w / w of a hydrophobic solvent (e.g., sesame oil);

[0281] c. about 40% w / w of an alcohol-based solvent (e.g., isopropyl alcohol);

[0282] d. about 2% w / w of a co-solvent (e.g., propylene glycol);

[0283] e. and about 53.8% w / w of a propellant (eg, 1,1,1,2-tetrafluoroethane).

[0284] Aerosol cans, valves and actuator packaging

[0285] In one aspect, the present disclosure provides a spray dosage form for oral application (e.g., buccal application or sublingual application), the spray dosage form comprising a pharmaceutical composition according to the present disclosure. In one embodiment, the spray dosage form is contained in a pressurized system comprising a can, a valve, and an actuator.

[0286] Developing formulations in pressurized systems requires that the formulations be stable in contact with the propellant (e.g., HFA 134a) as well as canister, valve, and actuator materials and coatings. Cannabinoids such as dronabinol may be potentially unstable to metal contact, therefore canisters, valves, and actuators with minimal metal contact are preferred.

[0287] In one embodiment, the containers and cans used in contact with the pharmaceutical compositions according to the present disclosure are metal. In one embodiment, the containers and cans are stainless steel or anodized aluminum. In another embodiment, the containers and cans are glass.

[0288] Suitable cans may include, but are not limited to, for example, 3M fluorinated ethylene propylene (FEP) coated cans and Presspart stainless steel and / or anodized aluminum cans which may optionally be coated or treated.

[0289] Suitable valves may include, but are not limited to, for example, 3M stainless steel crimp valves (with or without corrosion resistance treatment), Bespak BK357 metal crimp valves, Rexam 2D, pMDI and / or Inhalia valves, and Lindal Kemp 20 aluminum gold / silver anodized metal valves.

[0290] Suitable actuators may include, but are not limited to, Lindal actuators such as KNM3, NM19, NM19R, NM33, NM170, and NM171; Presspart actuators such as NM2, NM17, NM170, NM19, NM19R, and NM33; and Rexam actuators such as 9180, 8940, 4234, and AA994.

[0291] How to use

[0292] In some embodiments, the compositions and dosage forms of the present disclosure are useful for treating, alleviating, or reducing symptoms of pain (e.g., migraine, neuropathic pain, trigeminal neuralgia), dementia (e.g., Alzheimer's disease, mild cognitive impairment), sleep disorders (e.g., sleep apnea, narcolepsy), movement disorders (e.g., Tourette syndrome, Parkinson's disease), psychiatric disorders (e.g., post-traumatic stress disorder), or multiple sclerosis (e.g., pain associated with multiple sclerosis, incontinence associated with multiple sclerosis).

[0293] In some specific embodiments, the compositions and dosage forms of the present disclosure are useful for treating migraine.

[0294] It has been observed that cannabinoids, especially THC, show potential in treating Alzheimer's disease. Recent data strongly suggest that THC may be a potential therapeutic option for Alzheimer's disease through a variety of functions and pathways. See Cao C, Li Y, Liu H, Bai G, Mayl J, Lin X, Sutherland K, Nabar N, Cai J. The potential therapeutic effects of THC on Alzheimer's disease. Journal of Alzheimer's disease: JAD. 42 (3): 973-84, 2014. Some animal data show that THC reverses disease progression. In some specific embodiments, the pharmaceutical composition of the present disclosure can be used to treat or prevent Alzheimer's disease.

[0295] In some specific embodiments, the compositions and dosage forms according to the present disclosure can be used to treat spasticity (muscle stiffness / twitching) and / or symptom relief of neuropathic pain due to multiple sclerosis (MS). In certain embodiments, the compositions and dosage forms of the present invention can be used for analgesic treatment of cancer patients. In certain embodiments, cancer patients are those patients who still experience pain while receiving opioid therapy.

[0296] In some specific embodiments, compositions and dosage forms according to the present disclosure can be used to treat chemotherapy-induced emesis, nausea, and / or vomiting in cancer patients, to treat HIV / AIDS-related anorexia, and / or as an appetite stimulant.

[0297] In another aspect, the present disclosure provides a method for treating, ameliorating or alleviating the symptoms of a disease, disorder or condition in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure. The diseases, disorders or conditions include pain (e.g., migraine, neuropathic pain, trigeminal neuralgia), dementia (e.g., Alzheimer's disease, mild cognitive impairment), sleep disorders (e.g., sleep apnea, narcolepsy), movement disorders (e.g., Tourette syndrome, Parkinson's disease), psychiatric disorders (post-traumatic stress disorder), and multiple sclerosis (e.g., pain associated with multiple sclerosis, incontinence associated with multiple sclerosis).

[0298] In one embodiment, the present disclosure provides a method of treating migraine in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure.

[0299] In one embodiment, the present disclosure provides a method of treating, ameliorating or alleviating symptoms of Alzheimer's disease in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present disclosure.

[0300] In one embodiment, the present disclosure provides a method of treating or preventing Alzheimer's disease in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form of the present invention.

[0301] In some embodiments, the compositions and dosage forms are administered at least once a day. In other embodiments, the administration is performed more than once a day, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In one embodiment, the administration is once a day. In one embodiment, the administration is twice a day.

[0302] In some embodiments, the compositions and dosage forms of the present disclosure are administered orally.

[0303] Example

[0304] The following examples illustrate certain aspects of the present description. These examples should not be construed as limiting, as these examples merely provide a specific understanding and practice of the embodiments and their various aspects.

[0305] Infiltration and penetration solutions

[0306] A previously validated method was used, based on the FDA's SUPAC-SS guidance [FDA (CDER), 1997, Guidance for industry-SUPAC-SS Non-sterile Semisolid Dosage Form, Scale-up and postapproval changes: Chemistry, manufacturing and controls; in vitro release testing and in vivo bioequivalence documentation], in which 11 formulations were studied during the full study with n = 6 replicates.

[0307] Preliminary in vitro drug release studies were performed using two formulations (H1, a 0.8% w / w formulation and another 0.25% w / w formulation) to optimize the parameters used in the full in vitro drug release experiments. The synthetic membranes used in this study were selected based on membrane binding studies. Figure 2 As shown, the selected synthetic membrane was installed between the donor compartment and the receiving compartment. Before the in vitro drug release study, the selected membrane was installed between the donor compartment and the receiving compartment, and the receiving compartment was filled with the receiving fluid to evaluate the back diffusion through the synthetic membrane. Visual observations were performed at t = 24 and 48 h to evaluate whether the receiving fluid had back diffused into the donor compartment.

[0308] The parameters used for the preliminary in vitro drug release experiments were as follows:

[0309] (i) Individually calibrated Franz cells were used, where the average surface area and volume of each cell were approximately 2 cm 2 and 10mL.

[0310] (ii) Franz cells were fitted with the membrane type selected according to the binding experiments performed and filled with receiving fluid (25% ethanol in water, 50% ethanol in water or 2% Brij 98 w / v in 25% v / v ethanol in water).

[0311] (iii) Another Franz cell (n=1) was also installed with the selected membrane but without the addition of the formulation to serve as a blank.

[0312] (iv) The Franz cell was equilibrated in a water bath pre-calibrated to 37°C to achieve a membrane surface temperature of approximately 37°C.

[0313] (v) Infinite doses (5 actuations, approximately 500 μL) of the selected formulation were applied to the surface of a Franz cell (n=2 for two active formulations (one 0.25% formulation and one 0.8% formulation), n=1 for each placebo).

[0314] (vi) Additional Franz cells were dosed with 0.25% formulation (n=2, plus placebo formulation when n=1), where the dose was again unlimited (5 actuations), but with one minute between each actuation.

[0315] (vii) The Franz cell was protected from light during the study.

[0316] (viii) At each time point, 1 mL of receiving fluid was removed from the Franz cell receiving compartment via the side arm using a 1 mL syringe.

[0317] (ix) After each 1 mL sample was removed from the receiving compartment, 1 mL of fresh pre-heated receiving fluid was replaced, ensuring that there were no bubbles in the receiving compartment.

[0318] (x) The time points for the initial experiment were: t=0, 1, 2, 4, 6, 24, 30 and 48 h, however, the Franz cell was kept in the water bath and may have been sampled at other time points until the samples were analyzed to confirm that the in vitro drug release experiment had been completed, as evidenced by a plateau in dronabinol release.

[0319] (xi) The samples were transferred to amber HPLC vials and analyzed using standard HPLC methods.

[0320] Example 1: Preparation of dronabinol formulation

[0321] The formulations according to some embodiments of the present disclosure are prepared as follows:

[0322] (i) A premix of the formulation was prepared in 10 g batches using the formulation weights detailed in Table 1. The premix was prepared by weighing the required amounts of dronabinol in sesame oil, isopropyl alcohol (IPA), cosolvent (benzyl alcohol, dipropylene glycol and / or propylene glycol), flavoring (levomenthol or mint flavor), and film former (povidone, Eudragit E100 or Eudragit S100) in a 20 mL borosilicate vial.

[0323] (ii) Add PTFE magnetic follower to the formulation premix prepared in step (i) and stir on a magnetic stirring plate until the polymer is solvated and the formulation premix is ​​observed to be miscible.

[0324] iii) The required amount of the specific premix from step (ii) (as detailed in Table 3) was weighed into a 19 mL Pressart aluminum can according to the composition (g) in Table 3. The can was crimped with a 20 mm 100 μL metered dose Lindal valve using the crimping device on a Pamasol aerosol filling machine (SOP 3088).

[0325] (iv) Fill the canister from step (iii) with the required amount of HFA 134a using the aerosol filling apparatus of the Pamasol apparatus (to make a 10 g batch).

[0326] (v) Shake the jar vigorously by hand to ensure mixing of the premix and HFA 134a.

[0327] Tables 1 to 3 below illustrate the compositions of various non-limiting embodiments according to the present disclosure.

[0328] Table 1: Composition of active dronabinol formulations in cans (% w / w)

[0329]

[0330] Table 2: Composition of the active formulation as a premix for the preparation of a 10 g batch before preparing the active formulation in the tank (g)

[0331]

[0332] (-)*Not included

[0333] Table 3: Composition of can formulations with premix and HFA134a (g)

[0334]

[0335] Example 2: Level of dronabinol in can (% w / w)

[0336] In some embodiments, the formulation delivers a dose of 0.25 mg to 2 mg of dronabinol upon application. Table 4 details the dronabinol (% w / w) required in the canister to achieve such doses for different available actuator volumes (25, 50, 75, 85, and 100 μL). The miscibility of sesame oil in 40% IPA / HFA 134a has been determined to be 7.2% w / w, equivalent to 0.8% dronabinol, based on 10% w / v dronabinol in sesame oil. Therefore, the dose (mg) of dronabinol produced by each different actuator volume based on a 0.8% w / w dronabinol level in the canister has been given in Table 5.

[0337] Table 4: Calculated levels of dronabinol in the canister (% w / w) required to achieve 0.25 mg and 2.00 mg doses at different actuator volumes

[0338]

[0339] Table 5: Calculated dronabinol dosage for each actuator volume based on 0.80% w / w dronabinol level in the canister (maximum level observed from miscibility experiments with sesame oil and HFA 134a)

[0340]

[0341] As demonstrated in Tables 4 and 5, using dronabinol in sesame oil, the desired doses of dronabinol (0.25-2.00 mg) can be achieved using actuator volumes of 25-100 μL.

[0342] Example 3: Compositions with different levels of HFA 134a

[0343] Compositions containing dronabinol, isopropyl alcohol (IPA), sesame oil, benzyl alcohol (as a cosolvent), a film former (Eudragit E100, Eudragit S100 or povidone) and HFA 134a (as a propellant) in an amount ranging from 57% w / w to 63% w / w were prepared and visually observed. The results are summarized in Table 6 below. Herein and throughout the examples, the following abbreviations are used: SO (sesame oil), IPA (isopropyl alcohol), BA (benzyl alcohol), PG (propylene glycol) and DiPG (dipropylene glycol).

[0344]

[0345]

[0346] As shown by the results in Table 6, compositions containing up to 61% propellant (ie HFA 134a) were stable and remained homogeneous without phase separation after storage at 2-8°C for at least 72 hours.

[0347] Example 4: Compositions containing flavoring agents

[0348] Flavoring agents such as levomenthol and mint flavor were incorporated into a dronabinol (2.25% w / w) formulation in sesame oil containing benzyl alcohol as a cosolvent. The composition (% w / w) and visual observations of the formulations containing high concentrations of levomenthol (0.1% w / w) and mint flavor (0.05% w / w) are summarized in Table 7 below.

[0349]

[0350] As shown in Table 7 above, all formulations were observed to be single phase and therefore physically compatible.

[0351] Example 5: Stability Study

[0352] Formulations with different film formers (Eudragit E100 and Povidone) and different amounts of isopropyl alcohol, benzyl alcohol and propellant were prepared and their stability studied. A summary of the results is provided in Table 8 below.

[0353]

[0354] Example 6: Stability Assessment of Dronabinol Formulations

[0355] The composition (% w / w) of each formulation selected and prepared for stability is summarized in Table 9 to include the following components:

[0356] Higher levels of dronabinol in sesame oil (0.8% w / w)

[0357] Lower levels of dronabinol in sesame oil (0.25% w / w)

[0358] Different polymers, namely Povidone, Eudragit E100 and S100

[0359] Different co-solvents, namely benzyl alcohol, propylene glycol and dipropylene glycol

[0360] Flavoring agents, namely levomenthol and mint flavoring

[0361] Each formulation was prepared in 19 mL Pressart stainless steel canisters and 10 mL glass canisters using a 100 μL metered dose Lindal valve. For each formulation (active and placebo), 2 stainless steel canisters were prepared per time point (t=2 weeks and 4 weeks) and per condition (25°C and 2-8°C), and 1 glass canister was prepared per condition. The formulations were analyzed for dronabinol recovery, peak purity percentage, and visual compatibility at each time point and condition.

[0362] Table 9: Composition of active formulation in can, % w / w

[0363]

[0364]

[0365] All formulations were observed to be single phase after storage t=2 weeks at 2-8°C and 25°C, except for formulation H1, where phase separation was observed at 2-8°C. Since H1 was observed to be single phase after storage t=2 weeks at 25°C, and phase separation was only observed at lower temperatures, this would indicate that only minor changes to the levels of IPA and BA should be required to improve physical stability and obtain a single phase formulation. Formulations L3, L4, L5, and L6 were also observed to have phase separation after storage t=4 weeks at 2-8°C. Similar to formulation H1, the levels of IPA and BA can be changed to improve the physical stability of the formulation.

[0366] Example 7: Global in vitro permeation and penetration of dronabinol formulations

[0367] A comprehensive in vitro permeation and penetration study was conducted to evaluate the effects of dronabinol on the The delivery of dronabinol across the buccal membrane from dronabinol formulations according to the present disclosure with and without a film former ("polymer") was compared. These experiments were conducted using porcine buccal membranes, which, unlike rat buccal membranes, are non-keratinized and comparable to human buccal membranes. In this model, swallowing is not involved, where the inclusion of a film former (polymer) is expected to increase the in vivo mucoadhesive properties of the film former-containing formulations and further enhance dronabinol penetration compared to Sativex and other polymer-free formulations.

[0368] The following formulations were studied. Formulation H1v2 contained:

[0369] a. 0.8% w / w dronabinol;

[0370] b. 7.2% w / w sesame oil;

[0371] c. 40.0% w / w isopropyl alcohol;

[0372] d. 2.0% w / w benzyl alcohol;

[0373] e. 0.5% w / w Eudragit E100;

[0374] f. and 49.5% w / w 1,1,1,2-tetrafluoroethane.

[0375] Formulation H1C6 (also referred to as H1C6 with polymer because it contains a film former) contains:

[0376] a. 2.0% w / w dronabinol;

[0377] b. 2. 17% w / w sesame oil;

[0378] c. 40.0% w / w isopropyl alcohol;

[0379] d. 2.0% w / w propylene glycol;

[0380] e. 0.5% w / w Eudragit E100;

[0381] f. and 53.33% w / w 1,1,1,2-tetrafluoroethane.

[0382] Formulation H1V6NP, also known as polymer-free H1C6, comprises:

[0383] a. 2.0% w / w dronabinol;

[0384] b. 2. 17% w / w sesame oil;

[0385] c. 40.0% w / w isopropyl alcohol;

[0386] d. 2.0% w / w propylene glycol;

[0387] e. and 53.83% w / w 1,1,1,2-tetrafluoroethane.

[0388] Formulation L4v2 contains:

[0389] a. 0.25% w / w dronabinol

[0390] b. 2.25% w / w sesame oil;

[0391] c. 40.0% w / w isopropyl alcohol;

[0392] d. 2.0% w / w propylene glycol;

[0393] e. 0.5% w / w povidone;

[0394] f. and 55% w / w 1,1,1,2-tetrafluoroethane.

[0395] Figure 1 Shown are the mean amounts of dronabinol (μg) recovered from the donor chamber, surface, buccal membrane, receiver fluid, and buccal membrane+RF (combination of buccal membrane and receiver fluid) (n=6; ±SEM) after the final time point (t=24 h).

[0396] like Figure 1 As shown, it was observed that for all formulations tested, the highest levels of dronabinol were recovered from the donor compartment and buccal membrane surface.

[0397] The amount of dronabinol recovered from the buccal membrane was highest (μg) after application of H1C6 with polymer, where 56.49 ± 9.56 μg was recovered. The lowest recovery of dronabinol from the buccal membrane was with L4v2 without polymer, where 6.67 ± 0.57 μg was recovered. The rank order of the amount of dronabinol recovered from the buccal membrane from highest to lowest amount was as follows: H1C6 with polymer > H1C6 without polymer > Sativex > L4v2 with polymer > H1v2 with polymer > H1v2 without polymer > L4v2 without polymer. H1C6 with polymer showed statistically higher (p < 0.05) amounts of dronabinol recovered from the cheek compared to L4v2 with polymer, H1v2 with polymer, H1v2 without polymer, and L4v2 without polymer. Sativex only showed statistically higher (p<0.05) amounts of dronabinol recovered from the buccal membrane when compared to L4v2 without polymer.

[0398] It was observed that the level of dronabinol recovered from the receiving fluid after 24 h was highest in the sample dosed with H1C6 without polymer, where 16.38 ± 6.40 μg was recovered, and the lowest recovery of dronabinol was observed in H1v2 without polymer, where 1.58 ± 1.34 μg of dronabinol was observed. The rank order of highest to lowest amount of dronabinol recovered from the receiving fluid after 24 h was as follows: H1C6 without polymer > Sativex > H1C6 with polymer > L4v2 with polymer > H1v2 with polymer > L4v2 without polymer > H1v2 without polymer. It can be noted that there were no statistical differences between all formulations after the 24 h time point (p>0.05).

[0399] For H1C6, L4v2, and H1v2, the effect of the polymer (Eudragit E100 or povidone) on the permeation of dronabinol into and through the buccal membrane can be seen, with the amount of dronabinol (μg) recovered from the buccal membrane combined with the receiving fluid (cheek + RF) being slightly reduced due to the removal of the polymer. For H1C6 with polymer (Eudragit E100), a combined total amount of dronabinol recovered from the buccal membrane and receiving fluid of 62.38 ± 10.09 μg was observed, compared to a combined dronabinol recovery of 60.10 ± 9.41 μg for H1C6 without Eudragit E100. For H1v2, a dronabinol recovery of 19.04 ± 4.41 μg from the buccal membrane and receiving fluid was observed with the polymer (povidone), while a lower amount of dronabinol (13.35 ± 3.41 μg) was observed with the same formulation without povidone. After application of L4v2 containing polymer, the recovery of dronabinol from the buccal membrane and receptor fluid was observed to be 27.25 ± 6.96 μg with polymer (Eudragit E100) and 9.29 ± 1.39 μg without Eudragit E100. These results indicate that the presence of Eudragit E100 in the formulation does not appear to affect the permeation of dronabinol from the formulation.

[0400] ***

[0401] Since various changes can be made to the above subject matter without departing from the scope and spirit of the present disclosure, it is intended that all subject matter contained in the above description or defined in the appended claims be interpreted as descriptions and illustrations of the present disclosure. In view of the above teachings, many modifications and variations of the present disclosure are possible. Therefore, this specification is intended to cover all such substitutions, modifications and variations that fall within the scope of the appended claims.

[0402] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety, as if actually present in this specification.

Claims

1. A pharmaceutical composition comprising about 0.025% w / w to about 40% w / w of a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, a film former, and about 49% w / w to about 61% w / w of a propellant, wherein the pharmaceutical composition is an oral liquid pharmaceutical composition, and wherein the pharmaceutical composition is substantially anhydrous.

2. The pharmaceutical composition of claim 1, wherein the hydrophobic solvent is an oil-based solvent.

3. The pharmaceutical composition of claim 2, wherein the oil-based solvent is selected from sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof.

4. The pharmaceutical composition of claim 2 or 3, wherein the oil-based solvent is sesame oil.

5. The pharmaceutical composition of claim 1, wherein the hydrophobic solvent is C5-C 12 Alkane solvents.

6. The pharmaceutical composition of claim 1 or 5, wherein the hydrophobic solvent is pentane, hexane or heptane or a combination thereof.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the alcohol-based solvent is ethanol, isopropanol or n-propanol or a combination thereof.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the cosolvent is benzyl alcohol, propylene glycol, dipropylene glycol, glycerin, dimethicone 350 or dimethicone 1000 or a combination thereof.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the co-solvent is propylene glycol.

10. The pharmaceutical composition of any one of claims 1 to 8, wherein the co-solvent is benzyl alcohol.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the film former is a polymer selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, acrylic polymers, acrylic copolymers, methacrylate polymers, methacrylate copolymers, polyvinyl acetate, cellulose-based polymers, cellulose-based copolymers, and combinations thereof.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the film former is a methacrylate copolymer.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the film former is a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the cannabinoid is selected from (-)-trans-Δ 9 -Tetrahydrocannabinol (dronabinol), cannabidiol (CBD), pharmaceutically acceptable salts, solvates or derivatives thereof, and combinations thereof.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the cannabinoid is (–)-trans-Δ 9 - Tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the propellant is a hydrofluoroalkane.

17. A pharmaceutical composition as described in any one of claims 1 to 16, wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) or a chlorofluorocarbon selected from CFC 11, CFC 12 and CFC 114, and combinations thereof.

18. The pharmaceutical composition of any one of claims 1 to 17, comprising from about 0.25% w / w to about 10% w / w of a cannabinoid.

19. The pharmaceutical composition of any one of claims 1 to 18, comprising from about 0.25% w / w to about 2% w / w of a cannabinoid.

20. The pharmaceutical composition of any one of claims 1 to 19 comprising about 0.8% w / w cannabinoid.

21. A pharmaceutical composition as claimed in any one of claims 1 to 20 comprising about 2% w / w cannabinoid.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the hydrophobic solvent is present at about 2% w / w to about 10% w / w of the pharmaceutical composition.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the alcohol-based solvent is present at about 30% to 60% w / w of the pharmaceutical composition.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein the alcohol-based solvent is present at about 40% w / w of the pharmaceutical composition.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the co-solvent is present at about 0.5% w / w to about 5% w / w of the pharmaceutical composition.

26. The pharmaceutical composition of claim 25, wherein the co-solvent is present at 2% w / w of the pharmaceutical composition.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the pharmaceutical composition comprises from about 0.1% w / w to about 1% w / w of the film former.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the pharmaceutical composition comprises about 0.5% w / w of the film former.

29. The pharmaceutical composition of any one of claims 1 to 28, comprising about 49% w / w to about 54% w / w of propellant.

30. A pharmaceutical composition comprising: a. about 0.025% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof; b. about 2% w / w to about 10% w / w of a hydrophobic solvent; c. about 30% w / w to about 60% w / w of an alcohol-based solvent; d. about 0.5% w / w to about 5% w / w of a co-solvent; e. about 0.1% w / w to about 1% w / w of a film former; f. and from about 49% w / w to about 61% w / w of a propellant.

31. The pharmaceutical composition of any one of claims 1 to 30, further comprising a flavoring agent.

32. The pharmaceutical composition of claim 30, wherein the film former is present at about 0.5% w / w.

33. A spray comprising an oral liquid composition comprising from about 0.025% w / w to about 40% w / w of a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, a film former, and from about 49% w / w to about 61% w / w of a propellant, wherein the composition is substantially anhydrous and the spray is for oral administration.

34. The spray of claim 33, wherein the spray is for buccal application.

35. The spray of claim 33, wherein the spray is for sublingual application.

36. The spray of any one of claims 33 to 35, wherein the hydrophobic solvent is an oil-based solvent.

37. The spray of claim 36, wherein the oil-based solvent is selected from the group consisting of sesame oil, soybean oil, hydrogenated vegetable oil, and combinations thereof.

38. The spray of claim 36 or 37, wherein the oil-based solvent is sesame oil.

39. The spray of any one of claims 33 to 35, wherein the hydrophobic solvent is C5-C 12 Alkane solvents.

40. The spray formulation of claim 33 to 35 or 39, wherein the hydrophobic solvent is selected from the group consisting of pentane, hexane, heptane, and combinations thereof.

41. The spray of any one of claims 33 to 40, wherein the alcohol-based solvent is selected from the group consisting of ethanol, isopropanol, n-propanol, and combinations thereof.

42. The spray of any one of claims 33 to 41, wherein the co-solvent is present and is selected from the group consisting of benzyl alcohol, propylene glycol, dipropylene glycol, glycerin, dimethicone 350, dimethicone 1000, and combinations thereof.

43. A spray as claimed in any one of claims 33 to 42, wherein the co-solvent is present and is propylene glycol.

44. A spray as claimed in any one of claims 33 to 43, wherein the co-solvent is present and is benzyl alcohol.

45. The spray of any one of claims 33 to 44, wherein the film former is a polymer selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, acrylic polymers, acrylic copolymers, methacrylate polymers, methacrylate copolymers, polyvinyl acetate, cellulose-based polymers, cellulose-based copolymers, and combinations thereof.

46. ​​The spray of any one of claims 33 to 45, wherein the film former is a methacrylate copolymer.

47. The spray according to any one of claims 33 to 46, wherein the film former is a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.

48. A spray as described in any one of claims 33 to 47, wherein the cannabinoid is selected from (-)-trans-Δ 9 -Tetrahydrocannabinol (dronabinol), cannabidiol (CBD), pharmaceutically acceptable salts or derivatives thereof, and combinations thereof.

49. The spray composition of any one of claims 33 to 48, wherein the cannabinoid is (-)-trans-Δ 9 - Tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt or derivative thereof.

50. The spray according to any one of claims 33 to 49, wherein the propellant is a hydrofluoroalkane selected from the group of 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) or a chlorofluorocarbon selected from the group of CFC 11, CFC 12 and CFC 114, and combinations thereof.

51. The spray of any one of claims 33 to 50, wherein the propellant is 1,1,1,2-tetrafluoroethane (HFC-134a).

52. The spray of any one of claims 33 to 51 comprising from about 0.25% w / w to about 10% w / w cannabinoids.

53. The spray of any one of claims 33 to 52 comprising from about 0.25% w / w to about 2% w / w cannabinoids.

54. A spray as claimed in any one of claims 33 to 53 comprising about 0.8% w / w cannabinoids.

55. A spray as claimed in any one of claims 33 to 54 comprising about 2% w / w cannabinoids.

56. The spray of any one of claims 33 to 55, wherein the hydrophobic solvent is present at about 2% w / w to about 10% w / w of the pharmaceutical composition.

57. The spray of any one of claims 33 to 56, wherein the alcohol-based solvent is present at about 30% w / w to about 60% w / w of the pharmaceutical composition.

58. The spray of any one of claims 33 to 57, wherein the alcohol-based solvent is present at about 40% w / w of the pharmaceutical composition.

59. The spray of any one of claims 33 to 58, wherein the co-solvent is present at about 0.5% w / w to about 5% w / w of the pharmaceutical composition.

60. The spray formulation of any one of claims 33 to 59, wherein the co-solvent is present at about 2% w / w of the pharmaceutical composition.

61. The spray of any one of claims 33 to 60, wherein the film former is present at about 0.1% w / w to about 1% w / w of the pharmaceutical composition.

62. The spray of any one of claims 33 to 61, wherein the film former is present at about 0.5% w / w of the pharmaceutical composition.

63. The spray of any one of claims 33 to 62, wherein the propellant is present at about 49% w / w to about 54% w / w of the pharmaceutical composition.

64. A spray comprising an oral liquid composition comprising: a. about 0.025% w / w to about 2% w / w of dronabinol or a pharmaceutically acceptable salt thereof; b. about 2% w / w to about 10% w / w of a hydrophobic solvent; c. about 30% w / w to about 60% w / w of an alcohol-based solvent; d. about 0.5% w / w to about 5% w / w of a co-solvent; e. about 0.1% w / w to about 1% w / w of a film former; f. and from about 49% w / w to about 61% w / w of a propellant, wherein the composition is substantially anhydrous and the spray is for oral administration.

65. The spray of any one of claims 33 to 64, wherein the spray is a multi-dose spray delivering between 20 and 200 microliters of the composition per dose.

66. The spray of any one of claims 33 to 65, wherein the spray is contained in a metal can.

67. The spray of claim 66, wherein the metal can contains between about 10 ml and about 100 ml of the composition.

68. A pharmaceutical composition comprising a cannabinoid or a pharmaceutically acceptable salt or derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, and about 49% w / w to about 61% w / w of a propellant, wherein the pharmaceutical composition is an oral liquid pharmaceutical composition, and wherein the pharmaceutical composition is free of a film former and is substantially anhydrous.

69. The pharmaceutical composition of claim 68, wherein the hydrophobic solvent is an oil-based solvent.

70. The pharmaceutical composition of claim 69, wherein the oil-based solvent is selected from the group consisting of sesame oil, soybean oil, hydrogenated vegetable oils, and combinations thereof.

71. The pharmaceutical composition of claim 69 or 70, wherein the oil-based solvent is sesame oil.

72. The pharmaceutical composition of claim 68, wherein the hydrophobic solvent is C5-C 12 Alkane solvents.

73. The pharmaceutical composition of claim 68 or 72, wherein the hydrophobic solvent is selected from the group consisting of pentane, hexane, heptane, and combinations thereof.

74. A pharmaceutical composition as described in any one of claims 68 to 73, wherein the alcohol-based solvent is selected from the group consisting of ethanol, isopropanol, n-propanol, and combinations thereof.

75. A pharmaceutical composition as described in any one of claims 68 to 74, wherein the co-solvent is present and is selected from the group consisting of benzyl alcohol, propylene glycol, dipropylene glycol, glycerol, dimethicone 350, dimethicone 1000, and combinations thereof.

76. A pharmaceutical composition as described in any one of claims 68 to 75, wherein the cosolvent is present and is propylene glycol.

77. A pharmaceutical composition as described in any one of claims 68 to 76, wherein the co-solvent is present and is benzyl alcohol.

78. A pharmaceutical composition as described in any one of claims 68 to 77, wherein the cannabinoid is selected from (-)-trans-Δ 9 -Tetrahydrocannabinol (dronabinol), cannabidiol (CBD), pharmaceutically acceptable salts or derivatives thereof, and combinations thereof.

79. The pharmaceutical composition of any one of claims 68 to 78, wherein the cannabinoid is (-)-trans-Δ 9 - Tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt or derivative thereof.

80. The pharmaceutical composition of any one of claims 68 to 79, wherein the propellant is a hydrofluoroalkane.

81. A pharmaceutical composition as described in any one of claims 68 to 80, wherein the propellant is a hydrofluoroalkane selected from the group of 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) or a chlorofluorocarbon selected from the group of CFC 11, CFC 12 and CFC 114, and combinations thereof.

82. The pharmaceutical composition of any one of claims 68 to 81, wherein the propellant is 1,1,1,2-tetrafluoroethane (HFC-134a).

83. The pharmaceutical composition of any one of claims 68 to 82, comprising about 0.25% w / w to about 10% w / w of a cannabinoid.

84. The pharmaceutical composition of any one of claims 68 to 83, comprising about 0.25% w / w to about 2% w / w of a cannabinoid.

85. The pharmaceutical composition of any one of claims 68 to 84 comprising about 0.8% w / w cannabinoid.

86. The pharmaceutical composition of any one of claims 68 to 85, comprising about 2% w / w cannabinoid.

87. The pharmaceutical composition of any one of claims 68 to 86, wherein the hydrophobic solvent is present at about 2% w / w to about 10% w / w of the pharmaceutical composition.

88. The pharmaceutical composition of any one of claims 68 to 87, wherein the alcohol-based solvent is present at about 30% w / w to about 60% w / w of the pharmaceutical composition.

89. The pharmaceutical composition of any one of claims 68 to 88, wherein the alcohol-based solvent is present at about 40% w / w of the pharmaceutical composition.

90. The pharmaceutical composition of any one of claims 68 to 89, wherein the co-solvent is present at about 0.5% w / w to about 5% w / w of the pharmaceutical composition.

91. The pharmaceutical composition of any one of claims 68 to 90, wherein the co-solvent is present at about 2% w / w of the pharmaceutical composition.

92. The pharmaceutical composition of any one of claims 68 to 91, wherein the propellant is present at about 49% w / w to about 54% w / w of the pharmaceutical composition.

93. A pharmaceutical composition comprising: a. about 0.025% w / w to about 10% w / w of dronabinol or a pharmaceutically acceptable salt thereof; b. about 2% w / w to about 10% w / w of a hydrophobic solvent; c. about 30% w / w to about 60% w / w of an alcohol-based solvent; d. about 0.5% w / w to about 5% w / w of a co-solvent, e. and from about 49% w / w to about 61% w / w of a propellant.

94. A pharmaceutical composition as described in any one of claims 68 to 93, further comprising a flavoring agent.

95. A spray comprising an oral liquid composition comprising a cannabinoid or a derivative thereof, a hydrophobic solvent, an alcohol-based solvent, an optional co-solvent, and about 49% w / w to about 61% w / w of a propellant, wherein the composition is free of a film former and is substantially anhydrous, and wherein the spray is for oral administration.

96. The spray of claim 95, wherein the spray is for buccal administration.

97. The spray of claim 95, wherein the spray is for sublingual application.

98. The spray of any one of claims 95 to 97, wherein the hydrophobic solvent is an oil-based solvent.

99. The spray of claim 98, wherein the oil-based solvent is selected from the group consisting of sesame oil, soybean oil, hydrogenated vegetable oils, and combinations thereof.

100. The spray of claim 98 or 99, wherein the oil-based solvent is sesame oil.

101. The spray of any one of claims 95 to 97, wherein the hydrophobic solvent is C5-C 12 Alkane solvents.

102. The spray of claims 95 to 97 or 101, wherein the hydrophobic solvent is selected from the group consisting of pentane, hexane, heptane, and combinations thereof.

103. The spray of any one of claims 95 to 102, wherein the alcohol-based solvent is selected from the group of ethanol, isopropanol, n-propanol, and combinations thereof.

104. The spray of any one of claims 95 to 103, wherein the co-solvent is present and is selected from benzyl alcohol, propylene glycol, dipropylene glycol, glycerin, dimethicone 350, dimethicone 1000, and combinations thereof.

105. The spray of any one of claims 95 to 104, wherein the co-solvent is present and is propylene glycol.

106. The spray of any one of claims 95 to 104, wherein the co-solvent is present and is benzyl alcohol.

107. The spray composition of any one of claims 95 to 106, wherein the cannabinoid is selected from (-)-trans-Δ 9 -Tetrahydrocannabinol (dronabinol), cannabidiol (CBD) or pharmaceutically acceptable salts or derivatives thereof, and combinations thereof.

108. The spray composition of any one of claims 95 to 107, wherein the cannabinoid is (-)-trans-Δ 9 - Tetrahydrocannabinol (dronabinol) or a pharmaceutically acceptable salt or derivative thereof.

109. The spray of any one of claims 95 to 108, wherein the propellant is a hydrofluoroalkane selected from the group of 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) or a chlorofluorocarbon selected from the group of CFC 11, CFC 12 and CFC 114, and combinations thereof.

110. The spray of any one of claims 95 to 109, wherein the propellant is 1,1,1,2-tetrafluoroethane (HFC-134a).

111. The spray of any one of claims 95 to 110 comprising about 0.25% w / w to about 10% w / w cannabinoids.

112. The spray of any one of claims 95 to 111 comprising about 0.25% w / w to about 2% w / w cannabinoids.

113. The spray of any one of claims 95 to 112 comprising about 0.8% w / w cannabinoids.

114. The spray of any one of claims 95 to 113 comprising about 2% w / w cannabinoids.

115. The spray of any one of claims 95 to 114, wherein the hydrophobic solvent is present at about 2% w / w to about 10% w / w of the pharmaceutical composition.

116. The spray formulation of any one of claims 95 to 115, wherein the alcohol-based solvent is present at about 30% w / w to about 60% w / w of the pharmaceutical composition.

117. The spray formulation of any one of claims 95 to 116, wherein the alcohol-based solvent is present at about 40% w / w of the pharmaceutical composition.

118. The spray of any one of claims 95 to 117, wherein the co-solvent is present at about 0.5% w / w to about 5% w / w of the pharmaceutical composition.

119. The spray of any one of claims 95 to 118, wherein the co-solvent is present at about 2% w / w of the pharmaceutical composition.

120. The spray of any one of claims 95 to 119, wherein the propellant is present at about 49% w / w to about 54% w / w of the pharmaceutical composition.

121. A spray comprising an oral liquid composition comprising: a. about 0.025% w / w to about 10% w / w of dronabinol or a pharmaceutically acceptable salt thereof; b. about 2% w / w to about 10% w / w of a hydrophobic solvent; c. about 30% w / w to about 60% w / w of an alcohol-based solvent; d. about 0.5% w / w to about 5% w / w of a co-solvent, e. and from about 49% w / w to about 61% w / w of a propellant, wherein the composition is substantially anhydrous and the spray is for oral administration.

122. The spray of any one of claims 95 to 121, wherein the spray is a multi-dose spray delivering between 20 and 200 microliters of the composition per dose.

123. The spray of any one of claims 95 to 122, wherein the spray is contained in a metal can.

124. The spray of claim 123, wherein the metal can contains between 10 ml and 100 ml of the composition.

125. A pharmaceutical composition as described in any one of claims 1 to 32 and 68 to 94, wherein the composition is homogeneous.

126. The pharmaceutical composition of any one of claims 1 to 32, 68 to 94 and 125, wherein the composition remains stable when stored at about 4°C for at least two years or at room temperature for at least one month.

127. The spray of any one of claims 33 to 67 and 95 to 124, wherein the composition is homogeneous.

128. The spray of any one of claims 33 to 67, 95 to 124 and 127, wherein the spray remains stable when stored at about 4°C for at least two years or at room temperature for at least one month.

129. A method of treating, ameliorating or alleviating the symptoms of a disease, disorder or condition in a subject in need of said treatment, the method comprising administering to the subject a therapeutically effective amount of a composition as described in any one of claims 1 to 32, 68 to 94, 125 and 126 or a spray as described in any one of claims 33 to 67, 95 to 124, 127 and 128, wherein the disease, disorder or condition is selected from pain, dementia, sleep disorders, movement disorders, mental disorders and multiple sclerosis.

130. The method of claim 129, wherein the pain is migraine, neuropathic pain, or trigeminal neuralgia.

131. The method of claim 129, wherein the dementia is Alzheimer's disease or mild cognitive impairment.

132. The method of claim 129, wherein the sleep disorder is sleep apnea or narcolepsy.

133. The method of claim 129, wherein the movement disorder is Tourette syndrome or Parkinson's disease.

134. The method of claim 129, wherein the disease, disorder or condition is post-traumatic stress disorder.

135. The method of claim 129, wherein the disease, disorder or condition is migraine.

136. The method of claim 129, wherein the disease, disorder or condition is Alzheimer's disease.

137. The method of claim 129, wherein the subject is a cancer patient receiving opioid therapy.

138. The method of any one of claims 129 to 137, wherein the composition or spray is applied at least once a day.

139. The method of any one of claims 129 to 138, wherein the composition is administered orally.

140. A method of treating migraine in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a composition as described in any one of claims 1 to 32, 68 to 94, 125 and 126 or a spray as described in any one of claims 33 to 67, 95 to 124, 127 and 128.

141. The method of claim 140, wherein the composition or spray is applied at least once a day.

142. The method of claim 140 or 141, wherein the composition or spray is administered orally.

143. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a composition as described in any one of claims 1 to 32, 68 to 94, 125 and 126 or a spray as described in any one of claims 33 to 67, 95 to 124, 127 and 128.

144. The method of claim 143, wherein the composition or spray is applied at least once a day.

145. The method of claim 143 or 144, wherein the composition or spray is administered orally.

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