WO2024097327A1

WO2024097327A1 - Cannabinoid formulations and use for treatment of emotional disorders and sexual dysfunction

Info

Publication number: WO2024097327A1
Application number: PCT/US2023/036653
Authority: WO
Inventors: Philip E. Wolfson; Paul Freeman DALEY
Original assignee: Progressive Therapeutics Inc
Current assignee: Progressive Therapeutics Inc
Priority date: 2022-11-02
Filing date: 2023-11-02
Publication date: 2024-05-10
Anticipated expiration: 2025-05-02
Also published as: EP4611740A1

Abstract

The present invention features formulations and methods for the treatment of an emotional disorder or sexual dysfunction in a subject by administering to the subject a cannabinoid, such as (-)- trans-Δ⁸-tetrahydrocannabinol (delta-8-THC), complexed with a cyclodextrin.

Description

Attorney Docket No.: 51225-009WO2 CANNABINOID FORMULATIONS AND USE FOR TREATMENT OF EMOTIONAL DISORDERS AND SEXUAL DYSFUNCTION BACKGROUND OF THE INVENTION The invention relates to the field of formulations and methods thereof for the treatment of sexual dysfunction and emotional disorders and other medical conditions with symptoms that are related to emotional disorders or are of a somatic nature. Nonlimiting examples of emotional disorders include anxiety, depression, somatization, and other categories of emotional disorders as per the DSM-5-R. Anxiety disorders are the most commonly diagnosed mental illness in the United States. Nonlimiting examples of anxiety disorders include Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Social Anxiety Disorder (SAD), Obsessive-Compulsive Disorder (OCD), Specific Phobic Disorders (SPD), Post Traumatic Stress Disorder (PTSD), Agoraphobia, or Separation Anxiety Disorder (SeAD). Nonlimiting examples of depressive disorders include Dysthymia, Major Depression, Bipolar II Disorder, Postpartum Depression, Adjustment with Depression, and other depressive disorders. Nonlimiting examples of physical symptoms that may be treated by the above method include headaches; migraines; physical symptoms related to the menstrual cycle such as breast tenderness, cramps, headaches; symptoms of somatization disorders; fibromyalgia, various neurologic symptoms and disorders, and pain from a wide variety of causes. Emotional disorders, including anxiety disorders and depressive disorders, can be refractory to currently employed methods of treatment. Applicants have discovered that the concurrent administration of a cannabinoid complexed to a cyclodextrin can be useful for treating emotional disorders. SUMMARY OF THE INVENTION In a first aspect, the invention features a pharmaceutical composition in unit dosage form including (i) an inclusion complex including a cannabinoid and a cyclodextrin; and (ii) a pharmaceutically acceptable excipient. The cannabinoid can be selected from canaigre, cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC) (e.g., delta-9-THC or delta-8-THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV) (e.g., delta-9-THCV or delta-8-THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid (THCVA). In particular embodiments, the cannabinoid is selected from delta-9-THC, delta-8-THC, cannabinol (CBN), delta-9-THCV, delta-8-THCV, cannabidiol (CBD), and cannabivarin (CBV). The cyclodextrin can be a water soluble unsubstituted or substituted alpha- cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin. In particular embodiments the cyclodextrin is a beta-cyclodextrin selected from methyl beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and sulfobutylether beta-cyclodextrin. In some embodiments, the pharmaceutical composition includes from 5 mg to 20 mg of delta-9- THC (e.g., 5 mg to 10mg, 5 mg to 20 mg, 7.5 mg to 15 mg, 10 mg to 15 mg, or 10 mg to 20 mg of delta- 9-THC). In particular embodiments, the pharmaceutical composition includes from 5 mg to 40 mg of delta- 8-THC (e.g., 5 mg to 10 mg, 7.5 mg to 15 mg, 10 mg to 20 mg, 15 mg to 25 mg, 20 mg to 40 mg, or 30 Attorney Docket No.: 51225-009WO2 mg to 40 mg of delta-8-THC). In some embodiments, the pharmaceutical composition includes from 10 mg to 100 mg of CBN (e.g., 10 mg to 25 mg, 20 mg to 65 mg, 35 mg to 80 mg, 40 mg to 85 mg, or 50 mg to 100 mg of CBN). In particular embodiments, the pharmaceutical composition includes from 1 mg to 30 mg of delta- 9-THCV (e.g., 1 mg to 5 mg, 2 mg to 15 mg, 5 mg to 20 mg, 7 mg to 25 mg, or 10 mg to 30 mg of delta-9- THCV). In certain embodiments, the pharmaceutical composition includes from 1 mg to 30 mg of delta-8- THCV (e.g., 1 mg to 5 mg, 2 mg to 15 mg, 5 mg to 20 mg, 7 mg to 25 mg, or 10 mg to 30 mg of delta-8- THCV). In some embodiments, the pharmaceutical composition includes from 50 mg to 200 mg of CBD (e.g., 50 mg to 80 mg, 70 mg to 110 mg, 80 mg to 140 mg, 90 mg to 150 mg, 120 mg to 170 mg, or 150 mg to 200 mg CBD). In particular embodiments, the pharmaceutical composition includes from 1 mg to 30 mg of CBV (e.g., 1 mg to 10 mg, 5 mg to 12 mg, 10 mg to 15 mg, 12 mg to 20 mg, 15 mg to 25 mg, or 20 mg to 30 mg of CBV). The mole ratio of the cannabinoid to the cyclodextrin in the pharmaceutical composition can be from 1:1 to 1:20 (e.g., 1:1 to 1:2, 1:1 to 1:3, 1:1 to 1:5, 1:2 to 1:5, 1:3 to 1:10, or 1:5 to 1:20). In one embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition includes from 40 to 700 mg of the cyclodextrin (e.g., 40 mg to 100 mg, 75 mg to 200 mg, 100 mg to 300 mg, 150 mg to 350 mg, 200 mg to 500 mg, or 475 mg to 700 mg of the cyclodextrin). The pharmaceutical composition can be formulated for oral, pulmonary, sublingual, intranasal, intramuscular, intravenous, transdermal, or rectal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration. For example, the unit dosage form can be a film, strip, lozenge, or orally dissolving tablet. In some embodiments, the formulation further includes ketamine, norketamine, 6- hydroxynorketamine, or a pharmaceutically acceptable salt thereof. For example, each of the unit dosage forms can contain from about 10 to 500 mg (e.g., 25 ± 15 mg, 35 ± 15 mg, 45 ± 15 mg, 55 ± 15 mg, 65 ± 15 mg, 75 ± 15 mg, 85 ± 15 mg, 100 ± 15 mg, 120 ± 20 mg, 150 ± 20 mg, 170 ± 20 mg, 200 ± 20 mg, 250 ± 50 mg, 300 ± 50 mg, 350 ± 50 mg, 400 ± 50 mg, or 450 ± 50 mg of ketamine, norketamine, 6- hydroxynorketamine, or a pharmaceutically acceptable salt thereof. In some embodiments the ketamine, norketamine, 6-hydroxynorketamine, or a pharmaceutically acceptable salt thereof, is present as an inclusion complex with a cyclodextrin. In one particular embodiment, the pharmaceutical composition includes: (a) from 50 to 200 mg of ketamine, or a pharmaceutically acceptable salt thereof (e.g., 65 ± 15 mg, 75 ± 15 mg, 85 ± 15 mg, 100 ± 15 mg, 120 ± 20 mg, 150 ± 20 mg, or 175 ± 25 mg of ketamine), (b) from 50 to 200 mg of a beta-cyclodextrin (e.g., 65 ± 15 mg, 75 ± 15 mg, 85 ± 15 mg, 100 ± 15 mg, 120 ± 20 mg, 150 ± 20 mg, or 175 ± 25 mg of a beta-cyclodextrin), and (c) from 5 mg to 20 mg of delta-8-THC (e.g., 7.5 ± 2.5 mg, 10 ± 2.5 mg, 12.5 ± 2.5 mg, 15 ± 2.5 mg, or 18 ± 2 mg of delta-8-THC). In a related aspect, the invention features a method of treating an emotional disorder in a subject in need thereof, the method including administering to the subject a pharmaceutical composition of the invention in an amount that is effective for the treatment of the emotional disorder. For the amelioration of symptoms of an emotional disorder, the unit dosage forms can be administered once, twice, or three times daily. Attorney Docket No.: 51225-009WO2 In one embodiment of the above method, the emotional disorder is an anxiety disorder. The anxiety disorder can be selected from, or generalized to include, Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Social Anxiety Disorder (SAD), Obsessive-Compulsive Disorder (OCD), Specific Phobic Disorders (SPD), Post Traumatic Stress Disorder (PTSD), Agoraphobia, or Separation Anxiety Disorder (SeAD). In another embodiment of the above method, the emotional disorder is a depressive disorder. The depressive disorder can be selected from, or generalized to include, Dysthymia, Major Depression, Bipolar II Disorder, Postpartum Depression, or Adjustment Disorder with Depression. In a specific embodiment of the above method, the invention provides a method for treating a variety of physical symptoms that may or may not be related to an emotional disorder. Nonlimiting examples of physical symptoms that may be treated by the above method include headaches; migraines; physical symptoms related to the menstrual cycle such as breast tenderness, cramps, headaches; symptoms of somatization disorders; fibromyalgia, various neurologic symptoms and disorders, and pain from a wide variety of causes. In another aspect the invention features a method of enhancing sexual response and sensitivity in a human subject in need thereof, the method including administering to the subject a pharmaceutical composition of the invention in an amount that is effective for enhancing sexual response and sensitivity. The invention further features a method for improving sexual function in a human subject suffering from sexual dysfunction or otherwise in need of enhanced sexual function, the method including the step of administering to the subject a pharmaceutical composition of the invention in an amount that is effective for improving sexual function in the human subject. In certain embodiments, the improved sexual function is increased libido. The invention also features a method of treating female sexual dysfunction in a female subject, the method including the step of administering to the female subject a pharmaceutical composition of the invention in an amount that is effective for treating female sexual dysfunction. In some embodiments, administration is by a route selected from oral, pulmonary, sublingual, intranasal, intramuscular, intravenous, transdermal, rectal administration. In some embodiments, the complex is formulated in a lozenge for sublingual administration. In one particular embodiment the pharmaceutical composition is selected from sublingual films, strips, lozenges, or orally dissolving tablets. As used herein, “cannabinoid” refers to a class of chemical compounds that act on the cannabinoid receptors. Cannabinoids found in cannabis include, without limitation: canaigre, cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC) (e.g., delta-9-THC or delta-8- THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV) (e.g., delta-9-THCV or delta-8-THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid (THCVA). The term “pharmaceutically acceptable excipient,” as used herein, refers to any pharmacologically inactive excipient useful in the formulation of a pharmaceutical product, such as antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Excipients Attorney Docket No.: 51225-009WO2 include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. As used herein, the term “pharmaceutically acceptable salts” refers to salts of the active compounds of the invention that can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic or inorganic acid, or separately by reacting an acid function with a suitable organic or inorganic base. The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human. A "therapeutically effective amount" or “an amount sufficient” of a drug is an amount effective to ameliorate a symptom of a condition or disorder, such as sexual dysfunction or an emotional disorder (e.g., anxiety or depression). Using the methods of the invention a therapeutically effective amount of the cannabinoid complex alone or in combination with cyclodextrin complexed to ketamine, norketamine, 6- hydroxynorketamine, or a pharmaceutically acceptable salt thereof, is an amount effective to ameliorate one or more symptoms of a condition or disorder. The therapeutically effective amounts of cannabinoid, ketamine, and cyclodextrin administered in combination may be less than the therapeutically effective amounts required when each is administered alone. As used herein, the term “treating” refers to administering a pharmaceutical composition for therapeutic purposes. To “treat disease” or use for “therapeutic treatment” refers to administering treatment to a subject already suffering from a condition to improve or stabilize the subject’s condition. As used here, the term “sexual pleasure” refers to a variety of physiological and/or psychological aspects or conditions that affect the amount of enjoyment of sexual activity. Examples include, but are not limited to, threshold desire to commence sexual activity, physical sensitivity during sexual activity, psychological pleasure or awareness during sexual activity, ability to reach climax, amount of pleasure leading up to climax, quality of climax, duration of climax, and the like. As used here, the term “sexual response” refers to a variety of physiological and/or psychological aspects that affect the ability to perform sexual activities. In men, the most common condition is the inability to achieve or maintain an erection. In women, conditions that inhibit sexual response are more varied and complex but include, for example, inability or delay in becoming aroused while being kissed or touched in erogenous zones. In many cases such inability can be more psychological than physiological. As used herein, the term “sexual dysfunctions” refers to sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, sexual dysfunction due to a general medical condition, substance-induced sexual dysfunction and sexual dysfunction not otherwise specified. These sexual dysfunctions may be further defined by the nature of the onset of the disorder: either lifelong type Attorney Docket No.: 51225-009WO2 or acquired type; by the context in which the disorder occurs: either generalized type or situational type; and by the etiological factors associated with the disorder: either due to psychological factors or due to combined factors. Specifically, sexual desire disorders include hypoactive sexual desire disorder and sexual aversion disorder. Sexual arousal disorders include female sexual arousal disorder and male erectile disorder. Orgasmic disorders include female orgasmic disorder, male orgasmic disorder and premature ejaculation. Sexual pain disorders include dyspareunia and vaginismus. Sexual dysfunctions due to a general medical condition may result from neurological conditions (e.g. multiple sclerosis, spinal cord lesions, neuropathy and temporal lobe lesions), endocrine conditions (e.g. diabetes melitus, hypothyroidism, hypogonadal states and pituitary dysfunction), and vascular conditions and genitourinary conditions (e.g. testicular disease, Peyronie's disease, urethral infections, postprostatectomy complications, genital injury or infection, atrophic vaginitis, infections of the vagina and external genitalia, postsurgical complications such as episiotomy scars, shortened vagina, cystitis, endometriosis, uterine prolapse, pelvic infections and neoplasms). Substance-induced sexual dysfunction can occur in association with intoxication with the following classes of substance: alcohol; amphetamine (and amphetamine-like substances); cocaine; opioids; sedatives, hypnotic and anxiolytics; and other unknown substances. A decrease in sexual interest and orgasmic disorders may also be caused by prescribed medication including antihypertensives, histamine H2-receptor antagonists, antidepressants, neuroleptics, anxiolytics, anabolic steroids, and antiepileptics. Painful orgasm has been reported with fluphenazine, thioridazine and amoxapine. Priapism has been reported with the use of chlorpromazine, trazodone and clozapine, and following penile injections of papaverine or prostaglandin. Selective serotonin reuptake inhibitors may cause decreased sexual desire or arousal disorders. As used herein, the terms “female sexual dysfunction” or “FSD” refer generally to the impairment of the sexual function in a female. Sexual dysfunction in females includes inhibited orgasm. Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including female hypoactive sexual desire disorder (FHSDD or HSDD, used interchangeably herein), female orgasmic disorder (FOD), sexual anhedonia, female sexual interest/arousal disorder (FSIAD), and female sexual arousal disorder (FSAD). Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties. Sexual anhedonia includes decreased or absent pleasure in sexual activity. Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents. The woman can experience mild, moderate, or severe FSD. DETAILED DESCRIPTION The invention first provides a formulation a cannabinoid complexed to a cyclodextrin and the treatment of sexual dysfunction and emotional disorders therewith. The compositions of the invention may be designed to be short-acting, fast-releasing, long-acting, or sustained-releasing as described herein. The combination of a cyclodextrin with a cannabinoid, optionally further including ketamine, norketamine, or 6-hydroxynorketamine, can enhance the therapeutic efficacy of the pharmaceutical composition in comparison to administration of the cannabinoid alone. Cannabinoids

Cannabinoids useful in the compositions and method of the invention include, without limitation: canaigre, cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC) (e.g., delta-9-THC or delta-8-THC), cannabinol (CBN) and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV) (e.g., delta-9-THCV or delta-8-THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid (THCVA).

As described in the Examples, the complexation of the cannabinoid with a cyclodextrin enhances the effect of the cannabinoid in a manner that can be therapeutically beneficial.

Cyclodextrin Complexes

The pharmaceutical compositions of the invention include a cyclodextrin complexed to cannabinoids, and optionally, ketamine, norketamine, or 6-hydroxynorketamine.

Examples of a cyclodextrin for use in the inclusion complexes in the formulations of the invention include, but are not limited to, water soluble unsubstituted or substituted alpha-cyclodextrin, betacyclodextrin, and gamma-cyclodextrin. Examples of substituted beta-cyclodextrins that may be employed in the inclusion complexes herein include, but are not limited to, methyl beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and sulfobutylether beta-cyclodextrin. Examples of substituted gamma-cyclodextrins that may be employed in the inclusion complexes herein include, but are not limited to, hydroxypropyl gamma-cyclodextrin. Mixtures of cyclodextrins may also be employed. For example, a formulation comprising cannabinoid and a mixture of two or three or four or more cyclodextrins can also be used. Where a more than one cyclodextrin is employed, it may be of the same cyclodextrin class (e.g., two alpha-cyclodextrins) or different chemical classes (e.g., one alpha-cyclodextrin and one beta- or gamma- cyclodextrin). In one preferred embodiment, the cyclodextrin is hydroxypropyl beta-cyclodextrin or methyl beta-cyclodextrin.

In some embodiments, a cyclodextrin is obtained from a commercial source, including, but not limited to cyclodextrins sold under the following tradenames CAVASOL® W6 HP (Wacker Chemie AG, Munich, Germany), CAVASOL® W6 HP TL (Wacker Chemie AG, Munich, Germany), CAVAMAX® W6 Pharma (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 HP (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 HP Pharma (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 HP TL (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 M (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 M Pharma (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 M TL (Wacker Chemie AG, Munich, Germany), CAVASOL® W8 HP (Wacker Chemie AG, Munich, Germany), CAVASOL® W8 HP Pharma (Wacker Chemie AG, Munich, Germany), KLEPTOSE® HPB (Roquette Pharma, Geneva, III.), and CAPTISOL® (Cydex Pharmaceuticals, Inc. Lenexa, Kans.). In some embodiments, the cyclodextrin is CAVASOL® W7 M Pharma. In some embodiments, the cyclodextrin is KLEPTOSE® HPB.

In some embodiments, cannabinoid is fully included into the cavity of a cyclodextrin molecule. In some embodiments, cannabinoid is partially included into the cavity of a cyclodextrin molecule. In some embodiments of the inclusion complex, the molar ratio of the cannabinoid to cyclodextrin is from any of about 1 :1 to about 1 :300; about 1 :1 to about 1 :150; about 1 :1 to about 1 :100; about 1 :1 to about 1 :50,

SUBSTITUTE SHEET (RULE 26) about 1 :1 to about 1 :25; about 1 :1 to about 1 :10; about 1 :1 to about 1 :5; about 1 :1 to about 1 :4; about 1 :1 to about 1 :3; about 1 :1 to about 1 :2.5; and about 1 :1 to about 1 :2, or is about any of 1 :1 , 1 :2, and 1 :3.

The inclusion complexes described herein may increase the solubility of a cannabinoid. In one aspect, are provided methods for improving the solubility of cannabinoid in water comprising complexing cannabinoid with a cyclodextrin. In some embodiments, the solubility of cannabinoid in a cannabinoid inclusion complex, in deionized water at 20° C., is at least about 10-fold greater than the solubility of cannabinoid in uncomplexed form. In some embodiments, a cannabinoid inclusion complex increases the solubility of cannabinoid by at least any of about or by about 10-, 25-, 50-, 75-, 100-, 250-, 500-, 750-, 1000-, 1500-, 2000-, 3000-, or 4000-fold compared to the solubility of a cannabinoid in uncomplexed form.

In some embodiments, the uncomplexed cannabinoid is present in an oil-based carrier (e.g., arachis oil, sesame oil, castor oil, or neutral oil (e.g., MIGLYOL™ 810 or MIGLYOL® 812)), or in a nonaqueous ester solvent (e.g., benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate, or a mixture or combination of any thereof) and an alcohol (e.g., ethanol, benzyl alcohol, or a mixture or combination of any thereof).

The inclusion complexes described herein may provide improved pharmacokinetic properties for a cannabinoid. Such changes in pharmacokinetic properties may result in desired therapeutic effects, such as a more rapid onset of therapeutic effect and/or less prolonged and/or reduced effects of a disease or condition for which cannabinoid treatment is obtained.

The inclusion complexes described herein may result in increased oral bioavailability of a cannabinoid. In some embodiments, the oral bioavailability of a cannabinoid from an inclusion complex comprising the cannabinoid and a cyclodextrin is at least any of about or about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90% greater than the oral bioavailability of the cannabinoid alone under the same conditions.

To form an inclusion complex of cannabinoid and a cyclodextrin, cannabinoid may be admixed with the cyclodextrin at a molar ratio from about 0.2:1 to about 1 :300. In some embodiments, the molar ratio is about 0.5:1 to about 1 : 150, or about 1 :1 to about 1 :75, or about 1 :1 to about 1 :50, or about 1 :1 to about 125, or about 1 :1 to about 1 :10, or about 1 :1 to about 1 :5, or about 1 :1 to about 1 :3, or about 1 :1 to about 1 :2, or any of about 1 :1 , 1 :2, 13, 1 :4, 1 :5, 1 :6, and 1 :7.

In some embodiments of the methods of producing an inclusion complex, the solvent, mixed solvent, or buffer is heated to less than, greater than, or about any of 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 75° C., or 80° C. (e.g., before, during and/or after mixing). The solvent, mixed solvent, or buffer may be heated prior to and/or after being added to the cannabinoid and/or cyclodextrin. In some embodiments, the solvent, mixed solvent, or buffer is heated greater than the preferred temperature for less than, greater than, or about any of 0.1 hr, 0.2 hr, 0.3 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 7 hr, 10 hr, 15 hr, 24 hr, 36 hr, or 48 hr.

During the formation of the inclusion complex between a cannabinoid and a cyclodextrin, a suitable polymer may be added which may enhance the solubility and/or complexation ability of the cannabinoid and cyclodextrin inclusion complex. Suitable polymers include, for example, polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose, and PLASDONE® Povidone, and derivatives thereof. In some embodiments, the suitable polymer is a water-soluble polymer.

SUBSTITUTE SHEET (RULE 26) In some embodiments of the methods of producing an inclusion complex, the mixing is continued for at least any of about 0.1 hr, 02 hr, 0.3 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 4 hr, 10 hr, 24 hr, 36 hr, or 48 hr following formation of the suspension or solution. If heat is applied to the solvent, mixed solvent, or buffer during a method of producing an inclusion complex, the described mixing of the components may occur prior to, simultaneously with, and/or after the application of the heat.

In some embodiments, the method of producing an inclusion complex further comprises a step for drying the product obtained from the steps of a) admixing the cannabinoid and a cyclodextrin and b) adding a suitable amount of a solvent, mixed solvent or buffer to the mixture. In some embodiments, the drying comprises evaporation. In some embodiments, the evaporation occurs for greater than, less than, or about any of 0.1 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 5 hr, 10 hr, 1 day, or 5 days. In some embodiments, the evaporation is conducted under vacuum (e.g., less than any of about 0.75 atm, 0.5 atm, or 0.25 atm). In some embodiments, the evaporation is conducted under atmospheric pressure. I n some embodiments, the drying comprises dry heat. In some embodiments, the drying comprises spray-drying. In some embodiments, the drying comprises freeze-drying. In some embodiments, the drying comprises spraygranulation.

The method of producing an inclusion complex between a cannabinoid and a cyclodextrin can include the steps of: (a) mixing the appropriate amount of the cannabinoid and cyclodextrin with or without a suitable polymer; (b) adding a suitable amount of solvent, mixed solvent, and/or buffer to the mixture of step (a) with vigorous mixing until a paste or a slurry is formed; (c) continuing the mixing with further addition of solvent (e.g., water), mixed solvent, or buffer if necessary to maintain the paste or the slurry consistency, for a suitable period of time to form the inclusion complex; and (d) drying the product of step (c). In some embodiments of step (b), the buffer is a phosphate-citrate buffer and the pH is about 5. In some embodiments, the solvent added during steps (b) and (c) is heated. In some embodiments, wherein the solvent, mixed solvent, or buffer is deionized water and/or a buffer, the deionized water and/or a buffer is heated to about 60° C. In some embodiments, the mixing is preferably continued for a period of time greater than 0.2 hours. In some embodiments, the vigorous mixing until a paste or a slurry is formed is conducted at about 60° C.

An alternative approach for producing an inclusion complex between the cannabinoid and a cyclodextrin includes the steps of (a) mixing suitable amounts of the cannabinoid and a cyclodextrin with or without a suitable polymer; (b) adding of a suitable solvent, mixed solvent, and/or buffer to the mixture of step (a) with mixing until a slurry, suspension or solution is formed; and (c) allowing the formation of the inclusion complex by evaporation of the water over a period of time. In some embodiments of step (b), the buffer is a phosphate-citrate buffer and the buffer pH is about 5. In some embodiments, the solvent added during step (b) is heated. In some embodiments, wherein the solvent, mixed solvent, or buffer is deionized water and/or a buffer, the deionized water and/or a buffer is heated to about 60° C. In some embodiments of step (c), heat is applied to increase the evaporation rate. In some embodiments, the evaporation is conducted at 40° C. In some embodiments, evaporation in step (c) occurs for greater than about 1 hour. In some embodiments, the evaporation is conducted under vacuum.

In some embodiments, greater than any of about 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% of the cannabinoid in the pharmaceutical composition is in complexed form.

SUBSTITUTE SHEET (RULE 26) In certain embodiments, the pharmaceutical compositions further include ketamine, norketamine, or 6-hydroxynorketamine, optionally complexed to a cyclodextrin. Complexes formed between a cyclodextrin and ketamine, norketamine, or 6-hydroxynorketamine can be formed using the methods described above.

Ketamine, Norketamine, and 6-hydroxy norketamine

The compositions and methods of the invention can optionally include ketamine, norketamine, 6- hydroxynorketamine, or a pharmaceutically acceptable salt thereof.

ketamine norketamine

As used herein, the term “ketamine” includes ketamine in its racemic (R/S) form, in its R-(-) enantiomerically pure form, or in its S-(+) enantiomerically pure form.

As used herein, the term “norketamine” includes norketamine in its racemic (R/S) form, in its R-(-) enantiomerically pure form, or in its S-(+) enantiomerically pure form.

As used herein, "enantiomerically pure" refers to compositions consisting substantially of a single isomer (i.e., substantially free of the opposite isomer), preferably consisting of 90%, 92%, 95%, 98%, 99%, or 100% (w/w) of a single isomer. For example, when the methods of the invention include the administration of enantiomerically pure R-(-)-ketamine, the pharmaceutical composition administered can include at least 95% (w/w) S-(+)-ketamine, and less than 5% (w/w) R-(-)-ketamine.

Ketamine racemate is primarily used for the induction and maintenance of general anesthesia. Enantiomerically pure S-(+)-ketamine (aka esketamine) is available for medical use, administered either IV (intravenously) or IM (intramuscularly), under the brand name KETANEST®. Enantiomerically pure R- (-)-ketamine is also known as arketamine. Ketamine is converted metabolically through demethylation to norketamine, in vivo, at rates dependent on the route of administration. For use in anesthesia, S-(+)- ketamine has been reported to be twice as potent as R-(-)-ketamine, and norketamine has been reported to have one third the potency of ketamine (C. S. T. Aun, Br. J. Anaesthesia 83: 29-41 (1999)).

As used herein, the term “6-hydroxynorketamine” includes 6-hydroxynorketamine in any of its 2R,6R; 2S,6S; 2S,6R; and 2R,6S isomerically pure forms (shown below).

(2R,6R)-6-hydroxynorketamine (2S,6S)-6-hydroxynorketamine

SUBSTITUTE SHEET (RULE 26)

(2/R,6S)-6-hydroxynorketamine (2S,6/R)-6-hydroxynorketamine

As used herein, "isomerically pure" refers to compositions consisting substantially of a single diastereomer (i.e., substantially free of other isomers), preferably consisting of 90%, 92%, 95%, 98%, 99%, or 100% (w/w) of a single isomer. For example, when the methods of the invention include the administration of isomerically pure (2/R, 6/R)- 6-hydroxynorketamine, the pharmaceutical composition administered can include at least 95% (w/w) (2/R, 6/R)- 6-hydroxynorketamine, and less than 5% (w/w) other isomers of 6-hydroxynorketamine. Alternatively, the methods of the invention include the administration of isomerically pure (2S,6S)- 6-hydroxynorketamine, the pharmaceutical composition administered can include at least 95% (w/w) (2S,6S)- 6-hydroxynorketamine, and less than 5% (w/w) other isomers of 6-hydroxynorketamine.

Formulation of Pharmaceutical Compositions

Complexed cannabinoid-cyclodextrin may be contained in any appropriate amount in any suitable pharmaceutically acceptable excipient, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The pharmaceutically acceptable excipients can include any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. The composition may be provided in a dosage form that is suitable for the sublingual, buccal, oral, parenteral (e.g., intravenously, intramuscularly), pulmonary, intranasal, transdermal, vaginal, or rectal administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, sprays, vapors, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). Some examples of materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose, mannitol, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, diastearoyl phosphatidylethanolamine (DSPE) and its pegylated esters, such as DSPE-PEG750 and, DSPE-PEG2000, phosphatidic acid, phosphatidyl glycerol and phosphatidyl serine. Commercial grades

SUBSTITUTE SHEET (RULE 26) Attorney Docket No.: 51225-009WO2 of lecithin which are preferred include those which are available under the trade name Phosal® or Phospholipon® and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy-phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the formulation, according to the judgment of the formulator. Viscosity modifiers that may be used in pharmaceutical compositions of the present invention include, but are not limited to, caprylic/capric triglyceride (Migliol 810), isopropyl myristate (IPM), ethyl oleate, triethyl citrate, dimethyl phthalate, benzyl benzoate and various grades of polyethylene oxide. High viscosity liquid carriers used in sustained release pharmaceutical compositions include, but are not limited to, sucrose acetate isobutyrate (SAIB) and cellulose acetate butyrate (CAB 381-20). Non-limiting examples of binding agents that may be used in pharmaceutical compositions of the present invention include but are not limited to hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, hydroxypropyl methyl cellulose, or a polyvinylpyrrolidone. Non-limiting examples of osmotic agents that may be used in pharmaceutical compositions of the present invention include, but are not limited to, sorbitol, mannitol, sodium chloride, or other salts. Non-limiting examples of biocompatible polymers employed in the contemplated pharmaceutical compositions include but are not limited to poly(hydroxy acids), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly (vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, synthetic celluloses, polyacrylic acids, poly(butyric acid), poly(valeric acid), and poly(lactide-co- caprolactone), ethylene vinyl acetate, copolymers and blends thereof. Non-limiting examples of hygroscopic polymers that may be employed in the contemplated pharmaceutical compositions include, but are not limited to, polyethylene oxide (e.g., Polyox® with MWs from 4,000,000 to 10,000,000), cellulose, hydroxymethylcellulose, hydroxyethylcellulose, crosslinked polyacrylic acids, and xanthan gum. Non-limiting examples of rate-controlling polymers that may be employed in the contemplated pharmaceutical compositions include but are not limited to polymeric acrylate, methacrylate lacquer or mixtures thereof, polymeric acrylate lacquer, methacrylate lacquer, an acrylic resin including a copolymer of acrylic and methacrylic acid esters, or an ammonium methacrylate lacquer with a plasticizer. Pharmaceutical compositions according to the invention may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create a substantially constant concentration of the active compound within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the active compound within the body over an extended period of time; and (iii) formulations that sustain active compound action during a predetermined time period by maintaining a relatively, constant, effective active compound level in the Attorney Docket No.: 51225-009WO2 body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active compound (sawtooth kinetic pattern). Sublingual and buccal dosage forms Formulations for sublingual may be in the form of films, strips, lozenges, and orally dissolving tablets. An orally dissolving tablet (ODT) refers to pharmaceutical dosage form designed to be dissolved on the tongue rather than swallowed whole, or designed to dissolve on the sublingual or buccal mucosa for sublingual or mucosal administration. Alternatively, the dosage form can be a lozenge (for slower administration as the lozenge dissolved over the course of 5-10 minutes), or as a rapidly dissolving film (dissolving over the course of less than 2 minutes). The active compound is administered via absorption in the mouth (i.e., buccally or sublingually). The formulation excipients are edible and pharmaceutically acceptable using excipients known in the art for the preparation of films, strips, lozenges, and orally dissolving tablets. For example, a film is prepared typically using hydrophilic polymers that rapidly dissolves on the tongue, palatine tissue, or buccal cavity, delivering the active compound to the systemic circulation via dissolution when contact with liquid is made. Solid dosage forms for oral use Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non- toxic pharmaceutically acceptable excipients, described above. For example, and as discussed above, pharmaceutically acceptable excipients may include inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. The tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the active compound in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active compound until after passage of the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose). Furthermore, a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed. Attorney Docket No.: 51225-009WO2 The solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active compound). The coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, supra. For combination therapies, two drugs may be mixed together in the tablet, or may be partitioned. In one example, the first drug is contained on the inside of the tablet, and the second drug is on the outside, such that a substantial portion of the second drug is released prior to the release of the first drug. Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active compound is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active compound is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment. Formulations for oral use can include cannabis or a cannabinoid in the form of a food (e.g., a gummy bear or cookie infused with cannabis), or in the form of a beverage. Liquids for oral administration Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration. Formulation as a suspension provides the active compound in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents are, for example, naturally-occurring phosphatides (e.g., lecithin or condensation products of ethylene oxide with a fatty acid, a long chain aliphatic alcohol, or a partial ester derived from fatty acids) and a hexitol or a hexitol anhydride (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, and the like). Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and the like. Parenteral compositions The pharmaceutical composition containing cannabinoid complexed with cyclodextrin may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy, supra. Compositions for parenteral use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added (see below). The composition may be in form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from the active compound, the composition may include suitable parenterally acceptable carriers and/or excipients. The active drug(s) may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release. Furthermore, Attorney Docket No.: 51225-009WO2 the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents. As indicated above, the pharmaceutical compositions according to the invention may be in the form suitable for sterile injection. To prepare such a composition, the suitable active compound is dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer’s solution, and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate). Rectal compositions For rectal application, suitable dosage forms for a composition include suppositories (emulsion or suspension type), and rectal gelatin capsules (solutions or suspensions). In a typical suppository formulation, the active compound is combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water- soluble or dispersible bases like polyethylene glycols and polvoxyethylene sorbitan fatty acid esters. Various additives, enhancers, or surfactants may be incorporated. Vaginal compositions For vaginal application, suitable dosage forms for a composition include suppositories (emulsion or suspension type), and vaginal gelatin capsules (solutions or suspensions). In a typical suppository formulation, the active compound is combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water- soluble or dispersible bases like polyethylene glycols and polvoxyethylene sorbitan fatty acid esters. Various additives, enhancers, or surfactants may be incorporated. Intranasal and Inhalation Compositions For administration by inhalation, typical dosage forms include nasal sprays and aerosols. In a typically nasal formulation, the active compound is dissolved or dispersed in a suitable vehicle. The pharmaceutically acceptable vehicles and excipients (as well as other pharmaceutically acceptable materials present in the composition such as diluents, enhancers, flavoring agents, and preservatives) are selected in accordance with conventional pharmaceutical practice in a manner understood by the persons skilled in the art of formulating pharmaceuticals. Percutaneous compositions The pharmaceutical compositions may also be concurrently administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes. The formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters, and other kinds of transdermal drug delivery systems. The pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, Attorney Docket No.: 51225-009WO2 preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, and skin protective agents. Examples of emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives). Examples of antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole, and cysteine. Examples of preservatives are parabens, such as methyl or propyl p-hydroxybenzoate, and benzalkonium chloride. Examples of humectants are glycerin, propylene glycol, sorbitol, and urea. Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, N,N- dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, and AZONETM. Examples of chelating agents are sodium EDTA, citric acid, and phosphoric acid. Examples of gel forming agents are CARBOPOLTM, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone. Examples of ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate (TWEENTM)). The compositions may be adapted for direct application or for introduction into relevant orifice(s) of the body (e.g., rectal, urethral, vaginal or oral orifices). The composition may be applied by means of special drug delivery devices such as dressings or alternatively plasters, pads, sponges, strips, or other forms of suitable flexible material. Dosages The dosage of the cannabinoid-cyclodextrin complex to be administered can depend on several factors, including: the administration method, the condition or symptom to be treated, the severity of the condition or symptom, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect dosage used. Therapy Therapy according to the invention may be provided at home, the doctor’s office, a clinic, a hospital’s outpatient department, or a hospital. Treatment begins at the physician’s office so that the doctor can observe the therapy’s effects closely and make any adjustments that are needed. The duration of the therapy depends on the type and severity of the emotional disorder being treated, the age and condition of the patient, the stage and type of the patient’s emotional disorder, and how the patient responds to the treatment. The pharmaceutical compositions of the invention can be used to treat anxiety in an individual. Anxiety is broadly defined as a state of unwarranted or inappropriate worry often accompanied by restlessness, tension, distraction, irritability and sleep disturbances. This disproportionate response to environmental stimuli can hyperactivate the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, resulting in somatic manifestation of anxiety, including shortness of breath, sweating, nausea, rapid heartbeat and elevated blood pressure. Anxiety disorders represent a range of conditions and as a result have been classified into multiple distinct conditions, including Generalized Anxiety Attorney Docket No.: 51225-009WO2 Disorder (GAD), Panic Disorder (PD), Social Anxiety Disorder (SAD), Obsessive-Compulsive Disorder (OCD), Specific Phobic Disorders (SPD), Post Traumatic Stress Disorder (PTSD), Agoraphobia, or Separation Anxiety Disorder (SeAD). GAD is the most commonly occurring of the anxiety disorders and is characterized by excessive and persistent worries. In the general population the lifetime prevalence rate of GAD ranges from 4.1 to 6.6% with somewhat higher rates in women than in men. The individual with GAD worries about life events such as marital relationships, job performance, health, money, and social status. Individuals with GAD startle easily and may suffer from depression. Some of the specific symptoms of GAD include restlessness, motor tension, difficulty concentrating, and irritability. The severity of the symptoms over time may be linked to the changing nature of the environmental stressor. With increasing age, GAD symptoms become less severe. PD is a well-studied psychiatric condition that consists of multiple disabling panic attacks characterized by an intense autonomic arousal. In addition, heightened fear and anxiety states occur both during and between panic attacks. Approximately 3% of women and 1.5% of men have panic attacks. During a panic attack, the individual experiences multiple symptoms including light-headedness, a pounding heart and difficulty in breathing. SAD is a chronic disorder in which social interactions cause irrational anxiety. Individuals suffering from SAD may experience heightened anxiety, fear, self-consciousness, and embarrassment during everyday social interactions. Individuals suffering from SAD may experience fear of being humiliated, judged, and/or rejected during everyday social interactions. OCD is a common, chronic, and long-lasting disorder characterized by unreasonable, recurring thoughts and fears (e.g., obsessions) that lead to compulsive behaviors. Individuals suffering from OCD may experience unreasonable fear of germs or contamination, unwanted forbidden or taboo thoughts, aggressive thoughts towards themselves or others, or an obsessive desire to have things in a symmetrical or perfect order. Individuals suffering from OCD may engage in compulsive behaviors. Exemplary, nonlimiting compulsive behaviors include excessive cleaning and/or handwashing, ordering or arranging things in a particular, precise fashion, repeatedly checking whether a task is completed (e.g., whether a door is locked or an oven is off) or compulsive counting. SPD is a class of disorders characterized by persistent, unrealistic, intense anxiety about and fear of specific situations, circumstances, and objects. Nonlimiting examples of situations, circumstances, and objects that individuals suffering from SPD may have anxiety about or fear of include animals, heights, or thunderstorms. PTSD is an anxiety disorder that occurs in people who have experienced or witnessed a traumatic event. Nonlimiting examples of traumatic events that may cause PTSD in an individual include a serious accident, a terrorist act, war and/or combat, sexual violence, or the imminent threat of death, sexual violence, or serious injury. Individuals suffering from PTSD may experience intense, disturbing thoughts or feelings related to their traumatic experience which last long after the traumatic event has ended. Nonlimiting examples of intense, disturbing thoughts or feelings include flashbacks or nightmares, feelings of sadness, fear, or anger, and feelings of detachment and/or estrangement from other people. Agoraphobia is an anxiety disorder characterized by the fear of situations which are perceived to be unsafe and inescapable. Nonlimiting examples of situations individual suffering from agoraphobia may be afraid of include traveling on public transportation, visiting a shopping center, being in a crowd, being in an open space, being in an enclosed space, standing in line, or leaving their home. SeAD is an anxiety disorder characterized by excessive fear, anxiety, and distress about being away from home or loved ones. Nonlimiting examples of fears an individual suffering from SeAD may experience include fear of losing a parent or other loved one to an illness or disaster, or fear Attorney Docket No.: 51225-009WO2 that something bad will happen in the future that will lead to separation from home and/or loved ones (e.g., becoming lost or being kidnapped). The pharmaceutical compositions of the invention can be used to treat depression in an individual. Depressive disorders are broadly defined as serious mood disorders characterized by sadness severe enough or persistent enough to interfere with function and often by decrease interest in pleasure in activities. The origin of depressive disorders likely involves a combination of heredity factors, changes in neurotransmitter levels, altered neuroendocrine function, and psychosocial factors. Depressive disorders represent a range of conditions and as a result have been classified into multiple distinct conditions, including but not limited to Dysthymia, Major Depression, Bipolar II Disorder, and Adjustment Disorder with Depression. Dysthymia, also referred to as Persistent depressive disorder (PDD), is a chronic depressive disorder characterized by symptoms of depression that last for at least 2 years. Nonlimiting examples of symptoms an individual suffering from Dysthymia may experience include poor appetite or overeating, changes in sleep patterns (e.g., insomnia or hypersomnia), low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions, or feelings of hopelessness. Major Depression is depressive mood disorder characterized by persistently depressed mood causing a significant impairment in daily life. Nonlimiting examples of symptoms an individual suffering from Major Depression may experience include depressed mood, loss of interest or pleasure in almost all activities, significant, unintentional weight gain or loss (e.g., >5% change in body weight in one month), sleep disturbance (e.g., insomnia or hypersomnia), psychomotor changes (e.g., agitation or retardation) severe enough to be observable by others, tiredness, fatigue, or low energy, decreased efficiency with which routine tasks are completed, a sense of worthlessness or inappropriate, delusional guilt, impaired ability to think, concentrate, or make decisions, recurrent thoughts of death, suicidal ideation, or suicide attempts. Bipolar II Disorder is a depressive disorder characterized by a pattern of depressive episodes and hypomanic episodes. Nonlimiting examples of symptoms an individual suffering from Bipolar II Disorder may experience during a depressive episode include feelings of sadness, emptiness, or hopelessness, low motivation, loss of interest in activities, sleep disturbance (e.g., insomnia or hypersomnia), low energy, feelings of worthlessness or guilt, difficulty focusing, unintentional weight loss or gain, or suicidal thoughts. Nonlimiting examples of symptoms an individual suffering from Bipolar II Disorder may experience during a hypomanic episode include increased energy, activity, or agitation, an exaggerated sense of well-being and self-confidence, decreased need for sleep, unusual talkativeness, racing thoughts, distractibility or poor decision making. Adjustment Disorder with Depression is a depressive disorder characterized by the development of emotional or behavioral symptoms in response to an identifiable stressor occurring within 3 months of the onset of the stressor. Nonlimiting examples of symptoms an individual suffering from Adjustment Disorder with Depression may experience include low mood, tearfulness, or feelings of hopelessness. Individuals suffering from an emotional disorder, e.g., an anxiety disorder and/or a depressive disorder, may experience physical symptoms of the disorder. Nonlimiting examples of physical symptoms experienced by individuals suffering from an emotional disorder include body pains, headaches, joint pains, nausea, vomiting, fatigue, weakness, numbness, shortness of breathing, or shortness of breath. One or more of these symptoms can be ameliorated using the methods of the invention. Attorney Docket No.: 51225-009WO2 Examples The following examples are put forth to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Example 1: Preparation of a sublingual lozenge including delta-8-THC complexed with beta- cyclodextrin. The delta-8-THC was dissolved in ethanol and was slowly added to a stirred, clear solution of beta-cyclodextrin to form a milky solution, which was then freeze dried. The resulting solid was formulated into lozenges for sublingual administration, each lozenge containing 10 mg of delta-8-THC and 100 mg beta-cyclodextrin. Example 2: Anxiolytic effect of a sublingual lozenge including delta-8-THC complexed with beta- cyclodextrin. The lozenge of Example 1 was sublingually administered to a human subject. The resulting experience was mild and anxiolytic in effect. It was observed that the combination of cyclodextrin with the delta-8-THC was more powerful that the sublingual administration of delta-8-THC alone. Example 3: Preparation of a sublingual lozenge including delta-8-THC and ketamine, each complexed with beta-cyclodextrin. The delta-8-THC was dissolved in ethanol and was slowly added to a stirred, clear solution of beta-cyclodextrin to form a milky solution, which was then freeze dried. Ketamine hydrochloride is also included, optionally as a complex with beta-cyclodextrin prepared and freeze dried using methods analogous to those described in Example 1. The delta-8-THC, ketamine hydrochloride, and beta- cyclodextrin solids were formulated into lozenges for sublingual administration, each lozenge containing 10 mg of delta-8-THC, 100 mg ketamine hydrochloride, and 100 mg beta-cyclodextrin. Example 4: Anxiolytic effect of a sublingual lozenge including delta-8-THC and ketamine, each complexed with beta-cyclodextrin. The formulation of Example 3 was administered to human subjects. Subjects experienced a rapid onset of action that produces a trance state, a time-out from ordinary concerns, is anxiolytic, acts like MDMA in enabling access to difficult feelings intra and interpersonally, is socially enabling and produces a positive affective state. The combination in multiple subjects appears to enhance sexuality and sensuality. Duration of principle experience is about an hour with a tail of diminishing intoxication of another hour or more, Generally a lying down experience for 30 to 60 minutes. No subjects experienced nausea or vomiting. It was observed that the persistence of therapeutic effect, particularly a sense of equanimity and kindness can be for days. Subject also experience diminished anxiety and reactivity, and improved emotional balance. Attorney Docket No.: 51225-009WO2 Subjects experienced a recovery to baseline in less than about 3 hours. There were no reports of fatigue. The improvement in mood and anxiolytic effect observed for the sublingual lozenge including delta-8-THC and ketamine, each complexed with beta-cyclodextrin, was significantly enhanced relative to the administration of either delta-8-THC or ketamine alone as a single agent. Furthermore, the inclusion of cyclodextrin in the formulation further enhanced the anxiolytic effect of the delta-8-THC/ketamine combination therapy. Other Embodiments All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

Attorney Docket No.: 51225-009WO2 What is claimed is: CLAIMS 1. A pharmaceutical composition in unit dosage form comprising (i) an inclusion complex comprising a cannabinoid and a cyclodextrin; and (ii) a pharmaceutically acceptable excipient. 2. The pharmaceutical composition of claim 1, wherein the cannabinoid is selected from delta-9- THC, delta-8-THC, cannabinol (CBN), delta-9-THCV, delta-8-THCV, cannabidiol (CBD), and cannabivarin (CBV). 3. The pharmaceutical composition of claim 1 or 2, wherein the cyclodextrin is a water soluble unsubstituted or substituted alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin. 4. The pharmaceutical composition of claim 3, wherein the cyclodextrin is a beta-cyclodextrin selected from methyl beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and sulfobutylether beta- cyclodextrin. 5. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 5 mg to 20 mg of delta-9-THC. 6. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 5 mg to 40 mg of delta-8-THC. 7. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 10 mg to 100 mg of CBN. 8. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 1 mg to 30 mg of delta-9-THCV. 9. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 1 mg to 30 mg of delta-8-THCV. 10. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 50 mg to 200 mg of CBD. 11. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises from 1 mg to 30 mg of CBV. 12. The pharmaceutical composition of any one of claims 1-11, wherein the mole ratio of the cannabinoid to the cyclodextrin in the pharmaceutical composition is from 1:1 to 1:20. Attorney Docket No.: 51225-009WO2 13. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition comprises from 40 to 700 mg of the cyclodextrin. 14. The pharmaceutical composition of any one of claims 1-13, wherein the pharmaceutical composition is formulated for oral, pulmonary, sublingual, intranasal, intramuscular, intravenous, transdermal, or rectal administration. 15. The pharmaceutical composition claim 14, wherein the pharmaceutical composition is formulated for sublingual administration. 16. The pharmaceutical composition of claim 15, wherein the unit dosage form is a film, strip, lozenge, or orally dissolving tablet. 17. The pharmaceutical composition of any one of claims 1-16, further comprising ketamine, norketamine, 6-hydroxynorketamine, or a pharmaceutically acceptable salt thereof. 18. The pharmaceutical composition of claim 17, wherein the ketamine, norketamine, 6- hydroxynorketamine, or a pharmaceutically acceptable salt thereof, is present as an inclusion complex with a cyclodextrin. 19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises: (a) from 50 to 200 mg of ketamine, or a pharmaceutically acceptable salt thereof, (b) from 50 to 200 mg of a beta-cyclodextrin, and (c) from 5 mg to 20 mg of delta-8-THC. 20. A method of treating an emotional disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of any one of claims 1-19 in an amount that is effective for the treatment of the emotional disorder. 21. The method of claim 20, wherein the emotional disorder is an anxiety disorder. 22. The method of claim 21, wherein the anxiety disorder is selected from Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Social Anxiety Disorder (SAD), Obsessive-Compulsive Disorder (OCD), Specific Phobic Disorders (SPD), Post Traumatic Stress Disorder (PTSD), Agoraphobia, or Separation Anxiety Disorder (SeAD). 23. The method of claim 20, wherein the emotional disorder is a depressive disorder. 24. The method of claim 23, wherein the depressive disorder is selected from dysthymia, major depression, Bipolar II disorder, Postpartum depression, or adjustment disorder with depression. Attorney Docket No.: 51225-009WO2 25. The method of claim 20, wherein the method comprises ameliorating one or more physical symptoms associated with the emotional disorder, wherein the physical symptoms are selected from headache, migraine, physical symptoms related to the menstrual cycle such as breast tenderness, cramps and headaches, symptoms of somatization disorders, fibromyalgia, various neurologic symptoms and disorders, and pain from a wide variety of causes. 26. The method of any one of claims 20-25, wherein the pharmaceutical composition is administered to the subject by a route selected from oral, pulmonary, sublingual, intranasal, intramuscular, intravenous, transdermal, and rectal administration. 27. The method of claim 26, wherein the pharmaceutical composition is administered to the subject sublingually. 28. A method of enhancing sexual response and sensitivity in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of any one of claims 1- 19 in an amount that is effective for enhancing sexual response and sensitivity. 29. A method for improving sexual function in a human subject suffering from sexual dysfunction or otherwise in need of enhanced sexual function, said method comprising the step of administering to the subject a pharmaceutical composition of any one of claims 1-19 in an amount that is effective for improving sexual function in the human subject. 30. The method of claim 29, wherein the improved sexual function is increased libido. 31. A method of treating female sexual dysfunction in a female subject, said method comprising the step of administering to the female subject a pharmaceutical composition of any one of claims 1-19 in an amount that is effective for treating female sexual dysfunction.