Cannabidiolic acid esters for treating Prader-Willi syndrome

Abstract

The present invention provides compositions and methods for treating Prader-Willi syndrome (PWS). Specifically, the present invention provides pharmaceutical compositions and formulations comprising a cannabidiolic acid (CBDA) ester derivative, alone or in combination with one or more additional cannabinoid compounds, and a pharma- ceutically acceptable carrier, excipient, or diluent, for use in treating PWS.

Description

[Technical field]

[0001] The present invention relates to compositions and methods for treating Prader-Willi Syndrome (PWS). In particular, the present invention relates to pharmaceutical compositions and formulations comprising cannabidiolic acid (CBDA) ester derivatives, alone or in combination with one or more additional cannabinoid compounds, for use in treating PWS. [Background technology]

[0002] Prader-Willi syndrome (PWS) is a rare complex multisystem genetic disorder recognized as the most common known genetic cause of life-threatening obesity in humans. PWS results from genomic imprinting errors with lack of expression of paternally inherited imprinted genes in the chromosome 15q11-q13 region, commonly caused by paternal deletion, maternal disomy 15 where both chromosomes 15 are maternally inherited, or imprinted mutations in the 15q11-q13 region. Major clinical features include severe infantile hypotonia, hyperphagia with onset of early childhood obesity if uncontrolled, developmental delay with learning and behavioral problems, short stature with small limbs, and hypogonadism / hypopogonadism due to growth hormone and other endocrine deficiencies. Mild craniofacial dysmorphism with enamel hypoplasia and dry mouth is common. Psychiatric phenotypes, behavioral and autistic features correlate with specific PWS genetic subtypes (e.g., autism in those with maternal disomy 15). PWS occurs in approximately 1 in 15,000 people (Butler et al. 2019, Curr Pediatr Rev. 2019 Nov;15(4):207-244).

[0003] Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid compound present in the plant Cannabis sativa, and accounts for up to 40% of the cannabinoids in cannabis extracts (Grlic, Bull. Narc., 1976, 14:37-46). CBD is considered a lead compound for treating and preventing inflammatory and oxidative damage, see, for example, WO 1999 / 053917. [ka]

[0004] In contrast to the extensive knowledge about CBD, the literature on cannabidiolic acid (CBDA), also a major constituent of the Cannabis sativa plant, is very limited, which may be due to its instability. It was first isolated in 1955 (Krejci and Santavy, 1955, Acta Univ Palacki Olomuc 6:59-66). Analysis of the physical properties of its methyl ester, cannabidiolic acid methyl ester (CBDA-ME), led to its structure elucidation in 1965 (Mechoulam and Gaoni, Tetrahedron, 1965, 21:1223-1229). Its synthesis from CBD was then reported (Mechoulam and Ben-Zvi, J. Chem. Soc. Commun., 1969, 7:343-344).

[0005] The decarboxylation of CBDA to CBD is accelerated by heat, suggesting the relative instability of CBDA and therefore reducing its potential to function as a drug (Mechoulam, Academic Press, New York, 1973, 1-99; Citti et al., J. Pharm. Biomed. Anal., 2018, 16:532-540). As such, CBDA-ME remains a relatively unknown and understudied cannabinoid whose effects are only just beginning to be elucidated. [ka]

[0006] CBDA-ME is a derivative of CBDA that may be pharmacologically active in vivo. Pertwee et al. (Brit. J. Pharmacology, 2018, 175:100-112) reported that a methyl ester of CBDA, designated HU-580 (also referred to herein as EPM301), exhibited greater potency than CBDA in suppressing both acute and anticipatory nausea and signs of stress-induced anxiety in rats, and that it increased the 5-HT 1A Another recent study (Hen-Shoval et al., Behav. Brain Res., 2018, 351:1-3) supports the potent antidepressant effects of low doses (1 mg / kg) of CBDA-ME following oral ingestion in two rat models.

[0007] WO 2018 / 235079 describes a composition comprising a CBDA ester and a 5-HT 1A Its use in treating a state, disease or condition associated with the receptor is disclosed.

[0008] WO 2020 / 186010 discloses pharmaceutical compositions comprising cannabinoid acid ester compounds alone or in combination with one or more additional cannabinoid compounds. The PCT application discloses the use of the pharmaceutical compositions in the treatment of various diseases including joint diseases, skin diseases, gastrointestinal diseases, uterine related disorders, non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), diabetes, dyslipidemia, metabolic syndrome, hyperglycemia, obesity, and in lowering or maintaining cholesterol levels or lowering the LDL / HDL ratio.

[0009] A CBD oral solution has been proposed for the treatment of subjects with PWS and has been tested in a Phase 2 clinical trial [https: / / www.clinicaltrials.gov / ct2 / show / NCT02844933?term=insys].

[0010] There remains an unmet medical need for well-evaluated, effective therapies for PWS that can ameliorate its symptoms. Summary of the Invention

[0011] The present invention provides pharmaceutical compositions comprising a cannabinoid (wherein the cannabinoid component comprises a cannabidiolic acid (CBDA) ester, alone or in combination with one or more additional cannabinoid compounds) and a pharma- ceutically acceptable carrier, excipient or diluent for treating Prader-Willi syndrome. According to certain embodiments, the cannabinoid component comprises a CBDA ester in combination with one or more extracts of the cannabis plant, and a pharma- ceutically acceptable carrier, excipient or diluent.

[0012] In some embodiments, CBDA esters are more active in treating PWS than either CBDA or CBD. Compositions comprising CBDA esters exhibit significant long-term therapeutic effects in PWS. Without wishing to be bound by any particular theory or mechanism of action, the therapeutic effects of the compositions may be due to the stability of the CBDA esters.

[0013] We disclose herein that treatment with CBDA-ME reduces body weight, reduces fat mass (while preserving lean mass), improves ambulatory activity, normalizes lipid, glucose and insulin levels, reduces fat in the liver, and improves liver enzyme levels in a mouse model of PWS (Magel2 null mice).

[0014] According to one aspect, the present invention provides a method for treating PWS comprising administering to a subject a cannabinoid component comprising administering to said subject a CBDA ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds, and a pharma- ceutically acceptable carrier, excipient or diluent; [ka] During the ceremony, R1 and R2 are each independently a straight or branched, unsubstituted or substituted C1-C 15 Alkyl, linear or branched, unsubstituted or substituted C2-C 15 Alkenyl, and straight or branched, unsubstituted or substituted C2-C 15 alkynyl, and stereoisomers and salts thereof.

[0015] According to some embodiments, R1 is methyl. According to some embodiments, the cannabidiolic acid ester is CBDA-ME.

[0016] According to some embodiments, the CBDA ester in the composition of the present invention is represented by formula (Ia): [ka]

[0017] According to some embodiments, the CBDA ester in the composition of the present invention is represented by formula (Ib): [ka]

[0018] According to certain embodiments, the CBDA ester is (referred to herein as EPM301). [ka]

[0019] According to some embodiments, the pharmaceutical composition is for use in slowing, preventing the progression of, treating, or ameliorating one or more symptoms of PWS.

[0020] According to some embodiments, the pharmaceutical composition comprises an additional cannabinoid compound. According to some embodiments, the additional cannabinoid compound is CBD, cannabigerol (CBG), Δ 8 -Tetrahydrocannabinol (Δ 8 -THC), Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), cannabinol (CBN), Δ 9 (11)-Tetrahydrocannabinol (exo-THC), cannabichromene (CBC), tetrahydrocannabinol-C3 (THC-C3), tetrahydrocannabinol-C4 (THC-C4), tetrahydrocannabinol-C7 (THC-C7), esters thereof, and combinations thereof.

[0021] According to some embodiments, the one or more additional cannabinoid compounds are present in one or more extracts of the cannabis plant. According to some embodiments, the one or more additional cannabinoid compounds are obtained from one or more extracts of the cannabis plant.

[0022] According to some embodiments, the cannabis plant extract is obtained from a species or strain selected from the group consisting of Cannabis sativa, Cannabis indica, Cannabis ruderalis, hybrid strains, and combinations thereof. According to further embodiments, the cannabis plant extract is obtained from a strain selected from the group consisting of high-CBD strains, high-THC strains, and combinations thereof. According to some embodiments, the cannabis plant extract comprises at least one cannabinoid selected from the group consisting of CBD, THC, CBN, CBG, CBC, acids thereof, and combinations thereof.

[0023] According to some embodiments, the cannabis plant extract comprises about 1% (w / w) CBD. According to some embodiments, the cannabis plant extract comprises about 10% (w / w) CBD. According to some embodiments, the cannabis plant extract comprises about 25% (w / w) CBD.

[0024] According to some embodiments, the cannabis plant extract comprises about 1% (w / w) THC. According to some embodiments, the cannabis plant extract comprises about 10% (w / w) THC. According to some embodiments, the cannabis plant extract comprises about 25% (w / w) THC.

[0025] According to some embodiments the cannabis plant extract is formed by contact with a suitable solvent or combination of solvents. According to some embodiments the solvent is selected from the group consisting of polar solvents, hydrocarbon solvents, carbon dioxide, and combinations thereof.

[0026] According to some embodiments, the pharmaceutical composition is in the form of an emulsion, solution, gel, or dispersion. According to some embodiments, the pharma- ceutically acceptable carrier, excipient, or diluent comprises water, oil, or both. Each possibility represents a separate embodiment of the present invention.

[0027] According to some embodiments, the cannabinoid component can be emulsified, dissolved, dispersed or encapsulated in a formulation suitable for use in either an aqueous carrier or an oily carrier.Thus, according to some embodiments, the pharmaceutical composition is in the form of an emulsion, a solution or a dispersion.Each possibility represents a separate embodiment.Also, according to some embodiments, the pharmaceutical composition may include an aqueous carrier or an oily carrier.Each possibility represents a separate embodiment.

[0028] According to some embodiments, the pharmaceutical composition is formulated for inhalation. According to certain embodiments, the pharmaceutical composition is a dry powder formulation. According to some embodiments, the pharmaceutical composition is formulated for administration by vaporization.

[0029] According to alternative embodiments, the pharmaceutical composition is formulated in a form suitable for intranasal, oral, intravenous, intraarterial, or subcutaneous administration. Each embodiment represents a separate embodiment of the present invention. According to additional embodiments, the pharmaceutical composition is formulated for oral administration.

[0030] According to some embodiments, the pharmaceutical composition is a non-aqueous composition. It should be understood that a non-aqueous composition may include any dry composition or composition that includes a non-aqueous solvent or additive and contains 10% or less, 5% or less, 2% or less, or 1% or less water (w / w). According to some embodiments, the pharmaceutical composition is formulated in the form of a powder. According to some embodiments, the pharmaceutical composition is a powder suitable for a multi-dose reservoir dry powder inhaler (DPI).

[0031] According to another embodiment, the pharmaceutical composition is a liquid composition.

[0032] According to some embodiments, the pharmaceutical composition is formulated as a capsule, tablet, liquid, or syrup. According to certain embodiments, the dosage form is delivered in a solution, suspension, or is filled into a capsule, or is a granule or pellet that is compressed into a tablet.

[0033] According to some embodiments, the pharmaceutical composition further comprises a triglyceride, a fat, a lipid, an oil, a fatty acid, a solvent, or a mixture thereof. According to some embodiments, the excipient is selected from the group consisting of a triglyceride, a fat, a lipid, an oil, a fatty acid, a solvent, or a mixture thereof. According to certain embodiments, the pharmaceutical composition comprises an edible oil selected from the group consisting of copaiba oil, coconut oil, cottonseed oil, soybean oil, safflower oil, sesame oil, sunflower oil, castor oil, corn oil, olive oil, coconut oil, peanut oil, and poppy seed oil. Each possibility represents a separate embodiment of the present invention.

[0034] According to some embodiments, the pharmaceutical composition comprises an alcohol. According to some embodiments, the pharmaceutical composition comprises an alcohol and a second solvent. According to some embodiments, the alcohol is ethanol. According to certain embodiments, the second solvent is polyethylene glycol (PEG), propylene glycol, or both. Each possibility represents a separate embodiment of the present invention.

[0035] According to some embodiments, the pharmaceutical composition is formulated for sustained release of the CBDA ester. In certain embodiments, the pharmaceutical composition further comprises a release retardant or a mixture of release retardants. According to some embodiments, the pharmaceutical composition is at least partially coated with an enteric coating.

[0036] According to some embodiments, the CBDA ester is provided in a microencapsulated particle. According to certain embodiments, the CBDA ester is provided in a liposomal encapsulated particle.

[0037] According to some embodiments, the pharmaceutical composition comprises a phospholipid. According to certain embodiments, the pharmaceutical composition comprises a phospholipid selected from the group consisting of naturally occurring phospholipids and synthetic phospholipids. According to certain embodiments, the naturally occurring phospholipid is selected from the group consisting of soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, and combinations thereof. According to certain embodiments, the synthetic phospholipid is selected from the group consisting of phosphocholine, phosphoethanolamine, phosphatidic acid, phosphoglycerol, phosphoserine, mixed chain phospholipids, lysophospholipids, pegylated phospholipids, and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0038] According to some embodiments, the phospholipids may form micelles, emulsions, or liposomes. According to some embodiments, the phospholipids form micelles, emulsions, or liposomes. According to some embodiments, the pharmaceutical composition is in the form of a micelle, emulsion, or liposome.

[0039] According to some embodiments, the pharmaceutical composition comprises a cyclodextrin. According to certain embodiments, the cyclodextrin is selected from the group consisting of hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, and methyl-β-cyclodextrin (MβCD), and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0040] According to some embodiments, the excipient is selected from the group consisting of emulsifiers, buffers, pH adjusters, preservatives, antioxidants, stabilizers, and combinations thereof, Each possibility represents a separate embodiment of the present invention.

[0041] According to some embodiments, the pharmaceutical composition further comprises vitamins, antioxidants, minerals, and / or flavoring agents.

[0042] According to some embodiments, the composition comprises less than about 10% (w / w) cannabinoid component. According to additional embodiments, the composition comprises less than about 7% (w / w) cannabinoid component. According to further embodiments, the composition comprises less than about 5% (w / w) cannabinoid component. According to yet other embodiments, the composition comprises less than about 2% (w / w) cannabinoid component. According to some embodiments, the composition comprises less than about 1% (w / w) cannabinoid component. According to additional embodiments, the composition comprises less than about 0.5% (w / w) cannabinoid component.

[0043] According to some embodiments, the pharmaceutical composition comprises a unit dosage form of at least about 20 mg of CBDA ester. In certain embodiments, the dosage form comprises from about 20 mg to about 2,000 mg of CBDA ester. In certain embodiments, the dosage form comprises from about 20 mg to about 500 mg of CBDA ester. In certain embodiments, the dosage form comprises from about 50 mg to about 1,000 mg of CBDA ester. In certain embodiments, the dosage form comprises from about 200 mg to about 1,000 mg of CBDA ester. In certain embodiments, the dosage form comprises about 50 mg, 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 2000 mg, about 3000, about 4000, about 5000 mg, about 6000, about 8000, or about 10000 mg of CBDA ester. Each possibility represents a separate embodiment of the invention. According to some embodiments, the pharmaceutical composition comprises a unit dosage form of at least about 20 mg of cannabinoid component. In certain embodiments, the dosage form comprises about 20 mg to about 2,000 mg of cannabinoid component. In certain embodiments, the dosage form comprises about 20 mg to about 500 mg of cannabinoid component. In certain embodiments, the dosage form comprises about 50 mg to about 1,000 mg of cannabinoid component. In certain embodiments, the dosage form contains about 200 mg to about 1,000 mg of the cannabinoid component. In certain embodiments, the unit dosage form contains about 50 mg, 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 2000 mg, or about 5000 mg of the cannabinoid component. Each possibility represents a separate embodiment of the present invention.

[0044] The pharmaceutical compositions described herein can be administered with one or more other therapeutic agents. According to some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent for treating PWS.

[0045] According to an additional aspect, the present invention provides a method for treating PWS, comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition described herein.

[0046] According to some embodiments, treating includes slowing, preventing the progression of, curing, or ameliorating one or more symptoms of PWS.

[0047] According to some embodiments, treating includes treating behaviors associated with PWS.

[0048] According to certain embodiments, treating results in one or more of: (a) a decrease in compulsive behavior compared to placebo; or (b) a decrease in anxiety compared to placebo.

[0049] According to some embodiments, treating results in a reduction or elimination of persistent hunger, a reduction or elimination of excessive appetite (binge eating), a reduction or elimination of weight gain, a reduction or elimination of obesity. According to certain embodiments, treating results in a measured reduction in the Binge Eating Questionnaire for Clinical Trials (HQ-CT) total score.

[0050] According to some embodiments, the pharmaceutical composition is administered by inhalation from a vaporizer or metered dose inhaler. According to other embodiments, the pharmaceutical composition is administered orally.

[0051] According to some embodiments, the pharmaceutical composition is administered once daily, twice weekly, once weekly, once every two weeks, once every three weeks, or once a month.

[0052] According to some embodiments, the subject is a mammal. According to some embodiments, the subject is a human subject.

[0053] According to some embodiments, the pharmaceutical composition is administered by inhalation from a vaporizer or metered dose inhaler. According to other embodiments, the pharmaceutical composition is administered orally.

[0054] According to some embodiments, the pharmaceutical composition is administered once daily, twice weekly, once weekly, once every two weeks, once every three weeks, or once a month.

[0055] According to some embodiments, the subject is a mammal. According to some embodiments, the subject is a human subject.

[0056] According to some embodiments, the pharmaceutical composition is used in combination with other therapeutic agents for the treatment of PWS.

[0057] According to some embodiments, the method further comprises administering insulin, an insulin receptor agonist, Growth hormone-releasing hormone (GHRH), a GHRH receptor agonist, alpha-Melanocyte-stimulating hormone (αMSH), an alpha-MSH receptor agonist, oxytocin, an oxytocin receptor agonist, orexin, an orexin receptor agonist, Brain-derived neurotrophic factor (BDNF), a BDNF receptor agonist, vasopressin, a vasopressin receptor agonist, Neuropeptide Y (NPY), an NPY receptor agonist, Agouti Related Neuropeptide (AGRP), an AGRP receptor agonist, a gonadotropin, a gonadotropin receptor agonist, or a combination thereof. Each possibility represents a separate embodiment of the present invention.

[0058] According to some embodiments, treating ameliorates at least one PWS-associated symptom selected from the group consisting of hyperphagia, reduced metabolic rate, obesity, hypogonadism, decreased growth hormone production, decreased muscle tone, decreased stamina, decreased ability to concentrate, cognitive impairment, anxiety, growth failure, decreased conversion of immature hormones to mature and active forms, diabetes, and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0059] According to some embodiments, the treating improves muscle tone, hi some embodiments, the treating improves sucking reflex.

[0060] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description and figures given hereinafter. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0061] [Figure 1A] FIG. 1 shows the effect of different doses of CBDA-ME (EPM301) on body weight in WT or PWS mouse models when fed a high-fat diet (HFD). [Figure 1B] FIG. 1 shows the effect of different doses of CBDA-ME (EPM301) on body weight in WT or PWS mouse models when fed a high-fat diet (HFD). [Figure 1C] FIG. 1 shows the effect of different doses of CBDA-ME (EPM301) on body weight in WT or PWS mouse models when fed a high-fat diet (HFD). [Figure 1D] FIG. 1 shows the effect of different doses of CBDA-ME (EPM301) on body weight in WT or PWS mouse models when fed a high-fat diet (HFD). [Figure 1E] FIG. 1 shows the effect of different doses of CBDA-ME (EPM301) on body weight in WT or PWS mouse models when fed a high-fat diet (HFD). [Figure 1F] FIG. 1 shows the effect of different doses of CBDA-ME (EPM301) on body weight in WT or PWS mouse models when fed a high-fat diet (HFD). [Figure 2A] The effects of CBDA-ME on carbohydrate oxidation (FIG. 2A) and fat oxidation (FIG. 2B) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 2B] The effects of CBDA-ME on carbohydrate oxidation (FIG. 2A) and fat oxidation (FIG. 2B) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 3A] Shows the effect of CBDA-ME on food intake in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 3B] Shows the effect of CBDA-ME on food intake in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 3C] Shows the effect of CBDA-ME on food intake in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 4] FIG. 1 shows the effect of CBDA-ME on locomotor activity in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 5A] Shows the effect of CBDA-ME on lipid profile in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 5B] Shows the effect of CBDA-ME on lipid profile in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 5C] Shows the effect of CBDA-ME on lipid profile in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 5D] Shows the effect of CBDA-ME on lipid profile in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 6A] The effects of chronic treatment with CBDA-ME on blood glucose levels (Figure 6A), glucose tolerance and insulin sensitivity (Figure 6B-F) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 6B] The effects of chronic treatment with CBDA-ME on blood glucose levels (Figure 6A), glucose tolerance and insulin sensitivity (Figure 6B-F) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 6C] The effects of chronic treatment with CBDA-ME on blood glucose levels (Figure 6A), glucose tolerance and insulin sensitivity (Figure 6B-F) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 6D] The effects of chronic treatment with CBDA-ME on blood glucose levels (Figure 6A), glucose tolerance and insulin sensitivity (Figure 6B-F) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 6E] The effects of chronic treatment with CBDA-ME on blood glucose levels (Figure 6A), glucose tolerance and insulin sensitivity (Figure 6B-F) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 6F] The effects of chronic treatment with CBDA-ME on blood glucose levels (Figure 6A), glucose tolerance and insulin sensitivity (Figure 6B-F) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 7A] 1 shows the effects of CBDA-ME on alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 7B]1 shows the effects of CBDA-ME on alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 7C] 1 shows the effects of CBDA-ME on alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in WT or PWS mouse models fed a high-fat diet (HFD). [Figure 8A] The effect of CBDA-ME on liver triglycerides (FIG. 8A) and liver cholesterol (FIG. 8B) in WT or PWS mice models fed a high-fat diet (HFD). FIG. 8C shows histology images of liver with or without treatment in WT or PWS mice models fed a high-fat diet (HFD). [Figure 8B] The effect of CBDA-ME on liver triglycerides (FIG. 8A) and liver cholesterol (FIG. 8B) in WT or PWS mice models fed a high-fat diet (HFD). FIG. 8C shows histology images of liver with or without treatment in WT or PWS mice models fed a high-fat diet (HFD). [Figure 8C] The effect of CBDA-ME on liver triglycerides (FIG. 8A) and liver cholesterol (FIG. 8B) in WT or PWS mice models fed a high-fat diet (HFD). FIG. 8C shows histology images of liver with or without treatment in WT or PWS mice models fed a high-fat diet (HFD). [Figure 9A] The effects of CBDA-ME in a preventive model of PWS on weight gain (FIG. 9A), fat mass (FIG. 9B), and lean mass (FIG. 9C) are shown. [Figure 9B]The effects of CBDA-ME in a preventive model of PWS on weight gain (FIG. 9A), fat mass (FIG. 9B), and lean mass (FIG. 9C) are shown. [Figure 9C] The effects of CBDA-ME in a preventive model of PWS on weight gain (FIG. 9A), fat mass (FIG. 9B), and lean mass (FIG. 9C) are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] The present invention provides a method of treating PWS, comprising administering to a subject in need thereof a therapeutically effective amount of a CBDA ester, alone or in combination with one or more additional cannabinoid compounds, and a pharma- ceutically acceptable carrier, excipient, or diluent.

[0063] Without wishing to be bound by theory or mechanism of action, the highly stable compounds of the present invention allow for long-term biological activity for treating PWS.

[0064] PWS is caused by the loss of paternally expressed genes in the imprinted region of chromosome 15q. Subjects with PWS typically suffer from a variety of symptoms, including neurological, cognitive, endocrine, and behavioral abnormalities. Initially, the infant exhibits hypotonia (floppy baby syndrome) and experiences difficulties in sucking and feeding, which can lead to growth retardation. Subjects with PWS often have poor muscle tone, growth hormone deficiency, low levels of sex hormones, persistent hunger, and excessive appetite (hyperphagia). They overeat, leading to weight gain, obesity, and a high incidence of diabetes. Other symptoms appear, including short stature, poor motor skills, underdeveloped genitals, and mild intellectual and learning disabilities. PWS subjects may experience delayed speech and language development, as well as infertility. Behavioral symptoms may include cognitive impairment, cognitive rigidity, emotional lability and obsessive-compulsive behavior, autistic symptoms, psychotic episodes, and bipolar disorder with psychosis. Additional clinical symptoms may include excessive daytime sleepiness, scoliosis, osteopenia / osteoporosis, decreased gastrointestinal motility, sleep disorders, and decreased pain sensitivity.

[0065] The following description of some embodiments is made with the understanding that the present disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any way. An embodiment illustrated under any heading may be combined with an embodiment illustrated under any other heading.

[0066] Cannabinoid composition The term "cannabinoid" as used herein, in the claims, and in other applications, is used to mean any compound that interacts with cannabinoid receptors. Ligands for these receptor proteins include endocannabinoids (produced naturally in the body by humans and animals), phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). The term "cannabinoid acid" refers to the acid form of the above cannabinoids.

[0067] Suitable cannabinoids include certain tetrahydropyran analogues: THC, CBN, CBD, CBG, Δ 9 (11)-Tetrahydrocannabinol (exo-THC), CBC, tetrahydrocannabinol-C3 (THC-C3), tetrahydrocannabinol-C4 (THC-C4), tetrahydrocannabinol-C7 (THC-C7), salts, solvates, metabolites, and metabolic precursors thereof.

[0068] The term "cannabidiol" refers to CBD. As used in this application, CBD is obtained from industrial hemp extracts containing trace amounts of THC or from hemp extracts using high-CBD hemp cultivars. According to some embodiments, cannabidiol can be obtained from plant extracts or synthetically prepared (artificially produced).

[0069] The abbreviation "CBDA" is used herein to refer to cannabidiolic acid, which is the carboxylic acid form of CBD. The term "cannabidiolic acid ester" or "cannabidiol ester" refers to various molecules that are alkyl, alkenyl, alkynyl or aryl ester forms of CBDA. The abbreviation "CBDA-ME" is used herein to refer to cannabidiolic acid methyl ester, which is the methyl ester form of CBDA.

[0070] The common CBDA isomer has n-CH at the 2 position. 11 Although the term cannabidiol includes a 5-aminoethyl ether, it is understood that derivatives of CBDA may include other substituents, particularly alkyl, alkenyl, or alkynyl groups. Thus, the terms cannabidiol acid and CBDA ester refer to a derivative of CBDA in which the 2-position is an n-CH 11 or corresponding structures substituted with different chemical groups, in particular groups that are either alkyl, alkenyl or alkynyl groups. The terms "cannabidiolic acid" and / or "cannabidiolic acid ester" should be interpreted broadly with reference to all possible configurations and salts of the relevant formula.

[0071] It should be understood that the compounds provided herein may contain one or more chiral centers. Each of such chiral centers may be either (R) or (S) configuration. When the compounds of the present invention contain two or more chiral centers, each of those chiral centers may be independently (R) or (S) configuration. Thus, the compounds provided herein may be enantiomerically pure or may be stereoisomeric or diastereomeric mixtures.

[0072] According to one aspect, the present invention provides a pharmaceutical composition comprising a cannabinoid (wherein the cannabinoid component comprises a CBDA ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds), and a pharma- ceutically acceptable carrier, excipient or diluent, for use in treating PWS; [ka] During the ceremony, R1 and R2 are each independently a straight or branched, unsubstituted or substituted C1-C 15 Alkyl, linear or branched, unsubstituted or substituted C2-C 15 Alkenyl, and straight or branched, unsubstituted or substituted C2-C 15 alkynyl, and stereoisomers and salts thereof.

[0073] According to another aspect, the present invention provides a pharmaceutical composition comprising a cannabinoid (wherein the cannabinoid component comprises a CBDA ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds), and a pharma- ceutically acceptable carrier, excipient or diluent, for use in treating PWS; [ka] During the ceremony, R1 and R2 are each independently a straight or branched C1-C aryl group that is unsubstituted or substituted with one or more groups selected from the group consisting of hydroxyl, halogen, amino, thiol, and phosphate. 15 Alkyl, unsubstituted or linear or branched C2-C substituted with one or more groups selected from the group consisting of hydroxyl, halogen, amino, thiol, and phosphate. 15 Alkenyl, and straight or branched C2-C unsubstituted or substituted with one or more groups selected from the group consisting of hydroxyl, halogen, amino, thiol, and phosphate. 15 alkynyl, and stereoisomers and salts thereof.

[0074] According to one aspect, the present invention provides a pharmaceutical composition comprising a cannabinoid (wherein the cannabinoid component comprises a CBDA ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds), and a pharma- ceutically acceptable carrier, excipient or diluent, for use in treating PWS; [ka] During the ceremony, R1 and R2 are each independently a straight or branched, unsubstituted or substituted C1-C 15 Alkyl, linear or branched, unsubstituted or substituted C2-C 15 Alkenyl, and straight or branched, unsubstituted or substituted C2-C 15 alkynyl, and stereoisomers and salts thereof.

[0075] According to certain embodiments, one or more additional cannabinoid compounds are present in one or more extracts of cannabis plant. According to certain embodiments, one or more additional cannabinoid compounds are provided from one or more extracts of cannabis plant. In certain embodiments, one or more additional cannabinoid compounds are extracted from cannabis plant.

[0076] According to some embodiments, R1 is a linear or branched, substituted or unsubstituted C1-C 15 According to some embodiments, R is a linear or branched, substituted or unsubstituted C-C alkyl. 10 According to some embodiments, R1 is a linear or branched, substituted or unsubstituted C5-C 10 According to some embodiments, R1 is a linear or branched, substituted or unsubstituted C5-C 15 According to some embodiments, R1 is a linear or branched, substituted or unsubstituted C2-C 15 According to some embodiments, R is a linear or branched, substituted or unsubstituted C-C 10According to some embodiments, R is a linear or branched, substituted or unsubstituted C5-C 10 According to some embodiments, R is a linear or branched, substituted or unsubstituted C5-C 15 According to some embodiments, R is a linear or branched, substituted or unsubstituted C-C 15 According to some embodiments, R is a linear or branched, substituted or unsubstituted C-C 10 According to some embodiments, R is a linear or branched, substituted or unsubstituted C5-C 10 According to some embodiments, R is a linear or branched, substituted or unsubstituted C5-C 15 It is alkynyl.

[0077] According to some embodiments, R1 is a C1-C 15 According to some embodiments, R is a straight chain unsubstituted C-C alkyl. 15 According to some embodiments, R1 is a branched-chain substituted C3-C 15 According to some embodiments, R is a branched unsubstituted C3-C 15 It is an alkyl.

[0078] According to some embodiments, R1 is C2-C 15 According to some embodiments, R is a straight chain unsubstituted C-C alkenyl. 15 According to some embodiments, R is a branched-chain substituted C3-C alkenyl. 15 According to some embodiments, R is a branched unsubstituted C-C alkenyl. 15 It is alkenyl.

[0079] According to some embodiments, R1 is C2-C 15 According to some embodiments, R is a straight chain unsubstituted C-C 15According to some embodiments, R is a branched-chain substituted C4-C 15 According to some embodiments, R is a branched unsubstituted C4-C 15 It is alkynyl.

[0080] According to some embodiments, R1 is unsubstituted. According to some embodiments, R1 is a straight chain unsubstituted C1-C 10 According to some embodiments, R1 is a straight chain unsubstituted C1-C6 alkyl. According to some embodiments, R1 is a straight chain unsubstituted C1-C4 alkyl. According to some embodiments, R1 is methyl or ethyl. According to some embodiments, R1 is methyl.

[0081] According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C1-C 15 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C1-C 10 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C5-C 10 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C5-C 15 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C2-C 15 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C2-C 10 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C5-C 10 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C5-C 15 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C2-C 15 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C2-C 10According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C5-C 10 According to some embodiments, R2 is a linear or branched, substituted or unsubstituted C5-C 15 It is alkynyl.

[0082] According to some embodiments, R2 is a C1-C 15 According to some embodiments, R2 is a straight chain unsubstituted C1-C 15 According to some embodiments, R2 is a branched-chain substituted C3-C 15 According to some embodiments, R2 is a branched unsubstituted C3-C 15 It is an alkyl.

[0083] According to some embodiments, R2 is C2-C of the linear substitution. 15 According to some embodiments, R2 is a straight chain unsubstituted C2-C alkenyl. 15 According to some embodiments, R2 is a branched-chain substituted C3-C 15 According to some embodiments, R2 is a branched unsubstituted C3-C 15 It is alkenyl.

[0084] According to some embodiments, R2 is C2-C of the linear substitution. 15 According to some embodiments, R2 is a straight chain unsubstituted C2-C 15 According to some embodiments, R2 is a branched-chain substituted C4-C 15 According to some embodiments, R2 is a branched unsubstituted C4-C 15 It is alkynyl.

[0085] According to some embodiments, R2 is a straight chain unsubstituted C1-C6 alkyl. According to some embodiments, R2 is a straight chain unsubstituted C1-C4 alkyl. According to some embodiments, R2 is a C5H 11 It is.

[0086] According to some embodiments, the CBDA ester in the composition of the present invention is represented by formula (Ia): [ka]

[0087] According to some embodiments, the CBDA ester in the composition of the present invention is represented by formula (Ib): [ka]

[0088] According to a particular embodiment, the CBDA ester is a compound designated EPM301. [ka]

[0089] An "alkyl" group refers to a saturated aliphatic hydrocarbon, including linear or straight chain, branched chain, and cyclic alkyl groups. In one embodiment, an alkyl group has 1 to 15 carbons, and is defined herein as C1-C 15 In another embodiment, the alkyl group has 2-6 carbons and is referred to herein as C2-C6-alkyl. In another embodiment, the alkyl group has 2-4 carbons and is referred to herein as C2-C4-alkyl. Each possibility represents a separate embodiment of the present invention. The alkyl group can be unsubstituted or substituted with one or more groups selected from the group consisting of hydroxyl, halogen, amino, thiol, phosphate, and combinations thereof. Thus, the phrase "unsubstituted or substituted alkyl" refers to either an alkyl group that is unsubstituted (i.e., a hydrocarbon) or an alkyl group that is substituted with at least one of hydroxyl, halogen, amino, thiol, phosphate, and combinations thereof.

[0090] The terms "halo" and "halogen" refer to a fluoro, chloro, bromo, or iodo atom. Whenever a compound is said to be halogen-substituted, the compound may contain one or more halogens which may be the same or different.

[0091] An "alkenyl" group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, including linear or straight-chain, branched-chain, and cyclic alkenyl groups. In one embodiment, an alkenyl group has 2 to 15 carbon atoms (C2- 15 alkenyl). In another embodiment, an alkenyl group has 2 to 4 carbon atoms in the chain (C2-4 alkenyl). Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butenyl, and decenyl. An alkylalkenyl is an alkyl group, as defined herein, attached to an alkenyl group, as defined herein. An alkenyl group can be unsubstituted or substituted through any available carbon atom with one or more groups defined above for alkyl. Thus, the phrase "unsubstituted or substituted alkenyl" refers to either an alkenyl group that is unsubstituted (i.e., is a hydrocarbon) or an alkenyl that is substituted with at least one of hydroxyl, halogen, amino, thiol, phosphate, and combinations thereof.

[0092] An "alkynyl" group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, including straight and branched chains. In one embodiment, an alkynyl group has 2 to 15 carbon atoms in the chain (C2- 15 In another embodiment, an alkynyl group has 2 to 4 carbon atoms in the chain (C 2-4Alkynyl). Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, and decynyl. An alkylalkynyl is an alkyl group, as defined herein, attached to an alkynyl group, as defined herein. An alkynyl group can be unsubstituted or substituted through an available carbon atom with one or more groups as defined above for alkyl. Thus, the phrase "unsubstituted or substituted alkynyl" refers to either an alkynyl group that is unsubstituted (i.e., a hydrocarbon) or an alkynyl that is substituted with at least one of hydroxyl, halogen, amino, thiol, phosphate, and combinations thereof.

[0093] According to some embodiments, the additional cannabinoid compound is CBD, CBG, Δ 8 -THC, Δ 9 -Selected from the group consisting of THC, CBN, exo-THC, CBC, THC-C3, THC-C4, THC-C7, esters thereof and combinations thereof.

[0094] The CBDA ester or cannabinoid compound of formula (I) is intended to include any solvates thereof. The term "solvate" as used herein refers to a physical association of a compound disclosed herein with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain instances, the solvate can be isolated. "Solvate" encompasses both liquid-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is water.

[0095] In embodiments in which the CBDA ester is incorporated into the composition in solid form, the present disclosure also includes any polymorphs thereof. The term "polymorph" refers to a particular crystalline or amorphous state of a substance that can be characterized by particular physical properties, such as x-ray diffraction, electron diffraction, IR spectrum, Raman spectrum, melting point, etc.

[0096] Any of the cannabinoids disclosed herein, specifically the CBDA ester of formula (I), can be prepared by any method known to those skilled in the art. For example, it can be isolated or extracted from natural sources, or it can be prepared by synthetic or semi-synthetic means. For example, the cannabinoid can be isolated by extraction from the cannabis plant. Cannabis plants include, but are not limited to, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Each possibility represents a separate embodiment. These plants are natural sources of cannabinoids. According to some embodiments, certain cannabinoids are isolated or extracted from the cannabis plant and then derivatized to the CBDA ester of formula (I). However, it should be understood by those skilled in the art that some of the cannabinoid esters of formula (I) are not naturally occurring and therefore require chemical synthesis for their production.

[0097] The term "extract" as used herein refers to a product prepared by extraction by physical means (e.g., by grinding, pressing, heating, pulsed electric field assisted treatment, shearing treatment and pressure wave treatment), chemical means (e.g., by treatment with acid, base and / or solvent) and / or biochemical means. The term refers to a liquid substance obtained by extraction from a given substance, or a concentrate or essence that is free or substantially free of solvent. The term extract can be a single extract obtained from a particular extraction step or a series of extraction steps. An extract can also be a combination of extracts obtained from separate extraction steps or from separate raw materials. Thus, such combined extracts are also encompassed by the term "extract". Any method of extraction using a suitable solvent is encompassed. Exemplary extraction methods can be found, for example, in U.S. Pat. No. 6,403,126. Extracts can be obtained from any part of the plant, for example, from leaves, flowers, stems, roots, fruits and seeds. Extracts can be aqueous or oily.

[0098] According to some embodiments, the cannabis plant extract is formed by a suitable solvent or combination of solvents. According to some embodiments, the solvent is selected from the group consisting of polar solvents, hydrocarbon solvents, carbon dioxide, and combinations thereof. According to some embodiments, the cannabis plant extract is produced by a process comprising contacting cannabis plant material with a suitable solvent or combination of solvents. According to some embodiments, the process further comprises isolating a fraction soluble in the solvent. According to some embodiments, the process further comprises removing the solvent from the soluble fraction to obtain the extract.

[0099] Suitable solvents include, but are not limited to, water, ethanol, ethyl acetate, CO2 (e.g., liquid CO2 or supercritical CO2), methanol, acetone, and acetic acid. Suitable polar solvents include polar organic solvents, including, but not limited to, halogenated hydrocarbons (e.g., chloroform, dichloromethane), ethers (e.g., diethyl ether, tetrahydrofuran), alcohols (e.g., ethanol, methanol, isopropanol), esters (e.g., ethyl acetate), nitriles (e.g., acetonitrile), sulfones and sulfoxides (e.g., dimethyl sulfoxide, sulfolane), amides (e.g., dimethylformamide), and / or acids (e.g., acetic acid). Each possibility represents a separate embodiment of the invention. Suitable non-polar solvents include hydrocarbons, including, but not limited to, aliphatic hydrocarbons (e.g., hexane, pentane, heptane, petroleum ether) and / or aromatic hydrocarbons (e.g., benzene, toluene). Each possibility represents a separate embodiment of the invention. According to one embodiment, the solvent is ethanol. According to one embodiment, the solvent includes ethanol, such as aqueous ethanol. According to another embodiment, the extraction is by CO2. Specifically, the term "extract" refers to a liquid or semi-solid or resinous substance obtained by extraction from a plant as defined in the present application, i.e., an extract obtained from a cannabis plant, such as Cannabis sativa, Cannabis indica, and Cannabis ruderalis. In some embodiments, the term refers to a mixture of liquid or semi-solid resinous substances obtained by extraction from two or more different plants. In some embodiments, the term also refers to a compound purified from an extract. According to some embodiments, the term "extract" has the meaning of a mixture or combination of two or more extracts.

[0100] The term "cannabis extract" as used herein refers to one or more plant extracts from a cannabis plant. A cannabis extract contains one or more cannabinoids, as well as one or more non-cannabinoid components that are co-extracted with the cannabinoids from the plant material. Their respective weight ranges will vary depending on the starting plant material and the extraction method used. Cannabinoid-containing plant extracts can be obtained by various means of extraction of cannabis plant material. Such means include, but are not limited to, supercritical or subcritical extraction with CO2, extraction with hot or cold gas, and extraction with solvents. In some embodiments, the term refers to a mixture of liquid or semi-solid resinous material obtained by extraction from two or more different cannabis species. In some embodiments, the term also refers to compounds purified from the extracts. The term "cannabis plant" as used herein refers to plants of the cannabis genus, including, but not limited to, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. According to some embodiments, the cannabis plant is a CBD-rich strain of the cannabis plant or a THC-rich strain of the cannabis plant. Each possibility represents a separate embodiment.

[0101] According to some embodiments, the cannabis plant extract is obtained from a species or strain selected from the group consisting of Cannabis sativa, Cannabis indica, Cannabis ruderalis, hybrid strains, high-CBD strains, high-THC strains, and combinations thereof. According to some embodiments, the cannabis plant extract comprises at least one cannabinoid selected from the group consisting of CBD, THC, CBN, CBG, CBC, acids thereof, and combinations thereof.

[0102] According to some embodiments, the cannabis plant extract comprises about 1% (w / w) CBD. According to some embodiments, the cannabis plant extract comprises about 10% (w / w) CBD. According to some embodiments, the cannabis plant extract comprises about 25% (w / w) CBD. According to some embodiments, the cannabis plant extract comprises about 45% (w / w) CBD. According to some embodiments, the cannabis plant extract comprises about 1% to about 45% (w / w) CBD, including each value and subrange within the specified range. According to some embodiments, the cannabis plant extract comprises about 1% to about 10% (w / w) CBD, about 10% to about 25% (w / w) CBD, or about 25% to about 40% (w / w) CBD. Each possibility represents a separate embodiment of the present invention.

[0103] According to some embodiments, the cannabis plant extract comprises about 1% (w / w) THC. According to some embodiments, the cannabis plant extract comprises about 10% (w / w) THC. According to some embodiments, the cannabis plant extract comprises about 25% (w / w) THC. According to some embodiments, the cannabis plant extract comprises about 45% (w / w) THC. According to some embodiments, the cannabis plant extract comprises about 1% to about 45% (w / w) THC, including each value and subrange within the specified range. According to some embodiments, the cannabis plant extract comprises about 1% to about 10% (w / w) THC, about 10% to about 25% (w / w) THC, or about 25% to about 40% (w / w) THC. Each possibility represents a separate embodiment of the present invention.

[0104] The term "hybrid strain" refers to different strains of Cannabis that contain different amounts and / or ratios of various cannabinoid compounds. For example, Cannabis sativa usually has a relatively high THC / CBD ratio. Conversely, Cannabis indica has a relatively low THC / CBD ratio compared to Cannabis sativa (although the absolute amount of THC may be higher in Cannabis indica than in Cannabis sativa).

[0105] As used herein, the terms "high CBD strain" and "CBD-rich strain" refer to strains of the cannabis plant that contain CBD and, optionally, one or more additional cannabinoids, such as, but not limited to, THC, CBN, etc. According to some embodiments, CBD is the major component of high CBD strains.

[0106] As used herein, the terms "high THC strain" and "THC rich strain" refer to strains of the cannabis plant that contain THC and optionally one or more additional cannabinoids, such as, but not limited to, CBD, CBN, etc. According to some embodiments, THC is the primary component of high THC strains.

[0107] The cannabinoid component combinations of the present invention can generally be prepared by conventional methods as known in the art to produce a mixture in the above ratios. Such methods typically involve mixing CBDA esters with one or more additional cannabinoid compounds, or one or more extracts of the cannabis plant, in one or more steps, to a relatively homogeneous state, with or without the application of heat, cooling, vacuum, etc.

[0108] Pharmaceutical Compositions The compositions disclosed herein may be administered locally or systemically.

[0109] According to some embodiments, the pharmaceutical composition is formulated for inhalation. According to some embodiments, the pharmaceutical composition is a non-aqueous composition. According to certain embodiments, the pharmaceutical composition is a dry powder formulation. According to some embodiments, the pharmaceutical composition is formulated for administration by vaporization.

[0110] According to some embodiments, the pharmaceutical composition is a powder suitable for a multi-dose reservoir dry powder inhaler (DPI).

[0111] The term "dry powder" as used herein refers to a composition containing respirable dry particles that can be dispersed in an inhalation device and subsequently inhaled by a subject. Such dry powders may contain about 25% or less, about 20% or less, or about 15% or less of water or other solvents, or may be substantially free of water or other solvents, or may be anhydrous.

[0112] The powders described herein may contain one or more metal cation salts, which may be monovalent metal cation salts, divalent metal cation salts, or combinations thereof. Suitable salts for use in the dry powders include, for example, sodium salts, potassium salts, lithium salts, and any combinations thereof.

[0113] Preferably, the dry particles are highly dispersible and can be delivered to the patient's airways using a passive DPI that relies solely on the patient's own breathing pattern. In certain embodiments, the delivery of respirable dry particles to the airways is relatively independent of the patient's inspiratory flow rate, which means that the delivered dose is very similar to patients breathing at relatively high or low flow rates.

[0114] Respirable dry particles described herein can include physiologically or pharma- ceutically acceptable excipients. For example, pharma-ceutically acceptable excipients include any of the standard carbohydrates, sugar alcohols, and amino acids known in the art to be useful excipients for inhalation therapy, alone or in any desired combination. These excipients are generally relatively free-flowing particles, do not thicken or polymerize when in contact with water, are toxicologically harmless when inhaled as a dispersed powder, and do not significantly interact with the therapeutic agent in a manner that adversely affects the desired physiological action. Carbohydrate excipients useful in this regard include monosaccharides and polysaccharides. Exemplary monosaccharides include dextrose (also referred to as anhydrous and monohydrate, glucose and glucose monohydrate), galactose, mannitol, D-mannose, sorbose, and the like. Exemplary disaccharides include lactose, maltose, sucrose, trehalose, and the like. Exemplary trisaccharides include raffinose, and the like. Other carbohydrate excipients include maltodextrin and cyclodextrin. Representative sugar alcohols include mannitol and sorbitol.

[0115] The excipient may be present in an amount of less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 17%, less than about 15%, less than about 12%, less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%, all percentages by weight of the dry particles. Each possibility represents a separate embodiment of the present invention.

[0116] In some embodiments, the dry particles contain an excipient selected from leucine, maltodextrin, mannitol, and any combination thereof. In certain embodiments, the excipient is leucine, maltodextrin, or mannitol. Each possibility represents a separate embodiment of the present invention.

[0117] According to some embodiments, the pharmaceutical composition is formulated for inhalation, including a propellant. Pharmaceutically acceptable propellants include inhalable hydrofluoroalkanes (HFAs). These include, but are not limited to, HFA 134a (tetrafluoroethane), HFA 227 (heptafluoropropane), and mixtures thereof. Each possibility represents a separate embodiment of the present invention.

[0118] According to some embodiments, the pharmaceutical composition is formulated into a form suitable for intranasal, oral, intravenous, intraarterial, transmucosal, or subcutaneous administration, Each possibility represents a separate embodiment of the present invention.

[0119] According to additional embodiments, the pharmaceutical composition is formulated as a capsule, tablet, liquid, or syrup. Each possibility represents a separate embodiment of the invention. In certain embodiments, the dosage form is a granule or pellet that is delivered in a sachet, filled into a capsule, or compressed into a tablet.

[0120] According to some embodiments, the pharmaceutical composition further comprises a triglyceride, a fat, a lipid, an oil, a fatty acid, a cosolvent, or a mixture thereof. Each possibility represents a separate embodiment of the present invention. According to certain embodiments, the pharmaceutical composition comprises an edible oil or fat.

[0121] According to certain embodiments, the pharmaceutical composition comprises an edible oil selected from the group consisting of copaiba oil, palm oil, cottonseed oil, soybean oil, safflower oil, sesame oil, sunflower oil, castor oil, corn oil, olive oil, coconut oil, peanut oil, and poppy seed oil. Each possibility represents a separate embodiment of the present invention. According to certain embodiments, the pharmaceutical composition comprises copaiba oil.

[0122] According to some embodiments, the pharmaceutical composition comprises an alcohol and a solvent. According to some embodiments, the alcohol is ethanol. According to certain embodiments, the solvent is polyethylene glycol (PEG) or propylene glycol.

[0123] According to some embodiments, the pharmaceutical product further comprises vitamins, minerals, and / or flavoring agents. Each possibility represents a separate embodiment of the present invention.

[0124] According to some embodiments, the pharmaceutical composition is formulated for sustained release of the cannabinoid component. According to some embodiments, the pharmaceutical composition is formulated for sustained release of the CBDA ester. In certain embodiments, the pharmaceutical composition further comprises a release retardant or a mixture of release retardants. According to some embodiments, the pharmaceutical composition is at least partially coated with an enteric coating.

[0125] According to some embodiments, the composition is a gel in which the cannabinoid component or an acceptable salt thereof is encapsulated in a gel matrix. The gel composition of the present invention may comprise an oil-in-water (o / w) emulsion.

[0126] Solubilizers and emulsifiers are used to improve the bioavailability of the cannabinoid components, which refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby gains access to the site of action.

[0127] According to some aspects, within the compositions and methods of the present invention, the bioavailability enhancer is an edible oil or fat, a protective colloid, or both a protective colloid and an edible oil or fat. In another aspect, the bioavailability enhancer is also a lipophilic active agent flavoring agent. In other embodiments, the bioavailability of the lipophilic active agent in a subject is at least about 2-fold, 5-fold, or 10-fold greater than the bioavailability of the lipophilic active agent in a subject in the absence of the bioavailability enhancer.

[0128] According to some embodiments, the cannabinoid component is provided in a microencapsulated particle. According to some embodiments, the CBDA ester is provided in a microencapsulated particle. Encapsulation may result in the cannabinoid and other materials present in the cannabinoid material being in a liposomal encapsulated particle or other type of particle.

[0129] Micro- or nano-encapsulation may increase the bioavailability of cannabinoids, thereby increasing the potency of the cannabinoids after absorption through mucosa. Micro- or nano-encapsulation may result in particles with sizes between 20-40 nm. Micro- or nano-encapsulation facilitates the dissolution of the cannabinoid particles in an aqueous environment.

[0130] According to some embodiments, the pharmaceutical composition comprises at least one micelle-forming compound selected from the group consisting of polyoxyethylene ethers, esters or alcohols, alkali metal alkyl sulfates, bile acids, lecithin, hyaluronic acid, pharma- ceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, borage oil, evening primrose oil, trihydroxyoxo-cholanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein, salts thereof, and mixtures thereof. Each possibility represents a separate embodiment of the present invention. According to certain embodiments, the bile acid or bile salt is selected from the group consisting of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), taurodesoxycholic acid (TDCA), hyodeoxycholic acid (HDCA), taurocholic acid (TCA), glycocholic acid (GCA), and combinations thereof, with each possibility representing a separate embodiment of the present invention.

[0131] According to some embodiments, the pharmaceutical composition comprises a phospholipid. According to certain embodiments, the pharmaceutical composition comprises a phospholipid selected from the group consisting of naturally occurring phospholipids and synthetic phospholipids. According to certain embodiments, the naturally occurring phospholipid is selected from the group consisting of soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, and combinations thereof. According to certain embodiments, the synthetic phospholipid is selected from the group consisting of phosphocholine, phosphoethanolamine, phosphatidic acid, phosphoglycerol, phosphoserine, mixed chain phospholipids, lysophospholipids, pegylated phospholipids, and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0132] According to some embodiments, the phospholipids may form micelles, emulsions, or liposomes. Thus, according to some embodiments, the pharmaceutical composition is in the form of an emulsion comprising phospholipids as an emulsifier. According to some embodiments, the pharmaceutical composition is in the form of a micelle comprising phospholipids as a micelle former. According to some embodiments, the pharmaceutical composition is in the form of a liposome composition comprising phospholipids as a liposome former.

[0133] According to some embodiments, the pharmaceutical composition comprises a cyclodextrin. According to certain embodiments, the cyclodextrin is selected from the group consisting of hydroxypropyl β-cyclodextrin, sulfobutyl ether β-cyclodextrin, and methyl-β-cyclodextrin (MβCD), and combinations thereof.

[0134] According to some embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable solvent, i.e., a non-toxic solvent suitable for administration to a mammal without unacceptable adverse effects. The solvent may be an aqueous or non-aqueous solvent. Suitable solvents include alcoholic solutions, particularly ethanol.

[0135] Pharmaceutical compositions may optionally contain stabilizers and / or preservatives.Phenol compounds, i.e. compounds that contain one or more hydroxyl groups on a benzyl ring, are particularly suitable for this purpose, as they not only stabilize the composition, but also enhance the absorption of the composition.Preferred phenol compounds include phenol, methylphenol, and their mixtures.

[0136] The pharmaceutical compositions may also include one or more of the following additional additives: inorganic salts, antioxidants, protease inhibitors, colorants, and flavoring agents. Non-limiting examples of inorganic salts include sodium, potassium, calcium, and zinc salts, particularly sodium chloride, potassium chloride, calcium chloride, zinc chloride, and sodium bicarbonate.

[0137] Preparations administered orally may optionally be coated and formulated so as to provide slow, delayed or controlled release of the active ingredient therein.

[0138] The term "sustained release" as used herein refers to a composition that provides sustained, extended or prolonged release of a therapeutic agent. The term may further refer to a composition that provides a prolonged, extended or prolonged duration of action (pharmacokinetics) of a pharmaceutical composition comprising a therapeutically effective amount of the pharmaceutical composition of the present invention.

[0139] The pharmaceutical composition may include additional components, including but not limited to excipients as described herein. According to certain embodiments, one or more therapeutic agents of the dosage unit may be present in a sustained release formulation or a controlled release formulation, and the additional therapeutic agent may not be present in a sustained release formulation. For example, the cannabinoid component described herein may be present in a controlled release formulation or a controlled release formulation in the same dosage unit as another agent that may or may not be present in either a controlled release formulation or a controlled release formulation. Thus, in certain embodiments, it may be desirable to provide an immediate release of one or more of the agents described herein, and a controlled release of one or more other agents.

[0140] According to some embodiments, the composition further comprises at least one pharma- ceutically acceptable carrier.According to additional embodiments, the excipient is selected from the group consisting of an emulsifier, a buffering agent, a pH adjusting agent, an osmolality modifier, a preservative, an antioxidant, a stabilizer, and combinations thereof.

[0141] According to some embodiments, the pharma- ceutically acceptable carrier is an aqueous carrier, hi some embodiments, the aqueous carrier is a physiologically acceptable buffer having a physiological or near-physiological pH.

[0142] According to some embodiments, the composition further comprises at least one pharma- ceutically acceptable carrier. According to further embodiments, the excipient is selected from, but is not limited to, an emulsifier, a buffer, a pH adjuster, an osmolality modifier, a preservative, an antioxidant, a stabilizer, or any other pharma- ceutically acceptable excipient known in the art.

[0143] The pharmaceutical composition may comprise at least one physiologically acceptable film-forming agent, such as pullulan, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, methacrylic acid polymers, methacrylic acid copolymers, acrylic acid polymers, acrylic acid copolymers, polyacrylamides, polyalkylene oxides, carrageenan, polyvinyl alcohol, sodium alginate, polyethylene glycol, polyacrylic acid, glycolide, polylactide, methyl methacrylate copolymers, carboxyvinyl polymers, amylose, high amylose starch, hydroxypropylated high amylose starch, alginic acid, pea starch, dextrin, pectin, chitin, chitosan, levan, elsinan, and mixtures thereof. Additional film formers, including agents such as xanthan gum, tragacanth gum, guar gum, locust bean gum, acacia gum, gum arabic, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof, can be added to optimize properties such as tensile strength, stability, flexibility and brittleness.

[0144] According to some embodiments, the oral dosage formulation comprises a mixture of sodium carboxymethylcellulose and hydroxypropylcellulose or methylcellulose as film formers. The ratio of sodium carboxymethylcellulose to hydroxypropylcellulose (or methylcellulose) used to prepare the formulation is selected to provide the desired dissolution time and also to provide acceptable product handling characteristics.

[0145] According to some embodiments, the composition comprises less than about 10% (w / w) cannabinoid component. According to additional embodiments, the composition comprises less than about 7% (w / w) cannabinoid component. According to further embodiments, the composition comprises less than about 5% (w / w) cannabinoid component. According to yet another embodiment, the composition comprises less than about 2% (w / w) cannabinoid component. According to some embodiments, the composition comprises less than about 1% (w / w) cannabinoid component. According to additional embodiments, the composition comprises less than about 0.5% (w / w) cannabinoid component. It is understood that the w / w unit is intended to refer to the relative weight of the cannabinoid component in the composition. For example, if the total weight of the composition is 1 gram and the weight of the cannabinoid component therein is 50 milligrams, the composition is said to comprise 5% (w / w) cannabinoid component.

[0146] According to some embodiments, the pharmaceutical composition is in a solid or semi-solid form. The term "semi-solid" refers to a form that is capable of supporting its own weight and retaining its shape on the one hand, and of adapting its shape in response to external pressure on the other hand.

[0147] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the pharmaceutical compositions of the invention.

[0148] It should be understood that the amount of any active agent administered to a patient to treat the patient is administered in a therapeutically effective amount, taking into account the patient's weight and age, as determined by a physician, pharmacologist, and toxicologist of ordinary skill. In any event, if the drug is approved by a regulatory agency (e.g., the U.S. Food and Drug Administration), the therapeutically effective amount of the cannabinoid component is the amount approved by the regulatory agency.

[0149] According to some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0150] Preparation method The composition of the present invention can be formulated for inhalation as known in the art.In such formulation, CBDA-ME is prepared as inhalable dry powder or as aerosol solution in some embodiments.Dry powder formulations for inhalation therapy are described, for example, in U.S. Patent No. 10,588,870 to Lipp and Sung, U.S. Patent No. 5,993,805 to Sutton et al., U.S. Patent No. 6,921,527 to Platz et al., WO 1999016419 to Tarara et al., and WO 2000000215 to Bot et al.

[0151] The compositions of the present invention can be formulated as single-phase aqueous, emulsions or multiple emulsions. According to some embodiments, the compositions are formulated as emulsions. These emulsions can be oil-in-water (o / w) (including silicone-in-water) emulsions, water-in-oil (including water-in-silicone) (w / o) emulsions, or multiple emulsions such as oil-in-water-in-oil (o / w / o) or water-in-oil-in-water (w / o / w). It is understood that the oil phase can include silicone oil, non-silicone organic oil, or mixtures thereof. The compositions can include two immiscible phases that are mixed by shaking when used. Each possibility represents a separate embodiment of the present invention.

[0152] According to some embodiments, the compositions are made by preparing a dispersion of each component in a suitable solvent (dispersant), adjusting the pH of the dispersion with a pH adjuster, and, if necessary, mixing the dispersion with shear to allow formation of the desired matrix.

[0153] A common mode of administration of medical cannabis is to deliver cannabis extracts or pure cannabinoids orally by dissolving them in triglyceride oils such as vegetable oils. The oils are filled into capsules or used as is in various amounts. In contrast to inhalation, the oral route of administration of drugs is the most convenient for most people and is recognized as an acceptable mode of self-medication, such as taking pills. In such cases, an immediate release of cannabinoids is obtained, absorption is fast, and the duration of activity is intermediate, but longer than smoking or vaporization. The main disadvantage of dissolving cannabinoids in triglyceride oils is that high concentrations of cannabinoids cannot be reached in a single unit dose due to the limited solubility of cannabinoids, especially CBD, in vegetable oils. Thus, many products are "cannabis oils", which are cannabinoids dissolved in vegetable oils and administered in relatively large amounts. However, a limitation of this approach is the unpleasant taste and odor characteristic of vegetable oils and cannabinoids, which often results in poor patient compliance.

[0154] Those skilled in the art can select suitable presentation form and its preparation method based on general knowledge, taking into account the nature of the components used and the purpose of the composition.A kit containing the above composition is also contemplated.The composition of the present invention can be packaged in the form of a kit, separately from or together with a container, instruction manual, or instruction pamphlet.

[0155] How to use According to one aspect, the present invention provides a method for treating PWS comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a cannabinoid component, the cannabinoid component comprising a CBDA ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds, and a pharma- ceutically acceptable carrier, excipient or diluent; [ka] During the ceremony, R1 and R2 are each independently a straight or branched, unsubstituted or substituted C1-C 15 Alkyl, linear or branched, unsubstituted or substituted C2-C 15 Alkenyl, and straight or branched, unsubstituted or substituted C2-C 15 Alkynyl, and stereoisomers and salts thereof.

[0156] According to an additional aspect, the present invention provides a method for treating Prader-Willi syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a cannabinoid component, the cannabinoid component comprising a CBDA ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds, and a pharma- ceutically acceptable carrier, excipient or diluent; [ka] During the ceremony, R1 and R2 are each independently a straight or branched, unsubstituted or substituted C1-C 15 Alkyl, linear or branched, unsubstituted or substituted C2-C 15 Alkenyl, and straight or branched, unsubstituted or substituted C2-C 15 Alkynyl, and stereoisomers and salts thereof.

[0157] According to certain embodiments, one or more additional cannabinoid compounds are present in one or more extracts of the cannabis plant.

[0158] The term "effective amount," as in "therapeutically effective amount" of a therapeutic agent, refers to the amount of agent required to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of an agent can vary depending on factors such as the desired biological endpoint, the agent being delivered, the composition of the pharmaceutical composition, the target tissue or cell, and the like. More specifically, the term "effective amount" refers to an amount sufficient to produce a desired effect, e.g., reduce or ameliorate the severity, duration, progression, or onset of a disease, disorder, or condition, or one or more symptoms thereof; prevent the progression of a disease, disorder, or condition, cause regression of a disease, disorder, or condition; prevent the recurrence, occurrence, onset, or progression of symptoms associated with a disease, disorder, or condition, or enhance or improve the prophylactic or therapeutic effect of another therapy. For example, a "therapeutically effective amount" of a CBDA ester refers to an amount effective to prevent, ameliorate, or treat a particular disease or disorder. Similarly, a "therapeutically effective amount" of a combination of a CBDA ester and a second compound refers to an amount of the CBDA ester and an amount of the second compound that, in combination, are effective to ameliorate or treat a particular disease or disorder.

[0159] The term "treatment" or any grammatical variations thereof (e.g., treat, treating, treatment, etc.) as used herein includes, but is not limited to, alleviating the symptoms of a disease or condition; and / or reducing, suppressing, inhibiting, ameliorating, or affecting the progression, severity, and / or extent of a disease or condition.

[0160] As used herein, the term "subject" refers to a mammal, preferably a human.

[0161] In some embodiments, the pharmaceutical compositions described herein are for use in treating PWS. According to certain embodiments, the pharmaceutical compositions described herein are for use in treating or ameliorating at least one symptom associated with PWS.

[0162] According to some embodiments, the pharmaceutical composition is used in combination with other therapeutic agents for the treatment of PWS.

[0163] A beneficial effect can be demonstrated, for example, by a delay in the onset of clinical symptoms of a disease or condition in a susceptible subject, a reduction in the severity of some or all of the clinical symptoms of a disease or condition, a delay in the progression of a disease or condition, a reduction in the number of recurrences of a disease or condition, an improvement in the overall health or well-being of the subject, by other parameters specific to a particular disease or condition known in the art, and by combinations of such factors.

[0164] The route of administration can be any route and is determined based on the physician and the patient. All other routes of administration of a therapeutically effective amount of an agent for treating a patient treating PWS are contemplated herein, including but not limited to enteral (e.g., oral), or parenteral (e.g., intravenous, subcutaneous, or by inhalation), or other routes (e.g., intranasal, intradermal, subcutaneous, and transdermal).

[0165] According to some embodiments, the pharmaceutical composition is administered by inhalation. According to certain embodiments, the pharmaceutical composition is administered intranasally. According to other embodiments, the pharmaceutical composition is administered orally.

[0166] According to some embodiments, the pharmaceutical composition is administered twice a day, three times a day or more. According to some embodiments, the pharmaceutical composition is administered once a day, twice a week, once a week, once every two weeks, once every three weeks, or once a month. According to further embodiments, the composition is administered once every two months, once every three months, once every four months, once every five months, or once every six months.

[0167] In some embodiments, the pharmaceutical composition is administered for a period of more than 1 week. In some embodiments, the pharmaceutical composition is administered for a period of more than 4 weeks. In some embodiments, the pharmaceutical composition is administered for a period of more than 2 months. In some embodiments, the pharmaceutical composition is administered for a period of more than 3, 4, 5, or 6 months.

[0168] According to some embodiments, the effective dose of the cannabinoid component ranges from 0.1 to 500 mg / kg of body weight / day, 1 to 250 mg / kg of body weight / day, 2 to 100 mg / kg of body weight / day, or 5 to 30 mg / kg of body weight / day, which may be a single dose or may be divided throughout the day, with each possibility representing a separate embodiment of the present invention.

[0169] According to some embodiments, an effective dose of CBDA ester ranges from 0.1-500 mg / kg of body weight / day, 1-250 mg / kg of body weight / day, 2-100 mg / kg of body weight / day, or 5-30 mg / kg of body weight / day, which can be a single dose or divided throughout the day, with each possibility representing a separate embodiment of the present invention.

[0170] According to some embodiments, an effective dose of CBDA-ME ranges from 0.1-500 mg / kg of body weight / day, 1-250 mg / kg of body weight / day, 2-100 mg / kg of body weight / day, or 5-30 mg / kg of body weight / day, which can be a single dose or divided throughout the day, with each possibility representing a separate embodiment of the present invention.

[0171] According to other embodiments, the pharmaceutical composition is administered in a unit dosage form of about 0.05 g / kg / day to about 0.5 g / kg / day.

[0172] The active agents of the present invention are effective over a wide range of dosages. According to certain embodiments, the dosage of the cannabinoid component is 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, or 10000 mg per day orally. According to certain embodiments, the dosage of CBDA ester is about 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 1000 mg, 5000 mg, or 10000 mg per day by oral administration. According to certain embodiments, the dosage of CBDA-ME is about 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 1000 mg, 2000 mg, 5000 mg, or 10000 mg per day by oral administration.

[0173] According to some embodiments, the unit dosage form is administered with food at any time of the day, without food at any time of the day, with food after an overnight fast (e.g., with breakfast).

[0174] In some embodiments, it is contemplated that the method of treatment according to the present invention may involve combination therapy.In other words, the composition of the present invention can be administered in combination with one or more additional compounds or therapies, the latter using enteral or parenteral administration, including but not limited to inhalation, oral, intradermal, intramuscular, intravenous, subcutaneous, intranasal, and transdermal administration routes.

[0175] The following examples describe certain aspects of the present invention to illustrate the present invention and to provide a description of the method of the present invention to those skilled in the art. It should be noted that the term "and" or "or" is generally used in the sense of including "and / or" unless the context clearly indicates otherwise. As used herein, the term "about" when referring to a measurable value such as an amount, temporal duration, etc., is meant to include a variation of ±10%, more preferably ±5%, even more preferably ±1%, and even more preferably ±0.1% from the specified value, where such variation is appropriate for carrying out the disclosed method.

[0176] The examples should not be construed as limiting the invention, as they merely provide specific methodologies useful in understanding and practicing the invention and its various aspects. Although certain preferred and alternative embodiments of the invention have been described for the purpose of disclosing the invention, modifications to the disclosed embodiments may occur to those skilled in the art. EXAMPLES

[0177] Example 1. Synthesis of cannabidiolic acid (CBDA) The preparation process described in PCT application WO 2018 / 235079 was applied. A mixture of cannabidiol (CBD, 314 mg, 1 mmol) and a 2 molar solution of magnesium methyl carbonate (MMC / 2M, 1.5 ml, 3 mmol) in dimethylformamide (DMF) was heated at 130° C. for 3 h. The reaction was then cooled to 0° C., acidified with 10% hydrochloric acid and extracted with ether. The organic layer was washed with saline, dried over the drying agent magnesium sulfate (MgSO4) and then evaporated. The crude compound was then purified by column chromatography (20% ether-petroleum ether).

[0178] Example 2. Synthesis of cannabidiolic acid methyl ester (CBDA-ME) The preparation process described in PCT application WO 2018 / 235079 was applied. To a solution of cannabidiolic acid (CBDA) (175 mg, 0.488 mmol) in 2.5 ml of dichloromethane (CH2Cl2) was added 0.02 ml of methanol (CH3OH, 0.488 mmol) and 7.2 mg of 4-pyrrolidinopyridine (0.048 mmol). The reaction was stirred at room temperature for 5 min, followed by the addition of the coupling agent, N,N'-dicyclohexylcarbodiimide (DCC) (121 mg, 0.585 mmol) and stirring overnight. The solvent was then evaporated and the crude mixture was acidified with 5% hydrochloric acid and extracted with dichloromethane (CH2Cl2). The organic layer was washed with saturated aqueous sodium bicarbonate (NaHCO3) and dried over the drying agent magnesium sulfate (MgSO4) before being evaporated. The crude compound is then purified by column chromatography (2% ether-petroleum ether).

[0179] 1 H-NMR spectra were obtained using a Bruker AMX 300 MHz instrument with deuterated DMSO. Thin-layer chromatography (TLC) was performed on silica gel 60F254 plates (Merck). Column chromatography was carried out on silica gel 60 Å (Merck). Compounds were characterized using a 254 nm UV lamp.

[0180] 1 H NMR(300MHz, ((CD3)2SO))δ 6.18(1H, s, Ar), 5.07(1H, s), 4.44(1H, s), 4.41(1H, s), 3.82(3H, s), 3.35(1H, m), 2 .66(1H, m), 2.49(2H, t), 2.09(1H, b), 1.95(3H, s), 1.71-1.05(12, ms), 0.86(3H, t).

[0181] Example 3. Therapeutic effect of CBDA-ME in a Prader-Willi syndrome model We investigated the effects of CBDA-ME treatment using a Magel2 null mouse model of Prader-Willi syndrome.

[0182] research design The experimental protocol used was approved by the Animal Care and Use Committee of the Hebrew University of Israel, an AAALAC international accreditation body. null Mice and their wild-type littermate controls were maintained under a 12-h light / dark cycle and fed ad libitum. To produce diet-induced obesity, mice were fed either a high-fat diet (HFD) (60% fat, 20% protein, and 20% carbohydrate of calories; Research Diet, D12492) or a standard laboratory diet (STD, 14% fat, 24% protein, 62% carbohydrate; NIH-31 rodent diet) for 14–16 weeks. HFD-fed obese mice were then administered vehicle (1% Tween 80, 4% DMSO, 95% saline) or CBDA-ME (20 or 40 mg / kg) daily for 28 days by intraperitoneal (ip) injection. STD age-matched control mice received vehicle daily.

[0183] Test system description: Body weight was monitored daily. Total body fat and lean mass were determined by EchoMRI-100H™ (Echo Medical Systems LLC, TX, USA). At 20-22 weeks, mice were euthanized by cervical dislocation under deep anesthesia. Brains, kidneys, livers, fat pads, pancreas and muscles were removed, and livers and kidneys were also weighed. Samples were snap frozen or fixed in buffered 4% formalin. Trunk blood was collected for the determination of biochemical parameters.

[0184] method: Multiparameter metabolic assessment - Metabolic profiles of mice were assessed by using the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, NV, USA). Data acquisition and instrument control were performed using MetaScreen software version 2.2.18.0, and acquired raw data were processed using ExpeData version 1.8.4 with analysis scripts detailing all aspects of data transformation. Mice with ad libitum access to food and water (measured continuously) were exposed to a standard 12-h light / 12-h dark cycle that consisted of a 24-h acclimation period followed by 24-h sampling. Respiratory gases were measured using a GA-3 gas analyzer (Sable Systems, Inc., Las Vegas, NV, USA) using a negative pressure system in pull mode. Airflow was measured and controlled by a FR-8 (Sable Systems, Inc., Las Vegas, NV, USA) at a set flow rate of 2000 mL / min. Water vapor was measured continuously and mathematically corrected for the dilution effects of O2 and CO2. Effective body weight was calculated by ANCOVA. Fat oxidation (FO) and carbohydrate oxidation (CHO) were calculated as FO = 1.69 x VO2 - 1.69 x VCO2 and CHO = 4.57 x VCO2 - 3.23 x VO2, expressed as g / d / kg. 有効質量 This is expressed as:

[0185] Locomotor activity - Locomotor activity, locomotor activity and wheel running ability were quantified by the number of breaks of an infrared XYZ beam array with 0.25 cm beam spacing on a Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, NV, USA).

[0186] Glucose tolerance test (ipGTT) and insulin tolerance test (ipITT) - Overnight fasted mice were injected with glucose (1.5 g / kg, ip) followed by tail bleeding at 0, 15, 30, 45, 60, 90, and 120 min. Blood glucose levels were determined using a Contour glucometer (Bayer, Pittsburgh, PA). The next day, mice were fasted for 6 h, after which insulin (0.75 U / kg, ip; Eli Lilly) was administered and blood glucose levels were measured at the same intervals as above.

[0187] Blood biochemistry - Serum levels of cholesterol, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were determined using a Cobas C-111 chemistry analyzer (Roche, Switzerland). Fasting blood glucose was measured using a Contour glucometer.

[0188] Hepatic lipid content - Liver tissues were extracted and their triglyceride and cholesterol contents were determined using a Cobas C-111 chemistry analyzer (Roche, Switzerland) or the EnzyChrom™ Triglyceride Assay Kit (BioAssay Systems, Hayward Calif., USA).

[0189] Histopathology - First, 5 μm paraffin-embedded liver sections from five animals per group were stained with hematoxylin-eosin stain. Liver images were captured with a Zeiss AxioCam ICc5 color camera (Carl Zeiss AG, Jena, Germany) mounted on a Zeiss Axio Scope.A1 light microscope (Carl Zeiss AG, Jena, Germany) and taken from ten random 40× fields for each animal.

[0190] Statistical methods - Outcomes and time-dependent variables in multiple groups were compared by ANOVA followed by Tukey post-hoc test. Significance was set at P<0.05 using the following symbols: *P<0.05 vs. STD-Veh; #P<0.05 vs. HFD-Veh; ^P<0.05 vs. HFD-20 mg / kg CBDA-ME.

[0191] result: The metabolic profile of CBDA-ME was investigated in diet-induced obesity (DIO) and genetic-induced obesity (GIO) mice. Male Magel2 mice were fed a high-fat diet (HFD) for 14–16 weeks. null Mice and their wild-type littermate controls were made obese and then started treatment with daily ip injections of vehicle or CBDA-ME (20 mg / kg / day or 40 mg / kg / day) for 28 days. Age- and sex-matched STD mice served as controls. HFD-fed Magel2 null The increase in overweight and adiposity in mice was reduced by both doses of CBDA-ME, however, in WT mice, these effects were only observed at the higher dose of 40 mg / kg (Figure 1A-E). WT mice treated with 40 mg / kg were also the only group that showed a significant increase in lean body mass percentage (Figure 1F).

[0192] The changes in the metabolic profile of mice treated with CBDA-ME were demonstrated using indirect calorimetry assessment. As shown in Figure 2A-2B, CBDA-ME downregulated fat utilization and upregulated carbohydrate oxidation in WT mice. In comparison, Magel2 null Mice showed the opposite effect by further upregulating fat oxidation and downregulating carbohydrate oxidation. These metabolic differences were due to the Magel2 null This was associated with the ability of CBDA-ME to inhibit food intake and binge eating only in mice, an effect that was not observed in their WT littermate controls (Figure 3).

[0193] CBDA-ME was administered to WT mice and Magel2 mice. null The effect of GABA on the development of locomotor activity in both mice and control mice was reversed (Figure 4).

[0194] The reduction in body weight in CBDA-ME-treated DIO mice led to some improvement in lipid profile, with reduced HFD-induced hypercholesterolemia (Figure 5A). CBDA-ME did not affect serum HDL, which remained elevated (Figure 5B). Nevertheless, CBDA-ME reduced serum LDL levels (Figure 5C), which contributed to an increase in the HDL to LDL ratio (Figure 5D). These effects on lipid profile were more pronounced in mice treated with higher doses of CBDA-ME.

[0195] Long-term treatment with EPM301 improves Magel2 null CBDA-ME reduced fasting blood glucose levels only in WT mice and Magel2 mice (Figure 6A). null Both mice showed a reduction in obesity-induced glucose intolerance. This effect was observed in WT mice treated with EPM301 at a dose of 40 mg / kg, whereas CBDA-ME did not affect Magel2 at both doses tested. null The treatment was found to be effective in mice (Figures 6B, 6C). Insulin sensitivity was slightly improved in both genotypes under 40 mg / kg CBDA-ME (Figures 6D-F).

[0196] A higher dose of 40 mg / kg CBDA-ME significantly reduced obesity-associated hepatocellular injury, as documented by decreased serum levels of AST and ALT. No significant changes in ALP levels were recorded (Figures 7A-C). Similarly, HFD-induced hepatic steatosis was completely attenuated by EPM301, as reflected by increased hepatic triglyceride and cholesterol levels and increased hepatic lipid vacuoles (Figures 8A-C).

[0197] Conclusion: CBDA-ME is Magel2 null In mice, it significantly reduced body weight and food intake (hyperphagia), the main metabolic parameters associated with PWS.

[0198] CBDA-ME increased the Magel2 null CBDA-ME effectively reduced body weight in WT DIO mice, whereas only higher doses were found to be effective in WT mice. CBDA-ME (40 mg / kg) resulted in improvement in almost all parameters measured in WT DIO mice.

[0199] Example 4. Therapeutic effect of CBDA-ME in a PWS prevention model Research purpose The second study objective was to evaluate whether EPM301 treatment affects weight gain and adiposity in a mouse model of PWS.

[0200] Research design and methods Male 6 weeks old Magel2 null Mice and their wild-type littermate controls were maintained under a 12-h light / dark cycle and fed standard laboratory chow (STD, 14% fat, 24% protein, 62% carbohydrate; NIH-31 rodent chow) ad libitum.

[0201] treatment group Magel2 nullMice were treated with either EPM301 20 mg / kg / day or vehicle (1% Tween 80, 4% DMSO, 95% saline). WT siblings were treated with vehicle. All treatments were given by intraperitoneal (IP) injection for 18 weeks.

[0202] result Weight Gain: Results: EPM301 treatment Magel2 null The results showed that the mice gained weight similarly to the WT control mice, indicating that the vehicle-treated Magel2 null The weight gain was lower than that seen in mice. null Changes in mice were compared between WT controls and Magel2 null was significantly lower than that in vehicle-treated mice (Fig. 9A).

[0203] Fat amount: EPM301 treatment Magel2 null Fat mass in the mice was similar to that of WT control mice, whereas vehicle-treated Magel2 null The EPM301-treated Magel2 mice had a much higher fat mass, significantly higher than the WT control mice. null The lower fat mass seen in mice was due to the vehicle-treated Magel2 null This was statistically significant compared to mice (Figure 9B).

[0204] Lean mass: EPM301 treatment Magel2 null Mice were treated with vehicle Magel2 null The EPM301-treated Magel2 mice had significantly higher lean mass than the control mice. null Lean mass in the mice was similar to that of WT control mice (FIG. 9C).

[0205] conclusion The results showed that EPM301 treatment improved Magel2 nullWe showed that Magel2 prevented weight gain, fat mass, and increased lean mass in mice. These parameters were similar to those in WT control healthy mice, whereas vehicle-treated Magel2 null The mice gained more weight, had much higher fat mass and much lower lean mass.

[0206] While the present invention has been described hereinabove in its preferred embodiments, modifications can be made thereto without departing from the spirit and nature of the invention as defined in the appended claims.

Claims

1. A pharmaceutical composition for use in treating Prader-Willi syndrome (PWS), comprising a cannabinoid component (wherein the cannabinoid component comprises cannabidiolic acid (CBDA) ester represented by the structure of formula (I), alone or in combination with one or more additional cannabinoid compounds), and a pharmaceutically acceptable carrier, excipient or diluent, 【Chemical 1】 wherein, R １ and R ２ each independently represents a straight-chain or branched, unsubstituted or substituted C １ -C １５ alkyl, a straight-chain or branched, unsubstituted or substituted C ２ -C １５ alkenyl, and a straight-chain or branched, unsubstituted or substituted C ２ -C １５ alkynyl, and a pharmaceutical composition selected from the group consisting of their stereoisomers and salts.

2. R １ The pharmaceutical composition for use according to claim 1, wherein R is methyl.

3. The pharmaceutical composition for use according to claim 1, wherein the cannabidiolic acid ester is CBDA-ME.

4. The pharmaceutical composition for use according to claim 1, which is for use in alleviating, preventing, treating or improving one or more symptoms of PWS.

5. The pharmaceutical composition for use according to claim 1, which comprises the additional cannabinoid compound.

6. The additional cannabinoid compound is cannabidiol (CBD), cannabigerol (CBG), Δ ８ -tetrahydrocannabinol (Δ ８ -THC), Δ ９ -tetrahydrocannabinol (Δ ９ -THC), cannabinol (CBN), Δ ９ (11)-tetrahydrocannabinol (exo-THC), cannabichromene (CBC), tetrahydrocannabinol-C3 (THC-C3), tetrahydrocannabinol-C4 (THC-C4), tetrahydrocannabinol-C7 (THC-C7), esters thereof and combinations thereof, a pharmaceutical composition for use according to claim 5.

7. The pharmaceutical composition for use according to claim 5 or 6, wherein the one or more additional cannabinoid compounds are obtained from one or more extracts of cannabis plants.

8. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract is obtained from a strain selected from the group consisting of Cannabis sativa, Cannabis indica, Cannabis ruderalis, hybrid strains, and combinations thereof.

9. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract is obtained from a strain selected from the group consisting of high-CBD strains, high-THC strains, and combinations thereof.

10. The pharmaceutical composition according to claim 7, wherein the cannabis plant extract comprises at least one cannabinoid selected from the group consisting of CBD, THC, CBN, CBG, CBC, their acids and combinations thereof.

11. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract comprises about 1% (w / w) of CBD.

12. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract comprises about 10% (w / w) of CBD.

13. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract comprises about 1% (w / w) of THC.

14. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract comprises about 10% (w / w) of THC.

15. The pharmaceutical composition for use according to claim 7, wherein the cannabis plant extract is produced by a process comprising contacting the cannabis plant material with a suitable solvent or combination of solvents.

16. The pharmaceutical composition for use according to claim 15, wherein the solvent is selected from the group consisting of polar solvents, hydrocarbon solvents, carbon dioxide, and combinations thereof.

17. The pharmaceutical composition for use according to claim 1, which is in the form of an emulsion, gel, solution or dispersion.

18. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutically acceptable carrier, excipient or diluent comprises water, oil, or both.

19. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is formulated for inhalation.

20. The pharmaceutical composition for use according to claim 19, wherein the pharmaceutical composition is a dry powder formulation.

21. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is formulated in a dosage form suitable for intranasal, oral, intravenous, intra-arterial, or subcutaneous administration.

22. The pharmaceutical composition for use according to claim 1, wherein the excipient is selected from the group consisting of triglycerides, fats, lipids, oils, fatty acids, solvents or mixtures thereof.

23. The pharmaceutical composition for use according to claim 22, wherein the solvent is polyethylene glycol, propylene glycol or both.

24. The pharmaceutical composition for use according to claim 1, further comprising a phospholipid selected from the group consisting of naturally occurring phospholipids and synthetic phospholipids.

25. The pharmaceutical composition for use according to claim 24, wherein the naturally occurring phospholipid is selected from the group consisting of soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, and combinations thereof.

26. The pharmaceutical composition for use according to claim 24, wherein the synthetic phospholipid is selected from the group consisting of phosphocholine, phosphoethanolamine, phosphatidic acid, phosphoglycerol, phosphoserine, mixed chain phospholipids, lysophospholipids, pegylated phospholipids, and combinations thereof.

27. The pharmaceutical composition for use according to claim 1, which is in the form of micelles, emulsion or liposomes.

28. The pharmaceutical composition for use according to claim 1, further comprising cyclodextrin.

29. The pharmaceutical composition for use according to claim 28, wherein the cyclodextrin is selected from the group consisting of hydroxypropyl β-cyclodextrin, sulfobutyl ether β-cyclodextrin, and methyl β-cyclodextrin (MβCD).

30. The pharmaceutical composition for use according to claim 1, wherein the excipient is selected from the group consisting of an emulsifier, a buffer, a pH adjuster, a preservative, an antioxidant, a stabilizer, and combinations thereof.

31. The pharmaceutical composition for use according to claim 1, comprising less than about 10% (w / w) of the cannabinoid component.

32. The pharmaceutical composition for use according to claim 1, comprising less than about 7% (w / w) of the cannabinoid component.

33. The pharmaceutical composition for use according to claim 1, comprising less than about 5% (w / w) of the cannabinoid component.

34. The pharmaceutical composition according to claim 1, comprising less than about 1% (w / w) of the cannabinoid component.

35. The pharmaceutical composition according to claim 1, wherein the treating comprises treating behaviors associated with PWS.

36. The pharmaceutical composition according to claim 1, wherein the treating results in one or more of (a) a decrease in compulsive behavior compared to placebo, or (b) a decrease in anxiety compared to placebo, including administration by inhalation.

37. The pharmaceutical composition according to claim 1, wherein the treating results in a decrease in the measured value of the total score of the Hyperphagia Questionnaire (HQ-CT) for clinical trials.

38. The pharmaceutical composition according to claim 1, which is used in combination with at least one additional therapeutic agent for treating PWS.

39. The pharmaceutical composition according to claim 1, which is administered to the subject once or twice a day, once a week, once every two weeks, once every three weeks, or once a month.

Images