FIELD OF THE INVENTION

The present disclosure is in the field of medicinal cannabis. In particular, the disclosure concerns solid forms of cannabidiol, methods of making such solid forms, pharmaceutical compositions of such solid forms, and uses thereof for various medical treatments.

BACKGROUND OF THE DISCLOSURE

Cannabidiol (CBD) is a compound identified from cannabis that is pharmaceutically active. It is a phytocannabinoid and accounts for up to 40% of a cannabis extract. (Borgelt L M, et al., (2013),Pharmacotherapy,33(2): 195-209; Aizpurua-Olaizola, Oier, et al., (2016),Journal of Natural Products,79(2):324-331; Campos A C, et al., (2012),Philos. Trans. R. Soc. Lond. B Biol. Sci.,367(1607):3364-78). CBD is also found and isolated from other plants such as, e.g., hemp. CBD can also be produced and isolated by other methods of production including yeast manufacturing (see, WO2016/010827). CBD is presently used clinically in combination with (−)-trans-Δ9-tetrahydocannabinol (Δ9-THC) for treatment of neuropathic symptoms associated with multiple sclerosis (Morales et al., (2017)Front. Pharmacol.8:1-18). CBD is also being investigated as a single agent for use as a neuroprotective, treatment of hypoxia-ischemia events, addiction and uses as an anxiolytic, antipsychotic, analgesic, anti-inflammatory, anti-asthmatic, anti-epileptic and anti-cancer agent (Fasinu et al., (2016)Pharmacotherapy36(7):781-796; Fanelli et al., (2017)J. Pain Res.10:1217-1224; Morales et al., (2017)Front. Pharmacol.8:1-18; and Devinsky et al., (2017)N Engl J Med376(21): 2011-20).

Cocrystals are crystalline molecular complexes of two or more non-volatile compounds bound together in a crystal lattice by non-ionic interactions. Pharmaceutical cocrystals are cocrystals of a therapeutic compound, e.g., an active pharmaceutical ingredient (API), and one or more non-volatile compound(s) (referred to herein as coformer). A coformer in a pharmaceutical cocrystal is typically a non-toxic pharmaceutically acceptable molecule, such as, for example, food additives, preservatives, pharmaceutical excipients, or other APIs. A cocrystal of an API is a distinct chemical composition of the API and coformer(s) and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer(s) individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques. Cocrystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). As crystalline forms, cocrystals may possess more favorable solid state, physical, chemical, pharmaceutical and/or pharmacological properties or may be easier to process than known forms or formulations of the API. For example, a cocrystal may have different dissolution and/or solubility properties than the API, and can, therefore, be more effective in therapeutic delivery. A cocrystal may also affect other pharmaceutical parameters such as storage stability, compressibility and density (useful in formulation and product manufacturing), permeability, and hydrophilic or lipophilic character. New pharmaceutical compositions comprising a cocrystal of a given API, therefore, may have attractive or superior properties as compared to its natural state or existing drug formulations.

SUMMARY OF THE DISCLOSURE

In one aspect, the disclosure relates to a solid form comprising cannabidiol and the coformer L-proline.

In another embodiment, cannabidiol L-proline solid form has a molar ratio of cannabidiol to L-proline of about 1:1.

In another embodiment, the solid form of cannabidiol L-proline is crystalline.

In another embodiment, the solid form of cannabidiol L-proline is a cocrystal.

In another embodiment, cannabidiol L-proline cocrystal is anhydrous.

In another embodiment, cannabidiol L-proline cocrystal is cannabidiol L-proline Form A.

In another embodiment, cannabidiol L-proline Form A and has an x-ray diffraction pattern (XRPD) comprising one or more peaks at 5.3, 5.8, 9.4, 10.7, 11.1, 11.4, 11.7, 12.3, 15.4, 15.8, 16.4, 17.3, 18.7, 19.2, 19.4, 20.0. 20.8, 21.3, 23.1, and 24.5 degrees 2θ±0.2.

In another embodiment, cannabidiol L-proline Form A has an x-ray powder diffraction pattern substantially similar toFIG. 2.

In another embodiment, cannabidiol L-proline Form A has a DSC thermogram with a peak onset of approximately 146.4° C. or a peak maximum at about 147.8° C.

In another embodiment, cannabidiol L-proline Form A has a DSC thermogram which is substantially similar to the DSC thermogram ofFIG. 3.

Another embodiment of the disclosure includes pharmaceutical compositions comprising the aforementioned solid forms of cannabidiol L-proline.

In another embodiment, the pharmaceutical compositions of the solid forms of cannabidiol L-proline further comprise a pharmaceutically acceptable excipient or carrier.

Another aspect of the disclosure includes a solid form comprising cannabidiol and the coformer D-proline.

In an embodiment of this aspect, the solid form of cannabidiol and the coformer D-proline has a molar ratio of cannabidiol to D-proline is about 1:1.

In another embodiment, the solid form of cannabidiol D-proline is crystalline.

In another embodiment the solid form of cannabidiol D-Proline is a cocrystal.

In another embodiment the cocrystal form of cannabidiol D-Proline is cannabidiol D-Proline cocrystal Form A.

In another embodiment, the cocrystal is anhydrous.

In another embodiment, cannabidiol D-Proline Form A has an x-ray diffraction pattern comprising one or more peaks at 5.2, 5.8, 9.4, 10.6, 11.2, 11.5, 12.4, 12.7, 15.3, 15.7, 16.4, 17.4, 18.7, 19.2, 19.4, 20.2, 20.7, 21.2, 23.3, 24.0, 24.6, 25.6, and 26.2 degrees 2θ±0.2.

In another embodiment, cannabidiol D-Proline Form A has an x-ray powder diffraction pattern substantially similar toFIG. 7.

In another embodiment, cannabidiol D-Proline Form A has a DSC thermogram with a peak onset of approximately 154.3° C. or a peak maximum at about 155.5° C.

In another embodiment, cannabidiol D-Proline Form A has a DSC thermogram which is substantially similar to the DSC thermogram ofFIG. 8.

Another embodiment of the disclosure includes pharmaceutical compositions comprising the aforementioned solid forms of cannabidiol D-proline.

In another embodiment, the pharmaceutical compositions of the solid forms of cannabidiol D-proline further comprise a pharmaceutically acceptable excipient or carrier.

Another aspect of the disclosure are solid forms comprising cannabidiol and the coformer tetramethylpyrazine.

In an embodiment of this aspect, the cannabidiol tetramethylpyrazine solid form is crystalline.

In another embodiment, the cannabidiol tetramethylpyrazine solid form has a molar ratio of cannabidiol to tetramethylpyrazine that is about 1:1.

In another embodiment, the cannabidiol tetramethylpyrazine solid form is a cocrystal.

In another embodiment, the cannabidiol tetramethylpyrazine cocrystal has an x-ray diffraction pattern comprising one or more peaks at about 9.1, 14.6, 18.3, and 19.6 degrees 2θ±0.2.

In another embodiment, the cannabidiol tetramethylpyrazine cocrystal has an x-ray powder diffraction pattern substantially similar toFIG. 12.

In another embodiment, the cannabidiol tetramethylpyrazine cocrystal has a DSC thermogram with a peak onset of approximately 89.9° C. or a peak maximum at about 92.8° C.

In another embodiment, the cannabidiol tetramethylpyrazine cocrystal has a DSC thermogram which is substantially similar to the DSC thermogram ofFIG. 13

Another embodiment of the disclosure includes pharmaceutical compositions comprising the aforementioned solid forms of cannabidiol tetramethylpyrazine.

In another embodiment, the pharmaceutical compositions of the solid forms of cannabidiol tetramethylpyrazine further comprise a pharmaceutically acceptable excipient or carrier.

Another aspect disclosed herein are solid forms comprising cannabidiol and the coformer 4,4′dipyridyl.

In some embodiments, the cannabidiol 4,4′dipyridyl solid form is crystalline.

In some embodiments, the cannabidiol 4,4′dipyridyl solid form is a cocrystal.

In some embodiments, the cannabidiol 4,4′dipyridyl solid form has a molar ratio of cannabidiol to 4,4′ dipyridyl that is about 1:1.

In some embodiments, the cannabidiol 4,4′dipyridyl cocrystal is cannabidiol 4,4′ dipyridyl cocrystal Material A.

In some embodiments, the cannabidiol 4,4′dipyridyl cocrystal Material A has an x-ray diffraction pattern comprising one or more peaks at about 4.4, 7.7, 8.9, 9.2, 12.0, 15.0, 15.5, 16.3, 17.9, 18.4, 18.6, 18.9, 19.6, 20.3, 20.6, 21.6, 22.6, and 25.6 degrees 2θ±0.2.

In some embodiments, the cannabidiol 4,4′dipyridyl cocrystal Material A has an x-ray powder diffraction pattern substantially similar toFIG. 16.

In some embodiments, the cannabidiol 4,4′dipyridyl cocrystal Material A has a DSC thermogram with a peak onset of approximately 139.6° C. or a peak maximum at about 140.7° C.

In some embodiments, the cannabidiol 4,4′ dipyridyl cocrystal Material A has a DSC thermogram which is substantially similar to the DSC thermogram ofFIG. 17.

Another aspect disclosed herein is a solid form cannabidiol 4,4′dipyridyl Material B.

In some embodiments, cannabidiol 4,4′dipyridyl Material B has an x-ray diffraction pattern comprising peaks at about 7.7, 9.2, 10.6, 11.1, 11.9, 15.2, 16.2, 18.3, 19.6, 20.4, 20.8, 22.1, 22.3, 24.1 degrees 2θ±0.2 degrees 2θ±0.2.

In some embodiments, cannabidiol 4,4′dipyridyl Material B has an x-ray powder diffraction pattern substantially similar toFIG. 21.

Another embodiment of the disclosure includes pharmaceutical compositions comprising the aforementioned solid forms of cannabidiol 4,4′ dipyridyl.

In another embodiment, the pharmaceutical compositions of the solid forms of cannabidiol 4,4′dipyridyl further comprise a pharmaceutically acceptable excipient or carrier.

Another aspect of the disclosure includes methods for treating a disease or condition amenable to treatment with cannabidiol comprising administering one or more of the aforementioned solid forms of cannabidiol to a subject in need of treatment.

In some embodiments the disease or condition is selected from: central nervous system disorders; cardiovascular disorders; neurovascular disorders, cancers (alone or with other cancer agents), such as, without limitation, solid tumors, e.g., anaplastic ependymoma, Diffuse Intrinsic Pontine Glioma (DIPG), Glioblastoma multiforme, bladder, breast, head and neck, prostate, neuroendocrine, Non-Hodgkin's lymphoma, non-small cell lung, colorectal pancreatic, ovarian; reducing adverse effects of other cancer treatments, cancer metastasis; autoimmunity; multiple sclerosis; multiple sclerosis-related muscle spasms; Parkinson's disease; psychosis; epilepsy (convulsions and seizures), including, without limitation, treatment-resistant epilepsy, epilepsy in tuberous sclerosis complex, Dravet syndrome, febrile infection-related epilepsy syndrome (Fires) in the acute and chronic phases, Sturge-Weber Syndrome, status epilepticus, malignant migrating partial seizures, brain tumor-related epilepsy, seizures caused by early onset epilepsy such as Lennox-Gastaut Syndrome; psychiatric disorders; impaired cognitive function, including, without limitation, cognitive impairment in schizophrenia; anxiety; depression; bipolar disorders; inflammation; pain; fibromyalgia; hepatitis; epidermolysis bullosa; spasticity in neurodegenerative diseases; cachexia and anorexia; ocular hypertension in glaucoma; movement disorders, such as, without limitation, dystonic disorders; neuromuscular disorders; Prader Willi syndrome; spasms in Tourette syndrome; pseudobulbar affect; reducing drug dependence, such as without limitation, smoking, and opioid addiction; diabetes mellitus; graph versus host disease (GVHD); atherosclerosis; inflammatory bowel disease; autoimmune disorders, such as, without limitation, thyroid disease, Crohn's disease; ulcerative colitis; systemic lupus erythematosus (SLE); cutaneous lupus erythematosus; psoriasis; autoimmune uveitis; autoimmune hepatitis; rheumatoid arthritis, hypersensitivity lung diseases; hypersensitivity pneumonitis; delayed-type hypersensitivity; Sjogren's disease; acquired immunodeficiency syndrome, sarcoidosis; interstitial lung disease (ILD); scleroderma; dermatitis; use as an anti-oxidant; use as antipsychotic; iritis; conjunctivitis; keratoconjunctivitis; idiopathic bilateral progressive sensorineural hearing loss; aplastic anemia; pure red cell anemia; idiopathic thrombocytopenia; polychondritis; Graves ophthalmopathy; amyotrophic lateral sclerosis (ALS) and symptoms associated with ALS; primary biliary cirrhosis; ileitis; chronic inflammatory intestinal disease; celiac disease; irritable bowel syndrome; Alzheimer's disease; prion associated disease; fatty liver; sleep disorders, such as, without limitation, insomnia, sleep maintenance sleep disorders in Parkinson's, sleep disorders associated with posttraumatic stress disorder (PTSD); acne; cannabis withdrawal symptoms; OCD; PTSD; nausea, nausea related to cancer treatment; vomiting; emesis; motion sickness; and hypoxia-ischemia (acute stroke).

In some embodiments of the disclosure, a claim may “comprise” an aspect or embodiment. In other aspects or embodiments, a claim may “consist of” an aspect or embodiment. In still other embodiments, a claim may “consist essentially of” an aspect or embodiment.

