Increased bioavailability and efficacy of CBD via coadministration with tetramethylpyrazine

Abstract

This disclosure herein describes the use of cannabidiol (CBD) with tetramethylpyrazine (TMP) to improve the bioavailability and efficacy of CBD. Behavioral studies indicate that the oral administration of CBD with TMP has a strong anxiolytic effect, increases social behavior in stressed rats, and alleviates anhedonia-like symptoms in stressed rats. These effects were significantly greater than observed with CBD alone, most likely due to increased CBD exposure with TMP administration and / or a metabolism effect of the co-administration of CBD and TMP.

Description

INCREASED BIOAVAILABILITY AND EFFICACY OF CBD VIA COADMINISTRATION WITH TETRAMETHYLPYRAZINERELATED APPLICATIONS

[0001] This patent application claims the benefit of priority to U.S. serial no. 63 / 606,583, filed on December 05, 2023 and U.S. Serial no. 63 / 666,259 filed on July 1, 2024. Both applications are incorporated by reference herein.FIELD OF THE INVENTION

[0002] The present invention is in the field of pharmacodynamics, in particular an improvement in the oral bioavailability and efficacy of cannabidiol (CBD) when administered with tetramethylpyrazine.BACKGROUND OF THE DISCLOSURE

[0003] Cannabidiol (CBD), a principal constituent of the Cannabis sativa plant, is a drug gaining traction as a treatment option for neuropsychiatric disorders. Specifically, CBD displays anxiolytic (Onaivi et al., 1990) and anti-depressant properties (Xu et al., 2019) with little to no psychotropic effects (Alves et al., 2020). However, the therapeutic utility of CBD is limited by its physical and pharmacokinetic properties, including high lipophilicity-, polymorphism, poor solubility, and poor oral bioavailability (Xu et al., 2019).

[0004] To overcome CBD’s pharmacokinetic limitations, a novel cocrystal of CBD with the co-former tetramethylpyrazine (TMP) was developed to modify the pharmacokinetic properties of CBD while retaining the pharmacological drug activity. TMP is a constituent of the Ligusticum plant species commonly used in Asian traditional medicine (Lin et al., 2022). The CBD:TMP cocrystal is called ART12.i l. ART12. i l is a 1:1 ratio of CBD and TMP.SUMMARY OF THE DISCLOSURE

[0005] Disclosed herein are methods of improving the oral bioavailability of cannabidiol (CBD) in mammals comprising administering to subjects in need of treatment for conditions amenable to treatment with CBD or a combination of CBD and tetramethylpyrazine (TMP).

[0006] In some embodiments, the CBD and TMP comprise a solid form. The solid form can be crystalline. In some embodiments, the solid form is a cocrystal. In some embodiments the solid form has an x-ray diffraction pattern comprising one or more peaks at about 9.1. 14.6. 18.3. and 19.6 degrees 20 ±0.2. In other embodiments, the solid form has an x-ray powder diffraction pattern substantially similar to FIG. 7.

[0007] In still other embodiments, the solid form has a molar ratio of cannabidiol to tetramethylpyrazine of about 1: 1.

[0008] In yet other embodiments the solid form has a DSC thermogram with a peak onset of approximately 89.9 °C or a peak maximum at about 92.8 °C. In some embodiments, the solid form has a DSC thermogram which is substantially similar to the DSC thermogram of FIG. 8.

[0009] In some embodiments, the CBD and TMP or CBD:TMP cocrystal are a pharmaceutical composition which can include a pharmaceutically acceptable excipient or carrier.

[0010] Also disclosed herein are methods for treating a disease or condition in a subject having said disease or condition that is amenable to treatment with CBD and / or TMP, comprising administering to said subject CBD and TMP. In some aspects, the combination of CBD with TMP improves the bioavailability and efficacy of CBD. In some embodiments the CBD and TMP are coadministered or given sequentially.

[0011] In an aspect of the invention are methods of improving the oral bioavailability of cannabidiol (CBD) in mammals comprising administering to subjects in need of treatment for conditions amenable to treatment with CBD a combination of CBD and tetramethylpyrazine (TMP).

[0012] In other aspects, the CBD and TMP comprise a solid form.

[0013] In still other aspects the solid form of CBD-TMP ART12. 11 has an x-ray diffraction pattern comprising one or more peaks at about 9.1, 14.6, 18.3, and 19.6 degrees 20 ±0.2.

[0014] In another aspect the solid form of CBD-TMP ART12. 11 has an x-ray powder diffraction pattern substantially similar to FIG. 7.

[0015] In yet another aspect, the solid form of CBD-TMP ART12.1 lhas a molar ratio of cannabidiol to tetramethylpyrazine of about 1 : 1.

[0016] In an embodiment, the solid form of CMD-TMP has a DSC thermogram with a peak onset of approximately 89.9 °C or a peak maximum at about 92.8 °C.

[0017] In an embodiment, the solid form of CMD-TMP has a DSC thermogram which is substantially similar to the DSC thermogram of FIG. 8.

[0018] In an aspect of the disclosure, the CBD and TMP used for treatment are a pharmaceutical composition which may include a pharmaceutically acceptable excipient or carrier.

[0019] An aspect of the disclosure herein are methods for treating a disease or condition in a subject in need of treatment wherein the treatment includes administering to the subject cannabidiol and tetramethylpyrazine. In some embodiments the cannabidiol and tetramethylpyrazine are coadministered together or given sequentially.

[0020] In some embodiments the cannabidiol and tetramethylpyrazine used for treating a patient are a solid form such as a cocrystal. In some embodiments the solid form is a cocrystal of CBD and tetramethylpyrazine.

[0021] In other embodiments, the cannabidiol and tetramethylpyrazine are pharmaceutical compositions which may include a pharmaceutically acceptable excipient or carrier. In an embodiment, the pharmaceutical composition comprises a solid form of cannabidiol and tetramethylpyrazine. In some embodiments the CBD-TMP solid form has an x-ray diffraction pattern comprising one or more peaks at about 9.1, 14.6, 18.3, and 19.6 degrees 20±O.

[0022] In some embodiments the disease or condition treated with CBD and TMP is selected from one or more of central nervous system disorders, cardiovascular disorders, neurovascular disorders, neuromuscular disorders, cancers, autoimmune disorders, inflammatory disorders, pain disorders, sleep disorders, posttraumatic stress disorder, posttraumatic stress syndrome; anxiety disorders, personality disorders, social anxiety disorders, depression, nausea, and hypoxia-ischemia.

[0023] In some embodiments the disease or condition treated with CBD and TMP is selected from one or more of a solid tumor, cancer metastasis, multiple sclerosis, multiple sclerosis-related muscle spasms, Parkinson's disease, psychosis; epilepsy, 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. Lennox-Gastaut Syndrome, psychiatric disorders, impaired cognitive function, cognitive impairment in schizophrenia, anxiety, depression, bipolar disorders, fibromyalgia, hepatitis, epidermolysis bullosa, spasticity in neurodegenerative diseases, cachexia, anorexia, ocular hypertension in glaucoma, movement disorders, dystonic disorders, Prader Willi syndrome, spasms in Tourette syndrome, pseudobulbar affect, reducing drug dependence, addiction, smoking addiction, opioid addiction, diabetes mellitus, graph versus host disease (GVHD), atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, cutaneous lupus erythematosus, psoriasis, shingles pain, autoimmune uveitis, autoimmune hepatitis, hypersensitivity' lung diseases, hypersensitivity pneumonitis, delayed-type hypersensitivity, Sjogren's disease, thyroid disease, acquired immunodeficiency syndrome, sarcoidosis, rheumatoid arthritis, interstitial lung disease, scleroderma, dermatitis; 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 bil i ary cirrhosis, ileitis, chronic inflammatory intestinal disease, celiac disease, irritable bowel syndrome. Alzheimer's disease, prion associated disease, fatty liver; insomnia (onset and maintenance), sleep disorders in Parkinson's, acne, cannabis withdrawal symptoms, OCD, nausea, nausea related to cancer treatment, vomiting, emesis, motion sickness, and acute stroke.

[0024] In some embodiments the disease or condition treated with CBD and TMP is a cancer including, without limitation one or more of anaplastic ependymoma, DIPG. Glioblastoma multiforme, bladder, breast, head and neck, prostate, neuroendocrine. Non-Hodgkin's lymphoma, non-small cell lung, colorectal, pancreatic, and ovarian.

[0025] In some embodiments the disease or condition treated with CBD and TMP is an anxiety disorder.

[0026] In some embodiments the disease or condition treated with CBD and TMP is a personality disorder.

[0027] In another embodiment a subject with a social anxiety disorder is treated wtih CBD and TMP.

[0028] The method of any one of claims 22-24. wherein the CBD and TMP are administered together as a solid form

[0029] An aspect of the disclosure is the treatment of a subject in need of treatment wherein the subject is administered CBD and TMP. The CBD and TMP may be administered together or sequentially or the CBD and TMP administered may be a cocrystal.

[0030] In some embodiments the ratio of CBD to TMP is 1 : 1.

[0031] Disclosed herein are methods of treating a subject with a disorder selected from one or more of anxiety, depression, stress-induced depressive behavior, and anhedonia, wherein the subject is administered CBD and TMP.

[0032] In another aspect of the disclosure a subject in need of treatment is administered Img / kg to 20mg / kg of CBD-TMP solid form. In some embodiments the CBD-TMP solid form is ART12. i l.

[0033] In an embodiment of the disclosure the subject is treated with ART12. 11 at a dose of about Img / kg to about 20mg / kg of ART12.11. In some embodiments the dose of ART12.11 is about 3mg to about 17 mg or 33mg or the dose of ART12. 11 is about 3mg to about 15 mg or about 5mg to about 15 mg, or about 5mg or about 15 mg.Summary of the Disclosure

[0034] Poor solubility, oral bioavailability’ and rapid first-pass metabolism limit CBD’s therapeutic utility. Applicant’s patented 1 : 1 cocrystal of CBD with tetramethylpyrazine (TMP) is a single polymorph for oral administration that improves stability, solubility, and dissolution compared to CBD alone and as disclosed herein produces higher plasma levels (Cmax and AUC) of CBD compared to CBD alone or co-administered with TMP.

[0035] In a rodent model of stress induced anxiety, ART 12. 11 was compared at one-third the dose of CBD alone and was found to produce antianxiety' and antidepressive effects in contrast to CBD alone which had no effect. Artl2. 11 also improved cognition and sociability in animal studies whereas CBD had negative or no effect.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figures (1A-1D)- Figs. lA-B show the pharmacokinetic profiles of ART12. i l and CBD (both 10 mg / Kg) in fed and fasted beagle dogs measured after the first (day 1) and seventh (day 7) dose of test article (n=3); CBD levels are shown in graphs A and B. CBD-7COOH levels are present in graphs C and D.

[0037] Figures (2A-2B)- Fig. 2A ART 12.11 versus CBD+TMP oral pharmacokinetics in rats (fasted); Fig. 2B ART12. i l versus CBD + TMP oral pharmacokinetics rats (fed); Dosing: ART12. i l cocrystal suspension CBD:TMP 10:4.3 mg / kg, CBD+TMP suspension 10 mg / kg CBD + 4.3 mg / kg TMP.

[0038] Figure 3-shows a schematic of the behavior studies and dosing schedule in the experimental studies disclosed herein.

[0039] Figure 4 (A-D)- show results from Elevated-Plus Maze (EPM) studies in rats. Figure 4A- shows results of rats given VEH (no stress); VEH (stress): CBD (stress) and CBD-TMP (stress) as measured by % of time spent in open vs. closed arm (over 10 min); Fig. 4B-shows results in the EPM for open arm time (10 min) in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress); Figure 4C shows % open arm vs. closed arm choice over 10 minutes in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress): and Fig. 4D shows total entries over 10 minutes in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress); Fig. 4E shows an Elevated-Plus Maze test and EPM experiment in rats given CBD (10 mg / kg), TMP (1.5 mg / Kg), CBD (3.5 mg / Kg) + TMP (1.5 mg / Kg), ART12.i l (5 mg / kg) or ART12. i l (15 mg / kg).

[0040] Figure 5 (A-D) show the results of Light-Dark Box (LDB) studies in rats; Fig. 5A shows time in light chamber (10 min.) in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress); Fig. 5B shows the results of percent time spent in light versus dark chamber in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress); Fig. 5C shows the number of entries into the light chamber over 10 minutes in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress); Figure 5D shows latency of first entry into light chamber in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress).

[0041] Figure 6 (A-C) show the results of Open-Field Test (OFT) studies in rats. Fig. 6A- shows center entries over 10 min. in rats given VEH (no stress); VEH (stress); CBD (stress) and CBD- TMP (stress); Figure 6B- shows time in center over 10 min.; Figure 6C shows distance travelled in 10 min. in rates given VEH (no stress); VEH (stress); CBD (stress) and CBD-TMP (stress).

[0042] Figure 7-shows an XRPD pattern for cannabidiol tetramethylpyrazine cocrystal.

[0043] Figure 8-shows a differential scanning calorimetry thermogram for cannabidiol tetramethylpyrazine cocrystal.

[0044] Figure 9 (A-C)- Fig. 9A and 9B-show that when given intravenously (IV) CBD, TMP, and co-administered CBD and TMP showed similar PK profiles for both parent analyte and the major metabolite of CBD and TMP. Fig. 9C-In the fed state, orally administered ART12.i l led to increased plasma levels of parent CBD, and a major metabolite 7-COOH-CBD when compared to CBD alone or co-administered CBD plus TMP. Both the mean Cmax and mean AUCO-t for parent CBD analyte from ART12. i l (83.7 ng / ml; 355 h.ng / ml) were 10-12 times greater than CBD alone (10.2 ng / ml; 28.5 h.ng / ml) and 4-5 times greater than co-administered CBD plus TMP (17.8 ng / ml; 93.3 h.ng / ml).DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] Disclosed herein is the use of cannabidiol (CBD) together with tetramethylpyrazine (TMP) that results in improved bioavailability and efficacy of CBD. In some embodiments, the CBD and tetramethylpyrazine are a solid form of CBD and tetramethylpyrazine. In some embodiments, the solid form of CBD is a cocrystal of CBD and TMP. In some embodiments, the cocrystal of CBD:TMP is as described in U.S. Patent No. 10,604,467. IN some embodiments the CBD and TMP are administered as separate entities, i.e., not a cocrystal.

[0046] Cocrystallization improves the physical properties of CBD. ART12. 11 has a higher melting point than either individual component (see Table 1). CBD:TMP cocrystallization enables oral solid dosage formulations with enhanced bioavailability and clinical effects.Table 1- melting point comparisons

[0047] Fasted State Simulation Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF) have shown that ART12.i l is more soluble than CBD alone (Fig. 10). In addition. TMP solubility is reduced in ART12. i l in both FaSSIF and FeSSIF (data not shown).

[0048] Two pharmacokinetic studies were designed to test the bioavailability of ART12. i l compared to CBD alone in male beagle dogs. In study one, in the fasted state, the mean values for Cmax / Dose and AUCO-last / Dose were 15-fold and 35-fold higher, respectively, after administration of ART12.11 capsules compared to CBD alone. In the fed state, the exposure of CBD was comparable. A second, repeated dose study confirmed the initial findings, showing enhanced CBD (Figure lA-graph A) or CBD-7COOH (Figure 1A- graph C) levels after dose 1 in the fasted state. CBD and CBD- 7COOH levels were also increased over time after the seventh administration of ART12. i l in the fasted state. In the fed state, CBD levels were comparable on day 1 and 7 (Figure lA-graph B), but CBD-7COOH levels were higher on day 1 in the fed state (Figure 1 A-D).

[0049] Behavioral pharmacological studies were performed to test the efficacy of ART12.i l (5 mg / kg, PO) or ART12.i l (15 mg / kg) versus CBD alone (10 mg / kg,), TMP alone (1.5 mg / kg), CBD (3.5 mg / kg) + TMP (1.5 mg / kg) in rats exposed to a chronic unpredictable stress protocol for 2 weeks. Behavior testing was done 2 hours after the drug was administered. Behavior tests included Elevated-Plus Maze (EPM) (Fig. 3A and 3B), Light-Dark Box (LDB) (Fig. 4), Open- Field Test (OFT) (Fig. 5).

[0050] In the EPM study ART12.i l (5 mg / kg) reduced anxiety levels, specifically in the stressed condition. ART12. i l (5 mg) was superior to the TMP and CBD + TMP mixture. Anxiolytic effect observed in the CBD-TMP (5 mg / kg) dose with stress, whereas the 15 mg / kg dose of CBD-TMP did not produce these same effects (Figs. 3A and 3B.

[0051] ART12. i l (5 and 15 mg / kg) reduced anxiety levels in the Light-Dark Box (LDB) anxiety test. ART12. i l was superior to TMP and CBD + TMP mixture. ART12. i l significantly outperformed CBD, TMP and CBD + TMP mixture in the light-dark box (more time spent in the lightchamber, greater % of time in the light versus dark chamber and greater number of entries into the light chamber). In all cases, the effects of ART12. i l (5 mg / kg) were equal to or greater than the nonstressed controls and reversed the effects of 2 weeks chronic stress (Figs 4A and 4B).

[0052] As shown in figure 1 B and as described in Example 2 fed and fasted rats were orally dosed with an aqueous suspension of ART12.i l or CBD. The studies indicated that ART12.i l increases CBD and 7-COOH-CBD plasma exposure in both fasted and fed state.

[0053] The terms "administer," "administering", "administration," and the hke, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, transdermal, intraperitoneal, intramuscular, intravascular or infusion), inhaled, topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0054] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0055] In other embodiments a method of treatment can comprise a first stage wherein a pharmaceutical composition comprising CBD is administered and a second stage where TMP is administered. The first stage and the second stage may be sequential in time, spaced apart in time (minutes, days, weeks, or months), or overlapping in time. In addition, the sequential order of treatment stages can be reversed or repeated.

[0056] To be sure, any combination of treatment stages may be employed. By way of example, administration of CBD herein is “A” and the treatment with tetramethylpyrazine herein is “B”:A / B / A B / A / B B / B / A A / A / B A / B / B B / A / A A / B / B / B B / A / B / BB / B / B / A B / B / A / B A / A / B / B A / B / A / B A / B / B / A B / B / A / AB / A / B / A B / A / A / B A / A / A / B B / A / A / A A / B / A / A A / A / B / A

[0057] The dosage of the CBD:TMP cocrystal (ART. 12. 11) to a subject can depend on the disease state or particular condition of the subject, as well as other clinical factors (e.g., weight and condition of the human or animal and the route of administration of the cannabidiol). The cannabidiolcocrystal can be administered between several times per day to a single treatment protocol. Optionally, the cannabidiol cocrystal can be delivered according to the disclosed processes either acutely, during a one-time intervention, or chronically, for instance using multiple administrations or optionally a single administration of a timed or sustained releases system. For example, the cannabidiol cocrystal can be administered to the subject via a drug delivery' vehicle, such as a sustained release drug deliveryvehicle. It is to be understood that the present disclosure has application for both human and veterinary use. The methods of the present invention contemplate single as well as multiple administrations, given either simultaneously or over an extended period of time. In addition, the cannabidiol cocrystal can be administered in conjunction with other forms of therapy.

[0058] In one embodiment, the CBD:TMP cocrystal can be provided as a pharmaceutical composition using formulation methods known to those of ordinary skill in the art. These formulations can generally be administered by standard routes, such as non-parenterally, for example, buccally, sublingually, transdermally, via inhalation, or rectally. In other embodiments, the pharmaceutical composition is administered by direct injection into the subject, for example, parenterally, such as byinjection or infusion. Still further the pharmaceutical composition can be administered by oral administration (e.g., in a pill, capsule form, chewable as part of food, gum, or beverage, e.g., candy, gummy, coffee, etc.).

[0059] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0060] As used herein a "pharmaceutical composition" refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0061] Compositions of the present invention can include additional agents, in addition to the cannabidiol cocrystal. Such agents can be active agents, providing direct benefit to the patient inaddition to the treatment of condition provided by the cannabidiol cocrystal, or may be supporting agents, improving delivery, compatibility, or reactivity of other agents in the composition.

[0062] Compositions for parenteral delivery, e.g., via injection, of cannabidiol crystal can include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e g., olive oil and sesame oil) and injectable organic esters such as ethyl oleate. In addition, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like that can enhance the effectiveness of the cannabidiol cocrystal. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also include anti-oxidants, preservatives, wetting agents, emulsifying agents and dispersing agents.

[0063] Prevention of microorganism contamination may be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.

[0064] In one embodiment, the compositions can include pharmaceutically acceptable salts of the components therein, e.g., those that may be derived from inorganic or organic acids. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1 et seq., which is incorporated herein by reference. Pharmaceutically acceptable salts include the acid addition salts that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like. Salts formed with free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like. The salts may be prepared in situ during the final isolation and purification of the cannabidiol or separately via reaction of a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptonoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide. 2-hydroxy methanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, pivalate, propionate, succinate, tartate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myrist l and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

[0065] In one embodiment, the methods described herein can include use of timed release or sustained release deliver}’ systems as are generally known in the art. Such systems can be desirable, for instance, in situations where long term delivery of the cannabidiol cocrystal to the subject is desired. According to this particular embodiment, a sustained-release matrix can include a matrix made of materials, usually polymers, which are degradable by enzymatic or acid / base hydrolysis or by dissolution. Once located within the subject, such a matrix can be acted upon by enzymes and body fluids. The sustained-release matrix can be chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), poly glycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polyproteins. hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. Possible biodegradable polymers and their use are described, for example, in detail in Brem et al. (1991. J. Neurosurg. 74:441- 6). which is hereby incorporated by reference in its entirety).

[0066] When an effective amount of the CBD:TMP cocrystal is administered by intravenous or subcutaneous injection, the compositions can generally be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having proper pH, isotonicity, stability, and the like, is within the skill in the art. A pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection can contain, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or another vehicle as known in the art. The treatmentcomposition may also contain stabilizers, preservatives, antioxidants, or other additives known to those of skill in the art.

[0067] The terms '’enhance" or ‘’enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability7to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0068] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and nonfixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g.. a compound described herein, or a pharmaceutically acceptable salt thereof, and a coagent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0069] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine: domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0070] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophy lactically and / or therapeutically.

[0071] The compounds used in the method of the present invention may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0072] The compounds used in the method of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A. I. Vogel, A. R. Tatchell, B. S. Fumis, A. J. Hannaford, P. W. G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley - Interscience) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0073] The manufacture of a CBD:TMP cocrystal is described in US Patent No. 10,604,467.

[0074] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.. Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery' Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0075] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be done by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery’ via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery', topical application such as creams or ointments, injection.catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[0076] Also disclosed herein are methods for using cannabidiol in combination with tetramethylpyrazine or a cocrystal of CBD:TMP for treating medical conditions such as, without limitation, convulsions and / or seizures, for example convulsions / seizures associated with epilepsy; psychiatric disorders (without limitation, schizophrenia, anxiety disorders, personality disorders, social disorders); improving cognitive function, e.g., in subjects with schizophrenia; as an anti-inflammatory (e.g., without limitation, inflammatory bowel disease); pain (e.g., without limitation, chronic pain, neuropathic pain; nociceptive pain); hepatitis; spasticity' in neurodegenerative diseases, such as multiple sclerosis; multiple sclerosis-related muscle spasms, restless leg syndrome, cachexia and anorexia; ocular hypertension in glaucoma; spasms in Tourette syndrome; reducing drug dependence such as cannabis use disorder, cocaine dependence, and opiate addiction; diabetes mellitus; graph versus host disease (GVHD); atherosclerosis; as a neuroprotective agent, cancers, such as without limitation solid tumors, hematological malignancies and cancers that have metastasized; anemias, Crohn’s disease: ulcerative colitis; systemic lupus erythematosus (SLE); cutaneous lupus ery thematosus; psoriasis; autoimmune uveitis; autoimmune hepatitis; hypersensitivity lung diseases; hypersensitivity pneumonitis; delayed-type hypersensitiyity; Sjogren’s disease; autoimmune thyroid disease; acquired immunodeficiency syndrome, sarcoidosis; rheumatoid arthritis; interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis or other inflammatory diseases); scleroderma; dermatitis (including atopic dermatitis and eczematous dermatitis); iritis, conjunctivitis; keratoconjunctivitis; idiopathic bilateral progressive sensorineural hearing loss; aplastic anemia; pure red cell anemia; idiopathic thrombocytopenia; polychondritis; Graves ophthalmopathy; amyotrophic lateral sclerosis (ALS); primary biliary cirrhosis; ileitis; chronic inflammatory intestinal disease, celiac disease; irritable bowel syndrome, Alzheimer’s disease; prion associated disease; neurodegenerative disease, movement disorders, fatty' liver; insomnia and other sleep disorders; posttraumatic stress syndrome; hypoxia-ischemia (including acute stroke); or other conditions reported or under investigation to be treatable with cannabidiol treatment comprising, or consisting essentially of, or consisting of administering to a subject in need of treatment an effective amount of the cannabidiol cociystal.

[0077] In some embodiments the anxiety disorders include, yvithout limitation, generalized anxiety disorder, panic disorder yvith or yvithout agoraphobia, specific phobias, agoraphobia, social anxiety disorder, separation anxiety disorder and selective mutism.

[0078] In some embodiments the social disorders include, without limitation, talking to strangers, speaking in public, dating, making eye contact, entering rooms, using public restrooms, going to parties, eating in front of people, going to school or work, starting conversations, fear of being judged or watched by others, fear of being embarrassed or humiliated and fear of being the center of attention.

[0079] In some embodiments, the personality disorder is, without limitation, antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive- compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, or schizotypal personality' disorder.Methods of Dosing and Treatment Regimens:

[0080] In other embodiments, CBD and TMP or a CBD:TMP cocrystal, are used in the preparation of medicaments for the treatment of anxiety disorders, adjustment disorders, obsessive compulsive disorder, ADHD, social anxiety disorder and / or PTSD. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involve administration of pharmaceutical compositions that include CBD and TMP in therapeutically effective amounts to said subject.

[0081] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.EXAMPLESExample 1- Analytical WORKChemicals and suppliers

[0082] HPLC grade methanol and acetonitrile: Merck (Darmstadt, Germany), HPLC grade formic acid, acetic acid and ammonium formate: BDH Laboratory Supplies (Poole, UK). Otherchemicals: Sigma Aldrich (Helsinki, Finland), the highest purify available. Water was in-house freshly- prepared with a Direct-Q3 (Millipore Oy. Espoo, Finland) purification system and UP grade (ultra- pure, 18.2 MW).The test articles tetramethylpyrazine (TMP), cannabidiol (CBD), 2-hydroxymethyl-3,5,6- trimethylpyrazine (TMP-OH) and 7-carboxy cannabidiol (7-COOH-CBD) were purchased from Sigma Aldrich (Helsinki, Finland).Sample preparation:Sample preparation for analysis of TMP and TMP-OH

[0083] Standard samples were prepared by spiking blank 40 mg / ml BSA in PBS (10 pl standard spiking solutions + 90 pl blank BSA) to concentrations from 0. 1 ng / ml to 10 000 ng / ml with study compounds (TMP & TMP-OH). Quality control (QC) samples were prepared by spiking blank dog plasma (10 pl QC + 90 pl blank dog plasma) to concentrations of 0.3, 3, 30, 300 and 3000 ng / ml of the analytes. Standards and quality controls were treated with the same method as the samples. The results of standard samples and QC have been collated in Appendix Ila.

[0084] Samples were prepared for analysis by pipetting 100 pl of plasma and 400 pl acetonitrile, containing 1% formic acid and internal standard (20 ng / ml phenacetin). Samples were mixed 3 min and 300 pl of sample was transferred on Waters Ostro-plate (phospholipid removal plate) and eluted out using pressurized air (Water positive pressure processor). After processing, samples were diluted with 200 pl of UP-grade water.Sample preparation for analysis of CBD and 7-COOH-CBD

[0085] Standard samples were prepared by spiking blank dog plasma (10 pl standard spiking solutions + 90 pl blank plasma) to concentrations from 0.02 ng / ml to 10 000 ng / ml with studycompounds (CBD & 7-COOH-CBD). Qualify control (QC) samples were prepared by spiking blank dog plasma (10 pl QC + 90 pl blank dog plasma) to concentrations of 0.03, 0.3, 3, 30, 300 and 3000 ng / ml of the analytes. Standards and qualify controls were treated with the same method as the samples. The results of standard samples and QC have been collated in Appendix lib.

[0086] Samples were prepared for analysis by pipetting 100 pl of plasma and 400 pl acetronitrile, containing 1 % formic acid and internal standard (20 ng / ml 7-COOH-CBD-D3 and 5 ng / ml CBD-D9). Samples were mixed 3 min and 300 pl of sample was transferred on Waters Ostro- plate (phospholipid removal plate) and eluted out using pressurized air (Water positive pressure processor). After processing, samples were diluted with 200 pl of UP-grade water.Liquid chromatography-mass spectrometryTable 2- Analytical method for analysis of TMP and TMP-OHTable 3-Analytical method for analysis of CBD and 7-COOH-CBDPolarity: US- (UniSpray)Pharmacokinetic analysis

[0087] The pharmacokinetic parameters were calculated using Phoenix 64 (Build 6.4.0.768) WinNonlin (version 6.4) software, using non-compartmental methods (NCA). Nominal target doses were calculated based on the nominal content of CBD in capsules (150 mg) as well as individual animal weights (Appendix III). The terminal phase half-life (T1 / 2) was calculated by leastsquares regression analysis of the terminal linear part of the log concentration-time curve. The areaunder the plasma concentration-time curve (AUC) was determined with the linear trapezoidal rule for increasing values and log trapezoidal rule for decreasing values up to the last measurable concentration (AUCo-bst), and extrapolation of the terminal elimination phase to infinity was used when possible: the following criteria were considered:• Minimum of 3 points (not including Cmax) used to calculate lambda (with R2adjusted >0.85)• TI / 2 shorter than the time-span used to calculate lambda• AUCinf_Extrap % < 20%

[0088] The maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) were derived directly from the plasma concentration data.RESULTSIn vivo observations:

[0089] There were no generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobias, agoraphobia, social anxiety disorder, separation anxiety disorder and selective mutism adverse events or compound related side effects after administration of the study compound.Analysis of plasma samples:

[0090] The mean plasma concentration vs. time profiles for CBD, 7-COOH-CBD, TMP and TMP-OH are shown in Figures l(A-D). Calculated pharmacokinetic parameters are displayed in Tables 2a-h.

[0091] After p.o. administration of capsule containing plain CBD (150 mg) to fasted beagle dogs, plasma concentrations of CBD peaked between 0.500 and 3.00 h post-dosing with the mean value for Cmax / Dose of 1.16 kg*ng / ml / mg. The mean values for AUCO-last / Dose and Tl / 2 were 5.56 h*ng / ml and 6.11 h. Plasma concentrations of metabolite 7-COOH-CBD peaked between 1.00 and 3.00 h post-dosing with the mean Cmax of 6.44 ng / ml. The mean value for AUCO-last was 53.4 h*kg*ng / ml / mg. Overall, pharmacokinetics were variable between animals. After p.o. administration of capsule containing plain CBD (150 mg) to fed beagle dogs, plasma concentrations of CBD peaked between 1.00 and 2.00 h post-dosing with the mean Cmax of 39.6 kg*ng / ml / mg. The mean values for AUCO-last and Tl / 2 were 377 h* kg*ng / ml / mg and 6.94 h. Plasma concentrations of metabolite 7- COOH-CBD peaked at 3.00 h post-dosing with the mean Cmax of 110 ng / ml. The mean value for AUCO-last was 1540 h*ng / ml. Overall, pharmacokinetics were variable between animals. Exposure of CBD w as 79-fold higher in fed conditions compared to fasted conditions.

[0092] After p.o. administration of capsule containing CBD:TMP cocrystal (105.7 mg of CBD) to fasted beagle dogs, plasma concentrations of CBD peaked between 0.250 and 24.0 h postdosing with the mean Cmax / Dose of 23.4 kg*ng / ml / mg. The mean value for AUCO-last / Dose was 194 h*kg*ng / ml / mg. Plasma concentrations of metabolite 7-COOH-CBD peaked between 2.00 and 24.0 h post-dosing with the mean Cmax of 69.8 ng / ml. The mean value for AUCO-last was 736 h*ng / ml. Overall, pharmacokinetics were variable between animals. After p.o. administration of capsule containing CBD:TMP cocrystal (150 mg of CBD) to fed beagle dogs, plasma concentrations of CBD peaked between 0.75 and 1.00 h post-dosing with the mean Cmax / Dose of 1 15 kg*ng / ml / mg. The mean values for AUCO-last and Tl / 2 were 465 h*kg*ng / ml / mg and 7.00 h. Plasma concentrations of metabolite 7-COOH-CBD peaked between 3.00 and 24.0 h post-dosing with the mean Cmax of 98.7 ng / ml. The mean value for AUCO-last was 1320 h*ng / ml. Overall, pharmacokinetics were variable between animals. Exposure of CBD was 4.7-fold higher in fed conditions compared to fasted conditions.

[0093] After p.o. administration of capsule containing CBD:TMP cocrystal (44.3 mg of TMP) to fasted beagle dogs, plasma concentrations of TMP peaked between 0.250 and 1.00 h postdosing with the mean Cmax of 37.3 ng / ml. The mean value for AUCO-last was 66. 1 h*ng / ml. Plasma concentrations of metabolite TMP-OH peaked between 0.250 and 1.00 h post-dosing with the mean Cmax of 115 ng / ml. The mean value for AUCO-last was 237 h*ng / ml. Overall, pharmacokinetics were variable between animals. After p.o. administration of capsule containing CBD:TMP cocrystal (44.3 mg of TMP) to fed beagle dogs, plasma concentrations of TMP peaked between 0.250 and 0.500 h post-dosing with the mean Cmax of 96.5 ng / ml. The mean value for AUCO-last was 99.1 h*ng / ml. Plasma concentrations of metabolite TMP-OH peaked between 0.250 and 0.500 h post-dosing with the mean Cmax of 218 ng / ml. The mean value for AUCO-last was 363 h*ng / ml. Overall, pharmacokinetics were variable between animals.

[0094] After p.o. administration of capsule containing plain CBD (0 mg of TMP) to fasted and fed beagle dogs, TMP-OH was detected in plasma with Cmax remaining below 10 ng / ml in both conditions. It is known that dogs are fed with chow containing soy, and therefore, it is assumed that the compound is originates from the food.

[0095] After p.o. administration of capsule containing plain CBD (150 mg) and capsule containing CBD:TMP cocrystal (105.7 mg of CBD) in fasted state, the mean values for Cmax / Dose were 1.54 and 23.4 kg*ng / ml / mg, the mean values for AUCO-last / Dose were 5.56 and 194 kg*ng / ml / mg, respectively. Therefore, the mean values for Cmax / Dose and AUCO-last / Dose were15.2-fold and 34.9-fold higher after administration of capsules containing CBD:TMP cocrystal than after administration of capsules containing plain CBD.

[0096] After p.o. administration of capsule containing plain CBD (150 mg) and capsule containing CBD:TMP cocrystal (105.7 mg of CBD) in fed state, the mean values for Cmax / Dose for CBD were 102 and 115 kg*ng / ml / mg, whereas the mean values for AUCO-last / Dose for CBD were 545 and 465 kg*ng / ml / mg, respectively. Therefore, the mean values for Cmax / Dose and AUCO- last / Dose were comparable after administration of capsules containing CBD:TMP cocrystal and after administration of capsules containing plain CBD. When the mean values are compared for metabolite 7-COOH-CBD (dose normalized by using the dose of CBD) the mean values for Cmax / Dose were 10.0 kg*ng / ml / mg for plain CBD (150 mg) and 13.1 kg*ng / ml / mg for CBD:TMP cocrystal (105.7 mg of CBD). Similarly, the mean values for AUCO-last / Dose were 139 for plain CBD (150 mg) and 176 kg*ng / ml / mg for CBD:TMP cocrystal (105.7 mg of CBD). Thus, the mean values for Cmax / Dose and AUCO-last / Dose were comparable also for metabolite 7-COOH-CBD after administration of capsules containing CBD:TMP cocrystal and after administration of capsules containing plain CBD.

[0097] Table 4a. The calculated pharmacokinetic parameters for CBD and 7-COOH-CBD in dog plasma after p.o, administration of capsules containing plain CBD (150 mg) in a fasted state.#the dose of CBD used for normalization

[0098] Table 4b. The calculated pharmacokinetic parameters for TMP-OH in dog plasma after p.o. administration of capsules containing plain CBD (0 mg of TMP) in a fasted state.Table 4c. The calculated pharmacokinetic parameters for CBD and 7-C00H-CBD in dog plasma after p.o. administration of capsules containing CBD:TMP cocrystal (105.7 mg of CBD) in a fasted state.#the dose of CBD used for normalisationTable 4d. The calculated pharmacokinetic parameters for TMP and TMP-OH in dog plasma after p.o. administration of capsules containing CBD:TMP cocrystal (44.3 mg of TMP) in a fasted state.**due to the low value for R2(adjusted), data was not extrapolated to infinity; c.n.c. - could not calculate; *the value for R2(adjusted) <0.85 and thus values obtained by means of extrapolation should be viewed with cautionTable 4e. The calculated pharmacokinetic parameters for CBD and 7-C00H-CBD in dog plasma after p.o. administration of capsules containing plain CBD (150 mg) in a fed state.**due to the low value for R2(adjusted), data was not extrapolated to infinity: c.n.c. - could not calculate;*the value for R2(adjusted) <0.85 and thus values obtained by means of extrapolation should be viewed with caution;#the dose of CBD used for normalizationTable 4f. The calculated pharmacokinetic parameters for TMP-OH in dog plasma after p.o. administration of capsules containing plain CBD (0 mg of TMP) in a fed state.**due to the low value for R2(adjusted), data was not extrapolated to infinity; c.n.c. - could not calculate;Table 4g. The calculated pharmacokinetic parameters for CBD and 7-COOH-CBD in dog plasma after p.o. administration of capsules containing CBD:TMP cocrystal (105.7 mg of CBD) in a fed state.**due to the low value for R2(adjusted), data was not extrapolated to infinity; c.n.c. - could not calculate; *the value for R2(adjusted) <0.85 and thus values obtained by means of extrapolation should be viewed with caution;#the dose of CBD used for normalizationTable 4h. The calculated pharmacokinetic parameters for TMP and TMP-OH in dog plasma after p.o. administration of capsules containing CBD:TMP cocrystal (44.3 mg of TMP) in a fed state.**due to the low value for R2(adjusted), data was not extrapolated to infinity; c.n.c. - could not calculate; **the value for R2 (adjusted) <0.85 and thus values obtained by means of extrapolation should be viewed with cautionExample 2- Investigation of the Pharmacokinetic Parameters of TMP, CBD, and ART12: 11 in Various Formulations Following Oral and Intravenous Administration to Male Sprague Dawley Rats Objectives:

[0099] To provide plasma samples from male rats in both fasted and fed state following an oral or intravenous administration of the test materials in multiple formulations.

[0100] To quantify the concentration of the test material and three major metabolites (7- COOH-CBD, TMP-OH. 6-OH-CBD) in plasma samples from male rats.

[0101] To determine the pharmacokinetic parameters of the test materials in plasma following oral and intravenous administration.Outline of Study Design:

[0102] Table 5 Fifteen groups of rats will be dosed as followsM-male PO-oral IV Intravenous2. Material and Methods:

[0103] Table 6 -Animals will be obtained from Charles River Ltd. (Margate, Kent, UK) according to the following specifications:

[0104] Table 7 Housing and husbandry

[0105] Table 8 Test ItemName CannabidiolSource / supplierBatch / lot numberPhysical form / appearance Off-white solidMolecular weight (free acid / base) 314.47Molecular weight (salt)Chemical purityStorage conditions Room temperatureSafety precautions See MSDSName ART12:11Source / supplierBatch / lot numberPhysical form / appearanceMolecular weight (free acid / base)Molecular weight (salt)Chemical purityStorage conditions Room temperatureSafety precautions See MSDSName TetramethylpyrazineSource / supplierBatch / lot numberPhysical form / appearance White solidMolecular weight (free acid / base) 136.19Molecular weight (salt)Chemical purityStorage conditions Room temperatureSafety precautions See MSDSFormulation Specifications:

[0106] Table 9 Suspension Vehicle - 0.5% w / v HPMC

[0107] T able 10 Oral suspension formulation - TMP 1.72 mg / mL

[0108] Table 11

[0109] Table 12 Oral suspension formulation - CBD 4 mg / mL

[0110] Table 13-Oral suspension formulation - CBD (4 mg / mL): TMP (1.72 mg / mL) mix.

[0111] Table 14 Oral suspension formulation - ART12.1 1 cocrystal 5.72 mg / mL

[0112] Table 15 IV formulation - CBD at a nominal concentration of 0.2 mg / mL

[0113] Table 16 IV formulation - TMP at a nominal concentration of 0.2 mg / mL

[0114] Table 17 IV formulation - CBD and TMP at a nominal concentration of 0.2 mg / mL (0.4 mg / mL in total)

[0115] Table 18 Formulation method for Epidyolex at a nominal concentration of 100 mg / mL for oral dosingDose administration:

[0116] Dosing proceduresAnimals will be weighed the morning of dosing with doses being administered based on the bodyweight and the specified dose volume.Oral dosing apparatus will consist of an appropriately sized syringe and polypropylene gavage tube.Intravenous dosing apparatus will consist of a butterfly needle and syringe.Administration by weight• An appropriate volume of dose formulation, including an excess, will be taken up into the dose apparatus• Any trapped air will be expelled and the syringe primed with the exact volume• The apparatus will be weighed to determine the pre dose weight• Oral - The gavage tube will be carefully fed down the oesophagus of each animal then once confirmed in place the dose dispensed• Intravenous - Dose will be administered into a lateral tail vein as a single bolus (not used for blood collection).The empty dose apparatus will be weighed post dose to calculate the exact net doseweight administeredSample Collection and Processing

[0117] Whole blood and plasmaFollowing dosing, serial whole blood samples (ca. 200pL) will be collected into individual K2EDTA treated containers from a lateral tail vein. Samples will be collected at the following times post dose:IV - Pre dose then 30 minutes, 1 , 2, 3, 5, 8, and 24 hoursPO - Pre dose then 15, and 30 minutes and then 1 , 2, 4, 8, and 24 hoursWhole blood will be collected into tubes containing K2EDTA as an anticoagulant.Following collection whole blood samples will be mixed gently and placed into an electronic ice cube.As soon as practicable after collection (within 15 minutes), samples will be centrifuged (approximately 10,000 x g, 2 min, 4°C) and the resultant plasma aspirated into plain fully labelled tubes.All plasma will be stored at ca.-80°C.Following collection of the final samples, animals will be sacrificed by a Schedule One method and frozen until disposal.Bioanalysis

[0118] Plasma samples will be analysed for the test material and metabolite concentrations using ‘fit for purpose’ LC / MS / MS methods developed and optimised for use with plasma, based on the analytical methods detailed in information supplied by the Sponsor.Target analytical ranges to be established are as follows,TMO and TMP-OH 1 to 1000- ng / mL (Method 1)CBD, 6-OH-CBD, 7-COOH-CBD 0.5 to 2000 ng / mL (Method 2)Table 19Linearity Assessment

[0119] Assay Linearity - A calibration curve prepared in duplicate containing >8 concentration levels as well as control blank and zero (IS only).Acceptance criteria - A minimum of 60% of the calibration standards (non-zero samples) must be <±20% relative error (RE) (<±25% RE at the lower limit of quantitation) of their prepared nominal concentrations.Analytical method

[0120] Following successful method development and linearity assessment, the samples will be analysed using the LC-MS / MS method to determine concentrations of parent and metabolite in Method 1 and 2, as appropriate.

[0121] Each analytical batch of unknown samples will be prepared and analysed with a set of calibration standard samples and a set of quality control samples at LOW, MEDIUM and HIGH concentration levels. In addition, a system suitability test sample (SST) will be included. Whenever possible, unknown plasma samples will be analysed from low to high expected analyte(s) concentrations to help minimise any impact from analyte carryover which may occur.

[0122] Calibration curve acceptance - A minimum of 60% of the calibration standards (non-zero samples) must be <±20% relative error (RE) (<±25% RE at the lower limit of quantitation) of their prepared nominal concentrations.

[0123] Quality Control sample acceptance - 2 / 3rds<±20% RE, 50% <±20% RE at each concentration level.

[0124] Carryover - Ideally, any analyte carryover after the highest calibration standard sample should be <25% of the peak area of the lowest limit of quantification (LLOQ) calibration standard. Any internal standard carryover should be <5% of the internal standard peak area in thesame LLOQ calibration standard. If carryover is outside of these limits the potential impact on the accuracy of measurement of analyte in plasma samples will be reviewed. This may result in batch failure or the requirement to reanalyse specific unknown plasma samples which may have been detrimentally impacted. A detrimental impact of carryover will be considered as the potential to introduce a >20% bias in the determined analyte concentration in the plasma sample.Only data from accepted batches will be reported.

[0125] Extrapolated data may be reported up to circa. 120% of the top standard (at the discretion of the Sponsor). If determined sample concentration is greater than this, the sample extract may be diluted appropriately and re-analysed.Data acquisition and processing

[0126] All instrument control, data collection, peak area integration and storage will be performed using AB Sciex Analyst™ software. The mass spectrometer response (peak area ratio of analyte to internal standard) of each calibration standard will be calculated by Analyst™ software (version 1.7 or higher) and plotted against the nominal (prepared) concentration. A weighted (l / x2) least squares quadratic regression will be used to calculate an equation of the calibration line. Plasma concentrations will be back calculated from the calibration lines to 3 significant figures. Microsoft Excel software may be used to perform additional statistical calculations.Pharmacokinetic Parameters

[0127] Plasma pharmacokinetic parameters will be derived by non-compartmental analysis (linear / logarithmic trapezoidal) using WinNonlin (Version 8.2) software. One PK profile per animal will be generated.

[0128] The following parameters will be determined from the plasma concentration-time profile, if appropriate and sufficient data is available. Plasma concentrations below the limit of quantification of the assay, reported as BLQ, will be taken as zero before Cmax and omitted after Cmax.• Cmax (ng / mL)Maximum measured concentration• Tmax (h) Time at which maximum concentration was apparent• ti / 2 (h) Terminal half-life, if data allows• AUCo-t (h.ng / mL) Area under the curve from 0 to last quantifiable data point• AUCo- (h.ng / mL) Area under curve from time 0 to infinity (predicted)• AUC extrapolated Percent of AUC(O-inf) that is extrapolated (predicted)• CL / F* (mL / h / kg) Volume of plasma cleared of drug per unit time (predicted)• Vz / F* (mL / kg) Volume of distribution (predicted)• F Bioavailability of oral dose

[0129] The terminal half-life will only be calculated from a minimum of 3 data points, with a correlation coefficient greater than 0.7. In addition, the data points used in the calculation should cover a time period of a minimum period equal to that of the half-life. Where an estimate of the half-life could not be determined, the value n.d will be entered. If the terminal phase cannot be described then all other predicted parameters will also be given the value of n d.• for extravascular models, the fraction of dose absorbed (F) cannot be estimated, therefore, Volume of distribution and Clearance for these models are actually Volume / F and Clearance / F (where F=fraction of dose absorbed).Example 3- Light-Dark Box

[0130] The light-dark box test measures a rodent’s natural tendency to avoid brightly lit environments while preferring dark environments, and is a measure of unconditioned anxiety. The test apparatus consisted of two (50 x 25 x 37 cm) Plexiglas compartments divided by a wall with a 10 x 10 cm door. One side of the box had black walls and a lid to create a fully dark space while the other side is white with an open top and an overhead 1500 lux light. Anxiety-like behavior is measured based on number of total transitions between the light-dark environments, total time in the light environment and total time in the dark environment. Examining times spent in the light environment Before testing rats were handled for 5 min per day.Example 4: Elevated plus maze test:

[0131] The elevated plus maze (EPM) apparatus (black acrylic, 4 arms (10 x 50 cm) stemming from a 10 x 10 cm platform and forming a plus shape) was raised above the floor by 50 cm and was dimly illuminated (40 lux). Two opposite arms were enclosed with 40 cm high walls while other two arms were opened (except for 1 cm high ledge). Intra-PFC-injected rats were placed on the central platform (facing closed arm) and explored the maze for 10 min. Results are shown in Fig. 2.

[0132] Behavior was video recorded and analyzed offline (Behaview software; www.pmbogusz.net). The number of entries (all paws in) and the time spent in closed and open arms was scored.Example 5: Comparison of the pharmacokinetic profile of an orally administered aqueous suspension of ART12.11 to an orally co-administered aqueous suspension of CBD and TMP. Methods:

[0133] Male Sprague Dawley rats (n=3) were administered a single dose of either CBD (1 mg / kg intravenously [IV] or 10 mg / kg by oral gavage [PO]), TMP (1 mg / kg IV or 4.3 mg / kg PO). a co-administered mixture of CBD and TMP (1 mg / kg & 1 mg / kg IV or 10 mg / kg& 4.3 mg / kg PO) or ART12. 11 (14.3 mg / kg [containing 10 mg / kg CBD and 4.3 mg / kg TMP in a cocrystal] PO). Animals were dosed in the fed and fasted state. Serial blood samples were taken prior to dosing and at 30 minutes and 1, 2, 3, 5, 8, and 24 h from both the IV and PO dosed animals. Plasma samples were analyzed by LC-MS / MS to provide quantification of the test materials.Results:

[0134] When given IV CBD, TMP, and co-administered CBD and TMP showed similar PK profiles for both parent analyte and the major metabolite of CBD and TMP (Figure 1). In the fed state, orally administered ART12. 11 led to increased plasma levels of parent CBD, and a major metabolite 7-COOH-CBD when compared to CBD alone or co-administered CBD plus TMP (Figure 2). Both the mean Cmax and mean AUCO-t for parent CBD analyte from ART12. 11 (83.7 ng / ml; 355 h.ng / ml) were 10-12 times greater than CBD alone (10.2 ng / ml; 28.5 h.ng / ml) and 4-5 times greater than co-administered CBD plus TMP (17.8 ng / ml; 93.3 h.ng / ml).Conclusions:

[0135] The unique pharmaceutical properties that co-cr stallization provides translates into greatly increased exposures of CBD and a major metabolite 7-COOH-CBD from ART12.11 compared to CBD alone. The uplift observed is not due to systemic drug-drug interactions between CBD and TMP as demonstrated by their consistent IV PK profiles whether delivered as a single agent or co-administered together. Furthermore, the increased CBD and 7-COOH-CBD exposures observed from ART12. 11 upon oral dosing cannot be replicated by co-administering an equimolar equivalent dose of CBD and TMP. These results are supportive of further development of ART12. 11 co-crystal as an effective approach to dosing CBD in an oral solid dosage form.

Claims

WHAT IS CLAIMED IS:

1. A method of improving the oral bioavailability of cannabidiol (CBD) in mammals comprising administering to subjects in need of treatment for conditions amenable to treatment with CBD a combination of CBD and tetramethylpyrazine (TMP).

2. The method of claim 1, wherein the CBD and TMP comprise a solid form.

3. The solid form of claim 2 having an x-ray diffraction pattern comprising one or more peaks at about 9.1, 14.

6. 18.

3. and 19.6 degrees 20 ±0.2.

4. The solid form of claim 3 having an x-ray powder diffraction pattern substantially similar to FIG. 7.

5. The solid form of claim 4, wherein the molar ratio of cannabidiol to tetramethylpyrazine is about 1: 1.

6. The solid form of claim 2, which is crystalline.

7. The solid form of claim 2, which is a cocrystal.

8. The solid form of claim 2 having a DSC thermogram with a peak onset of approximately 89.9 °C or a peak maximum at about 92.8 °C.

9. The solid form of claim 8 having a DSC thermogram which is substantially similar to the DSC thermogram of FIG. 8.

10. A pharmaceutical composition comprising claim 1.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or carrier.

12. A method for treating a disease or condition in a subject having said disease or condition, comprising administering to said subject cannabidiol and tetramethylpyrazine.

13. The method of claim 12, wherein the cannabidiol and tetramethylpyrazine are coadministered or given sequentially.

14. The method of claim 12, wherein the cannabidiol and tetramethylpyrazine comprise a cocrystal.

15. The method of claim 14, wherein the cannabidiol and tetramethylpyrazine are pharmaceutical compositions.

16. The method of claim 15. wherein the cannabidiol and / or tetramethylpyrazine further comprise a pharmaceutically acceptable excipient or carrier.

17. The method of claim 12, wherein the pharmaceutical composition comprises a solid form of cannabidiol and tetramethylpyrazine.

18. The method of claim 17, wherein the solid form has an x-ray diffraction pattern comprising one or more peaks at about 9.1, 14.6, 18.3, and 19.6 degrees 20±O.

19. The method of claim 12, wherein the disease or condition is selected from one or more of central nervous system disorders, cardiovascular disorders, neurovascular disorders, neuromuscular disorders, cancers, autoimmune disorders, inflammatory disorders, pain disorders, sleep disorders, posttraumatic stress disorder, posttraumatic stress syndrome; anxiety disorders, personality disorders, social anxiety disorders, depression, nausea, and hypoxia-ischemia.

20. The method of claim 19, wherein the disease or condition is selected from one or more of a solid tumor, cancer metastasis, multiple sclerosis, multiple sclerosis-related muscle spasms. Parkinson's disease, psychosis; epilepsy, 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, Lennox-Gastaut Syndrome, psychiatric disorders, impaired cognitive function, cognitive impairment in schizophrenia, anxiety, depression, bipolar disorders, fibromyalgia, hepatitis, epidermolysis bullosa, spasticity in neurodegenerative diseases, cachexia, anorexia, ocular hypertension in glaucoma, movement disorders, dystonic disorders, Prader Willi syndrome, spasms in Tourette syndrome, pseudobulbar affect, reducing drug dependence, addiction, smoking addiction, opioid addiction, diabetes mellitus, graph versus host disease (GVHD), atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, cutaneous lupus erythematosus, psoriasis, shingles pain, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed- type hypersensitivity, Sjogren's disease, thyroid disease, acquired immunodeficiency syndrome, sarcoidosis, rheumatoid arthritis, interstitial lung disease, scleroderma, dermatitis; 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, cehac disease, irritable bowel syndrome, Alzheimer's disease, prion associated disease, fatty liver; insomnia (onset and maintenance), sleep disorders in Parkinson's, acne, cannabis withdrawal symptoms, OCD, nausea, nausea related to cancer treatment, vomiting, emesis, motion sickness, and acute stroke.

21. The method according to claim 19, wherein the cancer is selected from one or more of anaplastic ependymoma, DIPG, Glioblastoma multiforme, bladder, breast, head and neck, prostate, neuroendocrine, Non-Hodgkin's lymphoma, non-small cell lung, colorectal, pancreatic, and ovarian.

22. A method of treating an anxiety disorder comprising administering CBD and TMP to a subject in need of treatment.

23. A method of treating a personality disorder comprising administering CBD and TMP to a subject in need of treatment.

24. A method of treating a social anxiety disorder comprising administering CBD and TMP to a subject in need of treatment.

25. The method of any one of claims 22-24, wherein the CBD and TMP are administered together as a solid form.

26. The method of claim 25, wherein the CBD and TMP are administered together as a cocrystal.

27. The method of claim 26, wherein the ratio of CBD to TMP is 1: 1.

28. A method of treating a subject with a disorder selected from one or more of anxiety, depression, stress-induced depressive behavior, and / or anhedonia, comprising treating a subject with CBD and TMP.

29. The method of claim 28, wherein the subject is treated Img / kg to 20mg / kg of CBD-TMP solid form.

30. The method of claim 29, wherein the subject is treated with ART12. i l at a dose of about 1 mg / kg to about 20mg / kg of ART12.1 1.

31. The method of claim 30, wherein the dose of ART12.11 is about 3mg to about 17 mg.

32. The method of claim 30, wherein the dose of ART12.11 is about 3mg to about 17 mg.

33. The method of claim 30. wherein the dose of ART12. 11 is about 3mg to about 15 mg.

34. The method of claim 30 wherein the dose of ART12.11 is about 5mg to about 15 mg.

35. The method of claim 30 wherein the dose of ART12. 11 is about 5mg.

36. The method of claim 30 wherein the dose of ART12. 11 is about 15mg.

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