Cannabidiol preparations and uses thereof

Abstract

To provide cannabidiol (CBD)-containing therapeutic preparations containing CBD as an active ingredient, where the preparations include preparations containing only pure synthetic CBD and preparations containing naturally occurring CBD.SOLUTION: A plant-derived cannabidiol (CBD) preparation comprises 98% (w / w) or more of CBD and 2% (w / w) or less of other cannabinoids, where the 2% (w / w) or less of other cannabinoids include cannabinoids tetrahydrocannabinol (THC), cannabidiol-C1 (CBD-C1), cannabidivarin (CBDV), and cannabidiol-C4 (CBD-C4), and where the THC is present as a mixture of trans-THC and cis-THC.SELECTED DRAWING: None

Description

[Technical field]

[0001] Cannabidiol (CBD) is a cannabinoid chemically named 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol. Its empirical formula is C 21 H 30 O2 and its molecular weight is 314.46. CBD is a cannabinoid that occurs naturally in the Cannabis sativa L. plant. CBD is a white to pale yellow crystalline solid that is insoluble in water and soluble in organic solvents.

[0002] The present invention encompasses the surprising realization that some CBD preparations prepared from botanical sources are more effective in treating diseases or disorders than preparations of CBD that are synthetic or purified to the extent that other impurities in the form of other cannabinoids are not present.

[0003] Previous CBD compositions have been formulated such that no psychoactive components, such as tetrahydrocannabinol (THC), remain in the final CBD formulation. Surprisingly, the absence of such impurities reduces the effectiveness of CBD treatment.

[0004] Such CBD formulations are characterized by chemical constituents and / or functional properties that distinguish them from previous CBD compositions. One or more components of the formulations described herein unexpectedly provide synergistic effects when utilized in combination. [Background technology]

[0005] Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to constituents of the Cannabis plant or endogenous agonists of the cannabinoid receptors CB1 or CB2 (endocannabinoids). Virtually the only way these compounds are produced is by the Cannabis plant. Cannabis is a genus of flowering plants in the Cannabaceae family that includes the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis (sometimes considered part of Cannabis sativa).

[0006] The Cannabis plant contains a highly complex mixture of compounds. At least 568 unique molecules have been identified. Among these compounds are cannabinoids, terpenoids, sugars, fatty acids, flavonoids, other hydrocarbons, nitrogenous compounds, and amino acids.

[0007] Cannabinoids exert their physiological effects through various receptors, including but not limited to adrenergic receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, or GPR5. The principal cannabinoids present in the Cannabis plant are the cannabinoid acids tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), with minor amounts of their respective neutral (decarboxylated) cannabinoids. Additionally, Cannabis may contain lower levels of other cannabinoids.

[0008] Crude extracts obtained from cannabis plants containing CBD are used by patients suffering from diseases and disorders.However, such crude products are not suitable for use in pharmaceutical formulations.Their search for preparing more consistent CBD preparations for use in treating diseases or disorders has led to concerted efforts to prepare CBD synthetically or to remove all compounds other than CBD obtained from plant-derived cannabinoids, particularly psychoactive compounds such as THC.

[0009] The present invention encompasses the surprising discovery that certain formulations containing CBD have improved therapeutic efficacy compared to synthetic preparations of CBD that are completely free of trace cannabinoid impurities and crude extracts that have higher levels of trace cannabinoid impurities.

[0010] As noted, cannabinoids are a class of compounds that can be derived naturally from the Cannabis plant or can be produced synthetically by chemical synthesis.

[0011] Over 100 different cannabinoids produced by the Cannabis genus have been identified, as described in the Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3-15. These cannabinoids can be classified into different groups: phytocannabinoids; endocannabinoids and synthetic cannabinoids (which may be novel cannabinoids, phytocannabinoids or synthetically produced versions of endocannabinoids).

[0012] Phytocannabinoids are cannabinoids that occur naturally and can be found in the Cannabis plant. Phytocannabinoids can be isolated from plants to produce highly purified extracts. Phytocannabinoids can be obtained as neutral (decarboxylated form) or carboxylic acid forms, depending on the method used to extract the cannabinoids from plant material. For example, it is known that heating the carboxylic acid form decarboxylates most of the carboxylic acid form to a neutral form. Phytocannabinoids can only be produced from plants, but versions of phytocannabinoids can be produced synthetically, by chemical synthesis.

[0013] Endocannabinoids are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins expressed throughout the mammalian central and peripheral nervous systems (including the brain). The endocannabinoid system regulates various physiological and cognitive processes, including appetite, pain sensation, mood, and memory during fertility, pregnancy, prenatal and postnatal development, and is involved in mediating the pharmacological effects of the Cannabis genus.

[0014] Synthetic cannabinoids are compounds with cannabinoid-like structures that are not derived from the plant but are produced using chemical means.

[0015] Some cannabinoids are described in more detail below.

[0016] Cannabidiol (CBD) is the major cannabinoid constituent of Cannabis species, such as the hemp plant (Cannabis sativa). Unlike other cannabinoids, such as THC, cannabidiol does not bind to CB1 or CB2, or its binding to the receptors is negligible with respect to inducing pharmacological effects. Thus, cannabidiol does not cause central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little or no psychotropic (cannabis-like) activity, and its molecular structure and properties are substantially different from those of other cannabinoids.

[0017] Cannabidiol administration has been the subject of research in an attempt to provide alternative treatments for a variety of diseases and disorders that may respond to such treatment.

[0018] Tetrahydrocannabinol (THC) is the main psychoactive component of the Cannabis genus. THC is a partial agonist at the CB1 and CB2 receptors. Synthetic THC or dronabinol is approved for the treatment of anorexia in AIDS patients and nausea and vomiting caused by cancer chemotherapy. Cannabis-like side effects caused by THC include feeling high, nausea, vomiting, anxiety, depression and weakness.

[0019] Of the more than 100 naturally occurring cannabinoids identified in Cannabis sativa, seven are classified as CBD-type compounds, which are cannabinoids with the same absolute configuration as CBD: CBD, cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4) and cannabidiol monomethyl ether (CBDM).

[0020] Cannabidiol acid (CBDA) is the main form in which CBD exists in the cannabis plant. It is converted to CBD after decarboxylation.

[0021] Cannabidiol-C1 (CBD-C1), also known as cannabidiorcol, is a homologue of CBD with a shortened side chain due to four methylene bridges. CBD-C1 occurs naturally in plants that produce CBD in trace amounts.

[0022] Cannabidivarin (CBDV) is a homologue of CBD with a shortened side chain by two methylene bridges. CBDV is a non-psychoactive cannabinoid and has been shown to have anticonvulsant activity in mouse models of epilepsy.

[0023] Cannabidiol-C4 (CBD-C4), also known as nor-cannabidiol, is a homologue of CBD with a shortened side chain by one methylene bridge. CBD-C4 occurs naturally in plants that produce CBD in trace amounts. [Prior art documents] [Patent documents]

[0024] [Patent Document 1] EP2311475 [Non-patent literature]

[0025] [Non-Patent Document 1] Handbook of Cannabis, Roger Pertwee, Chapter 1, pp. 3-15 [Non-Patent Document 2] “Chemical composition, pharmacological profiling, and complete physiological effects of these medicinal plants, and more importantly the extracts from cannabis, remain to be fully understood.” Lewis, MM et al., ACS Omega, vol. 2, 6091–6103 (2017) [Non-Patent Document 3] the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research Summary of the Invention [Problem to be solved by the invention]

[0026] The present invention demonstrates that botanically derived purified CBD preparations containing trace amounts of the cannabinoids CBD-C1, CBDV, CBD-C4 and THC are more effective than synthetic CBD that does not contain trace amounts of cannabinoids. These data are particularly surprising, especially considering the fact that the concentrations of CBD in the botanically derived purified CBD preparations and the synthetic preparations are the same. The present invention further discloses the differences in the physicochemical properties of botanically derived purified CBD and synthetic CBD. [Means for solving the problem]

[0027] According to a first aspect of the present invention there is provided a cannabidiol (CBD) formulation comprising at least 98% (w / w) CBD and up to 2% (w / w) other cannabinoids, the 2% (w / w) or less other cannabinoids comprising the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC.

[0028] According to a second aspect of the present invention there is provided a cannabidiol (CBD) formulation for use as a medicine comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.

[0029] According to a third aspect of the present invention there is provided a cannabidiol (CBD) formulation for use in the treatment of neurodevelopmental diseases and conditions comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.

[0030] According to a fourth aspect of the present invention there is provided a cannabidiol (CBD) formulation for use in the treatment of epilepsy comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.

[0031] According to a fifth aspect of the present invention there is provided a cannabidiol (CBD) formulation for use in the treatment of schizophrenia comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.

[0032] Preferably, the formulation contains 1.5% (w / w) or less THC based on the total mass of the cannabinoids in the formulation. More preferably, the formulation contains about 0.01% to about 0.1% (w / w) THC based on the total mass of the cannabinoids in the formulation. Even more preferably, the formulation contains about 0.02% to about 0.05% (w / w) THC based on the total mass of the cannabinoids in the formulation.

[0033] In one embodiment of the invention, the mixture of trans-THC and cis-THC is present in a ratio of about 3.6:1 trans-THC:cis-THC. In a further embodiment of the invention, the mixture of trans-THC and cis-THC is present in a ratio of about 0.8:1 trans-THC:cis-THC.

[0034] Preferably, the formulation contains about 0.1% to about 0.15% (w / w) CBD-C1, relative to the total mass of cannabinoids in the formulation.

[0035] Preferably, the formulation contains about 0.2% to about 0.8% (w / w) CBDV, based on the total mass of cannabinoids in the formulation.

[0036] Preferably, the formulation contains about 0.3% to about 0.4% (w / w) CBD-C4, based on the total mass of cannabinoids in the formulation.

[0037] In one embodiment, at least a portion of at least one of the cannabinoids present in the CBD formulation is isolated from Cannabis plant material.

[0038] Preferably, at least a portion of the CBD present in the CBD formulation is isolated from Cannabis plant material.

[0039] Preferably, at least a portion of the THC present in the CBD formulation is isolated from the Cannabis plant material.

[0040] Preferably, at least a portion of the CBD-C1 present in the CBD formulation is isolated from Cannabis plant material.

[0041] Preferably, at least a portion of the CBDV present in the CBD formulation is isolated from Cannabis plant material.

[0042] Preferably, at least a portion of the CBD-C4 present in the CBD formulation is isolated from Cannabis plant material.

[0043] In a further embodiment of the invention, substantially all of at least one of the cannabinoids present in the CBD formulation is isolated from Cannabis plant material.

[0044] Preferably, substantially all of the CBD present in the CBD formulation is isolated from Cannabis plant material.

[0045] Preferably, substantially all of the THC present in the CBD formulation is isolated from the Cannabis plant material.

[0046] Preferably, substantially all of the CBD-C1 present in the CBD formulation is isolated from Cannabis plant material.

[0047] Preferably, all of the CBDV present in the CBD formulation is isolated from Cannabis plant material.

[0048] Preferably, all of the CBD-C4 present in the CBD formulation is isolated from Cannabis plant material.

[0049] In a further embodiment of the invention, substantially all of the cannabinoids present in the CBD formulation are isolated from Cannabis plant material.

[0050] Preferably, the Cannabis plant material is obtained from a Cannabis sativa, Cannabis indica, or Cannabis ruderalis plant.

[0051] Preferably, the Cannabis plant is a high-CBD Cannabis species.

[0052] In a further embodiment of the invention, at least a portion of at least one of the cannabinoids present in the CBD formulation is synthetically prepared.

[0053] Preferably, at least a portion of the CBD present in the CBD formulation is synthetically prepared.

[0054] Preferably, at least a portion of the THC present in the CBD formulation is synthetically prepared.

[0055] Preferably, at least a portion of the CBD-C1 present in the CBD formulation is synthetically prepared.

[0056] Preferably, at least a portion of the CBDV present in the CBD formulation is synthetically prepared.

[0057] Preferably, at least a portion of the CBD-C4 present in the CBD formulation is synthetically prepared.

[0058] In a further embodiment of the invention, substantially all of at least one of the cannabinoids present in the CBD formulation is synthetically prepared.

[0059] Preferably, substantially all of the CBD present in the CBD formulation is synthetically prepared.

[0060] Preferably, substantially all of the THC present in the CBD formulation is synthetically prepared.

[0061] Preferably, substantially all of the CBD-C1 present in the CBD formulation is synthetically prepared.

[0062] Preferably, substantially all of the CBDV present in the CBD formulation is synthetically prepared.

[0063] Preferably, substantially all of the CBD-C4 present in the CBD formulation is synthetically prepared.

[0064] Preferably, substantially all of the cannabinoids present in the CBD formulation are synthetically prepared.

[0065] In a further embodiment of the invention, the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease; Parkinson's disease; essential tremor; amyotrophic lateral sclerosis (ALS); Huntington's disease; Friedreich's ataxia; multiple sclerosis; frontotemporal dementia; prion disease; Lewy body disease; progressive supranuclear palsy; vascular dementia; normal pressure hydrocephalus; traumatic spinal cord injury; HIV dementia; alcohol-induced neurotoxicity; Down's syndrome; movement disorders of the central and / or peripheral nervous system; motor neuron disease (MND); spinal muscular atrophy; or any other related neurological or psychiatric neurodegenerative disease; brain injury; brain damage; brain dysfunction; dysgraphia; dysarthria; apraxia; agnosia; amnesia; dizziness; vertigo; coma; stroke; spinal cord injury; spinal cord injury; spinal cord disorder; central neuropathy. neuropathy);peripheral neuropathy;cranial neuropathy;trigeminal neuralgia;tumours of the nervous system;brain or spinal cord infections;encephalitis;meningitis;prion diseases;complex regional pain syndrome;autonomic nervous system disorders;autonomic neuropathy;autonomic dysbiosis;postural orthostatic tachycardia syndrome (POTS);neurocardiogenic syncope (NCS);multiple system atrophy (MSA);hereditary sensory autonomic neuropathy (HSAN);Holmes-Adie syndrome (HAS);sleep disorders;narcolepsy;pain;migraine;cluster headache;tension headache;back pain;lower back pain;neck pain;neuropathic pain;cancer pain;allodynia;arthritis pain;inflammatory pain;psychiatric neurological disorders;attention deficit hyperactivity disorder;autism;Tourette syndrome;obsessive-compulsive disorder;autism spectrum disorder;Rett syndrome;fragility Weak X syndrome;Angelman syndrome;hyperactivity disorder;mitochondrial disease;dystonia;cancer;brain cancer;glioma;breast cancer;liver cancer;lung cancer;pancreatic cancer;melanoma;ovarian cancer;gastric cancer;kidney cancer;bladder cancer;addiction;nicotine addiction;smoking;alcohol addiction;drug dependence;cannabis use disorder;psychiatric disorders;post-traumatic stress disorder;anxiety;early psychosis;schizophrenia;cognitive disorders;stroke;cardiac ischemia;coronary artery disease;thromboembolism;myocardial infarction;ischemia-related disorders;gastrointestinal disorders;inflammatory bowel disease;Crohn's disease;ulcerative colitis;nausea;vomiting;emetic syndrome;motion sickness;chemotherapy-induced nausea and vomiting;inflammation;arthritis;rheumatoid arthritis;osteoarthritis;diabetes;hypertension;poor insulin control;appetite suppression;anorexia;neonatal hypoxic-ischemic encephalopathy (NHIE);degenerative muscular skeletal disease;or Duchenne muscular dystrophy (DMD);

[0066] In further embodiments of the invention, the epilepsy is Dravet syndrome, Lennox-Gastaut syndrome, Fever Infection-Related Epilepsy Syndrome (FIRES), Dause syndrome, Sturge-Weber syndrome, CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasms (West syndrome); and Landau-Kleffner syndrome, refractory epilepsy, juvenile convulsions, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis (TSC); neuroplastic storage disorder, neuronal ceroid lipofuscinosis (NCL), Batten disease, encephalopathy, atony, idiopathic, absence seizures, partial seizures, simple partial seizures, or complex partial seizures. [Brief description of the drawings]

[0067] [Figure 1] FIG. 1 shows the biosynthetic pathway for cannabinoid production. [Diagram 2] FIG. 1 illustrates different chiral forms of tetrahydrocannabinol (THC). [Diagram 3] FIG. 1 shows a UPLC chromatogram detailing trace levels of cannabinoids in a botanically derived purified CBD preparation. [Figure 4] FIG. 1 shows the mass spectrum of cis-THC isolated from high-CBD plants. [Diagram 5] FIG. 1 shows HPLC / DAD traces showing the retention times of trans-THC (top) and cis-THC (bottom). [Figure 6] FIG. 1 shows a Spearman rank plot of trans-THC to cis-THC in CBD material during processing stages. [Figure 7] FIG. 1 shows the determination of the stereoisomeric form of cis-THC present in a purified CBD preparation of botanical origin. [Figure 8] FIG. 1 shows an HPLC comparison of purified CBD of botanical origin and synthetic CBD. [Figure 9] FIG. 1 shows autofluorescence spectra of purified CBD of botanical origin and synthetic CBD at 100 mM, representative of an excitation scan from 230 nm down to fixed fluorescence wavelengths at 400 or 440 nm. [Figure 10] FIG. 1 shows the autofluorescence spectra of purified CBD of botanical origin and synthetic CBD at 100 mM, representing an emission scan up to 800 nm over fixed excitation wavelengths of 326 / 370 nm for purified CBD of botanical origin and 328 / 334 / 344 nm for synthetic CBD. [Figure 11] FIG. 1 shows autofluorescence spectra of purified CBD of botanical origin and synthetic CBD at 100 mM, representative of an excitation scan from 230 nm down to fixed fluorescence wavelengths at 400 or 440 nm. [Figure 12] FIG. 1 shows the autofluorescence spectra of purified CBD of botanical origin and synthetic CBD at 100 mM, representing an emission scan up to 800 nm over fixed excitation wavelengths of 326 / 370 nm for purified CBD of botanical origin and 326 / 340 nm for synthetic CBD. [Figure 13] Experiment 1 - S-curve showing log dose of CBD versus anticonvulsant activity in the MES test. [Figure 14] Experiment 2 - S-curve showing log dose of CBD versus anticonvulsant activity in the MES test. [Figure 15] FIG. 1 shows novel versus familiar exploration time in rats treated with botanically derived purified CBD. [Figure 16] FIG. 1 shows novel versus familiar exploration time in rats treated with synthetic CBD. [Figure 17] FIG. 1 shows novel versus familiar exploration time in rats treated with botanically derived purified CBD supplemented with THC at 10 and 20% (w / w). [Figure 18]FIG. 1 shows the discrimination index in rats treated with botanically derived purified CBD supplemented with THC at 10 and 20% (w / w). [Figure 19] FIG. 1 shows the number of line crossings in rats treated with botanically derived purified CBD supplemented with THC at 10 and 20% (w / w). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; (iii) the terms "comprising" and "including" may be understood to encompass the listed or itemized components or steps, either by themselves or together with one or more additional components or steps; (iv) the terms "about" and "approximately" may be understood to allow for standard variations that would be understood by one of ordinary skill in the art; and (v) when ranges are stated, the endpoints are included.

[0069] About or Approximately: The term "about" or "approximately" as applied to a value or values ​​of interest means a value similar to a given reference value. In some embodiments, the term "about" or "approximately" refers to a range of values ​​that is 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of the given reference value (greater or less), unless otherwise indicated or clear from the context.

[0070] Administration: As used herein, the term "administration" generally refers to the administration of a composition to a subject or system. Those of skill in the art are aware of the various routes that may be utilized for administration to a subject, e.g., a human, in the appropriate circumstances. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some detailed embodiments, administration may be bronchial (e.g., by bronchial instillation), oral, dermal (e.g., may include one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, in certain organs (e.g., intrahepatic), mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), intravaginal, vitreous, etc. In some embodiments, administration can include dosing that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., discrete doses separated by a common period of time) dosing. In some embodiments, administration can include continuous dosing (e.g., perfusion) for at least one selected period of time.

[0071] Agent: In general, the term "agent" may be used herein to mean any chemical class of compound or entity, including, for example, polypeptides, nucleic acids, saccharides, lipids, small molecules, metals, or combinations or complexes thereof. In appropriate circumstances, as will be clear to one of skill in the art from the context, the term may be used to mean an entity that is or includes a cell or organism, or a fraction, extract, or component thereof. Alternatively, or in addition, as will be clear from the context, the term may be used to mean a natural product, i.e., the term is found in nature and / or obtained from nature. In some cases, again as will be clear from the context, the term may be used to mean one or more entities that are artificial, i.e., designed, created, and / or produced by manipulation by the hand of man and / or are not found in nature. In some embodiments, the agent may be used in an isolated or pure form; in some embodiments, the agent may be used in an unpurified form. In some embodiments, potential agents may be provided as a collection or library that can be screened, for example, to identify or characterize effective agents within that range. In some cases, the term "agent" can refer to a compound or entity that is or includes a polymer; in some cases, the term can refer to a compound or entity that includes one or more polymeric moieties. In some embodiments, the term "agent" can refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or one or more specific polymeric moieties. In some embodiments, the term can refer to a compound or entity that is devoid of any polymeric moieties or is substantially free of any polymeric moieties.

[0072] Amelioration: As used herein, refers to the prevention, reduction or alleviation of a condition in a subject, or the improvement of a subject's condition. Amelioration includes, but does not require, complete recovery or complete prevention of a disease, disorder or condition (e.g., radiation injury).

[0073] Biological activity, as used herein, refers to an observable biological effect or result achieved by an agent or entity of interest. For example, in some embodiments, a particular binding interaction is a biological activity. In some embodiments, modulation (e.g., induction, enhancement, or inhibition) of a biological pathway or event is a biological activity. In some embodiments, the presence or extent of a biological activity is assessed by detection of a direct or indirect product produced by the biological pathway or event of interest.

[0074] Cancer: The terms "cancer," "malignant," "neoplasm," "tumor," and "cancer" are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, such as to exhibit an abnormal growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, a tumor may be or include cells that are pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. The present disclosure specifically identifies certain cancers to which its teachings may be particularly relevant. In some embodiments, the relevant cancers may be characterized as solid tumors. In some embodiments, the relevant cancers may be characterized as hematological tumors. In general, examples of different types of cancer known in the art include hematopoietic cancers including, for example, leukemia, lymphoma (Hodgkin's and non-Hodgkin's), myeloma and myeloproliferative disorders; sarcoma, melanoma, adenoma, cancer of solid tissues, squamous cell carcinoma of the mouth, throat, larynx and lung, liver cancer, genitourinary cancers such as prostate, cervix, bladder, uterus and endometrial cancer as well as renal cell carcinoma, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancers of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the head and neck, breast cancer, gastrointestinal cancer and cancer of the nervous system, benign lesions such as benign lesions of papillomas, etc.

[0075] Carrier, as used herein, refers to an excipient, adjuvant, additive, or vehicle with which the composition is administered. In some exemplary embodiments, the carrier can include sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, the carrier is or includes one or more solid components.

[0076] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, sets of conditions, etc. that may not be identical to each other, but are sufficiently similar to allow a comparison between them so that a person skilled in the art can reasonably draw a conclusion based on the observed differences or similarities. In some embodiments, comparable sets of conditions, situations, individuals, or populations are characterized by multiple substantially identical characteristics and one or a few different characteristics. Those skilled in the art will understand what degree of identity is required in any given situation for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable in context. For example, those skilled in the art will understand that sets of conditions, individuals, or populations can be compared to each other when they are characterized by a sufficient number and type of substantially identical characteristics to ensure a valid conclusion that differences in results obtained or phenomena observed under or with different sets of conditions, individuals, or populations are caused by or indicate variations in the varying characteristics.

[0077] Composition: Those skilled in the art will appreciate that the term "composition" can be used to mean a separate physical entity that includes one or more specified components. In general, unless otherwise specified, a composition can be of any form, e.g., gas, gel, liquid, solid, etc.

[0078] Comprising: A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named element or step is essential, but other elements or steps can be added within the composition or method. To avoid redundancy, it is still understood that any composition or method described as "comprising" (or "comprises") one or more named elements or steps "consists of essentially the same named elements or steps" (or "consists of essentially the same named elements or steps) also describes a corresponding, more limited composition or method, meaning that the composition or method includes the named essential elements or steps, and can still include additional elements or steps that do not materially affect the basic and novel characteristics of the composition or method. It is understood that any composition or method described herein "comprising" one or more named elements or steps or "consisting essentially of" the named elements or steps, to the exclusion of any other unnamed elements or steps, It is also understood that "of"), corresponding, more limited, and close-ended compositions or methods are also described. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step can be substituted for that element or step.

[0079] Determining: Many methodologies described herein include a "determining" step. Those skilled in the art will understand upon reading this specification that such "determining" can be utilized or accomplished by use of any of a variety of techniques available to those skilled in the art, including, for example, the specific techniques explicitly referenced herein. In some embodiments, determining involves manipulation of the sample. In some embodiments, determining involves consideration and / or manipulation of data or information, for example, using a computer or other processing unit adapted to perform the relevant analysis. In some embodiments, determining involves receiving relevant information and / or material obtained from an information source. In some embodiments, determining involves comparing one or more characteristics of the sample or entity with a comparable reference.

[0080] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term "dosage form" can be used to mean a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Generally, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount of agent is the amount of the unit dosage form (or a whole fraction thereof) appropriate for administration according to a dosing regimen (i.e., according to a therapeutic dosing regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population. Those skilled in the art will appreciate that the total mass of a therapeutic composition or therapeutic agent to be administered to a particular subject is determined by one or more attending physicians and can include administration of multiple dosage forms.

[0081] Dosing regimen: Those skilled in the art understand that the term "dosing regimen" can be used to mean a set of unit doses (generally two or more) that are administered individually to a subject and are generally separated by a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may include one or more doses. In some embodiments, a dosing regimen includes multiple doses, each of which is separated by time from the other doses. In some embodiments, the individual doses are separated from each other by periods of equal length; in some embodiments, a dosing regimen includes multiple doses and at least two different periods that separate the individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen includes a first dose in a first dose, followed by one or more additional doses in a second dose that is different from the first dose. In some embodiments, the dosing regimen includes a first dosage in a first dosage amount, followed by one or more additional dosages in a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0082] Excipient: as used herein means a non-therapeutic agent that can be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0083] Improve, increase, inhibit, or reduce: As used herein, these terms, or grammatically comparable comparative terms, refer to values ​​that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved by an agent of interest can be "improved" relative to that obtained with a comparable reference agent. Alternatively, or in addition, in some embodiments, an assessed value achieved in a subject or system of interest can be "improved" relative to that obtained in the same subject or system under different conditions (e.g., before or after an event, e.g., before or after administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system different from the subject or system of interest, in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or prior exposure to a condition or agent, etc.). In some embodiments, a comparative term refers to a statistically relevant difference (e.g., which is of sufficient prevalence and / or magnitude to reach statistical relevance). Those skilled in the art will know, or will be readily able to determine, in a given context, the degree and / or prevalence of difference that is necessary or sufficient to reach such statistical significance.

[0084] In vitro: As used herein, the term "in vitro" refers to events that occur in an artificial environment, e.g., in a test tube or reactor, in cell culture, rather than within a multicellular organism.

[0085] In vivo: As used herein, refers to events that occur within multicellular organisms, e.g., humans and non-human animals. In the context of cell-based systems, the term can be used to refer to events that occur within living cells (e.g., as opposed to in vitro systems).

[0086] Isolated: As used herein, refers to a substance and / or entity that is (1) separated from at least some of the components with which it is associated when initially produced (in nature and / or in an experimental setting), and / or (2) designed, produced, prepared, and / or manufactured by the hand of man. In some embodiments, an isolated agent is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components.

[0087] Isomers: As is known in the art, many chemical entities (particularly many organic molecules and / or many small molecules) can exist in various structural (e.g., geometric / conformational) and / or optical isomeric forms. For example, any asymmetric center can exist in R and S configurations; double bonds can exist in Z and E conformational isomers; some structural elements can take on two or more tautomeric forms, etc. In some embodiments, as will be clear to one of skill in the art from the context, depictions or references to structures of certain compounds herein can represent all of their structural and / or optical isomers. In some embodiments, as will be clear to one of skill in the art from the context, depictions or references to structures of certain compounds herein are intended to encompass only the isomeric form depicted or referenced. In some embodiments, compositions including chemical entities that can exist in various isomeric forms include multiple such forms; in some embodiments, such compositions include only a single form. For example, in some embodiments, compositions that include chemical entities that can exist as various optical isomers (e.g., stereoisomers, diastereomers, etc.) include a racemic population of such optical isomers; in some embodiments, such compositions include only a single optical isomer and / or include multiple optical isomers that together retain optical activity. When more than one isomer is present in a composition, they may be present as a mixture in various ratios.

[0088] Mixtures: The phrase "mixtures" describes a combination of two or more different compounds or agents that occur in the same composition.

[0089] Moiety: Those of skill in the art will understand that a "moiety," as described herein, is a defined chemical group or entity that has a particular structure and / or activity.

[0090] Oral: As used herein, the phrases "oral administration" and "administered orally" have their art-understood meaning referring to administration of a compound or composition by mouth.

[0091] Parenteral: As used herein, the phrases "parenteral administration" and "administered parenterally" have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0092] Patient: As used herein, the term "patient" refers to any organism to which a provided composition is or can be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Representative patients include animals (e.g., mammals, e.g., mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, the patient exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed with one or more disorders or conditions. In some embodiments, the disorder or condition is or includes cancer, or the presence of one or more tumors. In some embodiments, the patient is undergoing or has undergone some therapy to treat and / or be diagnosed with a disease, disorder, or condition.

[0093] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharma- ceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a therapeutic regimen that exhibits a statistically significant probability of achieving an intended therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, including for oral administration, e.g., as liquids (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., as sterile solutions or suspensions, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, or in sustained release formulations; topical application, e.g., as creams, ointments, or controlled release patches or sprays applied to the skin, lungs, or buccal cavity; vaginally or rectally, e.g., as pessaries, creams, or foams; sublingually; ocularly; transdermally; or intranasally, in solid or liquid form, including those compatible with the lungs and other mucosal surfaces.

[0094] Pharmaceutically acceptable: As used herein, the phrase "pharmacologically acceptable" means compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response and other problems or complications with a reasonable benefit / risk ratio.

[0095] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutical acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, excipient, additive, or solvent encapsulating material, that carries or transports a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0096] Predestined: Predestined means deliberately selected, as opposed to, for example, occurring or being achieved randomly.

[0097] Prevent or prophylaxis: As used herein in relation to the occurrence of a disease, disorder, and / or condition means reducing the risk of developing a disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of a disease, disorder, or condition. Prevention may be considered complete if the onset of a disease, disorder, or condition is delayed for a predefined period of time.

[0098] Predominantly Present: As used herein, the term "predominantly present" refers to the amount of substance of an entity (e.g., a particular cannabinoid or isomer thereof) in a formulation or composition. For example, a cannabinoid may be predominantly present if it is at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% of the total cannabinoids in the formulation or composition.

[0099] Prevention: As used herein, the term "prevention" refers to delaying the onset of one or more symptoms of a particular disease, disorder, or condition, and / or reducing their frequency and / or severity. In some embodiments, prevention is assessed on a population basis, such that an agent is considered to "prevent" a particular disease, disorder, or condition if a statistically significant reduction in the occurrence, frequency, and / or intensity of one or more symptoms of the disease, disorder, or condition is observed in a population susceptible to the disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition is delayed for a predefined period of time.

[0100] Pure: As used herein, an agent or entity is "pure" if it is substantially free of other components. For example, a formulation that contains greater than about 90% of a particular agent or entity is generally considered to be a pure formulation. In some embodiments, the agent or entity is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.

[0101] Reference: As used herein, describes a standard or control relative to which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference composition may include one or more synthetic cannabinoids. In some embodiments, the reference composition may contain a different type of cannabinoid, a different isomeric form of cannabinoid, a different distribution of cannabinoids, a different content of cannabinoids, etc., compared to the test composition. In some embodiments, the reference or control is tested and / or determined substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a proven reference or control, optionally embodied in a tangible medium. Generally, as should be understood by one of skill in the art, a reference or control is determined or characterized by what is being evaluated under comparable conditions or circumstances. One of skill in the art will understand when sufficient similarity exists to justify the reliability of and / or comparison to a particular possible reference or control.

[0102] Response: As used herein, response to a treatment may refer to any beneficial change in the condition of a subject that occurs as a result of or correlates with the treatment. Such changes may include stabilization of the condition (e.g., prevention of deterioration that would occur in the absence of treatment), amelioration of symptoms of the condition, and / or improved likelihood of cure of the condition. Response may be measured according to a wide range of criteria, including clinical and objective criteria. Techniques for assessing response include, but are not limited to, clinical examination, positron emission tomography, chest X-ray CT scan, MRI, ultrasound, endoscopy, laparoscopy, the presence or level of tumor markers in samples obtained from the subject, cytology, and / or histology. The exact response criteria may be selected in any suitable manner, and it is noted that when comparing groups of cells or subjects, the groups to be compared are evaluated based on the same or comparable criteria for determining response rates. Those skilled in the art are able to select the appropriate criteria.

[0103] Solid Forms: As is known in the art, many chemical entities (particularly many organic molecules and / or many small molecules) can adopt a variety of different solid forms, e.g., amorphous forms and / or crystalline forms (e.g., polymorphs, hydrates, solvates, etc.). In some embodiments, such entities are available as a single such form (e.g., as a pure preparation of a single polymorph). In some embodiments, such entities are available as a mixture of such forms.

[0104] Subject: As used herein, the term "subject" refers to an organism, generally a mammal (e.g., a human, in some embodiments, including prenatal human forms). In some embodiments, subject refers to any organism (e.g., mammals, e.g., mice, rats, rabbits, non-human primates, and humans; insects; worms, etc.) and plants to which a provided compound or composition is administered in accordance with the present disclosure, e.g., for experimental, diagnostic, preventative, and / or therapeutic purposes. In some embodiments, the subject is afflicted with the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is one who has one or more distinctive characteristics of susceptibility or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or to whom a diagnosis and / or therapy is administered.

[0105] Substantially: As used herein, the term "substantially" refers to the qualitative condition of exhibiting a complete or nearly complete extent or degree of a desired characteristic or property. Those skilled in the art of biology understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or completeness or reach or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0106] Suffering from: An individual "suffering from" a disease, disorder, and / or condition has been diagnosed with and / or exhibits one or more symptoms of the disease, disorder, and / or condition.

[0107] Susceptible to: An individual who is "susceptible to" a disease, disorder, and / or condition is an individual who is at a higher risk of developing the disease, disorder, and / or condition than members of the general community. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition develops the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition does not develop the disease, disorder, and / or condition.

[0108] Symptoms are alleviated: In accordance with the present invention, "symptoms are alleviated" when one or more symptoms of a particular disease, disorder, or condition are reduced in magnitude (e.g., intensity, severity, etc.) and / or frequency. For purposes of clarity, delaying the onset of a particular symptom is considered one form of reducing the frequency of that symptom.

[0109] Systemic: As used herein, the terms "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" have their art-recognized meanings referring to the administration of a compound or composition so that it enters the system of the recipient.

[0110] Therapeutic Agent: As used herein, the phrase "therapeutic agent" generally refers to any agent that induces a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be therapeutic if a statistically significant effect is demonstrated across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, the appropriate population may be defined by various criteria, such as an age group, sex, genetic background, pre-existing clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a "therapeutic agent" is an agent that has been approved or requires approval by a government agency before it can be sold for administration to humans. In some embodiments, a "therapeutic agent" is a drug for which a prescription is required for administration to a human.

[0111] Therapeutic regimen: "Therapeutic regimen," as that term is used herein, means a dosing regimen whose administration across a relevant population can be correlated with a desired or beneficial therapeutic outcome.

[0112] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, active ingredient, formulation, composition, and / or combination) that, when administered as part of a treatment regimen, induces a desired effect (e.g., a desired biological, clinical, or pharmacological effect or response). In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, reduce the severity of, stabilize one or more characteristics of, and / or delay the onset of, a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition. In some embodiments, the term refers to an amount sufficient to effect at least a significant percentage (e.g., at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) of a population suffering from and / or susceptible to a disease, disorder, and / or condition. As will be appreciated by one of skill in the art, an effective amount of a substance can vary depending on such factors as the desired biological endpoint, the substance delivered, the target cells or tissues, etc. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that relieves, ameliorates, reduces, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of, one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0113] Treat: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of, one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, treatment refers to the administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays the onset of, reduces the severity of, and reduces the incidence of. In some embodiments, treatment can be administered to a subject who does not show signs of a disease, disorder, and / or condition. In some embodiments, treatment can be administered to a subject who shows only early signs of a disease, disorder, and / or condition, for example, to reduce the risk of developing pathology associated with the disease, disorder, and / or condition.

[0114] Unit dose: As used herein, the term "unit dose" refers to an amount administered as a single dose of a pharmaceutical composition and / or in a physically separate unit of a pharmaceutical composition. In many embodiments, a unit dose contains a predetermined amount of an effective agent. In some embodiments, a unit dose contains an entire single dose of an agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, administration of multiple unit doses is required or expected to be required to achieve a desired effect. A unit dose can be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined amount of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, and the like. It is understood that a unit dose can be in a formulation that includes any of a variety of components in addition to a therapeutic agent. For example, acceptable carriers (e.g., pharma- ceutically acceptable carriers), excipients, stabilizers, buffers, preservatives, and the like can be included, as described below. In many embodiments, it is understood by those skilled in the art that the appropriate total daily dosage of a particular therapeutic agent may include a portion or a plurality of unit doses, and may be determined, for example, by the attending physician within the scope of sound medical judgment. In some embodiments, the specific effective dosage level for any particular subject or organism may depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active compound used; the particular composition used; the age, weight, general health, sex and diet of the subject; the time of administration and rate of excretion of the particular active compound used; the duration of treatment; drugs and / or additional therapies used in combination with or simultaneously with the particular compound used, as well as factors well known in the medical field.

[0115] Detailed Description Cannabinoids are natural and synthetic compounds structurally or pharmacologically related to constituents of the Cannabis plant or endogenous agonists of the cannabinoid receptors CB1 or CB2 (endocannabinoids). Virtually the only way these compounds are produced is by the Cannabis plant. Cannabis is a genus of flowering plants in the Cannabaceae family that includes the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis (sometimes considered part of Cannabis sativa).

[0116] The Cannabis plant contains a highly complex mixture of compounds. At least 568 unique molecules have been identified. Among these compounds are cannabinoids, terpenoids, sugars, fatty acids, flavonoids, other hydrocarbons, nitrogenous compounds, and amino acids.

[0117] Cannabinoids exert their physiological effects through various receptors, including but not limited to adrenergic receptors, cannabinoid receptors (CB1 and CB2), GPR55, GPR3, or GPR5. The main cannabinoids present in Cannabis plants are the cannabinoid acids tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), with small amounts of their respective neutral (decarboxylated) cannabinoids. Additionally, Cannabis may contain lower levels of other cannabinoids in trace amounts. "Chemical composition, pharmacological profiling, and complete physiological effects of these medicinal plants, and more importantly the extracts from cannabis, remain to be fully understood." Lewis, MM, et al., ACS Omega, vol. 2, 6091-6103 (2017). Figure 1 shows an exemplary schematic diagram of the biosynthetic pathways of some phytocannabinoids.

[0118] Crude extracts obtained from cannabis plants containing CBD are used by patients suffering from diseases and disorders.However, such crude products are not suitable for use in pharmaceutical formulations.Their search for preparing more consistent CBD preparations for use in treating diseases or disorders has led to concerted efforts to prepare CBD synthetically or to remove all compounds obtained from plant-derived cannabinoids other than CBD, particularly psychoactive compounds such as THC.

[0119] The present invention encompasses the surprising discovery that botanically derived, purified CBD preparations suitable for medicinal use, containing one or more additional cannabinoids, exhibit enhanced therapeutic efficacy compared to previous CBD preparations distinct from the compositions disclosed herein.

[0120] These preparations are further distinct from purified or unpurified plant extracts, which are free of other impurities or are synthetically produced and therefore free of additional cannabinoids that would be produced by nature, and which contain some or all of the cannabinoids and non-cannabinoid compounds that are co-produced by the plant and co-extracted in this preparation of the extract. In some embodiments, the botanically derived purified CBD preparations of the present invention can be administered at lower dosages of CBD than synthetic or completely pure preparations of CBD.

[0121] Cannabinoids As noted, cannabinoids are a class of compounds that can be naturally derived from the Cannabis plant or can be synthetically produced by chemical synthesis.

[0122] Over 100 different cannabinoids produced by the Cannabis genus have been identified. These cannabinoids can be divided into different groups: phytocannabinoids, endocannabinoids and synthetic cannabinoids (which may be novel cannabinoids, phytocannabinoids or synthetically produced versions of endocannabinoids).

[0123] Phytocannabinoids are cannabinoids that occur naturally and can be found in the Cannabis plant. Phytocannabinoids can be isolated from plants to produce highly purified extracts. Phytocannabinoids can be obtained as neutral (decarboxylated form) or carboxylic acid forms, depending on the method used to extract the cannabinoids from plant material. For example, it is known that heating the carboxylic acid form decarboxylates most of the carboxylic acid form to a neutral form. Phytocannabinoids can only be produced from plants, but versions of phytocannabinoids can be produced synthetically, by chemical synthesis.

[0124] Endocannabinoids are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins expressed throughout the mammalian central and peripheral nervous systems (including the brain). The endocannabinoid system regulates various physiological and cognitive processes, including appetite, pain sensation, mood, and memory during fertility, pregnancy, prenatal and postnatal development, and is involved in mediating the pharmacological effects of the Cannabis genus.

[0125] "Synthetic cannabinoids" are compounds with cannabinoid-like structures that are not derived from plants but are produced using chemical means.

[0126] Some cannabinoids are described in more detail below. Although little is known about these cannabinoids, the CBD formulations and compositions described herein that include one or more of these components exhibit surprising efficacy, especially when compared to pure and / or synthetic CBD compositions.

[0127] Cannabidiol (CBD) CBD is the major cannabinoid constituent of Cannabis species, such as the hemp plant (Cannabis sativa). Unlike other cannabinoids, such as THC, CBD does not bind to CB1 or CB2, or its binding to the receptors is negligible with respect to inducing pharmacological effects. Thus, CBD does not cause central or peripheral nervous system effects mediated by CB1 or CB2 receptors. CBD has little or no psychotropic (cannabis-like) activity, and its molecular structure and properties are substantially different from those of other cannabinoids.

[0128] CBD administration is the subject of research in an attempt to provide alternative treatments for various diseases and disorders that may respond to such treatment.

[0129] In some embodiments, CBD is isolated from a Cannabis plant. In some embodiments, CBD is synthetically prepared. In some embodiments, CBD is present as (-)-trans-CBD.

[0130] Tetrahydrocannabinol (THC) THC is the primary psychoactive constituent of the Cannabis genus.

[0131] The THC molecule can exist in four different chiral forms, as shown in Figure 2. THC has two stereocenters, which allows for the existence of four stereoisomers: (+)-trans-THC; (-)-trans-THC; (+)-cis-THC and (-)-cis-THC. THC commonly occurs naturally as the (-)-trans-THC isomer (Hollister, 1970).

[0132] The THC molecule is (-)-trans-Δ 9 -tetrahydrocannabinol, however, (-)-trans-Δ 8 It is known that Δ-tetrahydrocannabinol homologues also exist. Those skilled in the art will recognize that reference to the compound THC is a Δ 8 or Δ 9 It is understood that homologs may be meant.

[0133] In some embodiments, THC is isolated from a Cannabis plant. In some embodiments, THC is synthetically prepared. In some embodiments, THC is present as (-)-trans-THC. In some embodiments, THC is present as (-)-cis-THC. In some embodiments, THC is present as (+)-trans-THC. In some embodiments, THC is present as (+)-cis-THC.

[0134] In some embodiments, THC is present as a mixture of isomers, hi some embodiments, the mixture includes one or more of (+)-trans-THC, (-)-trans-THC, (+)-cis-THC, and (-)-cis-THC.

[0135] Cannabidivarin (CBDV) CBDV is a homolog of CBD with a side chain shortened by two methylene bridges. In some embodiments, CBDV is isolated from a Cannabis plant. In some embodiments, CBDV is synthetically prepared. In some embodiments, CBDV is present as (-)-trans-CBDV.

[0136] Cannabidiol-C1 (CBD-C1) In some embodiments, CBD-C1 is isolated from a Cannabis plant. In some embodiments, CBD-C1 is synthetically prepared. In some embodiments, CBD-C1 is present as (-)-trans-CBD-C1.

[0137] Cannabidiol-C4 (CBD-C4) In some embodiments, CBD-C4 is isolated from a Cannabis plant. In some embodiments, CBD-C4 is synthetically prepared. In some embodiments, CBD-C4 is present as (-)-trans-CBD-C4.

[0138] CBD formulations The present disclosure provides several CBD formulations characterized by chemical constituents and / or functional properties that distinguish them from previous CBD compositions.

[0139] In some embodiments, the CBD formulations contain about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of other components with which they are initially associated. Preferably, the CBD formulations contain at least 98% CBD, based on the total mass of the cannabinoids in the formulation.

[0140] In some embodiments, the CBD comprises the (-)-trans-CBD isoform.

[0141] In some embodiments, the CBD formulation further comprises tetrahydrocannabinol (THC). In some embodiments, the CBD formulation comprises about 1%, about 2%, about 3%, about 4%, or up to about 5% THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the CBD formulation comprises 0.15% or less THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the CBD formulation comprises about 0.01% to about 0.1% THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the CBD formulation comprises about 0.02% to about 0.05% THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the CBD formulation comprises at least about 0.1% THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the CBD formulation comprises at least about 0.02% THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the THC is at least about 0.02% THC based on the total mass of the cannabinoids in the formulation. In some embodiments, the THC is at least about 0.02% THC based on the total mass of the cannabinoids in the formulation. 9 -Contains THC.

[0142] In some embodiments, THC is present as a mixture of different isomers. In some embodiments, THC includes trans-THC and cis-THC. In some embodiments, trans-THC and cis-THC are present in a ratio of about 5:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 3.5:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 2:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 1:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 0.8:1 (trans-THC:cis-THC).

[0143] In some embodiments, cis-THC is present as a mixture of (-)-cis-THC and (+)-cis-THC. In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 20:1 to 1:20 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 15:1 to 1:15 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 10:1 to 1:10 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 9:1 to 1:9 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 5:1 to 1:5 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 3:1 to 1:3 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 2:1 to 1:2 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 1:1 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 9:1 ((-)-cis-THC:(+)-cis-THC).

[0144] In some embodiments, the CBD formulation comprises one or more cannabinoids other than THC. In some embodiments, the CBD formulation comprises 2% or less of cannabinoids other than CBD, based on the total weight of the cannabinoids in the formulation.

[0145] In some embodiments, the CBD formulation comprises cannabidivarin (CBDV). In some embodiments, the CBDV comprises the (-)-trans-CBDV isoform. In some embodiments, the CBD formulation comprises about 0.2% to about 0.8% CBDV, based on the total mass of cannabinoids in the formulation.

[0146] In some embodiments, the CBD formulation comprises CBD-C4 (CBD-C4). In some embodiments, the CBD-C4 comprises the (-)-trans-CBD-C4 isoform. In some embodiments, the CBD formulation comprises about 0.3% to about 0.4% CBD-C4, based on the total mass of the cannabinoids in the formulation.

[0147] In some embodiments, the CBD formulation comprises CBD-C1 (CBD-C1). In some embodiments, the CBD-C1 comprises the (-)-trans-CBD-C1 isoform. In some embodiments, the CBD formulation comprises about 0.1% to about 0.15% CBD-C1, based on the total mass of cannabinoids in the formulation.

[0148] In some embodiments, at least a portion of at least one of the cannabinoids present in the CBD formulation is isolated from a Cannabis plant material. In some embodiments, at least a portion of the CBD present in the CBD formulation is isolated from a Cannabis plant material. In some embodiments, at least a portion of the THC present in the CBD formulation is isolated from a Cannabis plant material. In some embodiments, substantially all of at least one of the cannabinoids present in the CBD formulation is isolated from a Cannabis plant material. In some embodiments, substantially all of the CBD present in the CBD formulation is isolated from a Cannabis plant material. In some embodiments, substantially all of the THC present in the CBD formulation is isolated from a Cannabis plant material. In some embodiments, substantially all of the cannabinoids present in the CBD formulation are isolated from a Cannabis plant material. In some embodiments, the Cannabis plant material is obtained from a Cannabis sativa, Cannabis indica, or Cannabis ruderalis plant. In some embodiments, the Cannabis plant is a high-CBD Cannabis species. In some embodiments, the Cannabis plant is a high-CBD Cannabis species of Cannabis sativa L. In some embodiments, the Cannabis plant material comprises about 5% to about 20% CBD, based on the total weight of the cannabinoids in the formulation. In some embodiments, the Cannabis plant material comprises about 10% to about 15% CBD, based on the total weight of the cannabinoids in the formulation. In some embodiments, the Cannabis plant material comprises trans-THC and cis-THC, present in a ratio of about 3.5:1 (trans-THC:cis-THC). In some embodiments, the Cannabis plant material comprises trans-THC and cis-THC, present in a ratio of about 0.8:1 (trans-THC:cis-THC).

[0149] How to Make a CBD Preparation In the context of this specification, a "botanical drug substance" is an extract derived from Cannabis plant material which meets the definition of a "botanical drug substance" as set forth in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research: "A drug substance derived from one or more plants, algae, or macroscopic fungi. It is prepared from botanical raw materials by one or more of the following processes: pulverization, decoction, expression, aqueous extraction, ethanolic extraction, or other similar processes."

[0150] "Plant material" is defined as plants or plant materials (e.g., bark, wood, leaves, stems, roots, flowers, fruits, seeds, berries, or parts thereof) and exudates, and includes materials that fall within the definition of "botanical raw materials" in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research.

[0151] The method of the present invention can be used to extract cannabinoids from certain specific and defined plant materials known to contain such cannabinoids. Most commonly, but not necessarily, the "plant material" is a "plant material" or "botanical raw material" derived from one or more Cannabis plants. Most commonly, but not necessarily, the one or more Cannabis plants are certain specific and defined Cannabis plants cultivated to produce high yields of CBD.

[0152] The term "Cannabis plant" also encompasses wild-type Cannabis sativa and varieties thereof, including Cannabis chemovarietals that naturally contain different amounts of individual cannabinoids, Cannabis sativa plants being the result of genetic crossing, self-crossing, or hybrids thereof. Thus, the term "Cannabis plant material" should be construed to encompass plant material derived from one or more Cannabis plants. For the avoidance of doubt, this is hereby indicated to include dried Cannabis biomass. In some embodiments, at least a portion of the cannabinoid acids in such Cannabis plant material are decarboxylated.

[0153] Cannabis plant The present invention utilizes Cannabis plants and subspecies cultivated to have a specified, predetermined cannabinoid profile and content. In some embodiments, the cannabinoid can be CBD, THC, CBDA, CBDV, CBD-C1, or CBD-C4. In some embodiments, the Cannabis plant has a specified, predetermined terpene profile and content. In some embodiments, the Cannabis plant has a specified, predetermined sesquiterpene profile and content. In some embodiments, the Cannabis plant is a Cannabis sativa, Cannabis indica, or Cannabis ruderalis plant.

[0154] Cannabis cultivation In some embodiments, the Cannabis plant is propagated from cuttings taken from a mother plant. In some embodiments, the mother plant is produced from a single seed source. In some embodiments, the crop is produced by asexual propagation. In some embodiments, all of the plants in the crop are all female. In some embodiments, propagation with cuttings controls genotype consistency.

[0155] In some embodiments, the growth cycle is about 12 weeks. In some embodiments, through controlled growing conditions, the Cannabis plants take about 12 weeks to mature. In some embodiments, the Cannabis plants are watered with potable water throughout their growth cycle. In some embodiments, no synthetic herbicides or pesticides are used in the cultivation of the Cannabis plants. In some embodiments, strict sanitation conditions can be used to reduce pest infestation and disease, especially in the absence of herbicides or pesticides. In some embodiments, control of growth conditions to reduce or eliminate environmental stresses is used to optimize plant material yield, cannabinoid content, and / or control disease. In some embodiments, environmental stresses can include drought, insufficient sunlight, improper timing of the photoperiod, and unfavorable temperatures. Additionally, regular inspection of the plants during the growth cycle allows for the detection of any defective plants and pests. Although weeds should not be present due to the controlled growing conditions and medium, defective male plants can occur. Frequent inspections and biological control methods can be used to manage any possible pests and diseases.

[0156] In some embodiments, by controlling strict growth conditions, the Cannabis plant matures in approximately 12 weeks. In some embodiments, during the final growing week, dense resinous flowers develop. In some embodiments, by the end of approximately 11 weeks, cannabinoid biosynthesis is significantly slower and the plant is ready to be harvested.

[0157] Harvesting and processing of Cannabis In some embodiments, the whole plant is cut and dried in a temperature and / or humidity controlled environment. In some embodiments, the temperature is about 21° C. In some embodiments, the humidity is about 38-45% RH.

[0158] THC and CBD are the main bioactive constituents in BDS. However, these constituents are present as the carboxylic acids THCA and CBDA in BRM. The acid forms slowly decarboxylate over time during drying. Leaves and flowers are stripped from the larger stems to provide the botanical raw material (BRM). Under conditions of storage, losses during drying balance out at approximately 10%. Storage conditions for dried BRM depend on the physical state of the BRM. In some embodiments, the BRM is stored protected from light. In some embodiments, the BRM is stored at about 15-25°C. In some embodiments, the BRM is stored at about -20°C. In some embodiments, the BRM is stored at about 20°C. In some embodiments, the BRM is stored at about 38-42% RH.

[0159] Summary of exemplary production of BRM: Harvesting plants Drying (in the absence of light) Production of botanical raw materials (BRM) containing cannabinoid acids Grind to reduce particle size to less than 2000μm Decarboxylation of cannabinoid acids to their neutral forms (e.g., CBDA to CBD)

[0160] Exemplary BRM criteria derived from high CBD varieties are illustrated below in Table A.

[0161] [Table 1]

[0162] Characterization of CBD formulations - Visual Identification: Macroscopic characteristics allow the Cannabis plant to be differentiated from potential adulterants and substitutes. This is a visual identification against photographic standards.

[0163] - Identification by TLC: TLC effectively identifies Cannabis species using both retention values ​​of substance (Rf) and characteristic spot colors. Laboratory samples are prepared for TLC analysis by extracting the dried herb. Aliquots are spotted on the TLC plate in parallel with reference samples for THC and CBD. After exposure to Fast Blue B reagent, THC and THCA are present as pink spots, while CBD and CBDA are orange in color. Neutrals can be distinguished from acids by comparison of Rf values ​​with those obtained for the standards. Identity is confirmed by comparing the Rf and color of the sample spots with those obtained for the appropriate standards.

[0164] - Characterization by HPLC: HPLC effectively identifies Cannabis species using a comparison of cannabinoid retention times. The reversed-phase HPLC method is specific for CBD and CBDA and can therefore be used as an identity test. Biomass samples are extracted and centrifuged. Detection of all analytes is achieved at 220 nm with further confirmation of acidic analytes at 310 nm.

[0165] - Assay (CBD+CBDA): This assay can be used to monitor the CBD and CBDA content in the plant. The CBD and CBDA assays are determined using HPLC methods. The efficiency of the decarboxylation process can be determined by dividing the % w / w content of CBD by the total CBD+CBDA content.

[0166] - Foreign object: Foreign matter is assessed using the European Pharmacopoeia test method. Flowers, leaves and side stems are spread in a thin layer on a clean laboratory surface. Foreign matter is manually separated as completely as possible and weighed. Results are expressed as % foreign matter w / w in the herbaceous biomass sample. Foreign matter may comprise less than 2% of the biomass.

[0167] - Decarboxylation THC and CBD are the main bioactive compounds in the Cannabis genus. However, these compounds exist in the Cannabis plant as their respective carboxylic acids. To extract THC or CBD from Cannabis plant material, it is necessary to convert the storage precursor compounds of THCA and CBDA into their more easily extractable and pharmacologically active forms. THC and CBD acids naturally decarboxylate slowly over time. The traditional way to increase the rate of decarboxylation is by applying heat. However, THCA is not only converted to THC, but also to another cannabinoid, cannabinol (CBN).

[0168] A decarboxylation procedure is generally carried out within the present formulation of the starting material or botanical raw material (BRM) prior to the start of the extraction process.

[0169] - Example extraction process overview: BDS can be extracted from the decarboxylated BRM using liquid carbon dioxide methodology, which involves continuously passing liquefied carbon dioxide through the shredded biomass contained in a high pressure vessel. The crude extract is dissolved in ethanol, cooled to low temperatures, and then filtered to remove precipitated constituents such as waxes. Removal of the ethanol and water in a vacuum produces BDS containing high concentrations of CBD or THC, depending on the biomass used.

[0170] Additional methods for purifying and characterizing CBD preparations are disclosed and described in EP 2311475, the contents of which are incorporated herein by reference in their entirety.

[0171] Compositions and Formulations The CBD formulation can be formulated based on the intended mode of administration. For example, in some embodiments, administration can be ocular, oral, parenteral, topical, etc. In some embodiments, the CBD formulation can be formulated with one or more additives to enhance stability, increase shelf life, or enhance efficacy. In some embodiments, the CBD formulation is formulated for oral administration. In some embodiments, the CBD formulation includes sesame oil. In some embodiments, the CBD formulation includes ethanol. In some embodiments, the ethanol is absolute ethanol. In some embodiments, the CBD formulation includes a flavoring agent. In some embodiments, the flavoring agent can be a sweetener. In some embodiments, the sweetener can be an artificial sweetener, such as saccharin, acesulfame, aspartame, neotame, or sucralose. In some embodiments, the flavoring agent can be an artificial flavor. In some embodiments, the artificial flavor may be, for example, vanilla, lemon, orange, lime, grapefruit, yuzu, sudachi, apple, pear, peach, grape, blueberry, strawberry, raspberry, cherry, plum, Japanese plum, raisin, cola, guarana, neroli, pineapple, apricot, banana, melon, apricot, plum, cherry, raspberry, blackberry, tropical fruit, mango, mangosteen, pomegranate, papaya, combinations thereof, and the like.

[0172] The cannabinoid preparations disclosed herein can be formulated for administration according to methods known in the art.

[0173] use Diseases, Disorders, and Conditions The CBD formulations disclosed herein are useful for providing analgesia, neuroprotection, reducing inflammation, helping to alleviate nausea and vomiting, and treating epilepsy, anxiety, and glaucoma. Additionally, the CBD formulations disclosed herein are useful for providing symptomatic treatment or amelioration in patients suffering from neurological dysfunction or comorbidities associated with such disorders. In some embodiments, the CBD formulations disclosed herein are more effective in treating these disorders than previous CBD compositions. In some embodiments, the CBD formulations of the present invention can be administered at lower doses of CBD than synthetic CBD formulations containing the same or similar concentrations of CBD.

[0174] Pain is a common clinical problem faced by all clinicians. Millions of people in the United States suffer from severe pain that is chronically undertreated or inadequately managed according to numerous recent reports. Similarly, millions of people also suffer from severe nausea and / or frequent vomiting. Furthermore, many patients who suffer from chronic, undertreated or untraceable pain frequently suffer from lack of appetite, nausea and / or frequent vomiting. These patients present a greater clinical challenge because they are unable to receive effective administration of oral pain medications, thereby leaving the patient's pain unrelieved. Furthermore, the CBD formulations disclosed herein can reduce the patient's nausea and vomiting independent of any pain relief achieved. Thus, the disclosed CBD formulations are particularly useful in patients experiencing nausea and vomiting secondary to untreated or undertreated pain. In some embodiments, the CBD formulations disclosed herein are more effective at relieving pain than previous CBD compositions.

[0175] A notable percentage of the US population meets the diagnostic criteria for alcohol use disorders ("AUDs"). Consumption of excessive amounts of alcohol results in a variety of complex pharmacological effects that directly impact the ability to treat the condition. These effects include dependence that directly impacts the brain and leads to progressive neurodegeneration, executive dysfunction, and withdrawal-induced negative effects. The CBD formulations disclosed herein have neuroprotective, anxiolytic, and anticonvulsant effects that may be effective in preventing further brain damage in those with AUDs while at the same time reducing the frequency of relapse. In some embodiments, the CBD formulations disclosed herein are more effective than previous CBD compositions in treating these disorders.

[0176] Chronic cannabis addicts may become dependent and experience withdrawal symptoms when they attempt to stop using the drug. Taken together, cannabis dependence and withdrawal are referred to herein as cannabis use disorder. The CBD formulations disclosed herein are useful for treating cannabis use disorder. In some embodiments, the CBD formulations disclosed herein are more effective than previous CBD compositions in treating these disorders.

[0177] Dystonia is a neurological movement disorder with many known causes, characterized by involuntary, continuous muscle contractions that cause twisting and repetitive movements or abnormal postures. In some embodiments, the CBD formulations disclosed herein are useful for reducing the muscle contractions characteristic of this disorder. The CBD formulations disclosed herein are more effective in treating these disorders than previous CBD compositions.

[0178] The etiological pathology of many diseases is related to inflammatory processes regulated by the immune system of an individual. Inflammation can result in (1) an otherwise appropriate immune response to outside trauma, such as brain swelling secondary to closed head injury; (2) an overactive immune response, such as an allergic reaction or dermatitis; or (3) an inappropriate auto-immune response, such as multiple sclerosis, inflammatory bowel disorder, and some forms of arthritis. Regardless of the underlying cause of inflammation, it is therapeutically desirable in these situations to regulate the immune system and reduce the inflammatory response. The CBD formulations disclosed herein can regulate various steps in the immune response and may show some therapeutic benefits in the treatment of some inflammatory diseases, such as psoriatic arthritis. In some embodiments, the CBD formulations disclosed herein are more effective than previous CBD compositions in treating these disorders.

[0179] Rheumatoid arthritis affects approximately 0.5-1% of the US population, and autoimmune diseases in general affect over 20 million Americans. The pain associated with rheumatoid arthritis can often be disabling. Cannabinoids have been found to be useful as adjunctive treatments for joint pain secondary to rheumatoid arthritis and other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus. In some embodiments, the CBD formulations disclosed herein are more effective than previous CBD compositions in treating these disorders.

[0180] In addition to the therapeutic benefits discussed above, cannabinoids, such as CBD and CBD prodrugs, provide a variety of pharmacological benefits, including but not limited to anti-inflammatory, anticonvulsant, antipsychotic, antioxidant, neuroprotective, anticancer and immunomodulatory effects. The CBD formulations disclosed herein are more effective than previous CBD compositions in treating these disorders.

[0181] The present invention provides CBD formulations and compositions and uses for treating and / or preventing any of a variety of diseases, disorders, and / or conditions, including but not limited to those disclosed herein. In some embodiments, the present invention provides CBD formulations and compositions and uses for treating and / or preventing diseases, disorders, or conditions associated with neurological dysfunction or neuronal differentiation. In some embodiments, the diseases, disorders, or conditions associated with neurological dysfunction or neuronal differentiation are those in which neurogenesis is defective. Such diseases, disorders, or conditions are often related to the neuroplasticity of the brain and include, but are not limited to, seizure disorders, such as epilepsy. The seizure disorders are often associated with comorbid conditions, such as cognitive and psychiatric dysfunction, which may be due to the seizures themselves or to pharmaceuticals used to treat the seizures. Comorbid conditions known to occur in seizure disorders include, but are not limited to, the following: Musculoskeletal disorders, gastrointestinal and digestive disorders, respiratory disorders, chronic pain disorders, cerebrovascular accidents, migraines, neoplasia, arthritis / rheumatism, obesity, diabetes, infections, fractures, and allergies. Psychiatric conditions, such as depression, anxiety, autism spectrum disorders, interictal dysphoric disorder, interictal behavior syndrome, and psychosis of epilepsy. Cognitive conditions, such as cognitive impairment, language skills, socialization, attention deficit hyperactivity disorder, learning disabilities, mental retardation, and Alzheimer's disease / dementia.

[0182] In some embodiments, the disease or disorder is a seizure disorder. In some embodiments, the seizure disorder is epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, febrile infection-associated epilepsy syndrome (FIRES), Doze syndrome, Sturge-Weber syndrome, CDKL5 mutations; Aicardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasms (West syndrome); and Landau-Kleffner syndrome, refractory epilepsy, juvenile spasms, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis (TSC); neuroplastic storage disorder, neuronal ceroid lipofuscinosis (NCL), Batten disease, encephalopathy, atony, idiopathic, absence seizures, partial seizures, simple partial seizures, or complex partial seizures.

[0183] In some embodiments, the disease or disorder is a neurodegenerative disease; Alzheimer's disease; Parkinson's disease; essential tremor; amyotrophic lateral sclerosis (ALS); Huntington's disease; Friedreich's ataxia; multiple sclerosis; frontotemporal dementia; prion disease; Lewy body disease; progressive supranuclear palsy; vascular dementia; normal pressure hydrocephalus; traumatic spinal cord injury; HIV dementia; alcohol-induced neurotoxicity; Down's syndrome; movement disorders of the central and / or peripheral nervous system; motor neuron disease (MND); spinal muscular atrophy; or any other related neurological or psychiatric neurodegenerative disease. disease;brain injury;brain damage;brain dysfunction;dysgraphia;dysarthria;apraxia;agnosia;amnesia;dizziness;vertigo;coma;stroke;spinal cord injury;spinal cord injury;spinal cord disorder;central neuropathy;peripheral neuropathy;cranial nerve disorder;trigeminal neuralgia;tumor of the nervous system;brain or spinal cord infection;encephalitis;meningitis;prion disease;complex regional pain syndrome;autonomic nervous system disorder;autonomic neuropathy;autonomic dysbiosis;postural orthostatic tachycardia syndrome (POTS);neurocardiogenic syncope (NCS);multiple system atrophy (MSA);hereditary sensory autonomic neuropathy (HSAN);Ho Muz-Adie syndrome (HAS);Sleep disorders;Narcolepsy;Pain;Migraine;Cluster headaches;Tension headaches;Back pain;Lower back pain;Neck pain;Neuropathic pain;Cancer pain;Allodynia;Arthritis pain;Inflammatory pain;Neurological disorders;Attention deficit hyperactivity disorder;Autism;Tourette syndrome;Obsessive-compulsive disorder;Autism spectrum disorders;Rett syndrome;Fragile X syndrome;Angelman syndrome;Hyperactivity disorder;Tourette syndrome;Dystonia;Cancer;Brain cancer;Glioma;Breast cancer;Liver cancer;Lung cancer;Pancreatic cancer;Melanoma;Ovarian cancer;Gastric cancer;Kidney cancer;Bladder cancer;Addiction;Nicotine addiction;Smoking;Alcohol addiction;Drugs substance addiction; cannabis use disorder; psychiatric disorder; post-traumatic stress disorder; anxiety; early psychosis; schizophrenia; cognitive impairment; stroke; cardiac ischemia; coronary artery disease; thromboembolism; myocardial infarction; ischemia-related disease; gastrointestinal disorder; inflammatory bowel disease; Crohn's disease; ulcerative colitis; nausea; vomiting; emetic syndrome; motion sickness; chemotherapy-induced nausea and vomiting; inflammation; arthritis; rheumatoid arthritis; osteoarthritis; diabetes mellitus; hypertension; poor insulin control; appetite suppression; anorexia; neonatal hypoxic-ischemic encephalopathy (NHIE); degenerative skeletal muscle disease; or Duchenne muscular dystrophy (DMD).

[0184] Medication and Administration The exact regimen for administration of the compounds described herein may depend on the needs of the individual subject being treated, the type of treatment being administered, and / or the judgment of the attending medical professional. As used herein, the terms "subject" and "patient" include humans and animals. In some embodiments, the subject or patient is a human adult, a human adolescent, a human child, or a human infant. As will be appreciated by those skilled in the art, the dosage administered will depend on the condition being treated, the age, health, and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.

[0185] In some embodiments, the CBD formulation or pharmaceutical composition comprising CBD can be administered in a therapeutically effective amount. The therapeutically effective amount can be administered according to a dosing regimen comprising one or more unit doses. Generally, a therapeutically effective amount is sufficient to achieve a benefit in a subject (e.g., prevent, treat, regulate, cure, prevent and / or ameliorate a disease or disorder).

[0186] The therapeutically effective amount (and / or unit dosage) of a CBD formulation or pharmaceutical composition comprising it for any particular patient may depend on a variety of factors, including the disease or disorder being treated; the severity of the disease or disorder; the activity of a particular CBD formulation or pharmaceutical composition comprising it used; the age; weight; fitness; comorbidity status (e.g., other than the disease or disorder being treated); general health; sex; and diet of the patient; personal history; genetic characteristics; lifestyle parameters; the severity of the cardiac defect and / or the level of risk of cardiac defect; time of administration; route of administration; concomitant treatments or medications; and / or the rate of excretion or metabolism of a particular CBD formulation or pharmaceutical composition comprising it used; duration of treatment; combinations thereof; and other factors well known in the medical field. In view of the present disclosure, one skilled in the art can readily determine the appropriate dosage depending on these and other relevant factors. Furthermore, objective and subjective assays can be used in some cases to identify optimal dosage ranges. In some specific embodiments, appropriate doses or amounts to be administered can be estimated in light of the present disclosure from dose-response curves derived from in vitro or animal model test systems.

[0187] The present invention contemplates dosing regimens including single and multiple administrations of the CBD formulations or pharmaceutical compositions comprising the same described herein. The CBD formulations or pharmaceutical compositions comprising the same can be administered at regular intervals, depending on the nature, severity and extent of the subject's condition. In some embodiments, the CBD formulations or pharmaceutical compositions comprising the same can be administered periodically at regular intervals (e.g., once a year, once every six months, once every five months, once every three months, every two months (once a month), every other week (once a month), every week, daily, multiple times a day, or continuously).

[0188] The therapeutically effective amount can be administered according to a dosing regimen that can include multiple unit doses. For any particular CBD formulation or pharmaceutical composition containing it, the therapeutically effective amount (and / or the appropriate unit dose within an effective dosing regimen) can vary, for example, depending on the route of administration, combination with other pharmaceuticals.

[0189] In some embodiments, the CBD formulations described herein or pharmaceutical compositions comprising same can be administered as a single dose. In some embodiments, the CBD formulations described herein or pharmaceutical compositions comprising same can be administered at regular intervals. As used herein, administration at an "interval" indicates that a therapeutically effective amount is administered periodically (as distinguished from a single dose). The intervals can be determined by standard clinical techniques. In some embodiments, the CBD formulations described herein or pharmaceutical compositions comprising same can be administered bimonthly, monthly, twice monthly, every three weeks, every other week, weekly, twice weekly, three times weekly, daily, twice daily, every 6 hours, every 4 hours, every 2 hours, or every hour. The administration interval for a given individual does not have to be regular, but can vary over time depending on the needs of the individual.

[0190] In some embodiments, the CBD formulations described herein or pharmaceutical compositions comprising same are administered at regular intervals indefinitely. In some embodiments, the CBD formulations described herein or pharmaceutical compositions comprising same are administered at regular intervals for a defined period of time.

[0191] It is to be further understood that for any particular subject, a particular dosage regimen will need to be adjusted over time according to the individual needs, and that the professional judgment of the person administering or supervising the administration of enzyme replacement therapy, and the dosage ranges thereof set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed invention.

[0192] In some embodiments, the CBD formulation or pharmaceutical composition comprising the same is administered in one or more doses that provide about 0.1 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising the same is administered in one or more doses that provide about 0.5 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising the same is administered in one or more doses that provide about 1 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising the same is administered in one or more doses that provide about 5 mg / kg / day of CBD, e.g., for a 15 kg patient, 75 mg of CBD per day should be provided. In some embodiments, the CBD formulation or pharmaceutical composition comprising the same is administered in one or more doses that provide about 10 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising the same is administered in one or more doses that provide about 20 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising same is administered in one or more doses that provide about 25 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising same is administered in one or more doses that provide about 50 mg / kg / day of CBD. In some embodiments, the CBD formulation or pharmaceutical composition comprising same is administered in one or more doses that provide about 100 mg / kg / day of CBD.

[0193] In some embodiments, the CBD formulation or pharmaceutical composition comprising same is administered at a dosage of about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 1000 mg, about 1500 mg, or about 2000 mg of CBD.

[0194] In some embodiments, the CBD formulation or pharmaceutical composition comprising same can be administered as an adjunct to conventional therapy for a disease or disorder.

[0195] kit Some embodiments provide kits comprising a CBD formulation or a pharmaceutical composition comprising the same and instructions for use. In some embodiments, the kit further comprises a device (e.g., a spray, syringe, vaporizer, inhaler, patch, etc.) for administration of the CBD formulation or pharmaceutical composition comprising the same. EXAMPLES

[0196] Data demonstrating the physicochemical properties of purified CBD from botanical sources

[0197] Example 1: Exemplary methods for the production of botanically derived purified CBD preparations Methodology Overview The following describes the production of purified CBD (>98% w / w) of botanical origin, which has a known and consistent composition, that is used in the examples below.

[0198] Harvested plant material from Cannabis sativa L. plants was subjected to liquid carbon dioxide extraction to produce a botanical extract containing CBD in addition to other cannabinoids and non-cannabinoid constituents. The extract was then further purified by a solvent crystallization method to produce a purified CBD of botanical origin. The crystallization method specifically removed other cannabinoids and plant constituents to produce greater than 98% (w / w) CBD.

[0199] The botanical starting material and botanical extract can be controlled by standards. Exemplary botanical starting material standards for decarboxylated Cannabis plant material are listed in Table 1.1 below. In some embodiments, the isomer content for each cannabinoid can also be specified.

[0200] [Table 2]

[0201] Exemplary CBD formulations of botanically derived purified CBD are set forth below in Table 1.2. In some embodiments, the isomer content for each cannabinoid may also be specified.

[0202] [Table 3]

[0203] The purity of the botanical-derived purified CBD preparation was 98% or greater. The botanical-derived purified CBD contains THC as well as other cannabinoids such as CBDA, CBDV, CBD-C1, and CBD-C4.

[0204] Different chemical varieties of the Cannabis sativa L. plant have been produced to maximize the yield of certain chemical constituents, or cannabinoids. Some chemical varieties produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.

[0205] Production of CBD botanical drug substance The process for producing the plant extracts and intermediates is outlined below. a. growth b. Direct drying c. Decarboxylation d. Extraction using liquid CO2 e. Dewaxing with ethanol f. Filtration g. Evaporation

[0206] The high CBD chemical varieties were grown, harvested, dried, packaged, and stored in a dry room until required. The botanical raw materials (BRM) were finely chopped using an Apex mill fitted with a 1 mm sieve. The milled BRM was stored in a freezer prior to extraction.

[0207] Decarboxylation of CBDA to CBD was performed using heat: BRM was decarboxylated at 115°C for 60 minutes.

[0208] Extraction was performed using liquid CO2 to produce the botanical drug substance (BDS), which was then crystallized to produce the test material. The crude CBD BDS was winterized to purify the extract under standard conditions (2 volumes of ethanol at -20°C for approximately 50 hours). The precipitated wax was removed by filtration and the solvent was removed to produce the BDS.

[0209] Production of botanically derived, purified CBD preparations The manufacturing process for producing a botanically derived purified CBD preparation from BDS was as follows: a. C5~C 12 Crystallization with linear or branched alkanes b. Filtration c. Vacuum drying

[0210] The BDS generated using the above methodology was 12 The mixture was manually shaken to break up any clumps, and the sealed container was then placed in a freezer for approximately 48 hours. The crystals were isolated by vacuum filtration and cooled to C5-C. 12 The aliquots were washed with linear or branched alkanes and dried under a vacuum of <10mb at a temperature of 60°C until dry. The botanical-derived purified CBD preparations were stored in a freezer at -20°C in a pharmaceutical stainless steel container with an FDA food-approved silicone seal and clasp.

[0211] Example 2: Quantification of the stereochemistry of THC present in botanically derived purified CBD preparations As described above in Example 1, the cannabinoid THC is present in botanically derived, purified CBD preparations in an amount of 0.1% (w / w) or less, in some embodiments, THC is present in an amount of 0.02-0.1% w / w.

[0212] The THC molecule can exist in four different chiral forms, as shown in Figure 2. THC has two stereocenters, which allows for the existence of four stereoisomers: (+)-trans-THC; (-)-trans-THC; (+)-cis-THC and (-)-cis-THC. However, THC is known to occur naturally as the (-)-trans-THC isoform (Hollister, 1970).

[0213] The following example describes studies that were conducted to characterize the stereoisomers produced by high-CBD plants used to prepare the exemplary botanically-derived purified CBD formulations described in Example 1.

[0214] Detection and quantification of trace levels of THC in purified CBD of botanical origin Ultra-performance liquid chromatography (UPLC) was used to identify the major cannabinoids and trace levels of other cannabinoids. The presence of cannabinoids was confirmed by chromatographic comparison of standards and samples.

[0215] A pH adjusted, core-shell silica column was used in a UPLC system equipped with a Photo Diode Array or Tuneable UV detector and a QDa mass detector.

[0216] FIG. 3 demonstrates an exemplary chromatogram generated using a UPLC method to detect trace amounts of cannabinoids in a botanically-derived purified CBD preparation of the present invention.

[0217] As can be seen in Figure 3, there are peaks corresponding to the following cannabinoids: CBD-C1 has a relative retention time (RTT) of 1.937 min; CBDV has an RTT of 3.481 min; CBD-C4 has an RTT of 4.610 min; CBD has an RTT of 5.920 min; (±)-cis-THC has an RTT of 6.781 min and (±)-trans-THC has an RTT of 6.917 min.

[0218] The concentration of a compound present in a sample can be determined as % w / w using the following calculation:

[0219]

number

[0220] Since it is known that THC produced by THC plants is in the form of (-)-trans-THC, the presence of cis-THC in the exemplary botanically derived purified CBD preparation was surprising, and therefore the structure of cis-THC was elucidated.

[0221] Elucidating the structure of cis-THC The presence, isolation and identification of cis-THC was determined from botanical raw materials produced from high-CBD plants, resulting in the resulting botanically-derived purified CBD preparation described in Example 1.

[0222] Cis-THC was successfully isolated and purified from cannabidiol (CBD) botanical drug substance (BDS) using flash chromatography and preparative LCMS. The isolated material underwent extensive testing, including chromatographic and spectral techniques, in parallel with a synthetic cis-THC standard to identify the compound. It was also compared to its configurational isomer; trans-THC.

[0223] The identity of cis-THC was confirmed by four spectral and three chromatographic techniques. The spectra of the isolated plant material were compared to a synthetic sample, confirming the structure as cis-THC.

[0224] The identity of the botanically derived cis-THC was confirmed by the following techniques. · Determination of physical data and interpretation of molecular spectroscopy results including 1H-NMR, COSY-NMR, mass spectrometry and quadrupole time-of-flight. Comparison of the physical and spectral data of synthetically produced cis-THC with that of isolated plant material, which was further confirmed by comparison with the previously proposed structure of cis-THC from the literature.

[0225] FIG. 4 details the trace generated using mass spectrometry, which confirms the presence of cis-THC being isolated from the high-CBD plant material.

[0226] Example 3: Quantification of the ratio of trans-THC to cis-THC present in botanically derived purified CBD preparations As described in Example 1, the production of purified CBD preparations of botanical origin is a complex process involving several steps that result in different types of intermediate materials. First, high-CBD plants are harvested, dried, and baled to produce botanical raw material (BRM). The baled material is pelleted, extracted with liquid CO2, purified during a winterization process, and refined during a crystallization process. The CBD BRM starting material contains many different cannabinoid impurities that exist alongside the main compound CBD.

[0227] In this example, we sought to determine the ratio of trans-THC to cis-THC throughout the production process of a botanically derived purified CBD preparation.

[0228] The retention times of trans-THC and cis-THC are different using reversed-phase chromatography as shown in Figure 5. The polarities of these two compounds are slightly different, which results in closely eluting peaks in an isocratic method with baseline resolution.

[0229] The ratio of trans-THC to cis-THC was determined in samples obtained from materials at different phases of the process used to produce the botanically-derived purified CBD formulation described in Example 1.

[0230] The ratio of trans-THC to cis-THC changed throughout the process from decarboxylated CBD to botanically-derived purified CBD preparations, as shown in Table 3.1 below.

[0231] [Table 4]

[0232] As can be seen in Table 3.1 above, the ratio of trans-THC to cis-THC varies throughout the processing of purified CBD preparations of botanical origin. The botanical raw material after decarboxylation has a median ratio of 3.6:1 (trans-THC:cis-THC), and this ratio is smaller as it is processed with liquid carbon dioxide extracted material, which has a median ratio of 3.3:1 (trans-THC:cis-THC), and with material purified by winterization process, which has a median ratio of 3.2:1 (trans-THC:cis-THC). Finally, the C5-C 12 A further purification step of crystallization of the CBD material with linear or branched alkanes produces a median ratio of 0.8:1 (trans-THC:cis-THC).

[0233] The ratio of trans-THC to cis-THC at different processing stages was also plotted using Spearman rank correlation curves, which are detailed in Figure 6. A line was fitted to demonstrate the change in ratio during processing, with a very high confidence level. Such correlation demonstrates control over the processing stages of the botanically derived purified CBD preparation, with the retention of the cis-THC isomer favoring trans-THC.

[0234] As can be seen, botanically derived purified CBD preparations contain both trans-THC and cis-THC. The ratio of the two isomers in the final highly purified preparation is 0.8:1 (trans-THC:cis-THC).

[0235] Example 4: Quantification of the ratio of trans-THC to cis-THC present in crude CBD formulations Further testing was performed using CBD oil purchased from a CBD oil specialist to determine whether trans-THC and cis-THC were present in the crude CBD preparations and, if so, what the ratio of the two was.

[0236] Eight different crude CBD oil formulations were tested and all were found to contain a mixture of trans- and cis-THC. Table 4.1 below details the ratios found in these oils.

[0237] [Table 5]

[0238] As Table 4.1 demonstrates, the ratio of trans-THC to cis-THC varies within the different crude CBD oil formulations obtained from 2.3:1 to 4.4:1 (trans-THC:cis-THC), which are further removed from the botanically derived refined CBD material defined in the present invention.

[0239] Example 5: Quantification of the stereoisomeric forms of cis-THC present in botanically derived purified CBD preparations Example 3 demonstrates that botanically derived purified CBD preparations contain trans-THC and cis-THC in a median ratio of 0.8:1 (trans-THC and cis-THC). As described in Example 2 and Figure 2, the THC molecule has two stereocenters, which allows for the existence of four stereoisomers: (+)-trans-THC; (-)-trans-THC; (+)-cis-THC and (-)-cis-THC. This example sought to determine whether cis-THC exists as the (+)-cis-THC isomer, the (-)-cis-THC isomer, or a mixture of the two.

[0240] A chiral method using the principles of normal phase chromatography was developed which successfully separated (+)-cis-THC and (-)-cis-THC.

[0241] An amylose carbamate chiral column was used with a mobile phase using isocratic heptane with an ethanol modifier.

[0242] A cis-THC sample (98.2% pure by HPLC) was isolated from the purified CBD of botanical origin and run on the chiral method for chirality evaluation. The resulting traces are shown in FIG. 7. As shown in Trace C, the peaks present for (-)-cis-THC and (+)-cis-THC indicate that the cis-THC present in the purified CBD preparation of botanical origin is present as a mixture of both isomers.

[0243] The approximate ratio of (-)-cis-THC to (+)-cis-THC present, as determined by the area under the curve, was calculated to be 9:1. It is possible that a range of (-)-cis-THC to (+)-cis-THC ratios exists depending on the source and processing of the CBD material.

[0244] Example 6: Quantification of the composition of synthetically produced CBD Two different samples of synthetically produced CBD were obtained and run on HPLC to compare the composition of the synthetically derived CBD with that of purified CBD of botanical origin. Both preparations contained over 98% (w / w) CBD.

[0245] As can be seen in Figure 8, there are differences between CBD of synthetic origin and that of purified CBD of botanical origin: the purified CBD sample of botanical origin has peaks corresponding to CBD-C1, CBDV, CBD-C4, trans-THC and cis-THC, while the synthetically produced CBD does not contain these compounds.

[0246] Example 7: Autofluorescence properties of purified CBD of botanical origin and synthetic CBD The physical properties of the emission and excitation spectra of purified CBD of botanical origin and synthetic CBD were determined in this example.

[0247] method Test substances Botanically derived purified CBD (BOT) was tested in duplicate at six concentrations of 100 mM in 100% DMSO or 100% ethanol, and at 100 μM, 50 μM, 1 μM, 0.5 μM, and 0.01 μM in vehicle solutions containing PBS+0.1% ethanol or PBS+0.1% DMSO. The THC concentration in the botanically derived purified CBD used was 0.03% (w / w) THC.

[0248] Synthetic CBD (SYN) was tested in duplicate at five concentrations: 100 mM, 50 mM, 1 mM, 0.5 mM, and 0.1 mM in 100% ethanol or 100% DMSO.

[0249] Preparation of microplates 200 μL of each sample or buffer was added in duplicate to the microplate. Measurements were performed on an Ensight multimodal plate reader (Perkin Elmer).

[0250] Selection of excitation wavelength An excitation scan was used to detect the excitation peak for each test substance. The excitation scan was set from 230 to 380 nm and the emission wavelength was set to 400 nm or less. The excitation scan was also set from 230 to 420 nm and the emission wavelength was set to 440 nm or less. In both cases, a step increment of 2 nm was used for these scans.

[0251] Based on these analyses, the peak excitation wavelengths for two tentative fluorescence wavelengths were determined and used to identify the optimal excitation wavelength / second.

[0252] Fluorescence wavelength selection To confirm the emission peak of the test substance, an emission scan was performed using the excitation peak identified after the excitation scan. The excitation scan was set to start at a nominal excitation value of >50 nm for purified CBD of botanical origin and >20 nm for synthetic CBD, using a step increment of 2 nm. Wavelengths up to 800 nm were scanned for emission.

[0253] The wavelength giving maximum emission for the sample was defined as the optimal emission wavelength for the chosen excitation wavelength.

[0254] Presenting the data Raw data were derived from the software WorkOut Plus (version 2.5, Perkin Elmer, Waltham, Massachusetts, USA). All data extracted from the software were checked by two individuals for complete validation prior to data analysis.

[0255] These data were used to generate the data presented herein, where x represents wavelength (nm) and y represents fluorescence intensity, using WorkOut Plus software (version 2.5, Perkin Elmer).

[0256] The data was subsequently plotted as an XY graph using GraphPad Prism (version 8.0.2, La Jolla, USA).

[0257] result Excitation peak points for purified CBD of botanical origin and synthetic CBD in DMSO A specific autofluorescence spectrum distinct from the DMSO profile for each compound could only be detected at the highest concentration of 100 mM.

[0258] Representative spectroscopic data for each compound at a concentration of 100 mM is shown in FIG.

[0259] Using pure DMSO as a vehicle and with the fluorescence wavelength set at 400 or 440 nm, the excitation peak point was identified at 328 or 332 nm for the purified CBD of botanical origin; a monodisperse peak with a higher fluorescence reading for the purified CBD of botanical origin was used compared to the synthetic CBD.

[0260] Using pure DMSO as the vehicle and with the fluorescence wavelength set at 400 or 440 nm, excitation peak points were identified at 282 or 328 nm for the synthetic CBD; however, these overlap with the peaks for DMSO suggesting the absence of excitation peaks for this material in these conditions.

[0261] Emission peak points for purified CBD of botanical origin and synthetic CBD in DMSO Specific autofluorescence for each compound was only detectable at the highest concentration of 100 mM. The data suggested low specific fluorescence detection at all lower concentrations, similar to that of DMSO.

[0262] Representative spectroscopic data for each compound at a concentration of 100 mM is shown in FIG.

[0263] Using pure DMSO as a vehicle and excitation wavelengths set at 326 as identified from this study or 370 nm based on literature, emission peak points were identified at 398 or 428 nm for botanically derived purified CBD, with a monodisperse peak at 326 nm for higher fluorescence readings.

[0264] Using pure DMSO as vehicle and excitation wavelengths set at 328 / 334 / 344 / 284 nm, the excitation peak points were identified at 408 / 498 / 508 / 565 nm for the synthetic CBD, with a monodisperse peak at 565 nm for the higher fluorescence readings, which is not included in the spectrogram as it overlaps with the DMSO peak.

[0265] Excitation peak points for botanical-derived purified CBD and synthetic CBD in ethanol The ethanol profile and distinct specific autofluorescence spectra for each compound could only be detected at the highest concentration of 100 mM.

[0266] Representative spectroscopic data for each compound at a concentration of 100 mM is shown in FIG.

[0267] Using pure ethanol as the vehicle and with the fluorescence wavelength set at 400 nm, the excitation peak points were identified at 328 nm for the purified CBD of botanical origin and at 280 nm for the synthetic CBD.

[0268] Using pure ethanol as the vehicle and with the fluorescence wavelength set at 440 nm, the excitation peak points were identified at 330 nm for the purified CBD of botanical origin and at 328 nm for the synthetic CBD.

[0269] Emission peak points for botanically derived purified CBD and synthetic CBD in ethanol Specific autofluorescence for each compound was only detectable at the highest concentration of 100 mM. The data suggested low specific fluorescence detection at all lower concentrations, similar to that of ethanol.

[0270] Representative spectroscopic data for each compound at a concentration of 100 mM is shown in FIG.

[0271] Using pure ethanol as the vehicle and setting the excitation wavelength at 326 nm as identified in this study or 370 nm based on the literature, the emission peak points were identified at 404 nm or 560 nm for the botanically derived purified CBD.

[0272] Using pure ethanol as the vehicle and excitation wavelengths set at 326 and 340 nm, the excitation peak points were identified between 412 nm for both wavelengths in the case of synthetic CBD.

[0273] conclusion The data presented in this example suggest that there are differences in the excitation and emission wavelengths of purified CBD of botanical origin and synthetic CBD, and therefore clear differences in the biophysical properties of the two compounds.

[0274] Conclusions from data demonstrating the physicochemical properties of purified CBD of botanical origin The data presented above in Examples 2-7 describe the physicochemical properties of botanically-derived purified CBD preparations produced from high-CBD plants.

[0275] This purified CBD of botanical origin contains 98% or more (w / w) CBD and 2% or less (w / w) of other cannabinoids, the other cannabinoids being present in concentrations of 0.1% (w / w) or less THC, 0.15% (w / w) or less CBD-C1, 0.8% (w / w) or less CBDV, and 0.4% (w / w) or less CBD-C4.

[0276] These data further demonstrate that trans-THC and cis-THC are present in purified CBD of botanical origin, and further show that the ratio of trans-THC to cis-THC can be altered and controlled through processing and purification processes, ranging from 3.3:1 (trans-THC:cis-THC) in its raw, decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified.

[0277] Finally, these data demonstrate that the cis-THC found in purified CBD of botanical origin exists as a mixture of (+)-cis-THC and (-)-cis-THC isoforms.

[0278] Of note, the comparison of purified CBD from botanical sources is significantly different from the composition obtained from synthetic CBD. However, as provided by the teachings of the present invention, CBD preparations can be synthetically produced by producing compositions having dual components.

[0279] Data supporting the therapeutic efficacy of botanically derived, purified CBD The following examples describe data generated in vitro using cell lines and in animal studies, particularly in disease areas, that demonstrate the superior efficacy of botanically derived, purified CBD preparations over synthetic CBD preparations of the same concentration and purity.

[0280] The purity of the botanically derived purified CBD preparations used in these experiments was 98% or more. The CBD preparations contain 2% or less of other cannabinoids, including THC, CBDV, CBD-C1, and CBD-C4. THC is present at a concentration of 0.1% (w / w) or less; CBD-C1 at a concentration of 0.15% (w / w) or less; CBDV at a concentration of 0.8% (w / w) or less; and CBD-C4 at a concentration of 0.4% (w / w) or less.

[0281] THC exists as trans-THC and cis-THC in the botanically derived purified CBD preparations used in the following examples. The ratio of trans-THC to cis-THC was approximately 0.8:1 (trans-THC:cis-THC). Cis-THC was present as a mixture with (+)-cis-THC and (-)-cis-THC isoforms present.

[0282] Example 8: In vitro studies on neuroplasticity and growth cone development This example demonstrates that several concentrations of purified CBD of botanical origin are capable of inducing cell differentiation and neurite outgrowth.

[0283] A study was conducted to determine the effects of botanically derived purified CBD and synthetic CBD on human iPSC-derived cortical neural stem / progenitor cells (hNSCs) in vitro.

[0284] method Cultivation of human iPSC-derived cortical neural stem cells (hNSCs) Human iPSC-derived cortical neural stem cells (hNSCs) (Axol Bioscience Inc., UK) were cultured at a density of 1.0 × 10 in 100 mm diameter Petri dishes. 4 cells / cm 2 hNSCs were cultured as monolayers at 100° C. for 24 hours. The cells were collected from these initial cryotubes, suspended in Plating-XF medium, and plated on Petri dishes coated with SureBondXF 1× working solution prepared in D-PBS (without calcium or magnesium). The hNSCs were incubated at 37° C. and 5% CO2, and after 24 hours of incubation, the plating medium was replaced with fresh Neural Expansion-XF medium supplemented with the growth factors recombinant human EGF and recombinant human FGF2 (FGF2 and EGF final concentration 20 ng / mL (1×)). The cultures were re-fed with fresh Neural Expansion-XF supplemented with EGF and FGF2 every 2 days. When the hNSCs reached approximately 80% confluence, they were prepared for treatment. The cells were detached using pre-warmed Axol Unlock-XF, and after 3 min of incubation, the cells were resuspended in Neural Expansion-XF medium supplemented with EGF and FGF2. The cells (1 × 10 4 cells / cm 2 ) were seeded onto Petri dishes coated with SureBondXF 1X, and after 2 hours the medium was replaced with fresh Neural Expansion-XF supplemented with EGF and FGF2.

[0285] Experimental cannabinoid cell therapy hNSCs were cultured as previously described at a density of 1 × 10 on SureBondXF-coated coverslips in the presence of purified botanical CBD; synthetic CBD; or vehicle diluted in Neural Differentiation-XF medium (DM, growth factor free). 4 cells / cm 2 The cells were seeded at 37°C in a 5% CO2 / 95% air atmosphere for 3 to 5 days.

[0286] Cannabinoids were dissolved in 95% (v / v) ethanol and added to the culture medium to obtain a final concentration of 0.1 or 1 μM CBD.

[0287] Ethanol was added to vehicle-treated cells for the entire differentiation period of 3-5 days, with the final concentration never higher than 0.05% (v / v).

[0288] immunohistochemistry For immunohistochemistry, cells were fixed with 4% (w / v) paraformaldehyde. Nonspecific binding was blocked with 10% (v / v) fetal bovine serum and 0.1% (v / v) Triton X-100 and incubated with primary antibodies, i.e. mouse anti-Map2ab (Sigma-Aldrich; 1:200) and rabbit anti-GFAP (DAKO; 1:200) or rabbit anti-Gap43 (Synaptic System; 1:300) for 4 h at room temperature. Secondary antibodies - anti-mouse Alexa594 (Life Technologies; 1:100) and anti-rabbit Alexa488 (Life Technologies; 1:100) were used for immunofluorescence. Cells were then counterstained with DAPI, washed with PBS and coverslipped with Aquatex mounting medium (Merck, Darmstadt, Germany). Immunofluorescence was examined under an epifluorescence microscope (Leica AF6000) equipped with appropriate filters and then analyzed by microscope and image analysis software (Leica, LAS Images were captured using a digital camera (Leica, DFC340) connected to a 3D AF (photochromic achromatic AF). No immunoreactivity was found in samples treated to control for the specificity of each primary antibody used in the study, which was performed by removing the primary antibody before adding the appropriate secondary antibody.

[0289] Data collection and statistical analysis Digital Leica LAS AF2.2.0 software (Live Data Mode System) was used to count Map2ab+DAPI+ cells. Images were acquired with a Leica DMI6000 microscope equipped with appropriate blue (DAPI) and red (MAP2) filters to count differentiated cells as violet (mixture of DAPI, blue, and MAP2, red) and hNSCs as blue (DAPI only). For each experimental condition, cells from three different tubes were analyzed in triplicate each, and three frames were collected at 20× magnification. Data were analyzed with GraphPad Prism6 software, version 6.05 (GraphPad, Inc.) and are presented as mean ± SEM. Statistical differences between groups were determined by two-way ANOVA followed by a post hoc Bonferroni test for comparison between mean values. A confidence level of P<0.05 was used for statistical significance.

[0290] result Effects of botanically derived purified CBD and synthetic CBD on neurogenesis and neuronal differentiation of hNSCs Two different botanically derived purified CBD formulations were tested in cultured human neural stem cells (hNSCs). Batch 1 contained approximately 0.1% (w / w) THC and batch 2 contained 0.02% (w / w) THC. Doses of 0.1 and 1 μM were used for the botanically derived purified CBD and synthetic CBD.

[0291] As shown in Table 8.1 below, both batches of botanically derived purified CBD induced a significant increase in neurogenesis and neuronal differentiation of hNSCs, as indicated by an increase in the number of MAP2-MAP2+ cells after incubation with CBD for 3 or 5 days.

[0292] [Table 6]

[0293] A concentration of 1 μM of botanically derived purified CBD was found to be more potent than the 0.1 μM concentration for both batches and at both time points (days 3 and 5 of treatment). Interestingly, the same concentration of synthetic CBD had no significant effect on neurogenesis or neuronal differentiation relative to vehicle-treated cells.

[0294] Effects of botanically derived purified CBD and synthetic CBD on axonal outgrowth and neuronal differentiation of hNSCs This study examines the effect of two test compounds on the neuronal differentiation of hNSCs after 3 or 5 days of treatment using GAP43 immunohistochemistry. As shown in Table 8.2 below, after 3 and 5 days of treatment with purified CBD of botanical origin, neurogenesis was significantly increased by enhancing neurite outgrowth, as confirmed by the expression of GAP43 in the majority of cells.

[0295] [Table 7]

[0296] conclusion Together, these studies demonstrate that purified CBD of botanical origin, containing up to 2% of other cannabinoids, including THC, CBD-C1, CBDV and CBD-C4, is capable of inducing differentiation and neurite outgrowth.

[0297] Remarkably, synthetic CBD (which does not contain these other cannabinoids) does not appear to have any effect on the neurogenesis and differentiation of hNSCs when supplied at the same concentrations as botanically derived purified CBD.

[0298] The effects exhibited by purified CBD of botanical origin on neurogenesis and neurite outgrowth may be important for the treatment of neurodegenerative diseases or brain injury.

[0299] Example 9: Comparison of botanically derived purified CBD and synthetic CBD in a mouse model of epilepsy This example demonstrates the effects of botanically derived purified CBD and synthetic CBD in mice in the maximal electroshock seizure test.

[0300] method Animals and experimental conditions The study was performed with male C57B16 mice purchased from a licensed breeder (Charles River, UK) weighing between 23.6 and 31.2 g. Naive mice were acclimated to the treatment room in their home cages with food and water available ad libitum. Animals were housed in groups of 2-3 in standard cages with a 12 hr / 12 hr light / dark cycle. All animals were tail marked and weighed at the start of the study. Animals were randomly assigned to vehicle or treatment groups.

[0301] Antiepileptic drugs (AEDs) The following drugs were used in this study: synthetic CBD (SYN) and botanically derived purified CBD (BOT). The control vehicle used was (1:1:18), which is ethanol 5%, Kolliphor 5%, saline 90%, and is widely used across similar seizure studies. All drugs were dissolved in the control vehicle for comparison. Animals were administered ip (10 ml / kg) 60 minutes prior to the administration of the maximal electroshock seizure (MES) test. In addition to the vehicle group, dose groups were used for each treatment, including doses of 10, 50, 100 (experiment 1 only), 150 and 200 mg / kg for CBD (SYN) and CBD (BOT). The number of animals in each of these groups was 10 (n=10).

[0302] Two separate experiments were performed using two different batches of botanically derived purified CBD: in the first experiment, the concentration of THC in the botanically derived purified CBD was 0.02% (w / w) THC, and in the second experiment, the concentration of THC in the botanically derived purified CBD was approximately 0.1% (w / w) THC.

[0303] Maximal electroshock seizure (MES) test The protective activity of CBD(SYN) and CBD(BOT) was evaluated to determine the effective dose (ED) that protects 50% of mice against MES-induced tonic seizures. 50 The results were expressed as (mg / kg). Electroshock convulsions were produced by a fixed current intensity of 30 mA, delivering an electric shock to the cornea (for 0.2 seconds). Mice were individually assessed for seizures after this scheduled high level (30 mA), which delivered an electric shock to the cornea of ​​sufficient intensity to ensure tonic hindlimb extension seizures in 100% of control animals. Seizure induction was measured as an all-or-none effect recorded as present (+) or absent (0) for each animal. Data were collected by an observer blinded to the treatment for each animal and expressed as the total number of + and 0 for each treatment group. Percent inhibition of the relevant vehicle-treated group (degree of protection relative to vehicle-treated controls) was then generated.

[0304] statistical analysis All statistical tests were performed using the commercially available GraphPad Prism version 7.0 for Windows (GraphPad Software, San Diego, CA). The effective dose (ED) that protected 50% of mice against MES-induced tonic seizures for CBD(SYN) and CBD(BOT) was 50 The EDs (mg / kg) obtained from CBD (SYN and CBD) were calculated in Prism using a sigmoidal dose-response-variable slope and log-probit analysis. 50Values ​​were compared using a t-test approach to compare the two best, best-fit values ​​obtained from one experiment and to statistically assess the significance of the differences between them.

[0305] result The anticonvulsant effects of a given dose of CBD (SYN) and CBD (BOT 0.02% THC) were analyzed by sigmoidal curve analysis shown in FIG. 50 Values ​​were derived from these sigmoidal curves as follows: CBD(SYN): 77.63 mg / kg and CBD(BOT 0.02% THC): 70.22 mg / kg.

[0306] These ED 50 Values ​​were statistically compared using a t-test approach for the two best-fit values ​​obtained from one experiment. 50 The values ​​were determined to be statistically different (p=0.0013), as shown in Table 9.1 below.

[0307] The mouse dose was converted to a human equivalent dose (HED) of 10 mg / kg, assuming a human weighs 60 kg, and the difference in HED using CBD(SYN) versus CBD(BOT 0.02% THC) was 10.00%.

[0308] [Table 8]

[0309] The anticonvulsant effects of a given dose of CBD (SYN) and CBD (BOT 0.02% THC) were analyzed by sigmoidal curve analysis, as shown in Figure 14. ED 50 Values ​​were derived from these sigmoidal curves as follows: CBD(SYN): 77.40 mg / kg and CBD(BOT 0.1% THC): 57.94 mg / kg.

[0310] These ED 50Values ​​were statistically compared using a t-test approach for the two best-fit values ​​obtained from one experiment. 50 The values ​​were determined to be statistically different (p=0.0000015), as shown in Table 9.2.

[0311] The mouse dose was converted to a human equivalent dose (HED) of 10 mg / kg, assuming a human weighing 60 kg, and the difference in HED using CBD(BOT 0.08% THC) versus CBD(SYN) was 28.75%.

[0312] [Table 9]

[0313] conclusion The data generated in this study demonstrate that treatment with purified botanical CBD is more effective than synthetic CBD in a maximal electroshock model of epilepsy.

[0314] Such data are significant because they demonstrate that such CBD compositions may be useful in the treatment of epilepsy.

[0315] Example 10: Comparison of botanically derived purified CBD and synthetic CBD in an animal model of schizophrenia The effect of PCP in the novel object recognition (NOR) test is a model of visual recognition memory deficits similar to those observed in schizophrenia. The atypical antipsychotic drugs clozapine and risperidone can attenuate the deficits. This study was designed to determine whether botanically derived purified CBD and / or synthetic CBD can attenuate the deficits in novel object recognition caused by administration of PCP.

[0316] method Female hooded-Lister rats were used for this experiment. Rats were housed in groups of 5 under standard laboratory conditions with a 12-hr light-dark cycle, with lights on at 0700 hr. Testing was performed during the light phase. Rats were randomly assigned to two treatment groups and treated with vehicle, n=20 (distilled water, ip) or phencyclidine hydrochloride (PCP), n=100 (2 mg / kg, ip twice daily for 7 days). PCP was dissolved in distilled water. This was followed by a 7-day washout period before rats were tested, followed by acute treatment with CBD, risperidone or vehicle.

[0317] Risperidone (0.1 mg / kg) was dissolved in a minimum volume of acetic acid, made up to volume with distilled water, pH adjusted to 6 with 0.1 M NaOH and administered by ip route in a volume of 1 ml / kg 120 min before testing.

[0318] Botanically derived purified CBD was tested at 2, 10, 20 or 100 mg / kg, dissolved in 2:1:17 (ethanol:Cremofor:saline 0.9%) and administered by ip route in a volume of 5 ml / kg 60 min prior to testing. The THC concentration in the botanically derived purified CBD was 0.03% (w / w) THC.

[0319] Synthetic CBD at 1, 2, 5, 10 or 20 mg / kg was dissolved in 2:1:17 (ethanol:Cremofor:saline 0.9%) and administered by ip route in a volume of 5 ml / kg 120 min before testing.

[0320] Rats were allowed to habituate to the empty test box and behavioral testing room environment for 1 h on day 1. Rats were allowed to habituate for an additional 3 min before behavioral testing on day 2.

[0321] After a 3 min habituation period, rats were given two 3 min trials (T1 and T2) during which the objects were changed in their home cage with a 1 min interval between trials. Behavior during all trials was video recorded for subsequent blind scoring.

[0322] In the acquisition trial (T1), animals were left to explore two identical objects (A1 and A2) for 3 min. In the retention trial (T2), animals were left to explore the familiar object (A) and the novel object (B) from T1 for 3 min. The familiar object presented during T2 was a replica of the object presented in T1 to avoid any olfactory trials.

[0323] Object exploration was defined as the animal licking, sniffing, or touching the object with the forelimbs while sniffing it, but did not include the animal learning to, turning around, standing on, or sitting on the object. The exploration time of each object (A, B, familiar, and novel) in each trial was recorded using two stopwatches, and the following factors were calculated: total exploration time for both objects in acquisition trials, total exploration time for both objects in retention trials. Habituation of exploratory activity included exploration time as measured by the number of lines crossed for both trials.

[0324] All data were assessed using the D'Agostino and Pearson normality test. Non-normally distributed data were analyzed using Kruskal-Wallis followed by planned comparisons with Dunn's correction. Normally distributed data were analyzed using one-way ANOVA followed by planned comparisons with Sidak's correction. All analyses were performed using GraphPad Prism V7.03.

[0325] result As shown in FIG. 15, botanically derived purified CBD (2-100 mg / kg ip, 120 min ppt) attenuated (p=<0.05) subchronic PCP-induced deficits in novel object recognition in rats (n=9-10 per group) at a minimal effective dose (MED) of 2 mg / kg.

[0326] As shown in FIG. 16, synthetic CBD (2-100 mg / kg ip, 120 min ppt) attenuated subchronic PCP-induced deficits in novel object recognition in rats (n=8-10 per group) at a minimal effective dose (MED) of 10 mg / kg (p=<0.01).

[0327] Interestingly, the difference in potency (minimum effective dose) between synthetic and botanically derived purified CBD means that there is a significant difference in the amount of CBD required in a 70 kg human administered 20 mg / kg / day of CBD, as shown below: 2mg / kg / day rat dose = (2 x 0.16) = 0.32mg / kg / day in humans = (0.32 x 70) = 22.4mg / day for highly purified CBD of plant origin. 10 mg / kg / day rat dose = (10 x 0.16) = 1.6 mg / kg / day in humans = (1.6 x 70) = 112 mg / day for synthetic CBD.

[0328] Calculations are based on FDA dose conversion guidance from animal to human (to convert rat doses in mg / kg to human equivalent doses in mg / kg; rat doses are multiplied by 0.16).

[0329] conclusion Botanically derived purified CBD has been shown to be useful in attenuating subchronic PCP-induced deficits in novel object recognition in rats at a lower minimal effective dose (MED) than synthetic CBD, suggesting that it should be a useful treatment option in schizophrenia and related conditions.

[0330] Given the difference in potency, synthetic CBD would require five times the amount of CBD in humans than purified CBD from botanical sources. Such a difference in potency is important for CBD to be produced synthetically or from the plant root, even though it is an expensive compound.

[0331] Example 11: Comparison of high concentrations of THC in combination with botanically derived purified CBD in an animal model of schizophrenia The novel object recognition (NOR) test described in Example 9 above is a model of visual recognition memory deficits similar to those observed in schizophrenia. This test is designed to determine whether higher concentrations of THC, as commonly found in native CBD oil preparations, affect the ability of botanically derived purified CBD to attenuate the deficits in novel object recognition caused by administration of PCP in rats.

[0332] Proprietary CBD preparations generally contain between 3-20% (w / w) THC.

[0333] method The same method described in Example 10 above was used in this experiment.

[0334] Botanically derived purified CBD was tested at 20 mg / kg, with 10% (w / w) or 20% (w / w) THC added to the CBD. Botanically derived purified CBD containing 0.08% THC was brought to 10% THC and 20% THC with purified botanically derived THC.

[0335] Cannabinoids were dissolved in 2:1:17 (ethanol:Cremofor:0.9% saline) and administered by ip route in a volume of 5 ml / kg 120 min before testing.

[0336] Behavioral testing was performed as described in Example 10 above.

[0337] All data were assessed for normality using the D'Agostino and Pearson normality test. Non-normally distributed data were analyzed using Kruskal-Wallis followed by planned comparisons with Dunn's correction. Normally distributed data were analyzed using one-way ANOVA followed by planned comparisons with Sidak's correction. All analyses were performed using GraphPad Prism V7.03.

[0338] result Animals treated with botanically derived purified CBD containing 20% ​​(w / w) THC were found to be sedated, therefore no data were generated for novel object recognition in this group.

[0339] Some of the animals treated with botanically derived purified CBD containing 10% (w / w) THC were also found to be sedated, and therefore data were generated for only 5 of the 15 test animals in this group.

[0340] As can be seen in Figures 17 to 19, animals treated with purified botanical CBD at 20 mg / kg were able to attenuate subchronic PCP-induced deficits in novel object recognition. Interestingly, it was observed that this effect was abolished in animals treated with purified botanical CBD containing 10% (w / w) THC.

[0341] Figure 17 demonstrates that botanically derived purified CBD (20 mg / kg ip, 120 min ppt) attenuated (p=<0.001) subchronic PCP-induced deficits in novel object recognition in rats (n=15 per group), whereas the group treated with CBD (20 mg / kg) and THC (1.984 mg / kg, ip, 120 min ppt) abolished this effect (n=5), an effect similar to that observed in vehicle-treated PCP rats.

[0342] Figure 18 details the discrimination index (DI) in rats treated with purified CBD of botanical origin supplemented with 10 and 20% (w / w) THC. Rats treated with purified CBD of botanical origin (20 mg / kg ip, 120 min ppt) had a DI that was similar (p=<0.01) to that of rats not treated with PCP (n=15 per group), whereas the group administered CBD (20 mg / kg) and THC (1.984 mg / kg, ip, 120 min ppt) lost this effect (n=5).

[0343] Figure 19 details the number of line crossings in rats treated with botanically derived purified CBD supplemented with 10 and 20% (w / w) THC. Rats treated with THC (1.984 mg / kg, ip, 120 min ppt) and CBD (20 mg / kg) showed a reduced number of line crossings (n=5).

[0344] conclusion Thus, while the small concentrations of THC found in botanically derived purified CBD are effective, increasing the concentration of THC to the levels found in indigenous CBD preparations is likely to be detrimental to cognitive and social deficits.

[0345] Conclusions from the data demonstrating the therapeutic efficacy of botanically derived, purified CBD The data presented in Examples 8-11 above describe the pharmacological properties of botanically-derived, purified CBD preparations produced from high-CBD plants compared to synthetic CBD.

[0346] As the inventors determined in Examples 2-7, the botanically derived purified CBD used in these experiments has a precise composition that differs from that of the synthetic CBD, even though the two compositions have the same concentration of CBD.

[0347] These data demonstrate in three different models that botanically derived, purified CBD is more effective than synthetic CBD. These data are surprising, even though the compositional differences between the two types of CBD tested are only within the range of what might be considered impurities.

[0348] Such data is important in a number of ways. First, when treating patients with a disease or condition, medical professionals want to ensure the most effective treatment possible. These data indicate that botanically derived, purified CBD is more effective than synthetic CBD and therefore a more valuable treatment option, especially in patients suffering from difficult to treat conditions, such as many of the epilepsy syndromes, such as Dravet syndrome or Lennox-Gastaut syndrome.

[0349] Secondly, the findings from these experiments demonstrate that botanically derived purified CBD is effective at a lower minimum effective dose than synthetic CBD.Therefore, when administering botanically derived purified CBD, a smaller amount of the composition can be provided.This has many advantages, including lower cost, potentially reducing associated side effects, and patient compliance.

[0350] Furthermore, these data also demonstrate that the use of unpurified sources of CBD, such as those found in CBD oil retailers, does not provide the same effective benefits as observed with botanically derived, refined CBD. The adverse effects exhibited in cognition suggest that when the amount of THC in CBD is increased to intrinsic levels, such compositions are not suitable for the treatment of many diseases and conditions.

[0351] In summary, the precise composition of components within purified CBD of botanical origin is a major advantage: such a composition can be replicated using CBD of botanical origin or synthetically produced components.

Claims

1. 1. A cannabidiol (CBD) formulation comprising at least 98% (w / w) CBD and no more than 2% (w / w) other cannabinoids, wherein the no more than 2% (w / w) other cannabinoids include the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC, and wherein the formulation contains at least about 0.02% THC based on the total weight of the cannabinoids in the formulation.

2. 1. A cannabidiol (CBD) formulation for use as a medicine, comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids include the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC, and wherein the formulation contains at least about 0.02% THC based on the total weight of the cannabinoids in the formulation.

3. 1. A cannabidiol (CBD) formulation for use in the treatment of neurodevelopmental diseases and conditions, comprising at least 98% (w / w) CBD and no more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids include the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC, and wherein the formulation contains at least about 0.02% THC based on the total weight of the cannabinoids in the formulation.

4. 1. A cannabidiol (CBD) formulation for use in the treatment of epilepsy, comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids include the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC, and wherein the formulation contains at least about 0.02% THC based on the total weight of the cannabinoids in the formulation.

5. 1. A cannabidiol (CBD) formulation for use in the treatment of schizophrenia, comprising at least 98% (w / w) CBD and no more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids include the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC, and wherein the formulation contains at least about 0.02% THC based on the total weight of the cannabinoids in the formulation.

6. 6. A cannabidiol (CBD) formulation according to any one of claims 1 to 5, containing no more than 1.5% (w / w) THC, based on the total mass of cannabinoids in the formulation.

7. 7. The cannabidiol (CBD) formulation of claim 6, comprising about 0.02% to about 0.05% (w / w) THC, based on the total mass of cannabinoids in the formulation.

8. 8. The cannabidiol (CBD) formulation of claim 1, wherein the mixture of trans-THC and cis-THC is present in a ratio of about 3.6:1 trans-THC:cis-THC.

9. A cannabidiol (CBD) formulation described in any one of claims 1 to 7, wherein the mixture of trans-THC and cis-THC is present in a ratio of trans-THC:cis-THC of about 0.7:1 to about 2:

1.

10. 8. The cannabidiol (CBD) formulation of claim 1, wherein the mixture of trans-THC and cis-THC is present in a ratio of about 0.8:1 trans-THC:cis-THC.

11. 11. A cannabidiol (CBD) formulation according to any one of claims 1 to 10, comprising from about 0.1% to about 0.15% (w / w) CBD-C1, based on the total mass of cannabinoids in the formulation.

12. 12. A cannabidiol (CBD) formulation according to any one of claims 1 to 11, comprising about 0.2% to about 0.8% (w / w) CBDV, based on the total mass of cannabinoids in the formulation.

13. 13. A cannabidiol (CBD) formulation according to any one of claims 1 to 12, comprising about 0.3% to about 0.4% (w / w) CBD-C4, based on the total mass of cannabinoids in the formulation.

14. 14. A cannabidiol (CBD) formulation according to any one of claims 1 to 13, wherein at least a portion of at least one of the cannabinoids present in the CBD formulation is isolated from Cannabis plant material.

15. 15. The cannabidiol (CBD) formulation of claim 14, wherein at least a portion of the CBD present in the CBD formulation is isolated from Cannabis plant material.

16. 15. The cannabidiol (CBD) formulation of claim 14, wherein at least a portion of the THC present in the CBD formulation is isolated from Cannabis plant material.

17. 15. The cannabidiol (CBD) formulation of claim 14, wherein at least a portion of the CBD-C1 present in the CBD formulation is isolated from Cannabis plant material.

18. 15. The cannabidiol (CBD) formulation of claim 14, wherein at least a portion of the CBDV present in the CBD formulation is isolated from Cannabis plant material.

19. 15. The cannabidiol (CBD) formulation of claim 14, wherein at least a portion of the CBD-C4 present in the CBD formulation is isolated from Cannabis plant material.

20. 20. A cannabidiol (CBD) formulation according to any one of claims 1 to 19, wherein substantially all of at least one of the cannabinoids present in the CBD formulation is isolated from Cannabis plant material.

21. 21. The cannabidiol (CBD) formulation of claim 20, wherein substantially all of the CBD present in the CBD formulation is isolated from Cannabis plant material.

22. 21. The cannabidiol (CBD) formulation of claim 20, wherein substantially all of the THC present in the CBD formulation is isolated from Cannabis plant material.

23. 21. The cannabidiol (CBD) formulation of claim 20, wherein substantially all of the CBD-C1 present in the CBD formulation is isolated from Cannabis plant material.

24. 21. The cannabidiol (CBD) formulation of claim 20, wherein substantially all of the CBDV present in the CBD formulation is isolated from Cannabis plant material.

25. 21. The cannabidiol (CBD) formulation of claim 20, wherein substantially all of the CBD-C4 present in the CBD formulation is isolated from Cannabis plant material.

26. 26. A cannabidiol (CBD) formulation according to any one of claims 1 to 25, wherein substantially all of the cannabinoids present in the CBD formulation are isolated from Cannabis plant material.

27. 27. The cannabidiol (CBD) formulation of any one of claims 14 to 26, wherein the Cannabis plant material is obtained from a Cannabis sativa, Cannabis indica, or Cannabis ruderalis plant.

28. 27. The cannabidiol (CBD) formulation of any one of claims 14 to 26, wherein the Cannabis plant is a high-CBD Cannabis species.

29. 14. A cannabidiol (CBD) formulation according to any one of claims 1 to 13, wherein at least a portion of at least one of the cannabinoids present in the CBD formulation is synthetically prepared.

30. 30. The cannabidiol (CBD) formulation of claim 29, wherein at least a portion of the CBD present in the CBD formulation is synthetically prepared.

31. 30. The cannabidiol (CBD) formulation of claim 29, wherein at least a portion of the THC present in the CBD formulation is synthetically prepared.

32. 30. The cannabidiol (CBD) formulation of claim 29, wherein at least a portion of the CBD-C1 present in the CBD formulation is synthetically prepared.

33. 30. The cannabidiol (CBD) formulation of claim 29, wherein at least a portion of the CBDV present in the CBD formulation is synthetically prepared.

34. 30. The cannabidiol (CBD) formulation of claim 29, wherein at least a portion of the CBD-C4 present in the CBD formulation is synthetically prepared.

35. 14. A cannabidiol (CBD) formulation according to any one of claims 1 to 13, wherein substantially all of at least one of the cannabinoids present in the CBD formulation is synthetically prepared.

36. 36. The cannabidiol (CBD) formulation of claim 35, wherein substantially all of the CBD present in the CBD formulation is synthetically prepared.

37. 36. The cannabidiol (CBD) formulation of claim 35, wherein substantially all of the THC present in the CBD formulation is synthetically prepared.

38. 36. The cannabidiol (CBD) formulation of claim 35, wherein substantially all of the CBD-C1 present in the CBD formulation is synthetically prepared.

39. 36. The cannabidiol (CBD) formulation of claim 35, wherein substantially all of the CBDV present in the CBD formulation is synthetically prepared.

40. 36. The cannabidiol (CBD) formulation of claim 35, wherein substantially all of the CBD-C4 present in the CBD formulation is synthetically prepared.

41. 36. The cannabidiol (CBD) formulation of claim 35, wherein substantially all of the cannabinoids present in the CBD formulation are synthetically prepared.

42. The neurodegenerative disease or disorder is Alzheimer's disease; Parkinson's disease; essential tremor; amyotrophic lateral sclerosis (ALS); Huntington's disease; Friedreich's ataxia; multiple sclerosis; frontotemporal dementia; prion disease; Lewy body disease; progressive supranuclear palsy; vascular dementia; normal pressure hydrocephalus; traumatic spinal cord injury; HIV dementia; alcohol-induced neurotoxicity; Down's syndrome; movement disorders of the central and / or peripheral nervous system; motor neuron disease (MND); spinal muscular atrophy; or any other related neurological or psychiatric neurodegenerative disease; brain injury; brain damage; brain dysfunction; Dysgraphia; Dysarthria; Apraxia; Agnosia; Amnesia; Dizziness; Vertigo; Coma; Stroke; Spinal Cord Injury; Spinal Cord Injury; Spinal Cord Disorder; Central Neuropathy; Peripheral Neuropathy; Cranial Neuropathy; Trigeminal Neuralgia; Nervous System Tumor; Brain or Spinal Cord Infection; Encephalitis; Meningitis; Prion Disease; Complex Regional Pain Syndrome; Autonomic Nervous System Disorder; Autonomic Neuropathy; Autonomic Neuropathy; Postural Orthostatic Tachycardia Syndrome (POTS); Neurocardiogenic Syncope (NCS); Multiple System Atrophy (MSA); Hereditary Sensory and Autonomic Neuropathy (HSAN); Holmes-Addie Syndrome (HAS); Sleep Disorder ;Narcolepsy;Pain;Migraine;Cluster headache;Tension headache;Back pain;Low back pain;Neck pain;Neuropathic pain;Cancer pain;Allodynia;Arthritic pain;Inflammatory pain;Neurological disorders;Attention deficit hyperactivity disorder;Autism;Tourette syndrome;Obsessive-compulsive disorder;Autism spectrum disorder;Rett syndrome;Fragile X syndrome;Angelman syndrome;Hyperactivity disorder;Mitochondrial disease;Dystonia;Cancer;Brain cancer;Glioma;Breast cancer;Liver cancer;Lung cancer;Pancreatic cancer;Melanoma;Ovarian cancer;Gastric cancer;Kidney cancer;Bladder cancer;Addiction;Nicotine addiction;Smoking;Alcohol addiction;Drug dependence;Cannabis use disorder;Psychiatric disorders;Post-traumatic stress 4. The cannabidiol (CBD) formulation of claim 3, wherein the cannabidiol (CBD) formulation is for the treatment of: stress disorder; anxiety; early psychosis; schizophrenia; cognitive impairment; stroke; cardiac ischemia; coronary artery disease; thromboembolism; myocardial infarction; ischemia-related disease; gastrointestinal disorders; inflammatory bowel disease; Crohn's disease; ulcerative colitis; nausea; vomiting; emetic syndrome; motion sickness; chemotherapy-induced nausea; chemotherapy-induced nausea and vomiting; inflammation; arthritis; rheumatoid arthritis; osteoarthritis; diabetes; hypertension; inadequate insulin control; appetite suppression; anorexia; neonatal hypoxic-ischemic encephalopathy (NHIE); degenerative skeletal muscle disease; or Duchenne muscular dystrophy (DMD).

43. 5. The cannabidiol (CBD) formulation of claim 4, wherein the epilepsy is Dravet syndrome, Lennox-Gastaut syndrome, Fever-Infection-Related Epilepsy Syndrome (FIRES), Dause syndrome, Sturge-Weber syndrome, CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasms (West syndrome); and Landau-Kleffner syndrome, refractory epilepsy, juvenile convulsions, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis (TSC); neuroplastic storage disorder, neuronal ceroid lipofuscinosis (NCL), Batten disease, encephalopathy, atony, idiopathic, absence seizures, partial seizures, simple partial seizures, or complex partial seizures.

Images