WO2020021544A1

WO2020021544A1 - Cannabidiol and methylthio-butyl-isothiocyanate for treating inflammatory diseases

Info

Publication number: WO2020021544A1
Application number: PCT/IL2019/050831
Authority: WO
Inventors: Tamir GEDO
Original assignee: Bol Pharma Ltd.
Priority date: 2018-07-25
Filing date: 2019-07-23
Publication date: 2020-01-30

Abstract

The present invention provides compositions comprising cannabidiol (CBD) and 4-Methylthio- butyl-isothiocyanate (MTBI), and methods of using them for treating and/or ameliorating skin conditions.

Description

CANNABIDIOL AND METHYL THIO-BUTYL-ISOTHIOCYANATE FOR TREATING

INFLAMMATORY DISEASES

FIELD OF INVENTION

[0001] This invention is directed to compositions comprising cannabidiol (CBD) and Methylthio-butyl-isothiocyanate (MTBI) for treating inflammatory diseases.

BACKGROUND OF THE INVENTION

[0002] Inflammation is a localized protective reaction of cells/tissues of the body to allergic or chemical irritation, injury and/or infections. The symptoms of inflammation are characterized by pain, heat, redness, swelling and loss of function that result from dilation of the blood vessels leading to an increased blood supply and from increased intercellular spaces resulting in the movement of leukocytes, protein and fluids into the inflamed regions

[0003] Diseases and disorders are manifested through inflammatory responses as the body recognizes the injury and prepare to repair the damage. The inflammatory process is controlled by chemical mediators. These mediators are the substances released as plasma proteins, or that come from cells like mast cells, platelets, neutrophils and monocytes/macrophages. They are triggered by allergic or chemical irritation, injury and infections. These mediators, depending on the duration of injury determine the severity of inflammation and are termed pro -inflammatory fundamental factors.

[0004] These substances bind to specific target receptors on the cells and may increase vascular permeability, promote neutrophil chemotaxis, stimulate smooth muscle contraction, increase direct enzymatic activity, induce pain and/or mediate oxidative damage (Coleman, 2002). Examples of chemical mediators include: nitric oxide (NO), prostaglandins (PG), leukotrienes (LK), vasoactive amines (histamine, serotonin), and cytokines (tumor necrosis factor and interleukins- 1, 12). Although some of the cytokines (IL-3-4,-5,-6,-l0,-l3) released are beneficial by acting as anti-inflammatory mediators within the cells, these pro-inflammatory mediators present pathways through which disorders in the body may be eradicated or ameliorated.

[0005] Even though the innate cascade process of inflammation is complex, it is mainly divided into two parts i.e. acute and chronic which could either be beneficial or detrimental.

[0006] Acute inflammation is characterized by rapid onset and is of short duration. It is characterized by the exudation of fluids and plasma proteins, and the migration of leukocytes, most notably neutrophils into the injured area. This acute inflammatory response is believed to be a defense mechanism aimed at killing of bacteria, virus and parasites while still facilitating wound repairs.

[0007] Chronic inflammation is of a more prolonged duration and manifests histologically by the presence of lymphocytes and macrophages, resulting in fibrosis and tissue necrosis. The persistent chronic inflammation increases the development of the degenerative diseases such as rheumatoid arthritis, atherosclerosis, heart disease, Alzheimer, asthma, acquired immunodeficiency disorder(AIDS), cancer, congestive heart failure (CHF), multiple sclerosis (MS), diabetes, infections (bacteria, fungi, parasites), gout, IBD-inflammatory bowel disease, aging and other neurodegenerative CNS depression, all of which are associated with immunopathological that appears to play a key role in the onset of the condition.

[0008] These various diseases and disorders have been linked to increased expression of pro- inflammatory mediators which activates inflammatory cells by increasing the expression of pro- inflammatory cytokines, up-regulating genes that produce NF kappa B, NADPH oxidase, phospholipase A2, COX-1 and -2, 5-LOX, myeloperoxidase, iNOS, increasing oxygen consumption and producing many oxygen-free radicals that can finally lead to certain degenerative diseases (Giacosa and Filiberti, 1996; Vicenzi et ah, 1997; Charles et ah, 1999; Locati and Murphy, 1999). Nitric oxide (NO) is an example of reactive species that participates in normal physiological processes such as vasodilation and neurotransmission; however, overexpression may result in disease as observed in inflammation, asthma, cardiovascular disorders and organ transplant rejection (Coleman, 2002). Many other factors such as chronic lung and liver inflammation caused by tobacco smoking and alcohol consumption may lead to lung cancer and liver cirrhosis respectively, while the persistent inflammation of the stomach is caused by the bacterium, Helicobacter pylori which may lead to ulcers and ultimately to stomach cancer.

[0009] Inflammation is the most common problem in dermatology. Acute skin inflammation can result from exposure to radiation, allergens, or to contact with chemical irritants (soaps, hair dyes, etc.). This type of inflammation is typically resolved within 14 days. In contrast, chronic inflammation results from a sustained immune cell mediated inflammatory response within the skin itself. This inflammation is long lasting and can cause significant and serious tissue destruction.

[0010] The most effective and commonly used prescription drugs for treating inflammation are the corticosteroids, particularly the glucocorticoid related steroids. They are very effective for many forms of eczema, including atopic dermatitis, allergic contact dermatitis, seborrheic dermatitis (in concert with an anti-fungal agent), and are fairly effective in ameliorating the symptoms of psoriasis but corticosteroids carry devastating side effects. Corticosteroids are not particularly effective, in treating acute inflammation, like UVR induced sunburn, which is not primarily an immune cell driven inflammatory response.

[0011] Cannabis is known to have anti-inflammatory properties. The endocannabinoid system CB2 receptors are predominantly found in the immune system, or immune-derived cells with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis seen in animal models.

[0012] Cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC) are the two most well-known cannabinoids in the cannabis plant. Both A⁹-THC and CBD are neuroactive but only A⁹-THC is psychoactive (inducing the“high” feeling). CBD is not psychoactive and even attenuates the D⁹- THC-induced psychoactivity. As a result, strains with higher CBD concentrations are used for medical purposes, while strains having a higher concentration of A⁹-THC and lower CBD are used for recreational purposes.

[0013] Isothiocyanates (ITCs) are organosulfur compounds present in cruciferous vegetables, which have anticarcinogenic, anti-inflammatory, and antiproliferative activities. 4-methylthio- butyl-isothiocyanate (MTBI) is the major ITC in rocket seeds ( Eruca sativa ), the extract of which is used for treating skin disorders in traditional Middle Eastern medicine.

SUMMARY OF THE INVENTION

[0014] In one aspect, the present invention provides a composition comprising cannabidiol (CBD) and 4-Methylthio-butyl-isothiocyanate (MTBI).

[0015] In another aspect, the present invention provides a method for treating and/or ameliorating a skin condition in a subject, wherein said skin condition results from skin peeling treatment and/or from hair removal treatment, said method comprising administering to said subject the composition of the invention, thereby treating and/or ameliorating a skin condition in a subject.

[0016] In an additional aspect, the present invention provides a method for preventing skin aging, skin wrinkles, uneven pigmentation, skin dehydration, dermatitis, skin eczema, osteoarthritis, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, skin rush, skin allergy, skin burn, skin inflammation, dilated skin capillaries, psoriasis, atopic dermatitis, vitiligo, neuropathic pain, or diabetic neuropathic pain, or any combination thereof in a subject in need thereof, said method comprising administering to said subject the composition of the invention, thereby treating and/or ameliorating a skin condition in a subject. DETAILED DESCRIPTION

[0017] In a first aspect, the present invention provides a composition comprising cannabidiol (CBD) and an isothiocyanate.

[0018] In a further aspect, the present invention provides a composition comprising cannabidiol (CBD) and 4-Methylthio-butyl-isothiocyanate (MTBI).

[0019] In some embodiments, the composition further comprises a plant extract.

[0020] In some embodiments, the plant extract is a cruciferous plant extract or an extract from Angelica Sinensis.

[0021] In some embodiments, the MTBI is in the form of a plant extract. In some embodiments, the plant extract comprising isothiocyanate or MTBI is a major component of the composition as described herein.

[0022] In some embodiments of the first aspect, the isothiocyanate is 2-Propenyl-isothiocyanate, 3-Butenyl-isothiocyanate, 2R-2-Hydroxy-3-butenyl-isothiocyanate, 2S-2-Hydroxy-3-butenyl- isothiocyanate, p-Hydroxy-benzyl-isothiocyanate, Benzyl-isothiocyanate, 4-Methylthio-butyl- isothiocyanate, 3-Methyl-sulfonyl-propyl-isothiocyanate, or 4-Methyl- sulfinyl-butenyl- isothiocyanate, or any combination thereof. In some embodiments, the isothiocyanate is any known isothiocyanate having the general formula: R— N=C=S, wherein R can be any compatible substituent such as, for example, aryl, cycloalkyl, alkyl, alkenyl, alkynyl, heteroaryl, heteroalicyclic, hydroxy, thiohydroxy, halo and the like.

[0023] In some embodiments of the first aspect, the isothiocyanate is 2-Phenylethyl isothiocyanate (C6H5CH2CH2NCS), Phenethyl isothiocyanate (C6H5CH2CH2NCS), 4-(Boc- aminomethyljphenyl isothiocyanate (C13H16N202S), Fluorescein 5(6)-isothiocyanate (C21H11N05S), p-Tolyl isothiocyanate (CH3C6H4NCS), 4-Azidophenyl isothiocyanate (N3C6H4NCS), 4-Bromophenyl isothiocyanate (BrC6H4NCS), 4-Chlorophenyl isothiocyanate (C1C6H4NCS), 4-Isothiocyanato-but-l-ene (C5H7NS), 4-Brom-2-fluorbenzylisothiocyanate (C8H5BrFNS), 3-Brom-4-fluorbenzylisothiocyanate (C8H5BrFNS), 5-Brom-2- fluorbenzylisothiocyanate (C8H5BrFNS), 4-Chlor-2-fluorbenzylisothiocyanate (C8H5C1FNS), 3-Chlorbenzylisothiocyanate (C8H6C1NS), 4-(Trifluormethoxy)-benzylisothiocyanate (C9H6F3NOS), or 2,6-Difluorbenzylisothiocyanate (C8H5F2NS).

[0024] As used herein, the term“alkyl” describes a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g.,“1-20”, is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonamide, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, thiocarboxy, urea, thiourea, 0-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, guanyl, guanidino, and amino.

[0025] A“cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonamide, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, thiocarboxy, urea, thiourea, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, guanyl, guanidino, and amino.

[0026] An“alkenyl” group refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon double bond. An“alkynyl” group refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon triple bond.

[0027] An“aryl” group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonamide, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, thiocarboxy, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, guanyl, guanidino, and amino.

[0028] A“heteroaryl” group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonamide, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, thiocarboxy, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, C-carboxy, O-carboxy, guanyl, guanidino, and amino.

[0029] A“heteroalicyclic” group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be substituted or unsubstituted. When substituted, the substituted group can be, for example, lone pair electrons, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonamide, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, thiocarboxy, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, guanyl, guanidino, and amino. Representative examples are piperidine, piperazine, tetrahydro furane, tetrahydropyrane, morpholino and the like.

[0030] In some embodiments of the first aspect, the isothiocyanate is a synthetic isothiocyanate.

[0031] In some embodiments, the isothiocyanate is within a plant extract. In some embodiments, an isothiocyanate is isolated and/or purified from a plant extract.

[0032] In some embodiments, the phrase“cruciferous plant extract” refers to any extract made from a cruciferous plant. Plant extracts can be made by methods known in the arts including a polar extract such as an alcohol extract (e.g., ethanol, methanol, hexane, hydroalcohol, see for example Swanson R L et ah, 2004, Biol. Bull. 206: 161-72) or a non-polar extract (e.g., isooctane, see for example, Ng LK and Hupe M. 2003, J. Chromatogr A. 1011: 213-9; Diwanay S, et ah, 2004, J. Ethnopharmacol. 90: 49-55). For example, a plant extract can be made by placing a plant sample (e.g., leaves, seeds) in a mortar along with a small quantity of liquid (e.g., 10 ml of water, alcohol or an organic solvent for every 2 grams of plant sample) and grinding the sample thoroughly using a pestle. When the plant sample is completely ground, the plant extract is separated from the ground plant material via, centrifugation, filtering, cation-exchange chromatography, etc., and the collected liquid is further processed if need be (via a concentrating column etc), active ingredients can be separated from this extract via affinity chromatography, mass chromatography and the like. [0033] In some embodiments, an isothiocyanate is 4-methylthio-butyl-isothiocyanate. In some embodiments, 4-methylthio-butyl-isothiocyanate is obtained by the enzymatic hydrolysis of glucoerucin extracted from Eruca sativa.

[0034] In some embodiments, the composition of the present invention is a pharmaceutical or cosmeceutical composition including a carrier suitable for topical administration, intramuscular injection, subcutaneous administration, dermal, transmucosal (e.g., intragenitalia or intramouth) and/or intradermal administration.

[0035] A“pharmaceutical composition” or a“cosmetic (or cosmeceutical) composition” refers to a preparation of one or more of the active ingredients described herein with other chemical components such as pharmaceutically or physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition or cosmetic composition is to facilitate administration of the active ingredient to an organism.

[0036] In some embodiments, the composition is for use in treating an inflammatory disease, an allergy, or a skin rash.

[0037] In some embodiments, the composition is for use in treating and/or ameliorating skin aging, skin wrinkles, uneven pigmentation, skin dehydration, dermatitis, skin eczema, osteoarthritis, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, dilated skin capillaries, psoriasis, atopic dermatitis, vitiligo, neuropathic pain, or diabetic neuropathic pain, or any combination thereof.

[0038] In an additional aspect, the invention provides a kit comprising at least two compositions, wherein the first composition comprises cannabidiol (CBD) and the second composition comprises an isothiocyanate, or specifically MTBI.

[0039] In some embodiments, the invention provides a composition comprising 1 to 50% w/w of a plant extract. In some embodiments, the invention provides a composition comprising 10 to 90% w/w of a plant extract. In some embodiments, the invention provides a composition comprising 30 to 75% w/w of a plant extract. In some embodiments, the invention provides a composition comprising 5 to 50% w/w of a plant extract. In some embodiments, the invention provides a composition comprising 10 to 50% w/w of a plant extract. In some embodiments, the invention provides a composition comprising 10 to 40% w/w of a plant extract.

[0040] The phrase "w/w of a plant extract" refers to the weight percentage of the plant extract from the overall weight of the composition. In some embodiments, "w/w of a plant extract" refers to the weight percentage of the plant extract from the combined weight of CBD and the plant extract. [0041] In some embodiments, the invention provides a composition comprising CDB at a concentration of 0.1 to 200 mg per ml composition, 0.1 to 100 mg per ml, 0.1 to 50 mg per ml, 0.1 to 20 mg per ml, 0.5 to 10 mg per ml, 5 to 200 mg per ml, 2 to 25 mg per ml, 0.5 to 8 mg per ml, or 1 to 8 mg per ml composition.

[0042] In some embodiments, the invention provides a composition comprising an isothiocyanate and/or MTBI at a concentration of 0.1 to 800 mM, 0.2 to 200 pM, 5 to 100 pM, 0.5 to 100 pM, 1 to 80 pM, 2 to 50 pM, or 1 to 20 pM.

[0043] In some embodiments, the invention provides a composition or a kit as described herein for treating an inflammatory disease, reducing the severity of inflammation or reducing the risk of developing inflammation in a subject afflicted with oxidative stress. In some embodiments, the invention provides a composition or a kit as described herein for treating a skin inflammatory disease, reducing the severity of skin inflammation or reducing the risk of developing skin inflammation in a subject.

[0044] The compositions as described herein, comprise in some embodiments, Cannabidiol (CBD), or any functional derivative thereof (i.e. a CBD derivative possessing similar, equivalent, or increased efficacy). In some embodiments, the described compositions optionally further comprise at least one pharmaceutically acceptable carrier, diluent, excipient and/or additive.

[0045] The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that are substantially and/or essentially devoid of THC. In some embodiments a composition comprising CBD or any functional derivative thereof, as described herein is substantially and/or essentially devoid of THC. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 80% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 90% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 92% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 95% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 97% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 99% CBD or any functional derivative thereof. [0046] In some embodiments substantially and/or essentially devoid of THC is less than 10% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 7% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 5% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 3% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 1% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 0.5% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 0.3% by weight or weight/weight THC. In some embodiments substantially and/or essentially devoid of THC is less than 0.1% by weight or weight/weight THC. In the methods and compositions described herein, purified or substantially purified refers to greater than 80% w/w, 85% w/w, 90%, w/w 95% w/w or 97% w/w cannabidiol, or a functional variant thereof.

[0047] CBD, also termed 2-[(6R)-3-Methyl-6-prop-l-en-2-yl-lcyclohex-2-envyl]- 5pentylbenzene-l,3-diol, has the molecular formula of C21H30O2. The chemical structure of CBD is shown in Formula I:

[0048] Cannabidiol is insoluble in water but soluble in organic solvents, such as oil. Accordingly, CBD can be formulated for use in the described methods through use of any organic solvent known to the pharmaceutical arts, including, but not limited to edible oils. When formulated for oral administration, any edible oil can be used in the CBD formulation, including olive oil.

[0049] A CBD derivative is, in some embodiments, a metabolite of CBD such as but not limited to: (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series. A CBD derivative is characterized, in some embodiments, by a structure wherein at least one of the hydroxyl substituent groups is converted to a stable form thereof. In some embodiments a CBD derivative is an endocannabinoid derivative. In some embodiments, a CBD derivative is described in Frank D King; G Lawton; A W Oxford Progress in medicinal chemistry. Vol. 44. Pages 207-331, Elsevier Science, 2006 ISBN: 0080462103 9780080462103 which is hereby incorporated by reference in its entirety.

[0050] In some embodiments a composition as described herein further comprises cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), or any combination thereof. In some embodiments a composition as described herein further comprises at least two compounds selected from the group comprising: cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), or any combination thereof.

[0051] In some embodiments a composition as described herein has a w/w ratio of CBD to CBC, CBG, or CBN, or any combination thereof of 50: 1 to 5: 1 ; 40: 1 to 8: 1 ; 30:1 to 10: 1; or 25: 1 to 15: 1. In some embodiments, the above ratio is the ratio of CBD to at least two compounds selected from CBC, CBG, and CBN.

[0052] In some embodiments a composition as described herein comprises Tetrahydrocannabinol (THC). In some embodiments a composition as described herein comprises 1 to 120 mg/ml THC, 2 to 90 mg/ml THC, 5 to 80 mg/ml THC, 20 to 70 mg/ml THC, 20 to 50 mg/ml THC, or 40 to 90 mg/ml THC.

[0053] In some embodiments a composition as described herein is formulated to a suitable route of administration, selected from topical, oral, rectal, transmucosal, transnasal, intestinal and parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. In some embodiments the composition is formulated for delivery by sublingual administration, or by inhalation.

[0054] Oral administration of a composition as described herein, in some embodiments comprises a unit dosage form comprising tablets, capsules, lozenges, chewable tablets, suspensions, emulsions and the like. Such unit dosage forms comprise a safe and effective amount of the desired compound, or compounds, each of which is in some embodiments from about 0.7 mg to about 280 mg/70 kg, or in some embodiments, about 0.5 mg to about 210 mg/70 kg.

[0055] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms of a composition as described herein for peroral administration are well-known in the art. In some embodiments, tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. In some embodiments glidants such as silicon dioxide can be used to improve flow characteristics of the powder-mixture. In some embodiments coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents. In some embodiments, the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention, and can be readily made by a person skilled in the art.

[0056] In some embodiments the oral dosage form comprises predefined release profile. In some embodiments the oral or topical dosage form of the present invention comprises a dosage form (composition) or dosage forms having different release profile for the compounds described herein.

[0057] Peroral compositions, in some embodiments, comprise liquid solutions, emulsions, suspensions, and the like. In some embodiments, pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. In some embodiments, liquid oral compositions comprise from about 0.012% to about 0.933% w/w or w/v of the desired compound or compounds, or in some embodiments, from about 0.033% to about 0.7% w/v or w/w.

[0058] In some embodiments, compositions for use in the methods of this invention comprise solutions or emulsions, which in some embodiments are aqueous solutions or emulsions comprising a safe and effective amount of the compounds of the present invention and optionally, other compounds, intended for topical intranasal administration. In some embodiments, compositions comprise from about 0.01% to about 10.0% w/v or w/w of a subject compound. In some embodiments, compositions comprise from about 0.1% to about 2.0 w/w or w/v, which is used for systemic delivery of the compounds by the intranasal route.

[0059] In some embodiments, the pharmaceutical compositions are administered by intravenous, intra-arterial, or intramuscular injection of a liquid preparation. In some embodiments, liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In some embodiments the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration. In some embodiments, the pharmaceutical compositions are administered intra-arterially, and are thus formulated in a form suitable for intra-arterial administration. In some embodiments, the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.

[0060] Further, in some embodiments, the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, the compounds of the present invention are combined with an additional appropriate therapeutic agent or agents, prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

[0061] In some embodiments, pharmaceutical compositions of the present invention are manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0062] In some embodiments, the compounds/ingredients described hereinabove are included in the pharmaceutical or cosmetic composition of the present invention at a concentration suitable for achieving an anti-inflammatory effect or skin disease medication. In some embodiments, the pharmaceutical or cosmetic composition is buffered to a pH of 5.5-7.5 since. In some embodiments, a composition as described includes a dermatologically or topically acceptable carrier.

[0063] The phrase“dermatologically acceptable carrier”, refers, in some embodiments, to a carrier which is suitable for topical application onto the skin, i.e., keratinous tissue, has good aesthetic properties, is compatible with the active agents of the present invention and any other components, and is safe and non-toxic for use in mammals. An effective amount of carrier is selected from a range of about 20% to about 99.99%, or from about 40% to about 99.9%, , by weight, of the composition.

[0064] In some embodiments, a composition as described includes: dimethylsulfoxide, dimethylacetamide, dimethylformamide, a surfactant, azone, alcohol, acetone, propylene glycol, polyethylene glycol, or any combination thereof.

[0065] In some embodiments, a composition as described includes an emulsion carrier, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water- in-silicone emulsions, a cream, an ointment, an aqueous solution, a lotion or an aerosol.

[0066] In some embodiments, emulsions according to the present invention comprise a pharmaceutically effective amount of an agent disclosed herein and a lipid and/or an oil. Lipids and oils may be derived from animals, plants, or petroleum and may be natural or synthetic (i.e., man-made). In some embodiments, emulsions also comprise a humectant, such as but not limited to glycerin. In some embodiments, emulsions of the invention comprise from about 1% to about 10%, or from about 2% to about 5%, of an emulsifier, based on the weight of the carrier. Emulsifiers may be nonionic, anionic or cationic. Suitable emulsifiers are described in, for example, U.S. Pat. No. 3,755,560, issued to Dickert, et al. Aug. 28, 1973; U.S. Pat. No. 4,421,769, issued to Dixon, et al., Dec. 20, 1983; and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317-324 (1986). [0067] In some embodiments, the composition of the invention is a foam. In some embodiments, an emulsion comprises an anti-foaming agent to minimize foaming upon application to the keratinous tissue. In some embodiments, the composition of the invention comprises a water-in- silicone emulsion.

[0068] In some embodiments, topical compositions of the present invention comprise from about 30% to about 90% or from about 50% to about 85% or from about 70% to about 80% of a dispersed aqueous phase. The term“dispersed phase” is well-known to one skilled in the art it implies that the phase exists as small particles or droplets that are suspended in and surrounded by a continuous phase. The dispersed phase is also known as the internal or discontinuous phase.

[0069] Non-limiting examples of such optional ingredients include thickeners, acids, bases, salts, chelants, gums, water-soluble or dispersible alcohols and polyols, buffers, preservatives, sunscreening agents, colorings, and the like.

[0070] In some embodiments, a topical composition of the present invention comprises from about 25% to about 90% or from about 40% to about 80% or from about 60% to about 80%, water in the dispersed aqueous phase by weight of the composition.

[0071] In some embodiments, a topical composition of the present invention comprises an emulsifying agent. In some embodiments, a topical composition of the present invention comprises oil-in-water emulsion. Examples of suitable carriers comprising oil-in-water emulsions are described in U.S. Pat. No. 5,073,371 to Turner, D. J. et ah, issued Dec. 17, 1991, and U.S. Pat. No. 5,073,372, to Turner, D. J. et ah, issued Dec. 17, 1991 all of which are incorporated herein by reference in their entirety.

[0072] In some embodiments, a topical composition of the present invention comprises a surfactant. In some embodiments, a topical composition of the present invention comprises an anionic surfactant. In some embodiments a composition as described herein comprises from about 0.05% to about 10% or from about 1% to about 6% or from about 1% to about 3% of at least one hydrophilic surfactant which can disperse the hydrophobic materials in the water phase (percentages by weight of the topical carrier). In some embodiments, surfactants include any of a wide variety of known cationic, anionic, zwitterionic, and amphoteric surfactants. See, McCutcheon's. Detergents and Emulsifiers, North American Edition (1986), published by Allured Publishing Corporation; U.S. Pat. No. 5,011,681 to Ciotti et ah, issued Apr. 30, 1991; U.S. Pat. No. 4,421,769 to Dixon et al. issued to Dec. 20, 1983; and U.S. Pat. No. 3,755,560 all of which are hereby incorporated by reference in their entireties.

[0073] In some embodiments, a topical composition of the present invention comprises a cationic emulsifier such as but not limited to amino-amides. Nonlimiting examples of cationic emulsifiers include: stearamidopropyl PG-dimonium chloride phosphate, behenamidopropyl PG dimonium chloride, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl(myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof.

[0074] In some embodiments, a topical composition of the present invention comprises from about 25% to about 98% or from about 65% to about 95% or from about 70% to about 90% water by weight of the topical carrier. A pharmaceutical or a cosmetic composition of the present invention can be formulated in any of a variety of forms utilized by the pharmaceutical or cosmetic industry for skin application including solutions, lotions, sprays, creams, ointments, salves, gels, etc.

[0075] In some embodiments, pharmaceutical compositions for use in accordance with the present invention are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. In some embodiments, formulation is dependent upon the route of administration chosen.

[0076] In some embodiments injectables, of the invention are formulated in aqueous solutions. In some embodiments injectables, of the invention are formulated in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. In some embodiments, for transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0077] In some embodiments the preparations described herein are formulated for parenteral administration, e.g., by bolus injection or continuous infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. In some embodiments, compositions are suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0078] The compositions also comprise, in some embodiments, preservatives, such as benzalkonium chloride and thimerosal and the like; chelating agents, such as edetate sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfote and others; aromatic agents; viscosity adjustors, such as polymers, including cellulose and derivatives thereof; and polyvinyl alcohol and acid and bases to adjust the pH of these aqueous compositions as needed. The compositions also comprise, in some embodiments, local anesthetics or other actives. The compositions can be used as sprays, mists, drops, and the like.

[0079] In some embodiments, pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients, in some embodiments, are prepared as appropriate oily or water-based injection suspensions. Suitable lipophilic solvents or vehicles include, in some embodiments, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions contain, in some embodiments, substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. In some embodiments, the suspension also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.

[0080] In some embodiments, the active compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).

[0081] In some embodiments, the pharmaceutical composition or compositions are delivered in a controlled release system is formulated for intravenous infusion, implantable osmotic pump, transdermal patch, liposomes, or other modes of administration. In some embodiments a pump is used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In some embodiments, polymeric materials can be used. In yet some embodiments, a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer ( Science 249:1527-1533 (1990).

[0082] In some embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water-based solution, before use. Compositions are formulated, in some embodiments, for atomization and inhalation administration. In some embodiments, compositions are contained in a container with attached atomizing means.

[0083] In some embodiments the preparation of the present invention is formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides. [0084] In some embodiments, pharmaceutical compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. In some embodiments, a therapeutically effective amount means an amount of active ingredients effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.

[0085] In some embodiments, determination of a therapeutically effective amount is well within the capability of those skilled in the art.

[0086] Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tween™ brand emulsifiers; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the compound is basically determined by the way the compound is to be administered. If the subject compound is to be injected, in some embodiments the pharmaceutically-acceptable carrier is sterile, physiological saline, with a blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.

[0087] In addition, the compositions further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxy anisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.

[0088] Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, cellulose (e.g. Avicel™, RC-591), tragacanth and sodium alginate; typical wetting agents include lecithin and polyethylene oxide sorbitan (e.g. polysorbate 80). Typical preservatives include methyl paraben and sodium benzoate. In some embodiments, peroral liquid compositions also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0089] The compositions also include incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.

[0090] Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue- specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.

[0091] In some embodiments, compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline. In some embodiments, the modified compounds exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds. In some embodiments modifications also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. In some embodiments, the desired in vivo biological activity is achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.

[0092] In some embodiments, preparation of effective amount or dose can be estimated initially from in vitro assays. In some embodiments a dose can be formulated in animal models and such information can be used to more accurately determine useful doses in humans.

[0093] In some embodiments, toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro , in cell cultures or experimental animals. In some embodiments the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. In some embodiments the dosages vary depending upon the dosage form employed and the route of administration utilized. In some embodiments the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., Fingl, et al., (1975) "The Pharmacological Basis of Therapeutics", Ch. 1

P- 1]·

[0094] In some embodiments depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.

[0095] In some embodiments the amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0096] In some embodiments, compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier are also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0097] In some embodiments compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contain one or more dosage forms containing the active ingredient. In some embodiments the pack, for example, comprise metal or plastic foil, such as a blister pack. In some embodiments the pack or dispenser device is accompanied by instructions for administration. In some embodiments the pack or dispenser is accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, in some embodiments is labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

[0098] In some embodiments, the present invention further provides a method for inhibiting or reducing inflammation, a skin disease, a skin allergy, and/or skin rush in a subject in need thereof, comprising the step of administering to the subject a composition of the invention. In some embodiments, inflammation is an infection. In some embodiments, inflammation is psoriasis.

[0099] In an additional aspect, the present invention provides a method for treating and/or ameliorating a skin condition associated with: skin aging, skin wrinkles, uneven pigmentation, skin dehydration, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, or dilated skin capillaries, in a subject, comprising the step of administering to the subject a composition of the invention.

[00100] In another aspect, the present invention provides a method for treating and/or ameliorating a skin allergy, psoriasis, atopic dermatitis, vitiligo, and/or neuropathic pain in a subject, comprising the step of administering to the subject a composition of the invention.

[00101] In a further aspect, the present invention provides a method for treating and/or ameliorating a skin condition resulting from skin peeling and/or hair removal comprising the step of applying a composition as described herein onto an affected skin area.

[00102] In yet another aspect, the present invention further provides a prophylactic method for preventing a skin condition associated with skin peeling treatment and/or hair removal treatment comprising the step of applying a composition as described herein onto a treated skin area. In some embodiments, affected skin area comprises a rash and/or redness and/or a skin allergic condition and/or reaction.

[00103] In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is skin infection. In some embodiments, a skin peeling is chemical skin peeling. In some embodiments, a skin peeling is microdermabrasion. In some embodiments, hair removal treatment is laser hair removal treatment. In some embodiments, hair removal treatment is shave. In some embodiments, hair removal treatment is wax hair removal. In some embodiments, hair removal treatment is hair removal by a depilatory cream. In some embodiments, hair removal treatment is sugaring. In some embodiments, hair removal treatment is electrolysis.

[00104] In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is reduction in sensation in the treated skin area. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is reduction in an allergic skin reaction. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is skin scarring. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is skin blistering. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is a change in skin color and/or texture. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is a burn. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is scarring. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is hypopigmentation. In some embodiments, a skin condition associated with skin peeling treatment and/or hair removal treatment is skin rash. [00105] In some embodiments, the composition of the invention is used for treating and/or ameliorating: skin aging, skin wrinkles, uneven pigmentation, skin dehydration, dermatitis, skin eczema, osteoarthritis, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, dilated skin capillaries, psoriasis, atopic dermatitis, vitiligo, neuropathic pain, diabetic neuropathic pain or any combination thereof. In some embodiments, the composition of the invention is used for preventing: skin aging, skin wrinkles, uneven pigmentation, skin dehydration, dermatitis, skin eczema, osteoarthritis, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, skin rush, skin allergy, skin inflammation, dilated skin capillaries, psoriasis, atopic dermatitis, vitiligo, neuropathic pain, diabetic neuropathic pain or any combination thereof.

[00106] In another aspect, the present invention provides a method for treating a subject afflicted with an inflammatory disease, comprising administering to the subject the composition or compositions as described herein, thereby treating a subject afflicted with an inflammatory disease.

[00107] In some embodiments, treating an inflammatory disease is ameliorating an inflammatory disease. In some embodiments treating an inflammatory disease is inhibiting the progression of an inflammatory disease. In some embodiments treating an inflammatory disease is inhibiting inflammation. In some embodiments treating an inflammatory disease is minimizing the risk of inflammation in a subject susceptible to oxidative stress.

[00108] In some embodiments, the subject is a mammal. In some embodiments, the subject is a lab animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is a farm animal. In some embodiments, the subject is a human subject. In some embodiments, the subject is a peri-menopausal woman. In some embodiments, the subject is a woman suffering of estrogen excess.

[00109] In some embodiments, the subject is planned to undergo a skin peeling treatment or a hair removal treatment. The composition of the invention is administered in order to prevent side effect of said treatment, such as an allergy or a rash.

[00110] In some embodiments, the composition or compositions exert their inflammation inhibitory activity only in sites of inflammation. In some embodiments, inhibiting inflammation is specifically targeting inflammatory sites. In some embodiments, inhibiting inflammation is inhibiting an inflammation mediator at a site of inflammation and not at a site of no inflammatory activity.

[00111] Unless otherwise indicated, all numbers expressing, e.g., amounts or ratios of the CBD and other ingredients as defined above, used in this specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary by up to plus or minus 10% depending upon the desired properties to be obtained by the present invention.

Claims

1. A composition comprising cannabidiol (CBD) and 4-Methylthio-butyl-isothiocyanate (MTBI).

2. The composition of claim 1, further comprising an Angelica Sinensis extract.

3. The composition of claim 1, wherein said composition comprises from about 1% to about

50% w/w of a plant extract.

4. The composition of claim 1, wherein said CBD is at a concentration of from about 0.1 mg/ml composition to about 20 mg/ml composition.

5. The composition of claim 4, wherein said CBD is at a concentration of from about 0.5 mg/ml composition to about 8 mg/ml composition.

6. The composition of claim 1, wherein said MTBI is at a concentration of from about 0.2 mM to about 100 mM.

7. The composition of claim 6, wherein said MTBI is at a concentration of from about 1 pM to about 20 pM.

8. The composition of claim 1, further comprising tetrahydrocannabinol (THC).

9. The composition of claim 1, further comprising cannabichromene (CBC), cannabigerol (CBG), or cannabinol (CBN), or any combination thereof

10. The composition of claim 1, wherein said composition is an oral composition, a systemic composition, a topical composition, a rectal composition, a transmucosal composition, a trans- nasal composition, a trans-dermal, an intestinal composition or a parenteral composition.

11. The composition of claim 1, wherein said composition is a cosmeceutical composition.

12. The composition of claim 1, for use in treating an inflammatory disease, an allergy, or a skin rash.

13. The composition of claim 1, for use in treating and/or ameliorating skin aging, skin wrinkles, uneven pigmentation, skin dehydration, dermatitis, skin eczema, osteoarthritis, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, dilated skin capillaries, psoriasis, atopic dermatitis, vitiligo, neuropathic pain, or diabetic neuropathic pain, or any combination thereof.

14. A method for treating and/or ameliorating a skin condition in a subject, wherein said skin condition results from skin peeling treatment and/or from hair removal treatment, said method comprising administering to said subject the composition of claim 1, thereby treating and/or ameliorating a skin condition in a subject.

15. A method for preventing skin aging, skin wrinkles, uneven pigmentation, skin dehydration, dermatitis, skin eczema, osteoarthritis, excessive skin pigmentation, abnormal synthesis of melanin in the skin, visible opening of hair follicle, skin rush, skin allergy, skin bum, skin inflammation, dilated skin capillaries, psoriasis, atopic dermatitis, vitiligo, neuropathic pain, or diabetic neuropathic pain, or any combination thereof in a subject in need thereof, said method comprising administering to said subject the composition of claim 1, thereby treating and/or ameliorating a skin condition in a subject.

16. The method of claim 15, wherein said subject is planned to undergo a skin peeling treatment.

17. The method of claim 15, wherein said subject is planned to undergo a hair removal treatment.