Topical formulations comprising cannabidiol, method of preparing composition and method thereof

Abstract

To provide a composition suitable for topical delivery of cannabidiol to improve availability of cannabidiol at a local administration site of a mammal in a therapeutically effective amount necessary to reduce or alleviate local symptoms of psoriasis or arthritis, such as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and / or psoriatic arthritis.SOLUTION: A hydroalcoholic gel composition is disclosed for alleviating symptoms of psoriasis or arthritis, such as pain resulting from arthritic diseases and / or psoriatic arthritis, and / or neurological pain, such as pain resulting from sclerosis, e.g., multiple sclerosis, in a subject. Such a composition may comprise, inter alia, 0.1-20% cannabidiol, a skin penetration enhancer, ethanol, and one or more thickeners and / or gelling agents.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a topical aqueous alcohol gel composition containing cannabidiol for use as a cosmetic agent and / or for the treatment or alleviation of symptoms such as psoriasis symptoms in mammals, or pain caused by arthritis and / or psoriatic arthritis and / or neurological pain, for example, pain caused by sclerosis, for example, multiple sclerosis, etc., by topical local application.

Background Art

[0002] The clinical usefulness of various cannabinoids is well known to provide analgesia and neuroprotection, help reduce nausea and vomiting, and treat epilepsy, anxiety disorders, and glaucoma.

[0003] Cannabidiol ("CBD") is also well recognized for its mild analgesic effect and its anti-inflammatory effect in particular. Furthermore, it is also well known that cannabidiol lacks the psychoactive effects seen in many other cannabinoids including Δ<9>-tetrahydrocannabinol (THC). The latter (THC) is currently available in an oral dosage form sold under the trade name Marinol®.

[0004] Many diseases relate to inflammatory processes regulated by the immune system in an individual. Inflammation can be caused by hyperactive immune responses such as allergic reactions or dermatitis, certain forms of multiple sclerosis, autoimmune responses such as inflammatory bowel disease and arthritis. Regardless of the underlying cause of the inflammation, it is therapeutically desirable to regulate the immune system and reduce the inflammatory response leading to these diseases under these circumstances.

[0005] Psoriasis is a non-infectious, long-lasting autoimmune disease characterized by abnormal skin patches, typically small local patches or larger areas (e.g., over the whole body) of red, dry, itchy, and / or scaly skin. Skin damage can cause psoriatic skin changes (Koebner phenomenon).

[0006] The underlying mechanism is thought to involve the immune system reacting to skin cells that cause the overgrowth of keratinocytes. Keratinocytes make up about 90% of the epidermis. In normal skin, cell proliferation of epidermal cells results in a regeneration cycle of about 30 days, while in skin areas affected by psoriasis, cell proliferation has a regeneration cycle of only 3 - 5 days.

[0007] There are five main types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic. Plaque psoriasis typically appears as red spots with white scales on top. The affected areas are typically the back of the forearms, shins, groin area, and scalp or face. Fingernails and toenails are also often affected at some point, causing nail pits and / or changes in nail color. Pustular psoriasis is seen as blisters filled with small (non - infectious) pus. Inverse psoriasis forms red spots in skin folds. Psoriatic erythroderma can develop from any of the other types and typically occurs when the rash spreads very widely.

[0008] Psoriasis is generally considered a genetic disorder caused by environmental factors. Genetic factors are suggested to be predisposing factors for psoriasis. Symptoms can be exacerbated during winter and by the intake / use of certain drugs such as beta - blockers or NSAIDs. Infections and psychological stress can also contribute.

[0009] Currently, there is no cure for psoriasis, but various treatments can help control the symptoms. Treatments include steroid creams, vitamin D3 creams, ultraviolet light, and immunosuppressive drugs (e.g., methotrexate). Often, the symptoms of psoriasis can be managed with creams alone. Psoriasis is associated with an increased risk of psoriatic arthritis, lymphoma, cardiovascular disease, Crohn's disease, and depression. Psoriatic arthritis affects up to 30% of individuals with psoriasis.

[0010] Rheumatoid arthritis, psoriatic arthritis, and osteoarthritis cause pain in the affected joints, and the pain associated with rheumatoid arthritis can lead to functional impairment.

[0011] Certain cannabinoids have been shown to modulate various stages of the immune response and may exhibit some therapeutic benefit in the treatment of certain inflammatory diseases.

[0012] Cannabinoids are known to be useful as an adjunctive treatment for joint pain secondary to rheumatoid arthritis, psoriatic arthritis and osteoarthritis, as well as other autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus.

[0013] Cannabinoids are usually administered orally and thus affect the whole body of an individual. In addition to the above therapeutic benefits, cannabinoids present various pharmacological benefits including, but not limited to, anti-inflammatory, antispasmodic, antipsychotic, antioxidant, neuroprotective, anti-cancer and immunomodulatory effects.

[0014] Considering these systemic therapeutic advantages, it would be advantageous to develop a composition in which cannabidiol (CAS number 3956-29-1) is systemically delivered to achieve a therapeutically effective plasma concentration in a patient. However, cannabinoid oral dosage forms containing cannabidiol must overcome several obstacles to achieve systemic concentrations. First, cannabinoids containing cannabidiol are generally highly lipophilic. Thereby, their limited water solubility limits the amount of cannabinoid available for absorption in the gastrointestinal tract.

[0015] Cannabidiol, like other cannabinoids, is metabolized when absorbed from the human gastrointestinal tract. Thus, the overall effective uptake of orally administered cannabinoids such as cannabidiol into an individual varies from individual to individual and it is difficult to control its dosage. Therefore, in practice, it is very difficult to achieve a therapeutically effective plasma concentration in a patient by oral administration of cannabinoids, whereby some individuals are treated at doses that are too high and other individuals are administered doses lower than those required to achieve a therapeutically effective plasma concentration.

[0016] Thus, as described above, by providing an administration route that does not rely on absorption from the mammalian gastrointestinal tract and that does not undergo first-pass metabolism upon absorption from the gastrointestinal tract, there is provided a method of delivering a therapeutically effective amount of cannabidiol to a mammalian subject in need thereof for the topical treatment of one or more medical conditions responsive to cannabidiol, particularly skin conditions associated with psoriasis or pain associated with arthritis. One parenteral administration route for systemic delivery of cannabidiol is transdermal administration.

[0017] Unfortunately, due to its highly hydrophobic nature, cannabidiol is poorly absorbed through membranes such as mammalian skin, including human skin. Thus, successfully transdermally administering a therapeutically effective amount of cannabidiol to a mammalian subject in need of such treatment within a reasonable time frame is quite limited.

[0018] To increase skin penetration, it has been proposed to administer prodrugs of cannabidiol and / or other cannabinoids. The prodrug is then partially metabolized in the epidermis upon penetration into the epidermis and then, after penetration into the epidermis, is converted, for example, into cannabidiol and by-products. However, these by-products are undesirable because their physiological effects are unknown and they may cause unknown or undesirable side effects.

[0019] Thus, significant progress is still needed in the development of compositions suitable for topical compositions for skin cosmetic conditioning.

[0020] In particular, significant progress is still needed in the development of compositions suitable for topical delivery of cannabidiol to improve the availability of cannabidiol at the local administration site of a mammalian subject in a therapeutically effective amount necessary to reduce or alleviate the topical symptoms of psoriasis or arthritis, such as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and / or psoriatic arthritis.

[0021] Surprisingly, and unexpectedly, the inventors have been able to provide a composition that addresses the current needs and limitations of the prior art. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0022] Accordingly, an object of the present invention is to provide a novel composition, such as a topical composition, particularly (I) A cosmetic composition for improving the overall cosmetic appearance or condition, such as moisturizing / water retention, dryness, redness, reduction of the tendency to "become winter-like" skin, and / or reduction of wrinkle formation, and / or reduction of further occurrence of otherwise healthy skin wrinkles in a subject such as a human, mammal or other animal, etc. (II) A pharmaceutical composition for topical delivery of an active ingredient to improve the availability of an active ingredient, such as cannabidiol, menthol, camphor and / or eucalyptus oil, in a therapeutically effective amount necessary to reduce or relieve local symptoms of psoriasis and / or arthritis, such as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis or psoriatic arthritis, and / or neurological pain, such as pain caused by sclerosis, particularly multiple sclerosis, at the site of local administration in a subject such as a human, mammal or other animal, etc., and (III) A pharmaceutical composition suitable for topical delivery of an active ingredient, such as cannabidiol, menthol, camphor and / or eucalyptus oil, in a therapeutically effective amount necessary to reduce or relieve local symptoms such as skin or joint inflammation, local pain, redness, dryness and / or irritated skin, pruritus, etc. at the site of local administration in a subject such as a human, mammal or other animal, etc. to improve the availability of the active ingredient. can be considered to be provided. MEANS FOR SOLVING THE PROBLEM

[0023] In a first aspect, the present invention is an aqueous alcohol gel composition, a. cannabidiol present in an amount of 0.1 to 20%, such as 0.1 to 10% or more preferably 0.2 to 5% (by weight), and b. A skin penetration enhancer present in an amount of 0.5 to 1.5% (by weight), and c. Ethanol present in an amount of 10 to 30% (by weight), and d. One or more thickening agents or gelling agents present in a total amount of 0.4 to 2% (by weight), and e. Water in an amount of 100% (by weight) in total with respect to the composition, relates to an aqueous alcohol gel composition containing the same.

[0024] In some embodiments, cannabidiol is provided in crystalline or pure form. For example, a cannabidiol preparation contains less than 1.5%, 1.0% or 0.5% (by weight) of any one of cannabidiovaline (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabinol (CBN), and / or less than 1.0% of tetrahydrocannabinol (THC).

[0025] In a second aspect, the present invention relates to a composition according to the first aspect for use as a pharmaceutical composition in the topical local application for the treatment or alleviation of symptoms caused by arthritis, particularly rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis and / or psoriatic arthritis, such as pain, in a subject such as a human, mammal or other animal, and / or neurological pain, such as pain caused by sclerosis, such as multiple sclerosis.

[0026] In a third aspect, the present invention relates to the use of a composition according to the first or second aspect as a pharmaceutical for the treatment or alleviation of symptoms caused by arthritis, particularly rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis and / or psoriatic arthritis, such as pain, in a subject such as a human, mammal or other animal, and / or neurological pain, such as pain caused by sclerosis, such as multiple sclerosis.

[0027] In a fourth aspect, the present invention relates to a kit containing a composition according to the first or second aspect, including instructions for use.

MODE FOR CARRYING OUT THE INVENTION

[0028] Detailed Description of the Invention Definitions: In the context of the present invention, unless the context clearly indicates otherwise, the singular forms of words can include the plural, and vice versa. Thus, references to "a," "an," and "the" generally include each of the plural terms. For example, a reference to "ingredient" or "method" can include a plurality of such "ingredients" or "methods."

[0029] Similarly, the words "comprise," "comprises," and "comprising" should be interpreted inclusively rather than exclusively. Embodiments provided by the present disclosure may lack any element not specifically disclosed herein. Thus, the disclosure of an embodiment defined using the term "comprising" is also a disclosure of an embodiment "consisting essentially of the disclosed components" and an embodiment "consisting of the disclosed components." As used herein, particularly when a list of terms follows, terms such as "for example," "e.g.," or "such as" are merely illustrative and examples and should not be regarded as exclusive or inclusive. Any embodiment disclosed herein can be combined with any other embodiment disclosed herein.

[0030] The phrase "in some embodiments" can be used interchangeably with "in one or more embodiments."

[0031] Unless otherwise indicated, all percentages shown in this specification are on a weight basis relative to the total weight of the composition.

[0032] As used herein, "about" is understood to refer to a number within a range of values, e.g., within a range of + / - 10, + / - 5, + / - 2, + / - 1, + / - 0.5, + / - 0.1% of the referenced number. In some embodiments, the range is + / - 20% of the referenced number. Further, all numerical ranges herein are to be understood to include all integers, whole numbers, or fractions within that range. "About" may also indicate customary variations and / or uncertainties in the art.

[0033] "Subject" can be, for example, a human or an animal, such as a mammal, bird, reptile, livestock, or pet. The present disclosure should not be construed as limited to specific animals, humans, and / or demographics. In some embodiments, the subject is a human. In some embodiments, the subject is an animal. In some embodiments, the animal is a mammal such as a cat, dog, or horse. In some embodiments, the animal is a bird, reptile, livestock, or pet. In some embodiments, the subject is a human, such as an infant, child, adolescent, adult, or elderly person.

[0034] The present composition has a positive effect on normalizing the skin areas prone to psoriasis and the affected skin. Thus, topical application of the composition according to the present invention over a certain period of time reduces or even eliminates the symptoms of psoriasis (erythema, itching / scratching, and scaly skin) at the affected site. Initial tests have shown that topical use for a period of 1 to 3 weeks, by applying the aqueous alcohol gel 1 to 5 times a day to the affected skin area, reduces the redness of the skin and the scaly appearance of the spots, and significantly reduces the itching / scratching of the affected skin area. The aqueous alcohol gel causes inhibition of proliferation activity. Since psoriasis is an inflammatory skin disease that results in excessive proliferation of keratinocytes, the aqueous alcohol gel according to the present invention may be beneficial for the treatment of this disease.

[0035] The composition also appears to have a positive effect in the topical treatment of rheumatism. Thus, the topical application of the composition according to the invention reduces the pain from the joints affected by rheumatism. Thus, the composition can be used as a mild analgesic for topical application and thus can reduce the intake of other NSAIDs or other prescription drugs for rheumatism by the patient. In the case of mild rheumatism or during periods when the patient's pain level is low, the composition can further replace the NSAIDs or other drugs taken for the patient's rheumatism. Similarly, the composition also appears to have a positive effect on the topical treatment of neurological pain such as pain caused by sclerosis, such as multiple sclerosis.

[0036] The composition has a positive effect on the treatment, alleviation and / or reduction of conditions in subjects such as mammals, particularly humans. The above conditions can include psoriasis and / or psoriasis-related conditions such as arthritis, rheumatism and / or arthritis and / or rheumatism-related conditions such as joint pain, swollen joints, etc. The main effects of CBD on arthritis and / or psoriasis-related symptoms are shown in Table A. [Table 1]

[0037] The aqueous alcohol gel is further non-toxic and increases the transdermal delivery of cannabidiol in topical application to the skin. The absorption of cannabidiol through the skin / epidermis can be as high as over 46% of the applied cannabidiol. For comparison, when cannabidiol is administered orally, less than 10% is absorbed through the gastrointestinal tract.

[0038] Thereby, cannabidiol becomes more readily available in the epidermis to which the aqueous alcohol gel is applied and / or in the tissue under the skin, such as local areas of tendons, muscles, cartilage, etc. This reduces the amount of cannabidiol topically and locally administered to humans (compared to oral administration) without reducing the local effect of cannabidiol associated with the relief of symptoms from psoriasis and / or different types of arthritis, thus reducing or eliminating the side effects caused by oral administration and reducing costs.

[0039] Cannabidiol is lipophilic and thus readily soluble in ethanol, but cannabidiol is poorly soluble in aqueous media. Therefore, the aqueous alcohol gel is also excellent for dissolving cannabidiol. Thus, the dissolution of cannabidiol can be carried out by first dissolving cannabidiol in ethanol and then mixing the cannabidiol-containing ethanol fraction with the aqueous fraction containing the remaining components to prepare an aqueous alcohol gel. Furthermore, since ethanol is a good solvent for cannabidiol, the presence of ethanol in the aqueous alcohol gel also acts as a skin penetration enhancer for cannabidiol.

[0040] Cannabidiol is present in an amount of 0.1 to 20%, for example 0.1 to 10%. In in vitro experiments, it has been shown that a concentration of 0.1 to 5% (by weight), particularly 1% or more, of cannabidiol in the aqueous alcohol gel provides the above therapeutic effect.

[0041] The aqueous alcohol gel further contains at least one skin penetration enhancer present in an amount of 0.5 to 1.5% (by weight) in order to further enhance the skin penetration of highly lipophilic cannabidiol and / or other active ingredients including menthol, camphor and / or eucalyptus oil. Therefore, preferred penetration enhancers are oily substances. Preferred penetration enhancers include, for example, isopropyl myristate (Cas registration number: 110-27-0), g. dimethyl sulfoxide (DMSO) (Cas registration number: 67-68-5), urea / carbamide (Cas registration number: 57-13-6) or any combination thereof. The most preferred penetration enhancer is isopropyl myristate. In some embodiments, the aqueous alcohol gel contains a skin penetration enhancer of 0.5 to 1.5% (by weight) selected from isopropyl myristate, dimethyl sulfoxide (DMSO), urea, and any combination thereof.

[0042] A specific combination of isopropyl myristate and ethanol present in the aqueous alcohol gel significantly enhances the skin penetration of cannabidiol. Ethanol also promotes the skin penetration of cannabidiol. Skin contact with ethanol is thought to cause microcracks in the skin. The formation of microcracks enables other penetration enhancers as further described below, such as isopropyl myristate and / or camphor, menthol, etc. to exhibit increased skin penetration. Thereby, the skin penetration of cannabidiol is also further increased.

[0043] Ethanol present in the aqueous alcohol gel in an amount of 10 to 30% (by weight). Preferably, the aqueous alcohol gel contains 15 to 25% (by weight) of ethanol.

[0044] To provide a gel or gel-like texture to the aqueous alcohol gel, one or more thickeners or gelling agents are present in a total amount of 0.4 to 2% (by weight). Preferred thickeners / gelling agents are selected from acrylate cross-polymers, especially C10-C30 alkyl acrylate cross-polymers (e.g., commonly commercially available under the trade name Carbopol®), hydroxyethyl cellulose, xanthan gum, and / or any combination thereof. The amount of thickener mentioned is sufficient to ensure that the gel does not run off during application. In some embodiments, the aqueous alcohol gel comprises a thickener and / or gelling agent selected from acrylate cross-polymers, hydroxyethyl cellulose, xanthan gum, and / or any combination thereof.

[0045] The aqueous alcohol gel may also contain one or more pharmaceutically acceptable adjuvants, such as antioxidants, emulsifiers, pH adjusters, such as acids, bases or salts thereof, stabilizers, colorants, or any combination thereof.

[0046] One or more additional emulsifiers can be used to provide an emulsion of the aqueous phase and the oily substance present in the gel. Suitable emulsifiers are, for example, sodium stearoyl glutamate (e.g., commercially available as Carbopol®). The emulsifier is preferably present in a total amount of 0.01 to 0.03% (by weight). Examples of such suitable sodium stearoyl glutamate emulsifiers are indicated by the trade names Carbopol 980, Carbopol 974p, or Carbopol 9409.

[0047] The aqueous alcohol gel contains water in the amount of the remainder of the composition so as to total 100%. Unless otherwise specified, the water is drinking water quality, MilliQ water (e.g., purified water having a resistivity of at least 18.2 MΩ.cm (25 °C) and a TOC value of less than 5 ppb), or distilled water.

[0048] The aqueous alcohol gel may further comprise preferably 10 to 25% (by weight) of sodium chloride, in particular sea salt, or more preferably Dead Sea salt. The presence of sodium chloride in the aqueous alcohol gel has a positive effect with respect to psoriasis, as it helps to remove long-term pruritus and / or dead skin cells from the skin surface. In some embodiments, the composition comprises 10 to 15, 15 to 20, or 20 to 25% (by weight) of sodium chloride, such as Dead Sea salt.

[0049] The application of a skin moisturizer to skin prone to psoriasis further soothes the skin prone to psoriasis and reduces symptoms, in particular red scaly skin and / or itching / pruritus. Therefore, the composition preferably i. 0.01 to 1% (by weight) of an extract of aloe barbadensis leaves, ii. 1 to 5% (by weight) of panthenol, iii. 0.1 to 1 to 5% (by weight) of retinyl palmitate, iv. 0.5 to 5% (by weight) of glycerin, or one or more skin care or skin hydrating / water-retaining agents selected from any combination thereof. The moisturizer can also alleviate the drying of the skin (and thus the potential removal of the protective fat layer on the skin) resulting from the application of ethanol present in the aqueous alcohol gel. Furthermore, cannabidiol appears to enhance the effects of one or more of the above moisturizers, or vice versa, and can thus actually provide a synergistic effect in the regeneration and / or rehydration / hydration of the skin to which the composition is applied.

[0050] Unless otherwise specified, "aloe barbadensis leaves" refers to freeze-dried leaves, usually in powder form.

[0051] The preferred amounts of one or more skin care or skin hydrating / water-retaining agents are listed below. i. 0.01 to 0.5% (by weight), or more preferably 0.01 to 0.2% (by weight) of an extract of Aloe barbadensis leaves, ii. 1 to 5% (by weight), or more preferably 2 to 3% (by weight) of panthenol, iii. 0.1 to 1% (by weight), or more preferably 0.1 to 0.5% (by weight) of retinyl palmitate, iv. 0.5 to 5% (by weight), or more preferably 0.5 to 2.5% (by weight) of glycerin.

[0052] The topical composition may preferably further comprise one or more additional components selected from 0.5 to 5% (by weight) of menthol and / or 0.1 to 2% (by weight) of camphor. Preferably, menthol is present in an amount of 1 to 4% by weight or more preferably 1.5 to 3% (by weight). Camphor is preferably present in an amount of 0.2 to 1.0% (by weight) or more preferably 0.4 to 0.8% by weight. Further, in order to further enhance the skin permeability of highly lipophilic cannabidiol, eucalyptus oil can preferably be added in an amount of 0.5 to 1.5% (by weight), or more preferably 0.4 to 0.8% by weight.

[0053] Menthol, camphor and / or eucalyptus oil provide a cooling sensation when applied to the skin, thereby reducing or alleviating the pain level of joints affected by rheumatism. Further, camphor, menthol and / or eucalyptus oil also act as penetration enhancers and further improve the skin penetration of cannabidiol. In some embodiments, the aqueous alcohol gel comprises 0.5 to 5% (by weight) of menthol, 0.1 to 2% (by weight) of camphor and / or 0.5 to 1.5% (by weight) of eucalyptus oil.

[0054] The topical composition may preferably further comprise one or more pharmaceutically acceptable adjuvants selected from antioxidants, pH adjusters such as acids or bases, stabilizers, colorants or any combination thereof.

[0055] Preferred antioxidants are vitamin E (tocopherol) or one or more of its derivatives, articular tocopheryl acetate (CAS number 58 - 95 - 7). Antioxidants such as tocopheryl acetate can be present in a total amount of 1 - 3% (by weight). Furthermore, tocopheryl acetate is known to improve wound healing and reduce the formation of scar tissue when applied topically, which would be very beneficial regarding the treatment or alleviation of psoriasis symptoms.

[0056] Examples of other suitable antioxidants can include citric acid, ascorbic acid, and / or combinations thereof. The latter also acts as a pH adjuster. Phosphoric acid may also be applied as a pH adjuster and can ensure a stable pH in an aqueous alcohol gel by providing a phosphate buffer system therein.

[0057] For example, phytic acid (CAS number: 83 - 86 - 3) may be added. Phytic acid can release phosphate ions and thus can provide pH stability due to the generation of a phosphate buffering effect in the gel.

[0058] Alkaline pH adjusters generally include commonly used water - soluble and non - toxic bases such as sodium hydroxide or potassium hydroxide.

[0059] Preferably, the pH in the aqueous alcohol gel is 5 - 9, or preferably 6 - 8.5. In some embodiments, the pH of the gel mimics the pH of the skin, for example, a slightly acidic pH. Thus, in some embodiments, the pH is 4.5 - 6.5. In some embodiments, the pH of the aqueous alcohol gel is 4.5 - 5.5, 5.0 - 6.0, 5.5 - 6.5, 6.0 - 7.0, 6.5 - 7.5, 7.0 - 8.0, 7.5 - 8.5, or 8.0 - 9.0.

[0060] The cannabidiol used in the preparation of the aqueous alcohol gel may be a crystalline powder. The crystalline cannabidiol powder is obtained from natural cannabis plants and has a very high purity and very low or ultra-low levels of residual traces of other naturally occurring cannabinoids, particularly those with psychoactive effects such as THC, since the systemic psychoactive effects are undesirable side effects of the topical administration of the gel. Crystalline cannabidiol has very low levels of traces of other cannabinoids, less than 2% (by weight) in total, and contains less than 0.1% (by weight) of THC.

[0061] In some embodiments, crystalline CBD can be characterized as follows (Table B).

Table 2

Chemical Structure

[0062] Surprisingly, and unexpectedly, the inventors have found that the use of high-purity CBD, such as "crystalline CBD", provides one or more advantages in the formulation and use of the aqueous alcohol gels disclosed herein. First, CBD is typically provided dissolved in a carrier oil, such as a vegetable oil, for example, coconut oil or hemp seed oil. Generally, such "CBD oil" contains CBD at a concentration of about 10% (by weight). Thus, the use of CBD oil results in a formulation containing a large amount of (plant) oil. For example, a gel formulated at a CBD concentration of 1% contains 10% oil. In some embodiments, the use and / or presence of an oil, such as a vegetable oil, is undesirable in the formulation because the oil can cause an allergic reaction. Without wishing to be bound by any theory, considering many vegetable oils in topical compositions, including ointments, such as pain-relieving ointments, it is surprising that formulations containing vegetable oils are less efficient than those disclosed herein that do not contain vegetable oils. Second, providing CBD from CBD oil requires a significantly higher CBD dosage compared to pure CBD, such as crystalline CBD, to provide the same and / or equivalent effects. This is highly surprising because the prior art teaches that the presence of additional active ingredients in more crude CBD formulations, such as in CBD oil, provides beneficial synergistic effects.

[0063] In some embodiments, at least 10, 20, 50% or even more than 100% more CBD from CBD oil is required to provide the same effect compared to a formulation containing pure crystalline CBD.

[0064] In some embodiments, the aqueous alcohol gel composition does not contain vegetable oil and / or mineral oil. In some embodiments, the composition contains less than 5, 1, or 0.1% (by weight) of an oil, such as a vegetable oil and / or mineral oil.

[0065] In some embodiments, CBD is a "pure" or "crystalline" CBD, for example, a CBD composition containing less than 1.5% (by weight) of any one of cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabinol (CBN), and / or less than 1.0% (by weight) of tetrahydrocannabinol (THC). In some embodiments, "pure" or "crystalline" CBD contains less than 1.0% (by weight) of any one of CBDV, CBDA, CBG, CBN, and / or THC. In some embodiments, "pure" or "crystalline" CBD contains less than 0.50, 0.2, or 0.1% (by weight) of any one of CBDV, CBDA, CBG, CBN, and / or THC. In some embodiments, none of CBDV, CBDA, CBG, and CBN are present at a concentration exceeding 1.5% (by weight), and THC is not present at a concentration exceeding 1% (by weight). In some embodiments, none of CBDV, CBDA, CBG, CBN, and THC are present at a concentration exceeding 1.0, 0.5, 0.2, or 0.1% (by weight).

[0066] The composition is also applicable for use as a cosmetic skin care product that provides a water retention / humidifying effect to the epidermis. Furthermore, the properties of cannabidiolic acid as an antibacterial agent can also protect the skin surface from mild infections.

[0067] The compositions described herein may also be suitable for treating, reducing, and / or alleviating the symptoms of psoriasis. Generally, the severity of psoriasis can be divided into "mild" (i.e., less than 3% of the skin surface has psoriasis), "moderate" (3 - 10% of the skin surface has psoriasis), and "severe" (more than 10% of the skin surface has psoriasis).

[0068] In some embodiments, the aqueous alcohol gel composition is suitable for treating, reducing, and / or alleviating mild psoriasis symptoms.

[0069] In some embodiments, the aqueous alcohol gel composition is suitable for the treatment, reduction, and / or alleviation of moderate psoriasis symptoms.

[0070] In some embodiments, the aqueous alcohol gel composition is suitable for the treatment, reduction, and / or alleviation of severe psoriasis symptoms.

[0071] In some embodiments, the aqueous alcohol gel composition is suitable for the treatment, reduction, and / or alleviation of mild, moderate, and / or severe psoriasis symptoms, i.e., any combination of mild, moderate, and / or severe psoriasis symptoms.

[0072] An aqueous alcohol gel composition for topical local application for the purpose of reducing or alleviating the symptoms of psoriasis may also be referred to herein as a "psoriasis gel".

[0073] An aqueous alcohol gel composition for topical local application for the purpose of reducing or alleviating symptoms from psoriasis may include, for example, salts such as sea salt, such as Dead Sea salt, ethanol, water, panthenol, tocopheryl acetate, hydroxycellulose, cannabidiol, isopropyl myristate, retinyl palmitate, glycerin F, Aloe barbadensis leaf, and citric acid.

[0074] In some embodiments, the psoriasis gel includes Dead Sea salt, glycerin F, denatured ethanol 96%, isopropyl myristate, Aloe barbadensis leaf, water, panthenol, hydroxyethyl cellulose, cannabidiol CBD, xanthan, retinyl palmitate, tocopheryl acetate, and optionally sodium hydroxide, such as an aqueous sodium hydroxide solution.

[0075] Further examples of psoriasis gels suitable for the treatment / reduction and / or alleviation of psoriasis are shown above and / or below, including the appropriate ranges of each component.

[0076] A more preferred aqueous alcohol gel composition specifically prepared for topical local application for the purpose of reducing or alleviating symptoms from psoriasis is 0.1 to 20% (by weight) or more preferably 0.1 to 10% (by weight) of cannabidiol, 0.5 to 1.5% (by weight) of a skin penetration enhancer, particularly isopropyl myristate, 0.5 to 1.5% (by weight) of glycerin, 10 to 30% (by weight) of ethanol, One or more thickening agents or gelling agents in a total amount of 0.4 to 2% (by weight) as described above, 12 to 18% (by weight) of sodium chloride, particularly sea salt, or more preferably Dead Sea salt, 0.01 to 1% (by weight) of an extract of aloe barbadensis leaves, 1 to 5% (by weight) of panthenol, 0.1 to 1.5% (by weight) of retinyl palmitate, 0.5 to 5% (by weight) of glycerin, and Water in an amount up to a total of 100% with respect to the composition Comprising, consisting essentially of, and / or provided by combining them.

[0077] A further aqueous alcohol gel composition specifically prepared for topical local application for the purpose of reducing or alleviating symptoms from psoriasis is 0.5 to 2.0% (by weight) or more preferably about 1.0% (by weight) of cannabidiol, 0.3 to 1.5% (by weight) or more preferably about 0.9% (by weight) of a skin penetration enhancer, particularly isopropyl myristate, 0.1 to 0.5% (by weight) or more preferably about 0.2% (by weight) of glycerin, 10 to 30% (by weight) of ethanol or more preferably about 15% (by weight) of ethanol, particularly 96% ethanol, for example 96% denatured ethanol, One or more thickeners or gelling agents in an amount of 0.5 to 2.5% (by weight) or more preferably about 1.5% (by weight), in particular hydroxyethyl cellulose, Sodium chloride in an amount of 10 to 20% (by weight) or more preferably about 15.0% (by weight), in particular sea salt, or more preferably Dead Sea salt, An extract of Aloe barbadensis leaves in an amount of 0.01 to 1% (by weight) or more preferably about 0.05% (by weight), Panthenol in an amount of 1.5 to 4.0% (by weight) or more preferably about 2.75% (by weight), Retinyl palmitate in an amount of 0.1 to 0.5% (by weight) or more preferably about 0.3% (by weight), Glycerin in an amount of 0.1 to 0.3% by weight (by weight) or more preferably about 0.2% (by weight), An antioxidant in an amount of 0.01 to 0.03% (by weight) or more preferably about 0.02% (by weight), such as citric acid, in particular citric acid monohydrate, and Water in an amount up to a total of 100% (by weight) relative to the composition, for example 75.88 to 53.83% (by weight), more preferably about 61.28% (by weight), preferably water of drinking water quality It may contain, may consist essentially of, and / or may be provided by combining them.

[0078] Psoriasis gel causes inhibition of proliferation activity. Since psoriasis is an inflammatory skin disease that results in excessive keratinocyte proliferation, the test substance may be beneficial for the treatment of this disease, as shown in the examples described below.

[0079] A very preferred aqueous alcohol gel composition, particularly prepared for topical local application for the purpose of reducing or alleviating local symptoms caused by rheumatism in one or more joints, such as pain, and / or reducing the level of inflammation in one or more joints, and / or reducing neurological pain such as pain caused by sclerosis, such as multiple sclerosis, 0.1 to 10% (by weight) of cannabidiol, or more preferably 0.5 to 2.0% (by weight) of cannabidiol, 0.5 to 1.5% (by weight) of a skin penetration enhancer, particularly isopropyl myristate, 20 to 30% (by weight) of ethanol, One or more thickening agents or gelling agents in a total amount of 0.5 to 1.5% (by weight), or more preferably 0.8 to 1.2% (by weight) as described above, 1.5 to 2.5% (by weight) of menthol, 0.4 to 0.7% (by weight) of camphor, and Water in an amount up to 100% in total with respect to the composition is included.

[0080] A highly preferred aqueous alcohol gel composition specifically prepared for topical local application for the purpose of reducing or alleviating symptoms from psoriasis is 0.1 to 10% (by weight) or more preferably 0.5 to 2.0% (by weight) of cannabidiol, 0.5 to 1.5% (by weight) of a skin penetration enhancer, particularly isopropyl myristate, 0.5 to 1.5% (by weight) of glycerin, 10 to 20% (by weight) of ethanol, One or more thickening agents or gelling agents in a total amount of 0.4 to 2% (by weight) as described above, 12 to 18% (by weight) of sodium chloride, particularly sea salt, or more preferably Dead Sea salt, 0.01 to 1% (by weight) of an extract of aloe barbadensis leaves, 2 to 3% (by weight) of panthenol, 0.1 to 0.5% (by weight) of retinyl palmitate, 1 to 5% (by weight) of glycerin, and Water in an amount up to 100% in total with respect to the composition is included.

[0081] Although not wishing to be bound by any theory, the psoriasis gel is thought to cause an inhibition of proliferative activity. Since psoriasis is an inflammatory skin disease that results in the overproliferation of keratinocytes, the test substance may be beneficial for the treatment of this disease, as shown in the examples described below.

[0082] Treatment of psoriasis, such as mild, moderate and / or severe psoriasis, may include the application of psoriasis to the skin surface by gently massaging an appropriate amount of the gel onto the part of the body to be treated (e.g., 0.25 g - pea-sized to the hand, wrist or elbow (approx. 25 cm2), or two pea-sized amounts of 0.5 g each to the foot, ankle or knee (approx. 50 cm2)).

[0083] Dosage: 1 to 5 times a day, preferably 1 to 3 times a day, more preferably 1 to 2 times a day.

[0084] In some embodiments, the gel is washed from the skin surface after a certain period of time. As a skin care product, it is considered that certain skin-affine cosmetic substances may remain.

[0085] At the latest after about 30 minutes, 45 minutes or one hour, the skin is rinsed or washed with water such as warm tap water, mainly to remove excess salt.

[0086] An aqueous alcohol gel composition for topical local application for the purpose of reducing or alleviating symptoms resulting from rheumatoid arthritis in one or more joints, such as pain, and / or reducing the level of inflammation in one or more joints, may also be referred to herein as "arthritis gel".

[0087] The most preferred aqueous alcohol gel composition specifically prepared for topical local application for the purpose of reducing or alleviating local symptoms resulting from rheumatoid arthritis in one or more joints, such as pain, and / or reducing the level of inflammation in one or more joints, 0.2 to 5% (by weight), or more preferably 0.2 to 2% (by weight) of cannabidiol, 0.7 to 1.1% (by weight) of a skin penetration enhancer, particularly isopropyl myristate, 20 to 30% (by weight) of ethanol, As described above, a total of 0.5 to 1.5% (by weight), or more preferably a total of 0.8 to 1.2% (by weight) of one or more thickeners or gelling agents, 1.5 to 2.5% (by weight) of menthol, 0.4 to 0.7% (by weight) of camphor, 0.05 to 0.3% (by weight) of phytic acid (50% purity) and Water in an amount up to a total of 100% with respect to the composition is included.

[0088] The most preferred aqueous alcohol gel composition, which is particularly prepared for topical local application for the purpose of reducing or alleviating symptoms from psoriasis, 0.2 to 5% (by weight) or more preferably 0.2 to 2.0% (by weight) of cannabidiol, 0.7 to 1.1% (by weight) of a skin penetration enhancer, particularly isopropyl myristate, 0.5 to 1.5% (by weight) of glycerin, 10 to 20% (by weight) of ethanol, As described above, a total of 0.4 to 2% (by weight) of one or more thickeners or gelling agents, 12 to 18% (by weight) of sodium chloride, particularly sea salt, or more preferably Dead Sea salt, 0.01 to 0.1% (by weight) of an extract of Aloe barbadensis leaves, 2 to 3% (by weight) of panthenol (75% purity), 1.0 to 3.0% (by weight) of tocopherol acetate 0.1 to 0.5% (by weight) of retinyl palmitate, 1 to 3% (by weight) of glycerin, 0.01 - 0.03% (by weight) of sodium stearoyl glutamate (O / W emulsifier) 0.01 - 0.03% (by weight) of citric acid (monohydrate) and water in an amount up to a total of 100% with respect to the composition is included.

[0089] The psoriasis gel causes inhibition of proliferation activity. Psoriasis is an inflammatory skin disease that results in excessive proliferation of keratinocytes, so the test substance may be beneficial for the treatment of this disease, as shown in the examples described below.

[0090] The above composition is applicable for use as a pharmaceutical composition in the topical local application for the treatment or alleviation of symptoms resulting from arthritis, particularly rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis and / or psoriatic arthritis, especially pain, in a subject such as a human, mammal or other animal, such as a cat, dog or horse.

[0091] In some embodiments, the above composition is applicable for use as a medical composition in the topical local application for the treatment or alleviation of symptoms of psoriasis, particularly redness, dryness, itching, and / or scaly skin, in a subject such as a human, mammal or other animal.

[0092] The topical gel composition is topically applied 1 - 5 times a day to a local area of the epidermis of a subject such as a human, mammal or other animal. In some embodiments, the gel composition is applied 1 or 2 times a day. In some embodiments, the composition is applied 3, 4 or more times a day. A dosage suitable for a subject such as a human is, for example, 0.25 g (approximately the size of a pea) for an area of about 25 cm2 on the hand, wrist or elbow, or 2 pea-sized portions of 0.5 g each are applied to the foot, ankle or knee (e.g., 50 cm2).

[0093] In some embodiments, the gel composition disclosed herein is topically applied to the local skin area of the subject in an amount of 2 - 250, 5 - 100 or 10 - 50 mg / cm2 per application.

[0094] In some embodiments, one or more of the topical gel compositions disclosed herein are applied to relieve arthritis and / or pain conditions associated with one or more warm and / or swollen joints.

[0095] Generally, unless otherwise indicated, the compositions disclosed herein are topical compositions.

[0096] The compositions disclosed herein may also be cosmetic compositions. In some embodiments, the composition is a cosmetic skin moisturizer or a skin care composition.

[0097] Generally, the presence of alcohol in the compositions according to the invention is thought to provide a beneficial effect to the subject via rapid evaporation allowing a cooling effect on the treated skin surface.

[0098] Examples of the instructions for use of the gels disclosed herein are shown in Examples 11 and 12.

[0099] In some embodiments, the compositions disclosed herein are part of a kit that includes instructions for use such as those disclosed in Example 11 or 12. In many cases, the composition is packaged in a suitable container such as a container that can be repeatedly opened and closed or a disposable container. In some embodiments, the container is a disposable container such as a sealed bag. In some embodiments, the container is a glass or plastic container with a lid. In some embodiments, the container is a tube, such as a squeeze and / or collapsible tube, or another collapsible package known in the art. In some embodiments, the compositions disclosed herein are provided in a container such as a kit that may also include instructions for use.

[0100] Further embodiments of the invention are also disclosed in the following examples and figures.

Brief Description of the Drawings

[0101]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Example

[0102] Abbreviations NaF: Sodium fluoride LPS: Lipopolysaccharide IL: Interleukin TNF: Tumor necrosis factor PGE2: Prostaglandin E2 r.l.u.: Relative light unit SD: Standard deviation DMEM: Dulbecco's modified Eagle's medium FBS: Fetal bovine serum EF-1α: Elongation factor 1α

[0103] Example 1 Preparation of a Psoriasis Aqueous Alcohol Gel and a Placebo Psoriasis Gel for In Vitro Testing

[0104] The psoriasis gel and the placebo gel were produced using the following compositions.

Table 3

[0105] Ethanol was mixed with cannabidiol, glycerin, and isopropyl myristate at room temperature.

[0106] Water was mixed at room temperature with the remaining components. The ethanol fraction was then poured into the aqueous fraction and stirred until a homogeneous mixture was obtained. The thickening agent is added to the aqueous fraction before mixing with the ethanol fraction and / or to the mixture of the ethanol fraction and the water fraction.

[0107] For the placebo gel, all components were thoroughly mixed at room temperature.

[0108] Example 2 Preparation of Arthritis Aqueous Alcohol Gel and Placebo Arthritis Gel for In Vitro Tests

[0109] The arthritis gel and the placebo arthritis gel were manufactured as described in Example 1 using the following compositions.

Table 4

[0110] Example 3 Effect of Arthritis Gel / Placebo on the Survival Rate of Human Monocytes

[0111] Monocyte Cell Culture Human primary monocytes were prepared from the buffy coat of healthy human blood donors according to a standardized procedure.

[0112] Monocyte Cell Treatment and Alamar - Blue Assay For viability measurement, cells were seeded in 96 - well plates at a density of 220,000 cells / well.

[0113] The arthritis gel and the placebo arthritis gel (test articles prepared in Example 2) were each dissolved in cell culture medium. 1 μl of the stock solution or dilution was added per well (100 μl). Monocytes were seeded in 96 - well plates and incubated with a NaF (100 μg / ml) positive control, a medium control, and test items at increasing concentrations.

[0114] Monocytes were seeded in 96 - well plates and incubated with eight different concentrations of the test item.

[0115] NaF was used as a positive control and untreated cells were used as a negative control. The test concentrations of the test items are shown in Figure 1.

[0116] After 24 hours of incubation, 10 μl of AlamarBlue® (Biosource, USA) was added to each well. After 2 hours, fluorescence was measured with a fluorescence spectrophotometer using 544EX nm / 590 EM nm filter settings. The amount of fluorescence is proportional to the number of live cells and corresponds to the metabolic activity of the cells. Damaged and non-viable cells have a lower natural metabolic activity and thus produce a proportionally lower signal than healthy cells.

[0117] The active ingredient of alamarBlue® (resazurin) is a non-toxic cell-permeable compound that is blue and substantially non-fluorescent. When it enters cells, resazurin is reduced to resorufin, which produces a very bright red fluorescence. Viable cells continuously convert resazurin to resorufin, thereby producing a quantitative measure of viability and cytotoxicity.

[0118] The effect on cell viability in human monocytes is shown in Figure 1. The results are presented as % viability compared to the control (100%) (mean: n = 4 ± standard deviation).

[0119] The test items at up to 500 μg / ml, i.e., the arthritis gel and the placebo arthritis gel, were not cytotoxic.

[0120] Example 4 Effect of psoriasis gel / placebo on the viability of human monocytes

[0121] To test the cytotoxicity of the psoriasis gel and the placebo psoriasis gel on human monocytes, the test of Example 3 was repeated for the test items prepared in Example 1.

[0122] The results of the effect on cell viability in human monocytes are shown in Figure 2. The results are presented as % viability compared to the control (mean: n = 4 ± standard deviation).

[0123] None of the test items at a maximum of 1000 μg / ml were cytotoxic.

[0124] At concentrations of 500 μg / ml and above, the placebo shows "higher survival rates", which may be due to interference with fluorescence measurement.

[0125] Example 5 Effect of the arthritis gel on LPS-induced IL-6 release and PGE2 release

[0126] Human primary monocytes were isolated from buffy coats of three healthy human blood donors.

[0127] For ELISA measurement, the cells were seeded in 24-well plates at a density of 2,200,000 cells / well.

[0128] The monocytes were incubated for 24 hours with the test items prepared in Example 2 (five different concentrations, the concentrations used are shown in Figure 3).

[0129] LPS (10 ng / ml, Salmonella typhimurium SL1181) was added 30 minutes after the start of treatment with the test items.

[0130] After 24 hours, the supernatant was removed, centrifuged, and the concentration of IL-6 (Figure 3) was investigated by ELISA using the manufacturer's protocol (n = 6, three different donors).

[0131] The results shown in Figure 3 are expressed as % of the LPS value (LPS = 100%, mean: n = 6 ± standard deviation).

[0132] Both test items (placebo and arthritis verum) did not affect LPS-induced IL-6 release in human monocytes.

[0133] The effect on LPS-stimulated PGE2 release is shown in Figure 4.

[0134] The results are expressed as % of the LPS value (LPS = 100%, mean: n = 6 ± standard deviation).

[0135] At the highest concentration tested, the arthritis gel (veram) inhibited LPS-induced PGE2 release, while the arthritis placebo gel slightly enhanced LPS-induced PGE2 release.

[0136] Example 6 Effect of psoriasis gel on LPS-induced TNF release

[0137] Human monocytes from 3 different donors were stimulated with LPS (10 ng / ml) and incubated with the increasing concentrations of the test items prepared in Example 1, namely the psoriasis gel and the placebo psoriasis gel. The concentrations of the test items used are shown in Figure 5. The results are expressed as % of the LPS value (LPS = 100%, mean: n = 6 ± standard deviation).

[0138] Both test items (psoriasis gel (veram) and placebo) had no effect on LPS-induced TNFα release.

[0139] Example 7 Effect of psoriasis gel on keratinocyte proliferation.

[0140] The psoriasis gel (PG) and the placebo psoriasis gel (PPG) were tested for their effects on keratinocyte proliferation.

[0141] The following concentrations were investigated for their effects on proliferation: 10, 25, 50, 100, 250, 500, 1000 μg / ml.

[0142] Keratinocyte cell culture: The cell lines HaCaT and HaCaT-NucLight-Red (keratinocytes) were cultured in supplemented DMEM medium (DMEM complete medium) containing 10% FBS and 1% antibiotic penicillin / streptomycin in a humidified atmosphere of 37°C and 5% CO2. In our laboratory, HaCaT-NucLight-Red cells were generated by infection with a lentivirus encoding a nuclear-restricted red fluorescent protein under the EF-1α promoter.

[0143] Proliferation assay The IncuCyte (trademark) live-cell imaging system combined with the NucLight reagent provides a live-cell kinetic assay for the measurement of proliferation (Essen BioScience). HaCaT-NucLight-Red cells were seeded at a density of 5×103 cells / well in 96-well plates at 37°C in a humidified atmosphere of 5% CO2. The cell cultures were then treated with selected concentrations of the test substance in DMEM medium containing 10% FBS, and the plates were introduced into an IncuCyte ZOOM live-cell microscope (Essen BioScience), and images were taken every 24 hours for an additional 72 hours. The data were analyzed by the total integrated intensity (RCU×μm2×well) of the live content cell imaging system IncuCyte HD (Essen BioScience, Hertfordshire, UK). The assay for each concentration of the test item was performed in three wells.

[0144] HaCaT-NucLight-Red cells were treated with the test substance or placebo at indicated doses for 24, 48, and 72 hours. The proliferation activity was evaluated by the IncuCyte ZOOM live-cell imaging system. The results are shown in Table 7.

[0145] As shown in Figure 7, the test substance decreases proliferation compared to the placebo at a dose of 1000 μg / ml after 24, 48, and 72 hours. No significant changes were seen for the remaining doses (Figure 7).

[0146] Example 8 Human Test of Psoriasis Gel

[0147] Four subjects (all female) underwent a test of the psoriasis gel (veram / placibo) prepared according to Example 1.

[0148] As shown in Table 3 below, all four had active psoriasis patches. None of the subjects took other medications during the test period.

[0149] Each subject was required to evaluate the symptoms on a 0 - 10 scale (0 = asymptomatic, 10 = the worst symptoms experienced with psoriasis) before and during the test, i.e., 1 hour after applying the gel to the psoriasis spots listed in Table 3 and also as an average over a day. The same was true after testing the gel for the number of days listed in Table 3.

[0150] Each subject applied the psoriasis gel (veram or placebo) twice a day over the designated spots during the test period (the period listed in Table 3).

[0151] Subjects 1, 2, and 4 reported that a salt layer appeared approximately 1 hour after applying the gel. The salt layer was easily removed with a wet cloth.

[0152] Subjects 1, 2, and 4 all reported that the itching disappeared within 10 - 20 minutes after application. Subjects 1 and 4 reported experiencing a heat sensation immediately after applying the gel.

Table 5

[0153] This test clearly shows that veram psoriasis gel reduces the itching, scaling, erythema, and duration of psoriasis when applied twice a day. The placebo gel does not result in a significant reduction in the symptoms of itching, scaling, or erythema.

[0154] Example 9

[0155] Three subjects tested the arthritis gel. Two of the subjects had symptoms of osteoarthritis in their right elbows and the third subject had symptoms from the neck.

[0156] Each subject was required to evaluate their symptoms on a 0 - 10 scale (0 = no symptoms, 10 = worst pain ever experienced due to arthritis) as an average per day, before and during the test, i.e., 1 hour after applying the gel to the elbow / neck, and the same was done after testing the gel for several days.

[0157] None of the subjects took prescription medications for osteoarthritis. All three subjects took over - the - counter painkillers at the start of the test period. Subject 1 and 2 took ibuprofen three times a day (400 mg) during the test period, and Subject 3 took paracetamol four times a day 2×500 mg.

[0158] Each subject applied the arthritis gel (Veram) to the above joints twice a day during the test period (the period described in Table 4) or whenever pain occurred.

[0159] All three subjects reported slight pain relief within a few minutes after applying the gel and that the pain was close to 0 after 1 - 2 hours.

Table 6

[0160] This test clearly shows that the Veram arthritis gel reduces pain from joints when applied twice a day.

[0161] Example 10

[0162] Two subjects suffering from mild multiple sclerosis (MS) tested the arthritis gel equivalent and its effect on local neurological pain caused by MS. Both subjects had pain in their arms caused by MS. One subject experienced MS - related pain only in the right arm and the other subject experienced MS - related pain in both arms.

[0163] Each subject was required to evaluate neurological pain on a 0 - 10 scale (0 = asymptomatic, 10 = the worst pain ever experienced due to arthritis) as an average over the day, before and during the gel test, i.e., 1 hour after applying the gel to the right arm. The same was done after testing the gel for several days.

[0164] Both subjects were medicated for MS. In both cases, Rebif22 (registered trademark) (Interferon beta - 1a (CHO - cell, 22 mg)) was administered three times a week. No one reduced the weekly dose during the test. During periods of pain attacks, both subjects took ibuprofen 400 mg three times a day.

[0165] Each subject applied the arthritis gel (Veram) to the right arm twice a day during the test period (the period described in Table 5). The left arm of the second subject was not treated. The first subject had an MS attack in 14 days. The second subject had an MS attack in 60 days. Both subjects tested the arthritis gel for 14 days.

[0166] Both subjects reported some pain relief within minutes after applying the gel. Two hours later, the pain was close to 0 in the right arm, but not reduced in the left arm of the second subject.

Table 7

[0167] Conclusions regarding the test results:

[0168] Arthritis gel placebo and arthritis gel (Veram):

[0169] At the highest concentration tested (500 μg / ml), the arthritis gel AT - 0918 - 400 - 02 Veram inhibited LPS - induced PGE2 release, while the placebo slightly enhanced LPS - induced PGE2 release.

[0170] Prostaglandin E2 (PGE-2) is usually released by the blood vessel wall in response to infection or inflammation and acts on the brain to induce fever and / or the perception of pain. Therefore, by inhibiting LPS-induced PGE2 release, the Veram arthritis gel may also help to reduce the temperature rise in the local treatment area and the level of perceived pain.

[0171] Furthermore, camphor and menthol are known to improve blood circulation in the skin area where the camphor and / or menthol is topically applied. Therefore, the combination of menthol, camphor and cannabidiol in the aqueous ethanol gel not only improves the skin penetration of cannabidiol, but also appears to enhance each other and promote the reduction of pain in the vicinity of the local area treated with the arthritis gel.

[0172] Tests by the subjects in Example 9 clearly show that the Veram arthritis gel reduces pain from the joints. This effect is seen when applied at least twice a day.

[0173] Placebo psoriasis gel and psoriasis gel (Veram):

[0174] Both test items (placebo and Veram) had no effect on LPS-induced TNFα release.

[0175] The effects of the test items on the viability of HaCaT were preliminarily analyzed. None of the test items at up to 1000 μg / ml were cytotoxic.

[0176] Therefore, the following concentrations were investigated for their effects on proliferation: 10, 25, 50, 100, 250, 500, 1000 μg / ml.

[0177] Psoriasis gel (Veram) causes inhibition of proliferation activity. However, these effects are also observed with placebo, although to a lesser extent than with Veram and should be taken into account. Since psoriasis is an inflammatory skin disease that results in hyperproliferation of keratinocytes, the test substance may be beneficial in the treatment of this disease.

[0178] Furthermore, when tested on the subject(s) of Example 8, the test clearly shows that Veram psoriasis gel reduces the itching, scaling, erythema and duration of psoriasis. This effect is seen when applied at least twice a day. The placebo gel does not result in a significant reduction in the symptoms of itching, scaling or erythema.

[0179] Effect of arthritis gel (Veram) on neurological pain from MS: The test in Example 10 clearly shows that Veram arthritis gel reduces the pain from MS attacks. This effect is seen when applied at least twice a day.

[0180] Example 11 Instructions for use - Arthritis gel How does arthritis gel function? Arthritis gel is a gel preparation containing an alcohol / water mixture, - reduces the pain conditions occurring in rheumatoid arthritis, - provides a conductive cooling effect. Arthritis gel is a medical device. Its effectiveness and safety have been tested in accordance with the European Directive on Medical Devices (93 / 42 / EEC). Principle of action of arthritis gel: Arthritis gel is externally applied in the form of a gel preparation in the pain conditions of hot joints and swollen joints. This is used to assist in the external treatment of arthritis and reduce the pain conditions occurring in these patients. The main physical effect is brought about by the alcohol / water mixture. When the gel is applied to the skin, the alcohol evaporates, providing a faster conductive cooling effect on the treated skin surface. Applicable Fields The medical device is used to assist in the external treatment of arthritis and relieve the pain of hot joints and swollen joints. Dosage Method, Types and Periods of Application When, how often, and for how long should the arthritis gel be used? If necessary, it can be used several times a day from the tube, applied to the relevant body area, and massaged. Recommended dosage: Apply a pea-sized amount of 0.25 g to the hand, wrist, or elbow, and apply two pea-sized amounts of 0.5 g to the foot, ankle, or knee. If no improvement is seen within 2 - 3 days after the start of treatment, or if the symptoms have significantly worsened, consult a doctor. This product is for temporary use only. Do not use if you are allergic to alcohol or any of the ingredients. Precautions Keep out of reach of children. There is no evidence regarding the use of the gel during pregnancy or lactation. Contraindications The arthritis gel should not be used if there is a known allergy to any of the ingredients. Do not use this product on the skin surface simultaneously with other products. Interactions To avoid drug interactions, apply the medication at 1 - 2 hour intervals or consult a doctor. Explanation and Information on the Durability of the Medical Device The arthritis gel can only be used until the date marked "Expiry Date" on the carton. Pharmaceutical Form and Content The original package contains 50 ml of gel. Composition Active Ingredient: Alcohol / Water Mixture Other Ingredients: Menthol, Sodium Hydroxide Solution, Cannabidiol, Acrylate Crosspolymer, Isopropyl Myristate, Camphor, Phytic Acid No preservatives are used. Store in a cool, dry place away from direct sunlight. Minor color changes do not affect the effectiveness of this product. Use the opened tube within 30 days.

[0181] Example 12 Instruction Manual - Psoriasis Gel How does Psoriasis Gel work? Psoriasis Gel is a gel preparation containing Dead Sea salts, - Relieves and aids in the external treatment of psoriasis, - Promotes the desquamation process and reduces scaling and erythema associated with dryness. Psoriasis Gel is a medical device. Its effectiveness and safety have been tested in accordance with the European Directive on Medical Devices (93 / 42 / EEC). Principle of Action of Psoriasis Gel Psoriasis Gel is a topical preparation of Dead Sea salts in the form of a gel applied to the skin. The intended effects of the medical device are brought about by the Dead Sea salts. The mode of action is to promote the desquamation process and reduce scaling and erythema associated with dryness. After applying the gel, an osmotic pressure and moisturizing effect (moisture retention effect) occur. In this case, water is absorbed and retained in the gel by hypertonic saline. This is assisted by the physical conductive cooling effect from ethanol. Furthermore, Psoriasis Gel contains the main components within the medical device, improves the skin's water retention, and thus combats new scaling. Application Area Psoriasis Gel is used to relieve and aid in the external treatment of psoriasis with typical symptoms, such as dry, reddened, and scaly skin. Dosage Method, Type and Duration of Application When, how often, and for how long should Psoriasis Gel be applied? If necessary, the corresponding amount can be taken out of the tube several times a day, applied to the relevant body area, and massaged. Recommended Dosage: Apply 0.25 g (pea-sized) to the hands, wrists, or elbows, and 0.5 g (the size of two peas) to the feet, ankles, or knees. The gel must be rinsed off the skin surface within a maximum of 1 hour (to remove salts). Application to the skin surface and continuous application are possible up to 30 days. If no improvement is seen within 2 - 3 days after starting treatment, or if the symptoms have significantly worsened, consult a doctor. This product is for temporary use only. Do not use if there is an allergy to any of the ingredients. Precautions Keep out of reach of children. There is no evidence regarding the use of the gel during pregnancy or lactation. Contraindications The psoriasis gel should not be used if there is known hypersensitivity to any of the ingredients. Do not use this product on the skin surface simultaneously with other products. Interactions To avoid drug interactions, apply the medication at 1 - 2 hour intervals or consult a doctor. Explanation and information regarding the durability of medical devices The psoriasis gel can only be used until the date marked "Expiry Date" on the carton. Pharmaceutical form and content The original packaging is 50 ml of gel. Composition Active ingredient: Dead Sea salt Other ingredients: Ethanol / water, panthenol, tocopheryl acetate, hydroxyethyl cellulose, cannabidiol, isopropyl myristate, retinyl palmitate, glycerin F, Aloe Barbadensis leaf, citric acid The gel contains alcohol. This gel is contraindicated for use by people known to have an allergy to any of its ingredients. Store in a cool, dry place out of direct light.

Claims

1. An aqueous alcohol gel composition comprising: a. Cannabidiol present in an amount of 0.1 to 20%, such as 0.1 to 10% or more preferably 0.2 to 5% (by weight), optionally provided in crystalline form or in pure form; b. A skin penetration enhancer present in an amount of 0.5 to 1.5% (by weight); c. Ethanol present in an amount of 10 to 30% (by weight); d. One or more thickening or gelling agents present in a total amount of 0.4 to 2% (by weight); e. Water in an amount up to a total of 100% (by weight) based on the composition. An aqueous alcohol gel composition containing the above components.

2. The composition according to claim 1, wherein the cannabidiol used in the preparation of the gel is provided in crystalline form or in pure form.

3. The composition according to claim 1 or 2, wherein the cannabidiol contains less than 1.5%, 1.0% or 0.5% (by weight) of any one of cannabidiovaline (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabinol (CBN), and / or less than 1.0% of tetrahydrocannabinol (THC).

4. The composition according to any one of claims 1 to 3, containing less than 2.0, 1.0%, 0.5, or 0.1% (by weight) of an oil, such as vegetable oil and / or mineral oil.

5. The composition according to any one of claims 1 to 4, further comprising 10 to 25% (by weight) of sodium chloride, especially sea salt, or more preferably Dead Sea salt.

6. i. An extract of aloe barbadensis leaf in an amount of 0.01 to 1% (by weight); ii. Panthenol in an amount of 1 to 5% (by weight); iii. Retinyl palmitate in an amount of 0.1 to 1 to 5% (by weight); iv. Glycerin in an amount of 0.5 to 5% (by weight); or one or more skin care or skin water retention / humectant agents selected from any combination thereof. The composition according to any one of claims 1 to 5.

7. The composition according to any one of claims 1 to 6, further comprising one or more additional components selected from 0.5 to 5% (by weight) of menthol and / or 0.1 to 2% (by weight) of camphor and / or 0.5 to 1.5% (by weight) of eucalyptus oil.

8. The composition according to any one of claims 1 to 7, wherein the skin penetration enhancer is selected from isopropyl myristate, dimethyl sulfoxide (DMSO), urea, or any combination thereof.

9. The composition according to any one of claims 1 to 8, wherein the thickener and / or gelling agent is selected from acrylate crosspolymer, hydroxyethyl cellulose, xanthan gum, and / or any combination thereof.

10. The composition according to any one of claims 1 to 9, further comprising one or more pharmaceutically acceptable adjuvants selected from antioxidants, emulsifiers, pH adjusters, such as acids or bases, stabilizers, colorants, or any combination thereof.

11. The composition according to any one of claims 1 to 10, which is a topical composition.

12. The composition according to any one of claims 1 to 11, which is a skin moisturizing or skin care composition for cosmetics.

13. For use as a pharmaceutical composition in the topical treatment or alleviation of symptoms resulting from arthritis, particularly rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis, and / or psoriatic arthritis, particularly pain, and / or neurological pain, such as pain resulting from sclerosis, such as multiple sclerosis, in a subject such as a human, mammal, or other animal. The composition according to any one of claims 1 to 12.

14. For use as a pharmaceutical composition for alleviating pain conditions associated with one or more hot joints and / or swollen joints in a subject such as a human, mammal, or other animal. The composition according to any one of claims 1 to 13.

15. For use as a medical composition in the topical treatment or alleviation of psoriasis, particularly symptoms of redness, dryness, itching, and / or scaly skin, in a subject such as a human, mammal, or other animal. The composition according to any one of claims 1 to 6.

16. For use as a medical composition for alleviating pain conditions associated with one or more redness, dryness, itching, and / or scaly skin in a subject such as a human, mammal, or other animal. The composition according to any one of claims 1 to 15.

17. The composition according to any one of claims 10 to 14, wherein the topical gel composition is topically applied 1 to 5 times a day to a topical skin area of a subject such as a human, mammal or other animal.

18. The composition according to any one of claims 10 to 14, wherein the topical gel composition is topically applied to a topical skin area of a subject in an amount of 5 to 100 or 10 to 50 mg / cm2 per application.

19. A kit comprising the composition according to any one of claims 1 to 18 in a container and, optionally, instructions for use.

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