SKIN DISEASE

BACKGROUND OF THE INVENTION

[0001] Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by eczematous lesions, xerosis (dry skin) and pruritus (sensation of itching). AD usually starts in early infancy. The lifetime prevalence of AD is 10-30% in children and 1-3% in adults. The condition develops due to impaired skin barrier and altered immune reactivity. Staphylococcus aureus colonization, which occurs in 85-90% of patients, may aggravate AD due to secondary infections. Exotoxins and other substances released by S. aureus may act as allergens or superantigens. The yeasts Malassezia and Candida may also aggravate AD by triggering allergic reactions.

[0002] The mechanisms that promote the enhanced susceptibility to cutaneous infections in atopic dermatitis include skin barrier dysfunction, reduced skin lipid content, and abnormalities of the innate immune response.

[0003] As a defensive barrier, the epidermis protects internal organs from physical and chemical trauma, microorganism invasion, and ultraviolet radiation. It also aids in the regulation of transepidermal movement of water and electrolytes, including in preventing dehydration, which is essential for sustaining life. The main role of the epidermis is considered to be in the stratum corneum and the lipid matrix, located in the intercellular space. The occurrence of dysfunction in the epidermal barrier is an important factor in the physiopathogenesis of skin diseases, particularly atopic dermatitis.

[0004] The damaged barrier in AD is due to lipid depletion. The permeability barrier defect in AD is characterized by a global reduction in the contents of all three key lipids (i.e., cholesterol, FFA, and Cer), with a further reduction in ceramide content. Thus, correction of the barrier abnormality in AD requires topical applications, not only of sufficient quantities of all three key lipids that mediate barrier function, but also of lipids in a ceramide-dominant proportion that corrects the underlying lipid biochemical abnormality in AD.

[0005] Herbs that comprise anti-inflammatory and anti-allergic properties have been previously described in the art. These include Sanguisorba officinalis known in Traditional Chinese Medicine to treat eczema and pain in the skin and Silybum marianum previously described to comprise anti-inflammatory properties.

[0006] Current treatment of AD does not cure the disease but can control the severity and duration of symptoms. Such treatments include topical application of emollients and moisturizers and/or herbs to preserve and restore the compromised barrier function, cortico-steroids and calcineurin inhibitors. The latter two types of treatment are often used in acute conditions, but are not recommended for long-term use.

[0007] Therefore, there is a need for a topical composition comprising herbs for the long term treatment of atopic dermatitis and for cleaning the skin of a patient afflicted with a chronic inflammatory disease such as atopic dermatitis.

DESCRIPTION OF THE DETILAED EMBODIMENTS OF THE INVENTION

[0008] This invention is based on the finding that a topical composition comprising a combination of Sapindus mukurossi Fruit Extract, Taraktogenos kurzii Seed Oil, Portulaca oleracea Extract together with allantoin or glycerin or a combination thereof and a cosmetic or a dermatological acceptable carrier, was found effective in the treatment of chronic inflammatory skin diseases or disorders, such as dermatitis, especially contact dermatitis and atopic dermatitis.

[0009] The topical composition of the present invention is effective in the fields of medicaments and cosmetics. In some embodiments of the invention, the composition is used as soap or a cleaning composition for cleaning the skin of a subject having chronic inflammatory skin diseases or disorders, such as dermatitis, especially contact dermatitis and atopic dermatitis and reliving the skin dryness, itchiness and irritation.

[00010] In some embodiments of the invention, the composition further comprises detergents, such as, sodium cocoamphoacetate, decyl glucoside, ammonium laureth sulfate, disodium laureth sulfosuccinate or any combination thereof.

[0001 1 ] In some embodiments of the invention, the pH of the formulation is between 5.5-6.5. In contrast, the pH of the previous formulation was between 6.5-7.5.

[00012] In some embodiments of the invention, the total amount of the detergents is between 30-50% w/w.

[00013] In some embodiments of the invention, the total amount of the detergents is between 35-45% w/w.

[00014] According to some embodiments of the invention, the composition further comprises a viscosity enhancer such as PEG-150 distearate.

[00015] In some embodiments of the invention, the composition further comprises conditioners, such as without limitation, polyquaternium 10.

[00016] In some embodiments of the invention, the composition further comprises fragrance mixture, such as without limitation, pendadecalactone. [00017] According to some embodiments of the invention, the composition further a skin calmer such as without limitation, allantoin.

[00018] According to some embodiments the concentration of the allantoin ranges from 0.02% to 2%. According to some embodiments of the invention, the concentration of the allantoin acid is about 0. 2%.

[00019] The term "about" refers to ±10%.

[00020] In some embodiments of the invention, the formulation may comprise glycerin, allantoin of a combination thereof.

[00021 ] The expression "dermatologically acceptable carrier" as used herein, means a carrier that is compatible with the skin, scalp, hair, nail and the like.

[00022] The composition of the invention may be used as hand, facial and body soaps and detergents and other forms of skin cleansers. In come embodiments, the composition is a cleansing composition for the skin, to be used in daily use during bathing, washing, or cleaning of the body or face.

[00023] In some embodiments of the invention, the composition may include the above described plant extracts, allantoin and commercially available humectants or moisture agents which are capable of providing moisture properties to the cleansing composition are suitable for use in the present invention. The humectant is may be presented in an amount of from about 0 percent to about 10 percent, more preferably from about 0.5 percent to about 5 percent, based on the overall weight of the composition. Examples of suitable humectants are without limitation, water soluble liquid polyols selected from the group comprising glycerin, propylene glycol, hexylene glycol, butylene glycol, pentylene glycol, dipropylene glycol.

[00024] In some embodiments of the invention, the composition includes glycerin as a humectant wherein the concentration of the glycerin is between 0.3% to 10%.

[00025] In some embodiments of the invention, the composition includes glycerin wherein the concentration of the glycerin is between 1 % to 8%.

[00026] In some embodiments of the invention, the composition includes glycerin wherein the concentration of the glycerin is between 2% to 6%.

[00027] In some embodiments of the invention, the composition includes glycerin wherein the concentration of the glycerin is between 3% to 5%.

[00028] According to some embodiments of the invention, the concentration of the glycerin is about 3%. [00029] The composition may further contain humectants such as proteins or protein hydrolysates, amino acids, urea, sugars and derivatives, water-soluble vitamins, plant extracts, hydroxyacids, vitamins (e.g. D-panthenol), and/or allantoin.

[00030] The topical composition of the invention is particularly useful in the treatment and/or prevention of dermatitis, especially contact dermatitis and atopic dermatitis.

[00031 ] The compositions of the invention show high dermal compatibility and low irritation behavior when applied to human skin. Further, as can be seen by the Examples, it was surprisingly found that the moisturizing level of the aforementioned formulations as was measured by Trans Epidermal Water Loss (TEWL) and skin hydration assay is significantly lower than the moisturizing level of the formulations that were previously presented (termed here "old" or "previous") formulation.

[00032] In some embodiments of the invention, the composition of the invention shows a synergistic beneficial effect on various symptoms of atopic dermatitis, on skin dryness, irritation, itchiness and/or on TEWL.

[00033] As can be seen in Example 2 and 3, the composition prepared according to the embodiments of the invention will be assessed in atopic dermatitis patients. Parameters such as erythema and itching, as well as, the dryness of the skin and TWEL, will be measured by testing the new formulation of the invention as a cleansing composition.

[00034] Accordingly, in an embodiment of the invention, there is provided a method of treating and/or preventing a chronic inflammatory skin disease or disorder comprising the step of contacting the skin or the scalp of a subject in need with the composition of the invention.

[00035] Some embodiments of the invention are directed to the use of the composition of the invention in the manufacturing of a medicament for treating and/or preventing a chronic inflammatory skin disease or disorder.

[00036] Some embodiments of the invention are directed to the composition of the invention for use in treating and/or preventing a chronic inflammatory skin disease or disorder.

[00037] The term "preventing" refers to keeping a disease, disorder or condition from occurring in a subject. In some cases the subject may be at risk for developing the disease, but has not yet been diagnosed as having the disease. In some case, the term "preventing" refers to preventing the next cycle of the disease from occurring.

[00038] The term "chronic inflammatory skin disease(s) or disorder(s)" include dermatitis conditions and skin impairments such as: atopic dermatitis, contact dermatitis, allergic contact dermatitis, allergic dermatitis, seborrheic dermatitis, nummular dermatitis, chronic dermatitis of hands and feet, generalized exfoliative dermatitis, stasis dermatitis, neonatal dermatitis, pediatric dermatitis, generalized exfoliative dermatitis; stasis dermatitis; localized scratch dermatitis, toxic/irritating contact eczema, allergic contact eczema, type I or type IV, photoallergic contact eczema, contact urticaria, dyshidrosiform eczema, age-caused wrinkles, sun damage and itching.

[00039] Other dermatological disorders which may be treated by the composition of the invention are: Psoriasis: psoriasis vulgaris, flaking eczema, psoriasis pustulosa, psoriasis arthropatica, psoriatic erythroderma; Photodermatosis: radiodermatitis acuta and chronica (UV and ionizing radiation therapy), chronic actinic dermatitis, photourticaria (urticaria Solaris), polymorphic photodermatosis and other polymorphic photodermatosis; Prurigo: p. simplex acuta (strophulus, urticaria papulosa), subacuta, chronica; Deficinent ipoactive skin: localized scratch dermatitisrinophyma, ichthyosis, xerosis; Perioral dermatitis and cradle cup.

[00040] In an embodiment of the invention, there is provided a method for cleaning the skin of a subject afflicted with a chronic inflammatory skin disease or disorder comprising the step of contacting the skin or the scalp of a subject in need with the composition of the invention.

[00041 ] Some embodiments of the invention are directed to the use of the composition of the invention in the manufacturing of a medicament for cleaning the skin of a subject afflicted with a chronic inflammatory skin disease or disorder.

[00042] Some embodiments of the invention are directed to the composition of the invention for use in cleaning the skin of a subject afflicted with a chronic inflammatory skin disease or disorder.

[00043] Using routine methods, the topical compositions of the present invention may be formulated into a variety of preparations, depending on the intended use. These preparations include, but are not limited to, topical skin compositions for medical use, topical skin cosmetic compositions and hair-treatment compositions.

[00044] As topical skin compositions for medical use and topical skin cosmetic compositions, many forms of gels, ointments, soaps, creams and lotions may be used.

[00045] When the topical compositions of the present invention are used as cosmetic compositions, cosmetic or dermatological acceptable ingredients may be optionally incorporated in arbitrary combinations as desired and determined in accordance by a person skilled in the art. According to some embodiments, the compositions may include oils, fats, waxes, detergents, conditioners, pH modifiers, preservatives, solvents, viscosity modifiers, colorants, perfumes, dyestuffs and the like. [00046] The composition may be in a form of 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, a soap, a paste, a foam, an emulsion, a gel, a salves, an oil, a wash, a shampoos, a conditioners or an aerosol.

[00047] According to an embodiment of the invention, the compositions of the invention are administered once a day. According to other embodiments, the compositions are administered twice a day, three times a day or more.

[00048] According to an embodiment of the invention, the composition is administered chronically.

[00049] According to some embodiments of the invention, the composition is administered for about 10 days or more, 20 days, 30 days, 60 days, 90, 120 days or more.

[00050] In some embodiments of the invention, the composition further comprises cleaning agents or detergents that are typically anionic, cationic, non-ionic or amphoteric surfactants. Typical anionic surfactants are carboxylates, sulfonates, sulfates or phosphates, e.g. fatty acid soaps, salts of lauryl sulfate and salts of lauryl ether sulfate. Examples of cationic surfactants are aliphatic mono, di and polyamines derived from fatty and rosin acids, amine oxides, ethoxylated alkyl amines and imidazolines. Examples of non-ionic surfactants are polyoxyethylene surfactants, alkylphenol ethoxylates, carboxylic acid esters, e.g., mono and diglycerides, polyoxyethylene esters and fatty acid diethanolamine condensates. Amphoteric surfactants are those containing combinations of the anionic and cationic groups described above, particularly those containing both acid carboxyls and basic nitrogen groups. Typical amphoteric surfactants are imidazolines and betaines, e.g., lauric and myristic imidazolines and betaines, and amidopropylbetaines.

[00051 ] The topical pharmaceutical compositions may also comprise a suitable emulsifier which refers to an agent that enhances or facilitates mixing and suspending oil- in-water or water-in-oil. The emulsifying agent used herein may consist of a single emulsifying agent or may be a nonionic, anionic, cationic or amphoteric surfactant or blend of two or more such surfactants; preferred for use herein are nonionic or anionic emulsifiers. Such surface-active agents are described in "McCutcheon's Detergent and Emulsifiers," North American Edition, 1980 Annual published by the McCutcheon Division, MC Publishing Company, 175 Rock Road, Glen Rock, N.J. 07452, USA.

[00052] The CTFA Cosmetic Ingredient Handbook, Second Edition (1992) describes a wide variety of non-limiting cosmetic ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples of these ingredient classes include: abrasives, absorbents, aesthetic components such as fragrances, pigments, colorings/colorants, essential oils, skin sensates, astringents, etc. (e.g. , clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate), anti-acne agents, anti-caking agents, antifoaming agents, antimicrobial agents (e.g., iodopropyl butylcarbamate), antioxidants, binders, biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers or materials, e.g., polymers, for aiding the film-forming properties and substantivity of the composition (e.g., copolymer of eicosene and vinyl pyrrolidone), opacifying agents, pH adjusters, propellants, reducing agents, sequestrants, skin- conditioning agents (e.g., humectants, including miscellaneous and occlusive), skin soothing and/or healing agents (e.g. , panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol, and dipotassium glycyrrhizate), skin treating agents, thickeners, and vitamins and derivatives thereof.

[00053] The plant extracts used herein may be purified by the use of a polar solvent (i.e. polar extract) such as, ethyl alcohol (ethanol), butyl alcohol (butanol), methanol, water or proanol. The polar extracts of the present invention may comprise any percentage of a polar solvent. .

[00054] Alternatively, the plant extracts may be purified by the use of a non-polar solvent (i.e. non-polar extract) such as, without being limited to, isooctane. The non- polar extracts of the present invention may comprise any percentage of non-polar solvents.

[00055] Typically, hydrophobic molecules tend to be non-polar and thus non-polar solvents are used. Hydrophilic molecules tend to be polar and dissolve by water and/or other polar substances.

[00056] The active ingredients can be concentrated in the extract via affinity chromatography, mass chromatography and the like.

[00057] Typically, the plant extract of the present invention is an aqueous extract. In order to obtain a purified plant extract (e.g. with reduced levels of organic salts and/or heavy metals and/or starch in the plant extract), the aqueous plant extract is typically further purified using a resin chromatography such as a macroporous resin or other chromatography methods.

[00058] Thus, according to another embodiment, there is provided a method of preparing concentrated herbal extracts for treating and/or preventing atopic dermatitis, other allergic skin diseases and skin infections , the method comprising: (a) subjecting a plant to x 1 -10 volumes of water to produce an extract of the plant; and (b) reducing the amount of organic salts and/or heavy metals and/or starch in the plant extract using a macroporous resin which results in an elevated content of the active ingredients present in the plant extract.

EXAMPLES

Example 1

Comparison of exemplary new and previous cleanser formulations:

EXAMPLE 2

EVALUATION OF THE TRANS EPIDERMAL WATER LOSS (TWEL) FOLLOWING ADMINISTRATION OF THE FORMULATION 1 (CLEANSER -NEW FORMULATION) DESCRIBED IN EXAMPLE 1 .

METHOD

[00059] The transepidermal water loss (TEWL) of the skin is one of the most important parameter to analyse the barrier function of the skin. TEWL is defined as the evaporation of water from the body through the skin, excluding the water loss caused by sweating. A preparation that upholds or even improves the skin barrier function also causes a TEWL- reduction. Low TEWL-values reflect a low evaporation of water through the skin and a good water balance inside the skin.

[00060] The quantitative analysis of transepidermal water loss (TEWL) of the skin is done using an Evaporimeter. The measuring sensor of the Evaporimeter contains a duct, which is open at top side. This duct contains two sensors to measure the skin's humidity and two sensors to measure the skin's temperature. Temperature and humidity measuring sensor units are located on top of each other separated only bya little space between them. The humidity measuring sensors detect the vapour pressure in the diffusion zone directly over the skin.

[00061 ] With computer support the water is measured in g/hm ² according to

[00062] Fick ^' sches Law of diffusion: dm = -D ^* A ^* dc dm/dt = diffusion flow

dt dx

D = coefficient

A = Area

Dc/dx = density gradient

PROCEDURE

[00063] The Evaporimeter from DermaLab Systems Fa. Cortex Technologies is used for all studies of trans epidermal water loss of the skin.

[00064] The measuring sensor is placed on top of the skin surface without causing extra pressure before the measuring procedure was initiated. This is done in a way that the outer rim of the Teflon-duct fully enclosed the skin area. The measurements are performed in series of measurement per test skin area including 20 cycles each. All single data from this series of measurements are automatically collected and the mean value is automatically calculated. [00065] Subjects, both male and female are tested. The test areas were squares of 3 cm diagonal length on the body.

[00066] Skin measurement values are taken at three different locations on the body.

[00067] The test product is applied for a period of three week. The measurements with the Evaporimeter are performed before and after the three weeks of product application.

[00068] The product is applied on the body as soap.

[00069] The water loss is measured and analyzed for each test person in g/hm2.

[00070] The relative average TEWL-value (%) is calculated from all measured values obtained from each subject. The absolute differences between the calculated average TEWL-values indicates a change in TEWL capacity due to the applied preparation.

EXAMPLE 3

ASSESSMENT OF SKIN CONDITION IN ATOPIC DERMATITIS PAT I NETS FOLLOWING TREATMENT WITH FORMULATION 1 DESCRIBED IN EXAMPLE 1

[00071 ] The skin hydration, skin irritation, hypoallergenic tests and the level of the itching of the skin of the patients will be measured subjects afflicted with atopic dermatitis.