DESC:TECHNICAL FIELD OF THE INVENTION
The present invention relates to pharmaceutical, cosmetic and cosmeceutical compositions for topical application, comprising, urea and a permeation enhancer with enhanced permeability. This invention also relates to a topical skin composition comprising urea and pramoxine or its pharmaceutically acceptable salt, butters or moisturizer emulsifying agents, purified water and other ingredients to form useful therapeutic, dermatological, pharmaceutical, medical or cosmetic compositions for treatment of skin maladies and disorders, namely as moisturizer in subjects having Atopic dermatitis, xerosis, icthyosis and psoriasis, and also to reduce itchiness associated with the dry skin, eczema and restores the affected areas of skin to a normal condition with enhanced penetration. The present invention also relates to the process for preparing such compositions.
BACKGROUND OF THE INVENTION
Skin is composed of an epidermis and a dermis. The outermost layer of the epidermis is called stratum corneum. Stratum corneum consists of constantly renewing keratinized cells. A dynamic balance is maintained between desquamation and regeneration from the underlying epidermal cells. Normal skin has multiple functions such as serving as a diffusion and mechanical barrier. Alteration in the stratum corneum, such as hyperkeratosis and parakeratosis, may result in thickened and inflexible skin. The accumulation of retained keratinous material can result in skin inflexibility, scale formation, and a dry and rough texture. This altered skin results in dry skin conditions ranging from mild to severe, such as chapping, xerosis, hyperkeratosis, parakeratosis, psoriasis, ichthyosis, and atopic dermatitis. Effective treatment to relieve or prevent the symptoms of the dry skin conditions requires moisturizing and exfoliating of the altered keratinized cells.
Urea is a moisturizing agent that is used to hydrate and soften thickened corneous layers of the skin. U.S. Pat. No. 5,629,344 discloses using urea in an ophthalmic preparation to enhance hydration and soften keratin. Urea is used either in an aqueous-based solution or in the form of a cream (emulsion of the oil-in- water type), but such use has disadvantages due to the instability of urea that readily decomposes in aqueous solution to form carbon dioxide and ammonia. U.S. Pat. No. 3,666,863 discloses a formulation containing urea and lactic acid. Incorporation of lactic acid is shown to decrease the tendency of urea decomposition. While these formulations may relieve discomfort of associated scales and cracks, formulations containing urea alone appear not to be effective in correcting the underlying keratinization effects.
Urea is a polar, hygroscopic molecule produced endogenously by the human body and naturally found in the skin. Urea is a low-molecular-weight organic molecule composed of a carbonyl group attached to two amine residues. A reduction in the hygroscopic capacity of the skin can increase transepidermal water loss (TEWL), deregulate epidermal proliferation and inhibit skin desquamation, inducing hyperkeratosis and pruritus. Urea is a topical emollient and moisturizing, keratolytic and antipruritic agent. It is prescribed for the treatment of diverse dermatoses presenting with scaly and dry skin such as atopic dermatitis, ichthyosis, seborrheic dermatitis and psoriasis, among others. Urea-containing creams may present an unpleasant odor, caused by volatile amine, but it dissipates rapidly.
Urea plays an important role in moisture regulation and is key constituent of natural mositurizing factor (NMF). Urea is a hydrophobic bond breaker and may break up the micellar structure. Thus, urea may have an immediate effect on the intercellular lipids responsible for the barrier characteristics of the skin, which could explain why urea might act as an efficient penetration enhancer. It mainly increases moisturisation of stratum corneum.
Urea-containing preparations have been efficiently used in the treatment various afflictions related to dry skin. While preparations that contain urea concentration lower than 10 weight percentages have generally been used as skin moisturizers, preparations that contain urea concentration of 10 weight percentages or higher have been used as skin remedies, treating severe cases of dry, rough skin, such as ichthyosis and psoriasis. A representative example of a commercially available family of 40% urea-containing preparations is the Carmol®40 cream, gel and lotion (marketed by Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc.), which is known as a tissue softener.
As early as the 1960s, topical compositions containing urea were used in the treatment of various dermatological conditions. For example, Swanbeck (in Acta derm-vener., 48, 123, 1968) reported that soaking of pieces of horny layer from normal, ichthyotic and psoriatic skin in a 30% urea solution resulted in a considerable increase in the water binding capacity of the skin, and suggested that a cream containing urea in a concentration of 10% may be used for the treatment of ichthyosis and other hyperkeratotic conditions.
WO 86/00014 (to Weiner M.) discloses a method for the prevention and/or reduction of skin damage caused by ultraviolet radiation, which is effected by topically applying a composition comprising urea and a pharmaceutically acceptable carrier. The urea is used in this composition as an agent that moderates the effect of nitrate reduction products, which are formed as a result of exposure to ultraviolet radiation. According to the teachings of this reference, the preferred concentration of urea is from about 0.1 to about 40 weight percentages, more preferably between about 0.1 and about 20 weight percentages of the total weight of the composition. Further according to the teachings of this reference, the composition is applied to the skin in the form of conventional alcoholic lotions, liquid emulsions, creams, transparent gels, or aerosol sprays. This reference therefore fails to teach a composition that is directed to treat itchiness of dry skin associated with atopic dermatitis, xerosis, Icthyosis and psoriasis and is further not directed to topical urea compositions with enhanced penetration.
U.S. Pat. Nos. 6,281,239, 6,429,231 and 6,495,602, and U.S. Patent Application No. 2003064969 (all to Bradley Pharmaceuticals Inc.) disclose various compositions, all containing urea in concentrations of up to 40 weight percentages, in combination with other active ingredients such as, for example, anti-fungals (U.S. Pat. No. 6,281,239), sulfacetamide and sulfur (U.S. Pat. No. 6,429,231), astringents such as calcium acetate and aluminum sulfate (U.S. Pat. No. 6,495,602) and antimicrobials (U.S. Patent Application No. 2003064969), for the treatment of various dermatological conditions. Although the compositions disclosed in these patents and patent application are not limited to a particular form, some of these references teach that the composition is preferably applied in the form of a cream and/or a lotion. These references are therefore not directed to topical urea compositions for treating itchiness of dry skin associated with atopic dermatitis, xerosis, Icthyosis and psoriasis and is further not directed to topical urea compositions with enhanced penetration.
Pramoxine decreases the permeability of the neuronal membrane to sodium ions by reversibly binding to and inhibiting voltage-gated sodium channels. This results in stabilization of the membrane and, thereby inhibiting the ionic fluxes required for membrane depolarization, hence resulting in the failure to initiate a propagated action potential and subsequent conduction blockade. Pramoxine Hydrochloride role as permeation enhancer can be supported by theories as given below:
a) Pramoxine Hydrochloride partitions out faster to skin surface.
b) Pramoxine Hydrochloride disrupts the barrier by passing through water channels.
c) Pramoxine Hydrochloride has lesser chemical potential to stratum corneum
Thus there always remains a need for topical urea compositions with enhanced permeation comprising combination of urea, permeation enhancers like pramoxine, emulsifying agents, and other ingredients which reduces itching of the skin due to dryness, eczema or any other dry skin related conditions and which can offer minimal or no systemic side effects, and also with minimum or no irritancy to the skin and with enhanced permeation.

OBJECT OF THE INVENTION
The present invention relates to pharmaceutical, cosmetic and cosmeceutical compositions for topical application of urea with permeation enhancer for increased permeability, and their use in the treatment of medical, cosmetic and cosmeceutical conditions as a moisturizer indicated for itchiness and dryness associated with atopic dermatitis, xerosis, Icthyosis and psoriasis.
The present invention relates to a topical urea compositions comprising butters or moisturizers, pramoxine or its pharmaceutically acceptable salt.
The present invention relates to a topical urea compositions comprising butters or moisturizers, pramoxine or its pharmaceutically acceptable salt, preservatives, emulsifying agents, vehicle or base and process for preparing such compositions.
In one aspect the present invention relates to a topical composition comprising:
i) 0.1 % w/w – 15% w/w of Urea
ii) 0.1% w/w – 10% w/w of Pramoxine or its pharmaceutically acceptable salt and
iii) one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutically acceptable excipients of the present invention comprise:
i) one or more butters or moisturizing agents,
ii) one or more emulsifying agents,
iii) one or more gelling agents,
iv) and a base or vehicle.
In one aspect the present invention relates to a topical anti-itch composition comprising:
i) Urea
ii) Butters or moisturizing agents,
iii) pramoxine or its pharmaceutically acceptable salt,
iv) emulsifying agent,
v) gelling agent,
vi) and a base / vehicle

In one aspect the present invention relates to a topical anti-itch composition comprising:
i) 0.1 % w/w – 15% w/w Urea
ii) 1% to 7% w/w Butters or moisturizing agents,
iii) 0.1% w/w – 10% w/w pramoxine or its pharmaceutically acceptable salt,
iv) 1% w/w to 5% w/w emulsifying agent,
v) V) 1% w/w to 5% w/w gelling agent,
vi) and a base / vehicle

In another aspect the present invention relates to a topical anti-itch composition comprising:
i) Urea
ii) butters or moisturizing agents,
iii) pramoxine or its pharmaceutically acceptable salt,
iv) emulsifying agents,
v) emollient,
vi) gelling agent,
vii) humectant and
viii) a base/vehicle comprising of purified water along with one or more pharmaceutically acceptable excipients.

In still another aspect the present invention relates to a topical anti-itch composition comprising:
(i) Urea,
(ii) one or more butters or moisturizing agents,
(iii) pramoxine or its pharmaceutically acceptable salt,
(iv) one or more emulsifying agents,
(v) one or more emollients,
(vi) one or more gelling agents,
(vii) one or more humectant, and
(viii) a base/vehicle comprising purified water along with one or more pharmaceutically acceptable excipients.

In yet another aspect, the present invention relates to the process of preparing the topical urea compositions of the present invention.
In yet another aspect, the present invention relates to use of topical urea composition for treating and preventing itchiness associated with psoriasis, atopic dermatitis or other skin disorders, as a moisturizer for skin conditions such as dry skin, eczema, red skin, inflamed skin, and/or cracked skin, and the restoration of the affected areas of skin to a normal condition.
In an aspect of the present invention urea is present in the range of 0.1%w/w to 15%w/w of the total composition.
In an aspect of the present invention urea is present in an amount of 10%w/w of the total composition.
In an aspect of the present invention pramoxine or its pharmaceutically acceptable salt is present in the range of 0.1%w/w to 15%w/w of the total composition.

In an aspect of the present invention pramoxine or its pharmaceutically acceptable salt is in an amount of 1%w/w of the total composition
In another aspect, the topical composition of the present invention further comprises preservatives, chelating agents, antioxidants, pH adjusting agents.
DETAILED DESCRIPTION OF INVENTION
Dry skin is a common condition associated with a plurality of disorders and frequently requires therapeutic intervention.
Dermatologists often call dry skin in later life as “xerosis” or “ichthyosis”. Xerosis is a term used to describe abnormal skin dryness. Ichthyosis is a term used to describe a group of cutaneous disorders characterized by increased or aberrant keratinisation, and resulting in non-inflammatory scaling of the skin. There are at least twenty varieties of ichthyosis, including inherited and acquired forms. Further details regarding xerosis and ichthyosis can be found in “Atlas of Clinical Dermatology” by Anthony du Vivier, 3rd edition (Jul. 17, 2002) Publisher: Churchill Livingstone, which is incorporated herein by reference.
As is known in the art, the terms “moisturizer” (to add moisture) and “emollient” (to soften) are interchangeable as they describe different effects of the same agents on the skin, as is further detailed hereinunder.
“Moisturizers” is a general term used to describe substances that exert two basic actions: humectants, which are introduced into the stratum corneum to increase its water holding capacity; and occlusives, which provide a layer of oil on the surface of the skin to slow water loss and thus increase the moisture content of the stratum corneum. Some moisturizers contain both occlusives and humectants. For example, the moisturizer includes, but is not limited to, one or more of Phytosqualan, Allantoin, glycerin, diglycerin, propylene glycol, 1,3-propanediol, 1,2-pentanediol, polyethylene glycol-8, polyethylene glycol-32, methyl gluceth-10, methyl gluceth-20, PEG/PPG-17/6 copolymer, glycereth-7, glycereth-26, glyceryl glucoside, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PEG/PPG/polybutylene glycol-8/5/3 glycerin, sucrose, trehalose, rhamnose, mannose, raffinose, betaine, erythritol, xylitol, urea, glycereth-5 lactate, sodium hyaluronate, sodium polyglutamate, hydrolyzed sclerotium gum, pululan, tremellam, tamarindus indica seed polysaccharide, and so on. The content of the moisturizer in the composition is known in the art. Typically, the moisturizer is present in the composition of the invention in an amount of 1-30wt% based on the total weight of the component (C).
“Emollients” is a general term used to describe substances that cover the surface of the stratum corneum so as to prevent moisture loss, thus resulting in the closure of microcracks and fissures and restoration of the natural epidermal barrier. (Marie Loden, Clinics in Dermatology, 21, 145-157, 2003)
"Salts" include derivatives of an active agent, wherein the active agent is modified by making acid or base addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, or a combination comprising one or more of the foregoing salts. The pharmaceutically acceptable salts include salts and the quaternary ammonium salts of the active agent. For example, acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, or a combination comprising one or more of the foregoing salts. Preferably used salt is Hydrochloride.
The term "comprising" (and its grammatical variations) as used herein is meant to be open ended and used in the inclusive sense of "having" or "including" and not in the exclusive sense of “consisting only of." The term "consists essentially of," as used herein means the claimed elements and others, but is meant to exclude things that are inconsistent with the basic and novel characteristics of the inventions.
As used herein, the term “topical" is used in its conventional sense to mean delivery of a drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders. Topical administration, in contrast to transdermal administration, primarily provides a local rather than a systemic effect.
The term "composition" is intended to encompass a combination including active ingredients and judiciously selected pharmaceutically acceptable excipients. The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as filler, diluent, carrier, preservative, etc. The excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and are acceptable for veterinary use as well as human pharmaceutical or cosmetic use. The term includes both one and more than one such excipients. The skin care composition of the present invention may be in the form of lotions, liquids, creams, gel, etc. that are suitable for topical administration.
Useful pharmaceutical acceptable excipients of the present invention include, but are not limited to permeation enhancers, vehicles or diluents, moisturizers, plasticizers, film forming agents, chelating agents, thickening or gelling agents, neutralizers, emulsifying agents, emollients, humectants, preservatives, antioxidants, solvents, fragrance imparting agents, and the like, including any combinations of two or more thereof.
"Penetration enhancement" or "permeation enhancement" as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the agent permeates into and through the skin. A "permeation enhancer" is a material which achieves such permeation enhancement, and a "penetration enhancing amount" of an enhancer as used herein means an amount effective to enhance skin penetration of a selected agent to a desired degree, i.e., to effect the desired pharmacologic response.
The compositions for use according to the present invention may further comprise a penetration enhancer. The amount of penetration enhancer employed in the compositions of the present invention will vary depending upon the specific composition embodiment or transdermal formulation, i.e., serum, cream or foam, and the specific penetration enhancer selected. Typically, the amount of penetration enhancer employed in the compositions for use according to the present invention should be from about 0.01 wt%, preferably from about 0.05 wt% and most preferably from about 0.1wt% to about 5 wt% based upon the total weight of the composition. Examples of penetration enhancers that may be used in compositions include, but are not limited to, pramoxine or its pharmaceutically acceptable slats, fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid or glycolic acid, glycerol tri-, di- and monoesters, triacetin, short chain alcohols, amine oxides and mixtures thereof. Particular examples of permeation enhancers include oleyl alcohol, lauryl alcohol, isopropyl myristate, oleyl oleate, levulinic acid, ethanol, glycerol monooleate, methyl laurate, sorbitain monooleate, triacetin, aloe vera oil, benzothonium chloride, cetyl dimethylamine oxide, cetyl alcohol, cetyl lactate, cocamidopropyl betaine, cocoamine oxide diethanolamine, dimethyloctylamine oxide, 2-dodecoxyethyldimethylamine oxide, dimethyl-decylamine oxide, dimethylhexadecylamine oxide, dimethyl-tetradecylamine oxide, dimethyl isosorbide, dipropylene glycol, ethyl hexyl lactate and combinations thereof. The preferable permeation enhancer used in the present invention is Pramoxine or its pharmaceutically acceptable salt.
Other permeation enhancers useful with the present invention may be found in U.S. Patent Application Publication No. 2007/0269379. permeation enhancers include oleyl alcohol, lauryl alcohol, isopropyl myristate, oleyl oleate, levulinic acid, glycerol monooleate, methyl laurate, sorbitain monooleate, triacetin, cetyl alcohol, cetyl lactate, dimethyl isosorbide, dipropylene glycol, ethyl hexyl lactate, glycolic acid, lauramine oxide, lauryl betaine, lauryl lactate, lauryl laurate, isopropyl palmitate, myristyl alcohol, myristal lactate, octyl salicylate, oleamine oxide, oleic acid, oleyl betaine, salicylic acid, stearyl alcohol, stearyl lactate, triethanolamine triacetate and combinations thereof.
In an embodiment the pramoxine or it’s pharmaceutically acceptable salts i.e., hydrochloride salts is added as a penetration enhancer in addition to its anti-itch property. Pramoxine HCl provide short-term relief from itching by stopping nerves from sending pain signals. Pramoxin or pramoxine HCl is present in concentrations ranging from about 0.1%w/w to about 10% w/w of the total weight of the composition, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w or about 5% w/w of the total weight of the composition.
The terms “about” and “approximate,” when used along with a numerical variable, generally means the value of the variable and all the values of the variable within a measurement or an experimental error (e.g., 95% confidence interval for the mean) or within a specified value (e.g., ±20%, ±10%, ±5%) within a broader range. For instance, the term “about” typically means having a value falling within an accepted standard of error of the mean when considered by one of ordinary skill in the art. Preferably, the term “about” refers to ±20%, preferably ±10%, and more preferably ±5% of the value or range to which it refers.
In an aspect of the, the topical compositions of the present application comprise one or more base(s) or vehicle to prepare pharmaceutically acceptable topical dosage form.
In another aspect, the topical composition of the present application comprises one or more materials used as vehicle. The vehicle includes, but are not limited to, water or water-miscible solvents such as glycerin or propylene glycol and the like thereof.
In an aspect of the above embodiments, the topical anti-itch composition of the present application comprises one or more base(s) or vehicle in an amount from about 2% w/w to about 98% w/w, in an amount from about 5% w/w to about 95% w/w, in an amount from about 10% w/w to about 90% w/w, in an amount from about 15% w/w to about 90% w/w, in an amount from about 20% w/w to about 90% w/w, in an amount from about 30% w/w to about 90% w/w, in an amount from about 40% w/w to about 90% w/w, in an amount from about 50% w/w to about 90% w/w, in an amount of about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w or about 90% w/w, or about 95% w/w based on total weight of the composition.
The term “anti-itch” skin conditions as used herein refers to the dry skin condition that for example may arise from a bug bite, allergies, cold weather, a chronic skin condition like eczema, dermatitis, dry skin condition as such.
The term butters and moisturizing agents or mositurizers are used as synonymously. The topical compositions of the present invention include one or more butters as an excipient. Butters play a main role in healing the conditions, due to their unique fatty acid profiles and high contents of vitamins E and A that contribute to its protective and hydrating properties. Some butters also have natural UV protection which helps in effective skin moisturization and visibly reduces the appearance of fine lines and wrinkles. Butter helps to nourish and rejuvenate skin cells making the skin feel soft, silky and smooth. Representative examples of the butters that are usable in the context of present invention include, but are not limited to, cocoa butter, Shea butter, mango butter, aloe butter, pumpkin seed butter, kokum butter, mowrah butter, coconut lime verbena body butter, cranberry butter, Coconut Butter and Oil etc.
Shea butter has a unique fatty acid profile and the high content of vitamins E and A contributes to its protective and hydrating properties. Clinical trials have shown that Shea butter provides natural ultraviolet (UV) radiation protection, is an effective skin moisturizer, and visibly reduces the appearance of fine lines and wrinkles. It may be used in concentrations ranging from about 1% to about 7% w/w.
The topical anti-itch compositions of the present invention include one or more emulsifying agents. Examples of emulsifying agents that are useful for preparing compositions of the present invention include, but are not limited to, sodium lauryl sulfate, sodium laureth sulfate (or sodium lauryl ether sulfate), polysorbate 60, polysorbate 80, emulsifying wax, fatty acids having 12-18 carbon atoms, such as undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, cetostearyl alcohol, isostearic acid, aracel, oleic acid, hydroxyoleic acid, linoleic acid, and their derivatives, glyceryl stearate, Mono & Di glycerides NF (GMS Type II), propylene glycol monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate or sorbitan trioleate or mixtures thereof. In some embodiments, the emulsifying agent includes mixture of glyceryl stearate and polyethylene glycol-100 stearate (ARLACEL 165). Useful emulsifying agents further include emulsifying wax flakes, cetyl alcohol, acacia, carbomers, carrageenan, cetostearyl alcohol, ceresin wax, ceteareth-20, steareth-2, stearyl alcohol and any combinations thereof.
In an aspect of the above embodiments, the topical compositions of the present application comprises one or more emulsifying agent(s) or emulsifier in an amount from about 0.1% w/w to about 30% w/w, in an amount from about 0.5% w/w to about 20% w/w, in an amount from about 1% w/w to about 10% w/w, in an amount of about 1% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 8% w/w, about 9% w/w, or about 10% w/w based on total weight of the composition.
The topical compositions of the present invention may comprise a solubilizer. Suitable solubilizers include hexylene glycol, propylene glycol, polyethylene glycol or mixtures thereof. Preferred solubilizer includes propylene glycol. The amount of solubilizers employed in the composition is in the range of 1% to 20% (w/w) of total composition, e.g. 3% (w/w), 5% (w/w).
The topical compositions of the present invention may comprise an emollient or mixture of emollients. Suitable emollients include, for example, Medium chain glycerides (Caprylic capric triglycerides), stearyl alcohol, glyceryl monooleate, glyceryl monoricinoleate, glyceryl monostearate, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin alcohol, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoieate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and mixture thereof. In some embodiments the emollient includes mixture of polysorbate 80, cetyl acetate, stearyl acetate, oleyl acetate acetylated lanolin alcohol (Crodalan AWS) or mixtures thereof.
In an aspect of the above embodiments, the topical compositions of the present application comprises one or more emollients in an amount from about 0.1% w/w to about 30% w/w, in an amount from about 0.5% w/w to about 20% w/w, in an amount from about 1% w/w to about 10% w/w, in an amount of about 1% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 8% w/w, about 9% w/w, or about 10% w/w based on total weight of the composition.
The topical compositions of the present invention may comprise aqueous base as required. The oil phase excipients include the butters, emollients, emulsifying agents and others. The emulsifying agents help the dispersion of oil phase and aqueous phase. The amount of water employed in the compositions is in the range of 3% to 20% (w/w) of total composition, e.g. 5% (w/w), 10% (w/w).
The topical compositions of the present invention may further comprise a humectant. Examples of humectants that are useful in the context of the present invention include, but are not limited to, glycerin, propylene glycol, cyclomethicones, dimethicones, sorbitol, xylitol, urea, sugars and starches, sugar and starch derivatives (e.g., alkoxylated glucose), D-panthenol, hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine, 2-pyrrolidone-5-carboxylic acid, urea, and any mixtures thereof.
In an aspect of the above embodiments, the topical compositions of the present application comprises one or more humectants in an amount from about 0.1% w/w to about 30% w/w, in an amount from about 0.5% w/w to about 20% w/w, in an amount from about 1% w/w to about 10% w/w, in an amount of about 1% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 8% w/w, about 9% w/w, or about 10% w/w based on total weight of the composition.
The topical compositions of the present invention may further comprise a thickener. Suitable thickeners include carboxylic acid polymers like carbomers (e.g. Carbopol.RTM. 954), acrylates/vinyl neodecanoate crosspolymer (e.g. Aculyn 38), natural gums (e.g. guar, xanthan), cellulose derivatives (e.g. carboxy methylcellulose, methyl cellulose), PEG 6000, polyvinyl alcohol and mixtures thereof.
The topical compositions of the present invention may comprise one or more preservatives. Examples of preservatives include, but are not limited to, benzalkonium chlorate, bronopol, chlorhexidine, chlorocresol and its derivatives, mixture of methylisothiazolinone and phenoxyethanol (NEOLONE™ PE), phenoxyethanol, ethylic alcohol, phenethylic alcohol, potassium sorbate, diazolidinylurea, benzylic alcohol, parabens alone or in mixture.
The topical compositions of the present invention may comprise one or more pH adjusting agents. Such ingredients include dermatologically acceptable acids, bases and buffers. The pH of the compositions can range from about 4 to about 10, but preferably is in the range of about 5 to about 8, in particular from about 5 to about 7.5.
The topical compositions of the present invention may contain additional ingredients to improve the composition. Such ingredients include film formers, chelating agents, neutralizers, antioxidants, buffering agents. Examples of such ingredients are well known in the art.
Suitable chelating agents that can be used in the topical compositions of this invention comprise ethylene diamino tetraacetate salts (EDTA), in particular disodium and tetrasodium ethylene diamino tetraacetate salts, and the acid form thereof; diethylene triamino pentaacetate salts (DTP A) and the acid form thereof; propylene diaminotetraacetate salts (PDTA) and the acid form thereof; hydroxyethylethylene diaminotriacetate salts (HEDTA) and the acid form thereof; tetrahydroxypropyl ethylenediamine; pentetate salts such as pentasodium pentetate and the acid form thereof; etidronate salts such as tetrasodium etidronate, and the acid form thereof; nitrilotriacetate (NT A) salts and the acid form thereof; acrylic acid/acrylamidomethyl propane sulfonic acid copolymer polyacrylate salts, and the acid form thereof; phosphonate salts and the acid form thereof; poly- or metaphosphate salts and the acid form thereof; citrate salts and citric acid, galactaric acid and galactaric acid salts; iminodisuccinate salts and the acid form thereof; zeolithe; bentonite; laminar disilicate salts and the acid form thereof; N-acylethylenediaminotriacetate salts and the acid form thereof; phytic acid and phytic acid salts. Preferred chelating agents comprise EDTA salts and the acid form thereof.
As used herein, the word thickening agents and gelling agents are used synonymy and are interchangeable.
Specific non-limiting examples of suitable thickening agents include crosslinked anionic copolymers of acrylamide and of AMPS, e.g. in the form of a water-in-oil emulsion, such as those sold under the name SEPIGEL 305 (INCI name: Polyacrylamide/C13-14 Isoparaffin/Laureth-7) and under the name SIMULGEL 600 (CTFA name: Acrylamide/Sodium acryloyldimethyltaurate copolymer/Isohexadecane/Polysorbate 80); and those under the name SEPIPLUS 265 (Acrylamide/ammonium acrylate copolymer/polyisobutene/polysorbate 20), and those under the name SEPIMAX ZEN (ammonium 2-acrylamido 2-methylpropanesulfonate/dimethylacrylamide/hydrophobic chain copolymer, INCI: Polyacrylate Crosspolymer-6), all by SEPPIC. Other examples include those under the name SENSOGEL 200 (INCI: Hydroxyethyl acrylate/Sodium Acryloyl Dimethyl Taurate Copolymer by Applechem, Inc; those under the name Bluevisc AC (INCI: Acrylamide/Sodium acrylate Copolymer) by Blue Sun International; those under the name OPULYN 303B (INCI: Styrene Acrylamide Copolymer) by Univar Solutions; and those under the name Noevender EC-1 (INCI: Acrylates/Acrylamide/Copolymer) by Lubrizol.
The at least one thickening polyacrylamide or cellulose-based agent may be present in the compositions of the present invention in an amount greater than 0.05% by weight, such as greater than 0.1% by weight, such as greater than 0.5% by weight, such as greater than 1% by weight and may be less than 15% by weight, including all ranges and subranges therebetween such as, for example, from about 0.1% to about 15%, such as from about 0.1% to about 10%, such as from about 0.5% to about 10%, such as from about 0.75% to about 7.5%, such as from about 1% to about 5%, etc., with all weights being based on the weight of the composition.
Butylated hydroxy toluene (BHT) and analogs thereof, and various other components may be employed as stabilizers or anti-oxidants for the composition. Various pH-adjusting agents may be employed in compositions of the invention, including, by way of example, hydroxide salts (i.e., calcium hydroxide, sodium hydroxide, potassium hydroxide) and amines, such as triethanolamine. Triethanolamine (also known as Trolamine) is a preferred pH-adjusting agent.
The topical anti-itch compositions of the present invention can be manufactured using a method comprising:
a) preparing an oil phase by combining the oil soluble ingredients;
b) preparing an aqueous phase by combining water soluble ingredients in warm water, and adding a preservative;
and c) combining the aqueous phase of step b) and the oil phase of step a), followed by homogenization.
The oil soluble ingredients of the present invention are oil soluble moisturizers (contain ingredients that are readily soluble in oils or fats rather than water) emollients, emulsifiers, thickening or gelling agents.
The water soluble ingredients of the are water soluble moisturizers (are able to dissolve in water), anti-oxidants, chelating agent, preservatives, urea, pramoxine or its pharmaceutically acceptable salts and pH adjusting agent.

EXAMPLES
Example 1: compositions of the present invention
S.NO Name of Ingredients Example 1a
(%w/w) Example 1b
(%w/w) Example 1c
(%w/w) Example 1d
(%w/w)
1. Urea 5 6 10 10
2. Pramoxine HCl 0.5 1 1 1
3. Butters 3 3 3 3
4. Phytosqualan 1 3 5 2
5. Allantoin 1 - 0.5 5
6. Butylated Hydroxy toluene 1 1.5 0.1 0.7
7. Phenoxyethanol – Ethylhexylglycerin - 1.5 1 -
8. Emollients & Mixture 8 3.1 6 10
9. Sorbitan monostearate 3 2 0.5 3
10. Glyceryl Stearate (and) PEG-100 Stearate 1 1 3 1
11. Cetyl alcohol 4 10 6 5
12. Sepigel 305 3 5 2 9
13. Lactic acid & its salt 2 3 1 2
14. Disodium EDTA 0.1 0.1 0.1 0.1
15. Propylene glycol 10 12 10 10
16. pH adjusting agent 0.2 0.4 0.8 0.5
17. Fragrance 0.1 0.1 0.1 0.1
18. Purified Water QS QS QS QS

Brief Manufacturing Process:
1. Aqueous Phase:
a) Purified Water is charged into aqueous phase vessel and heated
b) Weighed quantity of Propylene Glycol is added to step a
c) Added disodium EDTA, allantoin, pH adjusting agent to the step b and stirred to form a clear solution,
d) Pramoxine was added to step c under stirring and a clear solution is formed
2. Oil Phase:
e) All ingredients of oil phase like butters and all are charged into oil phase vessel and heated with stirring until it gets melted and a clear solution is formed
3. Emulsification:
f) The oil phase was transferred to aqueous phase under stirring, cooled and homogenized
4. Final Mixing:
g) The preservative and fragrances were added to the above solution of step f and mixed uniformly.
,CLAIMS:We Claim:

1. A topical composition comprising:
i) 0.1 % w/w – 15% w/w of Urea,
ii) 0.1% w/w – 10% w/w of Pramoxine or its pharmaceutically acceptable salt, and
iii) one or more pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients comprise:
i) one or more butters or moisturizing agents,
ii) one or more emulsifying agents,
iii) one or more gelling agents,
iv) and a base or vehicle.

3. The topical composition as claimed in claim 1, wherein the urea is present in an amount of 10% w/w of the total composition.

4. The topical composition as claimed in claim 1, wherein the pramoxine or its pharmaceutically acceptable salt is present in an amount of 1%w/w of the total composition.

5. The topical composition as claimed in claim 2, wherein the butter is selected from one or more of cocoa butter, shea butter, mango butter, aloe butter, pumpkin seed butter, kokum butter, mowrah butter, coconut lime verbena body butter, cranberry butter, coconut butter, oil or mixtures thereof.

6. The topical composition as claimed in claim 5, wherein the butter is shea butter present in an amount of about 1% to about 7% w/w of the total composition.

7. The topical composition as claimed in claim 2, wherein the composition further comprises preservatives, chelating agents, antioxidants, pH adjusting agents.

8. The topical composition as claimed in claim 2, wherein the gelling agent is selected from one or more of polyacrylamide/C13-14 isoparaffin/Laureth-7, acrylamide/Sodium acryloyl dimethyltaurate copolymer/isohexadecane/polysorbate 80, polyacrylamide, cellulose-based agent or mixtures thereof and is present in an amount of 1% w/w to 5% w/w of the total composition.

9.The topical composition as claimed in claim 2, wherein the emulsifying agent is selected from one or more of sodium lauryl sulfate, sorbitan sesquioleate, polyglyceryl-2-sesquioleate, polyethylene glycol cetyl/stearyl ethers, polyoxyl 20 cetostearyl ether, sorbitan monostearate, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, polysorbate 80, Vitamin E TPGS or mixture of glyceryl stearate and polyethylene glycol-100 stearate mixtures thereof and is present in an amount of 1% w/w to 5% w/w of the total composition.

10. A process for preparing topical composition as claimed in claim 2, wherein the process comprises:
i) preparing an oil phase by combining the oil soluble ingredients;
ii) preparing an aqueous phase by combining water soluble ingredients in warm water, and adding a preservative; and
iii) combining the aqueous phase of step ii) and the oil phase of step i), followed by homogenization.