DESC:
FIELD OF INVENTION
The present invention relates to a stable topical cream formulations of clascoterone for treating dermatological conditions wherein clascoterone is present in solubilized form in the cream. The present invention also relates to treatment of dermatological conditions such as androgenetic alopecia, atopic dermatities and acne vulgaris by using stable topical cream formulations of clascoterone.

BACKGROUND OF THE INVENTION
Topical dermatological agents or pharmaceutical active agents have been employed for decades to treat or otherwise alleviate the symptoms of a variety of dermatological conditions not limited to bacterial infection, viral infection, fungal infection, auto-immune response, allergenic response, idiopathic, and the like. Topical formulations for application to the skin can be useful in cosmetic applications, for treating conditions of the upper skin layers and for transdermal administration of active agents to the local tissue underlying the skin or into the blood for systemic distribution. Use of a topical formulation, for instance, a pharmaceutical agent is advantageous in that it avoids firstpass metabolism, circumvents gastrointestinal (“GI”) absorption, can allow delivery of an active ingredient with a relatively short biological half-life and/or a narrow therapeutic window and facilitates uniform plasma concentration of the active ingredient, and/or can improve user compliance.

Various topical drug delivery systems are known in the art that generally include but not limited to cream, ointment, gel, solution, lotion, spray.

Androgen and androgen receptor play important role in several skin related diseases, such as androgenetic alopecia, atopic dermatitis and acne vulgaris.

Cortexolone derivatives in which the hydroxyl group at position C-17 a is esterified with short chain aliphatic or aromatic acids, and the derivatives of the corresponding 9, 11-dehydro derivative, are known to have an antiandrogenic effect. clascoterone, also known as cortexolone 17a-propionate is an androgen receptor inhibitor being developed as a topical cream and solution by Cassiopea for the treatment of androgen-dependent skin disorders, including atopic dermatitis, androgenetic alopecia and acne vulgaris. The exact mechanism of action of clascoterone for the topical treatment of acne vulgaris is unknown, the drug is believed to compete with the androgen dihydrotestosterone for binding to androgen receptors in the sebaceous gland and hair follicles to attenuate signaling necessary for acne pathogenesis.

Clascoterone is represented by formula I

In August 2020, FDA approved clascoterone (Winlevi®) for the first-in-class topical treatment of acne (acne vulgaris) in male and female patients 12 years and older. The clascoterone is present in the form of dispersion in the cream in Winlevi®.

U.S. Patent No. 8,143,240 and U.S. Patent No. 9,211,295 discloses 17a,21-dihydroxypregnene esters for example clascoterone with antiandrogenic activity and topical formulations like cream, gel, emulsion, or dispersion.

International publication no. WO 2009019138 discloses liquid or semi-liquid formulations of clascoterone for topical administration, such as for example, cream, gel, ointment, emulsion or dispersion containing cortexolone-17a-propionate in the range of 0.1 to 2% by weight, in a crystalline form selected from among solvate forms I, II, III or IV, both in solution and crystalline dispersion states. It discloses that the dispersion being obtained in an extemporaneous manner by precipitation of the crystalline active ingredient upon addition of water or aqueous solution to a solution containing the same active ingredient in an organic solvent or a mixture of organic solvents.

E.P. Patent Application 3108879 discloses a high concentration formulation of cortexolone - 17a-propionate suitable for treating alopecia. It focuses on a pharmaceutical formulation which is anhydrous and particularly contains less than about 5 weight percent water and concludes that the anhydrous formulation is more stable than the aqueous formulation.

Despite the knowledge of stability issues with solubilized clascoterone in an organic solvent which is more susceptible for the transesterification of clascoterone to cortexolone 21 propionate than clascoterone in suspended (undissolved) form and precipitation of clascoterone in presence of water, the inventors of the present invention are able to successfully develop a stable topical aqueous base cream formulation of clascoterone for treating dermatological conditions wherein clascoterone is present in solubilized form in the cream.

SUMMARY
The invention relates to a stable topical aqueous base cream formulation of clascoterone for treating dermatological conditions wherein clascoterone is present in solubilized form in the cream.

In particular, the invention provides a stable topical aqueous base cream formulation of clascoterone wherein clascoterone is solubilized in a mixture of one or more solubilizing agents.

The invention provides a stable topical aqueous base cream formulation in the form of an oil-in-water emulsion comprising;
a) clascoterone;
b) an aqueous phase; and
c) a non-aqueous phase.

In an embodiment, the invention provides a stable topical aqueous base cream formulation, wherein an aqueous phase comprise water and a non-aqueous phase may comprise of common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof.

In an embodiment, the invention provides a stable topical aqueous base cream formulation, wherein an aqueous phase comprise water and water miscible solvent(s) and a non-aqueous phase may comprise of common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof.

In another embodiment, the invention provides a stable topical aqueous base cream formulation of clascoterone further comprises pharmaceutically acceptable excipients selected from emollients, stiffening agents, solubilizing agents, surfactants, antioxidants, pH modifiers, chelating agents, and combinations thereof.

In another embodiment, the invention provides a stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in a mixture of one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvent(s);
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agents, and combinations thereof.

In another embodiment, the invention provides a stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in dimethyl isosorbide;
b) an aqueous phase comprising water and water miscible solvent(s);
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agent, and combinations thereof;
wherein the ratio of concentration of water to water miscible solvent in aqueous phase is in the range of 1:2 to 1:1.5, preferably 1:1.

In another embodiment, the invention provides a stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in a mixture of dimethyl isosorbide and one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvents;
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agent, and combinations thereof;
wherein the ratio of concentration of water to water miscible solvent in aqueous phase is in the range of 1:2 to 1:1.5, preferably 1:1.

In further embodiment, the invention provides a stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion wherein pH of said formulation is in the range of 4.2 to 4.6.

DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a stable topical cream formulation of clascoterone for topical application wherein clascoterone is present in solubilized form in the cream. Preferably topical cream formulation is an aqueous base cream formulation. The invention also relates to treatment of dermatological conditions such as androgenetic alopecia, atopic dermatities and acne vulgaris by using stable topical cream formulations of clascoterone.

Clascoterone is susceptible to trans-esterification to form cortexolone 21-propionate degradation impurity. Inventors of the present invention surprisingly found that dimethyl isosorbide inhibit trans-esterification of clascoterone to cortexolone 21-propionate. In accordance with the present invention the term “stable” refers to a formulation with formation of cortexolone 21-propionate degradation impurity within acceptable limit, preferably less than about 10% or less than about 5% or less than about 4% or less than about 3% or less than about 2% or less than about 1%.

In accordance with the present invention the term ‘cream’ refers to an emulsion semisolid dosage form used for external application on the skin preferably oil-in-water cream with water as the continuous phase with or without addition of water miscible solvent(s).

As used herein, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a “surfactant” is a reference to one or more surfactants and equivalents thereof known to those skilled in the art, and so forth and vice versa.

As used herein, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used.

In accordance with the present invention the term ‘topical application’ refers to the application to the surface of the skin.

In accordance with the present invention the term ‘solubilized’ refers to at least 80% of the drug is in dissolved form in the formulation or 85% of the drug is in dissolved form in the formulation or 90% of the drug is in dissolved form in the formulation or 95% of the drug is in dissolved form in the formulation or preferably 100% of the drug is in dissolved form in the formulation.

Particularly, the invention provides a stable topical aqueous base cream formulation in the form of an oil-in-water emulsion comprising;
a) clascoterone;
b) an aqueous phase; and
c) a non-aqueous phase.

More particularly, the invention provides a stable topical aqueous base cream formulation of clascoterone comprising an aqueous phase and a non-aqueous phase and a pharmaceutically acceptable excipients.

The stable cream formulation of the present invention comprises clascoterone, wherein clascoterone can be used in the polymorphic form of, but not limited to Form I, II, III IV or combinations thereof.

In accordance with the present invention the aqueous phase comprises water. The aqueous phase may further comprises water miscible solvents and excipients. The aqueous phase is more than 50% of the total formulation.

In accordance with the present invention, an aqueous phase comprises a water miscible solvent(s) in an amount sufficient to saturate water which helps to avoid crystallization of clascoterone in the aqueous phase and keep clascoterone in solubilized form. The water miscible solvents include but not limited to propylene glycol, polyethylene glycol, ethanol, methanol, acetone, tetrachloroethylene, toluene, methyl acetate, ethyl acetate or diethylene glycol monoethylether (also called as Transcutol P) combinations thereof. Preferably the water miscible solvent is propylene glycol. The formulation of the present invention may comprise water miscible solvent(s) in the range 25-50% w/w of the total formulation. In a preferred embodiment, the ratio of concentration of water to water miscible solvent(s) in aqueous phase is in the range of 1:2 to 1:1.5, preferably 1:1. In accordance with the present invention the aqueous phase comprises water and propylene glycol mixture wherein the ratio of water to propylene glycol is in the range of 1:2 to 1:1.5, more preferably 1:1. The aqueous phase may further comprises excipients.

In accordance with the present invention the non-aqueous phase comprises hydrocarbons that exist as a separate, immiscible phase when in contact with water. The non-aqueous phase of the invention may comprise of common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, glyceryl monostearate, silicone oils or combinations thereof. Example of suitable common oils includes but not limited to cottonseed, groundnut, germ, olive, castor, soybean, mineral, sesame oils or combinations thereof. Example of suitable fatty alcohol includes but not limited to carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyldodecanyl alcohol, cetearyl alcohol, lanolin alcohol or combinations thereof. Example of suitable fatty acids and/or esters includes but not limited to oleic acid, myristic acid, palmitic acid, palmitoleic acid, margaric acid, isostearic acid, stearic acid, linoleic acid, linolenic acid, and other fatty acids, glyceryl monostearate 40-55 or combinations thereof. The aqueous phase may further comprises excipients.

In accordance with the present invention the non-aqueous phase comprises fatty alcohols in the range of 2.5-8% w/w, mineral oils in the range of 5-10% w/w, glyceryl monostearate 40–55 in the range of 5-15% w/w of the total formulation.

In accordance with the present invention the term ‘pharmaceutically acceptable excipients’ refers to one or more non-active pharmaceutical substances used in the cream formulation. The formulation of the invention may comprise one or more substances selected from stiffening agents, emollients, solubilizing agents, surfactants, antioxidants, pH modifiers, chelating agents, solvents, cosolvents and combinations thereof. The pharmaceutically acceptable excipients may be present in aqueous phase, non-aqueous phase or both.

In accordance with the present invention the term “stiffening agent” refers to a substance or mixture of substances that increases the viscosity and/or consistency of the formulation or improves the rheology of the formulation. Stiffening agent comprises one or more substances selected from fatty alcohols such as C12-20 fatty alcohols, C16-18 fatty alcohols, fatty acids and/or esters, emulsifiers or combinations thereof. Suitable stiffening agents includes, but not limited to Sepineo 600, cetyl alcohol, stearyl alcohol, glyceryl monostearate 40–55, polyoxyethylene (80) sorbitan monooleate (also called as polysorbate 80), polyoxyl stearyl ether, polyethylene glycol hexadecyl ether. The formulation of the present invention may comprise stiffening agent in the range of about 2-10 % w/w, preferably 2-8% w/w, more preferably 2.5-5% w/w of the total formulation.

In accordance with the present invention the term “emollient” refers to an agent that softens or soothes the skin or soothes an irritated internal surface and improves oil content of the skin or other mucous membranes. Suitable emollient includes but not limited to glycerin, isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, diisopropyl adipate, dimethyl isosorbide, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco-glycerides, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, octyl hydroxystearate, almond oil, coconut oil, olive oil, palm oil, peanut oil and the like; fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid; monohydric alcohol esters of the fatty acids such as ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl myristate, isopropyl myristate, ethyl palmitate, isopropyl palmitate, methyl palmitate, methyl stearate, ethyl stearate, isopropyl stearate, butyl stearate, isobutyl stearate, amyl stearate, and isoamyl stearate; glycols such as ethylene glycol, diethylene glycol, polyethylene glycol, and propylene glycol; branched aliphatic alcohols such as lauryl alcohol, myristyl alcohol, and stearyl alcohol. In accordance with the present invention, the preferred emollients are glycols selected from ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol or combinations thereof. The formulation of the present invention may comprise emollient in the range of about 15-45% w/w, preferably 20-40% w/w, more preferably 25-30% w/w of the total formulation.

In accordance with the present invention the term “surfactant” refers to an agent that stabilizes mixtures of oil and water by reducing the surface tension at the interface between the oil and water molecules. Suitable surfactants may be anionic, amphoteric or non-ionic. Anionic surfactants include but not limited to alkyl sulfates, alkyl ether sulfates, alkylsulfonates, alkylaryl sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alkoylsarcosinates, acyl taurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, a-olefinsulfonates, and the alkali metal and alkaline earth metal salts and ammonium and triethanolamine salts thereof or combinations thereof. Amphoteric surfactants include but not limited to alkylbetaines, alkylamidopropylbetaines, alkylsulfobetaines, alkylglycinates, alkylcarboxyglycinates, alkylamphoacetates or apropionates, alkylamphodiacetates or a-dipropionates, and more specifically, cocodimethylsulfopropylbetaine, lauryl betaine, cocamidopropylbetaine, sodium cocamphopropionate or combinations thereof. Non-ionic surfactants include but not limited to oleic acid, linoleic acid, palmitic acid, stearic acid, polyethylene glycol hexadecyl ether, polyethylene sorbitol esters including polyoxyethylene (80) sorbitan monooleate (also called as polysorbate 80), polysorbate 20 or combinations thereof. In accordance with the present invention the preferred surfactant is polyoxyethylene (80) sorbitan monooleate. The formulation of the present invention may comprise surfactant in the range of about 0.2-1.5% w/w, preferably 0.5-1.5% w/w, more preferably 0.5-1.0% w/w of the total formulation.

In accordance with the present invention the term “humectant” refers to an agent that attract water from the air or from deeper in the skin. Humectants can be used in topical dosage forms to increase the solubility of a chemical compound's active ingredients, increasing the active ingredients' ability to penetrate skin, or its activity time. Suitable humectants include but not limited to triethylene glycol, tripropylene glycol, propylene glycol, glycerin, sorbitol (sugar alcohol), hexylene and butylene glycol, urea, collagen or combination thereof. In accordance with the present invention the preferred humectant is propylene glycol. The formulation of the present invention may comprise humectant in the range of about 5-45 % w/w, preferably 15-40% w/w, more preferably 25-30% w/w of the total formulation.

In accordance with the present invention suitable antioxidants include, but are not limited to, ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotene, alpha -tocopherol (vitamin E), ß-tocopherol, ?-tocopherol, d-tocopherol, ubiquinol, butylated hydroxyanisole (BHA), Propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), tertiary-butylhydroquinone (TBHQ), ascorbyl palmitate, erythorbic acid, 4-hexylresorcinol or combinations thereof. In accordance with the present invention the preferred antioxidant is butylated hydroxytoluene (BHT). The formulation of the present invention may comprise antioxidant in the range of about 0.05-5 % w/w of the total formulation.

In accordance with the present invention the term “solubilizing agents” refers to the agents that are added to pharmaceutical formulations to increase the solubility of poorly soluble drugs or to prepare a solution of a poorly soluble drugs. It thereby also increases the bioavailability of the drug. In aqueous based solutions, solubilizers are used to modify the polarity of water to allow an increase in the solubility of a nonpolar drug. In addition to solubility enhancement, some solubilizer excipients (for e.g. polyoxyethylene (80) sorbitan monooleate) may also function as emulsifiers by enabling the formation of emulsion formulations. Emulsifying agents are soluble in both oil and water as one end of the molecule is attracted to water (hydrophilic) and the other end is attracted to fats/oils (lipophilic). Suitable solubilizing agents include but not limited to C2 to C8 straight and branched chain alcohols, diols and triols, moisturizers and humectants such as glycerin, amino acids and amino acid derivatives, polyaminoacids and derivatives, pyrrolidone carboxylic acids and their salts and derivatives, surfactants such as sodium laurate sulfate, sorbitan monolaurate, emulsifiers such as cetyl alcohol, stearyl alcohol, thickeners such as methyl cellulose, ethyl cellulose, hydroxy methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and acrylic polymers, dimethyl isosorbide, propylene carbonate, benzyl alcohol, propylene glycol, diethylene glycol monoethylether or combination thereof. The formulation of the present invention may comprise solubilizing agents preferably selected from alcohols, diols and triols, emulsifiers and humectants such dimethyl isosorbide, propylene carbonate, benzyl alcohol and propylene glycol or combination thereof in the range of about 5-22% w/w, preferably 8-18% w/w, more preferably 10-15% w/w of the total formulation. The formulation of the present invention may comprise dimethyl isosorbide as solubilizing agents along with other solubilizing agents selected from propylene carbonate, benzyl alcohol and propylene glycol or combination thereof.

In accordance with the present invention the term “pH modifiers” refers to the agents that help to obtain and maintain the pH of the dosage form in an acceptable range, thus contributing towards maintaining the physicochemical stability of the dosage form. Suitable pH modifiers include but not limited to citric acid, dilute hydrochloric acid, sodium hydroxide or combination thereof.

In accordance with the present invention the term “chelating agents” refers to the agents that react with metal ions to form a stable, water-soluble complex. They are also known as chelants, chelators, or sequestering agents. It complexes with an inactivate metallic ions to prevent their adverse effects on the stability. Suitable chelating agents include but not limited to disodium EDTA, disodium calcium EDTA. In accordance with the present invention the preferred chelating agent is disodium edetate.

The invention provides a stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in a mixture of one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvent(s);
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agents, and combinations thereof.

The invention provides a stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in a mixture of dimethyl isosorbide and one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvent(s);
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollients stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agents, and combinations thereof.

The invention provides a stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in a mixture of one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvent(s);
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agents, and combinations thereof;
wherein the ratio of concentration of water to water miscible solvent in aqueous phase is in the range of 1:2 to 1:1.5, preferably 1:1.

In an embodiment, the invention covers a stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone is solubilized in a mixture of one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvents;
c) a non-aqueous phase comprising fatty alcohols, fatty acids and/or esters thereof and mineral oils; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, surfactant, pH modifier, chelating agent, and combinations thereof.

In another embodiment of the invention, clascoterone is solubilized in a mixture of one or more solubilizing agents selected from dimethyl isosorbide, propylene carbonate, benzyl alcohol, diethylene glycol monoethylether, vitamin E or combinations thereof.

The concentration of clascoterone present in solubilized form in a topical formulation according to the present invention is in the range of about 1-1.5 % w/w of the total formulation; preferably 1.0 % w/w of the total formulation.

In an embodiment, the invention provides a stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone is solubilized in a mixture of dimethyl isosorbide and one or more solubilizing agents selected from, propylene carbonate, benzyl alcohol, diethylene glycol monoethylether, vitamin E or combinations thereof;
b) an aqueous phase comprising water and propylene glycol;
c) a non-aqueous phase comprising cetyl alcohol, light mineral oil and glyceryl monostearate 40-55; and
d) a pharmaceutically acceptable excipients selected from polyoxyethylene (80) sorbitan monooleate, polyethylene glycol hexadecyl ether, vitamin E, citric acid, propylene glycols, cetyl alcohol and combinations thereof.

In an embodiment, the invention provides a stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone is solubilized in a mixture of dimethyl isosorbide and one or more solubilizing agents selected from propylene carbonate, benzyl alcohol, diethylene glycol monoethylether, vitamin E or combinations thereof;
b) an aqueous phase comprising water and propylene glycol;
c) a non-aqueous phase comprising cetyl alcohol, light mineral oil and glyceryl monostearate 40-55; and
d) a pharmaceutically acceptable excipients selected from polyoxyethylene (80) sorbitan monooleate, polyethylene glycol hexadecyl ether, vitamin E, citric acid, propylene glycols, cetyl alcohol and combinations thereof;
wherein pH of said formulation is adjusted to a value in the range of 4.2 to 4.6.

In another embodiment, the invention provides a stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone is solubilized in a mixture of dimethyl isosorbide and one or more solubilizing agents selected from propylene carbonate, benzyl alcohol, diethylene glycol monoethylether, vitamin E or combinations thereof;
b) an aqueous phase comprising water and water miscible solvents selected from propylene glycol, polyethylene glycol or combinations thereof;
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from polyoxyethylene (80) sorbitan monooleate, polyethylene glycol hexadecyl ether, vitamin E, citric acid, propylene glycols, cetyl alcohol and combinations thereof;
wherein the ratio of concentration of water to water miscible solvent in aqueous phase is in the range of 1:2 to 1:1.5, preferably 1:1;
wherein pH of said formulation is adjusted to a value in the range of 4.2 to 4.6.

In another embodiment, the invention provides a stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone is solubilized in a mixture of dimethyl isosorbide, propylene carbonate, benzyl alcohol;
b) an aqueous phase comprising water and propylene glycol;
c) a non-aqueous phase comprising cetyl alcohol, mineral oil and glyceryl monostearate 40-55; and
d) a pharmaceutically acceptable excipients selected from polyoxyethylene (80) sorbitan monooleate, polyethylene glycol hexadecyl ether, vitamin E, citric acid, or combinations thereof;
wherein the ratio of concentration of water to propylene glycol in aqueous phase is 1:1;
wherein pH of said formulation is adjusted to a value in the range of 4.2 to 4.6.

In yet another embodiment, a stable topical aqueous base cream formulation of clascoterone comprising aqueous phase, non-aqueous phase may be prepared by emulsification process comprising the steps of:
a) preparation of an aqueous phase;
b) preparation of a non-aqueous phase;
c) emulsification of step a and b to prepare emulsified base; and
d) preparation of drug phase and addition of step d to step c (to the emulsified base).

In yet another embodiment, a stable topical aqueous base cream formulation of clascoterone comprising aqueous phase, non-aqueous phase may be prepared by emulsification process comprising the steps of:
a) preparation of an aqueous phase by mixing water and water miscible solvents selected from propylene glycol, polyethylene glycol or combinations thereof and optionally adding pharmaceutically acceptable excipients;
b) preparation of a non-aqueous phase by mixing fatty alcohols, mineral oils, glyceryl monostearate 40-55 or combinations thereof and optionally adding pharmaceutically acceptable excipients;
c) emulsification by adding non-aqueous phase to aqueous phase under homogenization to form emulsified base and optionally adding pharmaceutically acceptable excipients;
d) preparation of drug phase by dissolving clascoterone in one or more solubilizing agents and optionally adding pharmaceutically acceptable excipients; and
e) addition of drug phase to the emulsified base.

Effect of dimethyl isosorbide on trans-esterification impurity:
The cream formulation was prepared with and without dimethyl isosorbide keeping the other excipients same as per table 1 to understand the effect of dimethyl isosorbide on trans-esterification of clascoterone to cortexolone 21-propionate impurity. These two formulations were kept on stability at 25°C/60%RH. The stability study results are shown in the Table 2.
Table 1
Ingredients A B
Clascoterone 1.0 1.0
Dimethyl Isosorbide - 7.0
Propylene Glycol 38.0 34.0
Benzyl Alcohol 1.5 1.5
Propylene Carbonate 5.0 5.0
Glyceryl monostearate 40-55 8.0 8.0
Cetyl Alcohol 11.0 12.0
Mineral Oil 6.0 9.0
Polyoxyethylene (80) sorbitan monooleate 0.2 0.2
Vitamin E 0.2 0.2
EDTA 0.05 0.05
Sepineo P600 - 0.2
Water 29.0 21.8
pH of the formulation 4.7 4.7

Table 2
Condition Impurity (Cortexolone 21-propionate)

A B
Initial 0.04 0.03
25°C/60%RH/7 Day 0.29 0.14
25°C/60%RH/15 Day 0.41 0.24
25°C/60%RH/21 Day 0.51 0.32
25°C/60%RH/1 M 0.60 0.41
25°C/60%RH/2 M 1.08 0.78

From the above results, it can be seen that, dimethyl isosorbide was successfully able to slow down the degradation of clascoterone to cortexolone 21-propionate impurity improving the stability of the cream formulation compared to the formulation without dimethyl isosorbide.

The following examples illustrate the invention and they do not any way limit the scope of the invention.

Example 1:
Table 3
Ingredients F1 (% w/w) F2 (% w/w) F3 (%w/w)
Clascoterone 1.0 1.0 1.0
Dimethyl Isosorbide - 7.0 7.0
Diethylene glycol monoethylether 10.0 - -
Propylene Glycol 30.0 30.0 30.0
Benzyl Alcohol 1.5 1.5 1.5
Propylene Carbonate 5.0 5.0 5.0
Glyceryl monostearate 40-55 11.0 12.0 12.0
Cetyl Alcohol 7.0 8.0 8.0
Mineral Oil 9.0 9.0 9.0
Polysorbate 80 - - 0.5
Vitamin E 0.04 0.2 0.2
Edetate Disodium 0.05 0.05 0.05
Sepineo P 600 - - 0.5
Polyethylene glycol hexadecyl ether 1.0 1.0 -
Butylated hydroxytoluene 0.2 - -
Purified Water 24.31 25.18 25.14
Dilute HCl QS to adjust QS to adjust pH QS to adjust pH

Preparation of Formulations F2 and F3:
An oil-in-water aqueous base cream formulation of clascoterone was prepared by using emulsification technique. Aqueous phase was prepared by maintaining purified water at 65°-75°C temperature and adding edetate disodium and propylene glycol under stirring till they got dissolved completely. Non-aqueous phase was prepared by mixing cetyl alcohol, mineral oil, glyceryl monostearate 40-55, vitamin E and Polysorbate 80/ polyethylene glycol hexadecyl ether at 55°-65°C temperature under stirring. Formulation was emulsified by adding non-aqueous phase to aqueous phase under homogenization at 55°-65°C temperature followed by the addition of sepineo P 600 under stirring (for F3 formulation only). The resulting emulsified base was allowed to cool down to 30°-35°C temperature. Meanwhile clascoterone was dissolved in mixture of dimethyl isosorbide, propylene carbonate and benzyl alcohol which was added to an emulsified base and mixed continuously till cream begin to set. The pH of the cream was adjusted to a value in the range of 4.2 to 4.6 by using dilute HCl.

Preparation of Formulation F1:
Formulation (F1) was prepared by similar process as above except solubilizing clascoterone in mixture of diethylene glycol monoethylether in place of dimethyl isosorbide and further using butylated hydroxytoluene.

Example 2:
Table 4
Ingredients F4 (%w/w)
Clascoterone 1.0
Dimethyl Isosorbide 5.0
Propylene Glycol 30.0
Benzyl Alcohol 1.5
Propylene Carbonate 5.0
Glyceryl monostearate 40-55 14.0
Cetyl Alcohol 2.5
Mineral Oil 10.0
Polysorbate 80 1.0
Vitamin E 0.05
Edetate Disodium 0.05
Butylated hydroxytoluene 0.2
Purified Water 29.00
Dilute HCl QS to adjust pH

An oil-in-water aqueous base cream formulation of clascoterone was prepared by using emulsification technique.

Aqueous phase was prepared by maintaining purified water at 65°-75°C temperature and adding edetate disodium, polysorbate 80 and 5% propylene glycol under stirring till it dissolved completely.

Non-Aqueous phase was prepared by mixing cetyl alcohol, mineral oil, glyceryl monostearate 40-55 and vitamin E at 55°-65°C temperature under stirring.

Formulation was emulsified by adding non-aqueous phase to aqueous phase under homogenization at 55°-65°C temperature followed by the addition of remaining 24 % propylene glycol under stirring. The resulting emulsified base was allowed to cool down to 30°-35°C temperature. Meanwhile clascoterone was dissolved in mixture of dimethyl isosorbide, propylene carbonate and benzyl alcohol which was added to an emulsified base and mixed continuously till cream begin to set. The pH of the cream was adjusted to a value in the range of 4.2 to 4.6 by using dilute HCl.

The three formulation F2, F3 and F4 were kept on stability at 25°C/60%RH and 2-8°C. The stability study results are shown in the Table 5.

Table 5
Time point Impurity (Cortexolone 21-propionate)
(25°C/60%RH) Impurity (Cortexolone 21-propionate)
(2-8°C)
F1 F2 F3 F4 F2 F3 F4
Initial 0.56 0.03 0.03 0.03 0.03 0.03 0.03
1M - 0.33 0.36 0.35 0.06 0.07 0.07
2M - 0.65 0.61 0.78 0.08 0.10 0.10
3M - 1.03 0.89 1.18 0.13 0.12 0.12
Observation No Precipitation of drug observed (100% drug present in dissolved form)

As can be seen from the results, the cream formulation of clascoterone according to present invention is surprisingly stable in the aqueous base cream and no precipitation of the clascoterone observed. The formulation with diethylene glycol monoethylether (Transcutol P) show higher level of impurity at zero time point (initial) and hence not studied further.
,CLAIMS:
1. A stable aqueous base topical cream formulation of clascoterone in the form of an oil-in-water emulsion comprising;
a) clascoterone solubilized in a mixture of one or more solubilizing agents;
b) an aqueous phase comprising water and water miscible solvent(s);
c) a non-aqueous phase comprising common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof; and
d) a pharmaceutically acceptable excipients selected from emollient, stiffening agent, solubilizing agent, surfactant, antioxidant, pH modifier, chelating agents, and combinations thereof.

2. The formulation according to claim 1, wherein solubilizing agents is dimethyl isosorbide.

3. The formulation according to claim 2, further comprising solubilizing agents selected from propylene carbonate, benzyl alcohol, diethylene glycol monoethylether, vitamin E or combinations thereof;

4. The formulation according to claim 1, wherein the aqueous phase comprising water and water miscible solvents, wherein the ratio of concentration of water to water miscible solvents in aqueous phase is in the range of 1:2 to 1:1.

5. The formulation according to claim 4, wherein water miscible solvent is selected from propylene glycol, polyethylene glycol or combinations thereof, wherein the ratio of concentration of water to water miscible solvent in aqueous phase is 1:1.

6. The formulation according to claim 1, comprising non-aqueous phase selected from common oils, fatty alcohols, fatty acids and/or esters thereof, mineral oils, petrolatum, waxes, silicone oils or combinations thereof.

7. The formulation according to claim 1, wherein concentration of clascoterone present in solubilized form in a topical formulation is from about 1 % to about 1.5%.

8. The formulation according to claim 1, wherein pH of the said formulation is in the range of 4.2 to 4.6.

9. A stable topical aqueous base cream formulation of clascoterone in the form of an oil-in-water emulsion comprising
a) clascoterone is solubilized in a mixture of dimethyl isosorbide and one or more solubilizing agents selected from propylene carbonate, benzyl alcohol, diethylene glycol monoethylether, vitamin E or combinations thereof;
b) an aqueous phase comprising water and propylene glycol, polyethylene glycol or combinations thereof;
c) a non-aqueous phase comprising cetyl alcohol, stearyl alcohol, light mineral oil, Glyceryl monostearate 40-55 or combinations thereof;
d) a pharmaceutically acceptable excipients selected from polysorbate 80, vitamin E, citric acid, propylene glycols, cetyl alcohol or combinations thereof;
wherein pH of said formulation is adjusted to a value in the range of 4.2 to 4.6.

10. The formulation according to claim 9, wherein the formulation is used for the treatment of acne vulgaris.