TOPICAL COMPOSITIONS COMPRISING A STEROID AND A VITAMIN D-RELATED COMPOUND

INTRODUCTION

Aspects of the present application provide formulations for the topical administration of an active agent. In embodiments, the present application provides formulations comprising at least one vitamin D-related compound and at least one corticosteroid, as active agents in the form of semisolid dosage forms. In aspects, the present application also provides processes for preparing formulations, and methods of using them.

Psoriasis, a chronic, idiopathic, genetically determined, and environmentally influenced disorder, has been treated empirically for centuries with varied success. Its association with arthropathy and its significant psychological consequences have necessitated a comprehensive team approach for optimal care. Psoriasis is a non contagious autoimmune disease that affects the skin and joints. It commonly causes red scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Skin rapidly accumulates at these sites and takes on a silvery-white appearance. Plaques frequently occur on the skin of the elbows and knees, but can affect any area including the scalp and genital areas. In contrast to eczema, psoriasis is more likely to be found on the extensor aspect of the joint. The disorder is a chronic recurring condition, varying in severity from minor localized patches to complete body coverage. Fingernails and toenails are frequently affected (psoriatic nail dystrophy) and can be seen as an isolated finding. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Ten to fifteen percent of people with psoriasis have psoriatic arthritis. The cause of psoriasis is not known, but it is believed to have a genetic component. There are many treatments available, but, because of its chronic recurrent nature, psoriasis is a challenge to treat.

Calcipotriene is a synthetic derivative of calcitriol or vitamin D. Calcipotriene has a chemical name (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1(a),3(P),24-triol, with the empirical formula C27H40O3, a molecular weight of 412.605, and structural Formula I.

Formula I

Corticosteroids are being increasingly used in the therapy of psoriasis. The corticosteroids are a class of compounds comprising steroids (lipids that contain a hydrogenated cyclopentoperhydrophenanthrene ring system) elaborated by the adrenal cortex (except sex hormones of adrenal origin), in response to the release of adrenocorticotropic or adrenocorticotropic hormone by the pituitary gland, or to any synthetic equivalent, or to angiotensin II. In pharmacologic doses, corticosteroids are used primarily for their anti-inflammatory and/or immunosuppressive effects. Topical corticosteroids, such as betamethasone dipropionate, are effective in treatment of corticosteroid-responsive dermatoses primarily because of their anti-inflammatory, antipruritic, and vasoconstrictive actions. Betamethasone dipropionate is an analog of prednisolone, has a high degree of corticosteroid activity and a slight degree of mineralocorticoid activity. Betamethasone dipropionate is of particular value when used in short courses for the treatment of more resistant dermatoses such as psoriasis (excluding widespread plaque psoriasis), atopic dermatitis and other skin conditions which do not respond satisfactorily to less active steroids.

Betamethasone dipropionate has a chemical name 9-fluoro-11(P),-17,21-trihydroxy-16(p)-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate and is represented by structural Formula II.

Formula II

Betamethasone dipropionate is a white to cream white crystalline powder. It is practically insoluble in water, sparingly soluble in ethanoi, and freely soluble in acetone and chloroform.

Topical betamethasone is available in various dosage forms, such as aerosol foam, cream, ointment, gel, and lotion formulations in the U.S. market. Other combination formulations of betamethasone dipropionate with calcipotriene hydrate and also with clotrimazole exist. Betamethasone dipropionate is commercially available under the brand names Diprolene AF® and Diprolene® which comprise 0.05% betamethasone base, and are applied to the affected skin areas once or twice daily.

U.S. Patent No. 4,871,723 discloses a method for treating psoriasis, by topically applying a composition comprising vitamin D and a wax carrier. Specifically, the patent discloses a composition comprising: a) a pharmaceutically effective amount of an active-type vitamin D3; b) a solvent selected from fatty acid esters, higher alcohols with 10 or more carbons, and propylene carbonate; and c) an oily carrier selected from white vaseline, yellow vaseline, and liquid paraffin.

U.S. Patent No. 6,753,013 discloses a pharmaceutical composition for dermal use, which contains at least one vitamin D or vitamin D analogue, at least one corticosteroid, and a solvent, polyoxypropylene-15-stearyl ether to enable the two active components to coexist without significant degradation, despite their different stability profiles. The compositions, however, are wax-based and include wax or similar excipients, such as soft white paraffin and paraffin liquid.

U.S. Patent No. 6,787,529 discloses a gel formulation comprising a vitamin D analogue such as calcipotriol, a corticosteroid such as betamethasone dipropionate, a viscosity increasing excipient like hydrogenated castor oil, and the solvent polyoxypropylene-15-stearyl ether.

U.S. Patent Application Publication No. 2005/0282788 discloses an anhydrous pharmaceutical composition for the treatment of psoriasis, comprising an organopolysiloxane elastomer such as a silicone agent, together with vitamin D or the vitamin D derivative calcitriol, and the corticosteroid betamethasone.

U.S. Patent Application Publication No. 2008/0064669 discloses a pharmaceutical composition for topical use comprising the vitamin-D compound calcipotriene and the corticosteroid betamethasone, in a solvent system consisting of a triglyceride, sorbitan fatty ester, cetearyl glucoside, PEG-n sorbitan stearate, acrylamide/sodium acryloyldimethyl taurate copolymer, and mixtures thereof.

International Application Publication No. WO 2010/039251 claims a storage stable ointment suitable for treating psoriasis, comprising a vitamin D compound, a corticosteroid, and a N,N-di(CrC8) alkylamino substituted, (C4-Ci8) alkyl (C2-Ci8) carboxylic ester in a petrolatum carrier, and optionally containing mineral oil, tocopherol, or both.

Several topical formulations available commercially are primarily incapable of providing the much-needed soothing effect to the affected areas, particularly in conditions such as psoriasis. Disadvantages of topical agents are variably that they can often irritate normal skin, can be time consuming, can pose discomfort during application, cannot be used for long periods, can stain clothing, or have a strong odour. As a result, it is sometimes difficult for people to maintain regular applications of these medications. Abrupt withdrawal of some topical agents, particularly corticosteroids, can cause an aggressive recurrence of the condition. This is known as a rebound of the condition.

There is a need for improved patient-compliant topical formulations that are effective in the treatment of skin disorders such as psoriasis, and which provide one or more of improved delivery of the active agent at the desired site of action, decreased inconvenience and irritation, increased ease of use for the patient, and longer durations of action.

SUMMARY

Aspects of the present application provide topical pharmaceutical composition in the form of an ointment comprising betamethasone dipropionate and calcipotriene monohydrate.

In aspects, topical pharmaceutical composition further comprises pharmaceutically acceptable excipients like solvents, antioxidants and ointment base.

In embodiments, the topical pharmaceutical composition, the solvent is selected from the group comprising of triglycerides, mineral oils, fatty acid esters, glycol ethers, N-methylpyrrolidone, fatty alcohol, coco-caprylate/caprate, polydimethylsiloxane, polyoxyethylene castor oil derivatives, polyoxylglycerides, polypropoxylated glucose methyl ether fatty acid ester derivatives, ethoxylated fatty alcohols, polyoxyethylene fatty acid ethers, straight chain or branched aliphatic alcohols, propylene glycol diester, hexylene glycol, fatty alcohol with its lactic acid ester, glucosides, octoxynol or any mixtures thereof.

In embodiments, the topical pharmaceutical composition, solvent is mixture of polypropoxylated 20 methyl glucose ether distearate and mineral oil.

In embodiments, the topical pharmaceutical composition wherein the antioxidant is selected from the group comprising of ascorbic acid, glutathione, lipoic acid, uric acid, carotenes, a-tocopherol, ubiquinol, butylated hydroxyanisole, butylated hydroxytoluene, sodium benzoate, propyl gallate tertiary-butylhydroquinone or any mixtures thereof.

In embodiments, the topical pharmaceutical composition wherein the ointment base is selected from hydrocarbon bases, absorption bases, water soluble bases, and emulsifying bases, wherein hydrocarbon bases include but not limited to hard paraffin, soft paraffin; absorption bases include but not limited to wool fat, beeswax; water soluble bases include but not limited to macrogol 200, 300, and 400, and emulsifying bases include but not limited to emulsifying wax and cetrimide.

In embodiments, the topical pharmaceutical composition in the form of an ointment comprising, calcipotriene monohydrate, betamethasone dipropionate, polypropoxylated 20 methyl glucose ether distearate, mineral oil, a-tocopherol, and white soft paraffin.

In embodiments the topical pharmaceutical composition provide for effective management of skin diseases or disorders, such as psoriasis vulgaris.

Aspects of the application provide processes for the preparation of a topical pharmaceutical composition comprising the steps of:

a) melting white soft paraffin;

b) dissolving and/or dispersing calcipotriene monohydrate in polypropoxylated 20 methyl glucose ether distearate and mixed in the molten state and adding to step a);

c) dispersing betamethasone dipropionate in mineral oil, adding alpha-tocopherol and mixing for uniformity;

d) adding step c) dispersion to molten wax drug solution of step b);

e) cooling the mixture to room temperature with stirring and filling into suitable containers and closures.

DETAILED DESCRIPTION

Aspects of the present application provide pharmaceutical topical compositions comprising at least one vitamin D-related compound and at least one corticosteroid as active agents, in a semisolid dosage form.

The term "vitamin D-related compound" includes vitamin D, its prodrugs, natural or synthetic analogues, and crystalline forms including anhydrate, hydrate, solvate, amorphous forms, and mixtures thereof. Examples of vitamin D compounds include calcipotriene (calcipotriol), calcitriol, tacalcitol, maxacalcitol. In specific embodiments, a vitamin D compound may be calcipotriene or any solvates, salts, esters, isomers, derivatives, or prodrugs thereof, e.g., calcipotriene hydrate.

In embodiments, compositions of the application comprise at least one corticosteroid, examples including alclometasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone acetate, dexamethasone nicotinate, dexamethasone propionate, dexamethasone sodium phosphate, dexamethasone valerate, diflorasone diacetate, diflucortolone valerate, fluandrenolide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortin butyl ester, fluticasone propionate, halcinonide, halobetasol propionate, halometasone monohydrate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone-17-butyrate-21-propionate, hydrocortisone aceponate, hydrocortisone acetate, hydrcortisone valerate, hydrocortisone butyrate, hydrocortisone probutate, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone furoate, prednisolone, prednisolone sodium phosphate, prednisolone acetate, prednisolone-17-valerate-21 -acetate, triamcinolone acetonide, triamcinolone acetate, triamcinolone diacetate, and prednicarbate. Other drug compounds are also useful, and this application further specifically contemplates the use of any combinations of steroid drugs.

In embodiments, a steroid active agent of the present application is betamethasone or any salts, esters, isomers, derivatives, or prodrugs thereof. In a specific embodiment, the active agent is betamethasone dipropionate. The active agent may be used in an amorphous form or a crystalline form, or mixtures thereof.

According to the application, unless otherwise specified, recitation of active agents, such as vitamin D-related compound or corticosteroid, is intended to include the drug compound or any solvates, salts, esters, isomers, conjugates, derivatives, or prodrugs thereof.

In embodiments, the easily manufactured formulations of the present application are non-irritant to the skin, non-toxic and well-tolerated thereby providing a high degree of patient compliance, and are extremely useful in the effective management of skin diseases or disorders, such as psoriasis vulgaris, steroid-responsive dermatoses and other associated diseases and disorders.

In embodiments, ointment formulations of the present application are useful in the management of psoriasis are further provide moisturizing and/or soothing effects at the site of application on the skin. In embodiments, the topical formulations reduce the dryness that accompanies the build-up of skin on psoriatic plaques. The formulations, when applied directly to psoriatic plaques, help to reduce inflammation, remove built-up scale, reduce skin turnover, and clear affected skin of plaques.

An ointment is a homogeneous, viscous, semi-solid preparation, most commonly a greasy, thick oil with a high viscosity that is intended for external application to the skin or mucous membranes. Ointments are used as emollients or for the application of active ingredients to the skin for protective, therapeutic, or prophylactic purposes and where a degree of occlusion is desired. Ointments are usually very moisturizing, and good for dry skin. They have a low risk of sensitization due to having few ingredients beyond the base oil or fat, and low irritation risk.

Some of the advantages of topical ointment formulations of the present application include non-irritancy to the site of application, ease of application, useful for long periods, non-staining to clothing, and not emitting or inducing strong or foul odors. As a result, it is easier for a subject in need thereof to maintain the regular application of the medications thus avoid abrupt withdrawal of steroid applications, which in turn prevents an aggressive recurrence of the disease condition.

The formulations of the present application can comprise one or more additional active agents that are useful in the management of psoriasis and associated pathological conditions, including synthetic, semi-synthetic, or naturally obtained active agents. The compositions of the present application are also useful in conjunction with other therapies, especially phototherapy.

In embodiments, formulations comprise at least one vitamin D-related compound and one corticosteroid as active agents, in semisolid dosage forms such as ointments, together with one or more excipients. The concentrations of vitamin D-related compound contained in the formulations of the present application range from about 0.0001 to about 5% w/w, or from about 0.004 to about 0.7% w/w, or about 0.005%w/w.

In embodiments, the corticosteroid used is betamethasone dipropionate, present in the topical compositions in concentrations from about 0.01 to about 0.5% w/w, or from about 0.025 to about 0.075% w/w, or about 0.064% w/w.

In embodiments, formulations of the present application are ointments comprising a hydrophobic phase and an antioxidant. In embodiments, the proportion of hydrophobic phase is about 0.5% to about 99% w/w with regard to the weight of the formulations.

In embodiments, the formulations of the present application include excipients such as, but not limited to, one or more of carriers, permeation or penetration enhancers, solvents, emollients, ointment bases, antioxidants and the like.

In embodiments, additionally excipients may include emulsifiers, coemulsifiers, cosolvents, preservatives, buffering agents, gelling or thickening agents, polymers, surfactants, soothing agents, pH modifiers, solubilizers, humectants, emollients, moisturizers, oily bases and the like.

A "carrier" is an organic or inorganic ingredient, natural or synthetic, with which an active ingredient is combined to facilitate application of a formulation. The amounts of carrier may be about 5% to about 99.99% by weight of the composition. In embodiments, the carrier can comprise any pharmaceutically acceptable fatty esters of natural fatty acids, triglycerides of animal or vegetable, medium chain triglycerides, mixtures of mono-, di- and/or triglycerides, waxes, hydrogenated vegetable oils, and mixtures thereof.

A 'solvent' is a liquid component that aids in the dissolution of a drug in the formulation. The solvents serve to maintain a solution of the drug in the composition. Some of the solvents can also enhance percutaneous penetration of drug and/or act as humectants. Various useful solvents include, without limitation, triglycerides (long chain and medium chain), mineral oils (light or heavy), fatty acid esters, glycol ethers, N-methylpyrrolidone, fatty alcohol, coco-caprylate/caprate, polydimethylsiloxane, polyoxyethylene castor oil derivatives, polyoxylglycerides, polypropoxylated glucose methyl ether fatty acid ester derivatives, ethoxylated fatty alcohols, polyoxyethylene fatty acid ethers, straight chain or branched aliphatic alcohols, propylene glycol diester, hexylene glycol, fatty alcohol with its lactic acid ester, glucosides, octoxynol and any mixtures thereof.

Mineral oil is a transparent, colorless, viscous oily liquid, without fluorescence in daylight. It is practically tasteless and odorless when cold, and has a faint odor of petroleum when heated. Mineral oil is used as an excipient in a wide variety of pharmaceutical formulations. It is used primarily as an excipient in topical pharmaceutical formulations, where its emollient properties are exploited as an ingredient in ointment bases; Mineral oil undergoes oxidation when exposed to heat and light. Oxidation begins with the formation of peroxides, exhibiting an 'induction period'.

Triglycerides, also termed as triacylglycerols, TAG, or triacylglycerides are esters derived from glycerol and three fatty acids. They are the main constituents of vegetable oils and animal fats. Triglycerides used herein are from long chain or medium chain acids. Some useful long chain triglycerides include vegetable oils, hydrogenated soya bean oil, hydrogenated cotton seed oil, peanut oil, olive oil, almond oil, sesame oil, safflower oil, and mixtures thereof. Hydrogenated cotton seed oil comprises 70% unsaturated fatty acids, including 18% monounsaturated (oleic), 52% polyunsaturated (linoleic), and 26% saturated (primarily palmitic and stearic) acids. Peanut oil comprises fatty acids such as oleic acid (56.6%) and linoleic acid (26.7%), and this oil also contains some palmitic acid, arachidic acid, arachidonic acid, behenic acid, lignoceric acid and other fatty acids. Almond oil comprises margaric acid, oleic acid, palmitic acid, palmitoleic acid, stearic acid, sterols, A7-avenasterol, A5-avenasterol, brassicasterol, cholesterol, campesterol, stigmasterol, B-sitosterol, and A7-stigmasterol. Sesame oil comprises palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and eicosenoic acid.

Medium chain triglycerides are alkyl (6 to 12 carbon atoms) fatty acid esters of glycerol. Coconut oil is composed of approximately 66% medium-chain triglycerides. Fractionated coconut oil is a fraction of the whole oil, in which the long-chain fatty acids are removed so that only medium chain saturated fatty acids remain. Fractionated coconut oil may also be referred to as caprylic/capric triglyceride oil or medium chain triglyceride (MCT) oil because it is primarily the medium chain caprylic (8 carbons) and capric (10 carbons) acids that make up the bulk of the oil. The fatty acids found in MCTs are called medium-chain fatty acids. Commercially available MCT products include Miglyol™ 810, Miglyol™ 812, and Myritol™ 318 (caprylic/capric acid triglyceride mixtures).

Glycol ethers, with the combination of ether and alcohol groups, and a hydrocarbon chain, in one molecule, provide versatile solvency characteristics with both polar and non-polar properties. The chemical hydrocarbon chain provides resistance to solubility in water, while ether or alcohol groups promote hydrophilic solubility performance. This surfactant-like structure provides the compatibility between water and a number of organic solvents, and the ability to couple unlike phases. Glycol ethers are characterized by their wide range of hydrophilic/hydrophobic balances. Diethylene glycol monoethyl ether is a representative of this class, and is marketed as TranscutoKS) products. Different grades are available, such as Transcutol® HP. Transcutol®P offers a grade of purity greater than 99.8%. This grade is suitable for topical, rectal and vaginal formulations. Transcutol®P can act as a solvent and solubilizer for many poorly soluble compounds. It is soluble in both water and oil, forming an intracutaneous drug depot. Quite versatile, can be formulated in gels, creams, and lotions.

N-methylpyrrolidone (NMP) is a chemical compound with a 5-membered lactam structure. It is a clear to slightly yellow liquid, miscible with water and solvents like ethyl acetate, chloroform, benzene, lower alcohols, and ketones.

Fatty alcohols are aliphatic alcohols derived from natural fats and oils, originating in plants, and also synthesized in animals and algae. Examples of fatty alcohols include, but are not limited to, stearyl alcohol, oleyl alcohol, and octyldodecanol. Stearyl alcohol is a white, waxy solid with a faint odor, while oleyl alcohol and octyldodecanol are clear, colorless liquids. Oleyl alcohol is an unsaturated fatty alcohol, similar to the saturated fatty alcohols stearyl alcohol and cetyl alcohol.

Examples of fatty acid esters include, but are not limited to, isopropyl myristate, isopropyl isostearate, isopropyl palmitate, diisopropyl adipate, dibutyl adipate, dicaprylyl carbonate, diethylhexyl carbonate. Isopropyl myristate is the ester of isopropyl alcohol and myristic acid, and is used in cosmetic and topical medicinal preparations where good absorption through the skin is desired. Dibutyl adipate, the diester of butyl alcohol and adipic acid, functions as a plasticizer, skin-conditioning agent, and solvent in cosmetic formulations. A solid fat that can be derived from vegetable, synthetic or animal sources is dicaprylyl carbonate. Dicaprylyl carbonate is a good emollient and does not leave an oily film on the skin.

Coco-caprylate/caprate is a traditional, medium spreading emollient. It is a clear, mildly yellow, medium polar oil with a slightly fatty odour. Due to its high spreading value, the product is suited for use in cosmetic and pharmaceutical skin care preparations, such as low fat emulsions and skin oils. It is typically used in amounts about 1-15% by weight of a composition.

Polydimethylsiloxanes (PDMS) belong to a group of polymeric organosilicon compounds that are commonly referred to as silicones. A PDMS is optically clear, and, in general, is considered to be inert, non-toxic and non-flammable. Examples include but are not limited to simethicone, dimethicone and the like.Dimethicone is used widely in skin-moisturizing lotions where it is listed as an active ingredient for the purpose of skin protection. Dimethicones of various viscosities are widely used in cosmetic and pharmaceutical formulations. In topical oil-in-water emulsions, dimethicone is added to the oil phase as an antifoaming agent. Dimethicone is hydrophobic and is also widely used in topical barrier preparations. Some cosmetic formulations use dimethicone and related siloxane polymers in concentrations of use up to 10-30% by weight. Dimethicone can be used in combination with diisopropyl adipate and isopropyl myristate, which function as penetration enhancers.

Polyoxyethylene castor oil derivatives are complex mixtures of various hydrophobic and hydrophilic components. Members within each range have different degrees of ethoxylation, expressed as moles/PEG unit, as indicated by their numerical suffix (n). The chemical structures of the polyethoxylated hydrogenated castor oils are analogous to polyethoxylated castor oils with the exception that the double bond in the fatty chain has been saturated by hydrogenation. Castor oil can be used in aqueous alcoholic or completely aqueous solutions. Polyoxyl 40 hydrogenated castor oil (also called macrogolglycerol hydroxystearate) can be used to solubilize vitamins, essential oils, and certain drugs. Cremophor® RH 40 is a commercially available product.

Polyoxylglycerides are mixtures of monoesters, diesters, and triesters of glycerol, and monoesters and diesters of polyethylene glycols (PEG). Examples of polyoxylglycerides include, but are not limited to, caprylocaproyl macrogol glycerides such as Labrasol®, oleoyl macrogol glycerides such as Labrafils®, and the like. Polyoxylglycerides have mean relative molecular masses between 200 and 400. Polyoxylglycerides are used as self-emulsifying and solubilizing agents in oral and topical pharmaceutical formulations. They are also used in cosmetic and food products.

Oleic acid is a mono-unsaturated omega-9 fatty acid, found in various animal and vegetable sources.

Essential oils are volatile and liquid aromatic compounds from natural sources, usually plants. Essential oils are also known as volatile, ethereal oils or aetherolea, or simply as the "oil of the plant from which they were extracted, such as oil of clove. Essential oils are usually lipophilic compounds that usually are not miscible with water. Essential oils are distinguished from aroma oils (essential oils and aroma compounds in an oily solvent), infusions in a vegetable oil, absolutes, and concretes. Typically, essential oils are highly complex mixtures of often hundreds of individual aroma compounds. Some examples of essential oils are anise oil, balsam oil, fenugreek oil, eucalyptus oil, rosewood oil, and lemon grass oil. Eucalyptus oil is composed of tannins, flavonoids, cineole, and volatile oils. Cineole is sometimes called eucalyptol.

In embodiments, propoxylated glucose esters and its derivatives are used as solvents. These include polypropoxylated glucose methyl ether with fatty acid ester derivatives. Examples of the polypropoxylated glucose methyl ether with fatty acid ester derivatives include, but are not limited to, polypropylene glycol (PPG) glucose stearyl ethers, like PPG glucose ethers of stearyl alcohol, e.g., PPG-5 methyl glucose ether distearate, PPG-20 methyl glucose ether distearate, PPG-50 methyl glucose ether distearate, and PPG-11 stearyl ether. PPG-20 methyl glucose ether distearate may be used in various concentrations. PPG-20 methyl glucose ether distearate may be used in various ratios in combination with other excipients.

In embodiments, PPG-20 methyl glucose ether distearate is present in a composition in amounts of about 0.005 to about 10%, by weight. In embodiments, PPG-20 methyl glucose ether distearate is present in a composition in amounts of about 0.05% to about 8%, by weight, or about 0.25% to about 4.75%, by weight.

Ethoxylated fatty alcohols are natural fatty alcohols. This naturally derived surfactant offers emulsifying and detergency for a variety of applications. Examples of the ethoxylated fatty alcohols include but not limited to laureth-4, laureth-9, laureth-23, and the like. They are commercially available in market as Brij® products.

Polyoxyethylene 15 stearyl ether is made by the reaction between ethylene oxide and stearyl alcohol. Stearyl alcohols come from animal fats and oils. The 11 or 15 designation is based on the 'units' of ethylene glycol produced in the reaction. C12-18 saturated fatty alcohol esters of caprylic/capric acid are used as an emollient for creams and lotions, and a solubilizer for oil soluble actives. Examples include, but are not limited to, dicaprylyl carbonate (commercially available as Cetiol® CC), C12-18 esters of caprylic/capric acid (commercially available as Cetior® LC PH), C12-15 alkyl benzoate (commercially available as Cetiol® AB), propylheptyl caprylate (commercially available as Cetiol® Sen soft), dicaprylyl ether (commercially available as Cetiol® OE), and the like.

Straight chain or branched aliphatic alcohols include, but are not limited to, ethanol, propanol, isopropanol, butanol, benzyl alcohol ,and the like. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. Benzyl alcohol is an antimicrobial preservative used in cosmetics, foods, and a wide range of pharmaceutical formulations. Concentrations of 5% v/v or more are employed as a solubilizer, while a 10% v/v solution is used as a disinfectant.

Hexylene glycol is a colorless liquid with a sweet odor. It is easily soluble in cold water, soluble in diethyl ether, alcohol, lower aliphatic hydrocarbons, in a variety of organic solvents and miscible with fatty acids.

Propylene glycol diesters like propylene glycol diacetate (PGDA) are colorless liquids with a slight ether-like odor. They are a low viscosity solvents with a comparatively high boiling point. PGDA is propylene oxide-based, or P series glycol ether acetate. It is used as a plasticizer for cellulose acetate.

Fatty alcohol lactic acid esters include, but are not limited to, lauryl lactate, myristyl lactate, cetyl lactate, stearyl lactate, and the like. Myristyl lactate is an ester of myristyl alcohol and lactic acid. It is used in cosmetics and personal care products; the ingredient is used in the formulation of moisturizers, cleansing products, and other skin care products.

Glucosides are chemically glycosides; a glycoside is a compound that contains a sugar (carbohydrate) molecule that is convertible into a sugar (called glycone) and a non-sugar component (called aglycone) by hydrolytic cleavage. Various grades of glycosides include, but are not limited to, methyl gluceth 10 or 20 and the like. Methyl gluceth or methyl polyethoxylated glucosides are effective humectants and viscosity modifiers with low irritant potential and a silky feeling on the skin.

Octoxynol is a non-ionic surfactant. Octoxynol-9 has a hydrophilic polyethylene oxide group (on average 9.5 ethylene oxide units) and a hydrocarbon lipophilic or hydrophobic group. It is used in cosmetic and topical preparations.

In embodiments, individual or any combinations or mixtures of the above mentioned solvents may be used.

In embodiments, combinations of medium chain triglycerides and menthol may be used in weight ratios of 1:4 to 4:1.

In embodiments, combinations of polyoxyethylene castor oil derivatives and ethoxylated fatty alcohols may be used in weight ratios of 1:4 to 4:1.

In embodiments, combinations of propoxylated glucose esters and ethoxylated fatty alcohols may be used in weight ratios of 1:4 to 4:1.

In embodiments, combinations of propoxylated glucose esters and C12-18 saturated fatty alcohol esters of caprylic/capric acid may be used in weight ratios of 1:4 to 4:1.

In embodiments benzyl alcohol, hexylene glycol, propylene glycol diacetate myristyl lactate, and methyl gluceth may be used.

In embodiments, propoxylated glucose esters (PPG-20 methyl glucose ether distearate) may be used in amounts of about 0.25% to about 4.75%, by weight.

In embodiments, combinations of propoxylated glucose esters (PPG-20 methyl glucose ether distearate) and mineral oil may be used.

In embodiments, combinations of propoxylated glucose esters (PPG-20 methyl glucose ether distearate) and mineral oil may be used in weight ratios of 1:12 to 12:1.

"Emollient" refers to substances that soften and soothe the skin. They are used to correct dryness and scaling of the skin. Various emollients include, but are not limited to, oils of natural origin such as 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, the 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, and glycols such as ethylene glycol, diethylene glycol, polyethylene glycol, and propylene glycol. Further, straight chain and branched aliphatic alcohols such as ethanol, propanol, isopropanol, hexanol, octanol, lauryl alcohol, myristyl alcohol, and stearyl alcohol are useful.

Ointment bases are oily bases, and include hydrocarbon bases, absorption bases, water soluble bases, emulsifying bases, and vegetable oils. Hydrocarbon bases include hard paraffin, soft paraffin, etc. Absorption bases include wool fat and beeswax. Water soluble bases include macrogol 200, 300, and 400. Emulsifying bases include emulsifying wax and cetrimide. Base may be selected from the glyceryl esters of saturated and unsaturated acids, especially polyunsaturated acids, having in particular from 10 to 24 carbon atoms, unsaturated fatty acids and in particular from polyunsaturated fatty acids. Waxes which are esters of glycerides and of polyunsaturated fatty acids can be used in the compositions according to the application, mention may be made in particular of the atomized glyceryl dipalmitostearate (Cie-Cia) sold under sold under the name Precirol® ATO 5 by Gattefosse, the atomized glyceryl behenate (022) sold for example under the name Compritol® by Gattefosse, and mixtures thereof. It is also possible to use waxes such as white beeswax, lanolin wax, China insect waxes; rice wax, carnauba wax, candelilla wax, ouricury wax, Alfa wax, cork fibre wax, sugarcane wax, Japan wax and sumac wax; montan wax, microcrystalline waxes, paraffins arid ozokerite; and mixtures thereof.

Antioxidants are substances that inhibit oxidation or suppress reactions promoted by oxygen or peroxides. Antioxidants, especially lipid-soluble antioxidants, can be absorbed into the cellular membrane to neutralize oxygen radicals and thereby protect the membrane. Suitable antioxdants for compositions of the present application include, but are not limited to, ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotenes, a-tocopherol (vitamin E), ubiquinol, butylated hydroxyanisole, butylated hydroxytoluene, sodium benzoate, propyl gallate (PG, E310), and tertiary-butylhydroquinone. The amount of antioxidant may be about 0.01% to about 20% w/w of the total weight of a composition.

A "permeation enhancer" or "penetration enhancer" is a component used to enhance the penetration rate of drugs through the skin or mucous membrane, such as by temporarily diminishing the impermeability of the skin or membrane. Permeation enhancers have also been called "accelerants" and "absorption promoters." There are numerous penetration enhancers that can be used. Various useful permeation enhancers include, for example: polyols and esters, including polyethylene glycol, polyethylene glycol monolaurate, and butanediol; sulfoxides, including dimethylsulfoxide and decylmethylsulfoxide; ethers, including diethylene glycol monoethyl ether (e.g., TranscutoKS) P) and diethylene glycol monomethyl ether; fatty acids, including lauric acid, oleic acid, and valeric acid; fatty acid esters, including isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; nitrogenous compounds including urea, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, and triethanolamine, terpenes, alkanones, organic acids, including salicylic acid, citric acid, and succinic acid, menthol, and any mixtures thereof. Further, one or more surfactants can also be used as a permeation or penetration enhancer. A permeation enhancer can be used in concentrations ranging from about 0.001-15%, or about 0.05-12%, or about 3-10%, of the total weight of a composition.

Aspects of the present application further provide processes for preparing formulations, embodiments comprising:

a) melting white soft paraffin;

b) dissolving and/or dispersing calcipotriene monohydrate in a solvent and mixing in the molten state and adding to step a);

c) dispersing betamethasone dipropionate in a solvent and adding alpha-tocopherol, mixing for uniformity;

d) adding the step c) dispersion to molten wax drug solution of step b);

e) cooling the mixture to room temperature with stirring and filling into suitable containers and closures.

Certain specific aspects and embodiments of this application will be further described in the following examples, being provided only for the purpose of illustration. The scope of the disclosure is not to be limited by the examples.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in hydrogenated soybean oil, hydrogenated cotton seed oil, peanut oil, or olive oil, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in vegetable oil, safflower oil, sesame oil, or almond oil, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in diethyleneglycol monoethyl ether, N-methylpyrrolidone, diisopropyl adipate, or dimethicone, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in simethicone, diisopropyl adipate/ isopropyl myristate, PEG 40 castor oil, caprylocaproyi macrogolglyceride, or oleyl alcohol, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in octyldodecanol, coco-caprylate/caprate, dicaprylyl carbonate, or dibutyl adipate, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in PPG-20 methyl glucose ether distearate, medium chain triglycerides, oleic acid, or eucalyptus oil, as required, and mixed with the paraffin in the molten state.
c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.
d) Adding the step c) dispersion to molten wax drug solution of step b).
e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in fractionated coconut oil, medium chain triglycerides, menthol, a combination of polyxol 40 hydrogenated castor oil and laureth-4, a combination of PPG-20 methyl glucose ether distearate and laureth-4, or polyoxyethylene-15 stearyl ether, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in oleoyl macrogol glycerides, C12-18 esters of caprylic/capric acid, C12-15 alkyl benzoate, propylheptyl caprylate, or dicaprylyl ether, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

EXAMPLE 9

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in benzyl alcohol, hexylene glycol, or propylene glycol diacetate, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.
Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in a mixture of PPG-20 methyl glucose ether distearate and Cetiol CC, myristyl lactate, methyl gluceth-20, or octoxynol-9, as required, and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved and / or dispersed in PPG-20 methyl glucose ether distearate and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

Stability data: Stability data of the combination compositions of example 11 A, B & D are described below in table 1.

Stability study was conducted for compositions A, B and D of Example 11 involving storing the formulation for 3 months in closed containers at accelerated conditions. All compositions were found to be stable.

Manufacturing procedure:

a) White soft paraffin is melted at 80°C and cooled to 70°C.

b) Calcipotriene monohydrate is dissolved in PPG-20 methyl glucose ether distearate and mixed with the paraffin in the molten state.

c) Betamethasone dipropionate is dispersed in mineral oil and alpha-tocopherol is added and mixed for uniformity.

d) Adding the step c) dispersion to molten wax drug solution of step b).

e) The mixture is cooled to room temperature with stirring and filled into suitable containers and closures.

We claim,

1. A topical pharmaceutical composition in the form of an ointment comprising betamethasone dipropionate and calcipotriene monohydrate.

2. The topical pharmaceutical composition according to claim 1, further comprises pharmaceutical acceptable excipients like solvents, antioxidants and ointment base.

3. The topical pharmaceutical composition according to claim 2, wherein the solvent is selected from the group comprising of triglycerides, mineral oils, fatty acid esters, glycol ethers, N-methylpyrrolidone, fatty alcohol, coco-caprylate/caprate, polydimethylsiloxane, polyoxyethylene castor oil derivatives, polyoxylglycerides, polypropoxylated glucose methyl ether fatty acid ester derivatives, ethoxylated fatty alcohols, polyoxyethylene fatty acid ethers, straight chain or branched aliphatic alcohols, propylene glycol diester, hexylene glycol, fatty alcohol with its lactic acid ester, glucosides, octoxynol or any mixtures thereof.

4. The topical pharmaceutical composition according to claim 3, wherein the solvent is mixture of polypropoxylated 20 methyl glucose ether distearate and mineral oil.

5. The topical pharmaceutical composition according to claim 2, wherein the antioxidant is selected from the group comprising of ascorbic acid, glutathione, lipoic acid, uric acid, carotenes, a-tocopherol, ubiquinol, butylated hydroxyanisole, butylated hydroxytoluene, sodium benzoate, propyl gallate tertiary-butylhydroquinone or any mixtures thereof.

6. The topical pharmaceutical composition according to claim 2, wherein the ointment base is selected from hydrocarbon bases, absorption bases, water soluble bases, and emulsifying bases, wherein hydrocarbon bases include but not limited to hard paraffin, soft paraffin; absorption bases include but not limited to wool fat, beeswax; water soluble bases include but not limited to macrogol 200, 300, and 400, and emulsifying bases include but not limited to emulsifying wax and cetrimide.

7. A topical pharmaceutical composition in the form of an ointment comprising calcipotriene monohydrate, betamethasone dipropionate, polypropoxylated 20 methyl glucose ether distearate, mineral oil, a-tocopherol, and white soft paraffin.

8. A process for the preparation of a topical pharmaceutical composition comprising the steps of:

a) melting white soft paraffin;

b) dissolving and/or dispersing calcipotriene monohydrate in polypropoxylated 20 methyl glucose ether distearate and mixed in the molten state and adding to step a);

c) dispersing betamethasone dipropionate in mineral oil and adding alpha-tocopherol, mixing for uniformity;

d) adding step c) dispersion to molten wax drug solution of step b);

e) cooling the mixture to room temperature with stirring and filling into suitable containers and closures.

9. The topical pharmaceutical composition according to claim 1, for effective management of skin diseases or disorders, such as psoriasis vulgaris.

10. The topical pharmaceutical composition comprising betamethasone dipropionate, calcipotriene monohydrate and one or more pharmaceutically acceptable excipients, substantially as described and illustrated herein.