WO2003086348A1

WO2003086348A1 - Allergic dermatitis formulation and method of treatment

Info

Publication number: WO2003086348A1
Application number: PCT/AU2003/000424
Authority: WO
Inventors: Kivalur Swaminathan; Kenneth Vincent Mason
Original assignee: Dermcare-Vet Pty Ltd
Priority date: 2002-04-08
Filing date: 2003-04-08
Publication date: 2003-10-23
Also published as: AUPS158502A0

Abstract

Formulations and methods of treatment are provided for topical application of anti-inflammatory steroids alone or in combination with anti-bacterial or antifungal drugs to animals. Included in the formulation is a polyethoxylated derivative of a fatty acid ester that imparts a smooth. non-greasy feel to the topically administered formulation. The formulation is useful for a variety of skin conditions due to the tolerance, efficacy and ease of use and application over large affected areas of the skin of both haired and non-haired animals. Conditions treated by the formulation include allergic dermatitis, inclusive of contact dermatitis, contact atopy, atopic dermatitis, and secondary complications in the form of bacterial infections such as by Staphylococcus species and fungal/yeast infections such as caused by Malassezia species.

Description

TITLE ALLERGIC DERMATITIS FORMULATION AND METHOD OF

TREATMENT FIELD OF THE INVENTION THIS INVENTION relates to formulations for topical application of anti- inflammatory steroids alone or in combination with anti-bacterial or antifungal drugs. The formulations are useful for a variety of skin conditions due to the tolerance, efficacy and ease of use and application over large affected areas of the skin of both haired and non-haired animals. Conditions treated by the present invention include allergic dermatitis, inclusive of contact dermatitis, atopic dermatitis, and secondary complications in the form of bacterial infections such as by Staphylococcus species and fungal/yeast infections such as caused by Malassezia species.

BACKGROUND OF THE INVENTION Atopic dermatitis is a genetically predisposed inflammatory and pruritic skin disease with characteristic clinical features. It is a well recognized disease in man and dogs but poorly understood in other mammals.

Atopic dermatitis is associated most commonly but not exclusively with immediate type hypersensitivity characterized by the production of IgE antibodies to environmental allergens. Affected animals and man (ie mammals) can have associated food allergies and commonly develop secondary infections with skin and mucosal commensal organisms namely the bacteria Staphylococcus spp. and the yeast Malassezia spp.

Recently there has developed a body of evidence that environmental allergens can be absorbed with skin contact as well as through the mucosal surfaces. Contact allergy occurs when an allergen is absorbed through the skin and produces inflammation. The immunological mechanism may then be via a cell-mediated mechanism or an IgE associated and cell mediated mechanism.

However, it will be appreciated that the traditional immunological understanding and mechanisms are becoming blurred, given that the mammalian immune system will vary in its response to foreign material. A problem associated with topical treatments of allergic dermatitis is the interference that haired skin has on the topical treatment. Systemic anti- inflammatory corticosteroids are the mainstay of treatment in haired mammals. Systemic anti-inflammatory steroids can have severe sided effects that affect most organs in the body. Topical treatments so far are limited to the non-haired skin and are thus limited in their usefulness without clipping of the hair. Clipping of the hair is not a practical preliminarily to topical treatment for cosmetic reasons.

Topical formulations of corticosteroids have been known since the 1950s as treatment for various inflammatory skin conditions such as atopic dermatitis, eczema etc. Topical steroidal preparations are also used in combination with antibacterial or antifungal agents in disease conditions that include an inflammatory component but all have been limited by practicality to non haired skin.

Typically, formulations of topical steroids have involved suspensions or solutions of the steroid substance in vehicles that are based on oils, waxes or organic solvents.

For example, United States Patent 5,958,391 recites a formulation that comprises 0.5-2.5% hydrocortisone (HC), 2.5-7.5% elemental sulfur, 90-97% in a vehicle which is hydrocarbon jelly and aqueous carboxypolymethylene. This is intended for scalp application.

United States Patent 4,918,065 describes a cream or ointment type of formulation of a steroid dispersed in a base consisting of both a water/oil and an oil/water emulsion with high proportions of waxy substances

Reference is also made to United States Patent 4,738, 956 which discloses pharmaceutical preparations with a mix of 20-40% fatty alcohol (C 12-22), 30- 60% of volatile silicone, 0.1-10% hydrocortisone and preservative, emulsifier etc. The aim was to provide a silky non-greasy delivery system capable of spreading the ingredient smoothly and evenly without leaving a residue and increasing percutaneous absorption and bioavailability. Referring now to United States Patent 4,370,322, there are described steroid formulations with only fatty substances as vehicle, such as dibutyl adipate, isopropyl myristate, wax and paraffin oil. United States Patent 4,363,806 describes and claims a formulation of steroid in a multiple emulsion vehicle which is a hydrophilic solvent-in-oil-in- water emulsion. The steroid is dissolved in propylene glycol (PG) and emulsified in an oil phase. The solvent-in-oil emulsion is emulsified in an aqueous solution giving rise to the emulsion.

Another type of formulation uses organic solvents such as alkanols and polyhydric alcohols. For example, United States Patent 3,899,580 describes topical corticosteroid formulations containing only 8-18% water and 60-90% solvents such as ethanol, PG and glycerine. In another example, United States Patent 4,353,896 describes a topical steroid formulation prepared in 15% dimethylsulphoxide as solvent as well as 10% isopropyl alcohol (IP A).

Reference is also made to United States Patent 4,775,529 disclosing a formulation of a steroid in a hydroalcoholic base of 15-50% PG, 20-40% IPA and 20-60% water, while United States Patents 5,002,938 and 5,110,809 disclose a formulation containing a steroid and an antifungal and 30-65%) of a lower alkanol solvent, 0-45% of a dihydroxy solvent or 0-40% of a trihydroxy solvent.

OBJECT OF THE INVENTION The present inventors have identified several limitation of prior art formulations.

Firstly, prior art formulations are typically based on viscous, solid or semisolid waxes and fatty ingredients and therefore in application to large areas of the skin or skin surfaces that are covered in hair, these prior art formulations do not lend themselves to even and extensive application. This results in poor appearance of skin and/or hair (such as matting of hair, stickiness, greasy appearance, smearing to surfaces that come in contact, loss of dosage by these means etc).

Secondly, the active ingredients in some cases are not dissolved and are subject to loss or poor bioavailability. Many formulations are based on high proportions of organic solvents such as ethanol, propylene glycol, isopropyl alochol and polyethylene glycol. These solvents either tend to irritate the skin or leave a greasy appearance on application. Thirdly, corticosteroids while useful in treating inflammatory skin conditions can have, in addition, undesirable side effects due to systemic absorption. The suppression of the HPA axis (hypothalamic-pituitary-adrenal) by systemic availability of steroids is well known. Other potential side affects are Gushing' s syndrome, glucosuria and hyperglycemia. The risk of side affects increase in cases where anti-inflammatory treatment is required over large areas of skin.

There is therefore a need for a formulation of a topical preparation containing a corticosteroid that is easy to apply over a large area of haired skin or non haired skin, is non-occlusive, leaves the skin with a non-greasy, non-sticky and smooth feel, does not interfere with but may even enhance the natural hair /coat lustre and feel and is not removed easily by contact with clothing and is highly efficacious.

The method and formulation of the present invention has overcome this problem and is a superior alternative to systemic corticosteroid treatment in the treatment of haired animals (mammals) with allergic dermatitis without the danger of systemic toxic side effects of corticosteroids.

It is therefore one object of the invention to provide a formulation of a topically active pharmaceutical drug in a semi-solid or gel form that is easy to apply over a large surface area of the haired skin and/or non-haired skin of a mammal.

Another object of the invention is to provide a formulation that has low amounts of waxy, oily and solid substances and solvents to minimize greasy feel, and that avoids accidental removal of product by contacting surfaces and irritation and drying of skin due to solvents. Practically this formulation and method relies on being applied after a shampoo and to the wet hair. Thus aiding in the spreadability and retaining the moisture in the skin and hair and even replacing shampoo removed sebum and natural conditioning oils.

Yet another object of the invention is to provide a formulation that has good cosmetic appeal and lends an acceptable appearance to skin and hair on application and which is stable for a long period. Still yet another object of the invention is to provide a formulation that has the active drug in a dissolved or substantially dissolved state to enable absorption through the skin.

A further object of the invention is to provide a method for treatment of haired skin and non-hair skin with a topically administered formulation of a steroid either alone or in combination with an anti-bacterial and/or an antifungal agent.

SUMMARY OF THE INVENTION In one aspect, the invention provides a topically administrable pharmaceutical formulation comprising:

(i) an anti-inflammatory steroid; and (ii) a polyethoxylated derivative of a fatty acid ester. Optionally, the topical formulation further comprises a therapeutically effective amount of an anti-bacterial, antiseptic or antifungal agent at 0.1-5% by weight of the formulation.

Preferably, the topically administrable pharmaceutical further comprises at least one other pharmaceutically acceptable carrier, diluent and/or excipient.

Said at least one other pharmaceutically acceptable carrier, diluent and/or excipient may include one or more of a solubilizer, emollient, moisturizer, hair and skin conditioner, preservative and/or stabilizer as are well understood in the art.

The topical formulations of the invention may be provided as mousse, gels, creams, lotions, foams, shampoos, liquids, aerosols and the like.

Preferably, the topical formulation is a gel or lotion. Accordingly in one embodiment, the present invention provides a formulation in the form of an anti-inflammatory gel for topical application. The formulation comprises a topical anti-inflammatory steroid at 0.01-2% by weight, a polyethoxylated fatty acid ester at 1-15%) by weight, a solubilizing agent such as

N-methylpyrrolidinone or propylene carbonate at 2-15% by weight, an aliphatic diol such as propylene glycol at 2-12% by weight, an aliphatic polyol such as polyethylene glycol 400 at 1-6% by weight, a skin and hair conditioner such as polyquaternium, at least one preservative, at least one stabilizer, at least one gelling agent and 50-80% by weight water.

In another aspect, the invention provides a method of treatment of allergic dermatitis in an animal, said method including the step of topically administering the pharmaceutical formulation of the first-mentioned aspect to said animal.

In yet another aspect, the invention provides a method of treatment of allergic dermatitis in an animal, said method including the step of topically administering an anti-inflammatory pharmaceutical formulation to a wet hair or wet skin surface of said animal. Suitably, the method of the invention provides topical administration to skin and/or hair surfaces of an animal. A particular advantage is that the skin and/or hair surface may be wet.

Preferably, the animal is a mammal.

More preferably, the animal is a companion animal such as a dog, cat, horse, rabbit and the like.

In a particular embodiment, the method includes topical administration of an antifungal compound and/or an anti-bacterial compound to treat secondary complications of allergy.

Preferred examples of secondary complications include bacterial infections such as by Staphylococcus species and fungal/yeast infections such as by Malassezia species.

In light of the foregoing, it will be appreciated that the formulation of the invention is substantially free of oils, waxes, fats and organic solvents. The formulation is easy to use and spread evenly, leaves only a small amount of residue due to evaporation and absorption of the liquid components and lends a silky, smooth, pleasant feel to the skin and hair.

Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. DETAILED DESCRIPTION OF THE INVENTION

The present inventors have surprisingly created a formulation which, when applied to wet hair after a shampoo bath, can effectively treat all the symptoms of allergic dermatitis and its complicating infections without the need for systemic administration and thereby avoids systemic toxic side effects of the pharmacologically-active ingredients.

Surprisingly, effective concentrations of a topically active steroid can be formulated in a dissolved state either alone or in combination with an antibacterial or antifungal substance into a semi-solid formulation. Moreover, the active drug substances are maintained in solution within the formulation despite usage of low levels of solubilizing excipients and solvents.

The present invention provides a formulation and method for treating allergic dermatitis such as to a food or environmental component acting as a sensitizer, including but not limited to food allergy, atopic dermatitis, insect bite allergy and contact dermatitis.

Other associated conditions that may be treated include intertrigo, Malassezia and fungal dermatitis, and/or Staphylococcus dermatitis.

Conventional methods of treating allergic dermatitis are to dose with systemic antiinflammatory steroids and, if needed, antibiotics and antifungal drugs. Steroids and antimicrobial drugs are also applied to a limited area of usually non-haired skin as an ointment, lotion or gel. To apply these to haired areas using conventional methods usually required clipping of the hair to allow penetration through the hair. If such treatments are applied to non-clipped haired skin then the hair will be sticky, oily and have a cosmetically unacceptable appearance.

The present invention provides a new method of treating allergic dermatitis and secondary complications thereof, especially in animals having haired skin, by applying a formulation to wet hair. The treatment of the present invention would, in the preferred course of events, occur after a shampoo bath and after rinsing the suds off, the formulation of the invention then applied to the wet coat/hair. In this way, the formulation with the anti-inflammatory steroid and any antimicrobial compound, if needed, will penetrate the haired coat and deposit the pharmaceutical active onto the skin to have its desired effect. The method of the invention thereby enables total coverage of animals that are covered all over with hair. The same treatment may be used in a conventional method of being applied to non-haired skin. A formulation in accordance with the present invention is provided for the treatment of infections and inflammatory conditions of the skin.

The formulation preferably has the semi-solid consistency of a mousse, gel, cream or lotion for ease of storage and application.

Preferably, the formulation of the present invention comprises from 0.01% to 2.0% by weight of an anti-inflammatory steroid. The steroid drugs that may be used in the formulation are exemplified but not limited to betamethasone, hydrocortisone, clobetasol, fluocinolide, triamcinolone, mometasone, fluticasone, desonide, prednisolone, methyl prednisolone, dexamethasone and their salts and derivatives such as furoate, propionate dipropionate, valerate and other alkyl esters.

Preferred antiinflammatory steroids include but are not limited to prednisolone, methylprednisolone, hydrocortisone, mometasone and their salts and derivatives.

In one embodiment, mometasone is mometasone furoate. Preferably, mometasone is at a concentration of 0.05-0.2% by weight.

Advantageously, mometasone is at a concentration of about 0.1 % by weight.

In another embodiment, prednisolone is present at a concentration of 0.1- 0.3% by weight. Advantageously, prednisolone is at a concentration of about 0.2 % by weight.

The formulation may also include an antifungal compound. Included in the scope of the invention are known (imidazole/triazole) antifungal agents such as miconazole, ketoconazole, clotrimazole, enilconazole, econazole, sulconazole, itraconazole, allylamine antifungals such as terbinafine, and butenafine and other antifungals such as nystatin, amphotericin and griseofulvin and their derivatives. The formulation may also include an anti-bacterial/antiseptic compound such as the antiseptic/antibacterials of all the guanidine classes, for example hexetidine, chlorhexidine, polyhexamethylene biguanide antibacterials/antiseptics of the phenolic class such as triclosan, o-chloro-m-cresol, o-, m-, p-xylenols, phenoxyethanol, and iodophors such as iodine, povidone-iodine complexes and iodine salts.

In addition to the therapeutically active substances, the formulation preferably comprises at least one solubilizing excipient from the class of polyethoxylated hydroxy fatty acid esters. By polyethoxylated hydroxy fatty acid esters is meant substances obtained by reacting varying amounts of ethylene oxide with hydroxy fatty acid esters.

Preferably, the excipient is one or more of substances obtained by reacting varying amounts of ethylene oxide with either castor oil or hydrogenated castor oil. More preferably, the solubilizing excipient is one or more of ricinoleyl glycerol nominally ethoxylated with 30-50 moles of ethylene oxide and trihydroxystearyl glycerol nominally ethoxylated with 7-60 moles of ethylene oxide. Several of the polyethoxylated hydroxy fatty acid esters are commercially available as mixtures and fractions of partially purified formulations. Preferably the excipient is one or more of products known as Polyoxyl (n) castor oil, where n =5, 9, 15, 35, 40 and 60 and Polyoxyl (n) hydrogenated castor oil where n= 40 and 60. Commercially available products useful in this invention are for example obtainable under the trade names Cremophor from BASF and Croduret from Croda Surfactants. The polyethoxylated hydroxy fatty acid ester excipient is included at a level sufficient to solubilise and maintain in solution the therapeutically active compounds in the final formulation.

Preferably, the polyoxyl (n) hydrogenated castor oil excipient is selected from the group consisting of polyoxyl 35 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil and polyoxyl 60 hydrogenated castor oil.

Preferably the polyoxyl (n) hydrogenated castor oil is used at a level of 1- 15% by weight of the total formulation. More preferably, the polyoxyl (n) hydrogenated castor oil is used at a level of 2-10% by weight of the total formulation.

The pharmaceutical formulation of the invention may further comprise at least one other pharmaceutically acceptable carrier, diluent or excipient. These include but are not limited to an effective amount of a moisturising, solubilising and substantive ingredient. Among the substances useful for this purpose are solubilizing agents such as N-methylpyrrolidinone or propylene carbonate and polyols such as propylene glycol, butylene glycol, hexylene glycol, sorbitol and polyethylene glycol of molecular weights up to 800. More preferably, N-methylpyrrolidinone propylene glycol and polyethylene glycol 400 are used for the purpose. The levels of incorporation of N-methylpyrrolidinone and propylene glycol are preferably from 2-15% by weight. Even more preferably, N-methylpyrrolidinone is included at 2-12% by weight. Polyethylene glycol is preferably present at 1-10% by weight. .

More preferably, polyethylene glycol is present at 2-8% by weight. The formulation of the present invention may further comprise one or more volatile silicones and/or silicone gums. Preferred volatile silicones are octamethylcyclotetrasiloxane, and decamethylcyclopentasiloxane. These are commercially available by the name of cyclomethicone. Preferred cyclomethicones are, for example, available under the trade names Dow Corning 244, 245, 344 and 345 fluids.

The silicone gums included in the formulation are preferably ultra-high viscosity polydimethylsiloxanes which are either trimethylsilyl or dimethylsilanol end-blocked. These are known as dimethicone and dimethiconol respectively. Commercially, the dimethicone and dimethiconol are available in blended form with volatile cyclomethicones. Suitable silicone gum blends are for example available under the trade names Dow Corning 1401, 1404, 1411 and 1501 fluids. Other mixtures of volatile cyclomethicones, dimethicones and dimethiconols known to those skilled in the art may also be used in the formulation to obtain the desired cosmetic effect. These are included within the scope of the present invention. The volatile cyclomethicone is included in the formulation preferably at a level of 1-12%, more preferably at 4-8% by weight. The silicone gum is incorporated within the formulation preferably at a level of 0.1-6%) and more preferably at 0.4-2.0% by weight. In addition to the constituents mentioned above, an effective amount of a thickener may be incorporated within the formulation to obtain the desired viscosity and consistency of the product. Suitable thickening agents for the purpose of the invention are acrylate polymers and co-polymers among the classes of polyacrylates, polymethacrylate, polymethylmethacrylates, polyacrylamides and their cross-linked derivatives, cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropylmehyl cellulose, and hydroxypropyl cellulose, naturally derived gums such as xanthan gum, acacia gum, carob gum, alginate derivatives and pectin.

Preferably the thickener is one or more of a cross-linked polyacrylic acid derivative, a polyacrylamide derivative or a cationic polyacrylate derivative. Suitable thickeners are available under the trade names of Salcare SC92, Salcare SC96 (Ciba Speciality Chemicals), Carbopol and Permulen (E F Goodrich), Aculyn 33 A, Aculyn 44 (Rohm and Haas), Methicel (The Dow Chemical Company) and Sepigel 305 (Seppic). The thickener is incorporated in an amount suitable to obtain the desired thickening effect. Preferably the thickener is used at a level of 0.1-8% by weight of the formulation. More preferably the thickener is incorporated at a level of 1- 5% in the composition.

Additionally, other ingredients such as hair and skin conditioners, metal chelates, antioxidants, pH modifiers, perfumes and colours may be included within the formulation.

Suitable hair and skin conditioners are low molecular weight and polymeric quaternary ammonium salts. The low molecular weight quaternary ammonium salts are well established in use as conditioning agents in the cosmetic industry. Suitable quaternary salts are, cetrimonium chloride, benzalkonium chloride, steartrimonium chloride, cocotrimonium chloride and so forth. Polymeric quaternary ammonium compounds commonly known as polyquatemium (CTFA adopted names) such as Polyquatemium 11 (quaternized copolymers of vinylpyrrolidone and dimethylaminoethyl methacrylate), Polyquatenium 7 (diallyl dimethyl ammonium chloride and acrylamide copolymer), Polyquatemium 37, Polyquatemium 32 are also suitable for use. These conditioners are used at a level of 0.1 -8%, more preferably at a level of 0.5- 3% by weight of dry substance.

A suitable metal chelant for use in the formulation is ethylene diamine tetraacetic acid (EDTA) or any of its salts such as sodium salt, potassium salt, ammonium salt and triethanolammonium salt, typically used at a level of 0.01 to 0.2% by weight of the formulation.

Optionally, an effective amount of antioxidant such as butyrated hydroxy anisole, butyrated hydroxy toluene or propyl gallate may be used at an effective dose to prevent oxidative degradation of the drug substances. Preferably the antioxidant is incorporated at 0.002-0.2% by weight of product. A pH adjuster or neutralizer, by which terms is implied an acid or base for regulating the pH of the formulation may be used to adjust the pH of the formulation to a range of 4-8, and preferably 5.5-7.0. The base used is for example, the hydroxide, carbonate, bicarbonate of sodium, potassium or ammonium or triethanolamine. An effective amount of preservative may also be included in to protect the formulation from spoilage during the shelf life of the product. Suitable preservatives are 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methy-4- isothiazoline-3-one, l,3-bis(hydroxymethyl)-5,5-dimethylhydantoin, sodium hydroxymethylglycinate, diazolidinyl urea, methyl paraben, propyl paraben, 2- bromo-2-nitropropane-l,3-diol, sorbic acid and benzyl alcohol.

Additionally, suitable oil and wax components may be included in the formulation of the invention to facilitate refatting and to relieve skin dryness. Several natural and semisynthetic glyceride esters and waxes are readily available to the skilled person. Suitable amounts of a pigment, colouring agent or perfume may be used to confer desirable usage characteristics to the product. A substantial portion of the formulation is water as the vehicle for the ingredients. Water preferably comprises 50-80% by weight or more preferably 60- 75% of the formulation of the invention.

The formulation of the invention is manufactured by the usual methods of dissolution, blending and mixing operations as are well known in the art of pharmaceutical and cosmetic manufacture.

So that the present invention may be readily understood and put into practical effect, the skilled addressee is referred to the following non-limiting examples. EXAMPLES

The topical formulations of this invention may be provided as mousse, gels, creams, lotions, foams, shampoos, liquids, aerosols and the like.

The following examples and accompanying tables provide embodiments of the pharmaceutical formulation of the invention, methods of preparing same and methods of administration to animals.

Example 1 A 0.2% prednisolone cream was prepared as per the following formulation (Table 1).

The required quantity of prednisolone, propylene glycol, polyethylene glycol 400 Cremophor RH40 and EDTA were weighed, 240g deionised water added and the mixture adjusted to pH 6.5 with triethanolamine and heated to 60- 70°C on a water bath with stirring until a clear solution was obtained. The mixture was then cooled to room temperature and 1300 g of deionised water added and stirred to obtain a clear solution. The required amounts of Salcare super 7 and Kathon CG was added and mixed.

In a separate container, Sepigel 305, Silicone 245 and Silicone 1501 were weighed and mixed well to get a uniform suspension. This mixture was then added slowly with vigorous stirring to the aqueous prednisolone solution described above. The balance of the required amount of water to make up to 2000g of product (about 248g) was added to the mixture. Stirring was continued until a smooth, viscous cream was obtained. Example 2

Referring to Table 2, the required quantities of miconazole nitrate, prednisolone, Croduret, propylene glycol, polyethylene glycol and EDTA were weighed into a container, 50 g of purified water added and the mixture heated, with stirring while sufficient triethanolamine was added to attain a pH of the mixture of about 6.5. When a clear solution was obtained, the mixture was cooled to room temperature and 300 g of purified water added with stirring.

The required quantity of chlorhexidine gluconate, preservative and conditioner were added to the mixture and stirred till clear. Silicone 245, silicone 1501 and Sepigel 305 were weighed into a separate container and stirred till a uniform suspension was obtained.

The silicone mixture was then added in a slow stream to the formulation with rapid stirring. The formulation was then made to a total amount of 500g with purified water. Stirring was continued intermittently until a smooth cream was formed.

Example 3 Formulation of the mometasone furoate composition set forth in Table 3 is as follows.

Cremophor RH40, N-methyl pyrrolidone, propylene glycol, polyethylene glycol 400, propyl gallate and BHT were weighed into a suitable vessel and heated to 45°C for 48 hrs.

To this warm mixture, mometasone furoate was added and stirred with heating to 65°C till a clear solution was obtained (mixture A).

EDTA was suspended in 500 g of water in a second container and neutralised with stirring by addition of triethanolamine until dissolved. The pH of this solution was adjusted to 5.0 with orthophosphoric acid. Salcare Super 7 was added and mixed till dissoled. Titanium dioxide was added and the mixture homogenised at 4000 rpm for 5 minutes (suspension B).

Capric/caprylic triglyceride, acetylated lanolin and phenoxyethanol were wighed into a third container and heated with mixing till a homogeneous mixture was obtained (mixture C). A fourth container was charged with silicone 1401, silicone 245 and sepigel 305. The contents were mixed until homogeneous (mixture D).

The mixture A was added to suspension B and stirred. Mixture C was then added and during vigorous mixing, mixture D was added in a thin stream. With continual mixing the balance of the water was added to a total 1.5 kg.

Stirring was continued till gel formation was complete and a smooth, uniform, semisolid lotion was formed.

Example 4

Four cases of dogs with allergic dermatitis were treated with the formulation of Example 1 and two dogs with secondary complications, were treated with the formulation described in Example 2. Four cases of dogs with allergic dermatitis were treated with the formulation in Example 3. The clinical signs (erythema, pruritus, ear inflammation, scale and alopecia) were each graded on a linear scale of 0 to 5 (to a cumulative score of 0-25). Allergic dogs were graded and treated according to the formulation and method of the invention once weekly for 4 to 8 weeks then re-examined and graded. The aggregate scores before and after are provided in Table 4.

Two cases (the first shown in Table 4) of dogs being treated for allergic dermatitis for 2 months with once weekly application of the formulation of Example 1 and Example 3 used as an after shampoo lotion had blood samples drawn for multiple biochemical analysis for organ function (particularly liver and kidney) and adrenal function test of the adrenal pituitary axis function (ACTH, Adrenocorticotropin stimulation test). The biochemical parameters of organ function and damage indicators, and the adrenal -pituitary axis were found to be normal.

Pharmaceutical formulations according to the present invention provide many advantages over the prior art. They may be applied over a large area of hair- covered or skin surfaces of an animal and thereby treat both allergic dermatitis and secondary conditions as hereinbefore described. Being essentially water-based, the pharmaceutical formulation of the invention is non-greasy, non-occlusive and provides a cosmetically appealing appearance after administration to an animal. The moisturising properties of the pharmaceutical formulation act to improve the feel of the animals skin after application.

Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. It will therefore be appreciated by those of skill in the art that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention.

In particular, it is noted that the concentrations of ingredients may be readily varied by the skilled person. It will also be appreciated that concentrations expressed in the range x-y% include all ranges within the stated range. Preferably, the ranges are integer ranges.

All computer programs, algorithms, patent and scientific literature referred to herein is incorporated herein by reference.

Table 1

Table 2

Table 3

Table 4

Claims

CLAIMS 1. A topically administrable pharmaceutical formulation comprising: (i) an anti-inflammatory steroid; and (ii) a polyethoxylated derivative of a fatty acid ester.

2. The topically administrable pharmaceutical formulation of Claim 1, wherein the polyethoxylated derivative of a fatty acid ester is used at 1-15% by weight of the total formulation.

3. The topically administrable pharmaceutical formulation of Claim 1, wherein the polyethoxylated derivative of a fatty acid ester is a polyoxyl (n) hydrogenated castor oil.

4. The topically administrable pharmaceutical formulation of Claim 2, wherein the polyoxyl (n) hydrogenated castor oil is selected from the group consisting of polyoxyl 35 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil and polyoxyl 60 hydrogenated castor oil.

5. The topically administrable pharmaceutical formulation of Claim 4 wherein the polyoxyl (n) hydrogenated castor oil is used at about 2-10% by weight of the total formulation.

6. The topically administrable pharmaceutical formulation of Claim 1 further comprising at least one pharmaceutically active ingredient selected from the group consisting of: an anti-bacterial compound; an antiseptic compound; and an antifungal compound.

7. The topically administrable pharmaceutical formulation of Claim 1 further comprising at least one other pharmaceutically acceptable carrier, diluent and/or excipient.

8. The topically administrable pharmaceutical formulation of Claim 7 wherein said at least one other pharmaceutically acceptable carrier, diluent and/or excipient is one or more of a solubilizer, emollient, moisturizer, hair and skin conditioner, preservative and/or stabilizer as are well understood in the art.

9. The topically administrable pharmaceutical formulation of Claim 1 wherein the anti-inflammatory steroid is mometasone or prednisolone or a salt or derivative thereof.

10. The topically administrable pharmaceutical formulation of Claim 9, wherein the anti-inflammatory steroid is mometasone or a derivative thereof.

11. The topically administrable pharmaceutical formulation of Claim 10, wherein the anti-inflammatory steroid is mometasone furoate.

12. The topically administrable pharmaceutical formulation of Claim 9, wherein mometasone is at a concentration of 0.01-2.0% by weight.

13. The topically administrable pharmaceutical formulation of Claim 12, wherein mometasone is at a concentration of about 0.1 % by weight.

14. The topically administrable pharmaceutical formulation of Claim 9 wherein prednisolone is present at a concentration of 0.1 -2.0% by weight.

15. The topically administrable pharmaceutical formulation of Claim 14 wherein prednisolone is at a concentration of about 0.2 % by weight.

16. The topically administrable pharmaceutical formulation of Claim 1 further comprising a therapeutically effective amount of an anti-bacterial, antiseptic and/or antifungal agent at 0.1-5% by weight of the formulation.

17. The topically administrable pharmaceutical formulation of Claim 16 comprising an antifungal agent selected from an imidazol/triazol antifungal, an allylamine antifungal, nystatin, amphotericin, griseofulvin and their derivatives.

18. The topically administrable pharmaceutical formulation of Claim 17, wherein the imidazol/triazol antifungal agent is selected from the group consisting of miconazole, ketoconazole, clotrimazole, enilconazole, econazole, sulconazole, itraconazole and their derivatives.

19. The topically administrable pharmaceutical formulation of Claim 17, wherein the antifungal is selected from the allylamine group consisting of terbinafine, butenafine and their derivatives or nystatin.

20 The topically administrable pharmaceutical formulation of Claim 16 wherein the anti-bacterial/antiseptic compound is selected from the group consisting of a guanidine compound, a phenol associated biocide and an iodophor.

21. The topically administrable pharmaceutical formulation of Claim 20 wherein the guanidine compound is selected from the group consisting of polyhexamethylene biguanide, hexetidine and chlorhexidine.

22. The topically administrable pharmaceutical formulation of Claim 20 wherein the phenol associated biocide is selected from the group consisting of triclosan, o-chloro-m-cresol, o-, m-, p-xylenols and phenoxyethanol.

23. The topically administrable pharmaceutical formulation of Claim 20 wherein the iodophor is selected from the group consisting of povidone-iodine complexes and iodine salts.

24. The topically administrable pharmaceutical formulation of Claim 1, which is a mousse, gel, cream, lotion, foam, shampoo, liquid or aerosol.

25. The topically administrable pharmaceutical formulation of Claim 24, which is a gel or lotion.

26. The topically administrable pharmaceutical formulation of Claim 1 in the form of an anti-inflammatory gel for topical application, comprising a topical anti- inflammatory steroid at 0.01-2% by weight, a polyethoxylated fatty acid ester at 1-15% by weight, N-methylpyrrolidinone at 2-15% by weight, propylene glycol at 2-12% by weight, polyethylene glycol 400 at 1-6% by weight, a polyquaternium skin and hair conditioner, at least one preservative, at least one stabilizer, at least one gelling agent and 50-80% by weight water.

27. A method of treatment of allergic dermatitis in an animal, said method including the step of topically administering the pharmaceutical formulation of Claim 1 to said animal.

28. The method of Claim 27, wherein the animal is a mammal.

29. A method of treatment of allergic dermatitis in an animal, said method including the step of topically administering an anti-inflammatory pharmaceutical formulation to a wet hair or wet skin surface of said animal.

30. The method of Claim 29, wherein the anti-inflammatory pharmaceutical formulation is the formulation of Claim 1.