WO2009084020A2

WO2009084020A2 - Topical composition comprising halobetasol and salicylic acid

Info

Publication number: WO2009084020A2
Application number: PCT/IN2008/000670
Authority: WO
Inventors: Ulhas Rameshchandra Dhuppad; Vasant Sitaram Khachane; Nitin Babulal Bhamre; Akhilesh Dayanand Sharma
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2007-10-18
Filing date: 2008-10-15
Publication date: 2009-07-09
Also published as: BRPI0805005A2; WO2009084020A3

Abstract

The present invention relates to topical pharmaceutical compositions, their uses an methods of manufacturing. Specifically, the present invention relates to topical composition comprising combination of halobetasol and salicylic acid.

Description

"TOPICAL COMPOSITION COMPRISING HALOBETASOL AND SALICYLIC

ACID"

PRIORITY DETAILS

This patent application claims priority to Indian Patent Application No. 2074/MUM/2007, filed on October 18, 2007, the contents of which are hereby incorporated as reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to topical pharmaceutical compositions, their uses and methods of manufacturing. Specifically, the present invention relates to topical formulations comprising combination of halobetasol propionate and salicylic acid. BACKGROUND OF THE INVENTION

The corticosteroids constitute a class of primarily synthetic steroids used topically as an anti-inflammatory and anti-pruritic agents. Halobetasol is used to treat swelling, inflammation, and, itching associated with skin conditions such as eczema, dermatitis, rashes, insect bites, and allergies. Corticosteroids are medicines used for reducing inflammation.

Inflammation of the skin happens due to the irritation of the skin, and is caused by the release of various substances that are important in the immune system. These substances cause blood vessels to widen, resulting in the irritated area becoming red, swollen, itchy and painful. When corticosteroid is applied to the skin it works by acting inside the skin cells to decrease the release of these inflammatory substances. This reduces swelling, redness and itch.

The different forms of superficial inflammatory diseases of the skin represent the most common reaction pattern seen by the dermatologist. The treatment of such diseases needs to be individualized. It is important to note that in conditions such as psoriasis and chronic eczema, the excessive amounts of keratin in the skin cells causes these cells to harden, and makes the skin become thickened and scaly. This not only makes the skin itchy and inflamed, but also reduces the degree to which anti-inflammatory medicines can penetrate through the skin to treat the inflammation, as a result decreasing the efficacy of the drug and consequently lead to inadequate treatment. Hence there is a need for such an effective formulation which can be effectively help penetrate the required drug in adequate amounts to enhance the efficacy of the formulation.

Halobetasol propionate

Chemically halobetasol propionate is 21-chloro-6α, 9-difluoro-11 ^β - methylpregna-1 , 4-diene-3-20-dione, 17-propionate, C₂₅H₃₁CIF2O5. It has the following structural formula:

Like other topical corticosteroids, halobetasol propionate has antiinflammatory, antipruritic and vasoconstrictive actions. The mechanism of the anti-inflammatory activity of the topical corticosteroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A₂ inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic ¹ acid. Arachidonic , acid, is released from membrane phospholipids by phospholipase A₂

Halobetasol is a synthetic super-potent corticosteroid structurally related to clobetasol, meant for topical dermatological use.

Being a steroid Halobetasol has multiple mechanisms of action including anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions. Anti-inflammatory effects arise from decreased formation, release, and activity of the mediators of inflammation (eg, kinins, histamine, liposomal enzymes, prostaglandins, leukotrienes), which reduce the initial manifestations of the inflammatory process. Corticosteroids inhibit margination and subsequent cell migration to the area of injury, and also reverse the dilation and increased vessel permeability in the area, resulting in decreased access of cells to the sites of injury. This vasoconstrictive action decreases serum extravasation, swelling, and discomfort. The immunosuppressive properties decrease the response to delayed and immβdiate hypersensitivity reactions (eg, type Ul and type IV). This arises from inhibition of the toxic effect from antigen and antibody complexes that precipitate in vessel walls creating cutaneous, allergic vasculitis, and by inhibiting the action of lymphokines, target cells, and macrophages that together produce allergic contact dermatitis reactions. Additionally, the access of sensitized T lymphocytes and macrophages to target όells may also be prevented by corticosteroids. The < antiproliferative effects reduce hyperplastic tissue characteristic of psoriasis.

Halobetasol propionate' is effective for the short-term (2 weeks or less) topical treatment of moderate-to-severe inflammatory and pruritic dermatoses such as atopic dermatitis, contact dermatitis, eczema, chronic eczematous dermatoses seborrheic dermatitis, and psoriasis.

Salicylic Acid:

Salicylic acid is a member of the class Non-steroidal anti-inflammatory drugs useful in the treatment of various dermatological disorders. In lower concentrations, it is an effective keratolytie used in the treatment of conditions such as dermatoses, psoriasis, and dandruff;' Salicylic acid is thus a valuable adjunct to dermatological therapy. Salicylic acid- in concentrations of 3% to 6% is useful in the treatment of various dermatological disorders.

Salicylic acid is a type of medicine called a keratolytie. It works by breaking down keratin, which is a protein that forms part of the skin structure. In conditions such as psoriasis and chronic eczema, excessive amounts of keratin in the skin cells causes these cells to harden, and makes the skin become thickened and scaly. This not only makes the skin itchy and inflamed, but also reduces the degree to which anti-inflammatory medicines can penetrate through the skin to treat the inflammation. Salicylic acid breaks down the keratin in the hardened and thickened skin, helping to shed skin cells from the area to which it is applied, and soften and improve the appearance of scaly skin. It also helps improve the penetration of the corticosteroid into the skin, making it more effective than if the corticosteroid was applied on its own. The combination of corticosteroid and salicylic acid in this medicine is therefore used to treat dry, scaly, inflammatory skin disorders such as eczema, dermatoses and psoriasis, where the thickened skin could otherwise prevent absorption of the corticosteroid.

US patent no. 4,619,921 assigned to Ciba-Geigy is directed to halobetasol propionate.

US patent publication no. 2006/0286177 assigned to CombinatoRx, lnc describes composition comprising bufexamac and a corticosteroid selected from clobetasol, triamcinolone, betamethasone, hydrocortisone, halobetasol, diflorasone, mometasone, halcinonide, fluticasone, prednisone, and dexamethasone.

DE2744826A assigned to EXPL MARQUES describes topical compositions for the treatment of dermatoses containing corticosteroids and salicylic acid.

EP735885B assigned to Schering describes combination of mometasone furoate and salicylic acid.

There remains the need to develop new pharmaceutical compositions that can be effectively used for treating skin diseases with lower side effects for the treatment of Lichenified skin lesions.

Without being bound by any theory, the inventors of the present invention believe that the topical*, composition^ comprising halobetasol propionate together with salicylic acid, of the present invention can be very effective for the topical treatment of Lichenified skin lesions. ^' SUMMARY OF THE INVENTION

One embodiment of the present invention provides a topical pharmaceutical composition comprising the combination of therapeutically effective amount of halobetasol propionate or its pharmaceutically acceptable salts/solvates there of, salicylic acid or its pharmaceutically acceptable salts/solvates of salicylic acid and a pharmaceutically acceptable carrier.

According to another embodiment of the present invention, suitable dosage forms for the combination of halobetasol propionate and salicylic acid include hydrous or anhydrous semisolids such as creams, gels, ointments, lotions and the like.

Another embodiment of the present invention provides the use of topical pharmaceutical composition comprising the combination of therapeutically effective amount of keratolytic agent such as salicylic acid and therapeutically effective amount of corticosteroid such as Halobetasol propionate or any other pharmaceutically acceptable salts/solvates there of for the topical treatment of Lichenified skin lesions.

Another embodiment of the present invention provides topical pharmaceutical composition comprising about 0.025 %w/w to 0.075 % w/w of halobetasol propionate and 3 %w/w to 6 % w/w of salicylic acid.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms "treating" or "treatment" of a state, disorder or condition mean: (1) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (2) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician.

The term "pharmaceutically acceptable" as used in connection with components includes those components approved by a governmental regulatory agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, such as humans.

As used herein, the terms "effective amount" or a "therapeutically effective amount" of a drug refers to a non-toxip but sufficient amount of the drug to provide the desired effect. The "effective amount" will vary depending on the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. An appropriate "effective amount" in any individual case may be determined by methods known in the art,

Active ingredient in the context of, present invention includes halobetasol propionate and salicylic acid.

The topical pharmaceutical compositions of the present invention are useful in delivering a< combination of halobetasol propionate and micronised salicylic acid for the treatment of lichenified skin lesions.

Lichenified skin lesions:

The term lichenification refers to a thickening of the skin cells of the epidermis, which is the outermost layer of the skin, into a leather-like or bark-like formation, there is also hyperpigmentation of the thickened skin surface and an accentuation of the normal, crisscross diamond shaped skin markings, it is the important feature of chronic phase of eczema. It is usually seen with chronic coalescence of popular lesions and also occurs as a response to persistent rubbing or scratching. ^{' •}> ^'

Lichenified lesions are very difficult , to treat; once established, they may persist for months , even with adequate, .therapy and avoidance of rubbing or scratching. Histologically the lesions may show hyperkeratosis and parakeratosis and a thickened layer of epidermis.

The disorders that have lichenified skin lesions are skin disorders like Psoriasis, atopic dermatitis, neurodermatitis (Lichen simplex chronicus), all the types of eczemas which hyperkeratόtic in the chronic phase including chronic allergic and irritant contact dermatitis, asteatotic dermatitis, nummular eczema, stasis dermatitis, and hand eczema.

Topical pharmaceutical composition in accordance with the present invention comprises about 0.025 % w/w to 0.075 % w/w of halobetasol propionate and about 3% w/w to 6 % w/w of salicylic acid.

Salicylic acid according to the present invention is preferably micronised salicylic acid. The term micronised salicylic acid as described in the present invention refers to salicylic acid having particle size with Dg₀ less than about 50 microns, preferably less than about 35 microns and more preferably less than about 25 microns. The particle size of salicylic acid is measured by dry method using Malvern Particle size analyzer (Malvern Mastersizer "S").

The topical pharmaceutical' compositions according to the present invention refers to use of composition externally over the skin in the form of ointment, cream, lotion, emulsion, paste, gel or the like and may contain appropriate conventional and pharmaceutically acceptable excipients/ additives selected from, but are not limited to preservatives, solvents, chelating agents, gelling agents, surfactants, buffering agents, viscosity builders, stiffening agents, emulsifiers, emollients, pH modifiers, Vehicles and the like and mixtures thereof that are typically used in the art for locally applied semisolid dosage forms.

Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery,¹ and, preferably, will provide for other desired characteristics as well, e.g., emollieηcy or the like. Ointment bases may be grouped in four classes: oleaginous bases; emulsifiable -bases; emulsion bases; and water-soluble bases.

Process for preparing topical ointment composition involves the following steps: (a) oil phase excipients were melted at about 65°C to 85⁰Q, (b) drug is dissolved in propylene glycol at about 65°C to 85°C, (c) the contents of step (b) and step (a) were added at about 65°C to 85⁰C to form a base, (d) the mixture of step (c) is homogenized for about 15 minutes for uniform mixing; and (e) homogenized mixture is cooled under stirring to about 30⁰C.

Creams are semisolid dosage forms containing one or more drug substances dissolved or dispersed in a suitable base, possessing relatively fluid consistency formulated as either water-in-oil or oil-in-water emulsions.

The cream base may be prepared by conventional techniques well known to those skilled in the art. Generally, a suitable process comprises admixing the various ingredients of the cream in appropriate relative amounts in any order that is convenient and thereafter, if necessary adjusting the pH to the final desired value. For example, the components, of the base may be mixed together at an elevated temperature of 65-75 ⁰C until an emulsion has formed, and therapeutic agent may be added after cooling the emulsified cream base, or during mixing, if it is stable to the temperatures employed. . Stiffening agents used according to the present invention are selected from, but are not limited to fatty alcohols or esters such as white soft paraffin, white bees wax, stearyl alcohol, cetyl alcohol, myristyl alcohol, cetomacrogol emulsifying wax, cetyl stearyl alcohol, glycerin monostearate and mixtures there of-, Emulsifiers according to the present invention are selected from, but are not limited to polyoxyethylene glycol monocetyl ethers, white beeswax, DEHYMULS® E, (dicotyl pentaerythrityl distearyl citrate, sorbitan sesquioleate, aluminium stearates), cetomacrogol, pojyoxyethylene 21 stearyl ether, polyoxyethylene 20 cetyl ether, polydxyethlene sorbitan monostearates, Polysorbate 60, polyoxyethylene sorbitan monoleates, tween 80, sorbitol monostearate (Span 60), glyceryl monostearate and mixtures there of.

Humectants according to the present invention include, but are not limited to, propylene glycol, glycerin, butylend glycol, sorbitol, triacetin and mixtures there of. As used herein, the term "viscosity builders" is intended to mean an agent which helps for increasing the viscosity of the final formulation and helps in building the consistency to the final formulation. The viscosity built up is dependent upon the degree of polymerization and the ability of the polymer to swell. Such compounds include, by way of example and without limitation, carbomer, xanthan gum and the like.

Buffering agents are μsed to maintain a suitable pH and are selected from sodium dihydrogen phosphate ^' dihydrate, dibasic sodium phosphate anhydrous (anhydrous sodium phosphate), alkali metal hydroxides such as spdium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixtures there of.

As used herein, the term "chelating agent" is intended to mean a compound which forms complex with metal ions and thus prevents the unwanted chemical reactions catalyzed by these ions. Such compounds include, by way of example and without limitation, disodium edetate and the like.

Preservatives according to the present invention are selected from, but are not limited to phenoxyethanol, benzyl alcohol, methylparaben, propylparaben, methylchloroisothiazolinone, methylisothiazolinone, Dimethicone 350, and poloxamer and mixtures thereof. Solvents/vehicles used according to the present . invention are selected from, but are not limited to propylene glycol, water, liquid paraffin, diethylene glycol monoethyl ether and mixtures thereof.

The composition of the present invention may also include minor amounts of conventional additives such as antioxidants like butylated hydroxytoluene, penetration enhancers, co-solvents, humectants, pH modifiers like triethanolamine, sodium hydroxide, emollients such as isopropyl palmitate, 2-

Octyldodecanol, light liquid paraffin or mixtures there of.

The invention is further exemplified with following examples and is not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or With the one known to the industry.

, EXAMPLES

Example - 1 : Ointment composition comprising Halobetasol propionate and salicylic acid.

Brief manufacturing process:

(a) The excipients of step (I) (white soft paraffin; white bees wax, DEHYMULS(R⁾ E (dicQcoyl pentaerythrityl distearyl citrate, sorbitan sesquioleate, beeswax, and aluminum stearates)) were heated at about 65°C to 85°C.

(b) Halobetasol propionate was dissolved in propylene glycol at about 65⁰C to 85°C.

(c) The contents of step (b) were added to the contents of step (a) under stirring at about 65°C to 85°C to form a base. ' (d) Salicylic acid was added to the base obtained from step (c) at about 6O⁰C to 68°C. (e) The mixture of step (d) is homogenized for about 15 minutes for uniform mixing and cooled under stirring to about 30°C.

Example 2: Cream composition comprising Halόbetasol propionate and salicylic acid.

Brief manufacturing process:

(a) Oil phase: The excipients of step (I) were heated at about 65°C to 85°C. (b) Aqueous phase: Disodium edetate was dissolved in water at about 65°C to 85°C.

(c) Emulsification and homogenization: The contents of step (b) were added to the contents of step (a) under stirring at about 65⁰C to 85⁰C, and homogenized for 10 minutes, and cooled to form cream base.

(d) Buffer phase: Dibasic sodium phosphate anhydrous was dissolved in water and added to the base of step (c) at about 40⁰C.

(e) Qrug phase: Halobetasol propionate (dissolved in diethylene glycol monoethyl ether) and salicylic acid (dissolved in propylene glycol) were added to cream base of step (d) at about 40°C.

(f) Triethanolamine and sodium hydroxide phase: Triethanolamine was added to cream base at 40⁰C and pH was adjusted to 5.0 with sodium hydroxide solution.

(g) Mixing: Stirring was continued and cooled to room temperature to form cream.

Example 3: Cream composition comprising Halobetasol propionate and salicylic acid.

Brief manufacturing process: (a) Oil Phase: Cetyl Alcohol, isopropyl isostearate, isopropyl palmitate and steareth-21 were heated up to 7O⁰C to 72⁰C in stainless steel container.

(b) Aqueous Phase: Diazolidinyl urea was dissolved in purified water and heated up to 70⁰C to 72°C in stainless steel container. (c) Emulsification: The contents of step (b) were added to the contents of step (a) under stirring at about 65⁰C to 85⁰C, and homogenized for 15 minutes and cooled.

(d) Drug phase: Halobetasol propionate and salicylic acid were dispersed in glycerin and added to cream base at about 40⁰C. (e) Methylchloroisothiazolinone and methylisothiazolinone were added to cream base at about 40°C.

(f) Mixing: Stirring was continued for about 25 minutes and cooled to room temperature.

Example 4:

The topical ointment composition of the present invention, Example 1 , comprising combination of Halobetasol propionate 0.05% w/w and salicylic acid (micronized) 3%w/w was evaluated for efficacy, safety and tolerability as compared to topical ointment composition containing combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w; halobetasol propionate Q-05%w/w ointment, mometasone furoate 0.05% ointment¹ and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses. Methods:

A prospective, randomized, double blind, multicentre, phase III study was undertaken in approximately 110 patients with a clinical diagnosis of plaque psoriasis and chronic dermatoses, Patients fulfilling the selection criteria were assigned to treatment with the composition as coded below for Groups A-E, topically daily every 12 hours for 2 weeks after obtaining their informed consent. The duration of the study was 3 weeks including a 2-week active treatment period preceded by a 1-week washout period. Coding:

GROUP A = Halobetasol U.ut>%w/w + ύancync MCIU ^IVII<JIUMI<-.CU; O /OW/W ointment (Example 1 of the present invention).

GROUP B = Mometasone Furoate 0.1% + salicylic acid 3% ointment

(Sensicort S^® from Zuventus Pharmaceuticals Ltd).

GROUP C = Halobetasol 0.05% ointment (Halovate^® from Glenmark

Pharmaceuticals Ltd).

GROUP D = Mometasone 0.05% ointment (Elocon^® from Fulford). GROUP E = Placebo.

The efficacy variables included changes in mean scores of pruritus/itching, scaling, erythema, oozing/crusting, lichenification and overall global assessment of efficacy by physician/patients and monitoring of treatment-emergent adverse events. Overall Global Assessment of Efficacy:

At the end of study, an overall, assessment of the efficacy of the medication was performed by both the physician and the patient by using 7 point scale. Physician's and Patients Gjobal evaluation is graded as:.

Results of the study:

The study data for assessment for efficacy of combination of Halobetasol 0.05%w/w and Salicylic acid 3%w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w ointment, halobetasol propionate 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses were pooled and results were analyzed using a non-parametric test. All tests were two tailed & p<0.05 were considered to be significant. ^f

Table 1 : Results of itching with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses

By ANOVA *P < 0.05 Significant @ Between Group P < 0.05 Significant

Table 1 shows that mean score of itching were 2.35 among Group A,

2.30 in Group B, 2.33 in Group C, 2.29 in Group D and 2.24 among Group E at baseline which was same and difference was not significant. After treatment at the end of 3^rd day mean score of itching had a significant fall in all the groups except in Group E, i.e. 49.8 % among Group A, 33.0 % in Group B, 32.2% in Group C, 18.3% in Group D and only 02.2% among Group E. Group A had more fall as compared to Group B, C and D and the difference was statistically significant. After the treatment at the end of 14^th day mean score of itching had a significant , fall i.e. 81.3 % in Group A, 66.2 % in Group B, 77.40 % in Group C, 59.8% in Group D and 15.2% among Group E.

Table 2: Results of changes in mean score of thickness with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3%w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3%w/w, halobetasol propionate 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.

By ANOVA ^*P < 0.05 Significant © Between Group P < 0.05 Significant

Table 2 shows that mean score of thickness were 2.32 among Group A, 2.29 in Group B, 2.30 in Group C, 2.36 in Group D and 2.40 among Group E at baseline which was same and difference was not significant. After treatment at the end of 3^rd day mean score of thickness had a significant fall in all the groups except in Group E i.e. 47.4% among Group A, 32.8% in Group B, 30.0% in Group C, 20.3% in Group D and only 5.0 among Group E. Group A had more fall as compared to Group B, C and D. After the treatment at the end of 14^th day mean score of thickness had a significant fall i.e. 92.2% in Group A, 78.6% in Group B, 76.5% in, Group C, 71.2% in Group D and 16.3% among Group E. If you compare fall was more among Group A as compared to Group B, C and D.

Table 3: Results of changes _; in mean score of pain with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate 0-05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.

By ANOVA *P < 0.05 Significant @ Between Group P < 0.05 Significant

Table 3 shows that Mean score of pain were 1.72 among Group A, 1.69 in Group B, 1.62 in Group C, 1.59 in Group D and 1.66 among Group E at baseline which was same and difference was not significant. After treatment at the end of 3^rd day mean score of pain had a fall in all the groups except in Group E i.e. 36.6% among Group A₁ 15.4% in Group B, 13.6% in Group C, 5.7% in Group D and 3.7% among Group E. After the treatment at the end of 14^th day mean score of pain had a significant fall i.e. 93.0% in Group A, 83.4% in Group B, 84.0% in Group C, 73.0% in Group D and 7.5% among Group E. The fall was more among Group A as compared tp Group B, C and Q.,

Table 4: Results of changes in mean score of crusting with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.

Table 4

Mean Score of Crusting ( X± SD)

Duration in Days Group A Group B Group C Group D Group E

Baseline 1.44 ± 0.72 1.39 ± 0-70 ' 1.36 ± OJδδ 1.38 ± 0.78 1.40 ± 0.79

*0.74 ± 0.71 *1.15 ± 0.72 "1.11 ± 0.69 ^•1.20 ± 0.55 51.35 ± 0.66

*Q.39 ± 0.58 *0.52 ± 0.66 *0.57.± 0.66 *0.84 ± 0.67 @1.30 + 0.70

14 *0.09 ± 0.32 *0.21 ± Q.40 ^*0.24 ± 0.37 ^*0.40 ± 0.52 I @1.28 ± 0.59

By ANOVA *P < 0.05 Significant: @, Between Group P < 0.05 Significant Table 4 reveals that mean score of crusting were 1.44 among Group A, 1.39 in Group B, 1.36 in Group C, 1.38 in Group D and 1.40 among Group E at baseline which was same and difference was not significant. After treatment at the end of 3^rd day mean score of crusting had a significant fall in all the groups except in Group E i.e. 48.6% among Group A, 17.3% in Group B, 18.4% in Group C, 13.0% in Group D and only 3.6 among Group E. After the treatment at the end of 14^th day mean score of crusting had a significant fall, i.e. 93.8% in Group A, 84.9% in Group B, 82.44% in Group C, 71.0% in Group D and 8,6% among Group E. The fall was more among Group A as compared to Group B, C and D.

Table 5: Results of changes in mean score of scaling with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate 0.05%w/w ointment, mometaspne furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses. ^■

By ANOVA *P < 0-05 Significant @ Between Group P < 0-05 Significant

Table 5 indicates that mean score of scaling were 2.42 among Group A, 2.39 in Group B, 2.51 in Group C₁ 2.49 in Group D and 2.44 among Group E at baseline which was same and difference was not significant. After treatment at the end of 3^rd day, mean score pf scaling had a significant fall in all the groups except in Group E i.e. 56.1 % among Group A; 42.1% in Group B, 42.6% in Group C, 24.5% in Group D and' 05.3 among Group E. After the treatment at the end of 14^th day, mean score of spaling had a significant fall i.e. 90.0% in Group A, 83.1 % in Group B, 79.7% in Group Ci 70.3% in Group D and 10.2% among Group E. The fall was more among Group A as compared to Group B, C and D but difference was not significant.

Table 6: Results of changes in mean score of redness with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1 %w/w and salicylic acid 3% w/w, halobetasol propionate 0.05%w/w, ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.

By ANOVA *P < 0.05 Significant ©.Between Group P < 0.05 Significant

Table 6 shows that mean score of redness were 1.95 among Group A, 2.01 in Group B, 1.89 in Group C, 1.90 in Group D and 1.93 among Group E at baseline which was same and difference was hot significant. After treatment at the end of 3^rd day, mean score of redness had a significant fall in group A but in other groups reduction were not significant i.e. 36.3% among Group A, 16.9% in Group B, 10.6% in Group C, 5.8% in Group D and only 4.7 among Group E. The fall was low in Group D & E as compared to other groups and Group A had more fall as compared to Group C and P. After the treatment at the end of 14^th day, mean score of redness had a significant fall i.e. 80.1 % in Group A, 70.3% in Group B, 67.7% in Group C, 47.9% in Group D and 11.9% among Group E.

Table 7: Results of changes in mean score of oozing with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate¹ 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the. treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.¹.

By ANOVA *P < 0.05 Significant @ Between Group P < 0.05 Significant

Table 7 indicates mean score of oozing were 1.78 among Group A, 1.75 in Group B, 1.70 in Group C, 1.81 in Group D and 1.82 among Group E at baseline which was same and difference was not significant. After treatment at the end of 3^rd day, mean score of oozing had a significant fall in all the groups except in Group D & E i.e. 43.3% among Group A, 23.4% in Group B, 21.9% in Group C, 9.4% in Qroup D and only 3.8 among Group E. The fall was significantly low in Group P ^ E as compared to Group A and had more fall as compared to Group B, C and D. After the treatment at the eiid of 14^th day, mean score of oozing had a significant fall i.e. 83.7% in Group A, 76.6% in Group B, 72.4% in Group C, 56.4% in Group D and 07.7% among Group E.

Table 8: Results of. overall global assessment of efficacy of treatment by physician with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque, psoriasis and chronic dermatoses.

By Chi - Square Test *P < 0.05 Significant compared to placebo

As per overall global assessment of efficacy of treatment by physicians, at the end of 14^th day, 95.3% of the cases treated with topical ointment composition of the present invention comprising combination of Halobetasol propionate 0.05% w/w and salicylic acid (micronized) 3%w/w,Group A, had a marked to complete resolution after the treatment which was more as compared to all other groups i.e. 60.0% in Group B, 76.2 % in Group C, 50.0% in Group D and not a single patient in Group E.

In cases treated with topical ointment composition of the present invention comprising combination of Halobetasol propionate 0.05% w/w and salicylic acid (micronized) 3% w/w (Group A) the results of marked to complete resolution were statistically significant as compared to Group B, C and D in global assessment for efficacy by physicians.

Table 9: Results of overall global assessment of efficacy of treatment by patients with combination of Halobetasol propionate 0.05% w/w and salicylic acid 3% w/w ointment (Example 1 of the present ^' invention) vs combination of mometasone furoate 0.1%w/w and salicylic acid 3% w/w, halobetasol propionate 0.05%w/w ointment, mometasone furoate 0.05% ointment and placebo in the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.

By Chi - Square Test *P < 0.05 Significant

As per overall global assessment of efficacy of treatment by patients, at the end of 14^th day, 95.3 % of the cases treated with topical ointment composition of the present invention comprising combination of Halobetasol propionate 0.05% w/w and salicylic acid (micronized) 3%w/w; Group A had a marked to complete resolution after the treatment which was more as compared to all other groups i.e. 65.0% in Group B, 81.0% in Group. C, 55.0% in Group D and not a single patient in Group E. Group A results of marked to complete resolution were statistically significant as compared to Group B, C and D.

For cases treated with topical ointment composition of the present invention comprising combination of Halobetasoi propionate 0.05% w/w and salicylic acid (micronized) 3% w/w (Group A), results of marked to complete resolution were statistically significant as compared to Mometasone 0.1%w/w + Salicylic Acid 3% w/w ointment group, Halobetasol propionate 0.Q5 %w/w ointment group, and Mometasone 0.05% w/w ointmeht (P < 0.05).

Treatment with the combination of Halobetasol propionate 0.05%w/w + Salicylic Acid (micronized) 3%w/w ointment proved to be effective in 95.3. % of the cases showing marked improvement to complete resolution of symptoms, the remaining 4.7 % cases also showed moderate improvement. This is superior to the results obtained by Bemhard J et al 1991 with Halobetasol, where efficacy was seen in 72.2 % cases and results obtained by Koo J et al 1998, with the combination of Mometasone 0.-1% w/w + Salicylic Acid 3%w/w ointment group, where efficacy was seen in 52.6 % cases.

Results showed that there was a faster and significant decrease (p<0.05) in the mean symptom/sign scores as well as the total scores 3^rd day onwards in the Halobetasol 0.05% w/w + Salicylic Acid (Micronized) 3% w/w ointment group as compared to other groups and this was significantly sustained till end of treatment (p<0.05). On further observation, it was noticed that thicker lesion (palmoplantar psoriasis and hyperkeratotic lesions) response was considerably superior in Halobetasol 0.05%w/w.+ Salicylic Acid (micronized) 3%w/w ointment group as compared with Mometasone 0.1 %w/w + Salicylic Acid 3%w/w ointment group which suggests that the difference is more marked due to presence of halobetasol in the combination as against Mometasone in combination with Salicylic acid.

Therapy with the combination of Halobetasol 0.05% w/w + Salicylic Acid (micronized) 3% w/w ointment of the present invention provided a better efficacy, quick relief from signs and symptoms, and had good tolerability.

Claims

We claim:

1. A topical composition comprising a combination of a) a therapeutically effective amount of halobetasol propionate or its salts; b) a therapeutically effective amount of salicylic acid or its salts; and c) a pharmaceutically acceptable carrier.

2. The topical pharmaceutical composition according to claim 1 , wherein said composition is an ointment, cream, lotion, solution or gel.

3. The topical composition according to claim 1 , wherein, halobetasol propionate constitutes from about 0.025w/w % ^'to 0.075% w/w, and salicylic acid constitutes from about 3% to about 6%w/w of the total composition.

4. The topical composition according to claim 1, wherein, halobetasol propionate constitutes 0.05 %w/w, and salicylic acid constitutes 3% w/w of the total composition.

5. The topical composition according to claim 1 , wherein the weight ratio of halobetasol propionate and salicylic acid ranges from 1 :40 to 1 :240.

6. The topical composition according 'to claims 1-5, further comprising solvents, vehicles, ointment/cream bases, emulsifiers, preservatives, buffers, emollients, humectants, surfactants, and transport enhancers or mixtures there of.

7. Use of halobetasol propionate and salicylic acid for the preparation of topical composition, according to claims 1-6,i for the treatment of lichenified skin lesions, plaque psoriasis and chronic dermatoses.

8. A method of treatment according 'to claim 7, wherein the composition is used for treatment of lichenified skin lesions caused by skin disorders including psoriasis, atopic dermatitis, neurodermatitis (Lichen simplex chronicus), eczemas which are hyperkeratotic in the chronic phase including chronic allergic and irritant contact dermatitis, asteatotic dermatitis, nummular eczema, stasis dermatitis, and hand eczema.

9. A method of treating lichenified skin'' lesions, plaque psoriasis' and chronic dermatoses, wherein the said method 'comprises topical application to the afflicted area, the composition comprising a combination of: a) a therapeutically effective amount of halobetasol propionate or its salts; and b) a therapeutically effective amount of salicylic acid or its salts, to a subject in need thereof.

10. A method of treatment according to claim 9, wherein the composition is used for treatment of lichenified skin lesions caused by skin disorders like psoriasis, atopic dermatitis, neurodermatitis (Lichen simplex chronicus), eczemas which are hyperkeratotic in the chronic phase including chronic allergic and irritant contact dermatitis, asteatotic dermatitis, nummular eczema, stasis dermatitis, and hand eczema.

11. A method according to claims 9-10, wherein, halobetasol propionate constitutes from about 0.025 %w/w to 0.075 %w/w, and salicylic acid constitutes from about 3%w/w to about 6%w/w of the total composition.

12. A method according to claim 11 , wherein, halobetasol propionate constitutes about 0.05%w/w, and salicylic acid constitutes about 3%w/w of the total composition.