FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
(SECTION 10)
"NOVEL FOAM COMPOSITION CONTAINING MOMETASONE FUROATE AND KETOCONAZOLE "
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at

Glenmark Pharmaceuticals Limited,Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East),
Mumbai - 400 099, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

The delivery of certain medicaments topically is well known in the art. Topical forms of medicament delivery include lotions, creams, pastes, gels, ointments, salves, milks, tinctures and solutions. The convenience of use and efficacy of a topical composition are in a large part determined by the form of the composition.
The challenge in topically applying a composition is achieving percutaneous penetration of the active agent to the site of treatment, in many cases the epidermis. At the same time, it is important that a composition should have desirable characteristics such as ease of application, smooth texture and application should result in no irritation, discomfort or inconvenience. Desirably, the composition should not leave a residue where applied.
Topical compositions in forms such as gels, ointments, lotions, creams, salves and pastes are often very viscous, requiring substantial rubbing to achieve penetration of the active agent to the affected skin layer, an act which often results in discomfort and irritation. Non-viscous creams and lotions require quick and dexterous application as they are inclined to flow off the site of treatment before penetration of the active ingredient is achieved.
In contrast, foams are well suited than the topical application of compositions. The advantages of foamable compositions for the topical application of pharmaceutical are well known in the art. In the field of pharmacology the rigid yet fluid nature of foamable compositions is desirable, allowing a foam to be applied in any orientation without run-off as well as the allowing the convenient application of foam evenly over large surfaces. Lastly, when a foam is applied, even by rubbing, onto damaged or sensitive skin, the foam acts as a cushion, allowing spreading without direct physical contact.
Foamable compositions are generally single or multi-phase liquids provided in a container, often together with a propellant to transport the composition from the container, transforming it into foam upon application. Another technique for the application of foams includes the "bag-in-a-can". In such products, the product may contain a low-boiling hydrocarbon like isopropane that has a boiling point of about 28.degree. C. Application
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NOVEL FOAM COMPOSITION CONTAINING MOMETASONE FUROATE
AND KETOCONAZOLE
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to a novel combination pharmaceutical composition of foam for topical administration, including, as the pharmaceutically active component one ingredient selected form the group of an antifungal agent and other ingredient selected form the group of steroidal anti-inflammatory agent, and process for preparing the same.
2. Description of the Related Art
The present invention relates to the field of pharmacology and more particularly, to a foamable composition especially useful for topical delivery in the form of foam of medicaments such as corticosteroids in combination with antifungal agents and methods for the preparation thereof and methods of treatment using the same.
The present invention relates to topical formulations useful for treating fungal diseases, canidiasis, intertriginous dermatitis and their related inflammation. In particular, the present invention relates to stable topical formulations containing an antifungal agent and an anti- inflammatory steroid.
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and agitation of the product at body temperature cause the isopropane to vaporize and generate the foam similar to a pressurized aerosol foaming system.
The physical characteristics of foam formed by a foamable composition are dependent upon the nature and relative amounts of components such as solvents, propellants and surfactants. One of the most important characteristics is whether a foam is long-lasting or quick-breaking, a qualitative description of the behavior of the foam towards shearing action encountered, for example, when the foam is rubbed into or spread over a surface onto which it has been applied, such as skin.
One method of producing quick-breaking foams is by the use of a foamable composition with a relatively high alcohol content. Upon contact with the skin the alcohol in such foams evaporates. Thus the foam relatively quickly collapses into a liquid when disturbed (e.g. by rubbing) or when warmed by body heat driving the active agent through the skin layers to the site of treatment. This allows a user to quickly dispense a desired amount to achieve a quick effect.
Corticosteroids are well known anti-inflammatory compounds, which are recognizably utilized in the treatment of acute inflammatory diseases such as allergic contact dermatitis, eczema, atopic eczema, asteatotic eczema, discoid eczema, infantile eczema and napkin dermatitis, psoriasis-plaque, seborrheic dermatitis, atopic dermatitis, dermatitis herpetiformis, neurodermatitis, lichen simplex chronicus, lichen planus, subacute cutaneous lupus erythematosus, papular urticaria (insect bite reactions), palmoplanar psoriasis, discoid lupus erythematosus, chronic hypertrophic lichen planus, granuloma annulare and keloid scars.
The topical application of corticosteroid compositions for the treatment of these and other skin ailments is well established in the art and is effected, inter alia, using foamable compositions.
Several formulations that are commercially available include Lotrisone® cream
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(clotrimazole 1%/betamethasone dipropionate 0. 064%), Daktacort® cream (miconazole nitrate 2%/hydrocortisone 1%) and Canesten® HC cream (clotrimazole 1%/hydrocortisone 1%). The steroid component, betamethasone valerate, Lotrisone®, is so strong that it can induce skin atrophy, striae, persistent tinea corporis and even growth retardation in children receiving Lotrisone® treatment (see, for example, Pediatr. Dermatol. 19(1) :78-81 (2002); Cutis 69(l):67-68 (2002); Am. Fam. Physician 65(10:2095- 2102 (2002)). The remaining two products have only 1% hydrocortisone, which is too low in potency to have significant anti-inflammatory properties [0012] In one example, Woodford et al. J. Pharmaceutical Science 66: 99-103 (1977) describe a corticosteroid foamable composition containing betamethasone benzoate, betamethasone valerate, clobetasol propionate, desonide, triamcinolone acetonide, flumethasone pivalate and hydrocortisone-17-butyrate, which produces a quick-breaking foam using CFC propellants.
U.S. Pat. No. 3,856,956 also teaches a corticosteroid foamable composition that includes CFC propellants. However, as it is well known that CFC gases damage the environment, the above foamable corticosteroid compositions were considered highly disadvantageous and efforts have been made to produce compositions devoid of CFC gases.
U.S. Pat. No. 5,352,437 teaches a crackly foamable composition, using n-butane as a propellant instead of CFC. The composition includes between 0.05% and 10% of a low hydrocarbon alcohol or a glycol and a high content of the propellant (between 60 and 95 weight percentages), and may optionally further include an active ingredient.
[In the art it is known that corticosteroids (as well as other pharmaceutically active compounds, especially esters) tend to decompose or isomerize to less than ideal structures, (see, for example, U.S. Pat. No. 5,914,122). It is thus important when providing a pharmaceutical composition, to evaluate the stability of the pharmaceutically active compound used therein.
U.S. Pat. No. 6,126,920 teaches a corticosteroid foamable composition that comprises an
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aliphatic alcohol (40%-90% w/w), water (10%-40% w/w), a fatty alcohol (0.5%-10% w/w), a surface-active agent (0.1%-55% w/w) and a buffer where an included corticosteroid is stable.
In U.S. Pat. No. 6,126,920 the nature of the propellant is not discussed but two commercial products based on this patent, Luxiq.RTM. and Olux.RTM. (Connetics.RTM., Palo Alto, Calif, USA), use a butane/propane mixture as a propellant and have no CFC based propellant.
In U.S. Pat. No. 6,126,920 it is reported that the only way to ensure the stability of the most active isomer of the active ingredient of the composition is by including a buffering agent selected from amongst acetic acid/sodium acetate, citric acid/sodium citrate and phosphoric acid/sodium phosphate, and it is desirable generally to buffer the composition to a pH of 3.0-6.0, preferably 4.0-5.0 and to this end the buffering agent may preferably be present in an amount of 0.01-1.0% w/w, more preferably 0.05-0.2% w/w. For betamethasone valerate it is reported that particularly preferred is an anhydrous citric acid/potassium citrate, to buffer the composition to pH 4.5, so as to stabilize the more active 17-valerate ester over the less active 21-valerate ester.
The use of a buffer system obviously increases the complexity and costs of manufacture of a composition made according to the teachings of U.S. Pat. No. 6,126,920.
US20040138179 patent assigned to topical formulations useful for treating fungal diseases, canidiasis, intertriginous dermatitis and their related inflammation. '179' patent talks about the stable topical formulations containing an antifungal agent and an antiinflammatory steroid in combination.This patent talks about the
There is thus a widely recognized need for, and it would be highly advantageous to have, a foamable composition that can be used to topically deliver pharmaceutical, which does not use CFC propellants and is further devoid of the disadvantages of compositions known in
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the art.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention is to make a novel , foam composition administered in combination containing one ingredient selected from the group of azole antifungal agent and second active ingredient is selected form the group of corticosteroidal anti-inflammatory agent.
Further aspect of the invention is to provide a process for preparing the foam composition containing one ingredient selected from the group of azole antifungal agent and second active ingredient is selected form the group of corticosteroidal anti-inflammatory agent.
In accordance with a third embodiment of the present invention, azole type antifungal agents include, for example, Ketoconazole, Econoazole, Miconazole, Itraconazole, Fluconazole, Clotrimazole, Griseofiilvin, Oxiconazole, Terconazole, Tioconazole, Clotrimazole, and Silver Sulfadiazine. Other representative antifungal agents are, for example, Ciclopirox olamine, Terbinafine , and steroidal anti-inflammatory agent as Desoximetasone, Mometasone furoate, Triamcinolone acetonide, Triamcinolone acetate, Fluocinolone acetonide, Hydrocortisone valerate, Mometasone furoate, Clocortolone privalate, Fluticasone propionate, Hydrocortisone butyrate, Predincarbate, Aclometasone dipropionate, Desonide, Hydrocortisone probutate Hydrocortisone
In a preferred embodiment, the antifungal agent is an azole type agent such as ketoconazole
In a preferred embodiment, the steroidal anti-inflammatory agent is Mometasone furoate.
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However, such a combination of the carrier of the present invention and a non-CFC propellant is also useful in implementing a general foamable composition, with or without an active ingredient.
Hence, according to another aspect of the present invention there is provided a foamable composition that comprises the non-CFC propellant and the carrier described hereinabove, which is devoid of a buffering agent.
In another aspect of the invention there is provided a composition for the treatment of fungal skin conditions including dandruff, seborrheic dermatitis, tinea, jock itch and the like, said composition characterised in that it is a foamable mousse applicable to the skin of the user in the substantial absence of water and without substantially immediate removal by washing.
In further aspect the pharmaceutically acceptable excipients for topical administration can
be a mixture of solvents, emollients, humectants, emulsifiers, and transport enhancer such
as natural or synthetic polymer, and lipids.
In a more preferred embodiment of this aspect of the invention, the mousse is a
temperature sensitive mousse, which breaks down rapidly when exposed to the skin
temperature.
In a preferred embodiment of this aspect of the invention, the composition is allowed to remain on the affected area for an extended period of time.
Solvents can be, for example, alcohols, esters, propylene glycol, butylene glycol, hexylene glycol, polyethylene glycols, polypropylene glycols, polyurethane compounds, including hydroxy-terminated polyurethanes, in particular polyolprepolymer-2, polyolprepolymer-14, or polyolprepolymer-15. Emollients can be, for example, white petrolatum, mineral oil, propylene glycol dicaprylate, lower fatty acid esters and lower alkyl ethers of propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, cetyl esters wax, spermaceti wax, white wax, isopropyl myristate, polyoxyethylene polyoxypropylene cetyl
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ether, polyoxypropylene methyl glucose ether, polyoxypropylene methyl glucose ether, 2-ethyl-l,3-hexanediol, propylene glycol dioctanoate, methyl gluceth-10, methyl gluceth-20, isodecyl neopentanoate, glycerin, mineral oil, etc. (preferably in an amount of up to about 40 wt %, more preferably about 5 to 30 wt %). Humectants can be, for example, glycerin and sorbitol. Emulsifiers can be, for example, glyceryl monostearate, glyceryl monoleate, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, and polyethylene glycol stearate.
Therefore, a preferred foamable pharmaceutical composition according to this aspect of the present comprises one or more active ingredient(s), a non-CFC propellant and an acceptable carrier configured to generate a quick-break foam, as is described hereinabove, and is being devoid of a buffering agent.
In one more aspect involves the process of preparation of the said foam by taking ethyl alcohol,mometasone furoate, Quaternium, polyvinyl pyrrolidone are taken and stir to make a clear solution. In another container ethyl alcohol, ketoconazole are taken and heated to 50°C, then added cetyl alcohol, steryl alcohol, Polawax A 31 to it and stirred to dissolve completely. This mixture is added to the above mixture of mometasone. In another container taken In one container taken polysorbate 80 and propylene glycol and stirred completely to get a clear solution.This solution is added to the mix of Mometasone and ketoconazole.The final weight of the composition is adjusted using Ethyl Alcohol. Then propellent is filled in individual container and individual container is passed through 60°c water for equilibrium pressure of propellent and vapour Pressure of Propellant is adjusted to 60-70 psig.
In further accordance of this invention the resultant topical composition is a physicochemically stable and aesthetically appealing composition.
Due to the intelligent selection of excipients helps in reducing the cost of the product.
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DEFINITIONS
The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) 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 (3) 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 subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
By "pharmaceutically acceptable" is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention generally relates to a novel combination pharmaceutical composition of foam for topical administration, including, as the pharmaceutically active
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component one ingredient selected form the group of an antifungal agent and other ingredient selected form the group of steroidal anti-inflammatory agent, and process for preparing the same.
The anti fungal agent is selected from the group of azole type antifungal agent for example, Ketoconazole, Econoazole, Miconazole, Itraconazole, Fluconazole, Clotrimazole, Griseoftilvin, Oxiconazole, Terconazole, Tioconazole, Clotrimazole, and Silver Sulfadiazine. Other representative antifungal agents are, for example, Ciclopirox olamine, Terbinafine.
Second ingredient selected form the group of steroidal anti-inflammatory agent for example Desoximetasone, Mometasone furoate, Triamcinolone acetonide, Triamcinolone acetate, Fluocinolone acetonide, Hydrocortisone valerate, Mometasone furoate, Clocortolone privalate, Fluticasone propionate, Hydrocortisone butyrate, Predincarbate, Aclometasone dipropionate, Desonide, Hydrocortisone probutate Hydrocortisone.
Solvents can be, for example, alcohols, esters, propylene glycol, butylene glycol, hexylene glycol, polyethylene glycols, polypropylene glycols, polyurethane compounds, including hydroxy-terminated polyurethanes, in particular polyolprepolymer-2, polyolprepolymer-14, or polyolprepolymer-15. Emollients can be, for example, white petrolatum, mineral oil, propylene glycol dicaprylate, lower fatty acid esters and lower alkyl ethers of propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, cetyl esters wax, spermaceti wax, white wax, isopropyl myristate, polyoxyethylene polyoxypropylene cetyl ether, polyoxypropylene methyl glucose ether, polyoxypropylene methyl glucose ether, 2-ethyl-l,3-hexanediol, propylene glycol dioctanoate, methyl gluceth-10, methyl gluceth-20, isodecyl neopentanoate, glycerin, mineral oil, etc. (preferably in an amount of up to about 40 wt %, more preferably about 5 to 30 wt %). Humectants can be, for example, glycerin and sorbitol. Emulsifiers can be, for example, glyceryl monostearate, glyceryl monoleate, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, and polyethylene glycol stearate.

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The formulation may also contain additional materials commonly used in drug formulation, e.g., chelating agents and fragrances.
The compositions can be used to treat any fungal disease which is complicated by inflammation. The compositions are especially useful to treat fungal diseases such as tinea pedis, tinea capitis, tinea corporis, tinea versicolor, tinea cruris, candidiasis and intertriginous dermatitis complicated by candidiasis.
EXAMPLE (1)
Reference is now made to the following examples, which together with the above description illustrate the invention in a non-limiting fashion.

STEP NAME OF INGREDIENTS Category
I Ethyl Alcohol (95%v/v) Solvent for API
Mometasone Furoate (Micronised) API
Quaternium 26 (Incroquat 26) Conditioner
Polyvinyl Pyrrolidone (PVP K-30) Foam Stabiliser
II Ethyl Alcohol (95%v/v) Solvent for API
Ketoconazole API
Cetyl Alcohol Maintains Foam Characteristics
Stearyl Alcohol Maintains Foam Characteristics
Emulsifying Wax (Polawax A-31) Emulsifier
III Purified Water Vehicle
Polysorbate 60 (Tween 60) Surfactant and foam enhancer
Propylene Glycol Humectant
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Propels the product from the
IV Propellant (SPARK) can and creates
(Propane/Butane) microstructure of foam upon
dispensing
MANUFACTURING PROCESS:
In a container ethyl alcohol,mometasone furoate, Quaternium, polyvinyl pyrrolidone
are taken and stir to make a clear solution.
In another container ethyl alcohol, ketoconazole are taken and heated to 50°c, then
added cetyl alcohol, steryl alcohol, Polawax A 31 to it and stirred to dissolve
completely. This mixture is added to the above mixture of mometasone.
In one container taken polysorbate 80 and propylene glycol and stirred completely to
get a clear solution.This solution is added to the mix of Mometasone and
ketoconazole.The final weight of the composition is adjusted using Ethyl Alcohol.
Then propellent is filled in individual container and individual container is passed
through 60°c water for equilibrium pressure of propellent.
Vapour Pressure of Propellant: 60-70 psig
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
Dated this twenty third( 23rd )day of May ,2006

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Taranpreet Lamba. (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited
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