DESC:TOPICAL COMPOSITIONS OF ANTIFUNGAL AGENT AND PRAMOXINE

FIELD OF THE INVENTION

The present specification relates to topical compositions comprising one or more antifungal agents and pramoxine. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION

Dermatophytes are fungi that invade and multiply within keratinized tissues (skin, hair, and nails) causing infection. Based upon their genera, dermatophytes can be classified into three groups: Trichophyton (which causes infections on skin, hair, and nails), epidermophyton (which causes infections on skin and nails), and microsporum (which causes infections on skin and hair). Based upon mode of transmission, these have been classified as anthropophillic, zoophilic, and geophilic. Further, based upon the affected site, these have been classified clinically into tinea capitis (head), tinea faciei (face), tinea barbae (beard), tinea corporis (body), tinea manus (hand), tinea cruris (groin), tinea pedis (foot), and tinea unguium (nail).

Dermatophytes are the most common agents of superficial fungal infections worldwide and widespread in the developing countries, especially in the tropical and subtropical countries, where the high environmental temperature and relative humidity promote their growth. The pathogenesis of dermatophyte infection involves complex interaction between the host, agent and the environment. The factors which predispose to such an infection are underlying diseases such as diabetes mellitus, lymphomas, immunocompromised status, or Cushing's syndrome, older age, which could produce severe, widespread, or recalcitrant dermatophytosis. Some areas of the body are more susceptible to the development of dermatophyte infections such as intertriginous areas (web spaces and groins) where excess sweating, maceration, and alkaline pH favor the growth of the fungus. Dermatophyte infections may present in a variety of forms, depending on the site and precise etiology.

A range of topical and systemic antifungal agents including a number of combination products are available for the treatment of dermatophyte or fungal infections. In general, topical antifungal therapies are favored over systemic treatments for superficial infections. Topical therapy is recommended for a localized infection because dermatophytes rarely invade living tissues. Topical therapy should be applied to the lesion and at least 2 cm beyond this area once or twice a day for at least 2-3 weeks, depending on which agent is used. Some of the topical antifungal agents are azoles and allylamines, has shown high rates of clinical efficacy. These agents inhibit the synthesis of ergosterol, a major fungal cell membrane sterol.

The topical azoles (e.g. eberconazole, econazole, ketoconazole, clotrimazole, miconazole, oxiconazole, sulconazole, sertaconazole, luliconazole) inhibit the enzyme lanosterol 14-alpha-demethylase, a cytochrome P-450–dependent enzyme that converts lanosterol to ergosterol. Inhibition of this enzyme results in unstable fungal cell membranes and causes membrane leakage. The weakened dermatophyte is unable to reproduce and is slowly killed by fungistatic action.

Allylamines (e.g.naftifine, terbinafine) and the related benzylaminebutenafine inhibit squaleneepoxidase, which converts squalene to ergosterol. Inhibition of this enzyme causes squalene, a substance toxic to fungal cells, to accumulate intracellularly and leads to rapid cell death. Allylamines bind effectively to the stratum corneum because of their lipophilic nature. They also penetrate deeply into hair follicles.

Eberconazole is an imidazole antifungal with a broad spectrum of activity, effective against a wide range of yeast and fungi such as dermatophytes, candidiasis, yeasts (Malassezzia furfur) and Pityriasisversicolor. Chemically it is known as 1-(2,4-dichloro-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5-yl)-1H-imidazole) , is shown in below figure.

Eberconazole is either fungicidal or fungistatic based on its concentration, having fungicidal activity at higher concentrations. It inhibits the ergosterol synthesis. At high concentrations, it promotes leakage of smaller molecules from the cell membrane. It has also shown to possess anti-inflammatory activity in vivo. This property is useful in conditions such as inflamed cutaneous mycoses, thus favoring the reduction of inflammatory symptoms and enhancing treatment compliance. Eberconazole 1% cream is available in the market as an antifungal agent having characteristic molecular structure, which is both lipophilic-hydrophilic.

Luliconazole is an antifungal that belongs to the azole class. Chemically, luliconazole is (2E)-2-[(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-ylacetonitrile. Its structural formula is:

Although the exact mechanism of action against dermatophytes is unknown, luliconazole appears to inhibit ergosterol synthesis by inhibiting the enzyme lanosteroldemethylase. Inhibition of this enzyme’s activity by azoles results in decreased amounts of ergosterol, a constituent of fungal cell membranes, and a corresponding accumulation of lanosterol. Luliconazole 1% cream is available in the market as an antifungal agent indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophytonrubrum and Epidermophytonfloccosum, in patients 18 years of age and older.

The chief symptoms associated with dermatophyte infections or tinea infections are itch, burning and general irritation of the skin which is largely associated with the body’s inflammatory response to the pathogen. Inflammatory symptoms are particularly pronounced in infections caused by zoophilic fungi such as M. canis. Itch is the dominant symptom for many patients; in particular, patients with tinea cruris (commonly known as jock itch) often experience severe pruritus. Pruritus is the most common symptom of skin disease and can best be defined as an unpleasant sensation that leads to a desire to scratch. Acute pruritus leads to chronic condition that may progress to pain when persistent scratching leads to maceration and the development of secondary infection. Dermatomycosis associated itch and pruritis have been shown to have a significant negative impact on skin-related quality of life.

It is often recommended to add a low-to-medium potency topical corticosteroid to the topical antifungal treatment regimen to relieve symptoms associated with dermatophyte infections. The key advantage of combining antifungal treatment with a corticosteroid is that the latter promotes the swift resolution of the inflammatory changes and symptoms commonly associated with mycoses, such as itching, burning and erythema. The steroid can provide rapid relief from the inflammatory component of the infection, but the steroid should only be applied for the first few days of treatment. Moreover prolonged use of steroids leads to persistent and recurrent infections, longer duration of treatment regimens, and adverse effects including but not limited to skin atrophy, striae, and telangiectasias.

Therefore, their remains an unmet need for a safer topical antifungal treatment which not only address the dermatophyte infections but also takes care of pruritic symptoms and thus improves the patient’s skin related quality of life.

Pramoxine hydrochloride, a topical anesthetics which is thought to exert anti-pruritic effects by stabilizing membranes of sensory nerves, effectively decreases itch in patients with xerosis, uremic pruritus, and psoriasis and has been used as a single agent or in combination with mild potency topical steroids or lactic acid lotion. Chemically it is known as 4-(3-(p-butoxyphenoxy)propyl)morpholine hydrochloride and has following structure. Pramoxine has also been used in cosmetic composition.

There is no approved drug product of antifungal agent comprising pramoxine currently available in any market for the improvement of antifungal treatment regimen to relieve symptoms associated with dermatophyte infections.

It is difficult to prepare an antifungal agent and pramoxine in a single composition as most of the antifungal agents are hydrophobic in nature and pramoxine is hydrophilic.

In an attempt to develop an improved topical antifungal composition, the present inventors have surprisingly found use of pramoxine along with an antifungal agent and one or more suitably selected pharmaceutically accepted excipients resulted in a composition, which are stable, having efficient for the treatment of dermatophyte infections or tinea infections with additional anti-pruritic effects, does not have unwanted side effects and have improved patient compliance.

SUMMARY OF THE INVENTION

The present specification relates to topical compositions comprising antifungal agents and pramoxine and process for preparing such compositions.

In one aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine, and
(iii) one or more pharmaceutically acceptable excipients.

In another aspect, the present specification relates to a topical composition comprising:
(i) eberconazole,
(ii) pramoxine, and
(iii) one or more pharmaceutically acceptable excipients.

In yet another aspect, the present specification relates to a topical composition comprising:
(i) luliconazole,
(ii) pramoxine, and
(iii) one or more pharmaceutically acceptable excipients.

In one aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine, and
(iii) one or more alkalizing agents.

In one aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine, and
(iii) one or more alkalizing agents, wherein pH of the composition is about 4.5 to about 6.5.

In yet another aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine,
(iii) one or more vehicles, and
(iv) one or more emulsifying agents.

In yet another aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine,
(iii) one or more vehicles,
(iv) one or more emulsifying agents, and
(v) one or more thickening agent.

In yet another aspect, the present specification relates to use of topical compositions for treating and preventing of dermatophyte infections or tinea infections, eczema, inflamed skin, for the relief of itching or pruritis and the restoration of the affected areas of skin to a normal condition.

In yet another aspect, the present specification relates to topical compositions of antifungal agent and pramoxine for the treatment of dermatophitic infections, wherein the composition results in reduced intensity of itching associated with underlying infection.
BRIEF DESCRIPTION OF FIGURES

Figure: 1 : Comparative IVRT study between the present invention (Example 1) and commercially available Ebernet® cream.

DESCRIPTION OF THE INVENTION

The present specification relates to topical compositions comprising antifungal agents and pramoxine and process for preparing such compositions.

In one aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine, and
(iii) one or more pharmaceutically acceptable excipients.

In another aspect, the present specification relates to a topical composition comprising:
(i) eberconazole,
(ii) pramoxine, and
(iii) one or more pharmaceutically acceptable excipients.

In yet another aspect, the present specification relates to a topical composition comprising:
(i) luliconazole,
(ii) pramoxine, and
(iii) one or more pharmaceutically acceptable excipients.

In one aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine, and
(iii) one or more alkalizing agents.

In one aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine, and
(iii) one or more alkalizing agents, wherein pH of the composition is about 4.5 to about 6.5.

In yet another aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine,
(iii) one or more vehicles, and
(iv) one or more emulsifying agents.

In yet another aspect, the present specification relates to a topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine,
(iii) one or more vehicles,
(iv) one or more emulsifying agents, and
(v) one or more thickening agent.

As used herein, the term “topical" is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders. Topical administration, in contrast to transdermal administration, primarily provides a local rather than a systemic effect.

The term "composition" is intended to encompass a combination including one or more active ingredients and pharmaceutically acceptable excipients.The excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and are acceptable for veterinary use as well as human pharmaceutical or cosmetic use. The term includes both one and more than one such excipients. The topical composition of the present specifications may be in the form of lotions, liquids, creams, gel, ointments, liniments, spray etc. that are suitable for topical administration.

The term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or "a little below" the endpoint. As used herein, the term "about" means a slight variation of the value specified, preferably within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present application.

The topical compositions of the present specification comprising one or more antifungal agents and pramoxine and pharmaceutically acceptable excipients.

As used herein, the term “antifungal agents” includes the agents which are used inthe treatment or prevention of dermatophyte infections or tinea infections or fungal infection. Typically the antifungal agents are selected from azoles group including triazoles and allylamines group. Examples of topical azoles include but not limited to eberconazole, econazole, ketoconazole, clotrimazole, miconazole, oxiconazole, sulconazole, sertaconazole, fenticonazole, luliconazole, fluconazole, bifonazoletioconazole, effinaconazole or pharmaceutically acceptable salts thereof. Examples of topical allylamines include but not limited to e.g. naftifine, terbinafine. Other antifungal agents include tavaborole, ciclopiroxolamine, tolnaftate etc. The amount of antifungal agents employed in the composition is in the range of about 0.1% to about 10% (w/w), 0.5% to 5% (w/w) of total composition, e.g. 1% (w/w).

In an embodiment of present specification, said antifungal agent is eberconazole. As used herein, the term "eberconazole" includes eberconazole or any pharmaceutically acceptable salts or esters or derivatives thereof, e.g. eberconazole nitrate. The amount of eberconazole or any pharmaceutically acceptable salts or esters or derivatives thereof employed in the composition is in the range of about 0.1 % to about 5% (w/w), 0.1 % to 2 % (w/w) of total composition, e.g. 1 % (w/w).

In another embodiment of present specification, said antifungal agent is luliconazole or any pharmaceutically acceptable salts or esters or derivatives thereof. The amount of luliconazole or any pharmaceutically acceptable salts or esters or derivatives thereof employed in the composition is in the range of about 0.1 % to about 10% (w/w), 0. 1 % to 5 % (w/w) of total composition, e.g. 1 % (w/w).

As used herein, the term "pramoxine" includes pramoxine or any pharmaceutically acceptable salts or esters or derivatives thereof, e.g. pramoxine hydrochloride. The amount of pramoxine or any pharmaceutically acceptable salts or esters or derivatives thereof employed in the composition is in the range of about 0.1 % to about 5% (w/w), 0. 1 % to 2 % (w/w) of total composition, e.g. 1 % (w/w).

Useful pharmaceutical acceptable excipients of the present specification include, but are not limited to vehicles or diluents, plasticizers, film forming agents, chelating agents, thickening or gelling agents, neutralizers, emulsifying agents, emollients, humectants, preservatives, antioxidants, solvents, fragrance imparting agents, and the like, including any combinations of two or more thereof.

The topical compositions of the present specification may comprise a vehicles or diluents or solvents. Suitable vehicles include hexylene glycol, propylene glycol, polyethylene glycol, water or mixtures thereof. Preferred vehicles includes propylene glycol and water mixture. The amount of vehicles employed in the composition is in the range of about 1% to about 80% (w/w) of total composition, e.g. 50% (w/w), 70% (w/w).

The topical compositions of the present specification include one or more emulsifying agents. Examples of emulsifying agents that are useful for preparing compositions of the present specification include, but are not limited to, sodium lauryl sulfate, sodium laureth sulfate (or sodium lauryl ether sulfate), polysorbate 60, polysorbate 80, emulsifying wax, fatty acids having 12-18 carbon atoms, such as undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, cetostearyl alcohol, isostearic acid, aracel, oleic acid, decyloleate, hydroxyoleic acid, linoleic acid, and their derivatives, glyceryl stearate, polyglycol esters of fatty acids (C12-20), propylene glycol monostearate, sorbitanmonolaurate, sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate or sorbitantrioleate or mixtures thereof.In some embodiments, the emulsifying agent includes mixture of glyceryl stearate and polyethylene glycol-100 stearate (ARLACEL 165). Useful emulsifying agents further include cetyl alcohol, acacia, carbomers, carrageenan, cetostearyl alcohol, ceresin wax, and any combinations thereof.

The topical compositions of the present specification may comprise an emollient. Suitable emollients include, for example, stearyl alcohol, formaldehyde glycerine, glyceryl monooleate, glyceryl monoricinoleate, glyceryl monostearate, cetyl alcohol, ispropylisostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyloleate, octadecan-2-ol, isocetyl alcohol, cetylpalmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin alcohol, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, medium-chain triglycerides, butyl myristate, isostearic acid, palmitic acid, isopropyl linoieate, lauryl lactate, myristyl lactate, decyloleate, myristylmyristate, and mixture thereof. In some embodiments the emollient includes mixture of polysorbate 80, cetyl acetate, stearyl acetate, oleyl acetate acetylated lanolin alcohol (Crodalan AWS).

The topical compositions of the present specification may further comprise a humectant. Examples of humectants that are useful in the context of the present invention include, but are not limited to, glycerin, propylene glycol, cyclomethicones, dimethicones, sorbitol, xylitol, urea, sugars and starches, sugar and starch derivatives (e.g., alkoxylated glucose), D-panthenol, hyaluronic acid, lactamidemonoethanolamine, acetamidemonoethanolamine, 2-pyrrolidone-5-carboxylic acid, urea, and any mixtures thereof.

The topical compositions of the present specification may further comprise a thickener. Suitable thickeners include carboxylic acid polymers like carbomers (e.g. Carbopol.RTM. 954), polyacrylamides, acrylates/vinyl neodecanoatecrosspolymer (e.g. Aculyn 38), medium-chain triglycerides, stearic acid, sorbitanmonostearate, natural gums (e.g. guar, xanthan), cellulose derivatives (e.g. carboxy methylcellulose, methyl cellulose), PEG 6000, polyvinyl alcohol and mixtures thereof. The thickener could be pH dependent or pH independent.

The topical compositions of the present specification include one or more alkalizing agents. Suitable examples of alkalizing agents that may be used in the present application include, but are not limited to, primary, secondary and tertiary aliphatic amines, ethanolamines such as triethanolamine (TEA), diethanolamine (DEA), monoethanolamine (MEA), and the hydroxide of alkaline metals, such as sodium hydroxide, potassium hydroxide and the like. Preferred alkalizing agents include triethanolamine (trolamine), the hydroxide of alkaline metals. The alkalizing agent helps to stabilize the antifungal agent and pramoxine in a single composition. The use of such alkalizing agents also aids to maintain the pH of the composition which is suitable to apply topically. The pH of the compositions can range from about 4 to about 10, but preferably is in the range of about 5 to about 8, most preferably is in the range of about 4.5to about 6.5.

The topical compositions of the present specification may further comprise one or more penetration enhancing agents. Suitable examples of penetration enhancing agent that may be used in the present specification include, but are not limited to, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether; dialkyl ethers and dialkyl ether esters such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, and ethylene glycol methyl ether acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate, isopropyl myristate, dimethyl sulfoxide (DMSO), oleic acid, oleyl alcohol, limonene, pramoxine or any suitable combinations thereof.

The topical compositions of the present specification may comprise one or more preservatives. Suitable examples of preservatives, that may be used in the present application include, but are not limited to, aliphatic or aromatic alcohols; glycols; parahydroxybenzoic acid derivatives (e.g. parabens); Vitamin E or its derivatives, ethyl alcohol, benzyl alcohol, propylene glycol, glycerin, benzoic acid/sodium benzoate, sorbic acid, methylparaben, propylparaben, benzalkonium chloride, bronopol, chlorhexidine, chlorocresol and its derivatives, mixture of methylisothiazolinone and phenoxyethanol (NEOLONE™ PE), phenoxyethanol, ethylic alcohol, phenethylic alcohol, potassium sorbate, diazolidinylurea, benzylic alcohol or combinations thereof.

The topical compositions of the present specification may include one or more antioxidants. The antioxidant may be selected from DL-alpha-tocopherol, butylhydroxy toluene (BHT), butylhydroxy anisole (BHA), ascorbylpalmitate, ascorbic acid, propyl gallate, or mixtures thereof. In some embodiments, the antioxidant may be pramoxine or any pharmaceutically acceptable salts or esters or derivatives thereof.

The topical compositions of the present specification may contain additional ingredients to improve the composition. Such ingredients include film formers, chelating agents, and buffering agents. Examples of such ingredients are well known in the art.

The topical compositions of the present specification can be manufactured using a method comprising:
a) preparing an aqueous phase by combining water soluble ingredients in warm water, and adding preservative;
b) adding the pramoxine in to the aqueous phase of step a) and dispersing it well;
c) preparing an oil phase by combining the oil soluble ingredients and heated upto 65°C -70°C and mixed it well;
d) adding the antifungal agents in to the oil phase of step c) and mixing it well;
e) preparing an emulsified bulk phase by combining the aqueous phase of step b) and the oil phase of step d), followed by stirring and homogenization.
f) adding required amount of alkalizing agents in to the emulsified bulk phase of step e) and mixing it well.
g) subsequently adding the thickening agents in to step f) with continuous stirring and homogenization.

The topical compositions of the present specification can also be manufactured using a method comprising:
a) preparing an aqueous phase by combining water soluble ingredients in warm water;
b) adding the pramoxine or pharmaceutically acceptable salts thereof in to the aqueous phase of step a) and dispersing it well;
c) preparing an oil phase by combining the oil soluble ingredients and heated up to 65°C -70°C and mixed it well;
d) adding the antifungal agents in to the oil phase of step c) and mixing it well;
e) preparing an emulsified bulk phase by combining the aqueous phase of step b) and the oil phase of step d), followed by stirring and homogenization.
f) adding required amount of alkalizing agents in to the emulsified bulk phase of step e) and mixing it well.

The term “aqueous phase” as referred herein includes vehicles or diluents or solvents or any other water soluble ingredients. The term “oil phase” as referred herein includes emulsifying agents, emollients or any other oil soluble ingredients.

The topical compositions of the present specification can be part of a kit or device and may be filled into tubes, jars, bottles, aerosol containers, and any other forms of packaging that facilitate application topically. The compositions are meant to be applied topically, either manually or by using a convenient applicator, for patient compliance and ease of application. The dose, number, and frequency of applications can be determined by a person skilled in the art of treating conditions, such as a physician, a dermatologist, and the like.

Laminated tubes may be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf life, excellent barrier properties, excellent sealability, resistance to print bleeding, tamper evident closures with nozzle seals available, and hot foil stamping. HDPE tubes may also be used for packaging. Examples are pre-printed monolayer plastic tubes made of LDPE/LLDPE blends by extrusion processes and fitted with snap-on flip caps made up of polypropylene.

The topical compositions of the present specification comprising antifungal agent and pramoxine can be used for the treatment of dermatophytic infections, wherein the composition results in reduced intensity of itching or irritation associated with underlying infection.The topical composition can be administered once daily or twice daily as required to the patient in need thereof.

The topical composition of the present specification can be used for treating and preventing dermatophyte infections or tinea infections, eczema, inflamed skin, for the relief of itching or pruritis and the restoration of the affected areas of skin to a normal condition.

The topical compositions of present specification are expected to reduce the pruritis associated with dermatophytic infections that are expected to reduce severity score.Various markers which are normally available to person of ordinary skill can be utilized establish change in intensity of itch either determined by VAS or by 5-D itch score or any other suitable method including but not limited to mycological clinical assessment. Reduction in erythema by VAS scale could also be one of the markers in determining the efficacy of the said composition.

The specification will now be described in greater detail by reference to the following non-limiting examples.

EXAMPLES

Examples A: Topical composition comprising Eberconazole & Pramoxine

Sr. No. Name of Ingredients Example 1
% w/w Example 2
% w/w Example 3
% w/w
1 Eberconazole Nitrate 1.19 1.19 1.19
2 Methyl Paraben 0.25 0.25 0.50
3 Pramoxine Hydrochloride 1 1 1.5
4 Emulsifying Cetostearyl alcohol (Type A) 10 15 15
5 Polyglycol esters - Fatty acids C12-20 4 2 5
6 Decyloleate 5 5 5
7 Propylene glycol 5 3 -
8 Hexylene glycol - - 5
9 Formaldehyde glycerine 2 2 1
10 Glycerine 2 2 -
11 Polyacrylamide 3 2 2
12 Trolamine 0.65 0.7 -
13 sodium hydroxide - - 0.5
14 Purified water 65.91 65.86 63.31

Process:
Aqueous phase preparation:
1. Purified water was taken in a main manufacturing vessel and heated to 65°C±10°C under stirring.
2. Glycerine, propylene glycol/hexylene glycol, and methyl paraben were added to the aqueous phase of step 1and mixed well.
3. Pramoxine hydrochloride was added to the aqueous phase of step 2 and mixed well.

Oil phase preparation:
4. Decyloleate was taken in to the dry oil phase vessel and heated to 65°C±10°C under stirring.
5. Polyglycol esters - Fatty acids C12-20 was added to the above mixture.
6. Emulsifying cetostearyl alcohol was added to the step 2 and mixed well.
7. Eberconazole nitrate was added to formaldehyde glycerin and the mixture was added to the oil phase of step 2 and stirred until a uniform dispersion was formed.

Emulsification phase:
8. Aqueous phase of step 3 was added slowly to Oil phase of Step 7 and homogenized slowly at 65°C±10°C.
9. Trolamine/sodium hydroxide was added to the emulsified phase of step 8 and maintained the bulk temperature to 65°C±10°C.
10. Subsequently the Polyacrylamide was added to step 9 and homogenized well and maintained the bulk temperature to 65°C±10°C.
11. Finally the bulk phase was cooled to 40-45°C with stirring.

Examples B: Topical composition comprising Luliconazole & Pramoxine

Sr. No. Name of Ingredients Example 4
% w/w Example 5
% w/w
1 Luliconazole 1 1
2 Methylparaben 0.14 -
3 Benzyl alcohol 1 2.5
4 Polysorbate 60 1 3
5 Cetostearyl alcohol 7 7
6 Propylene glycol 5 5
7 Isopropyl Myristate 3.5 5
8 Butylatedhydroxytoluene 0.05 0.05
9 Medium chain triglyceride 1 6
10 Stearic acid 5 -
11 Sorbitanmonostearate - 2
12 Sodium Hydroxide 0.15 0.11
13 Pramoxine Hydrochloride 1 1
14 Purified water 74.16 68.89

Process:
Aqueous phase preparation:
1. Purified water was taken in a main manufacturing vessel and heated to 65°C±10°C under stirring.
2. Pramoxine hydrochloride was added to the aqueous phase of step 1 and mixed well.
Oil phase preparation:
3. Polysorbate 60, cetostearyl alcohol, isopropyl myristate, butylatedhydroxytoluene, medium chain triglycerides, methylparaben, stearic acid, sorbitanmonostearate, propylene glycol were taken in to the dry oil phase vessel and heated to 70°C-75°C to form a clear colorless melted phase.
4. Luliconazole was added to the oil phase of step 3 and stirred until a uniform dispersion is formed.

Emulsification phase:
5. Oil phase of step 4 was added slowly in to the aqueous phase of Step 2 and homogenized slowly at 65°C±10°C.
6. The bulk phase of step 5 was cooled to 40-45°C with stirring.
7. Subsequently Benzyl alcohol was added into step 6 and mixed for 20min.
8. Sodium Hydroxide was added to the emulsified phase of step 7.
9. Finally the bulk phase was cooled to 30°C with stirring.

Stability study

The stability of the topical compositions of present specification were evaluated through accelerated stability studies. Compositions were prepared according to the formula and process of example 1 &5, and the composition were subjected to stability study at various temperature and humidity conditions. Table 1 &2 represents the study result data respectively. The compositions were found to be stable at accelerated conditions.

Table 1: Stability data of the topical composition comprising Eberconazole & Pramoxine (example 1)

Conditions Test Parameter Assay (%) Related substance (%) pH
Eberconazole Methyl Paraben Pramoxine HCl Highest unknown Total imp
Specification/
Interval (Month) (90.0-110.0) %w/w NMT 0.5 %w/w NMT 2.0 %w/w 4.5 -6.5
Initial 103.9 102.3 101.6 0.0 0.1 5.2
25°C/60%RH 1M 100.1 99.8 99.7 0.0 0.1 5.2
3M 103.8 102.3 100.7 0.0 0.1 5.3
6M 101.6 101.2 101.5 0.1 0.3 5.2
30°C/75%RH 1M 101.2 100.8 96.4 0.0 0.1 5.3
3M 103.2 102.0 100.2 0.0 0.1 5.3
6M 101.7 101.3 101.2 0.1 0.3 5.4
40°C/75%RH 1M 101.9 101.4 96.9 0.0 0.2 5.2
3M 103.5 102.2 99.3 0.0 0.1 5.3
6M 101.3 101.2 99.6 0.2 0.4 5.3

Table 2: Stability data of the topical composition comprising Luliconazole& Pramoxine (example 5)

Conditions Test Parameter Assay (%) Assay (%) Related substance (%) pH
Luliconazole Pramoxine HCl BHT Benzyl Alcohol Total imp
Specification/
Interval (Month) NLT 90.0% & NMT 110% NLT 80.0% & NMT 110.0% NMT 2.0 %w/w 4.5 -6.5
Initial 96.80 96.70 96.40 95.70 0.20 5.56
25°C/60%RH 1M 96.60 99.00 96.10 94.30 0.20 5.48
2M 96.70 97.50 96.20 92.90 0.19 5.50
3M 97.40 98.01 96.44 93.80 0.21 5.61
30°C/75%RH 1M 97.60 98.20 95.00 95.00 0.21 5.48
2M 96.20 97.20 95.40 92.30 0.21 5.53
3M 97.80 97.96 96.32 95.20 0.20 5.57
40°C/75%RH 1M 96.10 96.60 90.90 93.60 0.26 5.47
2M 96.90 97.10 92.20 91.70 0.31 5.58
3M 98.30 98.34 90.80 95.40 0.37 5.48

Comparative In Vitro-release Test (IVRT) study:

The effectiveness of the topical composition of present specification was evaluated through in vitro release testing method (IVRT) by using an automatic Franz diffusion cells (Hanson) assembled with a non-interactive synthetic membrane and results was compared with the reference product (Ebernet® cream 1% eberconazole marketed by Dr. Reddy’s Laboratories Ltd.). A composition was prepared according to the formula and process of example 1 and a sample of 300mg of the said composition was applied over the membrane in the donor cell, spreaded uniformly and the donor compartment was covered with glass disk and clamped properly. Subsequently the receptor cells was filled with receptor media (water : ethanol (30:70)) and programmed experiment was started. The sample was collected at different time points and injected in the HPLC system to determine the amount of eberconazole release. Similar test was performed for the reference product. The chromatographic analysis of drug release (eberconazole nitrate) indicates that the topical compositions comprising eberconazole nitrate and pramoxine hydrochloride according to the present specification has increased the drug release compared to the reference product (Figure 1). This IVRT data demonstrates that pramoxine hydrochloride and eberconazole nitrate combination has improved penetration of the drug in to the skin/membrane when compared to eberconazole alone, thereby would expect to increase the efficacy of the drug product.
,CLAIMS:We Claim:
1. A topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine or pharmaceutically acceptable salts thereof, and
(iii) one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein said antifungal agent is selected from one or more of eberconazole, econazole, ketoconazole, clotrimazole, miconazole, oxiconazole, sulconazole, sertaconazole, fenticonazole, luliconazole, fluconazole, bifonazoletioconazole, effinaconazole, naftifine, terbinafine, tavaborole, ciclopiroxolamine, tolnaftate or pharmaceutically acceptable salts thereof or combinations thereof.
3. The composition of claim 2, wherein the antifungal agent is eberconazole or luliconazole or pharmaceutically acceptable salts thereof.
4. The composition of claim 1, wherein said composition further comprising one or more alkalizing agents.
5. The composition of claim 4, wherein said alkalizing agents are selected from one or more primary, secondary and tertiary aliphatic amines, ethanolamines, triethanolamine and the hydroxide of alkaline metals or mixtures thereof.
6. The composition of claim 4, wherein the alkalizing agents is triethanolamine or sodium hydroxide.
7. The composition of claim 4, wherein pH of the composition is about 4.5 to about 6.5.
8. The composition of claim 1, wherein said excipients comprising one or more vehicles, and one or more emulsifying agents.
9. The composition of claim 8, wherein said vehicles are selected from one or more of hexylene glycol, propylene glycol, polyethylene glycol, water or mixtures thereof.
10. The composition of claim 8, wherein said emulsifying agents are selected from one or more of sodium lauryl sulfate, sodium laureth sulfate, polysorbate 60, polysorbate 80, emulsifying wax, undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, cetyl alcohol, cetostearyl alcohol, isostearic acid, aracel, oleic acid, decyloleate, hydroxyoleic acid, linoleic acid, glyceryl stearate, polyglycol esters of fatty acids (C12-20), propylene glycol monostearate, sorbitanmonolaurate, sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate or sorbitantrioleate, glyceryl stearate and polyethylene glycol-100 stearate, acacia, carbomers, carrageenan, ceresin wax or mixtures thereof.
11. The use of topical composition as claimed in claim 1 in a patient in need thereof for the treatment of dermatophyte infections or tinea infections, eczema, inflamed skin, for the relief of itching or pruritis and the restoration of the affected areas of skin to a normal condition.
12. The composition of claim 1, wherein said composition is adminstered topically once daily to a patient in need thereof.
13. A process for preparing a topical composition comprising one or more antifungal agent and pramoxine or pharmaceutically acceptable salts thereof, wherein said process comprises steps of:
a) preparing an aqueous phase by combining water soluble ingredients,
b) adding the pramoxine or pharmaceutically acceptable salts thereof in to the aqueous phase of step a,
c) preparing an oil phase by combining the oil soluble ingredients,
d) adding the antifungal agents in to the oil phase of step c,
e) preparing an emulsified bulk phase by combining the aqueous phase of step b and the oil phase of step d,
f) adding the alkalizing agents in to the emulsified bulk phase of step e.

14. The process as claimed in claim 13, wherein said alkalizing agents are selected from one or more primary, secondary and tertiary aliphatic amines, ethanolamines, triethanolamine and the hydroxide of alkaline metals or mixtures thereof.

15. The process as claimed in claim 13, wherein pH of the the composition is about 4.5 to about 6.5.
We Claim:
1. A topical composition comprising:
(i) one or more antifungal agent,
(ii) pramoxine or pharmaceutically acceptable salts thereof, and
(iii) one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein said antifungal agent is selected from one or more of eberconazole, econazole, ketoconazole, clotrimazole, miconazole, oxiconazole, sulconazole, sertaconazole, fenticonazole, luliconazole, fluconazole, bifonazoletioconazole, effinaconazole, naftifine, terbinafine, tavaborole, ciclopiroxolamine, tolnaftate or pharmaceutically acceptable salts thereof or combinations thereof.
3. The composition of claim 2, wherein the antifungal agent is eberconazole or luliconazole or pharmaceutically acceptable salts thereof.
4. The composition of claim 1, wherein said composition further comprising one or more alkalizing agents.
5. The composition of claim 4, wherein said alkalizing agents are selected from one or more primary, secondary and tertiary aliphatic amines, ethanolamines, triethanolamine and the hydroxide of alkaline metals or mixtures thereof.
6. The composition of claim 4, wherein the alkalizing agents is triethanolamine or sodium hydroxide.
7. The composition of claim 4, wherein pH of the composition is about 4.5 to about 6.5.
8. The composition of claim 1, wherein said excipients comprising one or more vehicles, and one or more emulsifying agents.
9. The composition of claim 8, wherein said vehicles are selected from one or more of hexylene glycol, propylene glycol, polyethylene glycol, water or mixtures thereof.
10. The composition of claim 8, wherein said emulsifying agents are selected from one or more of sodium lauryl sulfate, sodium laureth sulfate, polysorbate 60, polysorbate 80, emulsifying wax, undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, cetyl alcohol, cetostearyl alcohol, isostearic acid, aracel, oleic acid, decyloleate, hydroxyoleic acid, linoleic acid, glyceryl stearate, polyglycol esters of fatty acids (C12-20), propylene glycol monostearate, sorbitanmonolaurate, sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate or sorbitantrioleate, glyceryl stearate and polyethylene glycol-100 stearate, acacia, carbomers, carrageenan, ceresin wax or mixtures thereof.
11. The use of topical composition as claimed in claim 1 in a patient in need thereof for the treatment of dermatophyte infections or tinea infections, eczema, inflamed skin, for the relief of itching or pruritis and the restoration of the affected areas of skin to a normal condition.
12. The composition of claim 1, wherein said composition is adminstered topically once daily to a patient in need thereof.
13. A process for preparing a topical composition comprising one or more antifungal agent and pramoxine or pharmaceutically acceptable salts thereof, wherein said process comprises steps of:
a) preparing an aqueous phase by combining water soluble ingredients,
b) adding the pramoxine or pharmaceutically acceptable salts thereof in to the aqueous phase of step a,
c) preparing an oil phase by combining the oil soluble ingredients,
d) adding the antifungal agents in to the oil phase of step c,
e) preparing an emulsified bulk phase by combining the aqueous phase of step b and the oil phase of step d,
f) adding the alkalizing agents in to the emulsified bulk phase of step e.

14. The process as claimed in claim 13, wherein said alkalizing agents are selected from one or more primary, secondary and tertiary aliphatic amines, ethanolamines, triethanolamine and the hydroxide of alkaline metals or mixtures thereof.

15. The process as claimed in claim 13, wherein pH of the the composition is about 4.5 to about 6.5.