DESC:BACKGROUND OF THE INVENTION
Most of the topical diseases or disorders are results of inflammation caused by bacterial, fungal, viral infection. The most common topical diseases or disorders include eczema, psoriasis and dermatitis, including contact dermatitis, atopic dermatitis and seborrheic dermatitis. Dermatitis results from inflammatory processes that involve the upper dermis and epidermis of the skin.

Infections are caused by fungal, viral and microbial agents. Infections are treated systematically or topically by applying or using active agents in the form of creams, gels or ointments. Most commonly used active agents are antibiotic agents, antifungal agents, steroidal agents and/or antibacterial agents.

Antibiotics are the drugs which are used to treat bacterial infections. An antibiotic such as nadifloxacin is used to treat bacterial skin infections. The Nadifloxacin has chemical name (RS)-9-Fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid and has structural formula I:

Formula I: Nadifloxacin

Nadifloxacin is a topical fluroquinolone with broad spectrum activity against gram positive, negative and anaerobic organisms. Nadifloxacin inhibits the enzyme DNA gyrase that is involved in bacterial DNA synthesis and replication, thus inhibiting the bacterial multiplication.

Topical steroids in combination with anti-infectives are used to treat topical infections (generally skin infections) that have an inflammatory component. Steroids are extremely effective anti-inflammatory agents. They suppress various parts of the inflammatory reaction. Different topical steroids have different potency ranging from mild to very potent topical steroids. Mometasone Furoate is used as a topical steroidal anti-inflammatory agent. Like other corticosteroids, mometasone furoate possesses anti-inflammatory, antipruritic, and vasoconstrictive properties. Mometasone Furoate has chemical name 9a,21-dichloro-11ß,17-dihydroxy-16a-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) and has structural formula II:

Formula II: Mometasone furoate

Mometasone is a moderately potent topical steroid and often the first line and most commonly prescribed in dermatitis. Mometasone has good efficacy, minimal systemic penetration and good tolerability profile.

An antifungal agent is a drug that selectively eliminates fungal pathogens. As an antifungal, terbinafine is now being prescribed as first line agent due to its different mechanism of action and lesser resistance as compared to azole group. Terbinafine is mainly effective on the dermatophyte group of fungi. Terbinafine hydrochloride has chemical name (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1- naphthalene methanamine hydrochloride. and has structural formula III:

Formula III: Terbinafine HCl

Antifungal agents work by exploiting differences between mammalian and fungal cells to kill the fungal organism with fewer adverse effects to the host.

The combination of antifungal agents with a corticosteroid has been disclosed for the topical treatment of fungal diseases. The steroids may induce fungal spores to be more sensitive to treatment by an antifungal agent.

It would be advantageous to have a formulation that retains the advantages of combining an agent useful for treating fungal diseases with a steroid capable of reducing the associated inflammation, with the ability to rapidly eradicate fungal infections and eliminate the symptoms thereof, and as a consequence minimize the risk of undesirable side effects.

Combining two or more active ingredients in one pharmaceutical unit to improve patient compliance is known in literature. It can be either in the form of two or more active ingredients in immediate release form or a combination of immediate release and modified release form.

US publication number 20140057881A1 relates to topical composition for the treatment of skin conditions. The composition comprises an antifungal agent, an anti-inflammatory agent and an antimicrobial agent together with pharmaceutically acceptable excipients.

US Publication number 20120046259A1 relates to compositions comprising an antibiotic (quinolone or naphthyridinone), corticosteroid, and organic acid.

US Publication number 20130296387A1 relates to non-aqueous pharmaceutical formulations containing an anti-microbial agent for topical use. The anti-microbial agent covers in the invention can be anti-fungal agent, an antibiotic, an antiseptic, an antiviral or an anti-protozoal. The invention also covers terbinafine as antifungal agent and nadifloxacin as antibiotic agent.

US publication number 20150079175A1 relates to a topical pharmaceutical composition comprising a combination of methotrexate, alpha bisabolol and allantoin.

The prior arts teach various pharmaceutical compositions for topical application of dosage form and process of preparing the composition, but there exist a need to develop a formulation having excellent storage stability.

The inventors of the invention surprisingly found that it is possible to develop composition comprising combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients having excellent storage stability. This invention also provides stable pharmaceutical composition for topical use to subject.

SUMMARY OF THE INVENTION
The invention provides topical pharmaceutical composition comprising a combination of antibiotic agent, antifungal agent and steroid agent; specifically composition comprises combination of nadifloxacin, terbinafine and mometasone or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients.

This combination of the antibiotic, antifungal agent and the steroid demonstrates excellent storage stability and can be used for the treatment of mixed infections and dermatitis to subject. Further, the invention also provides process for preparing pharmaceutical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof.

In one general aspect, there is provided a topical composition comprising:
a) at least one anti-inflammatory agent,
b) at least one antifungal agent, and
c) at least one antimicrobial agent with one or more pharmaceutically acceptable excipient.

In another general aspect, there is provided a topical skin cream composition comprising:
a) about 0.05% w/w to about 0.20% w/w of anti-inflammatory agent,
b) about 0.5% w/w to about 2% w/w of antifungal agent,
c) about 0.5% w/w to about 2% w/w of antimicrobial agent, and
d) one or more pharmaceutically acceptable excipient; wherein the said composition is used for the treatment of a skin condition.

In another general aspect, there is provided a topical skin cream composition comprising:
a) about 0.01% w/w of anti-inflammatory agent,
b) about 1% w/w of antifungal agent,
c) about 1% w/w of antimicrobial agent, and
d) one or more pharmaceutically acceptable excipient; wherein the said composition is used for the treatment of a skin condition.

In another aspect, there is provided a topical composition comprises at least one antimicrobial agent; wherein the said antimicrobial agent is preferably nadifloxacin or pharmaceutically acceptable salt thereof.

In another aspect, there is provided a topical composition comprises at least one anti-inflammatory agent; wherein the said anti-inflammatory agent is preferably mometasone furoate.

In another aspect, there is provided a topical composition comprises at least one antifungal agent; wherein the said antifungal agent is preferably terbinafine hydrochloride.

In another general aspect, there is provided topical pharmaceutical composition comprising:
(a) nadifloxacin or pharmaceutically acceptable salt thereof,
(b) mometasone or pharmaceutically acceptable salt thereof,
(c) terbinafine or pharmaceutically acceptable salt thereof, and
(d) one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients are selected from group of emollients, viscosity modifying agent, humectants, stiffening agent, antioxidant, preservative, soothening agent, pH regulator or modifier, emulsifiers or mixture thereof and suitable solvent or vehicle.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of the nadifloxacin present in the composition ranges from about 0.5% w/w to about 2%w/w of the composition.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein amount of the mometasone furoate present in the composition ranges from about 0.05% w/w to about 0.20%w/w of the composition.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein amount of the terbinafine hydrochloride present in the composition ranges from about 0.5% w/w to about 2%w/w of the composition.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients comprises preservatives in the range of about 0.01% w/w to about 0.5% w/w of the composition.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients comprises emollient in the range of about 0.05% w/w to about 20.0% w/w of the composition.

In another general aspect, there is provided a topical composition comprising a combination of active agents or its pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients comprises humectant in the range of about 9% w/w to about 25.0% w/w of the composition.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein pH of the composition maintain in range of about 2.0 to about 6.0.

In another general aspect, there is provided topical pharmaceutical composition comprising:
(a) about 1% w/v of nadifloxacin or pharmaceutically acceptable salt thereof,
(b) about 0.10% w/v of mometasone or pharmaceutically acceptable salt thereof,
(c) about 1% w/v of terbinafine or pharmaceutically acceptable salt thereof, and
(d) one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided topical pharmaceutical composition comprising:
a) 1% w/v of nadifloxacin or pharmaceutically acceptable salt thereof,
b) 0.10% w/v of mometasone or pharmaceutically acceptable salt thereof,
c) 1% w/v of terbinafine or pharmaceutically acceptable salt thereof,
d) 15% w/v of liquid paraffin,
e) 15% w/v of propylene glycol, and
f) one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided topical pharmaceutical composition comprising 1% nadifloxacin, 0.10% mometasone furoate, 1% terbinafine hydrochloride, 15% liquid paraffin, 15% propylene glycol, 0.10% disodium edetate, 2% cetomacrogol, 7.20% cetostearyl alcohol, 3% microcrystalline wax, 0.03% vitamin-E, 0.18% methyl paraben, 0.02% propyl paraben, 0.10% activated dimethicone, 0.096% sodium hydroxide, 5% SalSphere SalCool and purified water.

In another general aspect, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides excellent stability in accelerated stability studies with low and high pH of the composition.

In another general aspect, there is provided a composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the present invention provides dosage form for topical application such as creams, ointments, gels, lotions, foams, powders, shampoos, liquid solutions.

In another general aspect, there is provided a composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the present invention provides dosage form for topical application as cream.

In another general aspect, there is provided a process for preparing topical skin cream composition comprising: about 0.5% w/w to about 2% w/w of antimicrobial agent, about 0.05% w/w to about 0.20% w/w of anti-inflammatory agent, and about 0.5% w/w to about 2% w/w of antimicrobial agent, wherein the said process comprises steps of:
a) preparation of aqueous phase and maintaining the temperature of aqueous phase to 73-75°C,
b) preparation of wax phase by heating at 85-90ºC under continuous stirring,
c) mixing of the aqueous phase and the wax phase, and
d) preparing dispersion of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof in purified water and mixing with step (c).

There is provided a process for preparing topical skin cream composition comprising: about 0.5% w/w to about 2% w/w of antimicrobial agent, about 0.05% w/w to about 0.20% w/w of anti-inflammatory agent, and about 0.5% w/w to about 2% w/w of antimicrobial agent, wherein the said process comprises steps of:
a) preparing an aqueous phase and maintaining the temperature of aqueous phase to 73-75°C,
b) preparing a wax phase by heating at 85-90ºC under continuous stirring,
c) mixing of the aqueous phase prepared in step (a) with the wax phase prepared in step (b) to form a uniform mixture,
d) preparing dispersion of the antifungal agent, the anti-inflammatory agent and the antimicrobial agent in purified water,
e) mixing of the solution prepared in step (d) with the uniform mixture of step (c), and
f) mixing one or more pharmaceutically acceptable excipients to the step (e).

In another general aspect, there is provided a process for preparing topical skin cream composition comprising: about 0.5% w/w to about 2% w/w of nadifloxacin, about 0.05% w/w to about 0.20% w/w of mometasone, and about 0.5% w/w to about 2% w/w of terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein said process comprises steps of:
a) preparation of aqueous phase and maintaining the temperature of aqueous phase to 73-75°C,
b) preparation of wax phase by heating at 85-90ºC under continuous stirring,
c) mixing of the aqueous phase and the wax phase,
d) preparing dispersion of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof in purified water and mixing with step (c), and
e) mixing of one or more pharmaceutically acceptable excipients to the step (d); wherein the aqueous phase comprises (i) purified water; (ii) disodium edetate; and optionally one or more pharmaceutically acceptable excipients and the wax phase comprises (i) heavy liquid paraffin; (ii) cetostearyl alcohol; (iii) microcrystalline wax; (iv) cetomacrogol 1000; (v) activated dimethicone; (vi) propylene glycol (vii) methyl paraben (viii) propyl paraben and optionally one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION
The terms "active," "active ingredient or ingredients" and “active agent or agents” are used interchangeably and are meant to refer to a substance intended to be delivered, the substance being capable of imparting a desired action or effect. Such substances include, but are not limited to, pharmaceuticals, medicaments, drugs, therapeutic agents, diagnostic agents, cosmetic agents, nutritional supplements and mixtures thereof. Without limiting the scope of the invention, such substances include pain relievers, cough and cold ingredients, anti-inflammatory, analgesic, antipyretic, anticholinergic or antispasmodics, antibiotics, sedatives, antifungal, steroid, stimulants, antihistamines, antiallergenic, diuretics, expectorants, hormones, antipsychotics, narcotics and mixtures thereof. More specifically such active agents include nadifloxacin, mometasone furoate and terbinafine hydrochloride.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, vehicle, suitable for administering or applying an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

The term “SalSphere” used as used herein refers to composition of water; glyceryl stearate, methyl diisopropyl propionamide, ethyl menthane carboxamide, menthyl lactate, butryospermum parkii (shea butter) extract, lauryl laurate, sorbitan stearate, searamidopropyl dimethylamine lactate, phenoxyethanol, and ethylhexyglycerin.

The term "mometasone " as used herein refers to mometasone base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof, more specifically mometasone is refers to mometasone furoate.

The term "terbinafine" as used herein refers to terbinafine base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof, more specifically terbinafine is refers to terbinafine hydrochloride.

The term "nadifloxacin" as used herein refers to terbinafine base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.

The term "subject" refers to an animal, preferably a human, who is the object of treatment, observation or experiment.

The term "skin condition" as used herein refers to disease related to skin infection or mixed infections and dermatitis.

The term “pharmaceutically acceptable salt” or “salt” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Such pharmaceutically acceptable salts thus includes but are not limited to acetate, hydrochloride salt, phenylacetate, trifluoroacetate, furoate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro phenylpropionate, salicylate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, xylenesulfonate, tartarate, and the like.

The invention provides topical pharmaceutical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients. This composition provides excellent storage stability and good tolerance. Further, the invention also provides process for preparing pharmaceutical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a topical composition comprises:
a) at least one anti-inflammatory agent,
b) at least one antifungal agent, and
c) at least one antimicrobial agent and one or more pharmaceutically acceptable excipient.

In another embodiment, there is provided a topical skin cream composition comprising:
a) about 0.05% w/w to about 0.20% w/w of anti-inflammatory agent,
b) about 0.5% w/w to about 2% w/w of antifungal agent,
c) about 0.5% w/w to about 2% w/w of antimicrobial agent, and
d) one or more pharmaceutically acceptable excipient; wherein the said composition is used for the treatment of a skin condition.

In another embodiment, there is provided a topical skin cream composition comprising:
a) about 0.01% w/w of anti-inflammatory agent,
b) about 1% w/w of antifungal agent,
c) about 1% w/w of antimicrobial agent, and
d) one or more pharmaceutically acceptable excipient; wherein the said composition is used for the treatment of a skin condition.

In another embodiment, there is provided a topical composition comprises (a) at least one antimicrobial agent; wherein the said antimicrobial agent is preferably nadifloxacin or pharmaceutically acceptable salt thereof, (b) at least one anti-inflammatory agent; wherein the said anti-inflammatory agent is preferably mometasone furoate, and (c) at least one antifungal agent; wherein the said antifungal agent is preferably terbinafine hydrochloride.

In another embodiment, there is provided a topical pharmaceutical composition comprising:
(a) nadifloxacin or pharmaceutically acceptable salt thereof,
(b) mometasone or pharmaceutically acceptable salt thereof,
(c) terbinafine or pharmaceutically acceptable salt thereof, and
(d) one or more suitable pharmaceutically acceptable excipients.

In another embodiment, there is provided a topical composition comprising:
(a) nadifloxacin or pharmaceutically acceptable salt thereof,
(b) mometasone or pharmaceutically acceptable salt thereof,
(c) terbinafine or pharmaceutically acceptable salt thereof with one or more suitable pharmaceutically acceptable excipients; wherein the composition is used topically.

In another embodiment, there is provided a composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients are selected from group of solvents or vehicles, emollients, viscosity modifying agent, humectants, stiffening agent, antioxidant, preservative, soothening agent, pH regulator or modifier and emulsifiers or mixture thereof.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of the nadifloxacin present in the composition ranges from about 0.5% w/w to about 2%w/w of the composition.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein amount of the mometasone furoate present in the composition ranges from about 0.05% w/w to about 0.20%w/w of the composition.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein amount of the terbinafine hydrochloride present in the composition ranges from about 0.5% w/w to about 2%w/w of the composition.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients comprises preservatives in the range of about 0.01% w/w to about 0.5% w/w of the composition.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients comprises emollient in the range of about 0.05% w/w to about 20.0% w/w of the composition.

In another embodiment, there is provided a topical composition comprising a combination of active agents or its pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the excipients comprises humectant in the range of about 9% w/w to about 25.0% w/w of the composition.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein pH of the composition maintain in range of about 2.0 to about 6.0.

In another embodiment, there is provided topical pharmaceutical composition comprising:
(a) about 1% w/v of nadifloxacin or pharmaceutically acceptable salt thereof,
(b) about 0.10% w/v of mometasone or pharmaceutically acceptable salt thereof,
(c) about 1% w/v of terbinafine or pharmaceutically acceptable salt thereof; and
(d) one or more suitable pharmaceutically acceptable excipients.

In another embodiment, there is provided topical pharmaceutical composition comprising:
a) 1% w/v of nadifloxacin or pharmaceutically acceptable salt thereof,
b) 0.10% w/v of mometasone or pharmaceutically acceptable salt thereof,
c) 1% w/v of terbinafine or pharmaceutically acceptable salt thereof,
d) 15% w/v of liquid paraffin,
e) 15% w/v of propylene glycol, and
f) one or more suitable pharmaceutically acceptable excipients.

In another embodiment, there is provided topical pharmaceutical composition comprising 1% nadifloxacin, 0.10% mometasone furoate, 1% terbinafine hydrochloride, 15% liquid paraffin, 15% propylene glycol, 0.10% disodium edetate, 2% cetomacrogol, 7.20% cetostearyl alcohol, 3% microcrystalline wax, 0.03% vitamin-E, 0.18% methyl paraben, 0.02% propyl paraben, 0.10% activated dimethicone, 0.096% sodium hydroxide, 5% SalSphere SalCool and purified water.

In another embodiment, there is provided a topical composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides excellent stability in accelerated stability studies with low and high pH of the composition.

In another embodiment, there is provided a composition comprising a combination of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the wherein the present invention provides dosage form for topical application such as creams, ointments, gels, lotions, foams, powders, shampoos, liquid solutions. Specifically the present invention provides topical dosage form in the form of cream.

There is provided a process for preparing topical skin cream composition comprising: about 0.5% w/w to about 2% w/w of nadifloxacin, about 0.05% w/w to about 0.20% w/w of mometasone, and about 0.5% w/w to about 2% w/w of terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the said process comprises steps of:
a) preparing an aqueous phase and maintaining the temperature of aqueous phase to 73-75°C,
b) preparing a wax phase by heating at 85-90ºC under continuous stirring,
c) mixing of the aqueous phase prepared in step (a) with the wax phase prepared in step (b) to form a uniform mixture,
d) preparing dispersion of the antifungal agent, the anti-inflammatory agent and the antimicrobial agent in purified water,
e) mixing of the solution prepared in step (d) with the uniform mixture of step (c), and
f) mixing one or more pharmaceutically acceptable excipients to the step (e).

In another embodiment, there is provided a process for preparing topical skin cream composition comprising: about 0.5% w/w to about 2% w/w of nadifloxacin, about 0.05% w/w to about 0.20% w/w of mometasone, and about 0.5% w/w to about 2% w/w of terbinafine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the said process comprises steps of:
a) preparation of aqueous phase and maintaining the temperature of aqueous phase to 73-75°C,
b) preparation of wax phase by heating at 85-90ºC under continuous stirring,
c) mixing of the aqueous phase and wax phase by heating at 85-90ºC under continuous stirring,
d) preparing dispersion of nadifloxacin, mometasone and terbinafine or pharmaceutically acceptable salt thereof in purified water and mixing with step (c), and
e) mixing of one or more pharmaceutically acceptable excipients to the step (d); wherein the aqueous phase comprises (i) purified water; (ii) disodium edetate; and optionally one or more pharmaceutically acceptable excipients and the wax phase comprises (i) heavy liquid paraffin; (ii) cetostearyl alcohol; (iii) microcrystalline wax; (iv) cetomacrogol 1000; (v) activated dimethicone; (vi) propylene glycol (vii) methyl paraben (viii) propyl paraben and optionally one or more pharmaceutically acceptable excipients.

Examples of emollients used in the composition of present invention are selected from group comprises but are not limited to white petrolatum, mineral oil, propylene glycol dicaprylate, lower fatty acid esters and lower alkyl ethers of propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, liquid paraffin (heavy) IP, activated dimethicone, cetyl esters wax, spermaceti wax, and white wax or mixture thereof.

Examples of humectants used in the composition of present invention are selected from group comprises but are not limited to glycerin and sorbitol; and emulsifiers may be glyceryl monostearate, propylene glycol, glyceryl monoleate, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, and polyethylene glycol stearate or mixture thereof.

Examples of emulsifier used in the composition of present invention are selected from group comprises but are not limited to glyceryl monostearate, glyceryl monoleate, cetomacrogol, stearic acid, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, and polyethylene glycol stearate or mixture thereof.

Examples of preservative used in the composition of present invention are selected from group comprises but are not limited to methyl paraben, propyl paraben, chlorocresol, potassium sorbate, benzoic acid and the like, or any combination thereof.

Examples of pH modifier/regulator used in the composition of present invention are selected from group comprises but are not limited to acid e.g. hydrochloric acid phosphoric acid, or a base e.g. diethanolamine, triethanolamine, sodium hydroxide, or known buffering agents, e.g. phosphates such as monobasic sodium phosphate, and dibasic sodium phosphate, and citrates or mixture thereof.

Examples of antioxidant used in the composition of present invention are selected from group comprises but are not limited to butylated hydroxy anisole, vitamin–E, butylated hydroxy toluene and the like, or any combination thereof.

Examples of smoothening agent used in the composition of present invention are selected from group comprises but are not limited to mannitol, sorbitol, SalSphere SalCool and xylitol or mixture thereof.

Examples of chelating agent used in the composition of present invention are selected from group comprises but are not limited to disodium EDTA, picolinic acid, nicotinic acid, neoaspergillic acid, methionine, lactic acid, salicyclic acid, tartaric acid or mixture thereof.

Examples of stiffening agent used in the composition of present invention are selected from group comprises but are not limited to cetearyl alcohol, cetyl alcohol, Cetostearyl alcohol, microcrystalline wax, white wax, yellow wax, paraffin, emulsifying wax or mixture thereof.

Vehicle is a substance that can chemically different liquid, solid or gas. Examples of solvent suitable for use in oral pharmaceutical composition are selected from group comprises but not limited to purified water, isopropyl alcohol, dichloromethane, glycerol, propylene glycol, ethanol, chlordiazepoxide hydrochloride or mixture thereof.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

EXAMPLES
Example 1: Topical Pharmaceutical Composition.
Table 1
Sr. No. Ingredient Quantity (%w/w)
1. Nadifloxacin (Micronized) IH 1.00
2. Mometasone Furoate (Micronized) IP 0.10
3. Terbinafine Hydrochloride BP 1.00
4. Liquid paraffin (Heavy) IP 12
5. Propylene Glycol IP 17
6. Disodium Edetate IP 0.09
7. Cetomacrogol -1000 BP 2.5
8. Cetostearyl Alcohol IP 6.5
9. Microcrystalline Wax IP 3.7
10. Vitamin -E (Pure alpha tocopherol) USP 0.03
11. Methyl Paraben IP 0.16
12. Propyl Paraben IP 0.018
13. Activated Dimethicone IP 0.12
14. Sodium Hydroxide IP 0.096
15. SalSphere SalCool 20 IH 6.7
16. Purified Water Q.S. to 100 %

Procedure:
1. Transferred 70% of total quantity of purified water in aqueous phase vessel and heated.
2. Disodium edentate added and dissolved in purified water of step 1 under stirring. Cool and maintain the temperature of this solution to 73-75°C.
3. Transferred one by one heavy liquid paraffin, cetostearyl alcohol, microcrystalline wax, cetomacrogol 1000 and activated dimethicone in the wax phase vessel.
4. Heated the content of step 3 to 85-90ºC under continuous stirring to get clear and homogeneous solution.
5. Transferred the wax phase of step 4 to main manufacturing vessel while passing through sieve under stirring and maintain the temperature of wax phase between 80-85°C.
6. Homogeniser of main manufacturing vessel was started and transferred approximately 33.0 % of solution from aqueous phase vessel to main manufacturing vessel while passing through sieve and maintaining the temperature of emulsion to 70-75°C.
7. Transferred balance water phase of step 2 to main manufacturing vessel while passing sieve and maintaining the temperature of emulsion to 70-75°C.
8. Transferred propylene glycol to wax phase vessel and heated up to 65 - 70ºC.
9. Dissolveed methyl paraben and propyl paraben in step 8, under stirring.
10. Transferred solution of step 9 to main manufacturing vessel while passing through sieve and stirred.
11. Cooled the content of step 10 up to 28-30°C.
12. Dissolved 0.3 % cetomacrogol in 16% of total purified water
13. Dispersed nadifloxacin, mometasone furoate and terbinafine hydrochloride in step 12 solution under stirring.
14. Transferred dispersion of step 13 to main manufacturing vessel under stirring.
15. Dissolved 0.1 % cetomacrogol in 3.0 % purified water.
16. 0.03% alfatocopherol was added to step 15 under stirring and transferred this dispersion to main manufacturing vessel.
17. 5 % Salsphere Salcool was added to main manufacturing vessel.
18. Dissolved sodium hydroxide in purified water and transferred to main manufacturing vessel.
19. Checked weight of bulk in main vessel and if required make up the bulk to 100.0% with purified water.
20. Fill the bulk in container.

Example 2: Nadifloxacin, Mometasone Furoate and Terbinafine Hydrochloride Composition.
Table 2
Sr. No. Ingredient Quantity (%w/w)
1. Nadifloxacin (Micronized) IH 1.00
2. Mometasone Furoate (Micronized) IP 0.10
3. Terbinafine Hydrochloride BP 1.00
4. Liquid paraffin (Heavy) IP 15.00
5. Propylene Glycol IP 15.00
6. Disodium Edetate IP 0.10
7. Cetomacrogol -1000 BP 2.00
8. Cetostearyl Alcohol IP 7.20
9. Microcrystalline Wax IP 3.00
10. Vitamin -E (Pure alpha tocopherol) USP 0.03
11. Methyl Paraben IP 0.18
12. Propyl Paraben IP 0.02
13. Activated Dimethicone IP 0.10
14. Sodium Hydroxide IP 0.096
15. SalSphere SalCool 20 IH 5.00
16. Purified Water Q.S. to 100 %

Procedure:
Same as described in example 1 of this invention.

Stability Data:
Tablet 3: Stability studies with low pH (2-3) of the composition
Sr. No. Tests Initial Accelerated
(40°C/ 75%RH) Real Time
(25°C/ 60% RH)
3 Month 6 month 3 Month 6 month
1 Description complies complies complies complies complies
2 pH 2.47 2.37 2.65 2.40 2.86
3 Assay
a Nadifloxacin 101.8 103.0 100.1 102.9 100.9
b Mometasone Furoate IP 105.2 104.8 105.0 105.1 101.0
c Terbinafine Hydrochloride BP 100.2 99.7 98.9 99.6 101.3
d Methyl Paraben IP 96.3 97.8 95.9 97.8 95.7
e Propyl Paraben IP 100.6 101.9 99.8 99.9 99.6

Tablet 4: Stability studies with high pH (4-6) of the composition
Sr. No. Tests Initial Accelerated
(40°C/ 75%RH) Real Time
(25°C/ 60% RH)
3 Month 6 month 3 Month 6 month
1 Description complies complies complies complies complies
2 pH 4.27 4.34 4.35 4.30 4.32
3 Assay
a Nadifloxacin 97.8 98.6 96.4 98.6 95.7
b Mometasone Furoate IP 97.4 98.1 96.3 97.7 96.4
c Terbinafine Hydrochloride BP 97.3 95.4 94.9 95.9 87.2
d Methyl Paraben IP 98.3 97.9 97.8 98.7 98.0
e Propyl Paraben IP 100.4 100.0 100.6 99.6 98.1

,CLAIMS:1. A topical skin cream composition comprising: a) about 0.05% w/w to about 0.20% w/w of anti-inflammatory agent; b) about 0.5% w/w to about 2% w/w of antifungal agent; c) about 0.5% w/w to about 2% w/w of antimicrobial agent; and d) one or more pharmaceutically acceptable excipient.

2. The topical composition of claim 1, wherein the antifungal agent comprises terbinafine hydrochloride.

3. The topical composition of claim 1, wherein the anti-inflammatory agent comprises mometasone furoate.

4. The topical composition of claim 1, wherein the antimicrobial agent comprises nadifloxacin.

5. A topical pharmaceutical composition comprising:
a) nadifloxacin or pharmaceutically acceptable salt thereof,
b) mometasone or pharmaceutically acceptable salt thereof,
c) terbinafine or pharmaceutically acceptable salt thereof, and
d) one or more suitable pharmaceutically acceptable excipients.

6. A topical pharmaceutical composition comprising:
a) about 1% w/v of nadifloxacin or pharmaceutically acceptable salt thereof,
b) about 0.10% w/v of mometasone or pharmaceutically acceptable salt thereof,
c) about 1% w/v of terbinafine or pharmaceutically acceptable salt thereof, and
d) one or more suitable pharmaceutically acceptable excipients.

7. A topical pharmaceutical composition comprising:
a) 1% w/v of nadifloxacin or pharmaceutically acceptable salt thereof,
b) 0.10% w/v of mometasone or pharmaceutically acceptable salt thereof,
c) 1% w/v of terbinafine or pharmaceutically acceptable salt thereof,
d) 15% w/v of liquid paraffin,
e) 15% w/v of propylene glycol, and
f) one or more suitable pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 5-7, wherein the pharmaceutical composition is in the form of cream.

9. The pharmaceutical composition according to claim 1, 5-7 wherein the pharmaceutical composition has pH in the range of 2-6.