Cross-reference to related application

This application claims the benefit of Indian Provisional Application 202021040485 filed on September 18, 2020, the contents of which are incorporated herein by reference.

Field of the invention

The present invention relates to a topical, foamable composition comprising Luliconazole, and pharmaceutically acceptable excipients selected from group consisting of surfactant, preservative, chelating agent, viscosifier, suspending agent, conditioner, emollient, pH adjuster and mixture thereof. The said composition has various advantages such as low irritant to the skin or eyes, produces excellent creamy foam, possesses a superior hair conditioning effect, and imparts an outstanding moisture feeling to the skin. It also causes lesser hair discoloration when compared to other antifungal topical composition.

Background of the invention

The present invention relates to topical compositions such as body and/or hair cleansing products, in particular but not limited to shampoo or lotion, comprising of one or more antifungal(s) such as luliconazole indicated for the topical treatment and prophylaxis of conditions in which the Malassezia spp. are involved. It is also used to reduce relapse rates and maintain remissions for Seborrheic dermatitis.

Fungal infections are a major health problem and an important cause of morbidity. Fungal infections may be categorized as superficial or invasive. Superficial fungal infections affect as many as 20%-25% of the world’s population and are associated with interference with daily activities, poor quality of life, and health care expenditure. Invasive fungal infections are usually encountered in the presence of one or more predisposing factors, such as in critically ill or immunocompromised patients and those with indwelling catheters and devices, and deep or systemic fungal infections are an important cause of hospitalization and mortality. Superficial fungal infections can be attributed to Dermatophytes, Candida, and Malassezia spp. infection. The genus Malassezia includes multiple lipid-dependent species, the most common being M. sympodialis, M. globosa, M. restricta, M. slooffiae, M. furfur, and M. obtus. Colonization by these species is especially dense in the scalp, upper trunk, and flexures, areas rich in sebaceous glands and their secretions. Malassezia spp. are the main cause of pityriasis versicolor and Malassezia folliculitis, and these are also believed to have an important role in seborrheic dermatitis.

Mammals, especially humans, due to their hair structure often experience fungus growth upon their skin and due to bacteria which can thrive in the environment of hair against the skin.

An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host. Commonly used antifungals includes but not limited to polyenes, azoles, allylamine and morpholines.

Topical antifungal therapy is preferred over oral antifungals due to various advantages like lack of systemic side effects and complications due to limited systemic absorption, very low incidence of drug interactions, ease of use, comparatively low cost of therapy, and additional benefit of antiinflammatory activity of several topical antifungals including azoles and allylamines.

Topical antifungals are products that treat fungal infections and which are applied directly to the skin, nails, or hair; vaginally; or inside the mouth. They are available as creams, gels, lotions, nail lacquers, ointments, powders, shampoos, sprays, and tinctures.

Azoles are synthetic and semi-synthetic compounds. Commonly used azole are ketoconazole, teraconazole, itraconazole, fluconazole, voriconazole Although luliconazole is the preferred fungicidal agent the following can also be used as fungicidal agent in combination with or in place of luliconazole: ketoconazole, amphotericin B, butaconazole, amorolfine, anidulafungin, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, dapsone, econazole, fluconazole, flucytosine, gentian violet, griseofulvin, haloprogin, itraconazole, micafungin, miconazole, naftifine, nystatin, oxiconazole, pimaricin, posaconazole, ravoconazole, rimocidin, silver sulfadiazine, sulconazole, terbinafine, terconazole, tolnaftate, undecylenic acid, or voriconazole.

Known medicated shampoos or lotion are, for example, the ketoconazole shampoos which are marketed in a 2% formulation and which show a beneficial effect in seborrheic-dermatitis after topical application. U.S. Pat. No. 5456851 discloses ketoconazole shampoos that exhibit better cosmetic attributes such as lathering and conditioning, and are acceptably stable to degradation so that they can be formulated to contain less than 2 % active ingredient.

WO 1996029045 discloses combinations of such a cytotoxic agent and an antifungal agent for the treatment of seborrheic dermatitis of the scalp; specifically disclosed is the combined use of an unidentified composition comprising 1.8 % coal tar and an unidentified solution comprising 2 % ketoconazole.

WO 2019070221 discloses topical pharmaceutical compositions, comprising luliconazole or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, hydrates or esters thereof and at least one pharmaceutically acceptable excipient.

WO 2017203456 discloses stable topical compositions comprising luliconazole. Further the present invention also relates to stable topical compositions comprising combination of luliconazole with a corticosteroid such as betamethasone or clobetasol. The compositions are free of an aliphatic alcohol and a ketone.

Ketoconazole shampoo known to possess severe adverse effects like hypersensitivity reactions, including anaphylaxis, angioedema, irritation to mucous membranes of eyes and scalp, hair discoloration, it also causes abnormal hair texture, removal of the curl from permanently waved hair, itching, alopecia, rashes and urticaria, skin burning sensation, skin irritation, dry skin, and application site reactions.

Thus, there is a need of a stable topical antifungal composition with lowest possible incidence of side effects, absence of symptoms such as irritation, pruritus and scaling; improved cosmetic acceptability, in particular, good cleansing properties, overall conditioning (wet and dry combing properties), absence of odour or stench.

Dandruff or seborrheic dermatitis are often accompanied by high or excessive oil or sebum production, and compositions having a beneficial effect thereon would clearly constitute a further advance in the treatment of dandruff.

Commonly used antifungal shampoo preparation contains parabens as a preservative. However, studies have shown that some parabens specifically mimic the activity of the hormone estrogen and therefore can interfere with estrogen production. Other commonly used preservatives like azolinones are found to be linked with lung toxicity, allergic reactions and possible neurotoxicity.

Further, commonly used antifungal shampoo or lotion preparation contains cocamide diethanolamide, and Sodium cocoyl sarcosinate/Sodium lauryl sarcosinate which having potential undesired side effects. Small doses of Cocamide diethanolamide can cause itchiness and rash. In large doses, it can be a carcinogen. Sodium cocoyl sarcosinate is harmful for the DNA in mammal cells. It also shows very high acute toxicity towards respiratory system.

There still exists a need for improved, easy to use and effective topical antifungal composition.

Summary of Invention

The present invention provides a topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients.

In another aspects of the invention, the present invention relates to topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients selected from the group consisting of surfactants, preservative, chelating agent, viscosifier, suspending agent, conditioner, emollient and mixture thereof.

In another aspects of the invention, the present invention relates to stable composition for topical application to a human comprising about 0.05% to about 10% w/w luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients selected from the group consisting of surfactants, preservative, chelating agent, viscosifier, suspending agent, conditioner, emollient and mixture thereof wherein the composition is not free of sodium lauryl ether sulfate.

In another aspects of the invention, the present invention relates to topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients wherein said composition possess improved cosmetic attributes such as but not limited to lathering, lesser hair discoloration, and conditioning of hair.

In another aspects of the invention, the present invention relates to topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients wherein said composition possess improved patient acceptance such as but not limited to lesser eyes and skin irritation.

In another aspect, there is provided a luliconazole for topical application, wherein the dosage form for topical application is selected from the group consisting of shampoo, lotion, gel, cream or ointment.

In another aspects of the invention relates to a pharmaceutical suspension composition for topical application to a human in the form of shampoo or lotion comprising about 0.5 % w/w to about 5% w/w luliconazole or its derivative wherein the composition does not contain any additional active agents such as salicylic acid or zinc pyrithione.

In yet another aspect of the invention is directed to a topical composition comprising luliconazole which is substantially free of Cocamide diethanolamide.

In yet another aspect of the invention is directed to a topical composition comprising luliconazole which is substantially free of sodium cocoyl sarcosinate.

In yet another aspect of the invention is directed to a topical composition comprising luliconazole which is substantially free of natural oil and surfactants such as parabens and azolinones.

In yet another aspect, there is provided a topical composition comprising luliconazole and pharmaceutically acceptable excipients such as cocamidopropyl betaine, bis-aminopropyl dimethicone and polyethylene glycol ether for beneficial effects. Cocamidopropyl Betaine used as conditioning agent, has skin hydrating properties and prevent skin from drying out; Bis- Aminopropyl Dimethicone has strong polarity, can interact with hydroxyl and carboxyl on hair surface, brings very good orientation and absorption property, helps in formation of a smooth and solid film on the hair and polyethylene glycol ether which is compatible with non-ionic, anionic, amphoteric, and cationic surfactants. In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 0.5 % w/w to about 5 % w/w of luliconazole; b) about 5 % w/w to about 30 % w/w of surfactant; c) about 0.5% w/w to about 3.5 % w/w of conditioner; and d) pharmaceutically acceptable excipients selected from the group consisting of preservative, chelating agent, suspending agent, viscosifier, emollient, pH adjuster, perfume, and mixture thereof. wherein all these percentages being expressed relative to the total weight of the composition.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 0.5 % w/w to about 5 % w/w of luliconazole; b) about 5 % w/w to about 25 % w/w of anionic surfactant selected from alkyl sulfate and alkyl ether sulfate salts such as sodium lauryl ether sulfate , disodium laureth sulfosuccinate, ammonium laureth sulfate, sodium myreth sulfate, sodium methyl 2- sulfolaurate, disodium 2-sulfolaurate, sodium C14-16 olefin sulfonate, and sodium lauroyl methyl isethionate, sodium lauryl sulfate and mixture thereof; c) about 0.25 % w/w to about 3 % w/w of non-ionic surfactant selected from 2- (Dodecyloxy)ethanol , 2-[2-(Dodecyloxy)ethoxy]ethanol , Polyethylene glycol ether of lauryl alcohol, Alcohols, Cl 2- 14, ethoxylated, coco glucosides, cocamidopropylamine oxide, and stearyl alcohol; d) about 0.1% w/w to about 2.5 % w/w of amphoteric surfactant selected from sodium laurimino dipropionate, cocamidopropyl betaine, cocoamidopropyl hydroxysultaine; e) about 0.5 %w/w to about 3.5 % w/w of conditioner selected from cetyltrimethyl ammonium chloride, behentrimonium or propyltrimonium, stearamidopropyl dimethylamine hydrolyzed silk, animal protein, glycerin, dimethicone and its derivatives like dimethicone and aminopropyldimethicone, simethicone, sodium caprylampho hydroxypropyl sultaine , sodium cocoampho propionate, disodium cocoampho diacetate , polyvinylpyrrolidone, propylene glycol, certain polymers like ampholytic terpolymer and or its derivatives, Polyquaternium-53 and mixture thereof. ; and f) pharmaceutically acceptable excipients.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 0.5 to about 5 % by weight of luliconazole along with surfactants and conditioner; and b) pharmaceutically acceptable excipients includes but not limited to preservatives such as Imidurea (Imidazolidinyl urea), benzoates (such as sodium benzoate, benzoic acid), nitrites (such as sodium nitrite), sulphites (such as sulphur dioxide) or sorbates (such as sodium sorbate, potassium sorbate), chelating agent such as diiospropyl oxalate, disodium EDTA, disodium EDTA-copper, EDTA, diethylene-triamine-pentaacetic acid (DTPA), iminodisuccinic acid (IDS), Ethylenediamine disuccinic acid (EDDS); emollients are choosen from petrolatum, lanolin, mineral oil, dimethicone, caprylic triglyceride, Jojoba oil, olive oil, grape seed oil, PEG-7 Glyceryl cocoate; suspending agent and viscosifierare chosen from cellulose, cellulose ether such as sodium carboxy methyl cellulose, polyacrylic acids, cross-linked polymers of acrylic acid, copolymers of acrylic acid with a hydrophobic monomer such as Carbopol Silk 100, Carbopol 420, Carbopol 488 or Carbopol 493, Carbopol 910, Carbopol 934, Carbopol 941, Carbopol 980, Carbopol 1342, Sodium Chloride and mixture thereof; pH adjuster such as hydrochloric acid, sodium hydroxide, ammonium hydroxide, magnesium hydroxide, sulphuric acid, phosphoric acid, citric acid, malic acid, tartaric acid.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 2 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of Polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53 ; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 Glyceryl cocoate; l) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; and n) pharmaceutically excipients such as sodium hydroxide; perfume and water.

In another aspect, there is provided a topical compostion of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 1 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of Polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53 ; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 Glyceryl cocoate; l) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; and n) pharmaceutically excipients such as sodium hydroxide; perfume and water.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 4 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of Polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53 ; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 Glyceryl cocoate; l) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer ; and n) pharmaceutically excipients such as sodium hydroxide; perfume and water.

In another aspect of the invention relates to a pharmaceutical composition for topical application the composition being in the form of suspension comprising a) about 2 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 glyceryl cocoate; 1) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; n) sodium hydroxide; o) perfume and p) water.

In another aspect of the invention relates to a pharmaceutical composition for topical application, the composition being in the form of suspension comprising a) about 1 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 glyceryl cocoate; 1) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; n) sodium hydroxide; o) perfume and p) water.

In another aspect of the invention relates to a pharmaceutical composition for topical application, the composition being in the form of suspension comprising a) about 4 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 glyceryl cocoate; 1) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; n) sodium hydroxide; o) perfume and p) water.

In another aspect of the invention, the pharmaceutical compositions comprising luliconazole having a dso of about 11 to about 20 pm, preferably from about 12 to about 16 pm. In another aspect, the pharmaceutical compositions comprising luliconazole having a dw from about 21 to about 50 pm, preferably from about 22 to about 30 pm. In another aspect, the pharmaceutical compositions comprising luliconazole having a dio from about 1 to about 10 pm, preferably from about 5 to about 10 pm.

In another aspect of the invention, the present invention relates to method of treating dandruff or seborrheic dermatitis , fungal infections associated with Malassezia spp. like pityriasis versicolor as well as dermatophytic infections like tinea capitis, tinea barbae of hairy areas for washing & treating the skin, hair or the scalp by the application of topical shampoo or lotion composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients.

In yet another aspect of the invention, the present invention relates to topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients for the treatment of dandruff or seborrheic dermatitis , fungal infections associated with Malassezia spp. like pityriasis versicolor as well as dermatophytic infections like tinea capitis, tinea barbae of hairy areas for washing & treating the skin, hair or the scalp.

In yet another aspect of the invention, the present invention relates to use of topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients for the treatment of dandruff or seborrheic dermatitis , fungal infections associated with Malassezia spp. like pityriasis versicolor as well as dermatophytic infections like tinea capitis, tinea barbae of hairy areas for washing & treating the skin, hair or the scalp. In another aspect, there is provided a luliconazole shampoo or lotion composition, wherein the extent of wrinkling and sloughing (mild) as well as incidences i.e. irritant properties of said shampoo or lotion were comparable with that of the marketed shampoo or lotion composition.

In another aspect, there is provided a luliconazole shampoo or lotion composition, wherein the said shampoo is comparable with marketed shampoo or lotion in terms of skin irritation potential.

In another aspect, there is provided a luliconazole shampoo or lotion composition, wherein the said shampoo or lotion have minimally irritating eye irritation potential and is comparable with marketed shampoo or lotion.

In another aspect, the invention is directed to methods of using such composition for the treatment of dandruff, Malassezia infections like Pityriasis versicolor, fungal infections like tinea barbae, tinea capitis, etc It also reduces relapse rates and maintains remissions for Seborrheic dermatitis.

In another aspect, the invention is directed to a process for preparation of aqueous shampoo or lotion of Luliconazole or one or more of its salts, comprising the steps of: 1. Disodium laureth sulfosuccinate, Laureth-3, purified water were taken and luliconazole API was added in it. Further it was stirred to get uniform dispersion. 2. Purified water was taken and acrylic polymer such as carbopol silk 100 was added in it. Further it was stirred to get uniform dispersion. 3. Sodium carboxymethylcellulose was added to step-2 and stirred to get uniform dispersion. 4. Step-01 was added to step-03 and stirred to get uniform dispersion. 5. Cocoamidopropyl betaine, dimethicone and aminopropyldimethicone, polyquarternium-53, disodium cocoampho diacetate, PEG-7 glyceryl cocoate were added one after another to step-04 and stirred to get uniform dispersion. 6. In suitable container purified water was taken and disodium edetate, imidurea dissolved under stirring to get uniform solution. 7. Step-05 was added to step-04 and stirred to get uniform dispersion. 8. Perfume was added to step-06 and stirred to get uniform dispersion.9. Sodium laureth sulfate paste 70% was added to step-07 and stirred to get uniform dispersion.10. pH of step-09 was adjusted using 3M sodium hydroxide solution to 6-7.5 11. Weight of batch was made by using purified water. Detailed description of the drawing:

Figure 1 and 2 is a bar graph depicting hair sensory evaluation of luliconazole anti -dandruff shampoo composition as described in example 3 with respect to marketed anti-dandruff shampoo sample and control sample.

Figure 3 and 4 shows cationic polymer deposition evaluation by Red 80 Dye method of luliconazole anti -dandruff shampoo composition as described in example 3 with respect to marketed anti-dandruff shampoo sample and control sample.

Description of the invention:

Luliconazole also known as NND-502, is an imidazole antifungal agent with a unique structure, as the imidazole moiety is incorporated into the ketene dithioacetate structure. Luliconazole is the R-enantiomer, and has more potent antifungal activity than lanoconazole, which is a racemic mixture. The chemical structure of luliconazole, i. e, (-)-(E)-[4-(2,4-dichlorophenyl)-l,3- dithiolan-2-ylidene]-l-imidazolylacetonitrile, is shown below

It has been shown to have potent activity against a variety of fungi, especially dermatophytes. Further, in vitro/in vivo studies have also shown favorable activity against Candida albicans, Malassezia spp. , and Aspergillus fumigatus. Luliconazole, although belonging to the azole group, has strong fungicidal activity against Trichophyton spp., similar to that of terbinafine. The strong clinical antifungal activity of luliconazole is possibly attributable to a combination of strong in vitro antifungal activity and favorable pharmacokinetic properties in the skin.

Superficial fungal infections can be attributed to dermatophytes, Candida, and Malassezia spp. infections. Dermatophytes are aerobic fungi and the most common offenders in superficial fungal infections. Physiologically, these dermatophytes have the ability to digest keratin for growth and replicate in the superficial layers of the epidermis. Consequently, in clinical practice, the body parts most affected by dermatophytic infection are those rich in keratin, such as the hair, skin, and nails. Candidiasis is an infection caused by yeasts of the genus Candida. Superficial infections of the mucous membranes and skin are most frequent, but Candida can also cause deep invasive disease, including septicemia, endocarditis, and meningitis.

The genus Malassezia includes multiple lipid-dependent species, the most common being M. sympodialis, M. globosa, M. restricta, M. slooffiae, M. furfur, and M. obtus. Colonization by these species is especially dense in the scalp, upper trunk, and flexures, areas rich in sebaceous glands and their secretions. Malassezia spp. are the main cause of pityriasis versicolor and Malassezia folliculitis, and are also believed to have a role in seborrheic dermatitis as well as dandruff.

Luliconazole 1% cream was approved in Japan in 2005 for the treatment of tinea infections, followed by approval in November 2013 by the US Food and Drug Administration for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms T. rubrum and E. floccosum, in patients 18 years of age and older. It is indicated for once-daily application for one week in tinea corporis/cruris and for 2 weeks in tinea pedis.

Various clinical studies have shown that, both luliconazole and ketoconazole to be effective in the treatment of pityriasis versicolor. However, over a 4-week period, luliconazole was found to be more effective than ketoconazole (Sarkar et al., Indian Dermatol Online J. 2016 Jul-Aug; 7(4): 335-336).

The present invention provides a topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients with lowest possible incidence of side effects, like absence of symptoms such as irritation, pruritus and scaling; improved cosmetic acceptability, in particular, good cleansing properties, overall conditioning (wet and dry combing properties), absence of odour or stench.

In another aspect, the invention is devoid of natural oil and surfactants like parabens, azolinones, thus potential side effects associated with them like; hormonal imbalance, lung toxicity, allergic reactions and possible neurotoxicity can be avoided.

In yet another aspect, the present invention provides pharmaceutical composition characterized in that the composition comprises therapeutically effective amount of luliconazole in the range of about 0.05 % to about 10 % w/w of the total composition. Preferably in the range of about 0.5 % w/wto about 5 % w/w, more preferably in the range of about 0.75% w/wto about 4.5% w/w, more preferably in the range of about 1 % w/w to about 4% w/w, more preferably about 1 % w/w, 2% or 4 % w/w of the total composition.

In yet another aspect of the present invention topical composition of luliconazole can be applied either at least once or twice in a week.

In another aspects of the invention, the present invention relates to topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients selected from the group consisting of surfactants, preservative, chelating agent, viscofier, suspending agent, conditioner, emollient, pH adjuster and mixture thereof.

The instant topical composition of luliconazole and pharmaceutically acceptable surface active agents include but not limited to anionic surfactant, non-ionic surfactant, amphoteric surfactant and cationic surfactant.

Anionic surfactants selected from but not limited to alkyl sulfate and alkyl ether sulfate salts such as sodium lauryl ether sulfate (SLES), ammonium laureth sulfate, sodium lauryl sulfate, disodium lauryl sulfosuccinate and ammonium lauryl sulfate, sodium myreth sulfate, sodium methyl 2- sulfolaurate, disodium 2-sulfolaurate, sodium Cl 4- 16 olefin sulfonate, and sodium lauroyl methyl isethionate or mixture thereof.

Non-ionic surfactants are usually mild and usually used as emulsifiers, conditioning ingredients, solubilizing agents, foam stabilizers etc. These include polyoxyethers of lauryl alcohol such as 2- (Dodecyloxy) ethanol (Laureth-1), 2-[2-(Dodecyloxy) ethoxy] ethanol (Laureth- 2), Polyethylene glycol ether of lauryl alcohol (Laureth-3; 2-[2-[2-(dodecyloxy) ethoxy] ethoxy] ethanol), Alcohols, Cl 2- 14, ethoxylated (Laureth-4), coco glucosides, cocamidopropylamine oxide, and stearyl alcohol; coco glucosides, cocamidopropylamine oxide, stearyl alcohol etc.

Amphoteric surfactants selected from but not limited to Betaines and amine oxides. Preferred amphoteric surfactants include sodium laurimino dipropionate (Mirataine™ H2C-HA), sodium cocoampho propionate (Miranol™ C2M-SF Cone.), cocamidopropyl betaine (Mirataine™ CB), cocoamidopropyl hydroxysultaine (Mirataine™ CBS), and Miranol™ JS Cone, (sodium caprylampho hydroxypropyl sultaine). The cationic surfactants function by adsorbing or absorbing to the hair shaft and modifying texture and appearance. They are mild and generally considered nontoxic. Cationic surfactants include but not limited to polyquaternium-7, C8-10 alkyl hydroxy ethyl dimethylammonium chloride or C8- 10 alkylamidodimethyl propylamine, alkyldimethyl amine oxides.

Mixtures of any of the above surface active agents may be used. Preferred is a mixture of anionic, non-ionic and amphoteric surfactants.

In yet another aspect, the present invention relates to pharmaceutical composition comprising surfactants in the range of about 0.01 %w/w to about 50% w/w of the total composition. Preferably in the range of about 2% w/w to about 40 %w/w, more preferably in the range of about 4% w/w to about 35% w/w, more preferably in the range of about 5% w/w to about 30% w/w, more preferably in the range of about 8% w/w to about 24% w/w of the total composition.

A conditioner is a substance or process that improves the quality of another material. The present invention provides pharmaceutical composition characterized in that the composition further comprises a conditioning agent. Commonly used conditioning substances include but not limited to cetyltrimethyl ammonium chloride, behentrimonium or propyltrimonium, stearamidopropyl dimethylamine hydrolyzed silk, animal protein, glycerin, dimethicone and its derivatives like dimethicone and aminopropyldimethicone (such as KF 8020), simethicone, sodium caprylampho hydroxypropyl sultaine (such as Miranol™ JS Cone.), sodium cocoampho propionate (such as Miranol™ C2M-SF Cone), disodium cocoampho diacetate (such as Miranol C2M), polyvinylpyrrolidone, propylene glycol, certain polymers like ampholytic terpolymer and or its derivatives, Polyquaternium-53 (such as Merquat 2003PR) or mixture thereof.

In yet another aspect, the present invention relates to pharmaceutical composition comprising conditioner in the range of about 0.05 % w/w to about 5% w/w of the total composition. Preferably in the range of about 0.1 % w/w to about 5 %w/w, more preferably in the range of about 0.5% w/w to about 3.5% w/w, more preferably in the range of about 0.8 % w/w to about 3% w/w of the total composition.

A preservative is a natural or synthetic chemical that is added to the composition to prevent decomposition by microbial growth or by undesirable chemical changes. Preservatives can be selected from but not limited to antimicrobial agents, antioxidants or chelating agents. Commonly used preservatives includes but not limited to benzoates (such as sodium benzoate, benzoic acid), nitrites (such as sodium nitrite), sulphites (such as sulphur dioxide) or sorbates (such as sodium sorbate, potassium sorbate). Some preservatives like chlorhexidine are effective over a narrower pH range (5-7), and above pH 8.0, however preservatives like Imidurea (Imidazolidinyl urea) are effective over this whole pH range (3-9), although optimum efficacy is seen at acidic pH. Imidurea (Imidazolidinyl urea) is used as an antimicrobial agent and preservative in cosmetics and toiletries.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising preservatives in the range of about 0.005% w/w to about 5 % w/w of the total composition. Preferably in the range of about 0.008% w/w to about 3 % w/w, more preferably in the range of about 0.01% w/w to about 2 % w/w, more preferably in the range of about 0.01% w/w to about- 1% w/w, more preferably about 0.15 w/w of the total composition.

Chelating agents are used in small amounts to react with metal ions present in hair care products or in the water, in order to improve stability or performance of the product. It provides protection against harmful metal-catalyzed reactions in the composition thereby improves stability of the composition. Commonly used chelating agents are selected from but not limited to diiospropyl oxalate, disodium EDTA, disodium EDTA-copper, EDTA, diethylene-triamine-pentaacetic acid (DTP A), iminodisuccinic acid (IDS), Eethylenediamine disuccinic acid (EDDS).

In yet another aspect, the present invention relates to a pharmaceutical composition comprising chelating agent in the range of about 0.005% w/w to about 5 % w/w of the total composition. Preferably in the range of about 0.005% w/w to about 4 % w/w, more preferably in the range of about 0.005% w/w to about 3 % w/w, more preferably in the range of about 0.005% w/w to about- 2% w/w, more preferably in the range of about 0.005 % w/w to about- 1 % w/w, more preferably in the range of about 0.01% w/w to about-0.5 % w/w, more about preferably 0.05% w/w of the total composition.

Emollients are used for protecting, moisturizing, and lubricating the skin. Commonly used emollients are selected from but not limited to petrolatum, lanolin, mineral oil, dimethicone, caprylic triglyceride, Jojoba oil, olive oil, grape seed oil, glyceryl cocoate.

In yet another aspect, the present invention relates to a pharmaceutical composition characterized in that the composition further comprises a suspending agent. Suitable suspending agents are selected from cellulose, cellulose ether like sodium carboxy methyl cellulose is an important cellulose ether, polyacrylic acids, cross-linked polymers of acrylic acid, copolymers of acrylic acid with a hydrophobic monomer, copolymers of carboxylic acid-containing monomers and acrylic esters, cross-linked copolymers of acrylic acid and acrylate esters, natural gums like guar gum, xanthan gum and crystalline long chain acyl derivatives. The long chain acyl derivative is desirably selected from ethylene glycol stearate, alkanolamides of fatty acids having from 16 to 22 carbon atoms and mixtures thereof. Ethylene glycol distearate and polyethylene glycol 3 distearate are preferred long chain acyl derivatives, since these impart pearlescence to the composition.

A viscosifier can be added to the current pharmaceutical composition to increase shampoo or lotion viscosity. However, over dosage of these viscosity modifiers may cause negative hair feel, thus it is necessary to optimize its concentration. Viscosifierare selected from but not limited to electrolytes like NH4CI, Sodium Chloride; natural gums selected from gum karaya, tragacanth, alginates; cellulose derivatives selected from hydroxy ethyl cellulose, methyl cellulose; Polyacrylic acid is available commercially as Carbopol selected from but not limited to Carbopol 420, Carbopol 488 or Carbopol 493, CarbopolSilk 100 polymer. Polymers of acrylic acid crosslinked with a polyfunctional agent may also be used; they are available commercially as Carbopol 910, Carbopol 934, Carbopol 941 and Carbopol 980. An example of a suitable copolymer of a carboxylic acid containing monomer and acrylic acid esters is Carbopol 1342. The viscosity of the pharmaceutical composition may range from about 10 cps to about 500 cps or preferably from about 20 cps to about 150 cps. In context of the present invention, the viscosity can be determined by various known instruments such as a Dynamic stress rheometer or Brookfield viscometer. In a preferred embodiment, the viscosity is determined by a Brookfield cone and plate viscometer by measuring torque transmission through a sample using a rotating spindle at 100 rpm.

Pharmaceutically suitable acceptable pH adjuster include, but are not limited to hydrochloric acid, sodium hydroxide, ammonium hydroxide, magnesium hydroxide, sulphuric acid, phosphoric acid, citric acid, malic acid, tartaric acid. The pH adjuster may be used in an amount sufficient to obtain a pH in the range of from about 2 to about 10, preferably from about 5 to about 8, and more preferably from 6 to 7.5.

Pharmaceutically suitable acceptable vehicles or solubilizers include, but are not limited to purified water, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Purified water may be used in an amount to make the composition 100% by weight of the total composition. Further suitable perfume selected to the give a pleasant and desirable scent to a person's hair or body.

In another aspects of the invention, the present invention relates to stable shampoo or lotion composition for topical application to a human comprising about 0.05% to about 10% w/w luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients selected from the group consisting of surfactants, preservative, chelating agent, viscosifier, suspending agent, conditioner, emollient and mixture thereof wherein the composition is not free of sodium lauryl ether sulfate.

In another aspects of the invention, the present invention relates to topical shampoo or lotion composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients wherein said composition possess improved cosmetic attributes such as but not limited to lathering, lesser hair discoloration, and conditioning of hair.

In another aspects of the invention, the present invention relates to topical shampoo or lotion composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients wherein said composition possess improved patient acceptance such as but not limited to lesser eyes and skin irritation.

In another aspects of the invention relates to a pharmaceutical suspension for topical application to a human in the form of shampoo or lotion comprising about 0.5 % w/w to about 5% w/w luliconazole or its derivative wherein the composition does not contain any additional active agents such as salicylic acid or zinc pyrithione.

In yet another aspect of the invention is directed to a topical composition comprising luliconazole which is substantially free of Cocamide diethanolamide.

In yet another aspect of the invention is directed to a topical composition comprising luliconazole which is substantially free of sodium cocoyl sarcosinate. In yet another aspect of the invention is directed to a topical composition comprising luliconazole which is substantially free of natural oil and surfactants such as parabens and azolinones.

In yet another aspect, there is provided a topical composition comprising luliconazole and pharmaceutically acceptable excipients such as cocamidopropyl betaine, Bis- Aminopropyl Dimethicone and polyethylene glycol ether for beneficial effects. Cocamidopropyl Betaine used as cleansing agent, has skin hydrating properties and prevent skin from drying out; Bis- Aminopropyl Dimethicone has strong polarity, can interact with hydroxyl and carboxyl on hair surface, brings very good orientation and absorption property, helps in formation of a smooth and solid film on the hair and polyethylene glycol ether which is compatible with non-ionic, anionic, amphoteric, and cationic surfactants.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 0.5 % w/w to about 5 % w/w of luliconazole; b) about 5 % w/w to about 30 % w/w of surfactant; c) 0.5% w/w to 3.5 % w/w of conditioner; and d) pharmaceutically acceptable excipients selected from the group consisting of preservative, chelating agent, suspending agent, viscosifier, emollient, pH adjuster, perfume, and mixture thereof. wherein all these percentages being expressed relative to the total weight of the composition.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 0.5 % w/w to about 5 % w/w of luliconazole; b) about 5 % w/w to 25 % w/w of anionic surfactant selected from alkyl sulfate and alkyl ether sulfate salts such as sodium lauryl ether sulfate (SLES), disodium laureth sulfosuccinate, ammonium laureth sulfate, sodium myreth sulfate, sodium methyl 2- sulfolaurate, disodium 2-sulfolaurate, sodium C14-16 olefin sulfonate, and sodium lauroyl methyl isethionate, sodium lauryl sulfate and mixture thereof; c) about 0.25 % w/w to about 3 % w/w of non-ionic surfactant selected from 2- (Dodecyloxy)ethanol, 2- [2-(Dodecyloxy)ethoxy] ethanol , Polyethylene glycol ether of lauryl alcohol (2-[2-[2-(dodecyloxy)ethoxy]ethoxy]ethanol), Alcohols, C12-14, ethoxylated, coco glucosides, cocamidopropylamine oxide, and stearyl alcohol; d) about 0.1% w/w to 2.5 % w/w of amphoteric surfactant selected from sodium laurimino dipropionate, cocamidopropyl betaine, cocoamidopropyl hydroxysultaine; e) about 0.5 %w/w to 3.5 % w/w of conditioner selected from cetyltrimethyl ammonium chloride, behentrimonium or propyltrimonium, stearamidopropyl dimethylamine hydrolyzed silk, animal protein, glycerin, dimethicone and its derivatives like dimethicone and aminopropyldimethicone, simethicone, sodium caprylampho hydroxypropyl sultaine, sodium cocoampho propionate, disodium cocoampho diacetate, polyvinylpyrrolidone, propylene glycol, certain polymers like ampholytic terpolymer and or its derivatives, Polyquaternium-53 and mixture thereof; and f) pharmaceutically acceptable excipients.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 0.5 to about 5 % by weight of luliconazole along with surfactants and conditioner; and b) pharmaceutically acceptable excipients includes but not limited to preservatives such as Imidurea (Imidazolidinyl urea), benzoates (such as sodium benzoate, benzoic acid), nitrites (such as sodium nitrite), sulphites (such as sulphur dioxide) or sorbates (such as sodium sorbate, potassium sorbate), chelating agent such as diiospropyl oxalate, disodium EDTA, disodium EDTA-copper, EDTA, diethylene-triamine-pentaacetic acid (DTPA), iminodisuccinic acid (IDS), Ethylenediamine disuccinic acid (EDDS); emollients are choosen from petrolatum, lanolin, mineral oil, dimethicone, caprylic triglyceride, Jojoba oil, olive oil, grape seed oil, PEG-7 Glyceryl cocoate; suspending agent and viscosifierare chosen from cellulose, cellulose ether such as sodium carboxy methyl cellulose, polyacrylic acids, cross-linked polymers of acrylic acid, copolymers of acrylic acid with a hydrophobic monomer such as Carbopol Silk 100, Carbopol 420, Carbopol 488 or Carbopol 493, Carbopol 910, Carbopol 934, Carbopol 941, Carbopol 980, Carbopol 1342, Sodium Chloride and mixture thereof; pH adjuster such as hydrochloric acid, sodium hydroxide, ammonium hydroxide, magnesium hydroxide, sulphuric acid, phosphoric acid, citric acid, malic acid, tartaric acid.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 2 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of Polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53 ; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 Glyceryl cocoate; l) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; and n) pharmaceutically excipients such as sodium hydroxide; perfume and water.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 1 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of Polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53 ; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 Glyceryl cocoate; l) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; and n) pharmaceutically excipients such as sodium hydroxide; perfume and water.

In another aspect, there is provided a topical composition of luliconazole in the form of shampoo or lotion dosage form comprising: a) about 4 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of Polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53 ; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 Glyceryl cocoate; l) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer ; and n) pharmaceutically excipients such as sodium hydroxide; perfume and water.

In another aspect of the invention relates to a pharmaceutical composition for topical application, the composition being in the form of suspension comprising a) about 2 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 glyceryl cocoate; 1) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; n) sodium hydroxide; o) perfume and p) water. In another aspect of the invention relates to a pharmaceutical composition for topical application, the composition being in the form of suspension comprising a) about 1 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of polyquaternium-53; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 glyceryl cocoate; 1) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; n) sodium hydroxide; o) perfume and p) water.

In another aspect of the invention relates to a pharmaceutical composition for topical application, the composition being in the form of suspension comprising a) about 4 % w/w of luliconazole; b) about 5% w/w of disodium laureth sulfosuccinate; c) about 2.25 % w/w of sodium lauryl ether sulfate; d) about 0.5 % w/w of polyethylene glycol ether of lauryl alcohol; e) about 0.3 % w/w of cocamidopropyl betaine; f) about 0.1 % w/w of dimethicone and aminopropyldimethicone; g) about 0.5 % w/w of disodium cocoampho diacetate, h) about 0.2 % w/w of Polyquaternium-53; i) about 0.15 w/w of Imidurea; j) about 0.05 % w/w of disodium EDTA; k) about 0.5 % w/w of PEG-7 glyceryl cocoate; 1) about 0.5 % w/w of sodium carboxy methyl cellulose; m) about 1 % w/w of acrylic acid polymer; n) sodium hydroxide; o) perfume and p) water.

In another aspect of the invention, the present invention relates to method of treating dandruff or seborrheic dermatitis , fungal infections associated with Malassezia spp. like pityriasis versicolor as well as dermatophytic infections like tinea capitis, tinea barbae of hairy areas forwashing & treating the skin, hair or the scalp by the application of topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients.

In yet another aspects of the invention, the present invention relates to topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients for the treatment of dandruff or seborrheic dermatitis, fungal infections associated with Malassezia spp. like pityriasis versicolor as well as dermatophytic infections like tinea capitis, tinea barbae of hairy areas for washing & treating the skin, hair or the scalp. In yet another aspects of the invention, the present invention relates to use of topical composition comprising luliconazole or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and pharmaceutically acceptable excipients for the treatment of dandruff or seborrheic dermatitis, fungal infections associated with Malassezia spp. like pityriasis versicolor as well as dermatophytic infections like tinea capitis, tinea barbae of hairy areas for washing & treating the skin, hair or the scalp.

In yet another aspect of the invention, there is provided a luliconazole shampoo or lotion composition, wherein the extent of wrinkling and sloughing (mild) as well as incidences i.e. irritant properties of said shampoo or lotion were comparable with that of the marketed composition.

In yet another aspect of the invention, there is provided a luliconazole shampoo or lotion composition, wherein the said shampoo or lotion is comparable with marketed in terms of skin irritation potential.

In yet another aspect of the invention, there is provided a luliconazole shampoo or lotion composition, wherein the said shampoo or lotion have minimally irritating eye irritation potential and is comparable with marketed shampoo.

In another aspect, the invention is directed to methods of using such composition for the treatment of dandruff, Malassezia infections like Pityriasis versicolor, fungal infections like tinea barbae, tinea capitis, etc. It also reduces relapse rates and maintains remissions for Seborrheic dermatitis.

In one embodiment, the invention provides a process for preparation of pharmaceutical topical composition of luliconazole comprising the steps of:

1. Disodium laureth sulfosuccinate, Laureth-3, purified water were taken and luliconazole API was added in it. Further it was stirred to get uniform dispersion. 2. Purified water was taken and Carbopol silk 100 was added in it. Further it was stirred to get uniform dispersion. 3. Sodium carboxymethylcellulose was added to step-2 and stirred to get uniform dispersion. 4. Step-01 was added to step-03 and stirred to get uniform dispersion.5. Cocoamidopropyl betaine, KF 8020, Merquat 2003PR, MiranolC2M, PEG-7 glyceryl cocoate were added one after another to step-04 and stirred to get uniform dispersion. 6. In suitable container purified water was taken and disodium edetate, imidurea dissolved under stirring to get uniform solution. 7. Step-06 was added to step-05 and stirred to get uniform dispersion. 8. Perfume was added to step-07 and stirred to get uniform dispersion. 9. SLES paste 70% was added to step-08and stirred to get uniform dispersion. 10. pH of step-09 was adjusted using 3M sodium hydroxide solution to 6-7.5. 11. Weight of batch was made by using purified water.

Further this topical composition was evaluated for quality control tests including but not limited to visual assessment and physiochemical controls such as pH, density, viscosity, surface tension, foam volume, wetting ability, foaming ability, foam stability, hair discoloration or conditioning on swatches of hair.

The term “active” as used herein means luliconazole or its salt, solvate, or some additional actives as described herein or combination thereof.

The term “derivatives” includes all pharmaceutically acceptable salts, solvates, esters, isomers, polymorphs of luliconazole and can be used interchangeably.

The invention provides pharmaceutical compositions comprising luliconazole having a dso of from about 11 to about 20 pm, preferably from about 12 to about 16 pm. In another aspect, the pharmaceutical compositions comprising luliconazole having a dw from about 21 to about 50 pm, preferably from about 22 to about 30 pm. In another aspect, the pharmaceutical compositions comprising luliconazole having a dio from about 1 to about 10 pm, preferably from about 5 to about 10 pm. In context of the present invention, the particle size can be determined by Malvern analyzer.

Foaming height of the composition was determined to ensure the foaming ability. The invention provides pharmaceutical compositions having a foaming height from about 100 to about 300 mm, preferably from about 150 to about 200 pm. In context of the present invention, the foaming height can be determined by Cylinder shake method.

The term "stable topical composition” is used to refer to a pharmaceutical composition for application to body surfaces such as the skin, or scalp to treat ailments. The composition may be in any of a range of dosage forms including but not limited to creams, foams, shampoos, powders, gels, lotions, patches, ointments, suspensions and solutions. The composition can be packed in various suitable containers such as tubes, bottle (such as amber color glass, HDPE), pump thereof. All numbers expressing quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about." The word "about" means plus or minus 10% of the stated number.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

The term "Substantially free' means an amount of a material that is less than 1%, 0.5%, 0.25%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of a composition.

The present invention is further illustrated by reference to the following examples which is for illustrative purpose only and does not limit the scope of the invention in any way.

Examples:

Example 1: Topical composition comprising Luliconazole The composition of example 1 can be prepared by using following process:

1. Disodium laureth sulfosuccinate, purified water and luliconazole were charged in a vessel.

Stirred to get uniform dispersion. Homogenized the phase till to get uniform slurry. 2. In another vessel purified water was taken and carbopol silk 100 was added in it. Further it was stirred to get uniform dispersion.

3. Sodium carboxy methyl cellulose was added to step-2 and stirred to get uniform dispersion.

4. Step-01 added to step-03 and stirred to get uniform dispersion. 5. Cocoamidopropyl betaine, KF8020, Merquat 2003PR, Miranol C2M, PEG-7 glyceryl cocoate were added one after another to step-04 and stirred to get uniform dispersion.

6. In suitable container purified water was taken and disodium edetate, Imidurea were dissolved in it under stirring to get uniform solution.

7. Step-06 was added to step-05 and stirred to get uniform dispersion. 8. Laureth-3 and perfume was added to step-07 and stirred to get uniform dispersion.

9. SLES paste 70% was added to step-08 and stirred to get uniform dispersion.

10. pH of step-09 was adjusted by using sodium hydroxide solution to 5.00-7.50

11. Weight of batch was made by using purified water. Example 2: Topical composition comprising Luliconazole

The composition of example 2 can be prepared by using following process:

1. Disodium laureth sulfosuccinate, purified water and luliconazole were charged in a vessel.

Further it was stirred to get uniform dispersion. Homogenized the phase till to get uniform slurry. 2. In another vessel purified water was taken and carbopol silk 100 added in it. Stirred to get uniform dispersion.

3. Sodium carboxymethylcellulose was added to step-2 and stirred to get uniform dispersion.

4. Step-01 added to step-03 and stirred to get uniform dispersion. 5. Cocoamidopropyl betaine, KF8020, merquat 2003PR, miranolC2M, PEG-7 glyceryl cocoate were added one after another to step-04 and stirred to get uniform dispersion.

6. In suitable container purified water was taken and disodium edetate, Imidurea dissolved in it under stirring to get uniform solution.

7. Step-06 was added to step-05 and stirred to get uniform dispersion. 8. Laureth-3 and perfume was added to step-07 and stirred to get uniform dispersion.

9. Sulfate free base was added to step-08 and stirred to get uniform dispersion.

10. pH of step-09 was adjusted using sodium hydroxide solution to 5.00-7.50

11. Weight of batch was made by using purified water. Example 3: Topical composition comprising Luliconazole

Manufacturing process for example 3A, 3B, 3C, 3E, 3F and 3G:

1. Disodium laureth sulfosuccinate, Laureth-3, purified water were taken and luliconazole API added in it. Further stirred to get uniform dispersion.

2. Purified water taken and Carbopol silk 100 added. Further stirred to get uniform dispersion.

3. Sodium carboxymethylcellulose added to step-2 and stirred to get uniform dispersion.

4. Step-01 added to step-03 and stirred to get uniform dispersion.

5. Cocoamidopropyl betaine, Dimethicone and aminopropyldimethicone (KF8020), Polyquaternium-53 (Merquat 2003PR), Disodium cocoampho diacetate (Miranol C2M), Glyceryl cocoate added one after another to step-04 and stirred to get uniform dispersion.

6. In suitable container purified water taken and disodium edetate, Imidurea dissolved under stirring to get uniform solution.

7. Step-06 added to step-05 and stirred to get uniform dispersion.

8. Perfume added to step-07 and stirred to get uniform dispersion. 9. SLES paste 70% added to step-08 and stirred to get uniform dispersion.

10. pH of step-09 adjusted using 3M sodium hydroxide solution to 6.00-7.00

11. Weight of batch made by using purified water. Manufacturing process for example 3D remains same except with the addition of sodium chloride in step 6and addition of polyquaternium-7 in step 5.

The compositions of batches 3D, 3E and 3F were subjected to stability studies at different conditions. The results of the same are as follows:

Stability Study data for example 3D, 3E and 3F:

Example 4: Evaluation of conditioning was carried out by two methods:

Method 4a: Sensory evaluation method using compositions containing luliconazole 2%w/w as described in example 3. The objective of this method is to check the softness, smoothness, and manageability of hair against marketed anti dandruff shampoo (the bench mark sample). Brief of protocol for Sensory evaluation of hair swatches by panel:

• Selection of hair swatches for evaluation.

• Each hair swatches weight should be 10 gm (± 10 %). • Before start the evaluation process, selected swatches washed with 14% active sodium laureth sulfate solution.

• Then wash with Test sample: (test sample quantity should be 10% of the hair swatches weight.)

• Dry the hair swatches with hair dryer in medium blow. After blow dry swatches comb one time and hair swatches are ready for Sensory evaluation against Control sample (Hair swatches washed with 14% active sodium laureth sulfate solution) and Benchmark.

Evaluation parameters to check hair sensory involved:

• Smoothness: Degree of easiness during fingers move down throughout the hair swatches without any resistance or hair tangling.

• Softness: When hair swatches touch with finger, how much cushiony or velvet like feel one would have over control swatches. Also easy to press and easily change shape or bends easily when you press it.

• Manageability: The tendency of the individual hair to repel each other during combing after three strokes of combing down hair swatches.

Conclusion: Luliconazole anti-dandruff shampoo samples were found to have better smoothness, softness & manageability shown in figure 1 and 2

Method 4b: Red 80 dye method using composition containing luliconazole 2%w/w as described in example 3.

The objective of this method was to check the conditioning via cationic polymer deposition.

The test sample was found to be better for softness, smoothness and manageability than marketed anti dandruff shampoo

Procedure:

• Wool cloth pieces of equal size (2cm x 8cm) was taken for cationic polymer deposition evaluation.

• Initially washed with 10% active sodium laureth sulfate solution by applying 0.4 gm of the solution and then gently rubbed out with 20 strokes for 40 sec. washing process repeated once again.

• After towel dry of swatches 0.4 gm test sample applied into each wool swatch, massaging the swatch by gently holding the swatch between the index finger and middle finger and passing the index finger and middle finger from root of the swatch to the tip, stroke rate should 1 stroke per 2 sec.

• Swatch washed under running tap water for 45 sec to 1.0 minute by massage the swatch unidirectional from root to tip.

• Swatch was dipped into 10 gm previously made Red 80 dye solution in a petri dish for 1 minute, then dip the swatch into a 1 liter beaker water for 20 times to rinse excess dye solution and dried the swatch for evaluation.

• Same process repeated for control sample to compare Red colour intensity by visually/instrumentally against test sample.

Conclusion: After evaluation it was concluded that batch of test samples anti dandruff shampoo reflected better conditioning agent deposition ability than marketed Antidandruff shampoo and control as the deposition of red dye is higher and quite visible as shown in figure 3 and 4.

Example 5: Toxicity study of Lulicon azole shampoo

Example 5a: Repeated dose 90 days dermal toxicity study in Rodents (Wistar Rats) with 14 days and 28 days recovery period using composition as described in example 3.

Objective: To determine toxicity, major toxic effects of Luliconazole shampoo (test item/sample) following the repeated dermal application for 90 consecutive days to Wistar rats and compare it with that of reference item.

No of animals and Groups: 212 animals (106 of each gender) randomized into 6 groups and 16 animals/each gender/ group (32 animals/group)

Methodology: Total Groups contained 1%, 2% and 4% of test item, Placebo group and reference marketed Shampoo 2% group and 2 reversal groups with Control and 4% group.

Topical application of Dose Volume= 2.5ml/kg body weight (undiluted test items) on 10% of the Total BSA.

Exposure contact period: 1 hour contact period

Before application, site of application was dabbed with moist cotton soaked in water to mimic the intended mode of administration in humans. The application area was covered with porous gauze and non-irritating tape to prevent the access and ingestion of test item by the animal during the exposure period After 1 hour duration, thorough cleaning and washing off of the test item was ensured

Duration of Dosing: 90 consecutive days

Conclusion: No Observed Adverse Effect Level (NOAEL) of Luliconazole shampoo (test sample) was found to be at 4% at 2.5 mL/kg b.w. when applied to Rodent species (Wistar rats) for a period of 90 consecutive days through topical application route followed by 14 and 28 day recovery period under the conditions tested.

Example 5b: Pilot Study Repeated dose 14 days dermal toxicity study with 7 days of observation in New Zealand White Rabbits among 7 groups using composition as described in example 3.

Objective: To assess and evaluate the dermal toxicity potential and major toxic effects of Luliconazole shampoo (test sample) compositions following the repeated dermal application for 14 days to New Zealand white Rabbits and to compare the dermal toxicity potential/irritation potential with active comparator/Reference item as well as with positive active control

No of animals and Groups: 30 animals (14 animals of each gender) randomized into 7 groups [2 animals/ gender/ group]

Groups: Two Formulations of 2% strength of test item (T 04 and T05) and their respective placebo formulation; negative control group (normal saline), positive control group (70% SLES paste) and reference item 2% Shampoo

Methodology: Topical application of Dose Volume= 2.5ml/kg body weight (undiluted test items) on 10% of the Total BSA.

Exposure contact period: 1 hour contact period

Before application, site of application was dabbed with moist cotton soaked in water to mimic the intended mode of administration in humans. The application area was covered with porous gauze and non-irritating tape to prevent the access and ingestion of test item by the animal during the exposure period. After 1 hour duration, thorough cleaning and washing off of the test item was ensured

Duration of Dosing: 14 days for test item groups, placebos and reference item. For active control group (70% SLES) Days of dosing 4 days. The animals were observed for 7 days after completion of dosing Conclusion: The extent of wrinkling and sloughing (mild) as well as incidences i.e. irritant properties of Luliconazole shampoo (test sample) formulation were comparable with that of the marketed shampoo.

Example 5c: Preclinical Repeated dose 90 days dermal toxicity study in New Zealand White Rabbits with 14 days and 28 days recovery period using formulation as described in examples 3.

Objective: To determine toxicity, major toxic effects of Luliconazole shampoo (test sample) following the repeated dermal application for 90 consecutive days (application for 5 days/week) to New Zealand white Rabbits with 14 and 28 days of recovery period as well as to compare the dermal toxicity potential or irritation of Luliconazole shampoo (test sample) with reference group. No of animals and Groups: 106 animals (53 animals/gender) were randomized into 9 groups [5 animals/gender/group and 6 animals/gender/group in reversal groups]

The 9 groups, Luliconazole shampoo (test sample) test item in graded strengths 1%, 2% and 4%; One normal saline group and placebo group, reference item group. Three reversal groups (Placebo, 4% and reference group)

Methodology in Brief: Topical application of Dose Volume= 2.5ml/kg body weight (undiluted test items) on 10% of the Total BSA.

Exposure contact period: 1 hour contact period

Before application, site of application was dabbed with moist cotton soaked in water to mimic the intended mode of administration in humans. The application area was covered with porous gauze and non-irritating tape to prevent the access and ingestion of test item by the animal during the exposure period

After 1 hour duration, thorough cleaning and washing off of the test item was ensured

Duration of Dosing: 5 days/week; 1 hour daily for 90 consecutive calendar days

Conclusion: The test item Luliconazole shampoo (test sample) 2% is comparable with reference marketed shampoo in terms of skin irritation potential. No Observed Adverse Effect Level (NOAEL) of Luliconazole shampoo (test sample) was observed at 4% at 2.5ml/kg body weight; when topically applied to New Zealand white Rabbits for a period of 90 days consecutive days (5 days/week application) Example 5d: Comparative Evaluation of Eye Irritation / Corrosion potential of Luliconazole shampoo (test sample) with Reference item in New Zealand White Rabbits using formulation as described in examples 3.

Objective: To assess and evaluate irritant/corrosive potential of Luliconazole shampoo (test sample) following single application in Rabbit eye; to obtain the information about the effects of ocular exposure in the undiluted and diluted form in comparison with the reference marketed shampoo.

No of animals and Groups: 15 animals (3 animals/group) ; 5 groups [placebo, test item, Diluted test item (15%) , Reference item and diluted reference item (15%)]

Test item / reference item was diluted with RO water to achieve 15 % dilution (e. g: 15 mL RO water will be added to 85 mL test item/reference item).

Methodology: Test item/reference item/placebo was instilled on day 1.

A volume of 0.1 mL of placebo/test item/reference item was directly instilled into the right eye. The left eye of each animal that was not treated with a test item / reference item, was treated with topical anesthetics, which served as a control.

The test item/reference item was instilled in the conjunctival sac of right eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second in order to prevent loss of the material. The eyes of the test animals were washed with saline after 15 minutes following application of the placebo / test item / reference item, if considered appropriate to remove residual placebo / test item / reference item. Eye washing was done slowly, such that pressure of wash solution should not damage the eye.

Eye observation for any lesions in conjunctiva, cornea, iris will be done and ocular reactions will be graded at 1 hour, 24 hours, twice daily till day 8

Conclusion: The test item and placebo items have minimally irritating eye irritation potential. The Eye Irritation potential of Luliconazole shampoo (test sample) and Placebo is comparable with that of the reference item when tested in undiluted and diluted form (15%) with single dose application in the eyes of the New Zealand white Rabbits.