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1. (WO2019003098) COMPOSITION PHARMACEUTIQUE TOPIQUE COMPRENANT DU MICONAZOLE ET DU LULICONAZOLE OU DES SELS DE CEUX-CI
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TOPICAL PHARMACEUTICAL COMPOSITION COMPRISING

MICONAZOLE AND LULICONAZOLE OR SALTS THEREOF

FIELD OF THE INVENTION

The present invention relates to topical pharmaceutical composition comprising Miconazole and Luliconzole or salts thereof in the treatment of fungal infection.

BACKGROUND OF THE INVENTION

An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host. Topical antifungals are products that treat fungal infections and which are applied directly to the skin, nails, or hair; vaginally; or inside the mouth. Fungal infections are caused by dermatophytes, yeasts, and molds. There are about 40 different species of dermatophyte, and they obtain their nutrients from keratinized material, so typically are the organisms responsible for fungal infections of the skin, scalp or nails. Yeasts are normal inhabitants of our skin but sometimes they grow unheeded which can result in symptomatic infections. Molds are an uncommon cause of fungal infections but they can cause tinea nigra (painless brown or black patches on the skin) or hard-to-treat nail infections.

Like antibiotics, antifungal agents are classified into different categories. Azole and imidazole antifungal agents include Luliconzole, Miconazole, Clotrimazole (mainly topical application), Ketoconazole, Butoconazole, Oxiconazole and Econazole. Triazoles include Itraconazole, Fluconazole, Voriconazole and Posaconazole. Echinocandins include Caspofungin, Micafungin and Anidulafungin. Antimetabolites include Flucytosine. Allylamines like Terbinafine, Naftifine, Butenafine. Miscellaneous antifungals include Ciclopirox olamine, Haloprogin, Undecylenic acid, Benzoic acid and Salicylic acid.

Miconazole nitrate is a synthetic antifungal agent. Chemically Miconazole nitrate is l-[2, 4-dichloro-B- {(2,4-dichlorobenzyl)oxy} phenethyl] imidazole mononitrate and its molecular weight is of 479.15. Its empirical formula is C18H14CI4N2OHNO3. Miconazole nitrate is represented by compound of structural formula I


(Formula I)

Miconazole nitrate is a white to almost white powder. It is soluble in water and organic solvents such as ethanol, dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF), propylene glycol or pyridine.

Miconazole nitrate topical cream (2%) was approved in USA prior to Jan 1 , 1982 under the trade name "Monistat-Derm" and was indicated for the treatment of tinea pedis (athlete's foot), tinea cruris and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes , and Epidermophyton floccosum, in the treatment of cutaneous candidiasis (moniliasis) and in the treatment of tinea versicolor.

Luliconazole is an azole antifungal agent. Chemically Luliconazole is (2E)-2-[(4R)-4-(2,4-dichlorophenyl)- 1 ,3-dithiolan-2-ylidene]-2-imidazol- 1 -ylacetonitrile and its molecular weight is of 354.28. Its empirical formula is C14H9CI2N3S2. Luliconazole is the R enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration. Luliconazole is represented by compound of structural formula II.

(Formula II)

Luliconazole drug substance is a pale to light yellow crystalline powder. It is low soluble in water and soluble in acetonitrile, dimethyl sulfoxide and methanol.

Luliconazole topical cream (1%) was approved in USA on Nov 14, 2013 under the trade name "Luzu" and is indicated for the treatment of interdigital tinea pedis, tinea cruris and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older.

US 20160243147 discloses topical paste comprising one or more antifungal agents along with an inert powder and pharmaceutically acceptable topical carrier. It generically discloses antifungal agent such as clotrimazole, ketoconazole, miconazole, oxiconazole, econazole, luliconazole, terbinafine, nystatin, fluconazole, voriconazole, itraconazole, caspofungin, micafungin, naftifine, butenafine, amorolfine, ravuconazole, posaconazole, flucytosine, sertaconazole, efinaconazole, enilaconazole, saperconazole, sulconazole, terconazole, tioconazole, nikkomycin Z, anidulafungin (LY303366), pimaricin, griseofulvin, haloprogin, tolnaftate, undecylenate or any combination thereof. Further, this patent application specifically discloses nystatin containing antifungal composition.

The commercially available product or product known in the prior art for Luliconazole or Miconazole suffers from several adverse effects such as application site reactions, contact dermatitis, cellulitis, irritation, burning, maceration; therefore, these product does not provide patient compliance in the treatment of antifungal infection.

Further Miconazole or Luliconazole by themselves are not efficient in the treatment of topical fungal infection; since alone they do not provide broad spectrum of antifungal activity which is required in topical fungal infection.

Thus, there is an unmet need in the art to provide topical antifungal composition which provides broad spectrum antifungal activity with minimum adverse effect in the treatment of fungal infection.

Accordingly, the present invention provides a topical pharmaceutical composition comprising Miconazole and Luliconazole or salts thereof which is not only efficient but has minimum side effects thereby resulting in better patient compliance in the treatment of topical fungal infection.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a novel topical pharmaceutical composition comprising miconazole and luliconazole or salts thereof.

It is another object of the present invention to provide a topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or salts thereof which provide broad spectrum of activity in the treatment of fungal infection.

It is a further object of the present invention to provide a topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or salts thereof which provide minimum side effects in the treatment of fungal infection.

It is yet another object of the present invention to provide a topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or a salt thereof which is efficacious and provide better patient compliance in the treatment of fungal infection.

It is a further object of the present invention to provide a topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or salts thereof when monotherapy of either Miconazole or Luliconazole is inadequate in the treatment of fungal infection.

In another further object of the present invention to provide a topical pharmaceutical composition comprising Miconazole or salts thereof, Luliconazole or salts thereof along with Lauromacrogols and urea.

SUMMARY OF THE INVENTION

In one aspect the present invention provides a novel topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or salts thereof.

In another aspect the present invention provides a novel topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or salts thereof along with one or more pharmaceutically acceptable excipients.

In a further aspect the present invention provides a novel topical pharmaceutical composition comprising miconazole or salts thereof, luliconazole or salts thereof, along with lauromacrogol and urea and one or more pharmaceutically acceptable excipients.

In another further aspect the present invention provides a process of manufacturing topical pharmaceutical composition comprising Miconazole or salts thereof and Luliconazole or salts thereof along with one or more pharmaceutically acceptable excipients.

In yet another aspect of the present invention is to provide process of manufacturing topical pharmaceutical composition comprising Miconazole or salts thereof Luliconazole or salts thereof, lauromacrogols, urea along with one or more pharmaceutically acceptable excipients.

In yet another further aspect the present invention provides a topical pharmaceutical composition comprising Miconazole or salts thereof and Luliconazole or salts thereof in the treatment of topical fungal infection.

In another aspect of the present invention is to provide topical pharmaceutical composition comprising Miconazole or salts thereof and Luliconazole or salts thereof, lauromacrogol and urea in the treatment of topical fungal infection.

DETAIL DESCRIPTION OF THE INVENTION

The present invention relates to a topical pharmaceutical composition comprising Miconazole or salts thereof and Luliconazole or salts thereof.

The salts of Miconazole are selected from nitrate, maleate, hemifumarate, and hemisuccinate and the like. The preferred salt of miconazole is nitrate.

Similarly the salts of Luliconazole are selected from formic acid, acetic acid, citric acid, tartaric acid, bitartaric acid, benzoic acid, lactic acid, malic acid, fumaric acid, succinic acid, gluconic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid and the like. In a preferred embodiment luliconazole is used in its base form.

The present topical composition comprising Miconazole or salts thereof and Luliconazole or salts thereof are effective in the treatment of fungal infections. Fungal infection includes any infection associated with fungi. In the present context, fungal infection particularly includes tinea pedis (athlete's foot), tinea cruris, tinea corporis, cutaneous candidiasis (moniliasis), tinea versicolor, jock itch, or ringworm, skin infections caused by dermatophytes or yeasts and other.

Spectrum of antifungal activity of Miconazole nitrate includes many fungi, including yeasts and dermatophytes. It is particularly active against Candida spp. (C. guilliermondii and C. tropicalis), Trichophyton spp. (Trichophyton mentagrophytes and Trichophyton rubrum), Epidermophyton spp. (E. floccosum), Microsporum spp. (M. canis), Pityrosporon orbiculare {Malassezia furfur) and other, but also possesses some activity against Gram-positive bacteria {Staphylococcus aureus).

Spectrum of antifungal activity of Luliconazole includes dermatophytes, yeasts, and some other fungi. It is particularly active against Trichophyton spp. (T. rubrum, T. mentagrophytes, T. tonsurans, T. verrucosum, T. violaceum, Microsporum canis and M. gypseum, Epidermophyton floccosum), Candida albicans, Malassezia furfur, Malassezia restricta, Malassezia slooffiae, and Malassezia sympodialis and other.

The present invention provides a novel topical pharmaceutical composition effectively treats fungal infections; wherein Miconazole acts by inhibiting the 14a-demethylation of lanosterol, which consequently leads to the inhibition of ergosterol synthesis in fungal cell membranes. Additionally, miconazole has been shown to induce reactive oxygen species in fungal biofilms, demonstrating a MIC value of >256μΜ against Candida species; Luliconazole acts by inhibiting the ergosterol synthesis by inhibiting the enzyme lanosterol demethylase. Inhibition of this enzyme's activity by azoles results in decreased amounts of ergosterol, a constituent of fungal cell membranes, and a corresponding accumulation of lanosterol.

The topical pharmaceutical composition can be prepared using routine skills and techniques known in the art.

The pharmaceutical composition according to present invention comprises a pharmaceutically effective amount of Miconazole and Luliconazole.

In a preferred embodiment the topical pharmaceutical composition of the present invention comprises Miconazole nitrate and Luliconazole. The concentration of Miconazole nitrate is at least 0.005%; preferably ranges from 0.25 to 4%; more preferably the concentration is 2% by weight of composition. The concentration of Luliconzole is at least 0.001%; preferably the concentration ranges from 0.05 to 2%; more preferably the concentration is 1% by weight of composition.

The topical pharmaceutical composition comprising miconazole or salts thereof and luliconazole or salts thereof according to present invention provides synergism which broadens the spectrum of activity, enhance the rate or extent of killing (ex. through synergy), minimize development of resistance and reduce toxicities in the treatment of topical fungal infection.

In another preferred embodiment, the topical pharmaceutical composition comprising miconazole or salts thereof and Luliconazole or salts thereof according to present invention may further contain lauromacrogol and urea. The concentration of lauromacrogol is at least 0.1%; preferably may ranges from about 0.1% to 5%; more preferably concentration may be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by weight of composition. The concentration of urea is at least 0.01%; preferably may ranges from about 0.05% to 10%; more preferably concentration may be 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by weight of composition.

It was found that the topical composition of the present invention provides soothing and anti-itching properties because of the addition of Lauromacrogols and urea.

The topical pharmaceutical composition of the present invention may be in the form of cream, ointment, gel, paste, lotion and spray for the treatment of topical fungal infections.

The topical pharmaceutical composition of the present invention may contain one or more pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipients are selected from the group consisting of bases, solubilizing or emulsifying agent, preservative, antioxidant, gelling agent, thickening agent, humectant, adsorbent, permeation enhancer, opacifying agent, chelating agent, acidifying or alkalizing or buffering agent and vehicle.

The example of bases includes but not limited to Carnauba wax, Cetyl alcohol, Cetyl ester wax, Emulsifying wax, Hydrous lanolin, Lanolin, Lanolin alcohols, Vegetable oils and Animal fat; Coconut oil, Bees wax, Olive oil, Spermaceti wax, Sesame oil, Almond oil, Alcohols, Acids and Esters; oleic acid, Oleyl alcohol, Palmitic acid, Lauryl alcohol, Laurie acid, Myristyl alcohol, Ethyl oleate, Isopropyl myristate, Ethylene glycol,

Hydrogenated and Sulphated oils; Hydrogenated castor, Cotton seed, Hydrogenated sulphated castor oils, Microcrystalline wax, Liquid Paraffin, Petrolatum, Propylene glycol, Polyethylene glycol, Stearic acid, Stearyl alcohol and Cetostearyl alcohol. The amount of base present in the composition ranges from about 1-50%; preferably about 2-40%; more preferably about 2-30% by weight of composition.

The examples of solubilizing or emulsifying agent includes but not limited to Polysorbate 20, Polysorbate 80, Polysorbate 60, Poloxamer, Emulsifying wax, Sorbitan monostearate, Sorbitan monooleate, Sodium lauryl sulfate, Propylene glycol monostearate, Natural gums like Acacia and Tragacanth, Monovalent and Bivalent soaps, Lanolin, Cholesterol or Cholesterol esters, Triethanolamine and its salts, Dodecyl benzene sulfonate, Diethylene glycol monoethyl ether and Docusate sodium. The amount of solubilizing or emulsifying agent present in the composition ranges from about 0.05-10%; preferably about 0.1-5%; more preferably about 1-3% by weight of composition.

The example of preservative includes but not limited to Chorocresol, Benzoic acid, Phenyl mercuric nitrate, Benzyl alcohol, Benzoic acid and its salts, Boric acid, Methyl paraben, Propyl paraben, Trihydrate and Anhydrous Sodium Acetate, Chlorhexidine, Formaldehyde, Glutaraldehyde, Imidazolidinyl urea, Trichlosan, Benzalkonium chloride and Chloroxylenol. The amount of preservative present in the composition ranges from about 0.01 -5%; preferably about 0.05-2.5%; more preferably about 0.1-1.0% by weight of composition.

The example of antioxidant includes but not limited to Butylated hydroxyl anisole, Butylated hydroxyl toluene, Propyl gallate, Polyols like Sorbitol, Xylitol and Maltitol, natural extracts like Quillaia or lactic acid or urea, Lithium Chloride, Ascorbic acid, Sodium Metabisulfite, Carotinoids, Carotenes such as a-carotene, β-carotene and Lycopene, Chlorogenic acid, Tocopherols, Uric acid, Zinc oxide (ZnO) and Zinc sulphate (ZnS04). The amount of antioxidant present in the composition ranges from about 0.01-5%; preferably about 0.01-2.5%; more preferably about 0.01- 1.0% by weight of composition.

The example of gelling agent includes but not limited to Carbomer/Carbopols, Pemulen®, cellulose derivatives such as Methyl Cellulose, Hydroxy Ethylcellulose, Hydroxy Propyl methylcellulose, Carboxy methyl cellulose, Hydroxy propyl cellulose, Glycerol or Propylene glycol gelled with suitable agents such as natural gums such as Xanthan gum and Tragacanth, Fenugreek Mucilage, Pectin, Poloxamers (Pluronics), Alginate, Gelatin, Starch, Polyvinyl alcohol, Povidone etc. The amount of gelling agent present in the composition ranges from about 0.01-5%; preferably about 0.1-2.5%; more preferably about 0.25-1.0% by weight of composition.

The examples of thickening agent include but not limited to Carbomer, Hydrogenated castor oil, Methyl cellulose, Sodium carboxyl methyl cellulose, Carrageenan, Colloidal silicon dioxide, Natural gum such as Gelatin, Tragacanth gum and Guar gum, Hydroxypropyl cellulose, Hydroxypropyl methyl cellulose, Polyethylene oxide, Alginic acid, Paraffin, Cetostearyl alcohol, Polyethylene glycol, PEG 200, PEG 300, PEG 400, PEG 600, Monoethanolamine, Triethanolamine, Glycerol, Polyoxyethylene sorbitan monooleate, and Poloxamers, Polyvinyl pyrrolidone, various alcohols such as Polyvinyl alcohol, Ethanol or Isopropyl alcohol and Fumed silica.

The example of humectant includes but not limited to Glycerin, Glyceryl triacetate, Propylene glycol, Polyethylene glycol, Sorbitol solution, 1,2,6 Hexanetriol, Isopropyl myristate, Petrolatum, Isopropyl palmitate, Hydrogenated castor oil, Mineral oil, Polyoxymethylene urea and Potassium sorbate.

The example of adsorbent includes but not limited to Magnesium carbonate, Calcium carbonate, Starch, Cellulose and its derivatives.

The example of Permeation enhancer includes but not limited to Isopropyl myristate, Propylene glycol, Ethanol, Isopropyl alcohol, Oleic acid, Polyethylene glycol, Phospholipids, Cyclodextrins, Black pepper {Piper nigrum), Pyrrolidones, Dimethyl sulphoxide (DMSO), Decyl methyl sulphoxide (DCMS), Terpenes (Cineole, Eugenol, D-limonene, Menthol, Menthone) and Urea.

The examples of opacifying agent include but not limited to higher fatty alcohols such as Cetyl, Stearyl, Cetostearyl alcohol, Arachidyl and Behenyl alcohols, solid esters such as Cetyl palmitate, Glyceryl laurate, various fatty acid derivatives such as Propylene glycol and Polyethylene glycol esters, inorganic materials such as, Magnesium aluminium silicate, Zinc oxide, Titanium dioxide or other sunblocking agents.

The example of chelating agent includes but not limited to Ethylene diamine tetraacetate, Dimercaprol, Dimercaptosuccinic acid, Penicillamine, Deferoxamine, Deferasirox, Citric acid, Maleic acid, Phosphoric acid and like.

The example of Acidifying or alkalizing or buffering agent includes but not limited to Anhydrous and Monohydrate Citric acid, Phosphoric acid, Sodium hydroxide, Potassium Hydroxide, Sodium Bicarbonate, Potassium sorbate, Monobasic and Dibasic sodium Phosphate and Trolamine.

The example of vehicle includes but not limited to Purified water, Hexylene glycol, Propylene glycol, Oleyl alcohol, Propylene carbonate, Mineral oil, Almond oil, Cottonseed oil, Ethyl oleate, Isopropyl myristate, Isopropyl palmitate, Myristyl alcohol, Octyldodecanol, Olive oil, Peanut oil, Safflower oil, Sesame oil, Soybean oil and Squalene. The amount of vehicle present in the composition ranges from about 10-60%; preferably about 20-50%; more preferably about 30-50% by weight of composition.

In another aspect of present invention is to provide process of preparing topical pharmaceutical composition comprising Miconazole or salts thereof and Luliconazole or salts thereof and pharmaceutically acceptable excipients in the treatment of topical fungal infection. The process of manufacturing topical composition according to present invention involves trituration method, levigation method, fusion method, chemical reaction method or emulsification method.

The manufacturing process involves admixing miconazole or salts thereof and luliconazole or salts thereof, lauromacrogol and urea; optionally along with one or more pharmaceutically acceptable excipient to form cream, ointment, gel, paste, lotion and spray.

The topical pharmaceutical composition comprising miconazole and luliconzole or salts thereof according to present invention provides synergism which broadens the spectrum of activity, enhance the rate or extent of killing (ex. through synergy), minimize development of resistance and reduce toxicities in the treatment of topical fungal infection.

The topical pharmaceutical composition comprising miconazole and luliconzole or salts thereof according to present invention were evaluated for the In-vitro antimicrobial activity.

The In-vitro antimicrobial activity of topical pharmaceutical composition comprising miconazole and luliconzole or salts thereof according to present invention was performed using disc diffusion method. The fungal test organisms used were Candida albicans, Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Candida tropicalis.

The In-vitro antimicrobial activity of topical pharmaceutical composition comprising miconazole and luliconzole or salts thereof according to present invention, miconazole or salts thereof composition alone, luliconzole or salts thereof composition alone were performed on test organism. From the illustration of zone of inhibition (Table No. 1), it was found that composition comprising miconazole and luliconzole or salts thereof according to present invention when tested against Candida albicans, Trichophyton rubrum, Trichophyton, mentagrophytes, Epidermophyton floccosum and Candida tropicalis; thus topical composition comprising miconazole and luliconzole or salts thereof according to present invention provides synergism which broadens the spectrum of activity in topical fungal infection.

The In-vitro antimicrobial activity of cream formulations was performed by disc diffusion method and details are summarized below:

Test Organisms: Candida albicans, Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Candida tropicalis.

Products (Test sample):

1. Placebo

2. Placebo + Drug A which can be prepared according to Example 14

3. Placebo + Drug B which can be prepared according to Example 15

4. Placebo + Drug A + Drug B

Drug A:, Luliconazole 1%,

Drug B: Miconazole nitrate 2%

Drug A+ Drug B: Luliconazole 1% + Miconazole nitrate 2%

Diluent Used: 50% Methanol in Phosphate Buffer

Incubation Temperature: 30+1 °C for 24 - 72 hrs

Summary of Test Method:

• Inoculum suspensions of dermatophytes were prepared in sterile saline from 7 to 10 days old PDA slants that had been incubated at 30°C.

• Hyphal fragments and conidia were harvested with sterile wet swabs in saline, vortexed for 20 seconds and then kept at room temperature for 15 to 20 min to enable heavy, hyphal fragments and conidia to settle down.

• Homogenous suspensions of the supernatant were collected in new sterile tubes, adjusted to 0.1 O.D. at 530 nm, and then adjusted to achieve concentration of 106

CFU/ml.

• Inoculum suspension of yeast was prepared in sterile saline and adjusted to 106 CFU/ml.

• 40 ml of Sabouraud's dextrose agar (for dermatophytes) and Muller Hinton agar supplemented with 2% Glucose and 0.5 μg/ml Methylene blue (For yeast) is melted, cooled to 55°C and then inoculated with 1ml of the organism suspension.

• The inoculated agar is poured into the assay plate, and allowed to solidify.

• 6 mm discs loaded with formulations is placed on the assay plate.

• Plates were incubated at respective time and temperatures.

· After incubation, zone of inhibition was measured.

Observation Table:

Table No. 1


have merged

The topical pharmaceutical composition comprising miconazole and luliconazole or salts thereof according to present invention is packaged in to collapsible tubes, jars, pot, bottle or single dose packets. The container material or packaging material of the present invention does not affect the quality of the preparation or does not allow diffusion of any kind into or across the material of the container into the preparation.

EXAMPLES:

The following Examples are provided solely for illustrative purposes and are not meant to limit the invention in any way.

Example 1:

Manufacturing Process:

1. Luliconazole was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate at room temperature.

2. Miconazole nitrate was added to step 1, mixed using stirrer and heated at 65-70 °C to form uniform liquid.

3. Butylated hydroxy toluene, methyl paraben, cetostearyl alcohol, stearyl alcohol were added to step 2, at 65-70 °C to form clear oil phase.

4. Aqueous phase was prepared separately by dissolving polysorbate 80 in water, mixed using stirrer and heated at 65-70 °C.

5. Oil phase of step 3 was added to aqueous phase of step 4, under continuous stirring and cooled to room temperature.

6. Formed cream was filled in tubes and tubes were sealed.

Example 2:

Sr. No. I ngredicnls ( 111" » )

! · Micoi lazole nitrate 20

2· Lulicc mazole 10

3- Medii im chain triglycerides 100

4· Isoprc >pyl myristate 50

5· Propy lene glycol 250

6· Cetos tearyl alcohol 60

7· Stearj A alcohol 60

8· Polys arbate 80 25

9· Sorbil an monooleate 25

10· Lauro macrogol 20 η · Urea 5

12· Methj paraben 1.5

13· Butyl. ited hydroxy toluene 0.1

14· Purifi ed water q.s.

Total weight 1000

Manufacturing Process:

1. Luliconazole, butylated hydroxy toluene and methyl paraben were dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate at room temperature.

2. Miconazole nitrate was added to step 1, mixed using stirrer and heated at 65-70 °C to form uniform liquid.

3. Cetostearyl alcohol, stearyl alcohol were added to step 2, at 65-70 °C to form clear oil phase.

4. Aqueous phase was prepared separately by dissolving urea and dispersing lauromacrogol and polysorbate 80 in water, mixed using stirrer and heated at 65- 70 °C.

5. Oil phase of step 3 was added to aqueous phase of step 4, under continuous stirring and cooled to room temperature.

6. Formed cream was filled in tubes and tubes were sealed.

Example 3:

Sr. No. I ngredients ( I11R. R)

1 · Micon azole nitrate 20

2· Lulico nazole 10

3- Mediu m chain triglycerides 100

4· Isopro pyl myristate 50

5· Propy ene glycol 250

6· Cetost earyl alcohol 60

· Steary [ alcohol 60

8· Polysc rbate 60 25

9· Sorbit. an monostearate 25

10- Methy 1 paraben 1.5 η · Butyla ted hydroxy toluene 0.1

12. Purifie id water q.s.

Total weight 1000

Manufacturing Process:

1. Mixture of medium chain triglycerides, isopropyl myristate, propylene glycol prepared at room temperature.

2. Luliconazole and miconazole nitrate were dissolved in step 1

Cetostearyl alcohol, stearyl alcohol, butylated hydroxy toluene, methyl paraben and sorbitan monostearate were added to step 1 , heated at 65-70 °C to form Oil phase.

Aqueous phase was prepared by mixing polysorbate 60 in Purified water, mixed using stirrer and heated at 65-70 °C.

Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and cooled to room temperature.

Formed cream was filled in tubes and tubes were sealed.

Example 4:

Manufacturing Process:

1. Mixture of medium chain triglycerides, isopropyl myristate and propylene glycol was prepared at room temperature.

2. Luliconazole and miconazole nitrate were dissolved in step 1.

Cetostearyl alcohol, stearyl alcohol, butylated hydroxy toluene, methyl paraben and sorbitan monostearate were added to step 1 , heated at 65-70 °C to form oil phase.

Aqueous phase was prepared by mixing polysorbate 20 in water, mixed using stirrer and heated at 65-70 °C.

Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and cooled to room temperature.

Formed cream was filled in tubes and tubes were sealed.

Example 5:

Manufacturing Process:

1. Luliconazole, butylated hydroxy toluene and methyl paraben was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol, and sorbitan monooleate at room temperature.

2. Miconazole nitrate was added to step 1, mixed using stirrer and heated at 65-70 °C.

3. Cetostearyl alcohol, stearyl alcohol were added to step 2, heated at 65-70 °C to form Oil phase.

4. Aqueous phase was prepared by mixing polysorbate 80 in water, mixed using stirrer and heated at 65-70 °C.

5. Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and allowed to cool at room temperature.

6. Formed lotion was filled in bottle.

Example 6:

Sr. No. I ngredients ( ing g)

1 · Mic anazole nitrate 20

2· Luli ^onazole 10

3· Med ium chain triglycerides 100

4· Isop ropyl myristate 50

5· Prop ylene glycol 250

6· Ceto stearyl alcohol 60

7· Stea ryl alcohol 60

8· Laui omacrogol 25

9· Sorb itan monooleate 25

10 Ure£ l 1 η · Metl lyl paraben 1.5

12· But} dated hydroxy toluene 0.1

13. pun ed water q.s.

Total weight 1000

Manufacturing Process:

1. Medium chain triglycerides, isopropyl myristate, propylene glycol, butylated hydroxy toluene, methyl paraben and sorbitan monooleate were mixed at room temperature

2. Cetostearyl alcohol and stearyl alcohol were added to ste l, mixed using stirrer and heated at 65-70 °C.

3. Luliconazole and miconazole nitrate were added to step 2, and mixed to form oil phase.

4. Aqueous phase was prepared by dissolving urea and dispersing lauromacrogol in water, mixed using stirrer and heated at 65-70 °C.

5. Oil phase of step 3 was added to aqueous phase of step 4, under continuous stirring and allowed to cool at room temperature.

6. Formed cream was filled in tubes and tubes were heat sealed.

Example 7:

Sr. No. I ngredients ( m« g)

1 · Micoi nazole nitrate 20

2· Lulict Dnazole 10

3- Medii im chain triglycerides 100

4· Isopn )pyl myristate 50

5· Propy lene glycol 250

6· Cetos tearyl alcohol 60

7· Stean f\ alcohol 60

8· Polye thylene glycol monooleate 25

9· Sorbii tan monooleate 25

10 Meth; yd paraben 1.5 η · Butyl ated hydroxy toluene 0.1

12· Purifi ed water q.s.

Total weight 1000

Manufacturing Process:

1. Medium chain triglycerides, isopropyl myristate, propylene glycol, butylated hydroxy toluene, methyl paraben and sorbitan monooleate were mixed.

2. Cetostearyl alcohol and stearyl alcohol were added to step 1, mixed and heated at 65-70 °C.

Luliconazole and miconazole nitrate were added to step 2, mixed using stirrer and heated at 65-70 °C.

Aqueous phase was prepared by dissolving polyethylene glycol monooleate in water, mixed using stirrer and heated at 65-70 °C.

Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and cooled at room temperature.

Formed cream was filled in tubes and tubes were sealed.

Example 8:

Sr. No. I ngredients ( 111" « )

1 · Mico nazole nitrate 20

2· Lulic onazole 10

3· Medi um chain triglycerides 100

4· Isopr apyl myristate 50

5· Propj flene glycol 250

6· Cetos tearyl alcohol 60

7· Stear yl alcohol 60

8· Urea 1

9· Laurc )macrogol 10

10 Polys orbate 80 15

1 1■ Sorbi tan monooleate 25

12· Meth yl paraben 1.5

13· Butyl ated hydroxy toluene 0.1

14· Purifi ed water q.s.

Total weight 1000

Manufacturing Process:

1. Luliconazole was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate using stirrer.

2. Miconazole was added to step 1 and mixed.

3. Cetostearyl alcohol, stearyl alcohol, butylated hydroxy toluene and methyl paraben were added to step 2, mixed and heated at 65-70 °C.

4. Aqueous phase was prepared by dissolving Polysorbate 80, urea and lauromacrogol in water, mixed using stirrer and heated at 65-70 °C.

5. Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and cooled at room temperature.

6. Formed cream was filled in tubes and tubes were sealed.

Example 9:

Sr. No. I ngredients ( lllg g)

!· Mico nazole nitrate 20

2· Lulic onazole 10

3· Medi um chain triglycerides 100

4· Isopr apyl myristate 50

5· Propj flene glycol 250

6· Cetos tearyl alcohol 60

7· Stear y\ alcohol 60

8· Urea 1

9· Laurc jmacrogol 10

10 Polys orbate 80 15

1 1■ Sorbi tan monooleate 25

12· Sodivi im benzoate 1.5

13· Butyl ated hydroxy toluene 0.1

14· Purifi ed Water q.s.

Total weight 1000

Manufacturing Process:

1. Luliconazole was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate using stirrer.

2. Miconazole was added to step 1 and mixed.

3. Cetostearyl alcohol, stearyl alcohol and butylated hydroxy toluene were added to step 2, mixed and heated at 65-70 °C.

4. Aqueous phase was prepared by dissolving sodium benzoate, polysorbate 80, urea and lauromacrogol in water, mixed using stirrer and heated at 65-70 °C.

5. Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and cooled at room temperature.

6. Formed cream was filled in tubes and tubes were sealed.

Example 10:

Sr. No. I ngredients ( 111" « )

1 · Mico nazole nitrate 20

2· Lulic onazole 10

3· Medi um chain triglycerides 100

4· Isopr opyl myristate 50

5· Prop ene glycol 250

6· Cetoi stearyl alcohol 60

7· Stear yl alcohol 60

8· Urea 1

9· Laun jmacrogol 10

10 Polys orbate 80 15

1 1■ Sorbi tan monooleate 25

12· Meth yl paraben 1.5

13· Butyl ated hydroxy toluene 0.1

14· Carb amer 974P 5

15· Trieti lanolamine q.s.

16. Purif led water q.s.

Total weight 1000

Manufacturing Process:

1. Carbomer 974P was dispersed in part of water, using stirrer.

Luliconazole was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate using stirrer.

Miconazole was added to step 2 and mixed.

Cetostearyl alcohol, stearyl alcohol, methyl paraben and butylated hydroxy toluene were added to step 3, mixed and heated at 65-70 °C.

Aqueous phase was prepared by dissolving polysorbate 80, urea and lauromacrogol in water, mixed using stirrer and heated at 65-70 °C.

Oil phase step 4 was added to aqueous phase step 5, under continuous stirring and cooled at room temperature.

Soaked carbomer from step 1 was added step 6 using stirrer and desired pH and consistency was achieved by dropwise addition of triethanolamine.

Formed gel was filled in tubes and tubes were sealed.

Example 11:

Sr. No. I ngredients ( m» « )

1 · Mico nazole nitrate 20

2· Lulic onazole 10

3· Medi um chain triglycerides 100

4· Isopr opyl myristate 50

5· Propj »4ene glycol 250

6· Cetos ,tearyl alcohol 60

7· Stear yl alcohol 60

8· Urea 1

9· Laun )macrogol 10

10 Polys orbate 80 15 η · Sorbi tan monooleate 25

12· Meth yl paralben 1.5

13· Butyl ated hydroxy anisole 0.1

14· Purif ied water q.s.

Total weight 1000

Manufacturing Process:

1. Luliconazole was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate using stirrer.

2. Miconazole was added to step 1 and mixed.

3. Cetostearyl alcohol, stearyl alcohol, butylated hydroxy anisole and methyl paraben were added to step 2, mixed and heated at 65-70 °C.

4. Aqueous phase was prepared by dissolving Polysorbate 80, urea and lauromacrogol in water, mixed using stirrer and heated at 65-70 °C.

5. Oil phase step 3 was added to aqueous phase step 4, under continuous stirring and cooled at room temperature.

6. Formed cream was filled in tubes and tubes were sealed.

Example 12:

Sr. No. l ni>redienls ( mii ίί)

1 · Micon azole nitrate 20

2· Lulico nazole 10

3· Propy ene glycol 300

4· Poleth ylene glycol 400 400

5· Poleth ylene glycol 8000 q.s.

Total weight 1000

Manufacturing Process:

1. Mixture of propylene glycol and polyethylene glycol 400 was prepared at room temperature.

2. Phase of step 1 was heated at 65-70°C.

3. Polyethylene glycol 8000 was added to step 2, mixed and heated at 65-70°C. 4. Miconazole nitrate and Luliconzole were added to step 3, allowed to cool to room temperature.

5. Formed ointment was filled in suitable container.

Example 13:

Sr. No. I ngredients ( mg g)

! · Mic onazole nitrate 20

2· Mec hum chain triglycerides 100

3· Isop >ropyl myristate 50

4· Pro] xylene glycol 250

5· Cet astearyl alcohol 60

6· Stet iryl alcohol 60

7· Pob ^sorbate 80 25

8· Sorl aitan monooleate 25

9· Met hyl paraben 1.5

10- But ylated hydroxy toluene 0.1

1 1. Pur] fled Water q.s.

Total weight 1000

Manufacturing Process:

1. Miconazole nitrate was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate prepared using stirrer at room temperature and heated at 65-70 °C to form uniform liquid.

2. Butylated hydroxy toluene, methyl paraben, cetostearyl alcohol, stearyl alcohol were added to step 1 , at 65-70 °C to form clear oil phase.

3. Aqueous phase was prepared separately by dissolving polysorbate 80 in water, mixed using stirrer and heated at 65-70 °C.

4. Oil phase of step 2 was added to aqueous phase of step 3, under continuous stirring and cooled to room temperature.

5. Formed cream was filled in tubes and tubes were sealed.

Example 14:

Sr. No. I ngredients ( mg g)

L Lull conazole 10

2· Mec hum chain triglycerides 100

3· Isop >ropyl myristate 50

4· Pro] xylene glycol 250

5· Cet astearyl alcohol 60

6· Stet iryl alcohol 60

7· Pob ^sorbate 80 25

8· Sorl aitan monooleate 25

9· Met hyl paraben 1.5

10- But ylated hydroxy toluene 0.1

1 1. Pur] fled Water q.s.

Total weight 1000

Manufacturing Process:

1. Luliconazole was dissolved in mixture of medium chain triglycerides, isopropyl myristate, propylene glycol and sorbitan monooleate prepared using stirrer at room temperature and heated at 65-70 °C to form uniform liquid.

2. Butylated hydroxy toluene, methyl paraben, cetostearyl alcohol, stearyl alcohol were added to step 1 , at 65-70 °C to form clear oil phase.

3. Aqueous phase was prepared separately by dissolving polysorbate 80 in water, mixed using stirrer and heated at 65-70 °C.

4. Oil phase of step 2 was added to aqueous phase of step 3, under continuous stirring and cooled to room temperature.

5. Formed cream was filled in tubes and tubes were sealed.