FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
PROVISIONAL SPECIFICATION (SECTION 10)
"TOPICAL PHARMACEUTICAL COMPOSITION CONTAINING
VORICONAZOLE"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
Glenmark Pharmaceuticals Limited,Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East),
Mumbai - 400 099, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION: AND THE MANNER IN, WHICH IT IS TO BE PERFORME
1

TOPICAL PHARMACEUTICAL COMPOSITION CONTAINING VORICONAZOLE
BACKGROUND OF THE INVENTION
Technical Field
The present invention generally relates to a topical pharmaceutical composition of voriconazole without containing poloxamer for the treatment of anti-fungal activity against dermatophytic infections of skin,hair and nail such as Tinea Pedis, Tinea Cruris, Tinea Corporis, Tinea Faciei , Tinea Mannum, Tinea Captitis ,Tinea barbae, Tinea unguium, Tinea incognito, Tinea imbricate, Ectothrix, Endothrix caused by Epidermophyton floccosum, Microsporum audouinii, Microsporum canis, Microsporum canis var. disortum, Microsporum cookei, Microsporum equinum, Microsporum ferrugineum, Microsporum fulum, Microsporum gallinae, Microsporum gypseum, Microsporum nanum, Microsporum persicolor, Microsporum sp., Trichophyton concentricum, Trichophyton equinum, Trichophyton mentagrophyes var. nodulare, Trichophyton mentagrophytes var. erinacei, Trichophyton mentagrophytes var. interdigitale, Trichophyton mentagrophytes var. mentagrophytes, Trichophyton mentagrophytes var. quinckeanum, Trichophyton rubrum, Trichophyton rubrum downy strain, Trichophyton rubrum granular strain, Trichophyton schoenleinii, Trichophyton soudanense, Trichophyton sp., Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum but not for the treatment of Otitis Externa.
Description of the Related Art
Voriconazole is a triazole that is structurally related to fluconazole. It is developed by Pfizer Pharmaceuticals and the trade name of voriconazole is Vfend™. Voriconazole is designated chemically as (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fiuoro-4-pyrimidinyl)-l-(lH -l,2,4-triazol-l-yl)-2-butanol with an empirical formula of
2

C16H14F3N50 and a molecular weight of 349.3.Structurally Voriconazole is known

As with all azole antifungal agents, voriconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol.
Voriconazole is a white to off white crystalline powder which is very low soluble in water and is not stable in water .
A fungal infection is caused by a type of fungus called a dermophyte that infects the top layer of the skin, hair or nails. Fungal infections of the skin are known as ringworm (tinea). There are many types of ringworm, including body ringworm (tinea corporis), jock itch (tinea cruris), athlete's foot (tinea pedis), scalp ringworm (tinea capitis), nail ringworm (tinea unguium), and beard ringworm (tinea barbae), which is rare. In most cases, these infections are not life threatening. However, they may lead to more serious bacterial infections in the elderly and those who have conditions that affect the immune system.
Tinea (say: tih-nee-uh) is a type of fungal infection of the hair, skin, or nails. When it's on the skin, tinea usually begins as a small red area the size of a pea. As it grows, it spreads out in a circle or ring. Tinea is often called ringworm because it may look like tiny worms are under the skin . Because the fungi that cause tinea (ringworm) live on different parts of the body, they are named for the part of the body they infect.
3

Scalp ringworm is found on the head, and body ringworm affects the arms, legs, or chest.
Voriconazole is a triazole medicine used to treat fungal infections. It is effective against a broad spectrum of fungi and is usually reserved for the treatment of serious Candida and mould infections. It is indicated for the treatment of the following infections:
Fluconazole-resistant serious invasive Candida infections (including C. krusei) Oesophageal candidiasis ,Invasive aspergillosis ,Serious fungal infections caused by Scedosporium spp and Fusarium spp and other serious fungal infections, in patients intolerant of, or unresponsive to, other therapy.
By considering the low solubility parameter of Voriconazole, US 20050112204 application assigned to Pfizer Inc claims an invention comprising voriconazole and one or more poloxamer to treating a fungal infection in a mammal, including man. This patent discloses the use of poloxamer increases the solubility of voriconazole. It has now, surprisingly, been found by the inventor that the topical composition of Voriconazole can be prepared without using poloxamers.
Also, WO 2005032528 application assigned to FAIRFIELD CLINICAL TRIALS, LLC. This invention relates to a method of treating otitis externa, and in particular otitis externa of fungal etiology, using topical medication, including antifungal agents such as, for example voriconazole.The inventor of this application also has surprisingly found that Voriconazole can also be used for the treatment of anti-fungal activity against dermatophytic infections of skin,hair and nail such as Tinea Pedis, Tinea Cruris, Tinea Corporis, Tinea Faciei , Tinea Mannum, Tinea Captitis ,Tinea barbae, Tinea unguium, Tinea incognito, Tinea imbricate, Ectothrix, Endothrix. The voriconazole topical application mentioned herein in this specification is not for the treatment of otitis externa.
4

So the inventors of the present invention discovered that Voriconazole topical without poloxamer can be used in the treatment of dermatophytic infection other than otitis externa.
SUMMARY OF THE INVENTION
The first object of the invention is to make a therapeutic topical composition of Voriconazole devoid of poloxamer.
The second object of this invention is to prepare a topical Voriconazole composition for the treatment of disease other than Otitis Externa.
Further aspect of the invention is the topical application of Voriconazole is used to treat the dermatophytic infections.
Yet another aspect of the invention is the topical application of Voriconazole is used to treat the dermatophytic infections can be formulated in the form of topical, nasal and other uses, in formulations such as creams, ointments, gels, solutions, sprays and other topical preparations not mentioned here.
Yet another aspect of the invention is to provide the most preferred therapeutic topical dosage form of Voriconazole application is cream composition.
In accordance with further embodiment of the present invention is Voriconazole topical application is found effective against dermatophytic infections of skin, hair and nais.
In accordance with further embodiment of the present invention is to provide Voriconazole topical application is found effective against dermatophytic infections of skin,hair and nail such as Tinea Pedis, Tinea Cruris, Tinea Corporis, Tinea Faciei, Tinea Mannum, Tinea Captitis ,Tinea barbae, Tinea unguium, Tinea incognito, Tinea imbricate, Ectothrix, Endothrix
5

Voriconazole topical application is found effective against dermatophyte infections of skin,hair and nail such as Tinea Pedis, Tinea Cruris, Tinea Corporis, Tinea Faciei, Tinea Mannum, Tinea Captitis ,Tinea barbae, Tinea unguium, Tinea incognito, Tinea imbricate, Ectothrix, Endothrixcaused by Epidermophyton floccosum, Microsporum audouinii, Microsporum canis, Microsporum canis var. disortum, Microsporum cookei, Microsporum equinum, Microsporum ferrugineum, Microsporum fulum, Microsporum gallinae, Microsporum gypseum, Microsporum nanum, Microsporum persicolor, Microsporum sp., Trichophyton concentricum, Trichophyton equinum, Trichophyton mentagrophyes var. nodulare, Trichophyton mentagrophytes var. erinacei, Trichophyton mentagrophytes var. interdigitale, Trichophyton mentagrophytes var. mentagrophytes, Trichophyton mentagrophytes var. quinckeanum, Trichophyton rubrum, Trichophyton rubrum downy strain, Trichophyton rubrum granular strain, Trichophyton schoenleinii, Trichophyton soudanense, Trichophyton sp., Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum but not for the treatment of Otitis Externa
Another aspect of the invention is the process of preparation of topical composition of Voriconazole for the treatment other than otitis externa which is cost effective and commercially viable.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to a pharmaceutical compositions containing Voriconazole for the treatment other than Otitis Externa and the formulations of the invention include voriconazole and pharmaceutically acceptable salts, solvates, or derivatives thereof (wherein derivatives include complexes, prodrugs and isotopically-labelled compounds, as well as salts and solvates thereof).
But surprisingly inventor of this application has found that Voriconazole in the form of dermatological topical application can also be used for the treatment of dermatological infections like Tinea Pedis, Tinea Cruris, Tinea Corporis, Tinea Faciei
6

, Tinea Mannum, Tinea Captitis ,Tinea barbae, Tinea unguium, Tinea incognito, Tinea imbricate, Ectothrix, Endothrix caused by Epidermophyton floccosum, Microsporum audouinii, Microsporum canis, Microsporum canis var. disortum, Microsporum cookei, Microsporum equinum, Microsporum ferrugineum, Microsporum fulum, Microsporum gallinae, Microsporum gypseum, Microsporum nanum, Microsporum persicolor, Microsporum sp., Trichophyton concentricum, Trichophyton equinum, Trichophyton mentagrophyes var. nodulare, Trichophyton mentagrophytes var. erinacei, Trichophyton mentagrophytes var. interdigitale, Trichophyton mentagrophytes var. mentagrophytes, Trichophyton mentagrophytes var. quinckeanum, Trichophyton rubrum, Trichophyton rubrum downy strain, Trichophyton rubrum granular strain, Trichophyton schoenleinii, Trichophyton soudanense, Trichophyton sp., Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum but not for the treatment of Otitis Externa
The terms "active agent" "active pharmacological ingredient" and "drug" are used interchangeably herein to refer to Voriconazole and its acceptable salts,solvates,hydrates thereof.
The term "effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder, condition or causing an action, is sufficient to effect such treatment or action. The "effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
7

The pharmaceutical composition described herein in this specification is applied topically and this pharmaceutical composition includes Stiffening agent, emulsifier,emmolient,spreading agent, preservatives, cream vehicle, chelating agent, humectants, solubilizer etc.This invention does not limit the use of only these ingredients in the pharmaceutical composition , but all those ingredients suitable for manufacturing the said topical composition can also be used that are known to the person skilled in the art.
As used herein, the term "Stiffening agent" also known as "forming agent" is intended to mean an agent which helps in giving a thick consistency to the topical applications. The stiffening agents includes by way of example and without limitation ingredients such as cetyl alcohol,stearyl alcohol,Glyceryl monostearate ,white soft paraffine etc.
As used herein, the term "emulsifier" is intended to mean a compound used is generally a nonionic, anionic, cationic, or amphoteric surfactant. Such compounds include but are not limited to ,Glyceryl stearate , glyceryl monostearate,cetomacrogols etc.
As used herein, the term "emmolient" is intended to mean a compound that are substances which soften and soothe the skin. They are used to correct dryness and scaling of the skin .Such compounds include but are not limited to liquid paraffine, white soft paraffin, polyoxyl 20 cetyl ether, polyethylene glycol Simethicone etc.
As used herein, the term "spreading agent " is intended to mean an agent that helps in distributing the drug in the topical composition uniformly on the surface of skin. Such compounds include, by way of example and without limitation, Silicone oil of varying viscosity,Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl laurate and dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C.sub.16 -C.sub.18 fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C.sub.12 -C.sub.18 chain length, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate,
8

waxy fatty acid esters, such as synthetic duck uropygial gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter and the like
As used herein, the term "preservative " is intended to mean an agent that protects the formulation from degradation or detonation by avoiding oxidation, hydrolysis, or photolytic chemical reactions. Such compounds include, by way of example and without limitation, phenoxyethanol, methylparaben and the like which specifically avoids the oxidative degradation of the formulation.
As used herein, the term "vehicle " is intended to mean an agent such but are not limited to water, low/medium chain alcohols, propylrnr glycol, liquid paraffine, etc.
As used herein, the term "chelating agent "is intended any suitable substance, but not limited to ethylenediamine tetra-acetic acid (EDTA) or any of the disodium, trisodium, dipotassium, and tripotassium salts of EDTA etc.
As used herein, the term "humectants " is intended to mean an agent that reduces the drying out the composition either in the pharmaceutical dosage form or when applied on the surface of skin. Such compounds include, but are not limited to sorbitol, xylitol, glycerol, maltose, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, sodium pyrrolidone carboxylate, lactic acid, sodium lactate, polyoxypropylene fatty acid esters, polyethylene glycol, etc., can be exemplified and the like.
As used herein, the term "solubilizer " is intended to mean an agent that is used in the composition to increase the solubility of therapeutically active compound , such compounds include but are not limited to ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof.
9

Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), the contents of which are incorporated by reference herein.
The examples mentioned below demonstrate some illustrative synthetic procedures for preparing the pharmaceutical compositions described herein. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the disclosure.
Voriconazole Cream 0.5 % w/w Example 1 :

STEP INGREDIENTS % OF FORM
1 White Soft Paraffin 7.000
Glyceryl Monostearate (SE) 2.000
Cetomacrogol 1000 2.500
Cetyl Alcohol 3.000
Stearyl Alcohol 3.000
Brij 58 (Polyoxyl 20 Cetyl Ether) 1.500
Liquid Paraffin 6.000
Dimethicone 350 0.200
Methylparaben 0.200
Propylparaben 0.020
II Purified Water 66.019
Disodium Edetate 0.050
Glycerine 2.000
ill Vorriconazole 0.511
Pharmasolve (N-Methyl 2 Pyrrolidone) 3.000
10

Polyethylene Glycol (PEG 400) 3.000
MANUFACTURING PROCESS
1 Oleagineous Phase
In ss container add White Soft Paraffin, Cetomarogol 1000, Glyceryl Monostearate,Cetyl Alcohol ,Stearyl Alcohol, Brij 58 (Polyoxyl 20 Cetyl Ether), Liquid Paraffin, Dimethicone 350, Methylparaben, Propylparaben.Heat on water bath up to 80°C to dissolve Voriconazole completely
2 Aqueous Phase
In ss container add Purified Water, Disodium Edetate, Glycerine, Heat on water bath up to 70°C to 72°C.
3 Emulsification Phase
Add step 1 to step 2 at 70°C under stirring and homogenise for 10 minutes.
4 Cooling After Emusification
After 10 minutes of homogenisation start cooling under stiring.
5 Polyethylene Glycol (PEG 400) Phase
Take required amount of Voriconazole , Add under stirring.Pharmasolve .dissolve completely.Use Polyethylene Glycol (PEG 400) ( For rinsing container) and Add slowly to main bulk at 40°C under stirring . Check pH and weight.
Example 2 :

STEP INGREDIENTS % OF FORM
1 White Soft Paraffin 7.000
Glyceryl Monostearate (SE) 2.000
11

Cetomacrogol 1000 2.500
Cetyl Alcohol 3.000
Stearyl Alcohol 3.000
Brij 58 (Polyoxyl 20 Cetyl Ether) 1.500
Liquid Paraffin 6.000
Dimethicone 350 0.200
Methylparaben 0.200
Propylparaben 0.020
II Purified Water 65.507
Disodium Edetate 0.050
Glycerine 2.000
III Voriconazole 1.023
Pharmasolve (N-Methyl 2 Pyrrolidone) 3.000
Polyethylene Glycol (PEG 400) 3.000
MANUFACTURING PROCESS
1 Oleagineous Phase
In ss container add White Soft Paraffin, Cetomarogol 1000, Glyceryl Monostearate,Cetyl Alcohol ,Stearyl Alcohol, Brij 58 (Polyoxyl 20 Cetyl Ether), Liquid Paraffin, Dimethicone 350, Methylparaben, Propylparaben.Heat on water bath up to 80°C to dissolve Voriconazole completely.
2 Aqueous Phase
In ss container add Purified Water, Disodium Edetate, Glycerine, Heat on water bath up to 70°C to 72°C.
3 Emulsification Phase
Add step 1 to step 2 at 70°C under stirring and homogenise for 10 minutes.
4 Cooling After Emusification
12

After 10 minutes of homogenisation start cooling under stiring.
5 Polyethylene Glycol (PEG 400) Phase
Take required amount of Voriconazole , Add under stirring.Pharmasolve .dissolve completely.Use Polyethylene Glycol (PEG 400) (For rinsing container) and Add slowly to main bulk at 40°C under stirring. Check pH and weight.
Example 3 :

STEP INGREDIENTS % OF FORM
1 White Soft Paraffin 7.000
Glyceryl Monostearate (SE) 2.000
Cetomacrogol 1000 3.500
Cetyl Alcohol 4.000
Stearyl Alcohol 4.000
Labrafil M 1944 CS (Oleoyl Macrogolglycerides) 2.000
Brij 58 (Polyoxyl 20 Cetyl Ether) 2.000
Liquid Paraffin 6.000
Dimethicone 350 0.200
Methylparaben 0.200
Propylparaben 0.020
II Purified Water 58.984
Disodium Edetate 0.050
Glycerine 2.000
III Voriconazole 2.046
Pharmasolve (N-Methyl 2 Pyrrolidone) 3.000
Polyethylene Glycol (PEG 400) 3.000
13

1 Oleagineous Phase
In ss container add White Soft Paraffin, Cetomarogol 1000, Glyceryl Monostearate,Cetyl Alcohol ,Stearyl Alcohol, Brij 58 (Polyoxyl 20 Cetyl Ether), Liquid Paraffin, Dimethicone 350, Methylparaben, Propylparaben.Heat on water bath up to 80°C to dissolve Voriconazole completely
2 Aqueous Phase
In ss container add Purified Water, Disodium Edetate, Glycerine, Heat it on water bath up to 70°C to 72°C.
3 Emulsification Phase
Add step 1 to step 2 at 70°C under stirring and homogenise for 10 minutes.
4 Cooling After Emusification
After 10 minutes of homogenisation start cooling under stiring.
5 Polyethylene Glycol (PEG 400) Phase
Take required amount of Voriconazole , Add under stirring.Pharmasolve .dissolve completely.Use Polyethylene Glycol (PEG 400) (For rinsing container) and Add slowly to main bulk at 40°C under stirring. Check pH and weight.
Dated this Eighteenth (18th) day of August, 2006

Taranpreet Lamba. (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited
14