FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"TOPICAL PREPARATION"
2. APPLICANT:


(a) NAME:
REMEDIA THERAPEUTICS PRIVATE LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
Act, 1956
(c) ADDRESS: Office # 1,3rd Floor, Karmalli Glass Tower, S. V. Road,
Panjim, Goa - 403 001, India.
3. PREAMBLE TO THEDESCRIPTION:
The following specification describes the invention.


Field of the Invention:
The present invention relates to non-greasy, antifungal composition for external application. More particularly, the invention relates to topical preparation comprising azole compounds to enhance absorption and thus effective treatment.
Background and prior Art:
Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death.
The azole antifungals currently in clinical use contain either two or three nitrogens in the azole ring and are thereby classified as imidazoles (e. g. ketoconazole, miconazole and clotrimazole) or triazoles (e. g. itraconazole and fluconazole), respectively. With the exception of Ketoconazole, use of the imidazoles is limited to the treatment of superficial mycoses, whereas the triazoles have a broad range of applications in the treatment of both superficial and systemic fungal infections. Another advantage of the triazoles is their greater affinity for fungal rather than mammalian cytochrome P-450 enzymes. Fluconazole is the current drug of choice for treatment of infectious caused by Candida species and C. neoformans.
Fluconazole has been widely used as effective anti-fungal agent in the clinical field. The chemical name of fluconazole is 2-(2,4-difluorophenyl)-l,3-bis (177-1,2,4-triazol-1 -yl) propan-2-ol and is expressed by Formula 1.



According to US4404216, the compound 2-(2,4-diflourophenyl)-l,3-bis (1,2,4-triazoI-l-yl)-propan-2-ol (Fluconazole - Formula I) belonging to the above group can be used as human fungicide. Fluconazole is one among other very effective human fungicide drug in the market.
Fluconazole, antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. Fluconazole is very slightly soluble in water and soluble in alcohol and commonly marketed under the trade name Diflucan or Trican. Like other imidazole and trjazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14a-demethylase.
Fluconazole is indicated for the treatment and prophylaxis of fungal infections where other antifungals have failed or are not tolerated (e.g. due to adverse effects), including Candidiasis, Tinea corporis, tinea cruris or tinea pedis, Onychomycosis, Cryptococcal meningitis.
U.S. Pat. No. 5,002,938 discloses topical antifungal gels containing imidazoles and 17-ester corticosteroids useful for treating fungal infections.
EP 1363626 discloses an antifungal preparation comprising (a) 0.1 to 5.0% by weight of fluconazole, (b) 1.0 to 40.0% by weight of one or more materials selected from fatty acid, fatty acid alcohol, higher fatty acid ester and lower alcohol, and (c) an external preparation base material, wherein the external preparation base material contains 1.0 to 20.0% by weight of a nonionic surfactant, 2.0 to 30.0% by weight of an oily material and 40.0 to 80.0%o by weight of water. The composition is formulated into a cream form or a gel form.
A composition useful for the topical treatment of inflammations associated with fungal infections of the skin or scalp consisting essentially of: (a) sulconazole and (b) a pharmaceutically acceptable carrier therefor, wherein the carrier contains a lower alcohol, a trihydroxy alcohol, a dihydroxy alcohol and water, is disclosed in US 5208015. Fluconazole is slightly soluble in water. Therefore, there is a need in the art to develop a topical formulation with better absorption to provide effective treatment.


Accordingly, the objective of the present invention is to provide an improved topical formulation comprising antifungal compound of azole group, a gelling agent, and one or more dissolution adjuvants.
Disclosure of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention provides an improved topical formulation comprising an antifungal compound, one or more dissolution adjuvants, a gelling agent, other pharmaceutical excipients and purified water as the vehicle.
This topically applied water based gel is non greasy, can be easily absorbed and is gentle on the skin. The water based gel of the current invention is gentle to the skin but hard on infected areas.
The formulation of the invention is non-greasy and easily penetrates into the skin providing enhanced absorption and thus effective therapy.
In a preferred embodiment, the invention provides topical formulation which comprises:
a) an antifungal compound in the range of 0.1% W/W to 5.0% WAV;
b) one or more dissolution adjuvants in the range of 0.5% W/W to 25% W/W;
c) gelling agent in the range of 0.05% W/W to 5.0% W/W and
d) purified water as a principle vehicle in the range of 20% WAV to 96% W/W.
Accordingly, anitfungal agents which belong to azole family are selected from Fluconzole, ketoconazole, Itraconazole, Ravuconazole, Posaconazole, Voriconazole and clo-trimaxazole that can be conveniently used in the range of 0.1% to 5.0%w/w.
The dissolution adjuvants are selected from polyhydroxy agents like propelene glycol, polyethelene glycol, glycerine, caster oil, sorbitol and lower alcohols like ethanol,

isopropanol etc. The topical formulation of the present invention comprises the dissolution adjuvants in the range of 0.5% W/W to 25% W/W.
The Gelling Agents are selected from the family of acrylic acid polymers like Carbomer 910, 934, 934P, 940, 941, 971P, 974P and the like. The gelling agent present is in amount ranging from 0.05% W/W to 5.0% WAV.
The compositions of the invention further comprises other suitable pharmaceutical aids such as antioxidants, preservatives, emulsifiers, Emollient like Cococaprilate caprate, chelating agents, alkalizing agent and a vehicle to deliver the drug. The vehicle is preferably purified water present in an amount of 20%) W/W to 96% W/W.
The topical composition of the present invention comprises one or more antioxidants like Butylated Hydroxyanisole, Butylated Hydroxytoluene, Propyl Gallate in the range of 0.001% W/W to 0.1% W/W.
The topical composition of the present invention comprises one or more preservatives like Methyl Paraben, Propyl Paraben, its salts, ethyl Paraben, Butyl Paraben, Sodium Benzoate, Phenoxyethanol etc used in the range of 0.01% WAV to 0.1% W/W
The chelating agents is sodium EDTA, preferably present in an amount of 0.005% W/W to 0.1 % WAV and the alkalizing agent, preferably diethyl amine present in an amount of 0.05% WAV to 2.5% WAV
In another preferred embodiment, the topical preparation of the present invention is achieved by dissolving parabens followed by disodium EDTA in purified water to obtain clear solution and mixing the same with azole compound dissolved in dissolution adjuvants. Finally, dispersing the gelling agent in the above solution under stirring and adjusting the pH between 6 to 7 with the aid of alkanizing agent and making up the volume with purified water to obtain clear gel.
It is critical that the fluconazole comprising topical composition should be in solubilized form to have improved therapeutic effect. Further, it is also required to have a non greasy


formulation to improve the feeling or discomfort when applied the composition onto the skin.
Accordingly, one preferred embodiment comprises the water based gel formulation which comprises
a) Fluconazole : 0.1% W/W to 5.0% W/W;
b) Gelling Agent: 0.05% W/W to 5.0% W/W;

c) Dissolution adjuvants like Polyols: 0.5% W/W to 25% W/W;
d) Preservatives: 0.01% W/W to 0.1% W/W;
e) Antioxidants: 0.001 % W/W to 0.1 % W/W;
f) Chelating Agents: 0.005% W/W to 0.1 % W/W;
g) Alkalizing Agent: 0.05% W/W to 2.5% W/W and
h) Vehicle: 20% W/W to 96% W/W
In yet another preferred embodiment, the invention provides Carbopol based emulsified gels prepared using two different approaches,
1) with alcohol and without parabens
2) without alcohol but with parabens
The emulsifier is selected from non-ionic surfactants like Cetomacrogol, Cremophore RH 40, etc.
In yet another preferred embodiment, the invention provides hydro alcoholic gel of carbopol prepared by dispersing carbopol in a mixture of water and isopropyl alcohol. Drug is dissolved in warm mixture of Propylene glycol and polyethylene glycol 400 and added to the Carbopol dispersion under stirring which is further neutralized by diethyl amine to a pH of around 6.5.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.


Examples
Example 1: Composition of the Gel

Sl.No. Ingredients % W/W
1 Fluconazole 0.5
2 Carbopol 974P 1.0
3 Propylene Glycol 0.5
4 Polyethylene Glycol 2.0
5 Methyl Paraben 0.18
6 Propyl Paraben 0.02
7 Disodium EDTA 0.05
8 Diethylamine (10% WAV solution in Water) Q.s
9 Purified Water Q.s.
Procedure:
1) Hot purified water (70°C-80°C) was collected in a suitable S.S. vessel, to this parabens were added and solution was cooled under continuous stirring to obtain clear solution at 25-30°C.
2) Disodium EDTA was added to solution in step 1 under stirring to obtain a clear solution.
3) In a separate vessel Polyethylene glycol 400 and Propylene glycol mixture was warmed to 50°C - 60°C. To this warm solution Fluconazole was added under continuous stirring to obtain a clear solution.
4) Fluconazole solution in step 3 was added to paraben solution in step 2 under stirring to obtain a clear solution.
5) Carbopol was dispersed in the bulk solution of step 4 under stirring and stirred to obtain a uniform dispersion.
6) 10% solution of Diethylamine was prepared and added to adjust the pH of the formulation to around 6.5 (6-7).
7) Weight was made up with purified water and gel was stirred further to obtain a clear gel.
7


Example 2: Emulsified gel:
Formulation containing Carbopol based emulsified gel were prepared with two different approaches,
1) with alcohol and without parabens
2) without alcohol but with parabens
Batches of the above two variants were formulated and subjected to stress testing which showed no change with respect to physical parameters. The batches were prepared by dissolving parabens in hot water (70-80°C). Carbopol was added to parabens solution (where parabens were present in formula) or to water/ Isopropyl alcohol mixture and dispersed. Warm mixture of propylene glycol and polyethylene glycol was used to dissolve drug and added to Carbopol dispersion. Cetomacrogol was heated to 70°C and to it Carbopol base was added under stirring at fast speed and neutralized with base to obtain pH 6-7.

Formula Emulsified gel base with Alcohol Emulsified gel base without Alcohol and with Parabens

%W/W %W/W
Fluconazole 0.5% 0.5%
Carbopol 974P 1.2% 1.2%
Propylene glycol 10.0% 10.0%
Isopropyl Alcohol 10.30% -
Methylparaben - 0.18%
Propylparaben - 0.02%
Cremophore RH 40 3.0% 3.0%
Cetomacrogol 1000 2.0% 2.0%
Cococaprilate caprate 3.0% 3.0%
Polyethylene glycol 400 5.0% 5.0%
Triethanolamine 0.8% 0.8%
DM Water Quantity Sufficient Quantity Sufficient


Example 3:
Hydro alcoholic Carbopol Gel:
Hydro alcoholic gel of carbopol was prepared by dispersing carbopol in a mixture of water and isopropyl alcohol. Drug was dissolved in warm mixture of Propylene glycol and polyethylene glycol 400 and added to the Carbopol dispersion under stirring which was further neutralized by diethyl amine to a pH of around 6.5.

Formula Hydro alcoholic gel base

%W/W
Fluconazole 0.5%
Carbopol 974P 1.0%
Propylene glycol 10.0%
Isopropyl Alcohol 10.30%
Disodium EDTA 0.05%
Polyethylene glycol 400 5.0%
Triethanolamine Q.s. to adjust pH to 6.5
DM Water Quantity Sufficient