FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
TOPICAL CREAM COMPOSITIONS OF SERTACONAZOLE NITRATE
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER
IN WHICH IT IS TO BE PERFORMED
1

FIELD OF THE INVENTION
The present invention relates generally to improved topical pharmaceutical formulations, their uses and methods of manufacturing. Specifically, the present invention relates to improved topical cream formulations of Sertaconazole or its pharmaceutically acceptable salts there of.
BACKGROUND OF THE INVENTION
Sertaconazole nitrate contains one asymmetric carbon atom and exists as a racemic mixture of equal amounts of R and S enantiomers.
Sertaconazole nitrate is designated chemically as (±)-l-[2,4-dichloro-B-[(7-chlorobenzo[6]thien- 3-yl)methoxy]phenethyl]imidazole nitrate. It has a molecular weight of 500.8. The molecular formula is C20H15C13N2OS • HNO3 and the structural formula is as follows:

HNOl

Sertaconazole nitrate is a white or almost white powder. It is practically insoluble in water, soluble in methanol, sparingly soluble in alcohol and in methylene chloride.
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Sertaconazole is an antifungal that belongs to the imidazole class of antifungals. While the exact mechanism of action of this class of antifungals is not known, it is believed that they act primarily by inhibiting the cytochrome P450-dependent synthesis of ergosterol. Ergosterol is a key component of the cell membrane of fungi, and lack of this component leads to fungal cell injury primarily by leakage of key constituents in the cytoplasm from the cell.
Sertaconazole nitrate cream is used for the topical treatment of interdigital tinea pedis in immunocompetent patients 12 years of age and older, caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.
Sertaconazole nitrate Cream 2%, is marketed under the trade name ERTACZO™, and contains sertaconazole nitrate in a white cream base of ethylene glycol and polyethylene glycol palmitostearate, glyceryl isostearate, light mineral oil, methylparaben, polyoxyethylened saturated glycerides and glycolized saturated glycerides, sorbic acid and purified water.
US5135943 assigned to Ferrer is directed to Sertaconazole and salts there of. This patent further exemplifies dermal cream composition in example 1. However, the cream formulation as prepared by following Example 1 has been found to give sticky/waxy feeling after application and also is highly viscous in nature.
However, inventors of the present invention have been able to develop topical cream formulation with improved feel and consistency by using reduced amount of waxes and by addition of Glyceryl monostearate.
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OBJECTIVES OF THE INVENTION
Accordingly, one of the objectives of the present invention is to provide topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of with improved feel and consistency.
Another objective of the present invention is to provide the process for preparing topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of.
Another objective of the present invention is to provide topical cream composition of in which the strength of Sertaconazole nitrate is l0mg /gm - 30mg/ gm.
Another objective of the present invention is to provide topical composition in which the dosage form is in the form of cream, ointment, gel, or lotion.
Accordingly, one of the objectives of the present invention is to provide the topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of with improved feel and consistency having reduced wax content in the range of 1-5%.
Accordingly, one of the objectives of the present invention is to provide the topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of with improved feel and consistency having emulsifier such as glyceryl monostearate.
In another objective of the present invention, the composition of Sertaconazole or its pharmaceutically acceptable salts there of is indicated for the topical treatment of interdigital tinea pedis in immunocompetent patients caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.
SUMMARY OF THE INVENTION
The present invention relates generally to improved topical pharmaceutical formulations, their uses and methods of manufacturing. Specifically, the present invention relates to improved topical cream formulations of Sertaconazole or its pharmaceutically acceptable salts there of.
4

DETAILED DESCRIPTION OF THE INVENTION
Creams are semisolid dosage forms containing one or more drug substances dissolved or dispersed in a suitable base, possessing relatively fluid consistency formulated as either water-in-oil or oil-in-water emulsions.
Consistency (i.e., thickness or firmness) is the most important characteristic among the many physical properties of a semi-solid substances and it is a measure of thickness or firmness.
This invention is concerned with novel compositions for use as carriers for therapeutic compounds. In particular it is concerned with so-called "creams" used as vehicle for topical application of active therapeutic agents, such as antibiotics.
According to the present invention there is provided a pharmaceutical composition comprising a cream base and a therapeutic agent characterized in that the cream base comprises: stiffening agents, emulsifiers, emollients, preservatives, buffers, vehicles and mixtures there of.
Stiffening agents used according to the present invention include fatty alcohols or esters such as stearyl alcohol, cetyl alcohol, myristyl alcohol, cetyl stearyl alcohol and glycerin monostearate and mixtures there of and are used in the range from 5-10%.
Emulsifiers according to the present invention include polyoxyethylene glycol monocetyl ethers, such as the material sold under the trade name cetomacrogol 1000, and polyoxyethlene sorbitan monostearates, such as the material sold under the trade name Polysorbate 60, or polyoxyethylene sorbitan monoleates, as sold under the trade name Tween 80, sorbitol monostearate (Span 60), glyceryl monostearate and mixtures there of and are used in the range from 4-10%.
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Emollients include 2-Octyldodecanol, "mineral oil" and mixtures there of and are used in the range from 5-10%. The term "mineral oil" as used herein includes any that is suitable for use in a topical pharmaceutical composition and includes mineral oil USP, light mineral oil NF, liquid paraffin BP and light liquid paraffin BP.
The composition of this invention may also include minor amounts of conventional additives such as viscosity modifiers, for example xanthan gum, and preservatives, such as phenoxyethanol or benzyl alcohol and mixtures thereof and are used in the range from 1-3%, aqueous phase consisting primarily of water constitutes about 72- 75 %. Also, it may be necessary to incorporate buffering agents to maintain a suitable pH.
The percentages mentioned in the present composition are based on the total weight of the composition which typically also contains from 1 to 3% by weight of a therapeutic agent, such as Sertaconazole nitrate.
It has been found that addition of glyceryl monostearate along with other emulsifiers /surfactants is an essential component of the invention to make a cream having better feel on application and provide the required consistency.
Composition of Sertaconazole nitrate cream according to the present invention is indicated for the topical treatment of interdigital tinea pedis in immunocompetent patients caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.
According to the present invention, Sertaconazole or its pharmaceutically acceptable salts there of refers to various salt forms preferably including Sertaconazole nitrate.
Instrument for measuring consistency is Brookfield CAP Viscometer, Model: CAP 2000+.
The cream base may be prepared by conventional techniques well known to those skilled in the art. Generally, a suitable process comprises admixing the various ingredients of the cream in appropriate relative amounts in any order that is convenient and thereafter, and if necessary, adjusting the pH to the final desired value. For example,
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the components of the base may be mixed together at an elevated temperature, for example 65-75 °C, until an emulsion has formed. The therapeutic agent may be added after cooling the emulsified cream base, or during mixing, if it is stable to the temperatures employed.
More preferably, preparation of Sertaconazole nitrate cream composition involves the following steps: i) heating oil phase excipients and water separately, ii) heated oil phase excipients and water were mixed together and homogenized for about 5-30 minutes, and iii) followed by addition of preservative and Sertaconazole nitrate and stirring is continued & cooled up to room temperature.
Viscosity Details of Prior art as well as present formulation
Instrument : Brookfield CAP Viscometer
Model : CAP 2000+
Prior Art
RPM : 900
Run time : 30 seconds
Temperature : 25°C
Spindle No. : 1
Viscosity : 0.70 to 0.90 poise (observed: 0.80 poise) Present invention
RPM : 900
Run time : 30 seconds
Temperature : 25°C
Spindle No. : 1
Viscosity : 0.60 to 0.80 poise (observed: 0.70 poise)
Table 1

S.No NAME OF INGREDIENTS Prior art composition in % (example 1 of US513S943) Formulation of the present invention in %
1. Sertaconazole Nitrate 2.000 2.000
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micronized
2. Stearyl alcohol 5.750 3.500
3. Cetyl alcohol 5.750 3.500
4. Myristyl alcohol 3.000 2.000
5. Glyceryl monostearate (NSE) - 2.000
6. Sorbitol monostearate 1.500 1.000
7. Polysorbate 60 3.500 3.500
8. 2-Octyldodecanol 5.750 4.000
9. Light liquid paraffin 5.750 4.000
10. Benzyl alcohol 1.000 1.000
11. Purified water 66.000 73.500
100 100
Viscosity in poise 0.80 0.70
Remarks Thick cream with sticky/waxy feeling after application with improved feel and required consistency
Marketed Sertaconazole nitrate cream (ERTACZO™), contains Sertaconazole nitrate in a white cream base of ethylene glycol and polyethylene glycol palmitostearate, glyceryl isostearate, light mineral oil, methylparaben, polyoxyethylened saturated glycerides and glycolized saturated glycerides, sorbic acid and purified water, having viscosity of 1.3 poise.
The invention is further exemplified with following examples and is not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
Example 1
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NAME OF INGREDIENTS % w/w Category
I Oil Phase
Stearyl Alcohol 3.500 Stiffening Agent
Cetyl Alcohol 3.500 Stiffening Agent
Myristyl Alcohol 2.000 Stiffening Agent
Glyceryl Monostearate (NSE) 2.000 Emollient, Emulsifier and Stabilizer
Sorbitol Monostearate 1.000 Emulsifier
Polysorbate 60 3.300 Emulsifier
2-Octyldodecanol 4.000 Emollient
Light Liquid Paraffin 4.000 Emollient
II Aqueous Phase
Purified Water 67.500 Vehicle
III Benzyl Alcohol 1.000 Preservative
IV Sertaconazole Nitrate Phase
Purified Water 6.000 Vehicle
Polysorbate 60 0.200 Emulsifier
Sertaconazole Nitrate, micronized 2.000 Antifungal
Total 100

Brief Manufacturing Process
1. Oil Phase
All Oil Phase Excipients were heated up to 70°C to 72°C
2. Aqueous Phase
Water is heated up to 70°C to 72°C
3. Emulsification and Homogenization
Oil Phase and aqueous Phase were added at 70°C to 72°C and homogenized for 10 minutes, and cooled
4. Benzyl Alcohol Phase
Benzyl Alcohol is added to the base obtained from step 3, at 65°C to 68°C
5. Sertaconazole Nitrate Phase
Disperse drug in mixture of Purified Water and Polysorbate 60 and then added to base at 40°C or below 40°C
6. stirring is continued & cooled up to room temperature.
Physical Parameters:
Description : white semisolid cream
pH at 25°C : 2 to 4 (observed: 3.18)
Viscosity : 0.60 to 0.80 poise (observed: 0.70 poise)
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We claim:
1. Topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of with improved feel and consistency.
2. Process for preparing topical cream composition of Sertaconazole or its
pharmaceutically acceptable salts there of comprising the following steps:
i) heating oil phase excipients and water separately,
ii) oil phase excipients and water were mixed together and homogenized for
about 5-30 minutes, and
iii) preservative and Sertaconazole nitrate are added to the mixture of step (ii) and cooled up to room temperature.
3. Topical cream composition according to claim 1, in which the strength of Sertaconazole nitrate is l0mg /gm - 30mg/ gm.
4. Topical cream composition according to claim 1, in which Sertaconazole or its pharmaceutically acceptable salts there of with improved feel and consistency having reduced wax content in the range of 1-5%.
5. Topical cream composition according to claim 1, in which Sertaconazole or its
pharmaceutically acceptable salts there of with improved feel and consistency
having glyceryl monostearate.
6. Topical cream composition of Sertaconazole according to any of the preceding claims further comprises stiffening agents, emulsifiers, emollients, preservatives, buffers, vehicles and mixtures there of.
7. Topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of with improved feel and consistency comprises stiffening agents selected from fatty alcohols or esters such as stearyl alcohol, cetyl alcohol, myristyl alcohol, cetyl stearyl alcohol and glycerin monostearate and mixtures there of, emulsifiers selected from polyoxyethylene glycol monocetyl ethers, and polyoxyethlene sorbitan monostearates, or polyoxyethylene sorbitan monoleates, sorbitol monostearate, glyceryl monostearate and mixtures there of, and emollients include 2-octyldodecanol, "mineral oil" and mixtures there of.
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8. Topical cream composition of Sertaconazole or its pharmaceutically acceptable salts there of is indicated for the topical treatment of interdigital tinea pedis in immunocompetent patients caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.

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ABSTRACT
The present invention relates generally to improved topical pharmaceutical formulations, their uses and methods of manufacturing. Specifically, the present invention relates to improved topical cream formulations of Sertaconazole or its pharmaceutically acceptable salts there of.