FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"NOVEL TOPICAL PHARMACEUTICAL COMPOSITION OF MUPIROCIN OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
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, HOD-corporate Bldg,
Wing-A, B.D. Sawant Marg, Chakala,Andheri(East),
Mumbai-400099.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to a novel pharmaceutical composition containing Mupirocin or a pharmaceutically acceptable salt thereof wherein the composition is prepared without using fatty alcohols. The present invention also relates to the process for preparing a stable composition of Mupirocin or a pharmaceutically acceptable salt thereof in the form of cream using Esters of Stearic acid.
2. Description of the Related Art
Mupirocin or a pharmaceutically acceptable salt thereof , calcium salt is chemically known as (alpha) E ,2 S ,3 R ,4 R , 5 S )-5-[(2 S ,3 S ,4 S ,5 S )-2, 3-Epoxy-5-hydroxy-4-methylhexyl] tetrahydro-3,4-dihydroxy-(beta)-methyl-2 H -pyran-2-crotonic acid, ester with 9-hydroxynonanoic acid, calcium salt (2:1), dihydrate And having structure,

Mupirocin or a pharmaceutically acceptable salt thereof used for the treatment of microbial infection apparently exerts its antimicrobial activity by reversibly inhibiting isoleucyl-transfer RNA, thereby inhibiting bacterial protein and RNA synthesis. Mupirocin or a pharmaceutically acceptable salt thereof has excellent in vitro activity against staphylococci and most streptococci but less activity against other gram-positive
and gram-negative bacteria. The drug will only be used topically because of its rapid and extensive systemic metabolism, as the topical delivery route offers continuity of drug administration, permits use of therapeutic agents with short biological half lives, provides
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treatment of cutaneous manifestations of diseases usually treated systemically delivers medication directly into the systemic circulation and fosters ease of use and total patient compliance.
Topical antibacterial compositions comprising Mupirocin or a pharmaceutically acceptable salt thereof are marketed in the UK by Beecham Research Laboratories under the trade names Bactroban Ointment and Bactroban Nasal. The first product is an ointment comprising a water soluble polyethylene glycol base whilst the second product comprises Mupirocin or a pharmaceutically acceptable salt thereof in a white soft paraffin based ointment containing a glycerin ester.
EP-A-0 069 423 (Gist-Brocades) discloses so-called "fatty-creams" for pharmaceutical topical compositions which comprise from 50 to 80% by weight of fatty materials, 1.5 to 5% by weight of hydrophilic, non-ionic surfactant and a therapeutic agent. Preferred compositions comprise cetyl stearyl alcohol, liquid paraffin, white soft paraffin and cetomacrogol 1000.
US6025389 (SmithKline Beecham Corporation) claims a pharmaceutical or veterinary composition comprising about 2.4% by weight of Mupirocin or a pharmaceutically acceptable salt thereof ; about 50.9% by weight mineral oil USP; about 6% by weight polyethylene glycol monocetyl ether; about 3.5% by weight stearyl alcohol; about 3.5% by weight cetyl alcohol; about 0.5% by weight phenoxyethanol; about 1% by weight benzyl alcohol; about 0.2% by weight xanthan gum; and about 32% by weight purified water.
The invention disclosed herein in this application does not contain stearyl alcohol and cetyl alcohol as mentioned in all the above prior arts. Stearyl alcohol and Cetyl alcohol acts as viscosity enhancing agent which is an essential for providing the consistency and texture to the cream as per the prior arts cited. Surprisingly inventors have found that cream formulation with Mupirocin or its pharmaceutically acceptable salts can be developed without the addition of such long chain fatty alcohols and still provide the same
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consistency and viscosity. The applicants of the present invention have used Esters of Stearic acid and its derivatives such as Glyceryl monostearate, PEG-100 stearate alone or mixtures thereof. Esters of Stearic acid and its derivatives acts as emulsifying agent as well as viscosifying agent in present invention disclosed herein .In addition to this it does not require the aid of other emulsifiers and provides excellent appearance & feel. These compounds also have solubilizing properties and also provide consistency and texture to the cream. Thus a physicochemical stable composition can be achieved by avoiding the use of stearyl alcohol and cetyl alcohol are the essential ingredients of all the prior arts.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention is to make a novel and stable pharmaceutical composition of Mupirocin or a pharmaceutically acceptable salt thereof and esters of stearic acid without using fatty alcohols for topical use.
In accordance with a second embodiment a process for preparing a stable pharmaceutical formulation is provided, the process comprising (a) Heat Mineral oil, Polyethylene glycol monocetyl ether, benzyl alcohol and Glyceryl stearate/PEG-100 stearate OR Glyceryl monostearate to 65 °C-70°C. Mix and maintained the temperature of oil phase at 65 °C-70°C. (b) Heat purified water to 60°C. Add phenoxyethanol under stirring. Disperse xanthan gum under stirring. Mix for 30 min. and maintained temperature of aqueous phase at 65 °C-70°C.and (c) Slowly add oil phase to aqueous phase and homogenize for 15 minutes. Under stirring, allow cream base to cool to 50 °C (d) under stirring, add Mupirocin or a pharmaceutically acceptable salt thereof to cream base at 50°C and Homogenize. The homogenized mass may be passed through triple roller mill to improve elegance of cream
In accordance with a third embodiment of the present invention, a stable pharmaceutical formulation is provided comprising (a) a therapeutically effective amount of Mupirocin or a pharmaceutically acceptable salt thereof and Glyceryl monostearate, Polyethylene glycol-100 stearate alone or mixtures thereof without using fatty alcohols for topical use.
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In accordance with the fourth embodiment of the present invention using self-emulsifying, acid stable blend of emulsifiers including Glyceryl monostearate & polyethylene glycol stearate (PEG-100 stearate) in a concentration range l%-20% to make a novel and stable pharmaceutical composition of Mupirocin or a pharmaceutically acceptable salt thereof.
In accordance with the another embodiment of the present invention using self-emulsifying, acid stable emulsifier Glyceryl monstearate which provides excellent appearance & feel to the emulsion and has also thickening & solubilizing properties to provide stabile cream formulation with concentration 1-20%.
In further accordance of this invention the resultant topical composition is a physicochemically stable and asthetically appealing composition.
In a further aspect, the present invention provides pharmaceutical or veterinary compositions for use in therapy.
In addition, in another aspect of this invention, the cream base per se as described may be used as a moisturising cream or emollient without the presence of a therapeutic agent.
Due to the intelligent selection of excipients helps in reducing the cost of the product.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The disclosed invention in this specification is a formulation is physicochemically stable topical application of Mupirocin or a pharmaceutically acceptable salt thereof using Esters of Stearic acid.
Esters of stearic acids like Glyceryl stearate and PEG-100 stearate which acts as emulsifying agent as well as viscosifying agent are used in present invention either alone or in combination.
Glyceryl stearate/PEG-100 stearate is self-emulsifying, acid stable blend of emulsifiers including glyceryl stearate & polyoxy-ethylene stearate (PEG-100 stearate)which is physically Off-white flakes, odorless, water-insoluble, dispersible in water & oil, saponification value 90 - 100, HLB Value: 11.2 (gives oil-in-water emulsions), pH Value: 5.5 - 7 (3 % solution) with Properties: self-emulsifying emulsifier blend for highly stable oil-in-water emulsions (enables water & oil to mix), does not require the aid of other emulsifiers, provides excellent appearance & feel, has also thickening & solubilizing properties (stabilizes essential oils).
Glyceryl monostearate is a monoester of glycerine and steric acid physically it is in the form of white flakes or powder, a lipophilic non-ionic surfactant with HLB of 3.6 - 4.2, Saponification value (mg KOH/g) 160 - 175 with excellent properties as emollient, emulsifier and thickening agent.
DEFINITIONS
The term "esters of stearic acid " as used herein means The simple esters with lower chain alcohols (methyl-, ethyl-, n-propyl-, isopropyl- and butyl esters) are used as emollients in cosmetics and other personal care products and as lubricants. Esters of fatty acids with more complex alcohols, such as sorbitol, ethylene glycol, diethylene glycol and polyethylene glycol are consumed in foods, personal care, paper, water treatment, metal working fluids, rolling oils and synthetic lubricants
The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or
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condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically 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.
By "pharmaceutically acceptable" is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
The term "mineral oil" as used herein includes any that is suitable for use in a topical pharmaceutical or veterinary composition and includes mineral oil USP, light mineral oil NF, liquid paraffin BP and light liquid paraffin BP. The mineral oil known as mineral oil USP is especially suitable.
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, including mixtures thereof.
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The cream base may be prepared by conventional techniques well known to those skilled in the art. Generally, a suitable process comprises comprising (a) Heat Mineral oil, Polyethylene glycol monocetyl ether, benzyl alcohol and Glyceryl stearate/PEG-100 stearate OR Glyceryl monostearate to 65 °C-70°C. Mix and maintained the temperature of oil phase at 65 °C-70°C. (b) Heat purified water to 60°C. Add phenoxyethanol under stirring. Disperse xanthan gum under stirring. Mix for 30 min. and maintained temperature of aqueous phase at 65 °C-70°C.and (c) Slowly add oil phase to aqueous phase and homogenize for 15 minutes. Under stirring, allow cream base to cool to 50 °C (d) under stirring, add Mupirocin or a pharmaceutically acceptable salt thereof to cream base at 50°C and Homogenize. The homogenized mass may be passed through triple roller mill to improve elegance of cream.
Compositions of the invention are intended for pharmaceutical or veterinary use. Compositions may optionally be provided in sterile condition, by incorporating a conventional sterilisation step into the above procedure. Alternatively, sterile ingredients may be mixed under aseptic conditions.
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EXAMPLE (1)
Mupirocin or a pharmaceutical^ acceptable salt thereof cream 2.15%w/w (equivalent to 2.0% Mupirocin or a pharmaceutical^ acceptable salt thereof free base).

S.No. Composition Formula 1(%)
1. Mupirocin calcium 2.15
2. Mineral oil 50.6
3. Polyethylene glycol monocetyl ether 6
4. Phenoxyethanol 0.5
5. Benzyl alcohol 1.0
6. Xanthan gum 0.2
7. Glyceryl monostearate/PEG-100 stearate 5
8. Purified Water qs
Brief Manufacturing Procedure
1. Oil phase
Heat Mineral oil, Polyethylene glycol monocetyl ether, benzyl alcohol and Glyceryl stearate/PEG-100 stearate to 65 °C-70°C. Mix and maintained the temperature of oil phase at 65 °C-70°C.
2. Aqueous phase
Heat purified water to 60°C. Add phenoxyethanol under stirring. Disperse xanthan gum under stirring. Mix for 30 min. and maintained temperature of aqueous phase at 65 °C-70°C.
3. Emulsification
Slowly add oil phase to aqueous phase and homogenized for 15 minutes. Under stirring, allow cream base to cool to 50 °C.
4. Drug addition:
Under stirring, add Mupirocin calcium to cream base at 50°C. Homogenize for 5 min.
5. Cooling
The homogenized mass may be passed through triple roller mill to improve elegance of
cream
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EXAMPLE (2)
Mupirocin or a pharmaceutical^ acceptable salt thereof cream 2.15%w/w (equivalent to 2.0% Mupirocin or a pharmaceutically acceptable salt thereof free base).

S.No. Composition Formula 2(%)
1 Mupirocin calcium 2.15
2 Mineral oil 50.6
3 Polyethylene glycol monocetyl ether 6
4 Phenoxyethanol 0.5
5 Benzyl alcohol 1.0
6 Xanthan gum 0.2
7 Glyceryl monostearate 5
8 Purified Water qs
Brief Manufacturing Procedure
1. Oil phase
Heat Mineral oil, Polyethylene glycol monocetyl ether, benzyl alcohol and Glyceryl monostearate to 65 °C-70°C. Mix and maintained the temperature of oil phase at 65 °C-70°C.
2. Aqueous phase
Heat purified water to 60°C. Add phenoxyethanol under stirring. Disperse xanthan gum under stirring. Mix for 30 min. and maintained temperature of aqueous phase at 65 °C-70°C.
3. Emulsification
Slowly add oil phase to aqueous phase and homogenized for 15 minutes. Under stirring, allow cream base to cool to 50 °C.
4. Drug addition:
Under stirring, add Mupirocin calcium to cream base at 50°C. Homogenize for 5 min.
5. Cooling
The homogenized mass may be passed through triple roller mill to improve elegance of
cream.
The above examples are provided to enable one skilled in the art to practice the invention
and are merely illustrative of the invention. The examples should not be read as limiting
the scope of the invention as defined in the features and advantages.

Dated this sixth (6th) day of July, 2006
Taranpreet Singh Lamba (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited
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