WO2008007182A2

WO2008007182A2 - Topical pharmaceutical compositions of mupirocin or pharmaceutically acceptable salts or esters thereof

Info

Publication number: WO2008007182A2
Application number: PCT/IB2007/001796
Authority: WO
Inventors: Nilendu Sen; Chandrakant S. Lokhande; Amoi S. Mandhare
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2006-07-07
Filing date: 2007-06-29
Publication date: 2008-01-17
Also published as: WO2008007182A3

Abstract

Stable topical pharmaceutical compositions comprising a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and one or more esters of a fatty acid are disclosed. Also disclosed are stable topical pharmaceutical compositions comprising a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and one or more esters of a fatty acid, which is substantially free of fatty alcohols.

Description

TOPICAL PHARMACEUTICAL COMPOSITIONS OF MUPIROCIN OR PHARMACEUTICALLY ACCEPTABLE SALTS OR ESTERS THEREOF

PRIORITY

[0001] This application claims the benefit under 35 U.S.C. § 1 19 to U.S.

Provisional Application No. 60/839,277, filed August 22, 2006, and entitled "NOVEL TOPICAL PHARMACEUTICAL COMPOSITION OF MUPIROCIN OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF", and to Indian Provisional Application 1076/MUM/2006, filed July 7, 2006, and entitled "NOVEL TOPICAL PHARMACEUTICAL COMPOSITION OF MUPIROCIN OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF", the contents of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

[0002] The present invention generally relates to topical pharmaceutical compositions containing mupirocin or a pharmaceutically acceptable salt or ester thereof and a process for their preparation.

2. Description of the Related Art

[0003] Mupirocin is an antibiotic produced by aerobically culturing Pseudomonas

Fluorescens. From the isolated mupirocin, the calcium salt can be prepared. Mupirocin calcium salt, also known as (α) 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), dehydrate, can be represented by the structure of Formula I.

(I) Mupirocin calcium is especially effective against gram-positive bacteria, but may also be used against gram negative bacteria. It inhibits bacterial protein synthesis by irreversibly binding to bacterial isoleucyl transfer-RNA synthetase.

[0004] Topical antibacterial compositions comprising mupirocin are marketed under the trade names Bactroban^® Ointment, Bactroban^® Nasal and Bactroban^® Cream, by SmithKline Beecham. The first contains mupirocin, while the other two contain crystalline mupirocin calcium dihydrate. The formulation of Bactroban^® Ointment is described in U.S Patent No. 4,524,075. The formulation of Bactroban^® Nasal is described in U.S Patent No. 4,790,989. The cream base of Bactroban^® Cream is described in world WO 95/10999 and U.S Patent No. 6,025,389.

[0005] EP-A-O 069 423 ("the '423 patent") discloses so-called "fatty-creams" for pharmaceutical topical compositions which contain from 50 to 80% by weight of fatty materials, 1.5 to 5% by weight of hydrophilic, non-ionic surfactants and a therapeutic agent. Preferred compositions disclosed in the '423 patent contain cetyl stearyl alcohol, liquid paraffin, white soft paraffin and cetomacrogol 1000.

[0006] U.S. Patent No. 6,025,389 discloses a pharmaceutical or veterinary composition containing 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.

SUMMARY OF THE INVENTION

[0007] In accordance with one embodiment of the present invention, a stable topical pharmaceutical composition is provided comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and (b) one or more esters of a fatty acid.

[0008] In accordance with a second embodiment of the present invention, a stable topical pharmaceutical composition is provided comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and (b) about

1% to about 20% w/w of one or more esters of a fatty acid. [0009] In accordance with a third embodiment of the present invention, a stable topical pharmaceutical composition is provided comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and (b) one or more esters of a fatty acid, wherein the composition is substantially free of fatty alcohols. [0010] In accordance with a fourth embodiment of the present invention, a stable topical pharmaceutical composition is provided comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and (b) one or more esters of stearic acid selected from the group consisting of glyceryl monostearate, glyceryl distearate, polyethylene glycol- 100 stearate and mixtures thereof. [0011] In accordance with a fifth embodiment of the present invention, a process for preparing a stable topical pharmaceutical composition is provided, the process comprising (a) forming a cream base comprising one or more esters of a fatty acid; and (b) adding mupirocin or a pharmaceutically acceptable salt or ester thereof to the cream base. [0012] In accordance with a fifth embodiment of the present invention, a process for preparing a stable topical pharmaceutical composition is provided, the process comprising (a) forming an oil phase comprising mineral oil, polyethylene glycol monocetyl ether, benzyl alcohol and one or more esters of a fatty acid; (b) forming an aqueous phase comprising purified water, phenoxyethanol and xanthan gum; (c) adding the oil phase to the aqueous phase under homogenization conditions to form a cream base; and (d) adding mupirocin or a pharmaceutically acceptable salt or ester thereof to the cream base.

[0013] The compositions of the present invention are advantageously formed without a fatty alcohol such as stearyl alcohol or cetyl alcohol. Fatty alcohols such as stearyl alcohol and cetyl alcohol act are viscosity enhancing agents which provide consistency and texture to the cream formulation. It has surprisingly been found that cream formulations containing mupirocin or a pharmaceutically acceptable salt or ester thereof can be developed without the addition of such long chain fatty alcohols and still provide the same consistency and viscosity. The present invention advantageously use esters of a fatty acid, e.g., stearic acid and its derivatives such as glyceryl monostearate and/or PEG-100 stearate, which act as emulsifying agents as well as viscosifying agents. DEFINITIONS

[0014] 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 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.

[0015] 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" can vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. [0016] 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. [0017] The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0018] The present invention is directed to physicochemically stable topical pharmaceutical compositions containing at least (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and (b) one or more esters of a fatty acid. In one embodiment, the stable topical pharmaceutical composition is substantially free of fatty alcohols [0019] Suitable pharmaceutically acceptable salts of mupirocin are well known in the art and include, for example, alkali metal salts such as sodium, lithium and the like; alkaline earth metal salts such as calcium and the like, other metal salts such as silver, aluminum, ammonium and substituted ammonium salts and the like. The salts may be anhydrous or may be in the form of pharmaceutically acceptable solvates, for example, alcoholates and, especially, hydrates. Preferred salts include the calcium, silver and lithium salts, with the calcium salt being most preferred. In the case of the calcium salt of mupirocin, such forms as the crystalline hydrated calcium salt or the crystalline dihydrate salt can be used. Suitable pharmaceutically acceptable esters of mupirocin are well known in the art and include lower alkyl esters, especially the methyl and ethyl esters. [0020] The fatty acid esters of component (b) of the pharmaceutical composition of the present invention can contain from about C₄ to about C₇₅ and preferably about C₆ to about C₂₄ fatty acid esters, i.e., several fatty acid moieties, the number and type varying with the esterifying agent. Fatty acids are a class of compounds containing a long hydrocarbon chain and a terminal carboxylate group and are characterized as unsaturated or saturated depending upon whether a double bond is present in the hydrocarbon chain. Therefore, an unsaturated fatty acid has at least one double bond in its hydrocarbon chain whereas a saturated fatty acid has no double bonds in its fatty acid chain. Examples of unsaturated fatty acids include myristoleic acid, palmitoleic acid, oleic acid, linolenic acid, and the like. Examples of saturated fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and the like. In one embodiment, the fatty acid ester is an ester of stearic acid.

[0021] The acid moiety may be supplied in a fully esterfied compound or one which is less than fully esterfied, e.g., glyceryl monostearate and glyceryl di-stearate, respectively. The fatty acid esters for use herein can be a fatty acid (e.g., stearic acid) esterified with a lower chain alcohol such as Ci-Ci₂ alcohols, e.g., methyl-, ethyl-, n- propyl-, isopropyl- and butyl esters of stearic acid and the like. The fatty acid esters for use herein can also be a fatty acid esterified with a polyol. Suitable polyols include those polyols containing from two to about 10 carbon atoms and from two to six hydroxyl groups. Suitable polyols include, but are not limited to, sorbitol, ethylene glycol, diethylene glycol, polyethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, 2-ethyl- 1,3-propanediol, 2-ethyl-2-butyl- 1,3-propanediol, neopentyl glycol, 2,2,4-trimethyl-l,3-pentanediol, trimethylolpropane (TMP), pentaerythritol and the like and combinations thereof.

[0022] Representative examples of esters of a fatty acid for use in the topical pharmaceutical compositions of the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, PEG- 15 stearate, PEG-40 stearate, PEG-100 stearate and the like and combinations thereof. In one embodiment, the fatty acid esters can be a blend of fatty acid esters, e.g., glyceryl stearate/PEG-100 stearate which is commercially available under the tradename Myrj^® 59 (ICI Surfactants; Wilmington, Del.). This blend is a self-emulsifying, acid stable blend of physically off-white flakes, is a odorless, water-insoluble, and dispersible in water and oil. The blend has a saponification value of about 90 to about 100, HLB value: about 11.2 (gives oil-in-water emulsions), pH value: about 5.5 to about 7 (3% solution).

[0023] Glyceryl monostearate is a monoester of glycerin and stearic acid and is commercially available under the Geleol (Gattefosse). Glyceryl monostearate is a lipophilic non-ionic surfactant with a HLB of about 3.6 to about 4.2, saponification value (mg KOH/g) 160 - 175 and is ordinarily in the form of white flakes or powder. [0024] Mineral oils suitable for use in a topical pharmaceutical or veterinary composition and include 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. [0025] The composition of this invention may also include minor amounts of conventional additives. Suitable additive include, but are not limited to, viscosity modifiers such as xanthan gum and the like, preservatives such as phenoxyethanol, benzyl alcohol and the like, and mixtures thereof.

[0026] A cream base may be prepared by conventional techniques well known to those skilled in the art. Generally, a suitable process includes admixing the various ingredients of the cream in appropriate relative amounts in any order that is convenient. For example, the components of the base may be mixed together at an elevated temperature, for example about 6O⁰C to about 7O⁰C, until an emulsion is formed. The therapeutic agent may be added after cooling the emulsified cream base, or during mixing, if it is stable to the temperatures employed.

[0027] In one embodiment, a suitable process includes at least (a) heating a mixture containing at least mineral oil, polyethylene glycol monocetyl ether, benzyl alcohol and one or more esters of stearic acid, e.g., glyceryl stearate/PEG-100 stearate or glyceryl monostearate, to a temperature sufficient to form an oil phase, e.g., about 65⁰C to about 70⁰C; (b) forming an aqueous phase by heating purified water to a suitable temperature, e.g., about 55°C to about 65°C, adding phenoxyethanol under stirring and then dispersing xanthan gum under stirring for a temperature and time period sufficient to form the aqueous phase, e.g., a temperature ranging from about 60⁰C to about 70⁰C and a time period ranging from about 15 minutes to several hours; (c) adding the oil phase to the aqueous phase and allowed to cool to form a cream base and (d) adding mupirocin or a pharmaceutically acceptable salt or ester thereof to the cream base. Alternatively, mupirocin or a pharmaceutically acceptable salt or ester thereof can be added in step (c) during formation of the cream base. If desired the process may further include passing the cream base containing mupirocin or a pharmaceutically acceptable salt or ester thereof through a triple roller mill to improve the elegance of cream.

[0028] The pharmaceutical compositions of the present invention are intended for pharmaceutical or veterinary use. The compositions may optionally be provided in a sterile condition, by incorporating a conventional sterilization step into the above procedure. Alternatively, sterile ingredients may be mixed under aseptic conditions. [0029] The following 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.

EXAMPLE 1

[0030] The ingredients and amounts for preparing the topical pharmaceutical composition of this example are set forth below in Table 1. TABLE l

¹ equivalent to 2.0% Mupirocin

² Cetomacrogol 1000

[0031] Manufacturing Procedure

[0032] Step 1: Preparation of oil phase

[0033] Mineral oil, polyethylene glycol monocetyl ether, benzyl alcohol and glyceryl monostearate/PEG-100 stearate were mixed and heated to 65°C to 7O⁰C.

[0034] Step 2: Preparation of aqueous phase

[0035] Purified water was heated to 60⁰C. Next, phenoxyethanol was added to the heated water under stirring and xanthan gum was dispersed in the solution under stirring and mixed for 30 minutes.

[0036] Step 3: Preparation of cream base (emulsification)

[0037] The oil phase was slowly added to the aqueous phase and homogenized for

15 minutes under stirring, and allowed to cool to 50⁰C to form a cream base.

[0038] Step 4: Drug addition

[0039] Mupirocin calcium was added to the cream base under stirring at 50⁰C and homogenized for 5 minutes.

[0040] Optional Step 5: Cooling

[0041] The homogenized mass prepared in step 4 may be passed through a triple roller mill to improve the elegance of the cream resulting in a cream that is uniform and smooth in texture.

EXAMPLE 2

[0042] The ingredients and amounts for preparing the topical pharmaceutical composition of this example are set forth below in Table 2. TABLE 2

¹ equivalent to 2.0% Mupirocin

² Cetomacrogol 1000

[0043] Manufacturing Procedure

[0044] Step 1 : Preparation of oil phase

[0045] Mineral oil, polyethylene glycol monocetyl ether, benzyl alcohol and glyceryl monostearate were mixed and heated to 65°C-70°C.

[0046] Step 2: Preparation of aqueous phase

[0047] Purified water was heated to 60⁰C. Next, phenoxyethanol was added to the heated water under stirring and xanthan gum was dispersed in the solution under stirring and mixed for 30 minutes.

[0048] Step 3: Preparation of cream base (emulsification)

[0049] The oil phase was slowly added to the aqueous phase and homogenized for

15 minutes under stirring, and allowed to cool to 50⁰C to form a cream base.

[0050] Step 4: Drug addition

[0051] Mupirocin calcium was added to the cream base under stirring at 50⁰C and homogenized for 5 minutes.

[0052] Optional Step 5: Cooling

[0053] The homogenized mass prepared in step 4 may be passed through a triple roller mill to improve the elegance of the cream resulting in a cream that is uniform and smooth in texture.

[0054] The viscosity of the cream formulation of this example was then compared to the viscosity of the Bactroban^® Cream formulation set forth in Table 3. TABLE 3

Bactroban Cream

Mupirocin calcium

Mineral oil

Polyethylene glycol monocetyl ether

Phenoxyethanol

Benzyl alcohol

Xanthan gum

Glyceryl monostearate

Cetyl alcohol stearyl alcohol

Purified Water equivalent to 2.0% Mupirocin

² Cetomacrogol 1000

[0055] The viscosity of the cream formulation of Example 2 and the Bactroban^®

Cream formulation was measured at 210 RPM at 25⁰C on a Brookfield Cone and Plate Viscometer CAP 2000+, using a spindle number 1.1 mg of the sample. The viscosity of the cream formulation of Example 2 was 4.133 Poise while the viscosity of the Bactroban^® Cream was 3.142 Poise. Thus, the viscosity of the cream formulation of the present invention was found to be relatively comparable to the Bactroban^® Cream. [0056] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A stable topical pharmaceutical composition comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof; and (b) one or more esters of a fatty acid, wherein the composition is substantially free of fatty alcohols.

2. The topical pharmaceutical composition of Claim 1, wherein the mupirocin is calcium mupirocin dihydrate.

3. The topical pharmaceutical composition of Claims 1 and 2, wherein the fatty acid ester is an about C₄ to about C₇₅ fatty acid ester.

4. The topical pharmaceutical composition of Claims 1 and 2, wherein the fatty acid ester is an about Ce to about C₂₄ fatty acid ester.

5. The topical pharmaceutical composition of Claims 1-4, wherein the fatty acid ester is an unsaturated fatty acid ester.

6. The topical pharmaceutical composition of Claim 5, wherein the unsaturated fatty acid ester is selected from the group consisting of an ester of myristoleic acid, ester of palmitoleic acid, ester of oleic acid, ester of linolenic acid and mixtures thereof.

7. The topical pharmaceutical composition of Claims 1-6, wherein the fatty acid ester is a saturated fatty acid ester.

8. The topical pharmaceutical composition of Claim 7, wherein the saturated fatty acid ester is selected from the group consisting of an ester of caproic acid, ester of caprylic acid, ester of capric acid, ester of lauric acid, ester of myristic acid, ester of palmitic acid, ester of stearic acid, ester of arachidic acid, ester of behenic acid, ester of lignoceric acid and mixtures thereof.

9. The topical pharmaceutical composition of Claims 1 and 2, wherein the fatty acid ester is selected from the group consisting of glyceryl monostearate, glyceryl distearate, PEG- 15 stearate, PEG-40 stearate, PEG-100 stearate and mixtures thereof.

10. The topical pharmaceutical composition of Claims 1-9, comprising about 1% to about 20% w/w of one or more of the esters of a fatty acid.

1 1. The topical pharmaceutical composition of Claims 1-10, further comprising one or more additives.

12. The topical pharmaceutical composition of Claims 1-1 1, in the form of a cream.

13. A stable topical pharmaceutical composition comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof; and (b) one or more esters of a fatty acid, wherein the composition is substantially free of fatty alcohols.

14. The topical pharmaceutical composition of Claim 13, in the form of a cream.

15. The topical pharmaceutical composition of Claims 13 and 14, wherein the mupirocin is calcium mupirocin dihydrate.

16. The topical pharmaceutical composition of Claims 13-15, comprising about 1% to about 20% w/w of one or more of the esters of a fatty acid.

17. The topical pharmaceutical composition of Claims 13-16, wherein the fatty acid ester is selected from the group consisting of glyceryl monostearate, glyceryl distearate, PEG- 15 stearate, PEG-40 stearate, PEG-100 stearate and mixtures thereof.

18. A process for preparing a stable topical pharmaceutical composition, the process comprising (a) forming a cream base comprising one or more esters of a fatty acid; and (b) adding mupirocin or a pharmaceutically acceptable salt or ester thereof to the cream base.

19. The process of Claim 18, comprising (a) forming an oil phase comprising mineral oil, polyethylene glycol monocetyl ether, benzyl alcohol and one or more esters of a fatty acid; (b) forming an aqueous phase comprising purified water, phenoxyethanol and xanthan gum; (c) adding the oil phase to the aqueous phase under homogenization conditions to form a cream base; and (d) adding mupirocin or a pharmaceutically acceptable salt or ester thereof to the cream base.

20. The process of Claim 18, comprising (a) forming an oil phase comprising mineral oil, polyethylene glycol monocetyl ether, benzyl alcohol and one or more esters of a fatty acid; (b) forming an aqueous phase comprising purified water, phenoxyethanol and xanthan gum; and (c) combining mupirocin or a pharmaceutically acceptable salt or ester thereof, the oil phase and the aqueous phase under homogenization conditions to form a cream.

21. The process of Claims 18-20, wherein the one or more of the esters of a fatty acid is present in an amount of about 1% to about 20% w/w.

22. The process of Claims 18-21, which is substantially free of fatty alcohols.

23. The process of Claims 18-22, wherein the mupirocin is calcium mupirocin dihydrate.

24. The process of Claims 18-23, wherein the fatty acid ester is selected from the group consisting of glyceryl monostearate, glyceryl distearate, PEG- 15 stearate, PEG-40 stearate, PEG-100 stearate and mixtures thereof.