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WO2008007182A2 - Compositions pharmaceutiques topiques de mupirocine ou sels ou esters de qualité pharmaceutique de ces composés - Google Patents

Compositions pharmaceutiques topiques de mupirocine ou sels ou esters de qualité pharmaceutique de ces composés Download PDF

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Publication number
WO2008007182A2
WO2008007182A2 PCT/IB2007/001796 IB2007001796W WO2008007182A2 WO 2008007182 A2 WO2008007182 A2 WO 2008007182A2 IB 2007001796 W IB2007001796 W IB 2007001796W WO 2008007182 A2 WO2008007182 A2 WO 2008007182A2
Authority
WO
WIPO (PCT)
Prior art keywords
ester
fatty acid
topical pharmaceutical
pharmaceutical composition
mupirocin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/001796
Other languages
English (en)
Other versions
WO2008007182A3 (fr
Inventor
Nilendu Sen
Chandrakant S. Lokhande
Amoi S. Mandhare
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glenmark Pharmaceuticals Ltd
Original Assignee
Glenmark Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Ltd filed Critical Glenmark Pharmaceuticals Ltd
Publication of WO2008007182A2 publication Critical patent/WO2008007182A2/fr
Anticipated expiration legal-status Critical
Publication of WO2008007182A3 publication Critical patent/WO2008007182A3/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • 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.
  • Mupirocin is an antibiotic produced by aerobically culturing Pseudomonas
  • Mupirocin calcium salt also known as ( ⁇ ) 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.
  • 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.
  • 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.
  • EP-A-O 069 423 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.
  • 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.
  • 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.
  • a stable topical pharmaceutical composition comprising (a) a therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt or ester thereof and (b) about
  • 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.
  • 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 stearic acid selected from the group consisting of glyceryl monostearate, glyceryl distearate, polyethylene glycol- 100 stearate and mixtures thereof.
  • a process for preparing a stable topical pharmaceutical composition 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.
  • a process for preparing a stable topical pharmaceutical composition 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.
  • 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.
  • 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.
  • treating 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.
  • terapéuticaally effective amount 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.
  • 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.
  • subject or "a patient” or "a host” as used herein refers to mammalian animals, preferably human.
  • 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.
  • the stable topical pharmaceutical composition is substantially free of fatty alcohols
  • 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.
  • 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.
  • the fatty acid esters of component (b) of the pharmaceutical composition of the present invention can contain from about C 4 to about C 75 and preferably about C 6 to about C 24 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.
  • the fatty acid ester is an ester of stearic acid.
  • 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-Ci 2 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.
  • TMP trimethylolpropane
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 6O 0 C to about 7O 0 C, 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.
  • 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 65 0 C to about 70 0 C; (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 60 0 C to about 70 0 C 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
  • mupirocin or a pharmaceutically acceptable salt or ester thereof can be added in step (c) during formation of the cream base.
  • 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.
  • 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.
  • sterile ingredients may be mixed under aseptic conditions.
  • Step 1 Preparation of oil phase
  • Step 2 Preparation of aqueous phase
  • Step 3 Preparation of cream base (emulsification)
  • Mupirocin calcium was added to the cream base under stirring at 50 0 C and homogenized for 5 minutes.
  • 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.
  • Step 1 Preparation of oil phase
  • Step 2 Preparation of aqueous phase
  • Purified water was heated to 60 0 C. 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.
  • Step 3 Preparation of cream base (emulsification)
  • Mupirocin calcium was added to the cream base under stirring at 50 0 C and homogenized for 5 minutes.
  • 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.
  • Cream formulation was measured at 210 RPM at 25 0 C 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.
  • the viscosity of the cream formulation of the present invention was found to be relatively comparable to the Bactroban ® Cream.

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  • Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques topiques stables comprenant une dose thérapeutique efficace de mupirocine ou bien un sel ou un ester de qualité pharmaceutique de ces composés ou bien un ou plusieurs esters d'un acide gras. L'invention concerne également des compositions pharmaceutiques topiques stables comprenant une dose thérapeutique efficace de mupirocine ou un sel ou ester de qualité pharmaceutique de ces composés ainsi qu'un ou plusieurs esters d'un acide gras qui est sensiblement exempt d'alcools.
PCT/IB2007/001796 2006-07-07 2007-06-29 Compositions pharmaceutiques topiques de mupirocine ou sels ou esters de qualité pharmaceutique de ces composés Ceased WO2008007182A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1076MU2006 2006-07-07
IN1076/MUM/2006 2006-07-07
US83927706P 2006-08-22 2006-08-22
US60/839,277 2006-08-22

Publications (2)

Publication Number Publication Date
WO2008007182A2 true WO2008007182A2 (fr) 2008-01-17
WO2008007182A3 WO2008007182A3 (fr) 2009-04-23

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PCT/IB2007/001796 Ceased WO2008007182A2 (fr) 2006-07-07 2007-06-29 Compositions pharmaceutiques topiques de mupirocine ou sels ou esters de qualité pharmaceutique de ces composés

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130150334A1 (en) * 2011-12-08 2013-06-13 Rigel Pharmaceuticals, Inc. Topical formulation for administering a compound
WO2020081109A1 (fr) * 2018-10-17 2020-04-23 Glenmark Pharmaceuticals Inc., Usa Crème à base de mupirocine en flacon pompe

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5635497A (en) * 1982-06-23 1997-06-03 Yamanouchi Europe B.V. Topical application compositions
ATE202467T1 (de) * 1993-10-22 2001-07-15 Smithkline Beecham Corp Neue zusammensetzung
CO4910145A1 (es) * 1996-10-01 2000-04-24 Smithkline Beecham Corp Uso

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130150334A1 (en) * 2011-12-08 2013-06-13 Rigel Pharmaceuticals, Inc. Topical formulation for administering a compound
US9040061B2 (en) * 2011-12-08 2015-05-26 Rigel Pharmaceuticals, Inc. Topical formulation for administering a compound
USRE47034E1 (en) * 2011-12-08 2018-09-11 Rigel Pharmaceuticals, Inc. Topical formulation for administering a compound
WO2020081109A1 (fr) * 2018-10-17 2020-04-23 Glenmark Pharmaceuticals Inc., Usa Crème à base de mupirocine en flacon pompe
US10709663B2 (en) 2018-10-17 2020-07-14 Glenmark Pharmaceuticals, Inc., Usa Mupirocin cream in pump device

Also Published As

Publication number Publication date
WO2008007182A3 (fr) 2009-04-23

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