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WO2012035380A1 - Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du clotrimazole et du furoate de mométasone, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci - Google Patents

Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du clotrimazole et du furoate de mométasone, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Download PDF

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Publication number
WO2012035380A1
WO2012035380A1 PCT/IB2010/056126 IB2010056126W WO2012035380A1 WO 2012035380 A1 WO2012035380 A1 WO 2012035380A1 IB 2010056126 W IB2010056126 W IB 2010056126W WO 2012035380 A1 WO2012035380 A1 WO 2012035380A1
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WIPO (PCT)
Prior art keywords
amount
vessel
mixture
api
cream
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Balkrishnana Selvaraj
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates to primary & secondary bacterial skin infections and inflammations and in particular it relates to the single dose treatment using a cream containing a corticosteroid in the form of Mometasone Furoate, an antifungal agent in the form of Clotrimazole and antibacterial agent in the form of Fusidic acid wherein the Fusidic acid has been made using Sodium Fusidate as the starting Active Pharmaceutical Ingredient (API).
  • a corticosteroid in the form of Mometasone Furoate
  • an antifungal agent in the form of Clotrimazole
  • antibacterial agent in the form of Fusidic acid wherein the Fusidic acid has been made using Sodium Fusidate as the starting Active Pharmaceutical Ingredient (API).
  • steroids to alleviate inflammation, irritation and itching caused by skin ailments. It is also well known that use of steroids compromises patient's immune system and exposes them to bacterial and fungal infections. Single dose therapies containing steroids, antifungals and antibacterials are well known.
  • Topical and systemic inflammatory treatment compositions typically employ a combination of corticosteroids in a base component.
  • the active ingredients typically comprise Corticosteroids such as Betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate and the like.
  • Fungal infections sometimes follow the use of antibiotics, which kill nonpathogenic as well as pathogenic bacteria, thereby providing a free field in the body for fungal invasion.
  • Topical and systemic fungal infections treatment compositions typically employ antifungal agents as active ingredients in a base component.
  • the active ingredients typically comprise antifungal agents such as Miconazole Nitrate, Terbinafine Hydrochloride, Ketoconazole, Clotrimazole and the like.
  • Topical and systemic bacterial infection treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component.
  • APIs typically comprise an antibiotic/antibacterial such as Fusidic acid and the like.
  • Fusidic acid in fine powder form is used as source API.
  • the small particle size enhances its dermal contact by providing a large specific surface area and penetration, and provides a smooth feel on application to skin.
  • a serious shortcoming of the fine size of Fusidic acid particles is that it presents an enormous surface area for contact and reaction with molecular Oxygen during manufacture, handling, and processing of the cream. This has serious implications to its chemical stability and results in rapid reduction in potency of the API (Fusidic acid) in the final cream formulation.
  • Stabilization of medicaments containing Fusidic acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include:
  • the invention discloses a dermaceutical cream containing Mometasone Furoate as a corticosteroid, an antifungal agent in the form of Clotrimazole and an antibacterial agent in the form of Fusidic acid, which Fusidic acid is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic acid under oxygen-free environment.
  • the cream of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional creams containing Fusidic acid.
  • the cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, Mometasone Furoate and Clotrimazole, in a cream base comprising a preservative, an acid, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.
  • Creams containing Fusidic acid that are made using Sodium Fusidate as starting API are not available.
  • Creams containing Fusidic acid that are made using Sodium Fusidate along with a corticosteroid in the form of Mometasone Furoate as starting APIs are not available.
  • Creams containing Fusidic acid that are made using Sodium Fusidate along with corticosteroid in the form of Mometasone Furoate and Clotrimazole as antifungal agent are also not available.
  • fusidic acid has very labile trans, sys, trans arrangement of these rings which forces ring B into a boat conformation.
  • fusidic acid readily undergoes acid mediated dehydration of C-l l hydroxy group to generate a C9-C11 double bond which on further isomerization followed by oxidization in the presence of oxygen leads to a mixture of biologically inactive fusidic acid derivatives.
  • carboxylic acid functional group present in the fusidic acid facilitates the above process more readily upon storage.
  • carboxylic acid promoted decomposition is not feasible.
  • sodium fusidate has superior solid state stability when compared to fusidic acid. This discovery of the inventor has also been corroborated through stability assessment of sodium fusidate and fusidic acid.
  • Tables 1 and 2 also show the comparison between the stability of the Fusidic acid and Sodium Fusidate as raw APIs.
  • the study was carried out using an in-house UPLC method developed by the applicant, which the applicant believes is a true stability-indicating method as opposed to the titration method suggested in British Pharmacopoeia (BP). This is because the BP method does not differentiate between the intact API and the degraded form.
  • a dermaceutical cream that uses Sodium Fusidate and steroids would exploit the benefit of the fact that Sodium Fusidate is more stable than Fusidic acid and it would also provide a cream formulation which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic acid and steroids.
  • Sodium Fusidate rather than Fusidic acid may be used as the starting API during the cream's manufacture.
  • Sodium Fusidate as starting material eliminates the drawback associated with the manufacture and storage of existing Fusidic acid creams.
  • the applicant has also discovered that the Fusidic acid and steroids cream prepared using Sodium Fusidate as the starting APIs showed good chemical stability, and efficacy.
  • the application discloses a cream containing steroids in the form of Mometasone Furoate and Fusidic acid (the API) that has been prepared using Sodium Fusidate as the starting API, in which Fusidic acid forms in-situ under totally oxygen free environment by slow addition of an acid, into a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates as an extremely fine dispersion when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen.
  • the cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, a steroid in the form of Mometasone Furoate in a cream base comprising an acid, a preservative, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.
  • the cream base of the present invention optionally further comprises an ingredient selected from a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • the present invention provides a novel cream that has been produced using Sodium Fusidate as the starting raw material, and which cream contains Fusidic acid of high therapeutic efficacy and of chemical stability that is generally superior to the commercially available creams containing Fusidic acid.
  • the Fusidic acid and steroid cream of the present invention has been manufactured in a totally oxygen free environment under purging with inert gas and applying vacuum. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic acid.
  • the cream of the present invention is used in the treatment of bacterial skin infections and inflammations.
  • the pH of the product of the present invention is between 3 to 6.
  • Sodium Fusidate ointments that are commercially available are greasy and cosmetically non elegant.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in a finely dispersed form for the product to be being efficacious. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug.
  • the product of the present invention is efficacious due to the pronounced antiinflammatory, antibacterial activity of the steroid and regenerated Fusidic acid which is available in reduced particle size than the conventional products, and in a finely dispersed form.
  • the average size of the fusidic acid particles in the present invention has been found to be approximately 1 ⁇ whereas that for the existing creams varies between 14 ⁇ to 22 ⁇ . Euqlly importantly, the minimum particle size observed was approx. 0.35 ⁇ whereas the minimum particle size observed for existing creams ranged between 4 ⁇ and 10 ⁇ . The cream of the present invention is therefore physically distinct from any of the existing creams and easily distinguishable.
  • Table 2A Particle Size Distribution of Fusidic Acid
  • the reduced particle size of the fusidic acid of the present invention is of particular significance as it has been achieved without compromising the stability of fusidic acid.
  • WO2007087806 by Leo Pharma have employed mechanical means such as mortar and pestle to mechanically grind fusidic acid for adding to a cream base.
  • mechanical means such as mortar and pestle to mechanically grind fusidic acid for adding to a cream base.
  • WO2007087806 is silent on the particle size achieved, it will be known to a person skilled in the art that its particle size of fusidic acid cannot be finer than that of the present invention.
  • the stability of the fusidic acid in creams produced by the teachings of WO2007087806 or any other fusidic acid creams that employ grinding of fusidic acid in presence of oxygen cannot be as good as that of the present invention as evidenced by the data included in Table 2A.
  • the inventor has screened different co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one of above co-solvents varying between 5% (w/w) to 40% (w/w) under inert gas purging and under vacuum and converted to Fusidic acid in-situ by adding an acid such as HC1, H 2 SO 4 , HNO 3 , Lactic acid and the like between 0.005% (w/w) and about 0.5% (w/w) under stirring and obtained Fusidic acid in more stabilized and solution form, which makes our final product in a cream base which easily penetrates the skin and highly efficacious, and also highly derma compatible by having a pH of about 3.0 to about 6.0.
  • co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one
  • a novel dermaceutical cream as described in the preferred embodiment 1 wherein said corticosteroid is added in the form of Mometasone Furoate, added in an amount between 0.005% (w/w) and about 2.5% (w/w) , and most preferably between 0.1% (w/w) ; and said antifungal agent is added in the from of Clotrimazole, added in an amount between 0.5% (w/w) and about 3.0% (w/w) by weight, preferably between 0.5% (w/w) and about 2.0% (w/w), and most preferably 1.0% (w/w); and said Fusidic acid is present in an amount between 0.1 % (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5%(w/w), and more preferably about 2.00 % (w/w), and in which the amount of said Sodium Fusidate used to form in situ said Fusidic acid is in the range between about
  • said preservatives is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w)
  • said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like, either singly or any combination thereof, in an amount between 1% (w/w) to 25% (w/w), preferably 20% (w/w), more preferably 15% (w/w)
  • said waxy material is selected from a group comprising white soft paraffin, liquid
  • an anti-oxidant is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, either singly or any combination thereof, in an amount between 0.001 % (w/w) to 5% (w/w), preferably 0.1% (w/w), more preferably 0.01% (w/w).
  • a novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 4 which further comprises a chelating agent, wherein said chelating agent is selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, in an amount between 0.01% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 5 which further comprises a humectant, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, in an amount between 5% (w/w) to 60% (w/w), preferably 50% (w/w), more preferably 48.5% (w/w).
  • a process to make a cream containing Mometasone Furoate, Clotrimazole and fusidic acid said cream being as disclosed in preferred embodiment 1 and embodiment 1 , said process comprising the step of using sodium fusidate as the raw active pharmaceutical ingredient and converting said sodium fusidate in situ into fusidic acid under oxygen-free environment in a cream base, to which Mometasone Furoate and Clotrimazole are added.
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), more preferably Benzoic acid, c. mixing the mixture using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 0 C,
  • waxy materials selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, either singly or any combination thereof, in an amount between 5% (w/w) to 20% (w/w), preferably 15% (w/w), more preferably!
  • a primary emulsifier preferably in the form of a non ionic surfactant, selected from a group comprising Cetostearyl alcohol, Cetomacrogo 1-1000, either singly or any combination thereof, wherein Cetostearyl alcohol is added in an amount between 1 % (w/w) to 15% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), and Cetomacrogo 1-1000 is added in an amount between 0.1 % (w/w) to 5% (w/w), preferably 1% (w/w), more preferably 0.5% (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80, in an amount between 1 to 5% w/w, more preferably 2% w/w and mixing the
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like, either singly or any combination thereof, in an amount between 5% (w/w) to 40% (w/w), preferably 30% (w/w), more preferably 25% (w/w), preferably propylene glycol, subjecting the contents of said API-vessel to inert gas flushing, said inert gas being preferably nitrogen, and adding sodium fusidate to the mixture, said sodium fusidate added in an amount between 0.1% (w/w) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said sodium fusidate in the mixture,
  • an acid selected from a group comprising acids such as HC1
  • H 2 SO 4 HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount from about 0.005% (w/w) to
  • Mometasone Furoate being added in an amount between 0.005% (w/w) and about 2.5% (w/w) by weight, preferably between 0.005% (w/w) and about 1.00% (w/w) , and most preferably about 0.1% (w/w); and adding in the third API - vessel propylene glycol in an amount 1 % (w/w) to 20% (w/w), preferably 10% (w/w), more preferably 15% (w/w), more preferably 13.5 % (w/w) and dispersing Clotrimazole in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, and said Clotrimazole being added in an amount between 0.5% (w/w) to about 2.0% (w/w), and most preferably about 1.0 % (w/w); and
  • API - vessel of step k to the said mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenising the mixture at 1000 to 3000 RPM under vacuum, preferably of a magnitude between minus 1000 to minus 300 mm of mercury,
  • step o cooling the contents of the mixing vessel of step g to 30 °C to 37 °C using circulation of cooled water from a cooling tower at 8 °C to 15 °C into the jacket of mixing vessel, p. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step o to a storage container.
  • the process described in embodiment no. 10 further incorporates after the step of adding a preservative, a step of adding a chelating agent, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, in an amount between 0.01% (w/w) to 1 % (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a chelating agent selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, in an amount between 0.01% (w/w) to 1 % (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • the process described in embodiments no. 10 and 11 further incorporates after the step of adding the chelating agent, a buffering agent , selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.01 % (w/w) to 2.00% (w/w), preferably 1.5 % (w/w), more preferably 1 % (w/w).
  • a buffering agent selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.01 % (w/w) to 2.00% (w/w), preferably 1.5 % (w/w), more preferably 1 % (w/w).
  • the process described in embodiments no. 10, 11 , and 12 further incorporate in the step h of embodiment 10, an anti oxidant selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001% (w/w) to 5% (w/w), preferably 0.1 % (w/w), more preferably 0.01 % (w/w).
  • an anti oxidant selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001% (w/w) to 5% (w/w), preferably 0.1 % (w/w), more preferably 0.01 % (w/w).
  • the process described in embodiments no. 10, 11 ,12 and 13 further incorporate a humectant in the step a of embodiment 10, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, in an amount between 5% (w/w) to 60% (w/w), preferably 50% (w/w), more preferably 48.5 % (w/w).
  • a humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, in an amount between 5% (w/w) to 60% (w/w), preferably 50% (w/w), more preferably 48.5 % (w/w).
  • a process to make a cream containing Mometasone Furoate and fusidic acid as described in embodiment no 8 comprising the steps of: a. heating purified water in the range from 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18% (w/w) in a water-phase vessel to 70 0 C to 80 0 C,
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, added in an amount between 0.05% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), the preferred preservative being Benzoic acid, optionally adding to said water-phase vessel of step b a chelating agent, or buffering agent , or a humectants added in combination thereof, wherein said chelating agent is preferably Disodium edetate, added in an amount preferably between 0.01 and 1 %, more preferably 0.1%, said buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount preferably 0.01% (w/w) to 2.00% (w/w), preferably 1% (w/w), more preferably 0.5% (w
  • step c mixing the mixture of said water-phase vessel of step c using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 ° C,
  • an emulsifying wax preferably Cetostearyl alcohol, in an amount preferably between 1 and 15 %, more preferably 12.5 % and a waxy material, preferably white soft paraffin, in an amount preferably between 5 and 20 %, more preferably 12.5 %, and melting them by heating to 70 ° C to 80 ° C,
  • a non ionic surfactant or emulsifier in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate 80 and 0.5% of Cetomacrogol 1000, and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 0 C, transferring the contents of the water-phase vessel of step d and oil-phase vessel of step f to a mixing vessel under vacuum conditions in the range of minus 1000 to minus 300 mm of mercury and at 70 0 C to 80 0 C and mixing the mixture at 10 to 50 RPM to form an emulsion,
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400adding propylene glycol, or any mixture thereof, in an amount preferably between 5% (w/w) and 30% (w/w), more preferably 25% (w/w), and optionally adding and dissolving an antioxidant, selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, added in an amount preferably between 0.01 and 0.1 %, more preferably 0.01 % Butylated Hydroxy Toluene in it by continuous mixing,
  • said inert gas preferably being nitrogen and adding Sodium Fusidate to the mixture and dissolving it in the mixture, said sodium fusidate being added in an amount between 0.1% (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5% (w/w) and more preferably about 2.08 % (w/w), k. adjusting the pH of the mixture in said first API-vessel of step j to below 2 by using an acid, in an amount preferably between 0.005 and 0.5 %; more preferably 4 % of 1 Molar Nitric acid solution,
  • Clotrimazole from the third API - vessel of step m to the said mixing vessel of step h with continuous stirring at 10 to 50 RPM and homogenising the mixture at 1000 to 3000 RPM under vacuum, preferably of a magnitude between minus 1000 to minus 300 mm of mercury,
  • a method of treating primary & secondary skin infections and inflammations comprising applying of a cream containing at least one corticosteroid and
  • Fusidate wherein said cream comprises Fusidic acid made using Sodium
  • Fusidate a cream base containing a preservative, primary and secondary emulsifiers, waxy materials, co-solvents, acids, and water.
  • a method of treating primary & secondary skin infections and inflammations comprising applying of a cream as described in the preferred embodiment 1 and any of embodiments 1 to 9.
  • APIs-stability experiments were carried out (see tables 4 - 6) using the product of the present invention. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the APIs over a period of time. Each gram of product of the present invention used for the tests contained Sodium Fusidate in the amount required to produce 2% (w/w) Fusidic acid in the finished product and appropriate amount of steroids and antifungals as mentioned below. Table 3 :
  • composition Sodium Fusidate + Mometasone Furoate + Clotrimazole Cream
  • PRODUCT SODIUM FUSIDATE + MOMETASONE FUROATE +
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 %; ii) Mometasone Furoate USP 0.1 %; iii) Clotrimazole IP 1 %
  • the product used for the stability studies tests contained approximately 10% extra APIs (overages). It was packaged in an aluminium collapsible tube and each gram of the product contained 20.8 mg of Sodium Fusidate (in conformance with BP), which is equivalent to 20 mg of Fusidic acid (BP conformant). Detailed test results for 24 products have been presented. The percent of sodium fusidate, the corticosteroid, and the antifungal used in all examples are measured w/w with respect to the final product.
  • the Fusidic acid in the present invention degrades more slowly than the conventional products.
  • the stability level of the Fusidic acid in the present invention remains within the acceptable limits throughout the shelf life of the product.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une crème dermaceutique contenant du furoate de mométasone comme corticostéroïde, un agent antifongique sous forme de clotrimazole et un agent antibactérien sous forme d'acide fusidique, ledit acide fusidique étant formé in situ à partir du fusidate de sodium utilisé comme matière première de départ, le fusidate de sodium étant converti en acide fusidique dans un environnement exempt d'oxygène. La crème de l'invention présente une stabilité de conservation et une dimension des particules plus fines de l'API supérieures à celles des crèmes classiques contenant de l'acide fusidique. La crème de l'invention contient de l'acide fusidique en tant que l'API formé in situ à partir du fusidate de sodium, du furoate de mométasone et du clotrimazole, dans une base de crème comprenant un conservateur, un acide, un cosolvant, des émulsifiants et une matière cireuse en association avec de l'eau, de préférence de l'eau purifiée.
PCT/IB2010/056126 2010-09-14 2010-12-30 Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du clotrimazole et du furoate de mométasone, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Ceased WO2012035380A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4775678A (en) * 1984-10-01 1988-10-04 Schering Corporation Clotrimazole cream
WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010106459A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de furoate de mométasone
WO2010122475A1 (fr) * 2009-04-20 2010-10-28 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du clotrimazole et du mométasone, et son procédé de fabrication

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4775678A (en) * 1984-10-01 1988-10-04 Schering Corporation Clotrimazole cream
WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010106459A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de furoate de mométasone
WO2010122475A1 (fr) * 2009-04-20 2010-10-28 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du clotrimazole et du mométasone, et son procédé de fabrication

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ABDA-BUNDESVEREINIGUNG DEUTSCHER APOTHEKERVERBÄNDE: "Rezepturhinweise: Fusidinsäure", 10 December 2008 (2008-12-10), pages 1 - 4, XP002582786, Retrieved from the Internet <URL:http://www.pharmazeutische-zeitung.de/fileadmin/nrf/PDF/1-Fusidinsaeu re.pdf> *
SUCHKOVA G S ET AL: "SODIUM FUSIDATE INACTIVATION UNDER THE EFFECT OF OXYGEN AND MOISTURE", BIOSIS,, 1 January 1981 (1981-01-01), XP002583216 *

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