WO2010106459A1 - Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de furoate de mométasone - Google Patents

Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de furoate de mométasone Download PDF

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WO2010106459A1
WO2010106459A1 PCT/IB2010/050994 IB2010050994W WO2010106459A1 WO 2010106459 A1 WO2010106459 A1 WO 2010106459A1 IB 2010050994 W IB2010050994 W IB 2010050994W WO 2010106459 A1 WO2010106459 A1 WO 2010106459A1
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amount
vessel
mixture
api
cream
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PCT/IB2010/050994
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Balkrishnan Selvaraj
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Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Balkrishnan Selvaraj
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Application filed by Sulur Subramaniam Vanangamudi, Madhavan Srinivasan, Neelakandan Narayanan Chulliel, Balkrishnan Selvaraj filed Critical Sulur Subramaniam Vanangamudi
Publication of WO2010106459A1 publication Critical patent/WO2010106459A1/fr

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    • 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
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

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 10 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).
  • Topical and systemic are currently employed for the treatment of above skin inflammations.
  • 25 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: • replacing Oxygen in pharmaceutical containers with inert gases such as
  • Fusidic acid cream in which Fusidic acid will be of greater stability at the time of the manufacture of the cream, and which will sustain its stability at an acceptable level throughout its shelf life.
  • 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. There is no published data on the stability of Sodium Fusidate as the API. - Sodium Fusidate is not considered to be inherently more stable as an API than 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 HPLC 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.
  • BP British Pharmacopoeia
  • 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 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 HCl, H 2 SO 4 , HNO3, Lactic acid and the like between
  • the stability of the product is confirmed by the stability studies performed for 3/6 months as per ICH guidelines.
  • the present invention discloses the following embodiments.
  • Preferred embodiment 1 A novel dermaceutical cream containing Mometasone Furoate as a corticosteroid, Clotrimazole as antifungal agent and Fusidic acid which is made in situ by conversion of sodium fusidate under oxygen-free environment, and a cream base containing at least one of each of a preservative, a primary and secondary emulsifiers, a waxy material, a co-solvent, an acid, and water, preferably purified water.
  • Embodiment 1 A novel dermaceutical cream as disclosed in the preferred embodiment 1, said cream further incorporating any of any of a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • Embodiment no. 2 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
  • 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 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 12.5% (w/w),
  • said co-solvent is 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 60% (w/w), preferably 50% (w/w), more preferably 48.5% (w/w),
  • said acid is selected from a group comprising acids such as HCl, H 2 SO 4 ,
  • HNO 3 Lactic acid and the like, either singly or any combination thereof, in an amount between 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), and
  • water in the amount in the range of 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18% (w/w), preferably purified water.
  • 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).
  • Embodiment no. 8 A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 1 to 7 wherein said conversion of Sodium Fusidate into said Fusidic acid and the following formation of said Fusidic acid in a finely dispersed form in the final cream base take place in an oxygen-free environment.
  • 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 ° C to 80 ° C, d.
  • 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
  • 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 12.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 ° C to 80 ° C, e.
  • a primary emulsifier preferably in the form of a non ionic surfactant, selected from a group comprising Cetostearyl alcohol, Cetomacrogol-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%
  • Cetomacrogol-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 mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the mixture at 70 ° C to 80 ° C, f.
  • 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 mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the mixture at 70 ° C to 80 ° C, f.
  • 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%
  • 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 prop
  • Mometasone Furoate dispersing Mometasone Furoate in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, said 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 k.
  • Clotrimazole added 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
  • Embodiment no. 11 In another embodiment of the present invention 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).
  • Embodiment no. 14 In a further embodiment of the present invention 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 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, c.
  • 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/w)
  • said humectant is preferably Propylene Glycol, added in an amount preferably 5% (w/w) to 40% (w/w), more preferably 25% (w/w), d.
  • an oil-phase vessel 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, f.
  • an emulsifying wax preferably Cetostearyl alcohol
  • a waxy material preferably white soft paraffin
  • 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 ° C to 80 ° C, g. 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 ° C to 80 ° C and mixing the mixture at 10 to 50 RPM to form an emulsion, h.
  • 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 adding in the third API - vessel propylene glycol in an amount 1 % (w/w) to 20% (w/w), preferably 10% (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, said Clotrimazole being added in an amount between 0.5% (w/w) to about
  • 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, q. cooling the contents of said mixing vessel of step h to 30 ° C to 37 ° C using circulation of cooled water from cooling tower at 8 0 C to 15 0 C into the jacket of mixing vessel, r. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step q to a storage container.
  • a method of treating primary & secondary skin infections and inflammations comprising applying of a cream containing at least one corticosteroid and Fusidic acid which is made in situ under oxygen-free environment using Sodium 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 + CLOTRIMAZOLE CREAM
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 % ii) Mometasone Furoate USP 0.1 % iii) Clotrimazole IP 1.0 %
  • 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. It is evident from the foregoing description that the present invention has the following distinctions and advantages over the commercially available comparable products:
  • 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.
  • the particle size of the Fusidic acid is finer and overall particle distribution in the cream is better, thereby providing better dermaceutical efficacy.

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Abstract

L'invention porte sur une crème dermaceutique contenant du furoate de mométasone en tant que corticostéroïde, un agent antifongique sous la forme de clotrimazole et un agent antibactérien sous la forme d'acide fusidique, lequel acide fusidique est fabriqué in situ à partir de fusidate de sodium en tant que matière première de départ, le fusidate de sodium étant converti en acide fusidique dans un environnement exempt d'oxygène. La crème de la présente invention a une stabilité de durée de vie supérieure et une dimension de particules plus fine de l'ingrédient pharmaceutique actif (API) que les crèmes classiques contenant de l'acide fusidique. La crème de la présente invention comprend de l'acide fusidique en tant qu'API qui a été fabriqué in situ à partir de fusidate de sodium, du furoate de mométasone et du clotrimazole, dans une base de crème comprenant un conservateur, un acide, un co-solvant, des émulsifiants et un matériau cireux en association avec de l'eau, de préférence de l'eau purifiée.
PCT/IB2010/050994 2009-03-17 2010-03-09 Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de furoate de mométasone WO2010106459A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035380A1 (fr) * 2010-09-14 2012-03-22 Sulur Subramaniam Vanangamudi 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

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Title
"Panorama Dermatologische Praxis", DER HAUTARZT ; ZEITSCHRIFT FÜR DERMATOLOGIE, VENEROLOGIE UND VERWANDTE GEBIETE, SPRINGER, BERLIN, DE LNKD- DOI:10.1007/S00105-007-1421-Y, vol. 58, no. 11, 8 November 2007 (2007-11-08), pages 915 - 919, XP019548207, ISSN: 1432-1173 *
ANONYMOUS: "Fucicort-Creme", 14 October 2004 (2004-10-14), XP002582673, Retrieved from the Internet <URL:http://www.pharmazie.com/graphic/A/64/1-25564.pdf> [retrieved on 20100518] *
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DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1981, SUCHKOVA G S ET AL: "SODIUM FUSIDATE INACTIVATION UNDER THE EFFECT OF OXYGEN AND MOISTURE", XP002583216, Database accession no. PREV198274045049 *
MARRAS F: "THERAPEUTIC USEFULNESS OF A CORTICOSTEROID ANTIBACTERIAL AND ANTIFUNGAL COMBINATION IN SKIN DISEASES OF VARIOUS ORIGINS", PHARMATHERAPEUTICA, CLAYTON-WRAY PUBLICATIONS, LONDON, GB, vol. 4, no. 2, 1 January 1985 (1985-01-01), pages 88 - 91, XP009133482, ISSN: 0308-051X *
PAZZAGLIA A: "THERAPEUTIC EFFECTS AND TOLERANCE OF AN EXTEMPORE COMBINATION OF AN ANTIBACTERIAL ANTI-INFLAMMATORY AND ANTIMYCOTIC CREAM IN SKIN DISEASES OF VARIOUS ORIGINS", PHARMATHERAPEUTICA, CLAYTON-WRAY PUBLICATIONS, LONDON, GB, vol. 4, no. 2, 1 January 1985 (1985-01-01), pages 122 - 125, XP009133483, ISSN: 0308-051X *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035380A1 (fr) * 2010-09-14 2012-03-22 Sulur Subramaniam Vanangamudi 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

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