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WO2010106503A1 - Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de nitrate de miconazole et de furoate de mométasone - Google Patents

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

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Publication number
WO2010106503A1
WO2010106503A1 PCT/IB2010/051144 IB2010051144W WO2010106503A1 WO 2010106503 A1 WO2010106503 A1 WO 2010106503A1 IB 2010051144 W IB2010051144 W IB 2010051144W WO 2010106503 A1 WO2010106503 A1 WO 2010106503A1
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amount
vessel
mixture
api
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Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kuppusamy Senthilkumar
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    • 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
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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, fungal skin infections and inflammations and in particular it relates to the single dose treatment using a steroid which is in the form of Mometasone Furoate, an antifungal agent in the form of Miconazole Nitrate, and an 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 steroid which is in the form of Mometasone Furoate, an antifungal agent in the form of Miconazole Nitrate, and an 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.
  • Sodium Fusidate is known to have been used to make dermaceutical medicaments for topical application.
  • these are in the form of ointment rather than cream.
  • Drawbacks of ointments over creams are well known and it's generally preferable to use creams rather than ointments for topical application.
  • Stabilization of medicaments containing Fusidic acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include:
  • 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 steroid, Miconazole Nitrate as an antifungal, 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, and Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, 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 as starting API along with Mometasone Furoate as a steroid, and Miconazole Nitrate as antifungal are not available.
  • 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 st ability- 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, Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal 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, antifungals and steroids.
  • Sodium Fusidate rather than Fusidic acid may be used as the starting API during the cream's manufacture.
  • Using Sodium Fusidate as starting material eliminates the drawback associated with the manufacture and storage of existing Fusidic acid creams.
  • the application discloses a cream containing Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal, and Fusidic acid 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 as the starting API, Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal in a cream base comprising a preservative, an acid, a co-solvent, a preservative, 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 cream of the present invention containing Fusidic acid 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 and to which Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal are added.
  • the cream of the present invention is used in the treatment of bacterial skin infections, fungal infections and inflammations.
  • the pH of the product of the present invention is from about 3 to 6.
  • Sodium Fusidate ointments that are commercially available are greasy and cosmetically non elegant.
  • the active drug penetrates the skin for the optimum bio-dermal efficacy.
  • 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, antifungal, antibacterial activity of the steroids, antifungals 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 from about 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 from about 0.005% (w/w) to 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.
  • the present invention is now described in terms of its embodiments.
  • 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 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), and
  • said preservatives is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, and added 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 emulsifier is selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like, either singly or any combination thereof, and added in an amount between 1% (w/w) and 25% (w/w), preferably 20% (w/w), more preferably
  • 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, and added in an amount between 5% (w/w) and 20% (w/w), preferably 15% (w/w), more preferablyl2.5% (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, and added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w),
  • said acid is selected from a group comprising acids such as HCl, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, and added in an amount between 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), and
  • water in an amount in the range between 5% (w/w) and 40% (w/w), preferably 10%) (w/w) to 30%) (w/w), more preferably 12%) (w/w) to 18%) (w/w), preferably purified water.
  • said buffering agent is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, either singly or any combination thereof, added in an amount 0.01% (w/w) and 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
  • said antioxidant is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, either singly or any combination thereof, added in an amount 0.001% (w/w) and 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, added in an amount 0.01% (w/w) and 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, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
  • a process to make a cream containing Mometasone furoate, Miconazole Nitrate, 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 Miconazole Nitrate are added.
  • 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, b. adding to said water-phase vessel 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) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), preferably benzoic acid.
  • 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% (
  • step b mixing the mixture of step b using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 0 C to 80 0 C, d. adding 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) and 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.
  • 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) and 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, Cetomacrogo 1-1000, either singly or any combination thereof, preferably Cetostearyl alcohol in an amount between 1% (w/w) and 15% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), and preferably Cetomacrogol-1000 in an amount between 0.1% (w/w) and 5% (w/w), preferably 2% (w/w), more preferably 1% (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% (w/w) and 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 0 C
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene GIy co 1-400 and the like, either singly or any combination thereof, in an amount between 5% (w/w) and 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) and 25% (w/w), preferably from about 0.5% (w/w) and 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said Sodium Fusidate in the mixture, i.
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene GIy co 1-400 and the like,
  • an acid 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, preferably Nitric acid to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), j.
  • Mometasone Furoate dissolving Mometasone Furoate in it by continuous mixing, said Mometasone Furoate being added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.05% w/w and about 1.00% w/w, and most preferably about 0.1% w/w, k.
  • a third API- vessel propylene glycol in an amount between 1% (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 13% (w/w) and dispersing Miconazole Nitrate in it by continuous mixing, said Miconazole Nitrate being added in an amount from about 0.5% (w/w) and 5.0% (w/w), preferably from about 0.5% (w/w) and 3.0%(w/w), and most preferably about 2.0% (w/w); to form a dispersion, followed by passing said dispersion through a colloid mill,
  • step g transferring the contents of the colloid milled Miconazole Nitrate from said third API-vessel of step k to said mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and vacuum preferably of a magnitude between minus 1000 and minus 300 mm of mercury, said inert gas being preferably nitrogen, o. cooling the contents of the mixing vessel of step g to 30 0 C to 37 0 C using circulation of cooled water from a cooling tower at 8 0 C to 15 0 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, added in an amount between 0.01% (w/w) and 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, added in an amount between 0.01% (w/w) and 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 chelating agent, a buffering agent selected from a group comprising Di Sodium Hydrogen
  • the process described in embodiments no. 10, 11, and 12 further incorporate in the step h of embodiment 10, an and oxidant selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001% (w/w) and 5% (w/w), preferably 0.1% (w/w), more preferably 0.01% (w/w).
  • an and oxidant selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001% (w/w) and 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, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
  • a humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
  • a process to make a cream containing mometasone furoate, Miconazole Nitrate and fusidic acid as described in embodiment nos 1 and 9 comprising the steps of:
  • 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, b.
  • 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) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), preferably Benzoic acid, c.
  • a chelating agent preferably being Disodium edetate added in an amount preferably between 0.01 and 1 %, more preferably 0.1%
  • said buffering agent preferably being Di Sodium Hydrogen Ortho Phosphate added in an amount preferably between 0.01% (w/w) and 2.00% (w/w), preferably 1.5% (w/w), more preferably 1.0%
  • said humectant preferably being Propylene Glycol added in an amount preferably 5% (w/w) to 60% (w/w), more preferably 30% (w/w), d.
  • step c mixing the mixture of water phase vessel in step c using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 ° C to 8O 0 C, e. adding to an oil-phase vessel an emulsifying wax, preferably Cetostearyl alcohol, in an amount preferably between 1 and 15 %, more preferably 12.5 % and waxy material White Soft Paraffin, in an amount preferably between 5 and 20 %, more preferably 12.5 %, and melting them by heating to 70 0 C to 80 0 C, f.
  • an emulsifying wax preferably Cetostearyl alcohol
  • a non ionic surfactant or emulsifier in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate 80 and 1% 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 under vacuum in the range of minus 1000 to minus 300 mm of mercury and at 70 0 C to 80 0 C the contents of the water-phase and oil- phase vessels to a mixing vessel and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM to form an emulsion, h.
  • cooling said emulsion to 45 0 C preferably by circulating cold water, preferably at 8 0 C to 15 0 C from a cooling tower in the jacket of the mixing vessel, i. adding in a first API-vessel a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 adding propylene glycol, or any mixture thereof, in an amount preferably 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, in an amount preferably between 0.01 and 0.1 %, more preferably 0.01 % Butylated Hydroxy Toluene in it by continuous mixing, j.
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, Poly
  • 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.
  • an acid selected from a group comprising acids such as HCl, H 2 SCU, HNO3, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
  • a third in a third API-vessel adding propylene glycol , in an amount preferably 1% (w/w) to 20% (w/w), more preferably 13% (w/w) and dispersing Miconazole Nitrate in it by continuous mixing to form a dispersion, said Miconazole Nitrate being added in an amount from about 0.5% (w/w) to about 5.0% (w/w), preferably from about 0.5% (w/w) to about 3.0%(w/w), and most preferably about 2.0% (w/w); followed by passing said dispersion through a colloid mill, n.
  • a method of treating primary & secondary bacterial & fungal skin infections and inflammations comprising applying of a cream containing at least one corticosteroid, one antifungal 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 bacterial & fungal 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.
  • PRODUCT SODIUM FUSIDATE + MOMETASONE FUROATE + MICONAZOLE NITRATE CREAM
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 % ii) Mometasone Furoate USP 0.1 % iii) Miconazole Nitrate IP 2.0 %
  • 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 % 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
  • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention porte sur une crème dermaceutique contenant du furoate de mométasone en tant que stéroïde, du nitrate de miconazole en tant qu'antifongique 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, lequel fusidate de sodium est converti en acide fusidique dans un environnement exempt d'oxygène. La crème de la présente invention a une stabilité de durée de conservation 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 contient de l'acide fusidique en tant qu'API qui a été fabriqué in situ à partir de fusidate de sodium, et du furoate de mométasone en tant que stéroïde, du nitrate de miconazole en tant qu'antifongique, 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/IB2010/051144 2009-03-17 2010-03-17 Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de nitrate de miconazole et de furoate de mométasone Ceased WO2010106503A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035376A1 (fr) * 2010-09-14 2012-03-22 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de miconazole et de furoate de mométasone
WO2012049539A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium, d'un corticostéroïde et d'un agent anti-fongique, et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
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", INTERNET CITATION, 14 October 2004 (2004-10-14), pages 1, XP002582673, Retrieved from the Internet <URL:http://www.pharmazie.com/graphic/A/64/1-25564.pdf> [retrieved on 20100518] *
MARRAS F: "THERAPEUTIC USEFULNESS OF A CORTICOSTEROID ANTIBACTERIAL AND ANTIFUNGAL COMBINATION IN SKIN DISEASES OF VARIOUS ORIGINS", PHARMATHERAPEUTICA, vol. 4, no. 2, 1985, 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, vol. 4, no. 2, 1985, pages 122 - 125, XP009133483, ISSN: 0308-051X *
SUCHKOVA G S ET AL: "SODIUM FUSIDATE INACTIVATION UNDER THE EFFECT OF OXYGEN AND MOISTURE", BIOSIS,, 1 January 1981 (1981-01-01), XP002583216 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035376A1 (fr) * 2010-09-14 2012-03-22 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de miconazole et de furoate de mométasone
WO2012049539A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium, d'un corticostéroïde et d'un agent anti-fongique, et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème

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