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WO2012035377A1 - Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du clotrimazole et du propionate de clobétasol, 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 propionate de clobétasol, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Download PDF

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Publication number
WO2012035377A1
WO2012035377A1 PCT/IB2010/056123 IB2010056123W WO2012035377A1 WO 2012035377 A1 WO2012035377 A1 WO 2012035377A1 IB 2010056123 W IB2010056123 W IB 2010056123W WO 2012035377 A1 WO2012035377 A1 WO 2012035377A1
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Prior art keywords
amount
vessel
mixture
api
cream
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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
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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 steroid which is in the form of Clobetasol Propionate, an antifungal agent in the form of Clotrimazole, 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).
  • API Active Pharmaceutical Ingredient
  • 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.
  • Topical and systemic fungal infections treatment compositions typically employ antifungal agents as active ingredients in a base component.
  • 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.
  • Fusidic acid As an alternative to Fusidic acid, Sodium Fusidate is known to have been used to make dermaceutical medicaments for topical application. However, 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.
  • Fusidic acid as an API Several aspects of Fusidic acid as an API are known:
  • 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 Clobetasol Propionate as a steroid, Clotrimazole 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, Clotrimazole as an antifungal and Clobetasol Propionate as a steroid, 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 along with Clobetasol Propionate as a steroid and Clotrimazole as an antifungal are not available.
  • Sodium Fusidate is not considered to be inherently more stable as an API than Fusidic acid.
  • BP Pharmacopoeia
  • a dermaceutical cream that uses Sodium Fusidate, Clotrimazole as an antifungal and Clobetasol Propionate as a steroid 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 Clobetasol Propionate as a steroid, Clotrimazole 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, Clotrimazole as an antifungal, Clobetasol Propionate as a steroid 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 Clobetasol Propionate as a steroid and Clotrimazole as an antifungal are added.
  • the cream of the present invention is used in the treatment of bacterial and fungal skin 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. It is essential that 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 average size of the fusidic acid particles in the present invention has been found to be less than 1.5 ⁇ whereas that for the existing creams varies between 14 ⁇ to 22 ⁇ . Euqlly importantly, the minimum particle size observed was approx. 0.6 ⁇ 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.
  • 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.
  • products such as those disclosed in WO2007087806 by Leo Pharma have employed 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. Moreover, the stability of the fusidic acid in creams produced by the teachings of WO2007087806 or indeed 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 2B.
  • 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 HC1, H 2 S0 4 , HN0 3 , 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.
  • 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.
  • a 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 between 0.01 % (w/w) and 2.00% (w/w), preferably 1.5% (w/w), more preferably 1.0% (w/w).
  • said anti-oxidant 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 between 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 between 0.01 % (w/w) and 1 % (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a chelating agent is 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 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 40% (w/w), preferably 35% (w/w), more preferably 30% (w/w).
  • a process to make a cream containing Clobetasol Propionate, 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 Clobetasol Propionate 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 0.0
  • 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 ° C to 80 ° C,
  • 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, 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 3% (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 % (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
  • 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) and 40% (w/w), preferably 30% (w/w), more preferably 20% (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 about 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,
  • 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 between about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
  • Clobetasol Propionate in an amount between 1 % (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 5% (w/w) and dissolving Clobetasol Propionate in the said mixture by continuous mixing, said Clobetasol Propionate being added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.005% w/w and about 1.00% w/w, and most preferably about 0.05% w/w, k.
  • Clotrimazole adding in a third API- vessel propylene glycol in an amount between 1% (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 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 about 0.5% w/w and about 5.0% w/w, preferably from about 0.5% w/w and about 3.0% w/w, and most preferably about 1.0%,
  • 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 about 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, in an amount between about 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 Qrtho Phosphate, Sodium Hydrogen Qrtho Phosphate and the like from about 0.01 % (w/w) and 2.00% (w/w), preferably 1.5 % (w/w), more preferably 1.0% (w/w).
  • a buffering agent selected from a group comprising Di Sodium Hydrogen Qrtho Phosphate, Sodium Hydrogen Qrtho Phosphate and the like from about 0.01 % (w/w) and 2.00% (w/w), preferably 1.5 % (w/w), more preferably 1.0% (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).
  • 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
  • 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 40% (w/w), preferably 35% (w/w), more preferably 30% (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 40% (w/w), preferably 35% (w/w), more preferably 30% (w/w).
  • a process to make a cream containing Clobetasol Propionate, Clotrimazole and fusidic acid as described in embodiment numbers 1 and 9 comprising the steps of: a. heating purified water in the range from 5% (w/w) to 60% (w/w), preferably 10% (w/w) to 50% (w/w), more preferably 30% (w/w) to 45% (w/w), in a water- phase vessel to 70 ° C to 80 °C,
  • 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,
  • step b adding to said water-phase vessel of step b any one of a chelating agent, a buffering agent, or a humectant, or any combination thereof; said 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 Qrtho 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. mixing the mixture of water phase vessel in step b using an agitator at 10 to
  • an emulsifying wax preferably Cetostearyl alcohol, in an amount preferably between 1 and 15 %, more preferably 12.5 %, and preferably Cetomacrogol-1000 in an amount between 0.1 % (w/w) and 3% (w/w), preferably 1 % (w/w), more preferably 0.5% (w/w) 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 °C to 80 ° C f.
  • an emulsifying wax preferably Cetostearyl alcohol
  • Cetomacrogol-1000 in an amount between 0.1 % (w/w) and 3% (w/w), preferably 1 % (w/w), more preferably 0.5% (w/w) 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 °C to 80 ° C f.
  • a non ionic surfactant or emulsifier in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate 80 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
  • 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 5% (w/w) and 30% (w/w), more preferably 20% (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,
  • 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 HC1, H 2 SO 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount between about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
  • Clobetasol Propionate is added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.005% w/w and about 1.00% w/w, and most preferably about 0.05% w/w,
  • step h mixing vessel of step h with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • 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:
  • Composition Sodium Fusidate + Clobetasol Propionate + Clotrimazole Cream
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 % 5 ii) Clobetasol Propionate USP/BP 0.05 % 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). The % of sodium fusidate,
  • antifungal and the corticosteroid 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 conventio nal produ cts

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Abstract

L'invention concerne une crème dermaceutique contenant du propionate de clobétasol comme stéroïde, du clotrimazole comme antifongique 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 clotrimazole en tant qu'antifongique et du propionate de clobétasol en tant que stéroïde, 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/IB2010/056123 2010-09-14 2010-12-30 Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du clotrimazole et du propionate de clobétasol, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Ceased WO2012035377A1 (fr)

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IN2530MU2010 2010-09-14
IN2530/MUM/2010 2010-09-14

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WO2012035377A1 true WO2012035377A1 (fr) 2012-03-22

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PCT/IB2010/056123 Ceased WO2012035377A1 (fr) 2010-09-14 2010-12-30 Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du clotrimazole et du propionate de clobétasol, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci

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Citations (5)

* 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
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010084458A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium, d'antifongiques et de stéroïdes
WO2010106502A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de propionate de clobétasol, son procédé de fabrication et procédé de traitement l'utilisant

Patent Citations (5)

* 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
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010084458A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium, d'antifongiques et de stéroïdes
WO2010106502A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à l'aide de fusidate de sodium, de clotrimazole et de propionate de clobétasol, son procédé de fabrication et procédé de traitement l'utilisant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
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] *
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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