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WO2012035379A1 - Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du nitrate de miconazole et du propionate de miconazole, 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 nitrate de miconazole et du propionate de miconazole, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Download PDF

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Publication number
WO2012035379A1
WO2012035379A1 PCT/IB2010/056125 IB2010056125W WO2012035379A1 WO 2012035379 A1 WO2012035379 A1 WO 2012035379A1 IB 2010056125 W IB2010056125 W IB 2010056125W WO 2012035379 A1 WO2012035379 A1 WO 2012035379A1
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WIPO (PCT)
Prior art keywords
amount
vessel
mixture
cream
api
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Balkrishnana Selvaraj
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

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 Fluticasone Propionate, 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 cream containing a steroid which is in the form of Fluticasone Propionate
  • an antifungal agent in the form of Miconazole Nitrate
  • 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).
  • 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.
  • 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 active ingredients typically comprise antifungal agents such as Miconazole Nitrate, Terbinafine Hydrochloride, Ketoconazole, Clotrimazole and the like. Numerous treatments, both topical and systemic, are available for the primary and secondary skin infection caused by sensitive Gram +ve organisms such as Staphylococcus aureus, Streptococcus spp etc.
  • Topical and systemic bacterial infection treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component.
  • the 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.
  • Degradation due to oxidation is a major cause of instability of currently available Fusidic acid creams. Table 1 show that the degradation in the API samples (Fusidic acid) exposed to oxygen ranged between 7.7% and 11 % for conditions ranging from room temperature to 45 °C when analysed at three months of exposure period at the above conditions.
  • 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.
  • dermaceutical cream containing Fluticasone Propionate as a steroid, Miconazole Nitrate as an antifungal, and an antibacterial in the form of Fusidic acid, and 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 Fluticasone Propionate 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, Miconazole Nitrate as an antifungal and Fluticasone 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 are not available.
  • Creams containing Fusidic acid that are made using Sodium Fusidate as starting API along with Fluticasone Propionate as a steroid and Miconazole Nitrate as an antifungal are not available.
  • fusidic acid has very labile trans, sys, trans arrangement of these rings which forces ring B into a boat conformation.
  • fusidic acid readily undergoes acid mediated dehydration of C-l l hydroxy group to generate a C9-C11 double bond which on further isomerization followed by oxidization in the presence of oxygen leads to a mixture of biologically inactive fusidic acid derivatives.
  • carboxylic acid functional group present in the fusidic acid facilitates the above process more readily upon storage.
  • carboxylic acid promoted decomposition is not feasible.
  • sodium fusidate has superior solid state stability when compared to fusidic acid. This discovery of the inventor has also been corroborated through stability assessment of sodium fusidate and fusidic acid.
  • Tables 1 and 2 also show the comparison between the stability of the Fusidic acid and Sodium Fusidate as raw APIs.
  • the study was carried out using an in-house UPLC method developed by the applicant, which the applicant believes is a true stability-indicating method as opposed to the titration method suggested in British Pharmacopoeia (BP). This is because the BP method does not differentiate between the intact API and the degraded form.
  • BP British Pharmacopoeia
  • a dermaceutical cream that uses Sodium Fusidate, Miconazole Nitrate as an antifungal and Fluticasone 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 Fluticasone Propionate as a steroid, 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, Miconazole Nitrate as an antifungal, Fluticasone 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 Fluticasone Propionate as a steroid and Miconazole Nitrate 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 H 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 approximately 1.1 ⁇ whereas that for the existing creams varies between 14 ⁇ to 22 ⁇ . Euqlly importantly, the minimum particle size observed was approx. 0.5 ⁇ 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.
  • WO2007087806 by Leo Pharma have employed mechanical means such as mortar and pestle to mechanically grind fusidic acid for adding to a cream base.
  • mechanical means such as mortar and pestle to mechanically grind fusidic acid for adding to a cream base.
  • WO2007087806 is silent on the particle size achieved, it will be known to a person skilled in the art that its particle size of fusidic acid cannot be finer than that of the present invention.
  • the stability of the fusidic acid in creams produced by the teachings of WO2007087806 or any other fusidic acid creams that employ grinding of fusidic acid in presence of oxygen cannot be as good as that of the present invention as evidenced by the data included in Table 2A.
  • the inventor has screened different co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one of above co-solvents varying 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 SO 4 , HNO 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 stability of the product is confirmed by the stability studies performed for 3months as per ICH guidelines.
  • said corticosteroid is added from about 0.005% to about 2.5% by weight, preferably from about 0.005% to about 1.00% by weight, and most preferably about 0.05% by weight, and further wherein said corticosteroid is Fluticasone Propionate, and said antifungal is added from about 0.5% to about 5.0% by weight, preferably from about 0.5% to about 3.0% by weight, and most preferably about 2.0% by weight; said antifungal preferably being Miconazole Nitrate, 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 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,
  • 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) to 20% (w/w), preferably 15% (w/w), more prefer ably 12.5% (w/w)
  • said co-solvent is selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glyco 1-400 and the like, either singly or any combination thereof, and added in an amount between 5% (w/w) to 40% (w/w), preferably 35% (w/w), more preferably 30% (w/w)
  • said acid is selected from a group comprising acids such as HC1, H
  • 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, to form a proportion between 0.01 % (w/w) to 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
  • a chelating agent is selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, to form a proportion 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, to form a proportion between 5% (w/w) to 40% (w/w), preferably 35% (w/w), more preferably 30% (w/w).
  • a process to make a cream containing Fluticasone Propionate, 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 Fluticasone Propionate and Miconazole Nitrate 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
  • 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, 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) to 20% (w/w), preferably 15% (w/w), more preferablyl2.5% (w/w), to an oil-phase vessel and melting said wax by heating to 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) to 15%
  • 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 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) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said Sodium Fusidate in the mixture,
  • an acid selected from a group comprising acids such as HC1
  • H 2 SO 4 , HNO 3 , Lactic acid and the like either singly or any combination thereof, preferably Nitric acid in an amount between about 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), adding in a second API- vessel propylene glycol in an amount between 1 % (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 5% (w/w) and purified water in an amount between 1 % (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 5% (w/w), and dissolving Surfactant, preferably Cetomacrogol-1000 in an amount between 0.1 % (w/w) to 3% (w/w), preferably 1 % (w/w), more preferably 0.5% (w/w) and dispersing Fluticasone Propionate in the said mixture by continuous mixing to form a dispersion, followed by passing said dispersion
  • step g transferring the contents of said first API-vessel of step i to the 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 under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • 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 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • step g cooling the contents of the mixing vessel of step g to 30 °C to 37 °C using circulation of cooled water from a cooling tower at 8 °C to 15 °C into the jacket of mixing vessel,
  • the process described in embodiment no. 10 further incorporates after the step of adding a preservative, 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) 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 about 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 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 % (w/w), more preferably 0.5% (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 % (w/w), more preferably 0.5% (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).
  • Glycerin, Sorbitol, Propylene glycol and the like either singly or any combination thereof, to form a proportion between 5% (w/w) to 40% (w/w), preferably 35% (w/w), more preferably 30% (w/w).
  • a process to make a cream containing Fluticasone Propionate, Miconazole Nitrate 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 0 C to 80 0 C,
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) to 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% (w/w), more preferably 0.5%
  • said humectant preferably being Propylene Glycol added in an amount preferably 5% (w/w) to 60% (w/w), more preferably 25% (w/w),
  • step b mixing the mixture of water phase vessel in step b using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 0 C to
  • 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 ° 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) to 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),
  • 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) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), adding in a second API- vessel propylene glycol in an amount between 1%
  • step h transferring the contents of said first API-vessel of step k to the 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,
  • a method of treating primary & secondary bacterial skin infections, fungal skin infections and inflammations comprising applying of a cream containing at least one corticosteroid, at least 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 skin infections, 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. Table 3: Composition of the Sodium Fusidate + Fluticasone Propionate + Miconazole Nitrate Cream
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 % ii) Fluticasone Propionate BP 0.05 % iii) Miconazole Nitrate IP 2.0 %
  • Measured parameter pH; Limits of measured parameter: 3-6
  • 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)
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  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
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  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une crème dermaceutique contenant du propionate de fluticasone comme stéroïde, du nitrate de miconazole 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 nitrate de miconazole en tant qu'antifongique et du propionate de fluticasone 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/IB2010/056125 2010-09-14 2010-12-30 Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium, du nitrate de miconazole et du propionate de miconazole, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Ceased WO2012035379A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
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
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010106460A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de nitrate de miconazole et de propionate de fluticasone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
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
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010106460A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium, de nitrate de miconazole et de propionate de fluticasone

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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