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WO2012035381A1 - Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium et du valérate de bétaméthasone, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci - Google Patents

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

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Publication number
WO2012035381A1
WO2012035381A1 PCT/IB2010/056127 IB2010056127W WO2012035381A1 WO 2012035381 A1 WO2012035381 A1 WO 2012035381A1 IB 2010056127 W IB2010056127 W IB 2010056127W WO 2012035381 A1 WO2012035381 A1 WO 2012035381A1
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WIPO (PCT)
Prior art keywords
vessel
cream
mixture
fusidic acid
amount
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Ceased
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PCT/IB2010/056127
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kausik Ghosh
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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
    • A61K31/56—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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • Betamethasone Valerate A Process To Make The Same, And A
  • the present invention relates to primary & secondary bacterial skin infections and inflammations and in particular it relates to the single dose treatment using a cream containing a corticosteroid in the form of Betamethasone Valerate 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 corticosteroid in the form of Betamethasone Valerate 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).
  • Topical and systemic inflammatory treatment compositions typically employ a combination of corticosteroids in a base component.
  • the active ingredients typically comprise Corticosteroids such as steroids like Betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate and the like.
  • Corticosteroids such as steroids like Betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate 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.
  • 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.
  • 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 precipitates It can be obtained from Sodium Fusidate by dissolving the latter in an aqueous phase and adding acid to the solution, whereby Fusidic acid precipitates.
  • the Fusidic acid precipitate is difficult to process into a cream form first due to its coarse and uneven particle size and second retrieving Fusidic acid from wet cake involves drying and further handling which deteriorates the Fusidic acid due to exposure to oxygen •
  • the stability of the API in a Fusidic acid cream is unreliable due to the thermolabile nature of Fusidic acid
  • Stabilization of medicaments containing Fusidic acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include:
  • the invention discloses a dermaceutical cream containing Betamethasone Valerate as a corticosteroid, 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 Betamethasone Valerate, in a cream base comprising a preservative, an acid, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.
  • Creams containing Fusidic acid that are made using Sodium Fusidate as starting API are not available.
  • Creams containing Fusidic acid that are made using Sodium Fusidate along with a corticosteroid in the form of Betamethasone Valerate as starting APIs 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.
  • Tables 1 and 2 also show the comparison between the stability of the Fusidic acid and Sodium Fusidate as raw APIs. The study was carried out using an in-house
  • UPLC method developed by the applicant, which the applicant believes is a true stability-indicating method as opposed to the titration method suggested in British Pharmacopoeia (BP). This is because the BP method does not differentiate between the intact API and the degraded form.
  • a dermaceutical cream that uses Sodium Fusidate and steroids would exploit the benefit of the fact that Sodium Fusidate is more stable than Fusidic acid and it would also provide a cream formulation which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic acid and steroids.
  • Sodium Fusidate rather than Fusidic acid may be used as the starting API during the cream's manufacture.
  • 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 Steroids in the form of Betamethasone Valerate and Fusidic acid (the API) that has been prepared using Sodium Fusidate as the starting API, in which Fusidic acid forms in-situ under totally oxygen free environment by slow addition of an acid, into a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates as an extremely fine dispersion when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen.
  • the cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, a steroid in the form of Betamethasone Valerate in a cream base comprising an acid, a preservative, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.
  • the cream base of the present invention optionally further comprises an ingredient selected from a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • the present invention provides a novel cream that has been produced using Sodium Fusidate as the starting raw material, and which cream contains Fusidic acid of high therapeutic efficacy and of chemical stability that is generally superior to the commercially available creams containing Fusidic acid.
  • the Fusidic acid and steroid cream of the present invention has been manufactured in a totally oxygen free environment under purging with inert gas and applying vacuum. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic acid.
  • the cream of the present invention is used in the treatment of bacterial skin infections and inflammations.
  • the pH of the product of the present invention is between 3 to 6.
  • Sodium Fusidate ointments that are commercially available are greasy and cosmetically non elegant. 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 average size of the fusidic acid particles in the present invention has been found to be less than 1 ⁇ whereas that for the existing creams varies between 14 ⁇ to 22 ⁇ . Equally importantly, the minimum particle size observed was appro x. 0.33 ⁇ 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 indeed any fusidic acid creams that use grinding methods to grind 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 product of the present invention is efficacious due to the pronounced antiinflammatory, antibacterial activity of the steroid and regenerated Fusidic acid which is available in reduced particle size than the conventional products, and in a finely dispersed form.
  • the inventor has screened different co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one of above co-solvents varying between 5% (w/w) to 40% (w/w) under inert gas purging and under vacuum and converted to Fusidic acid in- situ by adding an acid such as HC1, H 2 SO 4 , HNO 3 , Lactic acid and the like between 0.005% (w/w) and about 0.5% (w/w) under stirring and obtained Fusidic acid in more stabilized and solution form, which makes our final product in a cream base which easily penetrates the skin and highly efficacious, and also highly derma compatible by having a pH of
  • a novel dermaceutical cream as described in the preferred embodiment 1 wherein said corticosteroid is added in an amount between about 0.001 % (w/w) and about 5% (w/w) by weight, preferably between 0.005% (w/w) and about 2.00% (w/w) by weight, and more preferably between 0.05% (w/w) to 1.0%(w/w), even more preferably about 0.12% (w/w) and said Fusidic acid is present in an amount between 0.1% (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5%(w/w), and more preferably about 2.00 % (w/w), and in which the amount of said Sodium Fusidate used to form in situ said Fusidic acid is in the range between about 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
  • 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% (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, to form a proportion between 0.001 % (w/w) to 5% (w/w), preferably 0.1 % (w/w), more preferably 0.01% (w/w).
  • a novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 4 which further comprises a chelating agent, wherein said chelating agent is selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, 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 30% (w/w), more preferably 25% (w/w).
  • a process to make a cream containing betamethasone valerate 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
  • Betamethasone valerate is added.
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), more preferably Benzoic acid, c. mixing the mixture using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 0 C,
  • waxy materials selected from a group comprising White soft paraffin
  • Liquid Paraffin, Hard paraffin and the like either singly or any combination thereof, in an amount between 5% (w/w) to 20% (w/w), preferably 15% (w/w), more preferablyl2.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 0 C to 80 0 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, wherein Cetostearyl alcohol is added in an amount between 1 % (w/w) to 15% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), and Cetomacrogol-1000 is added in an amount between 0.1% (w/w) to 5% (w/w), preferably 1% (w/w), more preferably 0.5% (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80, in an amount between 1 to 5% w/w, more preferably 2% w/w and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80
  • 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, H2So4, HN03, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid to form a proportion from about 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
  • Betamethasone Valerate in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, 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, 1.
  • Betamethasone valerate from said second API- vessel of step j to said mixing vessel of step k with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under vacuum, preferably of a magnitude between minus 1000 to minus 300 mm of mercury,
  • 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, to form a proportion from 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, to form a proportion from 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 the chelating agent, a buffering agent , selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.01 % (w/w) to 2.00% (w/w), preferably 1% (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).
  • 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, to form a proportion between 5% (w/w) to 40% (w/w), preferably 30% (w/w), more preferably 25% (w/w).
  • a 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 30% (w/w), more preferably 25% (w/w).
  • a process to make a cream containing betamethasone valerate and fusidic acid as described in embodiment no 8 comprising the steps of: heating purified water in the range from 20% (w/w) to 75% (w/w), preferably 35% (w/w) to 50% (w/w), more preferably 40% (w/w) to 43% (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), the preferred preservative being Benzoic acid,
  • a chelating agent preferably Disodium edetate, in an amount preferably between 0.01 and 1 %, more preferably 0.1 %,
  • a buffering agent preferably Di Sodium Hydrogen Ortho Phosphate, in an amount preferably 0.01% (w/w) to 2.00% (w/w), preferably 1% (w/w), more preferably 0.5% (w/w).
  • humectant preferably Propylene Glycol
  • 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 non ionic Surfactant/emulsifier in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate 80 and 0.5% of Cetomacrogol 1000 and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 0 C,
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400adding propylene glycol, or any mixture thereof, in an amount preferably between 5% (w/w) and 30% (w/w), more preferably 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),
  • a second API-vessel adding propylene glycol , in an amount preferably between 1% (w/w) and 10% (w/w), more preferably 5% (w/w) and dispersing Betamethasone Valerate in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, transferring the contents of said first API-vessel of step m to said mixing vessel of step j 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 preferably being nitrogen,
  • Betamethasone valerate from said second API- vessel of step n to said mixing vessel of step j with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under vacuum, preferably of a magnitude between minus 1000 to minus 300 mm of mercury,
  • a method of treating primary & secondary skin infections and inflammations comprising applying of a cream containing at least one corticosteroid and Fusidic acid which is made in situ under oxygen-free environment using Sodium Fusidate, wherein said cream comprises Fusidic acid made using Sodium Fusidate, a cream base containing a preservative, primary and secondary emulsifiers, waxy materials, co-solvents, acids, and water.
  • a method of treating primary & secondary skin infections and inflammations comprising applying of a cream as described in the preferred embodiment 1 and any of embodiments 1 to 9.
  • APIs-stability experiments were carried out (see tables 3 - 20) using several products that are representative 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 and Betamethasone Valerate in the amount of 0.12% (w/w) in the finished product wherein all %ages are with respect to the final formulation.
  • Each gm contains:
  • Measured parameter pH; Limits of measured parameter: 3-6
  • product of the present invention is quite stable at ambient conditions and also at elevated temperature & humid conditions of storage.
  • composition of the typical cream of the preferred embodiment of the present invention and on which the experimental results presented in the foregoing description have been based are now provided.
  • 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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  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une crème dermaceutique contenant du valérate de bétaméthasone comme corticostéroïde 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 et du valérate de bétaméthasone, 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/IB2010/056127 2010-09-14 2010-12-30 Nouvelle crème dermaceutique fabriquée avec du fusidate de sodium et du valérate de bétaméthasone, procédé de fabrication de la crème et méthode de traitement utilisant celle-ci Ceased WO2012035381A1 (fr)

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IN2534MU2010 2010-09-14
IN2534/MUM/2010 2010-09-14

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WO2012035381A1 true WO2012035381A1 (fr) 2012-03-22

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CN105687206A (zh) * 2014-11-27 2016-06-22 四川海思科制药有限公司 一种夫西地酸戊酸倍他米松乳膏药物组合物及其制备方法

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WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010106458A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium et de valérate de bétaméthasone

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WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde
WO2010084457A1 (fr) * 2009-01-21 2010-07-29 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à partir de fusidate de sodium et de stéroïdes
WO2010106458A1 (fr) * 2009-03-17 2010-09-23 Sulur Subramaniam Vanangamudi Crème dermaceutique fabriquée à l'aide de fusidate de sodium et de valérate de bétaméthasone

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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 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105687206A (zh) * 2014-11-27 2016-06-22 四川海思科制药有限公司 一种夫西地酸戊酸倍他米松乳膏药物组合物及其制备方法

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