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WO2012035376A1 - A dermaceutical cream made using sodium fusidate, miconazole and mometasone furoate - Google Patents

A dermaceutical cream made using sodium fusidate, miconazole and mometasone furoate Download PDF

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Publication number
WO2012035376A1
WO2012035376A1 PCT/IB2010/056122 IB2010056122W WO2012035376A1 WO 2012035376 A1 WO2012035376 A1 WO 2012035376A1 IB 2010056122 W IB2010056122 W IB 2010056122W WO 2012035376 A1 WO2012035376 A1 WO 2012035376A1
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Prior art keywords
amount
vessel
mixture
api
cream
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French (fr)
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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to primary & secondary bacterial skin infections, fungal skin infections and inflammations and in particular it relates to the single dose treatment using a steroid which is in the form of Mometasone Furoate, an antifungal agent in the form of Miconazole Nitrate, and an antibacterial agent in
  • 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 active ingredients typically comprise antifungal agents such as Miconazole Nitrate, Terbinafine Hydrochloride, Ketoconazole, Clotrimazole and the like.
  • Topical and systemic bacterial infection treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component.
  • API active pharmaceutical ingredient
  • the APIs typically comprise an antibiotic/antibacterial such as Fusidic acid and the like.
  • Fusidic acid creams 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.
  • Fusidic acid particles presents an enormous surface area for contact and reaction with molecular Oxygen during manufacture, handling, and processing of the cream. This has serious implications to its chemical stability and results in rapid reduction in potency of the API (Fusidic acid) in the final cream formulation.
  • Sodium Fusidate is known to have been used to make dermaceutical medicaments for topical application.
  • these are in the form of ointment rather than cream.
  • Drawbacks of ointments over creams are well known and it's generally preferable to use creams rather than ointments for topical application.
  • Stabilization of medicaments containing Fusidic acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include:
  • the invention discloses a dermaceutical cream containing Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, and an antibacterial agent in the form of Fusidic acid, which Fusidic acid is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic acid under oxygen-free environment.
  • the cream of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional creams containing Fusidic acid.
  • the cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, and Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, in a cream base comprising a preservative, an acid, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.
  • Creams containing Fusidic acid that are made using Sodium Fusidate as starting API are not available. Creams containing Fusidic acid that are made using Sodium Fusidate as starting API along with Mometasone Furoate as a steroid, and Miconazole Nitrate as antifungal are not available.
  • Sodium Fusidate is not considered to be inherently more stable as an API than Fusidic acid.
  • 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.
  • a dermaceutical cream that uses Sodium Fusidate, Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal would exploit the benefit of the fact that
  • Sodium Fusidate is more stable than Fusidic acid and it would also provide a cream formulation which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic acid, antifungals and steroids.
  • the applicant therefore surprisingly discovered that in order to achieve greater stability of the API in a dermaceutical cream, Sodium Fusidate rather than Fusidic acid may be used as the starting API during the cream's manufacture. Using Sodium Fusidate as starting material eliminates the drawback associated with the manufacture and storage of existing Fusidic acid creams.
  • the application discloses a cream containing Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal, and Fusidic acid that has been prepared using Sodium Fusidate as the starting API, in which Fusidic acid forms in-situ under totally oxygen free environment by slow addition of an acid, into a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates as an extremely fine dispersion when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen.
  • the cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate as the starting API, Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal in a cream base comprising a preservative, an acid, a co-solvent, a preservative, emulsifiers and a waxy material along with water, preferably purified water.
  • the cream base of the present invention optionally further comprises an ingredient selected from a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • the present invention provides a novel cream that has been produced using Sodium Fusidate as the starting raw material, and which cream contains Fusidic acid of high therapeutic efficacy and of chemical stability that is generally superior to the commercially available creams containing Fusidic acid.
  • the cream of the present invention containing Fusidic acid has been manufactured in a totally oxygen free environment under purging with inert gas and applying vacuum. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic acid and to which Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal are added.
  • the cream of the present invention is used in the treatment of bacterial skin infections, fungal infections and inflammations.
  • the 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 average size of the fusidic acid particles in the present invention has been found to be approximately 1 ⁇ whereas that for the existing creams varies between 14 ⁇ to 22 ⁇ . Equally importantly, the minimum particle size observed was approx. 0.25 ⁇ 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 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 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 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.
  • co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one
  • said corticosteroid is added in an amount between 0.005% (w/w) and about 2.5% (w/w), preferably from about 0.05% (w/w) and about 1.00% (w/w), and most preferably from about 0.1% (w/w), and further wherein said corticosteroid is Mometasone furoate, and said antifungal is added from 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 2.0% (w/w); said antifungal preferably being Miconazole Nitrate, and said Fusidic acid is present in an amount between 0.1% (w/w) and about 25%
  • said preservatives is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, and added in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), said primary and secondary emulsifier is selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80,
  • 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 0.01 % (w/w) and 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
  • a novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 4 which further comprises a chelating agent, wherein said chelating agent is selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, added in an amount 0.01 % (w/w) and 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 5 which further comprises a humectant, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
  • Nitrate, and_fusidic acid said cream being as disclosed in preferred embodiment 1 and embodiment 1 , said process comprising the step of using sodium fusidate as the raw active pharmaceutical ingredient and converting said sodium fusidate in situ into fusidic acid under oxygen-free environment in a cream base, to which Mometasone furoate and Miconazole Nitrate are added.
  • 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 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) and 20% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 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, preferably Cetostearyl alcohol in an amount between 1 % (w/w) and 15% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), and preferably Cetomacrogol-1000 in an amount between 0.1 % (w/w) and 5% (w/w), preferably 2% (w/w), more preferably 1 % (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80, in an amount between 1 % (w/w) and 5% w/w, more preferably 2% w/w and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the
  • 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 25% (w/w), preferably propylene glycol, subjecting the contents of said API-vessel to inert gas flushing, said inert gas being preferably nitrogen, and adding sodium fusidate to the mixture, said sodium fusidate added in an amount between 0.1 % (w/w) and 25% (w/w), preferably from about 0.5% (w/w) and 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said Sodium Fusidate in the mixture,
  • 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 to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
  • Mometasone Furoate is added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.05% w/w and about 1.00% w/w, and most preferably about 0.1 % w/w, k.
  • Miconazole Nitrate being added in an amount from about 0.5% (w/w) and 5.0% (w/w), preferably from about 0.5% (w/w) and 3.0%(w/w), and most preferably about 2.0% (w/w); to form a dispersion, followed by passing said dispersion through a colloid mill,
  • step g 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, a step of adding a chelating agent, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, added in an amount between 0.01 % (w/w) and 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a chelating agent selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, added in an amount between 0.01 % (w/w) and 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • the process described in embodiments no. 10 and 11 further incorporates after the step of adding chelating agent, a buffering agent selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.01% (w/w) and 2.00% (w/w), preferably 1.0% (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) and 2.00% (w/w), preferably 1.0% (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) and 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) and 5% (w/w), preferably 0.1 % (w/w), more preferably 0.01 % (w/w).
  • the process described in embodiments no. 10, 11 ,12 and 13 further incorporate a humectant in the step a of embodiment 10, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
  • a humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
  • a process to make a cream containing mometasone furoate, Miconazole Nitrate and fusidic acid as described in embodiment nos 1 and 9 comprising the steps of: a. heating purified water in the range from 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18%
  • 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 c mixing the mixture of water phase vessel in step c using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 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 non ionic surfactant or emulsifier in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 adding propylene glycol, or any mixture thereof, in an amount preferably 5% (w/w) and 30% (w/w), more preferably 25% (w/w) and optionally adding and dissolving an antioxidant, selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, in an amount preferably between 0.01 and 0.1 %, more preferably 0.01 % Butylated Hydroxy Toluene in it by continuous mixing,
  • 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),
  • step h transferring the contents of said second API-vessel of step 1 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,
  • step h transferring the contents of the colloid milled Miconazole Nitrate from said third API-vessel of step m to said 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 vacuum preferably of a magnitude between minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • a method of treating primary & secondary bacterial & fungal skin infections and inflammations comprising applying of a cream containing at least one corticosteroid, one antifungal and Fusidic acid which is made in situ under oxygen-free environment using Sodium Fusidate, wherein said cream comprises Fusidic acid made using Sodium Fusidate, a cream base containing a preservative, primary and secondary emulsifiers, waxy materials, co-solvents, acids, and water.
  • a method of treating primary & secondary bacterial & fungal skin infections and inflammations comprising applying of a cream as described in the preferred embodiment 1 and any of embodiments 1 to 9.
  • the stability of the product is confirmed by the stability studies performed for 3months as per ICH guidelines.
  • PRODUCT SODIUM FUSIDATE + MOMETASONE FUROATE + MICONAZOLE NITRATE CREAM
  • Each gm contains:
  • Measured parameter pH Limits of measured parameter: 5-7
  • the product used for the Stability Studies tests contained approximately 10% extra APIs (overages). It was packaged in an aluminium collapsible tube and each gram of the product contained 20.8 mg of Sodium Fusidate (in conformance with BP), which is equivalent to 20 mg of Fusidic acid (BP conformant). Detailed test results for 24 products have been presented. The % of sodium fusidate, the corticosteroid, and the antifungal used in all examples are measured w/w with respect to the final product.
  • the stability level of the Fusidic acid in the present invention remains within the acceptable limits throughout the shelf life of the product
  • the particle size of the Fusidic acid is finer and overall particle distribution in the cream is better, thereby providing better dermaceutical efficacy

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Abstract

The invention discloses a dermaceutical cream containing Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, and an antibacterial agent in the form of Fusidic acid, which Fusidic acid is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic acid under oxygen-free environment. The cream of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional creams containing Fusidic acid. The cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, and Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, in a cream base comprising a preservative, an acid, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.

Description

A DERMACEU ICAL CREAM MADE USING SODIUM FUSIDATE, MICONAZOLE AND MOMETASONE FUROATE
5 Field Of Invention
The present invention relates to primary & secondary bacterial skin infections, fungal skin infections and inflammations and in particular it relates to the single dose treatment using a steroid which is in the form of Mometasone Furoate, an antifungal agent in the form of Miconazole Nitrate, and an antibacterial agent in
10 the form of, Fusidic acid wherein the Fusidic acid has been made using Sodium
Fusidate as the starting Active Pharmaceutical Ingredient (API).
Background Of The Invention
Use of steroids to alleviate inflammation, irritation and itching caused by skin
15 ailments is well known. 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.
20 Numerous single dose treatments, both topical and systemic, are currently
employed for the treatment of above skin inflammations. Topical and systemic inflammatory treatment compositions typically employ a combination of corticosteroids in a base component. The active ingredients typically comprise Corticosteroids such as Betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate and the like.
Fungal infections sometimes follow the use of antibiotics, which kill
nonpathogenic as well as pathogenic bacteria, thereby providing a free field in the body for fungal invasion.
Numerous treatments both topical and systemic are currently employed for the treatment of fungal infections. 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. In the cream form, the APIs typically comprise an antibiotic/antibacterial such as Fusidic acid and the like. In the currently available Fusidic acid creams, 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. However, 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 analyzed at three months of exposure period at the above conditions.
It is known that greater the exposure time of Fusidic acid as the raw API to Oxygen, greater the limitations on stabilising Fusidic acid in a formulation. However, there is no published data on the stability of Fusidic acid over a period of time.
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.
Several aspects of Fusidic acid as an API are known:
• It is thermolabile
• It is available in cream formulations
• 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. However, 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:
• replacing Oxygen in pharmaceutical containers with inert gases such as Nitrogen, Carbon dioxide, Helium and the like
• avoiding contact of the medicament with heavy metal ions which catalyze oxidation,
• storing the API at reduced temperatures throughout its shelf life before processing In practice this means stricter controls during the manufacture as well as storage of such API (storing it typically at 2°C to 8°C in air-tight containers throughout their shelf life). There is therefore a need to provide a 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.
There's a need to provide dermaceutical cream containing Mometasone furoate 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. Objects And Advantages Of The Invention
It is therefore one object of the present invention to provide a cream which contains Fusidic acid as the active API but which has greater stability of the API throughout its shelf life. It is a further objective of the present invention to provide a dermaceutical cream containing Mometasone furoate as a steroid, Miconazole Nitrate as an antifungal and an antibacterial agent in the form of Fusidic acid, 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. Brief Summary Of The Invention
The invention discloses a dermaceutical cream containing Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, and an antibacterial agent in the form of Fusidic acid, which Fusidic acid is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic acid under oxygen-free environment. The cream of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional creams containing Fusidic acid. The cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, and Mometasone Furoate as a steroid, Miconazole Nitrate as an antifungal, in a cream base comprising a preservative, an acid, a co-solvent, emulsifiers and a waxy material along with water, preferably purified water.
Detailed Description Of The Invention
We discussed earlier the known aspects of the topical preparations that have Fusidic acid and Sodium Fusidate as the APIs. It is evident from the current state of knowledge that:
- Creams containing Fusidic acid that are made using Sodium Fusidate as starting API are not available. Creams containing Fusidic acid that are made using Sodium Fusidate as starting API along with Mometasone Furoate as a steroid, and Miconazole Nitrate as antifungal are not available.
There is no published data on the stability of Sodium Fusidate as the API.
Sodium Fusidate is not considered to be inherently more stable as an API than Fusidic acid.
In the face of this, it has been surprisingly discovered that Sodium Fusidate as an API is significantly more stable than Fusidic acid and that Fusidic acid deteriorates more rapidly than Sodium Fusidate. A look at the chemical structures of sodium fusidate and fusidic acid reveals some interesting facts.
Figure imgf000008_0001
It is noticed that one of the most remarkable features of the fusidic acid structures is the unusual stereochemistry of the cyclopentanoperhydrophenanthrene ring system which differs fundamentally from that of other tetracyclic triterpenes and sterols. In contrast to the usual trans, and, trans arrangement of A, B, and C ring systems of sterols, fusidic acid has very labile trans, sys, trans arrangement of these rings which forces ring B into a boat conformation. To relieve this strain, 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.
Figure imgf000009_0001
In the solid state, carboxylic acid functional group present in the fusidic acid facilitates the above process more readily upon storage. Whereas in the case of sodium fusidate such carboxylic acid promoted decomposition is not feasible. So, 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.
There is no published data on the stability of Sodium Fusidate as the API. The applicant carried out experiments on Sodium Fusidate to evaluate its stability. It can be seen from Table 2 that the degradation of Sodium Fusidate over a temperature range of room temperature to 45 °C ranged between 2.45 % and 6%. 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.
Stability Analysis of Fusidic Acid:
Table 1 : Results Of 3 Months Old Fusidic Acid (API) Analysis By Stability Indicating HPLC Method And Titration Method
Figure imgf000010_0001
Name of the Sample: FUSIDIC ACID BP
Pack : Open (O) & Closed (C) Petri dish
Stability Analysis of Sodium Fusidate:
Table 2 : Results Of 3 Months Old Sodium Fusidate (API) Analysis By Stability Indicating HPLC Method And Titration Method
Name of the Sample: Sodium Fusidate BP
Pack: Open (O) & Closed (C) Petri dish
Sodium Fusidate Remarks
Percentage (%)
*Initial Assay(%)
S.No Conditions
(%) HPL
Titration HPLC Titration
C API
1 RT (O) 97.71 96.25 0.99 2.45 analysed
2 RT (C) 98.85 97.67 -0.15 1.03 After 3
98.7
3 45 °C (O) 97.07 92.65 1.63 6.05 Months
4 45°C (C) 97.16 92.96 1.54 5.74 In both studies the * Initial denotes the results of the samples tested at the time of receipt of the API from the supplier.
It can be observed from Tables 1 and 2 that:
· In the case of Fusidic Acid, there is about 7.7% loss in 3 Months at room temperature (open condition) and about 11% loss in 3 Months at 45°C (open condition).
• In the case of Sodium Fusidate, there is about 2.5% loss in 3 Months at room temperature (open condition) and about 6% loss in 3 Months at 45 °C (open condition).
The data thus shows that Sodium Fusidate as an API is more stable than Fusidic acid.
The applicants explored the possibility of making a cream (rather than an ointment) using Sodium Fusidate (rather than Fusidic acid) and Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal. Although Sodium Fusidate has been used in dermaceutical applications, it has not been possible to make creams that use Sodium Fusidate. This is because of the inherent alkalinity of Sodium Fusidate (pH 7.5 to 9), which means it cannot be used in a cream form therefore all products manufactured using Sodium Fusidate as starting material are ointments.
A dermaceutical cream that uses Sodium Fusidate, Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal would exploit the benefit of the fact that
Sodium Fusidate is more stable than Fusidic acid and it would also provide a cream formulation which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic acid, antifungals and steroids. The applicant therefore surprisingly discovered that in order to achieve greater stability of the API in a dermaceutical cream, 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 applicant has also discovered that the Fusidic acid, cream prepared using Sodium Fusidate as the starting API and Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal showed good chemical stability, and efficacy. The application discloses a cream containing Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal, and Fusidic acid that has been prepared using Sodium Fusidate as the starting API, in which Fusidic acid forms in-situ under totally oxygen free environment by slow addition of an acid, into a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates as an extremely fine dispersion when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen. The cream of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate as the starting API, Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal in a cream base comprising a preservative, an acid, a co-solvent, a preservative, emulsifiers and a waxy material along with water, preferably purified water.
The cream base of the present invention optionally further comprises an ingredient selected from a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
The present invention provides a novel cream that has been produced using Sodium Fusidate as the starting raw material, and which cream contains Fusidic acid of high therapeutic efficacy and of chemical stability that is generally superior to the commercially available creams containing Fusidic acid.
The cream of the present invention containing Fusidic acid, has been manufactured in a totally oxygen free environment under purging with inert gas and applying vacuum. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic acid and to which Mometasone Furoate as a steroid, and Miconazole Nitrate as an antifungal are added. The cream of the present invention is used in the treatment of bacterial skin infections, fungal infections and inflammations. The H of the product of the present invention is from about 3 to 6. On the other hand, 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.
Tests for determination of particle size of fusidic acid were carried out on several products available in the market containing fusidic acid and also on the present invention. An optical microscope (Carl Zeiss Axio Star Plus 2x to lOOx magnification) was used for this purpose. Table 2A provides the results. It can be seen from the results that the size of the fusidic acid particles is considerably smaller than that of fusidic acid in existing products. Whereas the maximum particle size observed for fusidic acid of the present invention is less than 3μιη, the maximum particle size observed for existing creams varies between 19 μιη to 42 μιη, with a majority of them having the maximum particle size between 30 μιη and 40 μιη. The average size of the fusidic acid particles in the present invention has been found to be approximately 1 μιη whereas that for the existing creams varies between 14 μιη to 22 μιη. Equally importantly, the minimum particle size observed was approx. 0.25 μιη whereas the minimum particle size observed for existing creams ranged between 4 μιη and 10 μιη. The cream of the present invention is therefore physically distinct from any of the existing creams and easily distinguishable.
Table 2A (Particle Size Distribution of Fusidic Acid) (All sizes in μηι)
PARTICLE SIZE DISTRIBUTION
Figure imgf000015_0001
Table 2B - Sample data for test results of table 2A
Figure imgf000016_0001
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 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. In contrast with this, 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. Although 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 any 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, H2SO4, HNO3, Lactic acid and the like from about 0.005% (w/w) to about 0.5% (w/w) under stirring and obtained Fusidic acid in more stabilized and solution form, which makes our final product in a cream base which easily penetrates the skin and highly efficacious, and also highly derma compatible by having a pH of about 3.0 to about 6.0.
The present invention is now described in terms of its embodiments.
Preferred embodiment no.l
A novel dermaceutical cream containing Mometasone furoate as a corticosteroid, Miconazole Nitrate as an antifungal, and Fusidic acid which is made in situ under oxygen-free environment using Sodium Fusidate, wherein said cream comprises Fusidic acid made in situ by a conversion of Sodium Fusidate, and a cream base containing at least one of each of a preservative, a primary and secondary emulsifiers, a waxy material, a co-solvents, an acid, and water, preferably purified water.
Embodiment no. 1
A novel dermaceutical cream as disclosed in the preferred embodiment 1, said cream further incorporating any of any of a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
Embodiment no. 2
A novel dermaceutical cream as described in preferred embodiment no. 1, wherein
said corticosteroid is added in an amount between 0.005% (w/w) and about 2.5% (w/w), preferably from about 0.05% (w/w) and about 1.00% (w/w), and most preferably from about 0.1% (w/w), and further wherein said corticosteroid is Mometasone furoate, and said antifungal is added from 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 2.0% (w/w); 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, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, and added in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), said primary and secondary emulsifier is selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like, either singly or any combination thereof, and added in an amount between 1% (w/w) and 25% (w/w), preferably 20% (w/w), more preferably 15.5% (w/w), said waxy material is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, either singly or any combination thereof, and added in an amount between 5% (w/w) and 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 Glycol-400 and the like, either singly or any combination thereof, and added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w), said acid is selected from a group comprising acids such as HC1, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, and added in an amount between 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), and water in an amount in the range between 5% (w/w) and 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18% (w/w), preferably purified water.
Embodiment no. 3
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 1 and 2, which further comprises a buffering agent, wherein said buffering agent is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, either singly or any combination thereof, added in an amount 0.01 % (w/w) and 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
Embodiment no. 4
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 1 to 3 which further comprises an anti-oxidant, wherein 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 0.001% (w/w) and 5% (w/w), preferably 0.1% (w/w), more preferably 0.01% (w/w).
Embodiment no. 5
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 4 which further comprises a chelating agent, wherein said chelating agent is selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, added in an amount 0.01 % (w/w) and 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
Embodiment no. 6
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 5 which further comprises a humectant, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
Embodiment no. 7
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 6 wherein sodium fusidate is converted in-situ under totally oxygen free environment by slow addition of an acid, into Fusidic acid of a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates into an extremely finely dispersed form when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream; all operations of converting sodium fusidate into Fusidic acid carried out preferably in an environment free of atmospheric oxygen.
Embodiment no. 8
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 1 to 7 wherein said conversion of Sodium Fusidate into said Fusidic acid and the following formation of said Fusidic acid in a finely dispersed form in the final cream base take place in an oxygen-free environment. Embodiment no. 9
A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 7 and 8 wherein said oxygen-free environment comprises a gaseous environment formed of inert gas selected from a group comprising carbon dioxide, nitrogen, helium and the like.
Preferred embodiment no. 2
A process to make a cream containing Mometasone furoate, Miconazole
Nitrate, and_fusidic acid, said cream being as disclosed in preferred embodiment 1 and embodiment 1 , said process comprising the step of using sodium fusidate as the raw active pharmaceutical ingredient and converting said sodium fusidate in situ into fusidic acid under oxygen-free environment in a cream base, to which Mometasone furoate and Miconazole Nitrate are added.
Embodiment no. 10
A process to make a cream containing Mometasone furoate, Miconazole Nitrate, and fusidic acid as described in the preferred embodiment nos. 1 and embodiment no. 1 wherein said step of using sodium fusidate as the raw active pharmaceutical ingredient and converting said sodium fusidate in situ into fusidic acid under oxygen-free environment in a cream base, to which Mometasone furoate and Miconazole Nitrate are added, further comprises the steps of:
a. heating purified water in the range from 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18% (w/w), in a water-phase vessel to 70 0 C to 80 0 C,
b. adding to said water-phase vessel a preservative, selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), preferably benzoic acid.
c. 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) and 20% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 0 C to 80 0 C,
adding to said oil-phase vessel 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 5% (w/w), preferably 2% (w/w), more preferably 1 % (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80, in an amount between 1 % (w/w) and 5% w/w, more preferably 2% w/w and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the mixture at 70 °C to 80 0 C,
transferring under vacuum in the range of minus 1000 to minus 300 mm of mercury and at 70 °C to 80 °C the contents of the water-phase and oil- phase vessels of steps c and e to a mixing vessel and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM to form an emulsion, cooling said emulsion to 45 °C preferably by circulating cold water, preferably at 8 °C to 15 °C from a cooling tower in the jacket of the mixing vessel,
in a first API- vessel adding 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 25% (w/w), preferably propylene glycol, subjecting the contents of said API-vessel to inert gas flushing, said inert gas being preferably nitrogen, and adding sodium fusidate to the mixture, said sodium fusidate added in an amount between 0.1 % (w/w) and 25% (w/w), preferably from about 0.5% (w/w) and 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said Sodium Fusidate in the mixture,
adjusting the pH of the mixture in said first API- vessel of step h to below 2 by using an acid, selected from a group comprising acids such as HC1, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
adding in a second API- vessel propylene glycol and heating to 60°C in an amount between 1 % (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 10% (w/w) and dissolving Mometasone Furoate in it by continuous mixing, said Mometasone Furoate being added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.05% w/w and about 1.00% w/w, and most preferably about 0.1 % w/w, k. 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 13% (w/w) and dispersing Miconazole Nitrate in it by continuous mixing, said
Miconazole Nitrate being added in an amount from about 0.5% (w/w) and 5.0% (w/w), preferably from about 0.5% (w/w) and 3.0%(w/w), and most preferably about 2.0% (w/w); to form a dispersion, followed by passing said dispersion through a colloid mill,
1. 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 and minus 300 mm of mercury, said inert gas being preferably nitrogen,
m. transferring the contents of said second API- vessel of step j 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 and minus 300 mm of mercury, said inert gas being preferably nitrogen,
n. transferring the contents of the colloid milled Miconazole Nitrate from said third API-vessel of step k to said mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at
1000 to 3000 RPM under inert gas flushing and vacuum preferably of a magnitude between minus 1000 and minus 300 mm of mercury, said inert gas being preferably nitrogen,
o. cooling the contents of the mixing vessel of step g to 30 °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,
p. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step o to a storage container.
Embodiment no. 11
In another embodiment of the present invention the process described in embodiment no. 10 further incorporates after the step of adding a preservative, a step of adding a chelating agent, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, added in an amount between 0.01 % (w/w) and 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
Embodiment no. 12
In yet another embodiment of the present invention 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) and 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w). Embodiment no. 13
In a further embodiment of the present invention 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) and 5% (w/w), preferably 0.1 % (w/w), more preferably 0.01 % (w/w).
Embodiment no. 14
In a further embodiment of the present invention the process described in embodiments no. 10, 11 ,12 and 13 further incorporate a humectant in the step a of embodiment 10, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
Embodiment no. 15
A process to make a cream containing mometasone furoate, Miconazole Nitrate and fusidic acid as described in embodiment nos 1 and 9 comprising the steps of: a. heating purified water in the range from 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18%
(w/w), in a water-phase vessel to 70 0 C to 80 0 C,
b. adding to said water-phase vessel a preservative, selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), preferably Benzoic acid, 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 Ortho Phosphate added in an amount preferably between 0.01 % (w/w) and 2.00% (w/w), preferably 1.5% (w/w), more preferably 1.0%; said humectant preferably being Propylene Glycol added in an amount preferably 5% (w/w) to 60% (w/w), more preferably 30% (w/w),
mixing the mixture of water phase vessel in step c using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 0 C to
80 ° C,
adding to an oil-phase vessel an emulsifying wax, preferably Cetostearyl alcohol, in an amount preferably between 1 and 15 %, more preferably 12.5 % and waxy material White Soft Paraffin, in an amount preferably between 5 and 20 %, more preferably 12.5 %, and melting them by heating to 70 ° C to 80 ° C,
adding to said oil phase vessel a non ionic surfactant or emulsifier, in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate
80 and 1 % of Cetomacrogol 1000 and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 0 C,
transferring under vacuum in the range of minus 1000 to minus 300 mm of mercury and at 70 °C to 80 °C the contents of the water-phase and oil- phase vessels to a mixing vessel and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM to form an emulsion, cooling said emulsion to 45 °C preferably by circulating cold water, preferably at 8 °C to 15 °C from a cooling tower in the jacket of the mixing vessel,
adding in a first API-vessel a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 adding propylene glycol, or any mixture thereof, in an amount preferably 5% (w/w) and 30% (w/w), more preferably 25% (w/w) and optionally adding and dissolving an antioxidant, selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, in an amount preferably between 0.01 and 0.1 %, more preferably 0.01 % Butylated Hydroxy Toluene in it by continuous mixing,
subjecting the contents of said first API-vessel to inter gas flushing, said inert gas preferably being nitrogen and adding Sodium Fusidate to the mixture and dissolving it in the mixture, said sodium fusidate being added in an amount between 0.1% (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5% (w/w) and more preferably about 2.08 % (w/w),
k. adjusting the pH of the mixture in said first API-vessel to below 2 by using an acid, selected from a group comprising acids such as HC1, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
1. in a second API- vessel adding propylene glycol and heating to 60°C, in an amount preferably 1 % (w/w) to 20% (w/w), more preferably 10% (w/w) and dissolving Mometasone furoate in it by continuous mixing, said Mometasone Furoate being added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.05% w/w and about 1.00% w/w, and most preferably about 0.1% w/w ,
m. in a third in a third API-vessel adding propylene glycol , in an amount preferably 1% (w/w) to 20% (w/w), more preferably 13% (w/w) and dispersing Miconazole Nitrate in it by continuous mixing to form a dispersion, said Miconazole Nitrate being added in an amount from about 0.5% (w/w) to about 5.0% (w/w), preferably from about 0.5% (w/w) to about 3.0%(w/w), and most preferably about 2.0% (w/w); followed by passing said dispersion through a colloid mill,
n. 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,
transferring the contents of said second API-vessel of step 1 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,
transferring the contents of the colloid milled Miconazole Nitrate from said third API-vessel of step m to said 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 vacuum preferably of a magnitude between minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
cooling the contents of the mixing vessel of step h 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,
turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step q to a storage container
Embodiment no. 16
A method of treating primary & secondary bacterial & fungal skin infections and inflammations said method comprising applying of a cream containing at least one corticosteroid, one antifungal and Fusidic acid which is made in situ under oxygen-free environment using Sodium Fusidate, wherein said cream comprises Fusidic acid made using Sodium Fusidate, a cream base containing a preservative, primary and secondary emulsifiers, waxy materials, co-solvents, acids, and water. Embodiment no. 17
A method of treating primary & secondary bacterial & fungal skin infections and inflammations said method comprising applying of a cream as described in the preferred embodiment 1 and any of embodiments 1 to 9.
It is thus clear that the process of the Invention uses a technology whereby Sodium Fusidate is precipitated as Fusidic acid as a result of a mixture of the water-based alkaline solution of SF and an acid. The precipitated fusidic acid, while still in the liquid (and thereby barred from exposure to atmospheric oxygen) is dissolved using a suitable solvent under the effect of inert gas.
The stability of the product is confirmed by the stability studies performed for 3months as per ICH guidelines.
Experimental Data APIs-stability experiments were carried out (see tables 4 - 6) using the product of the present invention. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the APIs over a period of time. Each gram of product of the present invention used for the tests contained Sodium Fusidate in the amount required to produce 2% (w/w) Fusidic acid in the finished product and appropriate amount of steroids and antifungals as mentioned below.
Table 3 :
Composition:
Sodium Fusidate + Mometasone Furoate + Miconazole Nitrate Cream
Figure imgf000034_0001
PRODUCT: SODIUM FUSIDATE + MOMETASONE FUROATE + MICONAZOLE NITRATE CREAM
PACK: Aluminum Collapsible tube
Composition
5 Each gm contains:
i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 % ii) Mometasone Furoate USP 0.1 % iii) Miconazole Nitrate IP 2.0 %
Table 4: Description Test, Batch No. SMN-04
lOMeasured parameter: Physical appearance
Best value of measured parameter: Homogeneous White to off White Viscous cream Method of measurement: Observation by naked eye
Figure imgf000035_0001
Table5: pH Test, Batch No. SMN-04
Measured parameter: pH Limits of measured parameter: 5-7
Method of measurement: Digital pH Meter
Conditions 1st 3rd
Initial Month 2nd Month Month
40°C 75% 4.22 4.21 4.21 4.20
RH
30°C 65% - 4.21 4.21 4.20
RH
25°C 60% - 4.21 4.20 4.20
RH
Temperature - 4.19 - - cycling
Freezthaw - 4.18 - - Table 6: Assay (%) Test, Batch No. SMN-04
Measured parameter: Assay (%)
Limits of measured parameter: 90-110
Method of measurement: HPLC Method
Figure imgf000036_0001
The product used for the Stability Studies tests contained approximately 10% extra APIs (overages). It was packaged in an aluminium collapsible tube and each gram of the product contained 20.8 mg of Sodium Fusidate (in conformance with BP), which is equivalent to 20 mg of Fusidic acid (BP conformant). Detailed test results for 24 products have been presented. The % of sodium fusidate, the corticosteroid, and the antifungal used in all examples are measured w/w with respect to the final product.
It is evident from the foregoing description that the present invention has the following distinctions and advantages over the commercially available comparable products:
It has been prepared using Sodium Fusidate which is more stable than Fusidic acid
It has a more stable and quality enriched Fusidic acid as the final API - 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
While the above description contains much specificity, these should not be construed as limitation in the scope of the invention, but rather as an exemplification of the preferred embodiments thereof. It must be realized that modifications and variations are possible based on the disclosure given above without departing from the spirit and scope of the invention. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.

Claims

A novel dermaceutical cream containing Mometasone furoate as a corticosteroid, Miconazole Nitrate as an antifungal, Fusidic acid, and a cream base containing at least one of each of a preservative, a primary and secondary emulsifier, a waxy material, a co-solvents, an acid, and water, preferably purified water characterized in that said fusidic acid is manufactured in situ under oxygen-free environment using Sodium Fusidate so that the average particle size of said fusidic acid in said cream is less than 2μιη..
A novel dermaceutical cream as claimed in claim 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 novel dermaceutical cream as claimed in claim 1, wherein
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 0.1 % by weight, and further wherein said corticosteroid is Mometasone furoate, 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, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, and added in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like, either singly or any combination thereof, and added in an amount between 1% (w/w) and 25% (w/w), preferably 20% (w/w), more preferably 15.5% (w/w), said waxy material is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, either singly or any combination thereof, and added in an amount between 5% (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), said co-solvent is selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like, either singly or any combination thereof, and added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w), said acid is selected from a group comprising acids such as HC1, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, and added in an amount between 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), and water in an amount in the range between 5% (w/w) and 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18% (w/w), preferably purified water.
A novel dermaceutical cream as claimed in claims 1 and 3, which further comprises a buffering agent, wherein said buffering agent is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, either singly or any combination thereof, added in an amount between 0.01% (w/w) and 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
A novel dermaceutical cream as claimed in claims 1 , 3 and 4 which further comprises an anti-oxidant, wherein 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 claimed in claims 1 and 3 to 5, 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 novel dermaceutical cream as claimed in claims 1 and 3 to 6, which further comprises a humectant, wherein said humectant is selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, added in an amount between 5% (w/w) and 60% (w/w), preferably 50% (w/w), more preferably 48% (w/w).
A novel dermaceutical cream as claimed in claims 1 and 3 to 7, wherein sodium fusidate is converted in-situ under totally oxygen free environment by slow addition of an acid, into Fusidic acid of a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates into an extremely finely dispersed form when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream; all operations of converting sodium fusidate into Fusidic acid carried out preferably in an environment free of atmospheric oxygen.
A novel dermaceutical cream as claimed in claims 1 to 8 wherein said conversion of Sodium Fusidate into said Fusidic acid and the following formation of said Fusidic acid in a finely dispersed form in the final cream base takes place in an oxygen-free environment.
A novel dermaceutical cream as claimed in claim 9 wherein said oxygen-free environment comprises a gaseous environment formed of inert gas selected from a group comprising carbon dioxide, nitrogen, helium and the like.
A process to make a cream containing Mometasone furoate, Miconazole Nitrate, and fusidic acid comprising the steps of:
a. heating purified water in the range from 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18% (w/w), in a water-phase vessel to 70 0 C to 80 0 C,
b. adding to said water-phase vessel a preservative, selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), preferably benzoic acid.
c. mixing the mixture of step b using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 0 C to 80 0 C, d. adding waxy materials, selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, either singly or any combination thereof, in an amount between 5% (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 0 C to 80 0 C,
adding to said oil-phase vessel 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 5% (w/w), preferably 2% (w/w), more preferably 1 % (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80, in an amount between 1 % (w/w) and 5% w/w, more preferably 2% w/w and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the mixture at 70 °C to 80 0 C,
transferring under vacuum in the range of minus 1000 to minus 300 mm of mercury and at 70 °C to 80 °C the contents of the water-phase and oil- phase vessels of steps c and e to a mixing vessel and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM to form an emulsion,
cooling said emulsion to 45 °C preferably by circulating cold water, preferably at 8 °C to 15 °C from a cooling tower in the jacket of the mixing vessel, in a first API- vessel adding 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 25% (w/w), preferably propylene glycol, subjecting the contents of said API-vessel to inert gas flushing, said inert gas being preferably nitrogen, and adding sodium fusidate to the mixture, said sodium fusidate added in an amount between 0.1 % (w/w) and 25% (w/w), preferably from about 0.5% (w/w) and 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said Sodium Fusidate in the mixture,
adjusting the pH of the mixture in said first API- vessel of step h to below 2 by using an acid, selected from a group comprising acids such as HC1, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
adding in a second API- vessel propylene glycol and heating to 60°C in an amount between 1 % (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 10% (w/w) and dissolving Mometasone Furoate in it by continuous mixing, said Mometasone Furoate being added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.05% w/w and about 1.00% w/w, and most preferably about 0.1 % w/w, 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 13% (w/w) and dispersing Miconazole Nitrate in it by continuous mixing, said Miconazole Nitrate being added in an amount from about 0.5% (w/w) and 5.0% (w/w), preferably from about 0.5% (w/w) and 3.0%(w/w), and most preferably about 2.0% (w/w); to form a dispersion, followed by passing said dispersion through a colloid mill,
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 and minus 300 mm of mercury, said inert gas being preferably nitrogen,
transferring the contents of said second API- vessel of step j 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 and minus 300 mm of mercury, said inert gas being preferably nitrogen,
transferring the contents of the colloid milled Miconazole Nitrate from said third API-vessel of step k to said mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and vacuum preferably of a magnitude between minus 1000 and minus 300 mm of mercury, said inert gas being preferably nitrogen, o. cooling the contents of the mixing vessel of step g to 30 °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,
p. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step o to a storage container.
12. A process to make a cream as claimed in claims 2 to 10, said process comprising the steps of: a. heating purified water in the range from 5% (w/w) to 40% (w/w), preferably 10% (w/w) to 30% (w/w), more preferably 12% (w/w) to 18%
(w/w), in a water-phase vessel to 70 0 C to 80 0 C,
b. adding to said water-phase vessel a preservative, selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably
0.3% (w/w), more preferably 0.2% (w/w), preferably Benzoic acid, c. optionally 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 Ortho Phosphate added in an amount preferably between 0.01 % (w/w) and 2.00% (w/w), preferably 1.5% (w/w), more preferably 1.0%; said humectant preferably being Propylene Glycol added in an amount preferably 5% (w/w) to 60% (w/w), more preferably 30% (w/w),
mixing the mixture of water phase vessel in step c using an agitator at 10 to 50 RPM while maintaining the temperature of said mixture at 70 0 C to
80 ° C,
adding to an oil-phase vessel an emulsifying wax, preferably Cetostearyl alcohol, in an amount preferably between 1 and 15 %, more preferably 12.5 % and waxy material White Soft Paraffin, in an amount preferably between 5 and 20 %, more preferably 12.5 %, and melting them by heating to 70 ° C to 80 ° C,
adding to said oil phase vessel a non ionic surfactant or emulsifier, in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate 80 and 1 % of Cetomacrogol 1000 and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to 80 0 C,
transferring under vacuum in the range of minus 1000 to minus 300 mm of mercury and at 70 °C to 80 °C the contents of the water-phase and oil- phase vessels to a mixing vessel and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM to form an emulsion, cooling said emulsion to 45 °C preferably by circulating cold water, preferably at 8 °C to 15 °C from a cooling tower in the jacket of the mixing vessel, i. adding in a first API- vessel a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 adding propylene glycol, or any mixture thereof, in an amount preferably 5% (w/w) and 30% (w/w), more preferably 25% (w/w) and optionally adding and dissolving an antioxidant, selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, in an amount preferably between 0.01 and 0.1 %, more preferably 0.01 % Butylated Hydroxy Toluene in it by continuous mixing,
j. subjecting the contents of said first API-vessel to inter gas flushing, said inert gas preferably being nitrogen and adding Sodium Fusidate to the mixture and dissolving it in the mixture, said sodium fusidate being added in an amount between 0.1% (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5% (w/w) and more preferably about 2.08 % (w/w),
k. adjusting the pH of the mixture in said first API-vessel to below 2 by using an acid, selected from a group comprising acids such as HC1, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid to form a proportion from about 0.005% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w),
1. in a second API- vessel adding propylene glycol and heating to 60°C, in an amount preferably 1 % (w/w) to 20% (w/w), more preferably 10% (w/w) and dissolving Mometasone furoate in it by continuous mixing, said Mometasone Furoate being added in an amount between about 0.005% w/w and about 2.5% w/w, preferably from about 0.05% w/w and about 1.00% w/w, and most preferably about 0.1% w/w ,
in a third in a third API-vessel adding propylene glycol , in an amount preferably 1% (w/w) to 20% (w/w), more preferably 13% (w/w) and dispersing Miconazole Nitrate in it by continuous mixing to form a dispersion, said Miconazole Nitrate being added in an amount from about 0.5% (w/w) to about 5.0% (w/w), preferably from about 0.5% (w/w) to about 3.0%(w/w), and most preferably about 2.0% (w/w); followed by passing said dispersion through a colloid mill,
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,
transferring the contents of said second API-vessel of step 1 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,
transferring the contents of the colloid milled Miconazole Nitrate from said third API-vessel of step m to said 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 vacuum preferably of a magnitude between minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
q. cooling the contents of the mixing vessel of step h 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,
r. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step q to a storage container.
13. A method of treating primary & secondary bacterial & fungal skin infections and inflammations said method comprising applying any of the creams as claimed in claims 1 to 10.
PCT/IB2010/056122 2010-09-14 2010-12-30 A dermaceutical cream made using sodium fusidate, miconazole and mometasone furoate Ceased WO2012035376A1 (en)

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