WO2012017383A1 - Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de béclométhasone, et du chlorhydrate de terbinafine et procédé de fabrication de celle-ci - Google Patents

Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de béclométhasone, et du chlorhydrate de terbinafine et procédé de fabrication de celle-ci Download PDF

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Publication number
WO2012017383A1
WO2012017383A1 PCT/IB2011/053428 IB2011053428W WO2012017383A1 WO 2012017383 A1 WO2012017383 A1 WO 2012017383A1 IB 2011053428 W IB2011053428 W IB 2011053428W WO 2012017383 A1 WO2012017383 A1 WO 2012017383A1
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WIPO (PCT)
Prior art keywords
amount
vessel
cream
mixture
fusidic acid
Prior art date
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PCT/IB2011/053428
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Sankar Haridas
Original Assignee
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Sankar Haridas
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Application filed by Sulur Subramaniam Vanangamudi, Madhavan Srinivasan, Neelakandan Narayanan Chulliel, Sankar Haridas filed Critical Sulur Subramaniam Vanangamudi
Publication of WO2012017383A1 publication Critical patent/WO2012017383A1/fr

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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
    • A61K31/57—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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/57—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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates to primary and secondary bacterial skin infections, skin inflammations, fungal skin infections and wounds including burn wounds.
  • a cream incorporating Fusidic Acid and a biopolymer in the 10 form of Chitosan, a Corticosteroid in the form of Beclomethasone Dipropionate, and an antifungal agent in the form of Terbinafine Hydrochloride, and the process of making it and using it in treating these infections, inflammations and wounds.
  • the Fusidic Acid in the said cream has been created in situ using Sodium Fusidate as the starting Active Pharmaceutical Ingredient (API).
  • Topical and systemic bacterial infection 20 treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component.
  • the APIs typically comprise an antibiotic/antibacterial such as Fusidic Acid, a Corticosteroid such as Beclomethasone Dipropionate, and an antifungal agent such as Terbinafine Hydrochloride, a biopolymer such as Chitosan and the like.
  • Fusidic Acid in fine powder form is used as source API.
  • the small particle size enhances its dermal contact by providing a large specific surface area and penetration, and provides a smooth feel on application to skin.
  • Sodium Fusidate is known 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.
  • Skin disorders can be broadly categorized as those arising from bacterial forms or fungi.
  • Antifungal or antibacterial compositions are traditionally applied as lotions, creams or ointments. Furthermore in many instances, it is difficult to ascertain whether the skin condition is due to a bacterial agent or a fungus.
  • One approach to treating skin disorders is through elimination by trial and error.
  • Antibacterial or antifungal compositions are applied in turn and response monitored and treatment modified.
  • a major disadvantage of this approach is that treatment needs to be applied many times a day during the treatment period. This is greatly inconvenient and also not cost effective for a majority of human population, particularly in the under-developed nations.
  • compositions There are several treatments available to treat skin disorders caused by bacteria or fungi. Typically, such compositions use steroids, antibacterial agents or antifungal agents, (or a fixed dose combination of these) and focus on these pharmaceutically active ingredients.
  • the composition of such formulations is such as to enhance their physical/chemical/bio-release profile.
  • the current approaches of skin treatment can be broadly categorized into two stages, a. healing b. restoration of skin to pre-ailment state.
  • the healing part comprises elimination, to the best possible extent, of the root cause of the disorder. This may be elimination of bacteria or fungi causing the infection through a suitable treatment of antibacterial or antifungal agents or reducing the inflammation through steroid treatment. While this treatment is under way, the ongoing compromised condition of the skin continues to be susceptible to secondary infections, which can be of quite serious nature. In the case of scratched or wounded skin, it is important for blood clotting to occur quickly as it reduces chances of secondary infections.
  • the focus of such treatments, which are administered through creams, lotions, ointments are on the action of active pharmaceutical ingredients.
  • Cream bases or ointment bases are merely viewed as carriers to take APIs to the sites of disorder.
  • the aspect of restoring the skin back to its pre-disorder state is almost completely left to nature. Therefore one key drawback of the existing skin treatment approaches is that they run the risk of secondary infections due to slow blood clotting and wound healing process.
  • several lacking aspects of the existing prescription derma products used for topical treatment of skin disorders This is manifested by the fact that the cream base matrix or the ointment base has been overlooked for any potential therapeutic benefits.
  • none of the available prior art suggests that:
  • Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcome of the main APIs is enhanced.
  • biopolymers biologically active polymers
  • the PCT application WO 2009063493 discloses a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Clobetasone Butyrate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin.
  • topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Clobetasone Butyrate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection.
  • WO 2009063493 also apparently surprisingly found that antibiotic action of Fusidic Acid and the anti- inflammatory effect of a corticosteroid such as Halobetasol, both play important roles in prevention of secondary bacterial infections in patients with non-infected dermatoses and in treatment of infected steroid responsive dermatoses such as secondarily infected dermatoses including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • infected steroid responsive dermatoses such as secondarily infected dermatitis including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • CCD corticosteroid responsive dermatoses
  • the invention disclosed in WO 2009063493 relates to a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Clobetasone Butyrate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin.
  • the present invention also relates to topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Clobetasone Butyrate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection.
  • Fusidic Acid and corticosteroid such as Clobetasone Butyrate
  • EP1787652 relates to a composition with antifungal properties, against foot fungus.
  • the invention comprises the use of Melaleuca Alternifolia essential oil in combination with at least one component chosen from the group consisting of
  • composition according to this invention has an improved antifungal effect and can be used for both preventive and therapeutic applications.
  • the composition comprises 2 to 8% by weight of Melaleuca Alternifolia essential oil and 0.5 to 1% by weight of a benzoate compound relative to the total composition. At this concentration an optimum level is achieved between antifungal activity and economic use of Melaleuca Alternifolia essential oil and benzoate compound.
  • US 20020009422 relates to a tanning product that treat tinea versicolor and promote tanning.
  • the product includes the active ingredients tolnaftate and Clotrimazole.
  • US 20020009422 claims novelty on the assertion that the product manages to overcome few problem faced by conventionally used therapeutic like unpleasant smell, dry and rough skin caused by the conventional treatment.
  • the applicant has devices a system for treating tinea versicolor which consists of three systems; a body wash having a mixture of a shampoo, an exfoliate and tolnaftate cream; a tanning lotion and anti-fungal topical having mixture of a lotion, a tanning bronzer and a Clotrimazole; and body spray having a mixture of a liquid tan enhancing body spray and tolnaftate cream.
  • US 4911932 describe a skin care composition having improved effectiveness in preventing and treating acute inflammatory skin conditions.
  • the composition consists of Clotrimazole and zinc oxide.
  • the composition of the invention may be added in either aqueous or oleaginous media. A thickener or stabilizer is added to prevent settling of the synergistic combinations and the resulting non-uniformity of the finished product upon standing.
  • CN 1931164 deals with the nanometer Clotrimazole emulsion medicine that consists of surfactant, oil, Clotrimazole and distilled water.
  • US 5,461,068 pertain to improved formulations for topical treatment of fungal diseases, and more particularly to solutions of imidazole derivatives such as
  • Clotrimazole of sufficient strength and stability for pharmaceutical use can accommodate a therapeutically significant concentration of the antifungal agents; thereby increasing the stability of the antifungal agents in solution for extended periods of time.
  • the solvent system comprises a primary carboxylic acid, a polar solvent, a solubilizer, a non-ionic or amphoteric surfactant, and water, in which imidazole derivatives can be dissolved.
  • cream base which cream base provides therapeutical value complementary to that provided by the main APIs and serves the purpose over and above that of being a mere carrier or delivery mechanism.
  • biopolymers Contain biologically active polymers
  • the so-called biopolymers without compromising the stability of the formulations. If the right biopolymer is not selected the stability of the formulation could be affected.
  • the present invention is directed to a medicinal composition for treating skin inflammations, fungal/bacterial skin infections and related wounds, and also other skin wounds including those caused by burns.
  • the cream also causes skin rejuvenation through an epithelisation process.
  • the cream comprises:
  • APIs active Pharmaceutical Ingredients
  • Fusidic Acid that has been generated in situ from Sodium Fusidate
  • Beclomethasone Dipropionate & Terbinafine Hydrochloride a) active Pharmaceutical Ingredients (APIs), in the form of Fusidic Acid that has been generated in situ from Sodium Fusidate, Beclomethasone Dipropionate & Terbinafine Hydrochloride.
  • a cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants.
  • the active ingredients namely Chitosan, Beclomethasone Dipropionate, Terbinafine
  • Hydrochloride and Fusidic Acid are incorporated in cream base for use in treating skin inflammations, fungal/ bacterial skin infections with allergy & itching, & wounds on human skin involving contacting human skin with the above- identified composition.
  • the invention also discloses a process to make the medicinal cream containing Fusidic Acid which is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic Acid under oxygen- free environment created using inert gas, preferably nitrogen, and Chitosan.
  • the cream produced by the process 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 produced by the process of the present invention contains Fusidic Acid as the API that has been formed in situ from Sodium Fusidate, Beclomethasone Dipropionate& Terbinafine Hydrochloride in a cream base comprising a preservative, an acid, a co-solvent, an emulsifier and a waxy material along with water, preferably purified water.
  • the cream produced by the process of the present invention further optionally contains an ingredient selected from a group comprising, a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • Creams containing Fusidic Acid that are made using Sodium Fusidate as starting API along with Beclomethasone Dipropionate as a steroid, and Terbinafine Hydrochloride as antifungal are not commercially 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.
  • Creams containing Chitosan and Fusidic Acid, which has been created in situ from Sodium Fusidate along with Beclomethasone Dipropionate as a steroid, and Terbinafine Hydrochloride as antifungal is not commercially available.
  • fusidic acid has very labile trans, sys, trans arrangement of these rings which forces ring B into a boat conformation.
  • fusidic acid readily undergoes acid mediated dehydration of C-l l hydroxy group to generate a C9-C11 double bond which on further isomerization followed by oxidization in the presence of oxygen leads to a mixture of biologically inactive fusidic acid derivatives.
  • carboxylic acid functional group present in the fusidic acid facilitates the above process more readily upon storage.
  • carboxylic acid promoted decomposition is not feasible.
  • sodium fusidate has superior solid state stability when compared to fusidic acid. This discovery of the inventor has also been corroborated through stability assessment of sodium fusidate and fusidic acid.
  • Tables 1 and 2 also show the comparison between the stability of the Fusidic Acid and Sodium Fusidate as raw APIs. The study was carried out using an in-house
  • HPLC method developed by the applicant, which the applicant believes is a true stability-indicating method as opposed to the titration method suggested in British
  • BP Pharmacopoeia
  • Sodium Fusidate rather than Fusidic Acid may be used as the starting API during the cream's manufacture.
  • Sodium Fusidate as starting material eliminates the drawback associated with the manufacture and storage of existing Fusidic Acid creams.
  • the Fusidic Acid cream prepared using Sodium Fusidate as the starting API and Beclomethasone Dipropionate as a steroid, and Terbinafine Hydrochloride as an antifungal showed good chemical stability and efficacy.
  • the application discloses a process of making a cream containing a biopolymer -
  • 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 created using inert gas, preferably nitrogen, 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 created using inert gas, preferably nitrogen.
  • the cream made using the process of the present invention contains Fusidic Acid as the API that has been formed in situ from Sodium Fusidate, a biopolymer Chitosan, Beclomethasone Dipropionate as a steroid, and Terbinafine Hydrochloride as an antifungal in a cream base comprising a preservative, an acid, a co-solvent, an emulsifier and a waxy material along with water, preferably purified water.
  • the active compounds Sodium Fusidate, Beclomethasone Dipropionate& Terbinafine Hydrochloride which may be employed in the process of the present invention as starting APIs are well known in the art of treating bacterial primary & secondary bacterial skin infections, skin inflammations and fungal skin infections.
  • the active compounds Sodium Fusidate, Beclomethasone Dipropionate & Terbinafine Hydrochloride require a base component to be used in the pharmaceutical composition that uses the compound, since the compound cannot, by themselves, be deposited directly on to human skin due to their harshness.
  • the base component usually contains a biopolymer, primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, purified water and the like.
  • the cream base of the cream made using the process 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 process to make 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 cream made using the process of the present invention has been manufactured in a totally oxygen free environment under purging with inert gas and applying vacuum, the inert gas being preferably nitrogen. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic Acid and to which Beclomethasone Dipropionate as a steroid, and Terbinafine Hydrochloride as an antifungal are added.
  • the cream of the present invention is used in the treatment of bacterial skin infections, fungal infections and inflammations. From the study of the prior art several lacking aspects of the existing topical treatment formulations in the field of prescription medications are evident. The prior art does not teach or suggest that:
  • Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcomes of the main APIs are enhanced.
  • biopolymers biologically active polymers
  • topical antibacterial agents examples include, but are not limited to Sodium Fusidate, Neomycin Sulphate, Calcium Mupirocin, Gentamycin, Silver Sulphadiazine, Ciprofloxacin, Framycetin Sulphate, Quinidochlor, Povidone-Iodine, Sisomicin, Nitrofural and the like.
  • Corticosteroids examples include, but are not limited to Beclomethasone Dipropionate, Clobetasone Butyrate, Betamethasone Valerate, Fluticasone Propionate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Betamethasone Dipropionate and the like.
  • Antifungals include, but are not limited to Terbinafine Hydrochloride, Miconazole Nitrate, Ketoconazole, Clotrimazole and the like.
  • suitable biopolymer examples include, but are not limited to Chitosan and the like.
  • Chitosan is a linear polysaccharide composed of randomly distributed ⁇ - (1-4)- linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is known to have a number of commercial uses in agriculture and horticulture, water treatment, chemical industry, pharmaceuticals and biomedics.
  • Chitosan It's known properties include accelerated blood clotting. However, it is not known to a person skilled in the art that Chitosan' s behavior with a pharmaceutical active ingredient such as an antibacterial or antifungal agent needs to be treated with caution does not know it. It is known to have film forming, mucoadhesive and viscosity-increasing properties and it has been used as a binder and disintegrating agent in tablet formulations. Chitosan generally absorbs moisture from the atmosphere / environment and the amount absorbed depends upon the initial moisture content, temperature and relative humidity of the environment.
  • Chitosan due to its unique physical property accelerates wound healing and wound repair. It is positively charged and soluble in acidic to neutral solution. Chitosan is bioadhesive and readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces. Chitosan's properties allow it to rapidly clot blood, and it has recently gained approval in the USA for use in bandages and other hemostatic agents.
  • Chitosan is nonallergenic, and has natural anti-bacterial properties, further supporting its use. As a micro-film forming biomaterial, Chitosan helps in reducing the width of the wound, controls the oxygen permeability at the site, absorbs wound discharge and gets degraded by tissue enzymes which are very much required for healing at a faster rate. It also reduces the itching by providing a soothing effect. It also acts like a moisturizer. It is also useful in treatment of routine minor cuts and wounds, burns, keloids, diabetic ulcers and venous ulcers.Chitosan used in the present invention comes in various molecular weights ranging from lkdal to 5000kdal.
  • Chitosan is discussed in the US Pharmacopoeia forum with regard to its functional excipient category and has been published in the official monograph - (USP 34) NF 29. Since Chitosan is basically a polymer, it is available in various grades depending upon the molecular weight. The various grades of Chitosan include Chitosan long chain, Chitosan medium chain & Chitosan short chain. The grades long, medium & short chain directly corresponds to the molecular weight of the Chitosan.
  • the long chain grade has a molecular weight in the range of 500,000- 5,000,000 Da
  • the medium chain grade has a molecular weight in the range of 1,00,000-2,000,000 Da
  • the short chain grade has a molecular weight in the range of 50,000-1,000,000 Da.
  • the molecular weight of the Chitosan plays an important role in the formulation.
  • Chitosan imparts a higher viscosity to the system and lower molecular weight Chitosan imparts a lower viscosity to the system.
  • medium chain grade Chitosan delivered an optimum level of viscosity to the formulation. Since the dosage form is a cream, appropriate levels of viscosity is required to achieve a good spreadability over the skin.
  • the inventors finalized the Chitosan medium chain grade for the present invention since it imparted the required rheologic properties to the cream without compromising the therapeutic activity of the actives, i.e. Sodium Fusidate, Beclomethasone Dipropionate & Terbinafine Hydrochloride as the starting actives and Chitosan.
  • the concentration of Chitosan medium chain grade was carefully arrived based on several in house trials and Preclinical animal studies for efficacy.
  • Topical anti-fungals are intended to target skin for fungal infections caused by fungi such as Tinea pedis, Tinea cruris, and Tinea corporis.
  • Typical antifungal agents include drugs like Terbinafine Hydrochloride, Clotrimazole, Ketoconazole, Miconazole nitrate, etc. Fungal infections are generally manifested with itching at the site.
  • Anti-fungals act by altering the permeability of the fungal membrane by inhibiting the synthesis of sterols.
  • Terbinafine Hydrochloride Terbinafine Hydrochloride
  • Terbinafine Hydrochloride is an antifungal agent. Chemically, Terbinafine hydrochloride is (E)-N- (6, 6-dimethyl-2-hepten-4-ynyl)-N-methyl-l- naphthalenemethanamine hydrochloride. The compound has the empirical formula C 2 1H 26 CIN, a molecular weight of 327.90.
  • Terbinafine is an allylamine, which has a broad spectrum of antifungal activity. At low concentrations Terbinafine is fungicidal against dermatophytes, molds and certain dimorphic fungi. The activity against yeasts is fungicidal or fungistatic, depending on the species. Terbinafine interferes specifically with fungal sterol biosynthesis by inhibition of squalene epoxidase in the fungal cell membrane. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death.
  • the enzyme squalene epoxidase is not linked to the cytochrome P450 system; hence Terbinafine does not influence the metabolism of hormones or other drugs.
  • the drug concentrates rapidly in skin, hair and nails at levels associated with fungicidal activity.
  • the cream has a rapid onset of action and can be effective with a short duration of treatment.
  • Topical Terbinafine is indicated in the treatment of fungal infections of the skin caused by dermatophytes such as Trichophyton, as well as yeast infections of the skin, principally those caused by the genus Candida (e.g., Candida albicans).
  • the cream is also indicated in the treatment of pityriasis (tinea) versicolor due to P. orbiculare (also known as M. furfur).
  • Topical corticosteroids are a powerful tool for treating skin diseases.
  • Corticosteroids include drugs such as Beclomethasone dipropionate, Clobetasone Butyrate, Betamethasone Dipropionate, Clobetasol propionate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate, etc.
  • drugs such as Beclomethasone dipropionate, Clobetasone Butyrate, Betamethasone Dipropionate, Clobetasol propionate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate,
  • Topical corticosteroids are classified by their potency, ranging from weak to extremely potent. They include weak potent steroids, moderate potent steroids, potent steroids, very potent steroids and extremely potent steroids.
  • the high potency steroids include Betamethasone Dipropionate, Betamethasone Valerate, Diflorasone Diacetate, Clobetasol Propionate, Halobetasol Propionate, Desoximetasone, Diflorasone Diacetate, Fluocinonide, Mometasone Furoate, Triamcinolone Acetonide, etc.
  • Low potency topical steroids include Desonide, Fluocinolone acetate, and Hydrocortisone acetate, etc.
  • Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.
  • Beclomethasone Dipropionate is a topically active corticosteroid which provides an exceptional combination of activity and safety having the chemical name, 9- Chloro-11 (beta), 17, 21-trihydroxy-16 (beta)-methylpregna-l, 4-diene-3, 20- dione 17, 21 -dipropionate.
  • corticosteroids are a class of compounds comprising steroid hormones secreted by the adrenal cortex and their synthetic analogs. In pharmacologic doses, corticosteroids are used primarily for their anti-inflammatory and/or immunosuppressive effects. Topical corticosteroids such as Beclomethasone Dipropionate are effective in the treatment of corticosteroid-responsive dermatoses primarily because of their anti-inflammatory, anti-pruritic, and vasoconstrictive actions. However, while the physiologic, pharmacologic and clinical effects of the corticosteroids are well known, the exact mechanisms of their actions in each disease are uncertain.
  • Beclomethasone Dipropionate has been shown to have topical and systemic pharmacologic and metabolic effects characteristic of the corticosteroid class of drugs.
  • corticosteroids The antiinflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes.
  • the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding.
  • the extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
  • Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees, are metabolized primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
  • Topical Anti-bacterials are intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance Staphylococcus Aureus (MRSA) etc.
  • Anti-bacterial acts by inhibiting cell wall synthesis by combining with bacterial ribosomes and interfering with mRNA ribosome combination.
  • anti-bacterial induce ribosome 's to manufacture peptide chains with wrong amino acids, which ultimately destroy the bacterial cell.
  • Sodium Fusidate belongs to the group of medicines known as antibiotics.
  • bacterial infections such as infections of the joints and bones by killing or stopping the growth of the bacteria responsible.
  • Sodium Fusidate inhibits bacterial protein synthesis by interfering with amino acid transfer from aminoacyl-sRNA to protein on the ribosomes.
  • Sodium Fusidate may be bacteriostatic or bactericidal depending on inoculum size. Although bacterial cells stop dividing almost within 2 minutes after contact with the antibiotic in vitro, DNA and RNA synthesis continue for 45 minutes and 1 to 2 hours, respectively.
  • Sodium Fusidate is virtually inactive against gram-negative bacteria. The differences in activity against gram-negative and gram-positive organisms are believed to be due to a difference in cell wall permeability.
  • Mammalian cells are much less susceptible to inhibition of protein synthesis by Sodium Fusidate than sensitive bacterial cells. These differences are believed to be due primarily to a difference in cell wall permeability.
  • Sodium Fusidate is indicated for the treatment of primary and secondary skin infections caused by sensitive strains of S. aureus, Streptococcus species and C. minutissimum.
  • Primary skin infections that may be expected to respond to treatment with Sodium Fusidate topical include: impetigo contagiosa, erythrasma and secondary skin infections such as infected wounds and infected burns.
  • Creams are topical preparation used for application on the skin.
  • Creams are semisolid emulsions, which are mixtures of oil and water in which APIs (Active Pharmaceutical Ingredients) are incorporated. They are divided into two types: oil-in-water (O/W) creams which compose of small droplets of oil dispersed in a continuous water phase, and water-in-oil (W/O) creams which compose of small droplets of water dispersed in a continuous oily phase.
  • Oil-in-water creams are user-friendly and hence cosmetically acceptable as they are less greasy and more easily washed with water.
  • An ointment is a viscous semisolid preparation containing APIs, which are used topically on a variety of body surfaces. The vehicle of an ointment is known as ointment base.
  • a base depends upon the clinical indication of the ointment, and the different types of ointment bases normally used are: ⁇ Hydrocarbon bases, e.g. hard paraffin, soft paraffin
  • Absorption bases e.g. wool fat, bees wax
  • the acidic scale of pH is from 1 to 7, and the base scale of pH is from 7 to 14.
  • Human skins pH value is some where between 4.5 and 6. Newborn baby's skin pH is closer to neutral (pH 7), but it quickly turns acidic. Nature has designed this probably to protect young children's skin, since acidity kills bacteria. As people become older, the skin becomes more and more neutral, and won't kill as many bacteria as before. This is why the skin gets weak and starts having problems.
  • the pH value goes beyond 6 when a person actually has a skin problem or skin disease. This shows that it is necessary to choose topical that have a pH value close to that of skin of a young adult. A slight shift towards the alkaline pH would provide a better environment for microorganisms to thrive.
  • cream formulations are available as creams. Active compounds in cream formulations are available in ionized state, whereas in case of ointments these are present in non -ionized state.
  • the cream formulations are the first choice of the formulators in design and development of topical dosage forms, as the cream formulations are cosmetically elegant, and also as the active compound is available in ionized state, and the drug can penetrate the skin layer fast which makes the formulation totally patient friendly.
  • the pH of the Chitosan Cream with antibacterial agent - Sodium Fusidate, Beclomethasone Dipropionate as a steroid, Terbinafine Hydrochloride as an antifungal of the present invention is from about 3 to 6.
  • ointments that are commercially available are greasy and cosmetically non elegant.
  • the penetration of skin is slow.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in colloidal or molecular dispersed state for the product being highly efficacious form. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug.
  • the product of the present invention is highly efficacious due to the pronounced antibacterial & wound healing activity of the active ingredients, which are available in ultra micro-size, colloidal form, which enhances skin penetration.
  • Topical Sodium Fusidate & Terbinafine Hydrochloride have profound efficacy in primary & secondary bacterial/fungal skin infections of varied etiology due to their antibacterial/antifungal properties.
  • a drawback of the monotherapy with any topical antibacterial/antifungal has been the relatively slow onset of the effect.
  • Chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments.
  • the combination of Chitosan with Sodium Fusidate, Beclomethasone Dipropionate, and Terbinafine Hydrochloride is unique and novel since this is not available commercially across the globe.
  • Another inventive aspect of the present invention is that the addition of a functional excipient in the cream base is not a straight forward process of mere addition.
  • the inventor has found that the compatibility of the functional excipient such as Chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product.
  • the inventors have found that well known excipients such as Xanthan Gum and carbomer, which have been variously used be used in combination with functional biopolymers such as Chitosan.
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy as stabilizing agents, cannot Materials, and Emulsifiers etc. Polymers are used as gelling agents, suspending agents, viscosity builders, release modifiers, diluents, etc. Surfactants are used as wetting agents, emulsifiers, solubilising agents release enhancers, etc.
  • polymers & surfactants may or may not possess ionic charge. They may be anionic or cationic or non-ionic in nature. If anionic excipients are included in the formulation they interact with cationic formulation excipients and produce products which are not homogenous, aesthetically not appealing and give rise to unwanted by products, possible allergens, impurities, toxic substances etc due to incompatibility.
  • the inventors carefully screened the excipients, which included the polymers and surfactants for developing a formulation. A thorough study was performed after screening the short listed excipients. The possible interactions between the excipients were given much focus and detailed experiments were done.
  • the inventors made some formulations of Sodium Fusidate, Beclomethasone Dipropionate & Terbinafine Hydrochloride (see tables 3 - 7) containing Xanthan Gum & Chitosan, Acrylic acid polymer & Chitosan, Sodium Lauryl Sulphate & Chitosan, Docusate Sodium & Chitosan and Gum Arabic & Chitosan.
  • Table 4 Fusidic Acid, Beclomethasone Dipropionate, Terbinafine Hydrochloride cream incorporating Chitosan and acrylic acid polymer.
  • Fusidic Acid provides relief against bacterial infections
  • Beclomethasone Dipropionate provides relief against skin inflammations
  • Terbinafine Hydrochloride provides relief against fungal infections
  • the aspects such as like skin protection, bleeding at the site, mobility of pathogens from one site to another, etc are not addressed so far in a single dose therapy that includes Fusidic Acid generated in situ from Sodium Fusidate.
  • This present invention with its single-dose application fills this gap by incorporating Chitosan and tapping the required benefits of skin protection (by way of film forming property), stopping the bleeding (by way of blood clotting property) and immobilization of pathogenic microbes (due to its cationic electrostatic property).
  • the unique innovative formulation of the present invention takes care of the skin conditions by treating them along with controlling the superficial bleeding at the site. It is well understood that if the superficial bleeding is left untreated, it will lead to secondary microbial infections.
  • the present invention advantageously provides a solution to this unmet need.
  • Preferred embodiment no. 1 A medicinal cream for topical treatment of bacterial skin infections, fungal skin infections, inflammations and for related wound healing including burns wound, wherein said cream comprises an antibacterial agent, Sodium Fusidate, an antifungal agent Terbinafine Hydrochloride, a Corticosteroid Beclomethasone Dipropionate and a biopolymer provided in a cream base, said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co-solvent, an acid, and water, preferably purified water.
  • Embodiment no. 1 A medicinal cream as disclosed in the preferred embodiment no 1, wherein said cream further comprising any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.
  • Embodiment no. 2 A medicinal cream as disclosed in the preferred embodiment no 1 and the embodiment no. 1 , wherein
  • said Fusidic Acid is present in an amount from about 0. l%(w/w) to about
  • the topical corticosteroid is from about 0.005%(w/w), to about 2.5%(w/w) by weight, preferably from about 0.005%(w/w), to about 1.00%(w/w) by weight, and most preferably from about 0.025%(w/w) by weight, and further wherein said corticosteroid is Beclomethasone Dipropionate, and
  • said antifungal is added from about 0.05%(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
  • said antifungal preferably being Terbinafine Hydrochloride
  • said biopolymer is in the form of Chitosan, added in an amount between about 0.01%(w/w) and about l%(w/w), preferably from about 0.01% w/w to about 0.5%w/w and most preferably about 0.1%w/w, the molecular weight of said chitosan is between 1 kDal and 5000 kdal,
  • said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like and added in an amount from about l%(w/w) to 20%(w/w); said waxy materials is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or any combination thereof, and added in an amount from about 5%(w/w) to 30%(w/w);said co-solvent is selected from a group comprising
  • said acid is selected from a group comprising HCL, H 2 SO 4
  • Embodiment no.3 A medicinal cream as disclosed in the preferred embodiment no 1 and embodiment 2 further comprising a buffering agent which is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.001 %(w/w) tol.00%(w/w).
  • a buffering agent which is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.001 %(w/w) tol.00%(w/w).
  • Embodiment no. 4 A medicinal cream as disclosed in the preferred embodiment no 1 and embodiments 2 and 3 further comprising an antioxidant which is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, and added in an amount from about 0.001 %(w/w) to l%(w/w).
  • an antioxidant which is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, and added in an amount from about 0.001 %(w/w) to l%(w/w).
  • Embodiment no. 5 A medicinal cream as disclosed in the preferred embodiment no 1 and embodiments nos.2 to 4 further comprising a chelating agent which is selected from a group comprising Disodium EDTA and the like, or any combination thereof, and added in an amount from about 0.05%(w/w) to l%(w/w).
  • Embodiment no.6 A medicinal cream as disclosed in the preferred embodiment no 1, and embodiments nos. 2 to 5 further comprising a humectant which is selected from a group comprising Glycerin, Sorbitol, Propylene Glycol and the like, or any combination thereof, and added in an amount from about 5%(w/w) to 50%(w/w).
  • Embodiment no. 7 A medicinal 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 medicinal cream as described in the preferred embodiment 1 and embodiment's 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 medicinal 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 2 discloses a process to make a dermaceutical cream containing Fusidic Acid, said process comprising the step of using Sodium Fusidate as the raw API and converting it in situ into Fusidic Acid under oxygen-free environment in a cream base.
  • Embodiment No. 10 In an embodiment of the present invention the process of making the composition is disclosed, wherein the step of converting the Sodium Fusidate in situ into Fusidic Acid of the preferred embodiment no. 2 comprises the steps of:
  • heating purified water in the range from 20%(w/w) to 75%(w/w), preferably 30%(w/w) to 50%(w/w), more preferably 25%(w/w) to 40%(w/w), in a water-phase vessel to 70°C to 80°C,
  • a primary emulsifier preferably in the form of a non ionic surfactant, selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, either singly or any combination thereof, wherein Cetostearyl alcohol is added in an amount between l%(w/w) and 20%(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) and 5%(w/w), preferably l%(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 l%w/w, and 5%w/w, preferably l%w/w to 3%w/w, more preferably 2%w/w and mixing the mixture thoroughly, preferably using an agitator
  • 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 50%(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 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, h.
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like,
  • an acid selected from a group comprising acids such as HCL, H 2 SO 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount from about 0.005%(w/w) to 0.5%(w/w), preferably 0.3%(w/w), more preferably 0.25%(w/w), i.
  • Beclomethasone Dipropionate added in an amount between 0.005%(w/w) and about 2.5%(w/w), preferably from about 0.005%(w/w) to about l%(w/w) and more preferably about 0.025%(w/w),
  • a preservative preferably Benzyl alcohol in an amount between 0.05%(w/w) and about 3%(w/w), preferably from about 0.5%(w/w) to about 2%(w/w) and more preferably about l%(w/w), and adding propylene glycol in an amount between l%(w/w) to 10%(w/w), preferably 5%(w/w), more preferably 4%(w/w) and dissolving Terbinafine Hydrochloride in it by continuous mixing to form a Solution, said Terbinafine Hydrochloride added in an amount between 0.05%(w/w) and about 5%(w/w), preferably from about 0.5%(w/w) to about 3%(w/w) and more preferably about l%(w/w),
  • API-vessel of step j to the said mixing vessel of step f 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 and minus 300 mm of mercury,
  • an acid selected from a group comprising acids such as HCL, H 2 SO 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Lactic acid to form a from about 0.005%(w/w) to 0.5%(w/w), preferably 0.3%(w/w), more preferably 0.05%(w/w), and purified water from about 0.1%(w/w) to 10%(w/w), preferably 8%(w/w), more preferably 5%(w/w) to form a mixture and dissolving a biopolymer, preferably Chitosan in an amount between about 0.01%(w/w) and about l%(w/w), preferably from about 0.01%(w/w) to about 0.5%(w/w) and most preferably about 0.
  • an acid selected from a group comprising acids such as HCL, H 2 SO 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Lactic acid to form a from about
  • the molecular weight of said chitosan is between 1 kDal and 5000 kDal, transferring the contents of the biopolymer-mixing vessel of step n to the mixing vessel of step f 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 f cooling the contents of the mixing vessel of step f 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,
  • step g of the embodiment no.10 above also serves as a humectant.
  • an additional humectant may be added, in the step a of embodiment 10, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, from about 5%(w/w) to 50%(w/w), preferably 10%(w/w) to 40%(w/w), more preferably 32%(w/w).
  • Embodiment No. 12 In another embodiment of the present invention the process described in embodiment no. 11 further incorporates adding a chelating agent, after the step of adding a preservative, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, from about 0.05%(w/w) to l%(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, from about 0.05%(w/w) to l%(w/w), preferably 0.5%(w/w), more preferably 0.1%(w/w).
  • Embodiment No. 13 In yet another embodiment of the present invention the process described in embodiments no. 11 and 12 further incorporate a buffering agent after the step of adding chelating agent selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.001% (w/w) to 1.00%(w/w), preferably 0.75%(w/w), more preferably 0.5%(w/w).
  • chelating agent selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.001% (w/w) to 1.00%(w/w), preferably 0.75%(w/w), more preferably 0.5%(w/w).
  • Embodiment No. 14 In a further embodiment of the present invention the process described in embodiments no.
  • 11 to 13 further incorporate an anti oxidants in the step g of embodiment 10 selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001 %(w/w) to 1 % (w/w) , preferably 0.1% (w/w) , more preferably 0.01% (w/w) .
  • an anti oxidants selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001 %(w/w) to 1 % (w/w) , preferably 0.1% (w/w) , more preferably 0.01% (w/w) .
  • Embodiment No. 15 Yet another process of making the composition as per the said earlier preferred embodiments & embodiments is disclosed, said process comprises the steps of:
  • heating purified water in the range from 20%(w/w) to 75%(w/w), preferably 30%(w/w) to 50%(w/w), more preferably 25%(w/w) to 40%(w/w), in a water-phase vessel to 70°C to 80°C,
  • a chelating agent is preferably Disodium edetate, added in an amount preferably between 0.05%(w/w), and l%(w/w) preferably 0.5%(w/w), more preferably 0.1%(w/w)
  • said buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount preferably 0.001 %(w/w) to 1.00%(w/w), preferably 0.75%(w/w),more preferably 0.5%(w/w) and said humectant is preferably Propylene Glycol, added in an amount preferably 5% (w/w) to 50%(w/w), preferably 10%(w/w) to 40%(w/w), more preferably 32%(w/w), mixing the mixture of said water-phase vessel of step b using an agitator at 10 to 50 RPM while maintaining the
  • an emulsifying wax preferably Cetostearyl alcohol, in an amount preferably between l%(w/w), and 20%(w/w), preferably 15%(w/w), more preferably 12.5%(w/w) and a waxy material, preferably white soft paraffin, in an amount preferably between 5%(w/w) and 30%(w/w), preferably 15%(w/w), more preferably 12.5%(w/w), and melting them by heating to 70°C to 80°C,
  • an emulsifying wax preferably Cetostearyl alcohol
  • a non ionic surfactant or emulsifier in an amount preferably between l%(w/w) and 5%(w/w), preferably l%(w/w) to 3%(w/w), more preferably 2%(w/w) of Polysorbate 80 and in an amount preferably between 0.1%(w/w) and 5%(w/w), preferably l%(w/w), more preferably 0.5%(w/w) of Cetomacrogol 1000 and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70°C to 80°C,
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, Poly Ethylene Glycol-400 adding propylene glycol, or any mixture thereof, in an amount preferably between 5%(w/w) and 50%(w/w), preferably 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, added in an amount between 0.001 %(w/w) and l%(w/w), preferably 0.1%(w/w),more preferably 0.01%(w/w) Butylated Hydroxy Toluene in it by continuous mixing, subjecting the contents of said first API-vessel a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, Poly Ethylene Glycol-400 adding propylene glycol, or any mixture
  • an acid selected from a group comprising acids such as HCL, H 2 SO 4 , HNO 3 , lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount preferably between 0.005%(w/w) and 0.5%(w/w), preferably 0.3%(w/w), more preferably 0.25%(w/w),
  • Beclomethasone Dipropionate added in an amount between 0.005%(w/w) and about 2.5%(w/w), preferably from about 0.005%(w/w) to about l%(w/w) and more preferably about 0.025 %(w/w),
  • a preservative preferably Benzyl alcohol in an amount between 0.05%(w/w) and about 3%(w/w), preferably from about 0.5%(w/w) to about 2%(w/w) and more preferably about l%(w/w), and adding propylene glycol in an amount between l%(w/w) to 10%(w/w), preferably 5%(w/w), more preferably 4%(w/w) and dissolving Terbinafine Hydrochloride in it by continuous mixing to form a Solution ,said Terbinafine Hydrochloride added in an amount between 0.05%(w/w) and about 5%(w/w), preferably from about 0.5%(w/w) to about 3%(w/w) and more preferably about l%(w/w),
  • an acid selected from a group comprising acids such as HCL, H 2 So 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Lactic acid from about 0.005%(w/w) to 0.5%(w/w), preferably 0.3%(w/w), more preferably 0.05%(w/w), and purified water from about 0.1%(w/w) to 10%(w/w), preferably 8%(w/w), more preferably 5%(w/w) mixture and dissolving the said biopolymer, Chitosan in an amount between about 0.01%(w/w), and about l%(w/w) by weight, preferably from about 0.01%(w/w), to about 0.5%(w/w), and most preferably about 0.1%(w/w), the molecular weight of said chitosan is between 1 kDal and 5000 kDal,
  • step p transferring the contents of the biopolymer mixture of step p to the mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • step h also serve as a humectant.
  • an additional humectant may be added, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, from about 5%(w/w) to 50%(w/w), preferably 10%(w/w) to 40%(w/w), more preferably 32%(w/w).
  • a method of treating primary & secondary bacterial & fungal skin infections and inflammations comprising applying of a cream containing at least one corticosteroid Beclomethasone Dipropionate, one antifungal Terbinafine Hydrochloride 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.
  • the cream obtained using the process of the present invention is homogenous and white to off white in color and viscous in consistency.
  • the pH of the product made using the process 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 penetrate 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.
  • Particle size analysis was carried out on the cream made using the process of the present invention and on some commercially available product samples (samples A, C, D, F, G, and K).
  • An optical microscope by Carl Zeiss (Axio Star Plus 2x to lOOx magnification) was used for this purpose. Maximum and minimum particle sizes, mean particle size and standard deviation and the coefficient of variation were assessed.
  • the particle size distribution analysis results indicated in table 8 clearly indicate the presence of Fusidic Acid of fine particle size in the product of the present invention, the size that is advantageously much reduced than the conventional products.
  • the maximum particle size observed for fusidic acid of the present invention is less than 6 ⁇
  • the maximum particle size observed for existing creams varies between 19 ⁇ to 40 ⁇ , with a majority of them having the maximum particle size between 30 ⁇ and 40 ⁇ .
  • the average size of the fusidic acid particles in the present invention has been found to be less than 2 ⁇ whereas that for the existing creams varies between 14 ⁇ to 19 ⁇ .
  • the minimum particle size observed was approx. 0.65 ⁇ whereas the minimum particle size observed for existing creams ranged between 5 ⁇ and ⁇ .
  • the cream of the present invention is therefore physically distinct from any of the existing creams and easily distinguishable. This is attributed to the fact that the instant product is made using Sodium Fusidate using in situ conversion of Sodium Fusidate to Fusidic Acid in a finely dispersed form. All of the measured parameters are better than those found for the commercially available creams containing Fusidic Acid. This is another clear advantage of the product disclosed herein over the commercially available products.
  • the reduced particle size of the fusidic acid of the present invention is of particular significance as it has been achieved without compromising the stability of fusidic acid.
  • products such as those disclosed in WO2007087806 by Leo Pharma have employed mechanical means such as mortar and pestle to mechanically grind fusidic acid for adding to a cream base.
  • WO2007087806 is silent on the particle size achieved, it will be known to a person skilled in the art that its particle size of fusidic acid cannot be finer than that of the present invention. Moreover, the stability of the fusidic acid in creams produced by the teachings of WO2007087806 or indeed in 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 8.
  • the product of the present invention is efficacious due to the pronounced antibacterial activity of the regenerated Fusidic Acid, antifungal activity of the Terbinafine Hydrochloride, anti-inflammatory activity of the Beclomethasone Dipropionate, which is available in reduced particle size than the conventional products, and in a finely dispersed form.
  • the inventor has screened different co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one of above co-solvents varying from about 5% (w/w) to 50%(w/w) under inert gas purging and under vacuum and converted to Fusidic Acid in-situ by adding an acid such as HCL, H 2 SO 4 , 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
  • the stability of the product is confirmed by the stability studies performed for 6 months as per ICH guidelines and a comparison of stress studies done for in- house product with those on samples of commercially available comparable products.
  • API-stability experiments were carried out (see tables 10 - 12) using the product of the present invention and products currently commercially available. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the API over a period of time. Tests were also carried out to assess the stability by subjecting the product to stress studies such as autoclave test and oxidative degradation test. Further, in vitro antimicrobial zone of inhibition studies and preclinical studies such as blood clotting studies & burns wound healing studies were also carried out over a period of time.
  • Each gram of product of the present invention used for the tests contained Sodium Fusidate as the starting raw material in the amount required to produce approximately 2%(w/w) Fusidic Acid, 0.025%(w/w) Beclomethasone Dipropionate & l%(w/w) Terbinafine Hydrochloride in the finished product.
  • the product used for the Stability Studies tests contained approximately 10% extra API (overages).
  • the product of the present invention used for studies contained Fusidic Acid cream prepared using Sodium Fusidate as starting material. It was packaged in an aluminum 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) and appropriate amount of steroids and antifungal as mentioned below.
  • composition of the final cream is given in the table 9 below.
  • composition Fusidic Acid 2.0%w/w (equivalent of Sodium Fusidate 2.08%w/w) Beclomethasone Dipropionate (0.025%w/w) + Terbinafine Hydrochloride (l%w/w) + Chitosan 0.1%(w/w) Cream
  • PRODUCT Sodium Fusidate + Beclomethasone Dipropionate + Terbinafine
  • the cream is applied after thorough cleansing and drying the affected area. Sufficient cream should be applied to cover the affected skin and surrounding area. The cream should be applied two - four times a day depending upon the skin conditions for the full treatment period, even though symptoms may have improved.
  • A. Wound Contraction Excision wound healing activity of the cream of the present invention was determined through animal testing. An excision wound 2.5 cm in diameter was inflicted by cutting away full thickness of the skin. The amount of contraction of the wound observed over a period indicated that the cream of present invention provides significantly improved wound contraction than a control (untreated wound).
  • Blood Clotting time was observed in both groups of animals, untreated control group and the test group of animals treated with the product of the present invention. Statistically significant decrease in the blood clotting time in treated group animals was observed when compared with that of the control group animals. The mean percent reduction of 50-60% was observed for the blood clotting time using the product of the present invention.
  • Chitosan growth support claimed possesses properties that have significant complimentary action on epidermal growth. This functional aspect of Chitosan is preserved in the product of the present invention
  • the film forming ability of the Chitosan incorporated in the cream allows better access of the antibacterial agent, Sodium Fusidate to the infected area and results in better functioning of these API.
  • the therapeutic efficacy of topically applied cream of the present invention is due to the pronounced antibacterial / antifungal activity of the Sodium Fusidate & Terbinafine Hydrochloride against the organisms responsible for skin infections, pronounced anti-inflammatory activity of the Beclomethasone Dipropionate against inflammations, the unique ability of actives to penetrate intact skin and wound healing & soothing properties of Chitosan.
  • the cream of the present invention incorporates a skin- friendly biopolymer in the form of Chitosan provides enhanced therapeutic outcomes. This is evident from the reduced blood clotting time, increased epithelial effect, and faster relief from infection and inflammation and wound contraction.
  • the cream of the present invention incorporates a biopolymer without compromising the stability of the cream matrix and without adversely affecting the functioning of known active pharmaceutical ingredients. This has been achieved through a careful selection of functional excipients to bypass undesirable aspects of physio- chemical compatibility/stability and bio-release.
  • the cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations.
  • novel cream of the present invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage hence will go a long way in achieving these social objectives.
  • a process for treating bacterial / fungal skin infections, inflammations and wound healing involving contacting human skin with the above-disclosed composition.

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  • Veterinary Medicine (AREA)
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  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
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Abstract

La présente invention concerne une composition médicinale destinée à traiter des inflammations de la peau, des infections fongiques/bactériennes de la peau et les plaies associées, et également d'autres plaies au niveau de la peau comprenant celles provoquées par les brûlures. La crème permet également un renouvellement de la peau par le biais d'un processus d'épithélisation. Les principes actifs sont le chitosane, le dipropionate de bétaméthasone, le chlorhydrate de terbinafine et l'acide fusidique. L'invention concerne également un procédé de fabrication de la crème médicinale contenant l'acide fusidique qui est formé in situ à partir du fusidate de sodium en tant que produit brut de départ, le fusidate de sodium étant converti en acide fusidique dans un environnement exempt d'oxygène créé en utilisant un gaz inerte, de préférence l'azote, et du chitosane. La crème produite par le procédé de la présente invention présente une stabilité de conservation plus grande et une taille des particules de principe actif plus fine que celles des crèmes conventionnelles contenant de l'acide fusidique. La crème produite par le procédé de la présente invention contient de l'acide fusidique comme principe actif qui a été formé in situ à partir de fusidate de sodium, du dipropionate de bétaméthasone et du chlorhydrate de terbinafine dans une base de crème comprenant un conservateur, un acide, un co-solvant, un émulsifiant et une substance cireuse ainsi que de l'eau, de préférence de l'eau purifiée.
PCT/IB2011/053428 2010-08-02 2011-08-02 Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de béclométhasone, et du chlorhydrate de terbinafine et procédé de fabrication de celle-ci WO2012017383A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
FR3039399A1 (fr) * 2015-07-31 2017-02-03 Int Drug Licensing Creme pour l'admnistration de steroides et son procede de preparation
CN115414321A (zh) * 2022-10-20 2022-12-02 山东新时代药业有限公司 一种丙酸倍氯米松乳膏及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3039399A1 (fr) * 2015-07-31 2017-02-03 Int Drug Licensing Creme pour l'admnistration de steroides et son procede de preparation
CN115414321A (zh) * 2022-10-20 2022-12-02 山东新时代药业有限公司 一种丙酸倍氯米松乳膏及其制备方法

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