WO2011101825A1 - Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère, du clotrimazole et de la clobétasone, et procédé de réalisation associé - Google Patents

Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère, du clotrimazole et de la clobétasone, et procédé de réalisation associé Download PDF

Info

Publication number
WO2011101825A1
WO2011101825A1 PCT/IB2011/050713 IB2011050713W WO2011101825A1 WO 2011101825 A1 WO2011101825 A1 WO 2011101825A1 IB 2011050713 W IB2011050713 W IB 2011050713W WO 2011101825 A1 WO2011101825 A1 WO 2011101825A1
Authority
WO
WIPO (PCT)
Prior art keywords
amount
vessel
cream
mixture
added
Prior art date
Application number
PCT/IB2011/050713
Other languages
English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kuppusamy Senthilkumar
Sankar Haridas
Original Assignee
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kuppusamy Senthilkumar
Sankar Haridas
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sulur Subramaniam Vanangamudi, Madhavan Srinivasan, Neelakandan Narayanan Chulliel, Kuppusamy Senthilkumar, Sankar Haridas filed Critical Sulur Subramaniam Vanangamudi
Publication of WO2011101825A1 publication Critical patent/WO2011101825A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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

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 form of Chitosan, a corticosteroid in the form of Clobetasone Butyrate, and an 10 antifungal agent in the form of Clotrimazole, and the process of making it and using it in treating these infections, inflammations and wounds.
  • 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 treatment compositions typically employ at least one active pharmaceutical ingredient (API) in 20 combination with a base component.
  • the APIs typically comprise an antibiotic/antibacterial such as Fusidic Acid, a corticosteroid such as Clobetasone Butyrate, and an antifungal agent such as Clotrimazole, 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.
  • Fusidic Acid cream in which Fusidic Acid will be of greater stability than the stability of the Fusidic Acid in the conventional creams, particularly at the time of the manufacture of the cream, and which will sustain its stability at an acceptable level throughout its shelf life.
  • 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 of bacterial agent or a fungus 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.
  • the word healing as related to compromised skin conditions are not only about prevention, control, elimination of the source cause such as bacteria or fungi but also to restore the skin to its pre-infection state.
  • 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 is 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.
  • 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
  • incorporation of a functionally bioactive excipient polymer in cream matrix while retaining the functional stability of the API in a single dose format of dermaceutical cream involves resolution of problems specific to the physical stability of cream matrix.
  • Fusidic Acid has been used in cream form.
  • 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.
  • 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 Clotrimazole, benzoic acid and sodium benzoate.
  • EP1787652 claims novelty on the assertion that the 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 describes a skin care composition having improved effectiveness in preventing and treating acute inflammatory skin conditions.
  • the composition consists of Clotrimazole and zinc oxide.
  • US 4911932 claims novelty on the assertion that the formulation is an improved skin care compositions, which can be used for the prevention and treatment of diaper rash. According to the applicant, the improvement in the formulation is achieved because of the synergistic combination of active ingredients, 0.25% 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 which consist of surfactant, oil, Clotrimazole and distilled water.
  • US 5,461,068 pertains 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.
  • the said composition 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.
  • US 6,001,864 deals with an antifungal composition wherein an imidazole-type antifungal compound in the form of Clotrimazole is combined with a quaternary ammonium salt. It is claimed that the Clotrimazole is more potentiated active and has higher therapeutic effect.
  • the composition is effective against both Trichophyton and Candida.
  • the applicant also claims on the bases that combination disclosed in the present application has never been used before.
  • 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.
  • 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:
  • the active ingredients namely Chitosan, Clobetsaone Butyrate, Clotrimazole 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 cream produced by the process of the present invention contains Fusidic Acid as the API that has been formed in situ from Sodium Fusidate, Clobetsone Butyrate & Clotrimazole 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 Clobetasone Butyrate as a steroid, and Clotrimazole 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.
  • 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.
  • 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 Clobetasone Butyrate as a steroid, and Clotrimazole as an antifungal showed good chemical stability and efficacy.
  • the application discloses a process of making a cream containing a biopolymer - Chitosan, Clobetasone Butyrate as a steroid, and Clotrimazole as an antifungal, and Fusidic Acid (the API) that has been prepared using Sodium Fusidate as the starting API, in which Fusidic Acid forms in-situ under totally oxygen-free environment 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 Fu
  • 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, Clobetasone Butyrate as a steroid, and Clotrimazole 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, Clobetasone Butyrate & Clotrimazole 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 Clobetasone Butyrate as a steroid, and Clotrimazole as an antifungal are added.
  • the cream of the present invention is used in the treatment of bacterial skin infections fungal infections and inflammations.
  • 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 Clobetasone Butyrate betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate and the like.
  • Antifungals include, but are not limited to Clotrimazole, Miconazole Nitrate, Terbinafine Hydrochloride, Ketoconazole, 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 -(l-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 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. 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 molecular weight of the Chitosan plays an important role in the formulation. Higher molecular weight Chitosan imparts a higher viscosity to the system and lower molecular weight Chitosan imparts a lower viscosity to the system. However the 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, ie Sodium Fusidate, Clobetasone Butyrate & Clotrimazole 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-fungal 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 Clotrimazole, Ketoconazole, and Miconazole nitrate, Terbinafine Hydrochloride 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
  • Clotrimazole is a synthetic antifungal agent having the chemical name
  • Clotrimazole is a broad-spectrum antifungal agent that is used for the treatment of dermal infections caused by various species of pathogenic dermatophytes, yeasts, and Malassezia furfur. The primary action of clotrimazole is against dividing and growing organisms.
  • Mechanism of Action The fungicidal concentration of clotrimazole caused leakage of intracellular phosphorus compounds into the ambient medium with concomitant breakdown of cellular nucleic acids and accelerated potassium efflux.
  • Clotrimazole appears to be well absorbed in humans following oral administration and is eliminated mainly as inactive metabolites. Following topical and vaginal administration, however, clotrimazole appears to be minimally absorbed. Protein binding of Clotrimazole is about 90%. Clotrimazole is metabolized in liver
  • Clotrimazole Cream is indicated for the topical treatment of candidiasis due to Candida albicans and tinea versicolor due to Malassezia furfur.
  • Clotrimazole is also available as a nonprescription item which is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis.
  • topical Corticosteroids due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis.
  • Topical corticosteroids are a powerful tool for treating skin diseases.
  • Corticosteroids include drugs such as Clobetasone Butyrate ,Betamethasone dipropionate, Beclomethasone dipropionate, Clobetasol propionate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate, etc.
  • drugs such as Clobetasone Butyrate ,Betamethasone dipropionate, Beclomethasone dipropionate, Clobetasol propionate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocort
  • 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 Clobetasone Butyrate 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.
  • Clobetasone Butyrate is a topically active corticosteroid which provides an exceptional combination of activity and safety having the chemical name 21-chloro- 9-fluoro-16b-methyl-3,l l,20-trioxopregna-l, 4-dien-17-yl butanoate
  • 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 clobetasone 17-butyrate are effective in the treatment of corticosteroid-responsive
  • 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.
  • 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-bacterial is intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance Staphylococcus Aureus (MRS A) etc.
  • Anti-bacterial act by inhibiting cell wall synthesis by combining with bacterial ribosome's 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. It is used to treat bacterial infections, such as infections of the joints and bones by killing or stopping the growth of the bacteria responsible.
  • the molecular formula of Sodium Fusidate is C3iH47Na0 6 .
  • the chemical name is 3 ⁇ ,l l ⁇ ,16 ⁇ -Trihydroxy 29- ⁇ -8 ⁇ , 9B, 13 ⁇ , 14B-dammara-17(20) [10,21-cis], 24-dien-21-oic acid 16-acetate, sodium salt. It is a white colour crystalline powder soluble in one part of water at 20 °C.
  • 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.
  • 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.
  • 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
  • ointment base The choice of 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
  • 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 topicals 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.
  • the topical products 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, Clobetasone Butyrate as a steroid, Clotrimazole 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.
  • Topical Sodium Fusidate & Clotrimazole 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 a formulation the properties of antibacterial, antifungal, and anti- inflammatory agents as well as Chitosan are optimized.
  • Chitosan is film forming, biocompatible, non- allergenic material it helps in protecting the skin by acting as a barrier. It further controls the superficial bleeding caused by scratching and also arrests the mobility of pathogens due to its cationic charge.
  • 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, Clobetasone Butyrate, Clotrimazole 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 as stabilizing agents, cannot be used in combination with functional biopolymers such as Chitosan.
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy 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.
  • 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.
  • Fusidic Acid provides relief against bacterial infections
  • Clobetasone Butyrate provides relief against skin inflammations
  • Clotrimazole 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).
  • Therapeutic value addition by incorporation of a functional excipient in the form of a Chitosan which is a biopolymer in the cream matrix is an integrated sub-set of the following functional attributes of the biopolymer:
  • 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.
  • the present invention with its single-dose therapy reduces the overall treatment time of a serious skin disorder significantly.
  • 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 Clotrimazole, a corticosteroid Clobetasone Butyrate 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 0.1% (w/w) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w), and more preferably about 2.00 % (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) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w) and more preferably about 2.08 % (w/w), and
  • the topical corticosteroid is from about 0.001% (w/w) to about 5% (w/w) by weight, preferably from about 0.01% to about 1% by weight and most preferably about 0.05% (w/w) by weight, of Clobetasone Butyrate, 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 1.0% by weight; said antifungal preferably being Clotrimazole, and said biopolymer is in the form of Chitosan, added in an amount between about 0.01% and about 1% by weight, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.1% w/w,
  • 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) to 10% (w/w) preferably 1% (w/w), more preferably 0.5%.
  • 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) to 10% (w/w) preferably 1% (w/w), more preferably 0.5%.
  • 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 1 % (w/w) preferably 0.1% (w/w), more preferably 0.01%.
  • 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 1 % (w/w) preferably 0.1% (w/w), more preferably 0.01%.
  • 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 1% (w/w) preferably 0.5% (w/w), more preferably 0.1% (w/w)
  • 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 1% (w/w) preferably 0.5% (w/w), more preferably 0.1% (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) preferably 35% (w/w), more preferably 30%(w/w).
  • 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) preferably 35% (w/w), more preferably 30%(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 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 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.
  • 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) most preferably 29% (w/w), in a water-phase vessel to 70 ° C to 80 °C,
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), more preferably Benzoic acid,
  • 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 30% (w/w), preferably 15% (w/w), more prefer ably 12.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 ° C to 80 ° C,
  • a primary emulsifier preferably in the form of a non ionic surfactant, selected from a group comprising Cetostearyl alcohol, Cetomacrogol- 1000, either singly or any combination thereof, wherein Cetostearyl alcohol is added in an amount between 1% (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 1% (w/w), more preferably 0.5% (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span- 80 and the like, preferably Polysorbate-80, in an amount between 1 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
  • 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 20% (w/w), preferably 15% (w/w), preferably 10%(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 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 % (
  • Clobetasone Butyrate added in an amount between 0.001% (w/w) and about 5% (w/w), preferably from about 0.01% (w/w) to about 1% (w/w) and more preferably about 0.05 % (w/w), k.
  • Clotrimazole added in a third API- vessel propylene glycol in an amount between 5% (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 10% (w/w) and dispersing Clotrimazole in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, said Clotrimazole added in an amount between 0.5% (w/w) and about 5% (w/w), preferably from about 0.5%
  • API - vessel of step k to the said mixing vessel of step g 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 HC1, 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 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 1% w/w, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.1% w/w,
  • 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 1% (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 10.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
  • a buffering agent selected from 0.001% (w/w) to 10.00% (w/w), preferably 1.0% (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 h 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 in the step h 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).
  • 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) most preferably 29% (w/w) in a water-phase vessel to 70 ° C to 80 ° C,
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, 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), the preferred preservative being Benzoic acid, c.
  • said chelating agent is preferably Disodium edetate, added in an amount between 0.05 and 1 %(w/w), preferably 0.5%(w/w), more preferably 0.1%
  • said buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount 0.001% (w/w) to 10.00% (w/w), preferably 1.% (w/w), more preferably 0.5% (w/w)
  • said humectant is preferably Propylene Glycol, added in an amount 5% (w/w) to 50% (w/w), preferably 35%(w/w), more preferably 30% (w/w), mixing the mixture of said water-phase vessel of step c using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70°C to 80°C, adding to an oil-phase vessel an emulsifying wax,
  • a non ionic surfactant or emulsifier in an amount preferably between 1 and 5 (w/w), more preferably 2 (w/w) of Polysorbate 80 and between 0.1 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, PolyEthylene Glycol-400adding propylene glycol, or any mixture thereof, in an amount between 5% (w/w) and 20% (w/w), preferably 15%(w/w), more preferably 10% (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 preferably between 0.001% (w/w) and 1 % (w/w), preferably 0.1%(w/w),more preferably 0.01 % (w/w) Butylated Hydroxy Toluene in it by continuous mixing,
  • step j adjusting the pH of the mixture in said first API-vessel of step j to below 2 by using 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),
  • 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),
  • Clotrimazole added in a third API- vessel propylene glycol in an amount between 5% (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 10% (w/w) and dispersing Clotrimazole in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, said Clotrimazole added in an amount between 0.5% (w/w) and about 5% (w/w), preferably from about 0.5% (w/w) to about 3% (w/w) and more preferably about 1 % (w/w),
  • step h transferring the contents of said first API-vessel of step k 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 under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas preferably being nitrogen,
  • an acid selected from a group comprising acids such as HC1, H 2 S0 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) to form a mixture and dissolving the said biopolymer, Chitosan in an amount between about 0.01% and about 1% by weight, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.1% w/w,
  • an acid selected from a group comprising acids such as HC1, H 2 S0 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
  • step h transferring the contents of the biopolymer mixture of step q 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, cooling the contents of said mixing vessel of step h to 30 0 C to 37 0 C using circulation of cooled water from cooling tower at H 0 C to 15 0 C into the jacket of mixing vessel,
  • step i also serves 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 35%(w/w), more preferably 30% (w/w).
  • 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 Clobetasone Butyrate, one antifungal Clotrimazole 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 colour and viscous in consistency.
  • the pH of the product made using the process of the present invention is from about 3 to 6.
  • 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 5 ⁇
  • 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 3 ⁇ whereas that for the existing creams varies between 14 ⁇ to 19 ⁇ .
  • the minimum particle size observed was approx. 1.6 ⁇ whereas the minimum particle size observed for existing creams ranged between 5 ⁇ and 10 ⁇ .
  • 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.
  • the product of the present invention is efficacious due to the pronounced antibacterial activity of the regenerated Fusidic Acid, antifungal activity of the Clotrimazole , anti- inflammatory activity of the Clobetasone Butyrate which are 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 40% (w/w) under inert gas purging and under vacuum and converted to Fusidic Acid in- situ by adding an acid such as HC1, H 2 S0 4 , 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
  • 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.
  • Composition Fusidic Acid 2.0% (equivalent of Sodium Fusidate 2.08% w/w) +
  • PRODUCT Sodium Fusidate + Clobetasone Butyrate + Clotrimazole Cream
  • composition i) Sodium Fusidate IP equivalent to Fusidic Acid IP 2.0 ii) Clobetasone Butyrate BP 0.05 % iii) Clotrimazole IP 1.0 % Table 10: Description Test, Batch No. SBL-01
  • product of the present invention is quite stable at ambient conditions and also at elevated temperature & humid conditions of storage. This is a major advantage over the currently available Fusidic Acid creams.
  • the stability of the product is further ascertained by the shelf-life prediction of the formulation using arrhenius plot of degradation employing Nova-LIMS software.
  • the antimicrobial/antibacterial activity of the product is confirmed by the in vitro Zone of Inhibition studies for the product. The results obtained clearly indicate the statistical significance.
  • 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.
  • 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).
  • one benefit of the cream of the present invention is that it facilitates significantly faster epithelisation of the skin 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.
  • 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 & Clotrimazole against the organisms responsible for skin infections, pronounced antiinflammatory activity of the Clobetasone Butyrate against inflammations, the unique ability of actives to penetrate intact skin and wound healing & soothing properties of Chitosan.
  • the cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations.
  • the 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une crème dermaceutique contenant du butyrate de clobétasone en tant que corticostéroïde, un agent antifongique sous la forme de clotrimazole et un agent antibactérien sous la forme d'acide fusidique, ledit acide fusidique étant formé in situ à partir de fusidate de sodium en tant que produit brut de départ, et ledit fusidate de sodium étant converti en acide fusidique dans un environnement exempt d'oxygène. La crème de la présente invention possède une meilleure stabilité de conservation, et une taille de particule de principe actif plus fine, que les crèmes classiques contenant de l'acide fusidique. La crème de la présente invention contient de l'acide fusidique en tant que principe actif qui a été formé in situ à partir de fusidate de sodium, du butyrate de clobétasone et du clotrimazole, dans une base de crème qui comprend un conservateur, un acide, un co-solvant, des émulsifiants et un matériau cireux avec de l'eau, de préférence de l'eau purifiée.
PCT/IB2011/050713 2010-02-22 2011-02-22 Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère, du clotrimazole et de la clobétasone, et procédé de réalisation associé WO2011101825A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN55MU2010 2010-02-22
IN55/MUM/2010 2010-02-22

Publications (1)

Publication Number Publication Date
WO2011101825A1 true WO2011101825A1 (fr) 2011-08-25

Family

ID=44022999

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2011/050713 WO2011101825A1 (fr) 2010-02-22 2011-02-22 Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère, du clotrimazole et de la clobétasone, et procédé de réalisation associé

Country Status (1)

Country Link
WO (1) WO2011101825A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012017369A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du dipropionate de bétaméthasone, du clotrimazole et son procédé de fabrication
WO2012017381A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du dipropionate de béclométhasone, du clotrimazole et son procédé de fabrication

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4911932A (en) 1984-01-18 1990-03-27 Johnson And Johnson Consumer Products, Inc. Skin care compositions
US5461068A (en) 1993-09-29 1995-10-24 Corwood Laboratories, Inc. Imidazole derivative tincture and method of manufacture
US6001864A (en) 1995-06-07 1999-12-14 Taisho Pharmaceutical Co., Ltd. Antifungal agent
US20020009422A1 (en) 2000-07-24 2002-01-24 Hauan Diana L. Combination tanning and antifungal topical system for treating tinea versicolor
US20030206958A1 (en) * 2000-12-22 2003-11-06 Cattaneo Maurizio V. Chitosan biopolymer for the topical delivery of active agents
CN1931164A (zh) 2006-09-20 2007-03-21 西北农林科技大学 一种硝酸咪康唑纳米乳液药物及其制备方法
EP1787652A1 (fr) 2005-11-16 2007-05-23 Happy Foot Composition avec une propriété antifungale et son utilisation
WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
WO2009063493A2 (fr) 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde
WO2010122491A1 (fr) * 2009-04-20 2010-10-28 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde et un agent antifongique, et son procédé de fabrication
WO2010122475A1 (fr) * 2009-04-20 2010-10-28 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du clotrimazole et du mométasone, et son procédé de fabrication

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4911932A (en) 1984-01-18 1990-03-27 Johnson And Johnson Consumer Products, Inc. Skin care compositions
US5461068A (en) 1993-09-29 1995-10-24 Corwood Laboratories, Inc. Imidazole derivative tincture and method of manufacture
US6001864A (en) 1995-06-07 1999-12-14 Taisho Pharmaceutical Co., Ltd. Antifungal agent
US20020009422A1 (en) 2000-07-24 2002-01-24 Hauan Diana L. Combination tanning and antifungal topical system for treating tinea versicolor
US20030206958A1 (en) * 2000-12-22 2003-11-06 Cattaneo Maurizio V. Chitosan biopolymer for the topical delivery of active agents
EP1787652A1 (fr) 2005-11-16 2007-05-23 Happy Foot Composition avec une propriété antifungale et son utilisation
WO2007087806A1 (fr) 2006-02-02 2007-08-09 Leo Pharma A/S Composition topique comprenant une substance antibactérienne
CN1931164A (zh) 2006-09-20 2007-03-21 西北农林科技大学 一种硝酸咪康唑纳米乳液药物及其制备方法
WO2009063493A2 (fr) 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde
WO2010122491A1 (fr) * 2009-04-20 2010-10-28 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde et un agent antifongique, et son procédé de fabrication
WO2010122475A1 (fr) * 2009-04-20 2010-10-28 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du clotrimazole et du mométasone, et son procédé de fabrication

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABDA-BUNDESVEREINIGUNG DEUTSCHER APOTHEKERVERBÄNDE: "Rezepturhinweise: Fusidinsäure", PHARMAZEUTISCHES LABORATORIUM, GOVI-VERLAG PHARMAZEUTISCHER VERLAG GMBH, pages 1 - 4, XP002582786, Retrieved from the Internet <URL:http://www.pharmazeutische-zeitung.de/fileadmin/nrf/PDF/1-Fusidinsaeu re.pdf> [retrieved on 20100518] *
BOWEN P: "Particle Size Distribution Measurement from Millimeters to Nanometers and from Rods to Platelets", JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY, TAYLOR AND FRANCIS GROUP, NEW YORK, NY, US, vol. 23, no. 5, 1 January 2002 (2002-01-01), pages 631 - 662, XP009102859, ISSN: 0193-2691, DOI: DOI:10.1081/DIS-120015368 *
RAVI KUMAR M N V: "A review of chitin and chitosan applications", REACTIVE & FUNCTIONAL POLYMERS, ELSEVIER SCIENCE PUBLISHERS BV, NL LNKD- DOI:10.1016/S1381-5148(00)00038-9, vol. 46, no. 1, 1 November 2000 (2000-11-01), pages 1 - 27, XP004224437, ISSN: 1381-5148 *
SUCHKOVA G S ET AL: "SODIUM FUSIDATE INACTIVATION UNDER THE EFFECT OF OXYGEN AND MOISTURE", BIOSIS,, 1 January 1981 (1981-01-01), XP002583216 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012017369A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du dipropionate de bétaméthasone, du clotrimazole et son procédé de fabrication
WO2012017381A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du dipropionate de béclométhasone, du clotrimazole et son procédé de fabrication

Similar Documents

Publication Publication Date Title
WO2010109434A2 (fr) Crème médicinale antibactérienne, antifongique et contenant des stéroïdes, et procédé pour la préparer
US8895542B2 (en) Medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer and a process to make it
US20120035144A1 (en) Medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer, a corticosteroid, and an antifungal agent, and a process to make it.
WO2010122475A1 (fr) Crème médicinale à base d&#39;acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du clotrimazole et du mométasone, et son procédé de fabrication
WO2010109424A1 (fr) Crème médicinale antibactérienne renfermant des stéroïdes et du chitosane, et son procédé de production
WO2010109423A1 (fr) Crème médicinale antifongique à base de stéroïdes et comprenant du chitosane, et son procédé de fabrication
WO2011101826A1 (fr) Crème médicinale contenant de l&#39;acide fusidique fabriquée à l&#39;aide de fusidate de sodium et incorporant un biopolymère, de la terbinafine et de la dexaméthasone et son procédé de fabrication
WO2011101825A1 (fr) Crème médicinale d&#39;acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère, du clotrimazole et de la clobétasone, et procédé de réalisation associé
WO2012017381A1 (fr) Crème médicinale à base d&#39;acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du dipropionate de béclométhasone, du clotrimazole et son procédé de fabrication
WO2012017383A1 (fr) Crème médicinale à l&#39;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
WO2012023082A1 (fr) Crème médicamenteuse à base d&#39;acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d&#39;hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant
WO2011101831A2 (fr) Crème médicinale à base d&#39;acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du butyrate de clobétasone, et un antifongique - du chlorhydrate de terbinafine, et son procédé de fabrication
WO2012017372A1 (fr) Crème médicinale à l&#39;acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du propionate de clobétasol, et du nitrate de miconazole et procédé de fabrication de celle-ci
WO2011101824A1 (fr) Crème médicinale contenant de l&#39;acide fusidique fabriquée à l&#39;aide de fusidate de sodium et incorporant un biopolymère, du miconazole, de la dexaméthasone et son procédé de fabrication
WO2010122476A1 (fr) Crème médicinale à base d&#39;acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du miconazole et du mométasone, et son procédé de fabrication
WO2011101828A1 (fr) Crème médicinale d&#39;acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère et de la bétaméthasone, et procédé de réalisation associé
WO2010122493A1 (fr) Crème médicinale à base d&#39;acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde et un agent antifongique, et son procédé de fabrication
WO2010122494A1 (fr) Crème médicinale à base d&#39;acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et du mométasone, et son procédé de fabrication
US20120040927A1 (en) Medicinal antifungal and steroid cream incorporating a biopolymer and a process to make it.
WO2012023081A1 (fr) Crème médicinale contenant de l&#39;acide fusidique obtenue à l&#39;aide de fusidate de sodium, et contenant un biopolymère, de l&#39;acétate d&#39;hydrocortisone (corticostéroïde), et du nitrate d&#39;oxiconazole (agent antifongique), et son procédé de fabrication de cette crème
WO2012017371A1 (fr) Crème médicinale à base d&#39;acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du propionate de clobétasol, du chlorhydrate de terbinafine et son procédé de fabrication
WO2011101829A2 (fr) Crème médicinale à base d&#39;acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du dipropionate de bétaméthasone, et un antifongique - du nitrate de miconazole, et son procédé de fabrication
WO2012023079A1 (fr) Crème d&#39;acide fusidique médicinale utilisant du fusidate de sodium et incorporant un biopolymère, du propionate de fluticasone et du nitrate d&#39;oxiconazole, et son procédé de fabrication
WO2012049539A1 (fr) Crème médicinale à base d&#39;acide fusidique réalisée au moyen de fusidate de sodium, d&#39;un corticostéroïde et d&#39;un agent anti-fongique, et par incorporation d&#39;un biopolymère, procédé permettant de fabriquer une telle crème
WO2012049544A1 (fr) Crème médicinale à base d&#39;acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d&#39;un biopolymère, d&#39;un acétate d&#39;hydrocortisone en tant que corticostéroïde, et de clotrimazole en tant q&#39;agent antifongique, et procédé permettant de fabriquer une telle crème

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11712009

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11712009

Country of ref document: EP

Kind code of ref document: A1