WO2010122492A1 - Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et un corticostéroïde, et son procédé de fabrication - Google Patents

Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et un corticostéroïde, et son procédé de fabrication Download PDF

Info

Publication number
WO2010122492A1
WO2010122492A1 PCT/IB2010/051720 IB2010051720W WO2010122492A1 WO 2010122492 A1 WO2010122492 A1 WO 2010122492A1 IB 2010051720 W IB2010051720 W IB 2010051720W WO 2010122492 A1 WO2010122492 A1 WO 2010122492A1
Authority
WO
WIPO (PCT)
Prior art keywords
cream
amount
vessel
mixture
added
Prior art date
Application number
PCT/IB2010/051720
Other languages
English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kuppusamy Senthilkumar
Original Assignee
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kuppusamy Senthilkumar
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 filed Critical Sulur Subramaniam Vanangamudi
Publication of WO2010122492A1 publication Critical patent/WO2010122492A1/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
    • A61K31/56—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

Definitions

  • a medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer and a corticosteroid, and a process to make it
  • the present invention relates to primary and secondary bacterial skin infections, skin inflammations, and wounds including burn wounds.
  • a cream incorporating fusidic acid and a biopolymer in the form of chitosan, a corticosteroid in the form of Hydrocortisone acetate, 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 treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component.
  • APIs typically comprise an antibiotic/antibacterial such as Fusidic acid and the like.
  • Fusidic acid in fine powder form is used as source API.
  • the small particle size enhances its dermal contact by providing a large specific surface area and penetration, and provides a smooth feel on application to skin.
  • a serious shortcoming of the fine size of Fusidic acid particles is that it presents an enormous surface area for contact and reaction with molecular Oxygen during manufacture, handling, and processing of the cream. This has serious implications to its chemical stability and results in rapid reduction in potency of the API (Fusidic acid) in the final cream formulation.
  • Sodium Fusidate is known to have been used to make dermaceutical medicaments for topical application.
  • these are in the form of ointment rather than cream.
  • Drawbacks of ointments over creams are well known and it's generally preferable to use creams rather than ointments for topical application.
  • Stabilization of medicaments containing Fusidic acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include: • rep lacing Oxygen in pharmaceutical containers with inert gases such as Nitrogen,
  • 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.
  • 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 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.
  • 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 addition of biologically active polymers is a complex process in which the stability of the formulations could be compromised if the right biopolymer or naturally interacting formulation excipients or process parameters are not well thought through and optimized to enhance and complement therapy outcomes at the drug design stage itself.
  • US 5,961,997 disclose antipruritic composition
  • the composition preferably further comprises lidocaine and pramoxine and more preferably further comprise lidocaine, pramoxine and hydrocortisone acetate.
  • the composition relieves itching in patients suffering from a variety of dermatoses or pruritis.
  • US 5,961,997 claims novelty on the basis that the pharmaceutical composition contains effective concentrations of relevant chemicals, while helping in avoiding components which causes allergenic, irritating, acne-causing, comedogenic, irritant dermatitis, photosensitivity, or allergic contact sensitization and yet is aesthetically pleasing.
  • the antipruritic composition of the invention is oil-free, fragrance-free, lanolin-free and free of formaldehyde-releasing preservatives
  • US 6,352,691 disclose a therapeutic after-shave care lotion comprising Aloe Vera gel, Vitamin C (Ascorbic acid), Vitamin E (tocopherol), and Hydrocortisone Acetate.
  • US 6,352,691 claims novelty on the assertion that the produce will provides effective relief from discomforts associated with shaving, immediate relief of irritation symptoms upon application, initiates repair of damaged skin, shall eliminate the necessity for tedious long term treatment to relieve shaving symptoms and discomforts, help in combating pseudofolliculitis, shall decrease the intensity of the natural inflammatory response caused by shaving and moisturize and nourishes the damaged skin
  • US 200211 1298 relates to a moisturizing skin ointment composition consisting of polymyxin B Sulfate, bacitracin zinc, neomycin, hydrocortisone acetate and white petrolatum.
  • hydrocortisone present in the composition alleviates problems associated with itching of dry skin because the ointment penetrates the dermis almost immediately, the moisturizing properties of petrolatum allows the full benefit of the antibiotic products and hydrocortisone to remain on/in the skin through several washings thereby alleviating the need to reapply several times a day.
  • US 6,767,534 deals with a post hair removal skin lotion composition for use in reducing inflammation and irritation of skin immediately following hair removal by shaving, waxing, tweezing, electrolysis, or use of depilatory products, and for repairing skin damage resulting from these methods.
  • the composition comprises deionized water, Aloe vera gel, soybean oil, alpha lipoic acid, stearic acid, glyceryl monostearate, propylene glycol, lauramide DEA, vitamin E (tocopherol), hydrocortisone acetate, vitamin C (ascorbic acid), carbomer, hydroxymethylcellulose, methylparaben, propylparaben, and polyquaternium-15.
  • the composition claims novelty over the existing prior art on the assumption that the current composition is more suitable for the prevention and treatment of skin damage caused by shaving and other processes used for hair removal. It also claims to provide an effective treatment for pseudofolliculitis and to prevent long- term damage to the skin.
  • 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.
  • Another object of the present invention is to provide a medicinal cream that is effective in treatment of skin inflammations, bacterial skin infections, wounds including burn wounds.
  • Further objects of the present invention are to provide prescription medicinal formulations for topical skin treatment that: Can deliver skin healing or regeneration beyond the activity of Sodium Fusidate, & Hydrocortisone acetate such that the therapeutic outcomes of the main APIs are enhanced.
  • Figure 1 Non-homogeneous nature of creams containing chitosan with non- compatible excipient such as carbomer
  • Figure 2 Film formation using chitosan
  • the present invention is directed to a medicinal composition for treating skin inflammations, 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: a) a biopolymer in the form of Chitosan, b)Active Pharmaceutical Ingredients (APIs), in the form of fusidic acid that has been generated in situ from sodium fusidate & Hydrocortisone acetate, c) a cream base containing primary and secondary emulsif ⁇ ers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants, and d) water.
  • APIs Active Pharmaceutical Ingredients
  • the active ingredients namely chitosan, Hydrocortisone acetate and fusidic acid, are incorporated in cream base for use in treating skin inflammations, 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, & Hydrocortisone acetate 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 is made using Sodium Fusidate as starting API are not available.
  • Creams containing chitosan and fusidic acid which has been created in situ from sodium fusidate is not commercially available.
  • 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 Pharmacopoeia (BP). This is because the BP method does not differentiate between the intact API and the degraded form.
  • BP British Pharmacopoeia
  • a dermaceutical cream that uses Sodium Fusidate would exploit the benefit of the fact that Sodium Fusidate is more stable than Fusidic acid and it would also provide a cream formulation which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic acid.
  • 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 Hydrocortisone acetate as a steroid, showed good chemical stability and efficacy
  • the application discloses a process of making a cream containing a biopolymer - Chitosan, Hydrocortisone acetate as a steroid, 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 Fusidic acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen created using inert
  • 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, and Hydrocortisone acetate as a steroid, 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 & Hydrocortisone acetate 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 skin infections, and skin inflammations.
  • the active compounds Sodium Fusidate & Hydrocortisone acetate 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 Hydrocortisone acetate as a steroid, is added.
  • the cream of the present invention is used in the treatment of bacterial skin infections and inflammations.
  • 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.
  • the addition of biologically active polymers is a complex process in which the stability of the formulations could be compromised if the right biopolymer is not selected.
  • Incorporation of a functionally bio-active 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.
  • Suitable topical antibacterial agents include, but are not limited to Neomycin Sulphate, Sodium Fusidate, Calcium Mupirocin, Gentamycin, Silver Sulphadiazine, Ciprofloxacin, Framycetin Sulphate, Quinidochlor, Povidone-Iodine, Sisomicin, Nitrofural and the like.
  • Corticosteroids which may be used, include, but are not limited to Betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Dexamethasone Acetate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate and the like.
  • 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 1 kdal 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 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. 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,& Hydrocortisone acetate 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 corticosteroids are a powerful tool for treating skin diseases.
  • Corticosteroids include drugs such as Betamethasone dipropionate, Beclomethasone dipropionate, , Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate, etc.
  • drugs such as Betamethasone dipropionate, Beclomethasone dipropionate, , Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone
  • 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.
  • Hydrocortisone is a member of synthetic steroids used as anti-inflammatory and antipruritic agent. Hydrocortisone has the chemical name Pregn-4-ene-3,20-dione, 11,17,21- trihydroxy-, (H ⁇ )-. Its molecular formula is C21H30O5 and molecular weight 362.47. It is a white to off-white crystalline powder insoluble in water and slightly soluble in alcohol and in chloroform.
  • Hydrocortisone Acetate is a low potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses.
  • Hydrocortisone Acetate is a low potency synthetic corticosteroid with antiinflammatory, antipruritic, and vasoconstrictive properties. Hydrocortisone Acetate depresses formation, release, and activity of endogenous mediators of inflammation, including prostaglandins, kinins, histamine, liposomal enzymes, and complement system; modifies body's immune response. Hydrocortisone Acetate has been shown to have a wide range of inhibitory effects on multiple cell types (e.g. mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (e.g. histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti- inflammatory actions of corticosteroids may contribute to their efficacy in asthma and in skin lesions.
  • endogenous mediators of inflammation including prostaglandins, kinins, histamine, liposomal enzymes, and complement
  • Mechanism Of Action They enter cells where they combine with steroid receptors in cytoplasm and then the combination enters nucleus where it controls synthesis of protein, including enzymes that regulate vital cell activities over a wide range of metabolic functions including all aspects of inflammation formation of a protein that inhibits the enzyme phospho lipase A 2 which is needed to allow the supply of arachidonic acid.
  • Arachidonic acid is essential for the formation of inflammatory mediators. They also act on cell membranes to alter ion permeability and modify the production of neurohormones.
  • Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses.
  • topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.
  • Corticosteroids are bound to plasma proteins in varying degrees.
  • Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
  • Hydrocortisone Acetate is a low potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses.
  • Topical Anti-bacterials are intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance Staphylococcus Aureus (MRSA) etc.
  • Anti-bacterials act by inhibiting cell wall synthesis by combining with bacterial ribosomes and interfering with mRNA ribosome combination.
  • 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 C31 H47.
  • the chemical name is 3 ,11 , 16B-Trihydroxy 29- nor-8 , 9B, 13 , 14 ⁇ -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 2O 0 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.
  • 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 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.
  • 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
  • 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 topicals that have a pH value close to that of skin of a young adult.
  • 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,& Hydrocortisone acetate as a steroid, of the present invention is from about 3 to 6.
  • ointments that are commercially available are greasy and cosmetically non elegant.
  • the active compound in an ointment is in non- ionized form, the penetration of skin is slow.
  • the active drug penetrates the skin for the optimum bio -dermal efficacy.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in 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. Rationale for combining fusidic acid made from sodium fusidate, hydrocortisone acetate, and chitosan:
  • Topical Sodium Fusidate has profound efficacy in primary & secondary bacterial skin infections of varied etiology due to it's antibacterial properties.
  • a drawback of the monotherapy with any topical antibacterial has been the relatively slow onset of the effect.
  • fusidic acid along with Hydrocortisone acetate and chitosan in a formulation, the properties of antibacterial, 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.
  • the properties of Sodium Fusidate, Hydrocortisone acetate and chitosan's skin regenerative aspects are well exploited in the present invention and the maximum therapeutic benefit is passed on to the patient thereby aiding in faster healing. This ensures that the patient would benefit for the treatment of skin inflammations, wounds, burns with bacterial infections.
  • chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments.
  • 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.
  • 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.
  • Table 7 Fusidic Acid, Hydrocortisone acetate,.cream incorporating chitosan and gum arabic
  • Table 7 Fusidic Acid, Hydrocortisone acetate,.cream incorporating chitosan and gum arabic
  • the above products (tables 3 to 7) are examples of products that do not form homogeneous creams, but produce non-homogeneous creams of the type illustrated in figure 1. Yet the proportions stated in these examples are the ones that a person skilled in the art may use based currently available knowledge. Only after a thorough and extensive trials and errors would it be possible to arrive at right types and proportions of excipients.
  • Fusidic acid provides relief against bacterial infections
  • Hydrocortisone acetate provides relief against skin inflammations.
  • 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: formation of a micro-film on the skin surface accelerated blood clotting as compared to creams that do not contain film- forming biopolymers electrostatic immobilisation of surface microbes due to cationic charge of the biopolymer significant enhancement of the skin epithelisation or regeneration which is of particular help in skin damage caused by severe infections as well as wounds and burns
  • 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, inflammations and for related wound healing including burns wound, wherein said cream comprises an antibacterial agent, Sodium Fusidate, a corticosteroid Hydrocortisone acetate 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 novel dermaceutical 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
  • said hydrocortisone acetate is added from about 0.005% to about 2.5% by weight, preferably from about 0.05% to about 2.00% by weight, and most preferably from about 1% by weight, and
  • said chitosan is 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 0.25% w/w
  • 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 1% (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 Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400, Isopropyl Myristate and the like, or any combination thereof, and added in an amount from about 5% (w/w)
  • said preservative is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 0.5% (w/w); said water is added in the amount in the range of 10% (w/w) to 50% (w/w), preferably 15% (w/w) to 40% (w/w), more preferably 20% (w/w) to 35% (w/w), preferably purified water.
  • Embodiment no.3 A novel 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 1.00% (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) to 1.00% (w/w).
  • Embodiment no. 4 A novel 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).
  • 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).
  • Embodiment no. 5 A novel 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).
  • Embodiment no.6 A novel 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. 9 A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 7 and 8 wherein said oxygen-free environment comprises a gaseous environment formed of inert gas selected from a group comprising carbon dioxide, nitrogen, helium and the like.
  • Preferred embodiment 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: a. heating purified water in the range from 10% (w/w) to 50% (w/w), preferably 15% (w/w) to 40% (w/w), more preferably 20% (w/w) to 35% (w/w), in a water-phase vessel to 70 ° C to 80 ° C, b.
  • 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
  • a primary emulsifier preferably in the form of a non ionic surfactant, selected from a group comprising Cetostearyl alcohol, Cetomacrogo 1-1000, either singly or any combination thereof, wherein Cetostearyl alcohol is added in an amount between 1% (w/w) and 15% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), and Cetomacrogo 1-1000 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
  • cooling said emulsion to 45 0 C preferably by circulating cold water, preferably at 8 0 C to 15 0 C from a cooling tower in the jacket of the mixing vessel, h. in a first API-vessel adding a co-solvent, selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like, either singly or any combination thereof, in an amount between 5%
  • H 2 SO 4 HNO3, Lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount from about 0.005% (w/w) to
  • step g transferring the contents of said first API- vessel of step i to the mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • an acid selected from a group comprising acids such as HCl, H2So4, HNO3, 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 0.1% (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 1% w/w, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.25% w/w, n.
  • 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 0.25% w/w, n.
  • Embodiment No. 1 1 the co-solvent of step h of the embodiment no. 10 above also serves as a humectant.
  • an additional humectant may be added, in the step a of embodiment 7, selected from a group comprising Glycerin, Sorbitol,
  • Propylene glycol and the like either singly or any combination thereof, to form a from about 5% (w/w) to 40% (w/w), preferably 30% (w/w), more preferably 25% (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, to form a from about 0.01% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 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, to form a from about 0.01% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 0.1% (w/w).
  • a preservative selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof
  • 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 0.01% (w/w) to 2.00% (w/w), preferably 1.0% (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 0.01% (w/w) to 2.00% (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. 1 1 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 5% (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 5% (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: a. heating purified water in the range from 10% (w/w) to 50% (w/w), preferably 15% (w/w) to 40% (w/w), more preferably 20% (w/w) to 35% (w/w) in a water-phase vessel to 70 ° C to 80 ° C, b.
  • 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.
  • chelating agent is preferably Disodium edetate, added in an amount preferably between 0.01 and 1 %, more preferably 0.1%
  • buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount preferably 0.01% (w/w) to 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w)
  • humectant is preferably Propylene Glycol, added in an amount preferably 5% (w/w) to 60% (w/w), more preferably 25% (w/w), d.
  • step c 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 0 C, e. adding to an oil-phase vessel an emulsifying wax, preferably Cetostearyl alcohol, in an amount preferably between 1 and 15 %, more preferably 12.5 % and a waxy material, preferably white soft paraffin, in an amount preferably between 5 and 20 %, more preferably 12.5 %, and melting them by heating to 70 0 C to 80 0 C, f.
  • an emulsifying wax preferably Cetostearyl alcohol
  • a non ionic surfactant or emulsifier in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate 80 and 0.5% of Cetomacrogol 1000, and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 ° C to 80 ° C, g. transferring the contents of the water-phase vessel of step d and oil-phase vessel of step f to a mixing vessel under vacuum conditions in the range of minus 1000 to minus 300 mm of mercury and at 70 ° C to 80 ° C and mixing the mixture at 10 to 50 RPM to form an emulsion, h.
  • Toluene in it by continuous mixing j. subjecting the contents of said first API-vessel to inter gas flushing, said inert gas preferably being nitrogen and adding Sodium Fusidate to the mixture and dissolving it in the mixture, said sodium fusidate being added in an amount between 0.1% (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5% (w/w) and more preferably about
  • an acid selected from a group comprising acids such as HCL, H 2 S O 4 , HNO3 , lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount preferably between 0.005%
  • a biopolymer-mixing vessel adding an acid, selected from a group comprising acids such as HCl, H 2 S0 4 , HNO3, 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 0.1% (w/w), and purified water from about 0.1% (w/w) to 10%
  • an acid selected from a group comprising acids such as HCl, H 2 S0 4 , HNO3, 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 0.1% (w/w), and purified water from about 0.1% (w/w) to 10%
  • step 0 transferring the contents of the biopolymer mixture of step 0 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, q.
  • the co-solvent of 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, to form a from about 5% (w/w) to 40% (w/w), preferably 30% (w/w), more preferably 25% (w/w).
  • Embodiment no. 16 A method of treating primary & secondary bacterial skin infections and inflammations said method comprising applying of a cream containing at least one corticosteroid Hydrocortisone acetate, 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 emulsif ⁇ ers, waxy materials, co-solvents, acids, and water.
  • Embodiment no. 17 A method of treating primary & secondary bacterial 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.
  • Sodium Fusidate ointments that are commercially available are greasy and cosmetically non elegant. It is essential that the active drug penetrates the skin for the optimum bio -dermal efficacy.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in a finely dispersed form for the product to be being efficacious. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug.
  • the product of the present invention is efficacious due to the pronounced antibacterial activity of the regenerated Fusidic acid, antiinflammatory activity of the Hydrocortisone acetate 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, PolyEthyleneGlyco 1-400 & 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 HCl, H 2 SO 4 , HNO3, Lactic acid and the like from about
  • API-stability experiments were carried out (see tables 9 - 11 ) 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 oxydative 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, & 1% (w/w) Hydrocortisone acetate 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.
  • Example- Table 8 Composition :Fusidic acid 2% (equivalent of Sodium Fusidate 2.08% w/w) + Hydrocortisone acetate (l%w/w) + Chitosan 0.25% (w/w) Cream
  • PRODUCT SODIUM FUSIDATE + HYDROCORTISONE ACETATE CREAM
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 % ii) Hydrocortisone Acetate IP 1.0 %
  • 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 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 60 - 70% 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 activity of the Sodium Fusidate against the organisms responsible for skin infections, pronounced antiinflammatory activity of the Hydrocortisone acetate 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.
  • 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)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition destinée au traitement d'inflammations cutanées, d'infections cutanées d'origine bactérienne et de plaies apparentées, ainsi que d'autres plaies cutanées telles que celles résultant de brûlures. La crème de l'invention favorise également le rajeunissement de la peau par un processus d'épithélisation. La crème contient: a) un biopolymère sous forme de chitosane; b) des principes pharmaceutiques actifs (API) sous forme d'acide fusidique produit in situ à partir du fusidate de sodium et d'acétate d'hydrocortisone; c) une crème-base contenant un émulsifiant principal et un émulsifiant secondaire, des matières cireuses, des cosolvants, des acides, des conservateurs, des tampons, des antioxydants, des chélateurs et des agents humectants; et d) de l'eau. L'invention concerne en outre un procédé de fabrication de crème médicinale contenant de l'acide fusidique produit in situ à partir du fusidate de sodium, la conversion en acide fusidique étant réalisée dans un milieu exempt d'oxygène créé avec un gaz inerte. La crème de l'invention présente une durée de conservation supérieure et une granulométrie des API plus fine que celles des crèmes classiques contenant de l'acide fusidique.
PCT/IB2010/051720 2009-04-20 2010-04-20 Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et un corticostéroïde, et son procédé de fabrication WO2010122492A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1021MU2009 2009-04-20
IN1021/MUM/2009 2009-04-20

Publications (1)

Publication Number Publication Date
WO2010122492A1 true WO2010122492A1 (fr) 2010-10-28

Family

ID=42543031

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/051720 WO2010122492A1 (fr) 2009-04-20 2010-04-20 Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et un corticostéroïde, et son procédé de fabrication

Country Status (1)

Country Link
WO (1) WO2010122492A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012049541A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère et d'un corticostéroïde, et procédé permettant de fabriquer une telle crème

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030206958A1 (en) * 2000-12-22 2003-11-06 Cattaneo Maurizio V. Chitosan biopolymer for the topical delivery of active agents
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030206958A1 (en) * 2000-12-22 2003-11-06 Cattaneo Maurizio V. Chitosan biopolymer for the topical delivery of active agents
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
RAMSAY C A ET AL: "The treatment of atopic dermatitis with topical fusidic acid and hydrocortisone acetate", JEADV. JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL LNKD- DOI:10.1016/0926-9959(96)00032-3, vol. 7, no. SUPPL. I, 1 July 1996 (1996-07-01), pages S15 - S22, XP002582785, ISSN: 0926-9959, [retrieved on 20021011] *
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 *
SCHÖFER HELMUT ET AL: "Fusidic acid in dermatology: an updated review", EUROPEAN JOURNAL OF DERMATOLOGY, JOHN LIBBEY EUROTEXT, FR, vol. 20, no. 1, 1 January 2010 (2010-01-01), pages 6 - 15, XP009133480, ISSN: 1167-1122 *
SUCHKOVA G S ET AL: "SODIUM FUSIDATE INACTIVATION UNDER THE EFFECT OF OXYGEN AND MOISTURE", BIOSIS,, 1 January 1981 (1981-01-01), XP002583216 *
WILKINSON J D: "Fusidic acid in dermatology", BRITISH JOURNAL OF DERMATOLOGY, vol. 139, no. SUPPL. 53, December 1998 (1998-12-01), pages 37 - 40, XP002596714, ISSN: 0007-0963 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012049541A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère et d'un corticostéroïde, et procédé permettant de fabriquer une telle crème

Similar Documents

Publication Publication Date Title
US20120022019A1 (en) Medicinal Steroids Cream And A Process To Make It
US20120028943A1 (en) Medicinal Cream Made Using Fluticasone Propionate And Chitosan And A Process To Make The Same
WO2010119385A1 (fr) Crème médicinale à base d'acide fusidique produite au moyen de fusidate de sodium et incorporant un biopolymère et son procédé de fabrication
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.
US20120270835A1 (en) Medicinal Cream Made Using Hydrocortisone Acetate and A Process To Make The Same
WO2010122475A1 (fr) 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
WO2010109424A1 (fr) Crème médicinale antibactérienne renfermant des stéroïdes et du chitosane, et son procédé de production
WO2011101826A1 (fr) Crème médicinale contenant de l'acide fusidique fabriquée à l'aide de fusidate de sodium et incorporant un biopolymère, de la terbinafine et de la dexaméthasone et son procédé de fabrication
US20120040927A1 (en) Medicinal antifungal and steroid cream incorporating a biopolymer and a process to make it.
WO2010122493A1 (fr) 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
WO2012023082A1 (fr) Crème médicamenteuse à base d'acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d'hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant
WO2011101825A1 (fr) 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
WO2012017381A1 (fr) 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
WO2010122494A1 (fr) Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et du mométasone, et son procédé de fabrication
WO2011101831A2 (fr) Crème médicinale à base d'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
WO2012017383A1 (fr) 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
WO2010122476A1 (fr) Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, du miconazole et du mométasone, et son procédé de fabrication
WO2012017372A1 (fr) Crème médicinale à l'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'acide fusidique fabriquée à l'aide de fusidate de sodium et incorporant un biopolymère, du miconazole, de la dexaméthasone et son procédé de fabrication
WO2011101828A1 (fr) Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère et de la bétaméthasone, et procédé de réalisation associé
WO2010122492A1 (fr) Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère et un corticostéroïde, et son procédé de fabrication
WO2012049541A1 (fr) Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère et d'un corticostéroïde, et procédé permettant de fabriquer une telle crème
WO2012049544A1 (fr) Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère, d'un acétate d'hydrocortisone en tant que corticostéroïde, et de clotrimazole en tant q'agent antifongique, et procédé permettant de fabriquer une telle crème
WO2012023081A1 (fr) Crème médicinale contenant de l'acide fusidique obtenue à l'aide de fusidate de sodium, et contenant un biopolymère, de l'acétate d'hydrocortisone (corticostéroïde), et du nitrate d'oxiconazole (agent antifongique), et son procédé de fabrication de cette crème
WO2011101829A2 (fr) Crème médicinale à base d'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

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: 10719093

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: 10719093

Country of ref document: EP

Kind code of ref document: A1