WO2010122494A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2010122494A1
WO2010122494A1 PCT/IB2010/051722 IB2010051722W WO2010122494A1 WO 2010122494 A1 WO2010122494 A1 WO 2010122494A1 IB 2010051722 W IB2010051722 W IB 2010051722W WO 2010122494 A1 WO2010122494 A1 WO 2010122494A1
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Prior art keywords
cream
amount
vessel
mixture
added
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PCT/IB2010/051722
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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
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Application filed by Sulur Subramaniam Vanangamudi, Madhavan Srinivasan, Neelakandan Narayanan Chulliel, Kuppusamy Senthilkumar filed Critical Sulur Subramaniam Vanangamudi
Publication of WO2010122494A1 publication Critical patent/WO2010122494A1/fr

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    • 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
    • A61K31/575—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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 and wounds including burn wounds.
  • a cream incorporating fusidic acid and a biopolymer in the form of chitosan, and a corticosteroid in the form of Mometasone Furoate 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: • replacing Oxygen in pharmaceutical containers with inert gases such as
  • 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.
  • 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 Mometasone furoate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin.
  • topical pharmaceutical compositions comprising a combination of fusidic acid and corticosteroid such as Mometasone furoate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection.
  • WO 2009063493 also apparently surprisingly found that antibiotic action of fusidic acid and the anti-inflammatory effect of a corticosteroid such as Halobetasol, both play important roles in prevention of secondary bacterial infections in patients with non-infected dermatoses and in treatment of infected steroid responsive dermatoses such as secondarily infected dermatoses including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • infected steroid responsive dermatoses such as secondarily infected dermatitis including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • CCD corticosteroid responsive dermatoses
  • the invention disclosed in WO 2009063493 relates to a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • topical pharmaceutical compositions comprising a combination of fusidic acid and corticosteroid such as Mometasone furoate 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 Mometasone furoate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection
  • EP2092935 relates to aerosolized formulations for the treatment of asthma that contain mometasone furoate and formoterol fumarate and processes for preparing same.
  • the formulation is substantially free of CFCs and also has utility in metered dose pressurized inhalers (MDI's).
  • MDI's metered dose pressurized inhalers
  • the formulation comprises effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1, 1,2,3,3,3, -heptaflouopropane , additionally it consist of dry powder surfactant.
  • EP2092935 claims novelty on the assertion that the aerosol suspension formulation is non-toxic, substantially free of CFCs, has improved stability, it is also easily manufacturable and is substantially free of a carrier and excipients.
  • the applicant has also disclosed a process for the production of the formulation wherein dry powder of the active agents and the surfactant is mixed together and filled into a metered dose inhaler canister, followed by crimping the canister with a metering valve, and filling it with nonchlorofluorocarbon propellant.
  • PCT/IN2008/000577 provides a treatment of inflammatory dermatoses associated with secondary bacterial infections using a combination therapy of a topical antibiotic and a topical steroid.
  • the composition comprises a combination of fusidic acid and corticosteroid mometasone furoate.
  • the application further discloses yet another formulation comprising fusidic acid and corticosteroid such as halobetasol propionate useful in treatment of infected steroid responsive dermatoses.
  • PCT/IN2008/000577 claims novelty on the assertion that the applicant had found a combination which is very effective for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • the applicant has disclosed 2 formulations of which the first formulation consists of a) 1% w/w - 5%w/w of fusidic acid; b) 0.05% w/w to 2%w/w of Mometasone furoate; and c) a pharmaceutically acceptable carrier and the second formulation comprises a) 1 % w/w - 5% w/w of fusidic acid; and b) 0.01% to 2% w/w of Halobetasol propionate; and c) a pharmaceutically acceptable carrier.
  • the first composition is effective in the treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, allergic contact dermatitis, psoriasis and atopic dermatitis with secondary bacterial infections of skin while the second is useful for the treatment of 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 eczema's 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.
  • the formulation is available in the forms include hydrous or anhydrous semisolids such as creams, gels, ointments and lotions.
  • WO2008126076 discloses a topical cream composition comprising low dose mometasone furoate for the treatment of corticosteroid responsive dermatoses.
  • the composition can be safely applied over large surface areas of the skin (including areas with wrinkles and/or hair), and can be used for extended periods of time (e.g., greater than 3 weeks) without any adverse effects.
  • the cream composition of the present invention is apparently safe for the use of babies and infants under 2 years old.
  • 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.
  • 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 & Mometasone furoate c) a cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants. d) water.
  • APIs Active Pharmaceutical Ingredients
  • the active ingredients namely chitosan, Mometasone furoate, 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, & Mometasone furoate 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 chitosan and fusidic acid which has been created in situ from sodium fusidate is not commercially available.
  • Fusidate has been used in dermaceutical applications, it has not been possible to make creams that use Sodium Fusidate. This is because of the inherent alkalinity of Sodium Fusidate (pH 7.5 to 9), which means it cannot be used in a cream form therefore all products manufactured using Sodium Fusidate as starting material are ointments.
  • a dermaceutical cream that uses Sodium Fusidate that uses Sodium Fusidate
  • 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 application discloses a process of making a cream containing a biopolymer - Chitosan, Mometasone Furoate 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 gas, preferably nitrogen.
  • the cream made using the process of the present invention contains Fusidic acid as the API that has been formed in situ from Sodium Fusidate, a biopolymer - Chitosan, and Mometasone Furoate 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, & Mometasone Furoate which may be employed in the process of the present invention as starting APIs are well known in the art of treating bacterial primary & secondary bacterial skin infections, and skin inflammations.
  • the active compounds Sodium Fusidate & Mometasone Furoate 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 Mometasone Furoate 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.
  • 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 is regarded as a non-toxic and non-irritant material. It is biocompatible with both healthy and infected skin and has been shown to be biodegradable as it is derived from shrimps, squids and crabs. 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.
  • 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, & Mometasone Furoate 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.
  • Mometasone Furoate is a synthetic corticosteroid with anti- inflammatory activity Chemically, Mometasone Furoate is 9 ⁇ ,21 -dichloro- 11 ⁇ , 17-dihydroxy- 16 ⁇ - methylpregna-l,4-diene-3,20-dione 17-(2-furoate), with the empirical formula C27H30CI2O6, and a molecular weight of 521.4.
  • Mometasone Furoate is a white to off-white powder practically insoluble in water, slightly soluble in octanol, and moderately soluble in ethyl alcohol. It is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses.
  • Mometasone Furoate is a medium-potency synthetic corticosteroid with antiinflammatory, antipruritic, and vasoconstrictive properties.
  • Mometasone Furoate have 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.
  • mediators e.g. histamine, eicosanoids, leukotrienes, and cytokines
  • Unbound Mometasone Furoate cross cell membranes and bind with high affinity to specific cytoplasmic receptors. Inflammation is decreased by diminishing the release of leukocytic acid hydrolases, prevention of macrophage accumulation at inflamed sites, interference with leukocyte adhesion to the capillary wall, reduction of capillary membrane permeability, reduction of complement components, inhibition of histamine and kinin release, and interference with the formation of scar tissue.
  • the antiinflammatory actions of Mometasone Furoate are thought to involve phosp ho lipase A 2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.
  • Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone.
  • Mometasone Furoate is primarily and extensively metabolized in the liver by the CYP3A4 isozyme to multiple metabolites. Elimination: Terminal 1 1 A of Mometasone Furoate is about 5 h. Excretion up to 7 days is primarily in the feces (74%) and, to a lesser amount, in the
  • Mometasone Furoate is a medium 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 C31H47.
  • 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 20 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.
  • cream formulations are available as creams. Active compounds in cream formulations are available in ionized state, whereas in case of ointments these are present in non -ionized state.
  • the cream formulations are the first choice of the formulators in design and development of topical dosage forms, as the cream formulations are cosmetically elegant, and also as the active compound is available in ionized state, and the drug can penetrate the skin layer fast which makes the formulation totally patient friendly.
  • the pH of the Chitosan Cream with antibacterial agent - Sodium Fusidate & Mometasone Furoate 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.
  • fusidic acid along with mometasone furoate & 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.
  • 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
  • Polymers are used as gelling agents, suspending agents, viscosity builders, release modifiers, diluents, etc.
  • Surfactants are used as wetting agents, emulsifiers, solubilising agents release enhancers, etc.
  • polymers & surfactants may or may not possess ionic charge. They may be anionic or cationic or non-ionic in nature. If anionic excipients are included in the formulation they interact with cationic formulation excipients and produce products which are not homogenous, aesthetically not appealing and give rise to unwanted by products, possible allergens, impurities, toxic substances etc due to incompatibility.
  • the inventors carefully screened the excipients which included the polymers and surfactants for developing a formulation. A thorough study was performed after screening the short listed excipients. The possible interactions between the excipients were given much focus and detailed experiments were done.
  • Table 4 _Fusidic acid, Mometasone furoate cream incorporating chitosan and acr lic acid ol mer
  • Table 5 Fusidic acid,_Mometasone furoate.cream incorporating chitosan & sodium lauryl sulphate
  • Table 7 Fusidic Acid,_Mometasone furoate.acid cream incorporating chitosan and gum arabic
  • Fusidic acid provides relief against bacterial infections
  • Mometasone furoate 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 inventive efforts involved in developing the platform technology covered by incorporation of a functional biopolymer in prescription dermaceutical products is: in identification of the complementary therapeutic value that such incorporation delivers in identification of issues related to physio-chemical stability of the product resulting from the incorporation of the biopolymer in providing a single dose format where the bacterial skin infection, & inflammation has been identified
  • 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, inflammations and for related wound healing including burns wound, wherein said cream comprises an antibacterial agent, Sodium Fusidate, a corticosteroid Mometasone furoate 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 emulsif ⁇ er, 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 mometasone furoate is added from about 0.005% to about 2.5% by weight, preferably from about 0.05% to about 1.00% by weight, and most preferably from about 0.1% by weight
  • - 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
  • 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).
  • 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).
  • 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).
  • 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%
  • Embodiment no. 7 A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos. 1 to 6 wherein sodium fusidate is converted in-situ under totally oxygen free environment by slow addition of an acid, into
  • Fusidic acid of a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic acid regenerates into an extremely finely dispersed form when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic acid in the final cream; all operations of converting sodium fusidate into Fusidic acid carried out preferably in an environment free of atmospheric oxygen.
  • Embodiment no. 8 A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 1 to 7 wherein said conversion of Sodium Fusidate into said Fusidic acid and the following formation of said Fusidic acid in a finely dispersed form in the final cream base take place in an oxygen-free environment.
  • Embodiment no. 9 A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments no. 7 and 8 wherein said oxygen-free environment comprises a gaseous environment formed of inert gas selected from a group comprising carbon dioxide, nitrogen, helium and the like.
  • Preferred embodiment 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 5% (w/w) to 40% (w/w), preferably 5% (w/w) to 30% (w/w), more preferably 7% (w/w) to 15% (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 0.3% (w/w), more preferably 0.2% (w/w), more preferably Benzoic acid, c. mixing the mixture using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70 ° C to 80 ° C, d.
  • 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, c. mixing
  • waxy materials selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, either singly or any combination thereof, in an amount between 5% (w/w) and 20% (w/w), preferably 15% (w/w), more preferablyl2.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 ° C to 80 ° C, e.
  • 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%
  • Cetomacrogo 1-1000 is added in an amount between 0.1% (w/w) and 5% (w/w), preferably 1.5% (w/w), more preferably 1% (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80, in an amount between 1 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 0 C to 80 ° C, f.
  • 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 0 C to 80 ° C, f.
  • a mixing vessel transferring under vacuum in the range of minus 1000 to minus 300 mm of mercury and at 70 0 C to 80 0 C the contents of the water-phase and oil- phase vessels to a mixing vessel and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM to form an emulsion, g. 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%
  • 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%
  • an acid selected from a group comprising acids such as HCl
  • 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 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.25% (w/w), j. adding in a second API-vessel propylene glycol in an amount between 1% (w/w) to 40% (w/w), preferably 35% (w/w), more preferably 25% (w/w), heating to 6O 0 C and dissolving Mometasone Furoate in it by continuous mixing, k.
  • a biopolymer-mixing vessel adding 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.
  • an acid selected from a group comprising acids such as HCl, H2So4, HNO3, Lactic acid and the like, either singly or any combination thereof,
  • step g transferring the contents of the biopolymer-mixing vessel of step m 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, o. cooling the contents of the mixing vessel of step g to 30 0 C to 37 0 C using circulation of cooled water from a cooling tower at 8 0 C to 15 0 C into the jacket of mixing vessel, p. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step o to a storage container.
  • Embodiment No. 11 In an embodiment of the present invention, the co-solvent of step h of the embodiment no. 10 above also serves as a humectant. However, in another embodiment of the invention, 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 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).
  • 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 0.01% (w/w) to 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w).
  • a buffering agent selected from 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 5% (w/w) to 40% (w/w), preferably 5% (w/w) to 30% (w/w), more preferably 7% (w/w) to 15% (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. adding to said oil phase vessel a non ionic surfactant or emulsifier, in an amount preferably between 1 and 5 %, more preferably 2 % of Polysorbate
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400adding propylene glycol, or any mixture thereof, in an amount preferably between 5% (w/w) and 30% (w/w), more preferably 25% (w/w), and optionally adding and dissolving an antioxidant, selected from a group comprising
  • H2SO4 , HNO3 , 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), 1. adding in a second API- vessel propylene glycol in an amount between 1%
  • 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% (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 0.25% w/w, p.
  • 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% (
  • step i 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. cooling the contents of said mixing vessel of step h to 30 ° C to 37 ° C using circulation of cooled water from cooling tower at 8 ° C to 15 ° C into the jacket of mixing vessel, r. turning off the agitator and the homogenizer and removing the mixture of the mixing vessel of step q to a storage container.
  • 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 Mometasone furoate, 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 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, anti inflammatory activity of the Mometasone furoate 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, & 0.1% (w/w) Mometasone furoate 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 2.0% (equivalent of Sodium Fusidate 2.08% w/w) + Mometasone Furoate 0.1% w/w + Chitosan 0.25% w/w Cream
  • PRODUCT SODIUM FUSIDATE + MOMETASONE FUROATE CREAM PACK: Aluminum Collapsible tube
  • Each gm contains: i) Sodium Fusidate BP equivalent to Fusidic Acid BP 2.0 %, and ii) Mometasone Furoate USP 0.1 %
  • Measured parameter pH; Limits of measured parameter: 3-6
  • product of the present invention is quite stable at ambient conditions and also at elevated temperature & humid conditions of storage. 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.
  • table 8 A comparison of table 8 with tables 3 to 7 will illustrate the difference in the products that would be based on the conventional drug design and the innovative approach adopted in the present invention. .
  • 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 55-65% 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 Mometasone furoate 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.

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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 du furoate de mométasone; 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 la crème médicinale contenant de l'acide fusidique produit in situ à partir du fusidate de sodium utilisé comme matière première de départ, 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.
PCT/IB2010/051722 2009-04-20 2010-04-20 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 WO2010122494A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035375A1 (fr) * 2010-09-14 2012-03-22 Sulur Subramaniam Vanangamudi Nouvelle crème dermaceutique fabriquée à l'aide de fusidate de sodium et de furoate de mométasone, son procédé de fabrication et procédé de traitement l'utilisant
WO2012049543A1 (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

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