WO2010109423A1 - Crème médicinale antifongique à base de stéroïdes et comprenant du chitosane, et son procédé de fabrication - Google Patents

Crème médicinale antifongique à base de stéroïdes et comprenant du chitosane, et son procédé de fabrication Download PDF

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WO2010109423A1
WO2010109423A1 PCT/IB2010/051286 IB2010051286W WO2010109423A1 WO 2010109423 A1 WO2010109423 A1 WO 2010109423A1 IB 2010051286 W IB2010051286 W IB 2010051286W WO 2010109423 A1 WO2010109423 A1 WO 2010109423A1
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Prior art keywords
cream
skin
chitosan
combination
group
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PCT/IB2010/051286
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
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Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
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Publication of WO2010109423A1 publication Critical patent/WO2010109423A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to a composition for treating fungal skin infections & skin inflammation, along with skin rejuvenation. More particularly, the present invention relates to a pharmaceutical cream comprising a biopolymer, a corticosteroid and an antifungal active ingredient.
  • 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.
  • compositions There are several treatments available to treat skin disorders caused by bacteria or fungii. 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 imflammation 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
  • 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 optimised to enhance and complement therapy outcomes at the drug design stage itself.
  • Patent applications EP2092935 provides an insight into the typical way steroids such as Mometasone Furoate are used towards topical prescription derma products, even though the product described in EP2092935 is an aerosolized formulation and not a cream.
  • EP2092935 relates to aerosolized formulations for the treatment of asthma that contain mometasone furoate and formoterol fumarate and processes for preparing same.
  • 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. Further 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/GB2007/004373, US 6,899,897, US 6,080,744, US 6,537,970 are examples of typical usage of antifungals such as clotrimazole in prescription derma products.
  • PCT/GB2007/004373 provides medicaments and methods for the treatment of infections caused or contributed to by multi-drug resistant Staphylococcus species using effective amount of Clotrimazole, and its derivatives. It claims novelty on the assertion that the pharmaceutical composition according to the invention possesses ability of inhibiting methicillin resistant Staphylococcus species.
  • the composition described in the invention by the applicant is used for oral administration, it can be used topically at the site of an infection, or intravenously.
  • the said composition can also be used for sterilizing or cleaning solutions to decontaminate furniture, floors, equipment including for example specialized hospital equipment and/or surgical equipment
  • US 6,899,897 discloses a biological dressing comprising a sticky film of gum resin - benzoin, a pharmacologically active agent - clotrimazole is left on the skin or mucous membrane after the volatile solvent - ethanol has evaporated.
  • the composition further may include penetration enhancer. It claims novelty over the assertion that the dressing disclosed herewith is a clean and inexpensive vehicle/carrier of topically applied medications increasing the convenience and effectiveness of the treatment and decreasing the necessary time for the treatment. This is apparently associated with less waste and lower cost and improved treatment.
  • the film formed is apparently extends retention on the skin since it is resistant to water and abrasion by clothing.
  • US 6,537,970 deals with a composition comprising clindamycin and clotrimazole used for the treatment of vaginal infection. It claims novelty over the conventional therapy because of the unique combination of various mycotoxins present in the composition and synergetic effect of the same. It is also claimed that the said composition can be used for the treatment of bacterial infection, fungal infection and mixed infection. The treatment can also be carried out either orally or topically.
  • US 6,080,744 deals with a topical composition for medical, veterinary or dental use containing active antimycotic ingredients like, clotrimazole, ketoconazole, miconazole, nystatin, tolnaftate, propionic acid, sodium propionate, undecelynic acid and zinc undecelynate in a natural base such that the composition is capable of defeating a wide range of fungi and can clear topical fungal infection. It claims advantage over the existing prior art on the bases that the ingredients used in the composition is blended in natural - cream base, also it is effective over a wide range of mycological illnesses and helps in speedy recovery.
  • active antimycotic ingredients like, clotrimazole, ketoconazole, miconazole, nystatin, tolnaftate, propionic acid, sodium propionate, undecelynic acid and zinc undecelynate
  • active antimycotic ingredients like, clotrimazole, ketoconazole, miconazole, n
  • cream base matrix as a functional element of the cream rather than a mere carrier for the main APIs
  • 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.
  • 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 composition for treating fungal skin infections & skin inflammation, along with skin rejuvenation containing
  • the active ingredients namely chitosan, a corticosteroid, and an anti fungal agent, are incorporated in cream base for use in treating fungal skin infections and skin inflammations due to allergy & itching, & wounds on human skin involving contacting human skin with the above identified composition.
  • the present invention provides a uni-dose multi-API formulation for topical skin treatment in the field of prescription medicaments.
  • the prescription medication is distinct in its use as compared with the so-called cosmeceuticals.
  • the cosmeceuticals are aimed towards beautification or betterment of a more-or-less intact skin or of a skin not suffering from a serious disorder.
  • prescription skin formulations are aimed to provide treatment for serious skin disorders resulting from infections and wounds.
  • 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 are enhanced.
  • biopolymers biologically active polymers
  • incorpora 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.
  • the active compounds which may be employed in the present invention are either acid or basic actives or their salts well known in the art of treatment of fungal infections, topical corticosteroids and a bio polymer for treating wounds and rejuvenating human skin involving contacting human skin with the above identified composition.
  • biopolymer examples include, but are not limited to chitosan and the like.
  • Suitable topical Corticosteroids include, but are not limited to, Betamethasone dipropionate, Beclomethasone dipropionate, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Diflorasone diacetate, Prednicarbate, Hydrocortisone acetate and the like.
  • topical antifungal agents include, but are not limited to, Miconazole, Oxiconazole, Clotrimazole, Econazole, Ketoconazole, Terbinafine, Naltifine, Ciclopirax, Tolnaftate, Amphotericin B, and Nystatin and the like.
  • This acid or basic active compounds or their salts require a base component to be used in the pharmaceutical composition that uses the compounds, since the compounds cannot, by themselves, be deposited directly on to human skin due to their harshness.
  • the base component usually contains primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, humectants and the like.
  • Chitosan is a linear polysaccharide composed of randomly distributed ⁇ -(l-4)- linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is known to have a number of commercial uses in agriculture and horticulture, water treatment, chemical industry, pharmaceuticals and biomedics.
  • Chitosan generally absorbs moisture from the atmosphere / environment and the amount absorbed depends upon the initial moisture content, temperature and relative humidity of the environment.
  • Chitosan due to its unique physical property accelerates wound healing and wound repair. It is positively charged and soluble in acidic to neutral solution. Chitosan is bioadhesive and readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces. Chitosan's properties allow it to rapidly clot blood, and it has recently gained approval in the USA for use in bandages and other hemostatic agents.
  • Chitosan is nonallergenic, and has natural anti-bacterial properties, further supporting its use. As a micro-film forming biomaterial, Chitosan helps in reducing the width of the wound, controls the oxygen permeability at the site, absorbs wound discharge and gets degraded by tissue enzymes which are very much required for healing at a faster rate. It also reduces the itching by providing a soothing effect. It also acts like a moisturizer. It is also useful in treatment of routine minor cuts and wounds, burns, keloids, diabetic ulcers and venous ulcers. Chitosan used in the present invention comes in various molecular weights ranging from lkdal to 5000kdal.
  • Chitosan is discussed in the USP 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 correspond 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.
  • 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 both the actives and chitosan.
  • the concentration of chitosan medium chain grade was carefully arrived based on several inhouse 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 acetate,
  • Topical corticosteroids are classified by their potency, ranging from weak to extremely potent. They include weak potent steroids, moderate potent steroids, potent steroids, very potent steroids and extremely potent steroids.
  • the high potency steroids include Betamethasone Dipropionate, Betamethasone Valerate, Diflorasone Diacetate, Clobetasol Propionate, Halobetasol Propionate, Desoximetasone, Diflorasone Diacetate, Fluocinonide, Mometasone Furoate, Triamcinolone Acetonide, etc.
  • Low potency topical steroids include Desonide, Fluocinolone acetate, Hydrocortisone acetate, etc.
  • Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.
  • Topical anti-fungals are intended to target skin for fungal infections caused by fungi such as Tinea pedis, Tinea cruris, and Tinea corporis.
  • Typical antifungal agents include drugs like Clotrimazole, Ketoconazole, Miconazole nitrate, Terbinafine Hydrochloride etc.
  • Fungal infections are generally manifested with itching at the site.
  • Antifungals act by altering the permeability of the fungal membrane by inhibiting the synthesis of sterols.
  • 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 (OAV) 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.
  • OAV oil-in-water
  • W/O water-in-oil creams
  • 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 skin's pH value is some where between 4.5 and 6. Newborn baby's skin pH is closer to neutral (pH 7), but it quickly turns acidic. Nature has designed this probably to protect young children's skin, since acidity kills bacteria. As people become older, the skin becomes more and more neutral, and won't kill as many bacteria as before. This is why the skin gets weak and starts having problems.
  • the pH value goes beyond 6 when a person actually has a skin problem or skin disease. This shows that it is necessary to choose topicals that have a pH value close to that of skin of a young adult. A slight shift towards the alkaline pH would provide a better environment for microorganisms to thrive.
  • 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 cream of the present invention with a functional biopolymer such as Chitosan, steroids, anti fungal agent is from about 3 to 6.
  • a functional biopolymer such as Chitosan, steroids, anti fungal agent
  • 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 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 antifungal/antiinflammatory & wound healing activity of the active ingredients, which are available in ultra micro-size, colloidal form, which enhances skin penetration.
  • Topical antifungal agents have profound efficacy in dermatoses of varied etiology due to its antifungal properties.
  • a drawback of the monotherapy with any topical antifungal has been the relatively slow onset of the anti- inflammatory effect compared to steroids.
  • Steroids provide much wanted rapid relief of the pruritus. Combining antifungal agents with topical corticosteroids is expected to provide fast relief because of the steroid effect and a lingering post treatment antifungal effect allowing for an overall reduction in intermittent use of the product.
  • topical steroids of high potency are used for a duration of one to two weeks; for low potency steroids the period may be three to four weeks.
  • antifungals & chitosan in a formulation, the properties of steroids, antifungals and chitosan are optimized. As chitosan is film forming, biocompatible, non-allergenic material it helps in protecting the skin by acting as a barrier. It further controls the superficial bleeding caused by scratching and also arrests the mobility of pathogens due to its cationic charge.
  • Chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments.
  • the combination of Chitosan with corticosteroid and Antifungal is unique and novel since this is not available commercially across the globe.
  • Another inventive aspect of the present invention is that the addition of a functional excipient in the cream base is not a straight forward process of mere addition.
  • the inventor has found that the compatibility of the functional excipient such as chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product.
  • the inventors have found that well known excipients such as Xanthan
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy Materials, 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. Since the dosage is for the treatment of ailing patients, these incompatibilities in the products cannot be accepted and these add more complication to the patients.
  • tablettes 1 to 5 are examples of products that do not form homogeneous creams, and produce non-homogeneous creams of the type illustrated in figure 1. Yet the proportions stated in these examples are some things 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.
  • steroids provide relief against inflammation and antifungals provide relief against fungal infections.
  • 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.
  • 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.
  • the value addition is an integrated sub-set of the following functional attributes of the biopolymer: - formulation 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
  • the unique innovative formulation of the present invention takes care of the skin conditions by treating them along with controlling the superficial bleeding at the site. It is well understood that if the superficial bleeding is left untreated, it will lead to secondary microbial infections.
  • the present invention advantageously provides a solution to this unmet need.
  • the present invention with its single-dose therapy reduces the overall treatment time of a serious skin disorder significantly.
  • a novel dermaceutical cream for topical treatment of fungal skin infections, inflammations, and for related wound healing wherein said cream comprises an antifungal agent, a corticosteroid, 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.
  • said antifungal agent is added in an amount between about 0.5% w/w and about 10% w/w, more preferably between 0.5 and 5.0% w/w; said corticosteroid is added in an amount between about 0.001 % (w/w) and about
  • biopolymer is in the form of chitosan, added in an amount between about
  • chitosan being 0.01% and about 1% by weight, preferably added in an amount 0.01% w/w to about 0.5% w/w and most preferably about 0.25% w/w, said chitosan being
  • 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 and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w); said acid is selected from a group comprising HCl, H 2 SCU, HNO 3 , Lactic acid and the like, or any combination thereof,
  • Embodiment no. 4 is a diagrammatic representation of Embodiment no. 4:
  • 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 0.05% (w/w) to 5% (w/w).
  • Embodiment no. 5 is a diagrammatic representation of Embodiment no. 5 :
  • 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 is a diagrammatic representation of Embodiment no. 6:
  • a humectant which is selected from a group comprising Glycerin, Sorbitol, and the like, or any combination thereof, and added in an amount between 5% (w/w) and 50% (w/w).
  • Embodiment no. 7 A process of making a cream is disclosed, said process comprising the steps of providing an antifungal agent, a corticosteroid, and a biopolymer in a 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, and mixing all the ingredients together to form a homogeneous cream.
  • Embodiment no. 8 is a diagrammatic representation of Embodiment no. 8:
  • Embodiment no. 9 is a diagrammatic representation of Embodiment no. 9:
  • Example-I Table 6: Betamethasone Valerate(0.12%) + Miconazole Nitrate (2%) + Chitosan (0.25%) Cream
  • Example-II Table 7: Clobetasol Propionate (0.05%) + Miconazole Nitrate (2%) + Chitosan (0.25%) Cream
  • APIs-stability experiments were carried out (see tables 8 - 13 ) using the product of the present invention. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the APIs over a period of time.
  • Each gram of product of the present invention used for the tests contained appropriate amount of steroids and antifungals.
  • the product used for the Stability Studies tests contained approximately 10% extra APIs (overages). It was packaged in an aluminium collapsible tube. Detailed test results for 2 products have been presented. The % of the corticosteroid, and the antifungal used in all examples are measured w/w with respect to the final product.
  • Each gm contains: i) Betamethasone Valerate IP 0.12 % w/w ii) Miconazole Nitrate IP 2.0 % w/w Table 8: Description Test, Batch No. BVM-Ol Measured parameter: Physical appearance
  • Measured parameter pH Limits of measured parameter: 3-6 Method of measurement: Digital pH Meter
  • Measured parameter Assay (%); Limits of measured parameter: 90-110; Method of measurement: HPLC Method
  • Each gm contains: i) Clobetasol Propionate - BP 0.05 % w/w ii) Miconazole Nitrate - IP 2.0 % w/w
  • 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 that achieved through application of a conventional cream.
  • 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 20-70% was observed for the blood clotting time using the product of the present invention.
  • topically applied cream of the present invention is due to the pronounced antifungal activity of the actives against the organisms responsible for skin infections, the antiallergic & anti-inflammatory property of corticosteroids, 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. 2.
  • the cream of the present invention incorporates a biopolymer without compromising the stability of the cream matrix. 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. 4.
  • novel cream of the present invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage - hence will go a long way in achieving these social objectives.
  • a process for treating fungal skin infections, skin inflammations, and wound healing involving contacting human skin with the above-disclosed composition.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pour le traitement des mycoses et des inflammations cutanées, et pour le rajeunissement de la peau. Plus particulièrement, cette invention concerne une crème pharmaceutique comprenant un biopolymère, un corticostéroïde et un ingrédient actif antifongique. La composition de l'invention pour le traitement des mycoses et des inflammations cutanées, et pour le rajeunissement de la peau contient : a) un biopolymère se présentant sous la forme du chitosane, b) une combinaison d'ingrédients actifs utilisée dans le traitement des mycoses et des inflammations cutanées, c) une base de crème comprenant des émulsifiants primaires et secondaires, des matières cireuses, des co-solvants, des acides, des conservateurs, des tampons, des anti-oxydants, des chélateurs et des humectants, et d) de l'eau. Les ingrédients actifs, à savoir le chitosane, un corticostéroïde et un agent antifongique, sont incorporés dans la crème de base destinée à être utilisée dans le traitement des mycoses et des inflammations cutanées.
PCT/IB2010/051286 2009-03-25 2010-03-24 Crème médicinale antifongique à base de stéroïdes et comprenant du chitosane, et son procédé de fabrication WO2010109423A1 (fr)

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IN710/MUM/2009 2009-03-25

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010119368A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de nitrate de miconazole et de chitosane et son procédé de préparation
WO2010119387A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de nitrate de miconazole, de propionate de fluticasone et de chitosane et son procédé de préparation
WO2010119366A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de propionate de fluticasone et de chitosane et son procédé de préparation
WO2016199000A1 (fr) * 2015-06-10 2016-12-15 Subramaniam Vanangamudi Sulur Crème médicale préparée en utilisant du propionate d'halobêtasol et en incorporant un biopolymère et procédé pour la préparer

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US6075056A (en) * 1997-10-03 2000-06-13 Penederm, Inc. Antifungal/steroid topical compositions
US20020146440A1 (en) * 2001-04-09 2002-10-10 Smith Sadie N. Mult-purpose skin balm including skin balm for psoriasis
US20030206958A1 (en) * 2000-12-22 2003-11-06 Cattaneo Maurizio V. Chitosan biopolymer for the topical delivery of active agents
EP1958638A1 (fr) * 2007-02-14 2008-08-20 Polichem S.A. Utilisation de chitosanes pour augmenter la vitesse de pousse des ongles

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US4946870A (en) * 1986-06-06 1990-08-07 Union Carbide Chemicals And Plastics Company Inc. Delivery systems for pharmaceutical or therapeutic actives
US6075056A (en) * 1997-10-03 2000-06-13 Penederm, Inc. Antifungal/steroid topical compositions
US20030206958A1 (en) * 2000-12-22 2003-11-06 Cattaneo Maurizio V. Chitosan biopolymer for the topical delivery of active agents
US20020146440A1 (en) * 2001-04-09 2002-10-10 Smith Sadie N. Mult-purpose skin balm including skin balm for psoriasis
EP1958638A1 (fr) * 2007-02-14 2008-08-20 Polichem S.A. Utilisation de chitosanes pour augmenter la vitesse de pousse des ongles

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010119368A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de nitrate de miconazole et de chitosane et son procédé de préparation
WO2010119387A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de nitrate de miconazole, de propionate de fluticasone et de chitosane et son procédé de préparation
WO2010119366A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de propionate de fluticasone et de chitosane et son procédé de préparation
WO2010119368A3 (fr) * 2009-04-13 2011-05-26 Sulur Subramaniam Vanangamudi Crème médicale à base de nitrate de miconazole et de chitosane et son procédé de préparation
WO2010119387A3 (fr) * 2009-04-13 2011-05-26 Sulur Subramaniam Vanangamudi Crème médicale à base de nitrate de miconazole, de propionate de fluticasone et de chitosane et son procédé de préparation
WO2010119366A3 (fr) * 2009-04-13 2011-05-26 Sulur Subramaniam Vanangamudi Crème médicale à base de propionate de fluticasone et de chitosane et son procédé de préparation
WO2016199000A1 (fr) * 2015-06-10 2016-12-15 Subramaniam Vanangamudi Sulur Crème médicale préparée en utilisant du propionate d'halobêtasol et en incorporant un biopolymère et procédé pour la préparer

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