WO2010109434A2 - Crème médicinale antibactérienne, antifongique et contenant des stéroïdes, et procédé pour la préparer - Google Patents

Crème médicinale antibactérienne, antifongique et contenant des stéroïdes, et procédé pour la préparer Download PDF

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Publication number
WO2010109434A2
WO2010109434A2 PCT/IB2010/051306 IB2010051306W WO2010109434A2 WO 2010109434 A2 WO2010109434 A2 WO 2010109434A2 IB 2010051306 W IB2010051306 W IB 2010051306W WO 2010109434 A2 WO2010109434 A2 WO 2010109434A2
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Prior art keywords
cream
skin
combination
chitosan
group
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PCT/IB2010/051306
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English (en)
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WO2010109434A3 (fr
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 WO2010109434A2 publication Critical patent/WO2010109434A2/fr
Publication of WO2010109434A3 publication Critical patent/WO2010109434A3/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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 bacterial skin infections, fungal skin infections & skin inflammation, along with skin rejuvenation. More particularly, the present invention relates to a pharmaceutical cream comprising a biopolymer, a corticosteroid, an antifungal and an antibacterial 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. Furthermore in many instances, it is difficult to ascertain whether the skin condition is due to a bacterial agent or a fungus.
  • Antibacterial or antifungal compositions are applied in turn and response monitored and treatment modified.
  • a major disadvantage of this approach is that treatment needs to be applied many times a day during the treatment period. This is greatly inconvenient and also not cost effective for a majority of human population, particularly in the under-developed countries.
  • 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 is enhanced.
  • biopolymers biologically active polymers
  • Patent applications EP2092935 and PCT/IN2008/000577 provide 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/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.
  • PCT/IN2008/000577 claims novelty over the existing prior art 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.
  • 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 bacterial skin infections, fungal skin infections & skin inflammation, along with skin rejuvenation containing a) a biopolymer in the form of Chitosan b) A combination of active ingredients used in treating bacterial skin infections, fungal skin infections & skin inflammations, c) A cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants, and d) Water.
  • the active ingredients namely chitosan, a corticosteroid, an antifungal agent and an antibacterial agent, are incorporated in cream base for use in treating bacterial skin infections, fungal skin infections and skin inflammation 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
  • 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.
  • 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 bacterial infections, 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 examples include, but are not limited to, Sodium Fusidate, Calcium Mupirocin, Gentamycin, Neomycin, Silver Sulphadiazine, Ciprofloxacin, Framycetin Sulphate, Quinidochlor, Povidone-Iodine, Sisomicin, Nitrofural 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.
  • Chitosan 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,
  • Halobetasol propionate Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate, etc.
  • 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.
  • Topical Anti-bacterials are intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance
  • MRSA Staphylococcus Aureus
  • Anti-bacterials act by inhibiting cell wall synthesis by combining with bacterial ribosomes and interfering with mRNA ribosome combination. In another hypothesis it is believed that anti-bacterials induce ribosomes to manufacture peptide chains with wrong amino acids, which ultimately destroy the bacterial cell.
  • Topical antibacterial agents include, but are not limited to, Sodium Fusidate, Calcium Mupirocin, Gentamycin, Neomycin, Silver Sulphadiazine, Ciprofloxacin, Framycetin Sulphate, Quinidochlor, Povidone-Iodine, Sisomicin, Nitrofural and the like.
  • 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 generally manifest with itching at the site.
  • Antifungals act by altering the permeability of the fungal membrane by inhibiting the synthesis of sterols.
  • Creams are semi- solid 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
  • An ointment is a viscous semisolid preparation containing APIs, which are used topically on a variety of body surfaces.
  • the vehicle of an ointment is known as ointment base.
  • the choice of a base depends upon the clinical indication of the ointment, and the different types of ointment bases normally used are:
  • Hydrocarbon bases e.g. hard paraffin, soft paraffin
  • Absorption bases e.g. wool fat, bees wax
  • the acidic scale of pH is from 1 to 7, and the base scale of pH is from 7 to 14.
  • Human skins pH value is some where between 4.5 and 6. Newborn baby's skin pH is closer to neutral (pH 7), but it quickly turns acidic. Nature has designed this probably to protect young children's skin, since acidity kills bacteria. As people become older, the skin becomes more and more neutral, and won't kill as many bacteria as before. This is why the skin gets weak and starts having problems.
  • the pH value goes beyond 6 when a person actually has a skin problem or skin disease. This shows that it is necessary to choose topicals that have a pH value close to that of skin of a young adult.
  • cream formulations are available in ionized state, whereas in case of ointments these are present in non-ionized state.
  • the cream formulations are the first choice of the formulators in design and development of topical dosage forms, as the cream formulations are cosmetically elegant, and also as the active compound is available in ionized state, and the drug can penetrate the skin layer fast which makes the formulation totally patient friendly.
  • the pH of the Chitosan Cream with steroids, antibacterial & antifungal agents 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 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, antifungal, anti inflammatory & wound healing activity of the active ingredients, which are available in ultra micro-size, colloidal form, which enhances skin penetration.
  • Topical antibacterial and antifungal agents have profound efficacy in primary & secondary bacterial & fungal skin infections of varied etiology due to their antibacterial/antifungal properties.
  • a drawback of the monotherapy with any topical antibacterial or antifungal has been the relatively slow onset of the effect of the anti-inflammatory effect compared to steroids.
  • Steroids provide much wanted rapid relief of the pruritus. Combining antibacterial & antifungal agents with topical corticosteroids is expected to provide fast relief because of the steroid effect and a lingering post treatment antibacterial & 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.
  • chitosan By employing steroids, antibacterial, antifungal & chitosan in a formulation, the properties of steroids, antibacterials, antifungals and 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.
  • 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 stabilising agents, cannot be used in combination with functional biopolymers such as chitosan.
  • 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. Generally 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.
  • 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. As we have discussed earlier, in a combination therapy, steroids provide relief against inflammation, antifungals provide relief against fungal infections and antibacterials provide relief against bacterial infections. However, 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.
  • 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: 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 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 fungal infection, bacterial infection and 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 1 A novel dermaceutical cream for topical treatment of bacterial skin infections, fungal skin infections & inflammations, and for related wound healing, wherein said cream comprises an antibacterial agent, 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.
  • Embodiment no. 1 A novel dermaceutical 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 wherein
  • said antibacterial agent is added in an amount between about 0.5% w/w and about 15% w/w, more preferably between 0.5 and 5.0% w/w; - said antifungal agent is added in an amount between about 0.5% w/w and about
  • said corticosteroid is added in an amount between about 0.001% (w/w) and about 5% (w/w), preferably between about 0.001 % and about 2.5% w/w, and,
  • said biopolymer is in the form of chitosan, added in an amount between about 0.01% and about 1% by weight, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.25% w/w said chitosan being US pharmacopeia conformant with regard to its functional excipient category and selected from any grades such as Long Chain, Medium Chain & Short Chain, and has a molecular weight in the range between 5OkDa to 5000 kDa, .
  • said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span- 80 and the like 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, from about 5% (w/w) to 30% (w/w); said co-solvent is selected
  • said preservative is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, or any combination thereof, from about 0.05% (w/w) to 0.5% (w/w); said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 35% (w/w) to 50% (w/w), more preferably 40% (w/w) to 43% (w/w), preferably purified water.
  • Embodiment no. 3 A novel cream as disclosed in the preferred embodiment no. 1 and the embodiment no. 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, from about
  • Embodiment no. 4 A novel cream as disclosed in the preferred embodiment no. 1 and the embodiments no. 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, from about 0.05% (w/w) to 5% (w/w).
  • an antioxidant which is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, from about 0.05% (w/w) to 5% (w/w).
  • Embodiment no. 5 A novel cream as disclosed in the preferred embodiment no. 1 and the embodiments no. 2 to 4, further comprising a chelating agent which is selected from a group comprising Disodium EDTA and the like, or any combination thereof, from about 0.05% (w/w) to 1% (w/w).
  • Embodiment no. 6 A novel cream as disclosed in the preferred embodiment no. 1 and the embodiments no. 2 to 4, further comprising a humectant which is selected from a group comprising Glycerin, Sorbitol, and the like, or any combination thereof, from about 5% (w/w) to 50% (w/w).
  • Embodiment no. 7 A process of making a cream is disclosed, said process comprising the steps of providing an antibacterial agent, 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 A process of making a cream as disclosed in the embodiment no. 7, wherein the ingredients further comprise any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.
  • Embodiment no. 9 A novel cream as disclosed in any of the foregoing embodiments, wherein chitosan has a molecular weight range of lkdal to 5000kdal.
  • Example-I Table ⁇ : Hydrocortisone Acetate + Sodium Fusidate + Miconazole Nitrate + Chitosan Cream
  • Example-II Table 7: Dexamethasone Acetate + Framycetin Sulphate + Clotrimazole + Chitosan Cream
  • APIs-stability experiments were carried out (see tables9- 17) 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, antifungals and antibacterials. 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 3 products have been presented. The % of the corticosteroid, antifungal and the antibacterial used in all examples are measured w/w with respect to the final product.
  • Measured parameter pH; Limits of measured parameter: 3-6 Method of measurement: Di ital H Meter
  • PRODUCT FRAMYCETIN SULPHATE + DEXAMETHASONE ACETATE + CLOTRIMAZOLE + CHITOSAN CREAM PACK: Aluminum Collapsible tube
  • Each gm contains: Framycetin Sulphate IP 1.0 % w/w; Dexamethasone Acetate IP 0.1 % w/w; Clotrimazole IP 1.0 % w/w
  • Measured parameter Assay (%); Method of measurement: HPLC Method Limits of measured parameter: 90-110
  • Measured parameter pH; Limits of measured parameter: 3-6 Method of measurement: Di ital H Meter
  • PRODUCT CALCIUM MUPIROCIN + FLUTICASONE PROPIONATE + MICONAZOLE NITRATE + CHITOSAN CREAM
  • Each gm contains: i) Calcium Mupirocin USP Equivalent to Mupirocin USP 2.0 % w/w; ii) Fluticasone Propionate IP 0.05 % w/w iii) Miconazole Nitrate IP 2.0 % w/w Table 15: Assay (%) Test, Batch No. MFM-Ol
  • Measured parameter pH; Limits of measured parameter: 3-6 Method of measurement: Di ital H Meter
  • 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 group 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.
  • the therapeutic efficacy of topically applied cream of the present invention is due to the pronounced antibacterial/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. It is evident from the foregoing discussion that the present invention offers the following advantages and unique aspects over the currently available dermaceutical compositions for bacterial/fungal infections & inflammations: 1.
  • 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 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.
  • a process for treating bacterial skin infections, fungal skin infections, skin inflammations, and wound healing involving contacting human skin with the above-disclosed composition.

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Abstract

La présente invention concerne une composition pour traiter des infections bactériennes cutanées, des infections fongiques cutanées et une inflammation cutanée, ainsi que pour rajeunir la peau. Plus particulièrement, la présente invention concerne une crème pharmaceutique comprenant un biopolymère, un corticostéroïde, un antifongique et un principe actif antibactérien. L'invention concerne une composition pour traiter des infections bactériennes cutanées, des infections fongiques cutanées et une inflammation cutanée, ainsi que pour rajeunir la peau, contenant a) un biopolymère sous forme de chitosane, b) une combinaison de principes actifs utilisés dans le traitement d'infections bactériennes cutanées, d'infections fongiques cutanées et d'inflammations cutanées, c) une base de crème contenant des émulsifiants primaires et secondaires, des matériaux cireux, des co-solvants, des acides, des conservateurs, des agents tampons, des antioxydants, des agents chélatants et des humidifiants, et d) de l'eau. Les principes actifs, à savoir le chitosane, un corticostéroïde, un agent antifongique et un agent antibactérien, sont incorporés dans une base de crème pour une utilisation dans le traitement d'infections bactériennes cutanées, d'infections fongiques cutanées et d'inflammation cutanée.
PCT/IB2010/051306 2009-03-25 2010-03-25 Crème médicinale antibactérienne, antifongique et contenant des stéroïdes, et procédé pour la préparer WO2010109434A2 (fr)

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Cited By (16)

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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
WO2010119367A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base d'acétate d'hydrocortisone et son procédé de préparation
WO2010119365A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de clotrimazole et de chitosane et son procédé de préparation
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
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
WO2012023079A1 (fr) * 2010-08-17 2012-02-23 Sulur Subramaniam Vanangamudi Crème d'acide fusidique médicinale utilisant du fusidate de sodium et incorporant un biopolymère, du propionate de fluticasone et du nitrate d'oxiconazole, et son procédé de fabrication
WO2012049541A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère et d'un corticostéroïde, et procédé permettant de fabriquer une telle crème
WO2012049544A1 (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, d'un acétate d'hydrocortisone en tant que corticostéroïde, et de clotrimazole en tant q'agent antifongique, et procédé permettant de fabriquer une telle crème
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
WO2012049542A1 (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, de mométasone en tant que corticostéroïde et de clotrimazole en tant qu'agent anti-fongique, et procédé permettant de fabriquer une telle crème
WO2014204718A1 (fr) * 2013-06-18 2014-12-24 Cmpd Licensing, Llc Compositions pharmaceutiques sèches pour l'administration topique de médicaments oraux, pour l'administration par voie nasale et le traitement des troubles auditifs
US9999604B2 (en) 2016-11-17 2018-06-19 Cmpd Licensing, Llc Compounded solutions of diclofenac and lidocaine and methods
US10525025B2 (en) 2016-11-17 2020-01-07 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11737975B2 (en) 2016-11-17 2023-08-29 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11826330B2 (en) 2016-11-17 2023-11-28 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11986448B2 (en) 2016-11-17 2024-05-21 Cmpd Licensing, Llc Compounded compositions and methods for treating pain

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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
WO2010119367A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base d'acétate d'hydrocortisone et son procédé de préparation
WO2010119365A2 (fr) * 2009-04-13 2010-10-21 Sulur Subramaniam Vanangamudi Crème médicale à base de clotrimazole et de chitosane et son procédé de préparation
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
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
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
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
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
WO2010119367A3 (fr) * 2009-04-13 2011-09-01 Sulur Subramaniam Vanangamudi Crème médicale à base d'acétate d'hydrocortisone et son procédé de préparation
WO2010119365A3 (fr) * 2009-04-13 2011-10-27 Sulur Subramaniam Vanangamudi Crème médicale à base de clotrimazole et de chitosane et son procédé de préparation
WO2012023079A1 (fr) * 2010-08-17 2012-02-23 Sulur Subramaniam Vanangamudi Crème d'acide fusidique médicinale utilisant du fusidate de sodium et incorporant un biopolymère, du propionate de fluticasone et du nitrate d'oxiconazole, et son procédé de fabrication
WO2012049541A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère et d'un corticostéroïde, et procédé permettant de fabriquer une telle crème
WO2012049544A1 (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, d'un acétate d'hydrocortisone en tant que corticostéroïde, et de clotrimazole en tant q'agent antifongique, et procédé permettant de fabriquer une telle crème
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
WO2012049542A1 (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, de mométasone en tant que corticostéroïde et de clotrimazole en tant qu'agent anti-fongique, et procédé permettant de fabriquer une telle crème
WO2014204718A1 (fr) * 2013-06-18 2014-12-24 Cmpd Licensing, Llc Compositions pharmaceutiques sèches pour l'administration topique de médicaments oraux, pour l'administration par voie nasale et le traitement des troubles auditifs
US9468601B2 (en) 2013-06-18 2016-10-18 Cmpd Licensing, Llc Dry pharmaceutical compositions for topical delivery of oral medications, nasal delivery and to treat ear disorders
US9925141B2 (en) 2013-06-18 2018-03-27 Cmpd Licensing Llc Dry pharmaceutical compositions for topical delivery of oral medications, nasal delivery and to treat ear disorders
US9999604B2 (en) 2016-11-17 2018-06-19 Cmpd Licensing, Llc Compounded solutions of diclofenac and lidocaine and methods
US10525025B2 (en) 2016-11-17 2020-01-07 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US10610503B2 (en) 2016-11-17 2020-04-07 Cmpd Licensing, Llc Compounded solutions of diclofenac and lidocaine and methods
US11737975B2 (en) 2016-11-17 2023-08-29 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11826330B2 (en) 2016-11-17 2023-11-28 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11986448B2 (en) 2016-11-17 2024-05-21 Cmpd Licensing, Llc Compounded compositions and methods for treating pain

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