WO2012023082A1 - Crème médicamenteuse à base d'acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d'hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant - Google Patents

Crème médicamenteuse à base d'acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d'hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant Download PDF

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WO2012023082A1
WO2012023082A1 PCT/IB2011/053407 IB2011053407W WO2012023082A1 WO 2012023082 A1 WO2012023082 A1 WO 2012023082A1 IB 2011053407 W IB2011053407 W IB 2011053407W WO 2012023082 A1 WO2012023082 A1 WO 2012023082A1
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amount
cream
vessel
fusidic acid
added
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PCT/IB2011/053407
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Sankar Haridas
Original Assignee
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Sankar Haridas
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Application filed by Sulur Subramaniam Vanangamudi, Madhavan Srinivasan, Neelakandan Narayanan Chulliel, Sankar Haridas filed Critical Sulur Subramaniam Vanangamudi
Publication of WO2012023082A1 publication Critical patent/WO2012023082A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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

Definitions

  • the present invention relates to primary and secondary bacterial skin infections, skin inflammations, fungal skin infections and wounds including burn wounds.
  • a cream incorporating Fusidic Acid and a biopolymer in the form of Chitosan, a corticosteroid (such as Hydrocortisone acetate), and an antifungal agent (such as Terbinafine Hydrochloride), and the process of making it and using it in treating these infections, inflammations and wounds.
  • Fusidic Acid in the said cream has been created in situ using Sodium Fusidate as the starting Active Pharmaceutical Ingredient (API).
  • Topical and systemic bacterial infection treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component.
  • the APIs typically comprise an antibiotic/antibacterial such as Fusidic Acid, corticosteroid such as Hydrocortisone acetate, an antifungal agent such as Terbinafine Hydrochloride, a biopolymer such as Chitosan and the like.
  • Fusidic Acid creams 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.
  • Antibacterial/antifungal/steroidal 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 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 are 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.
  • biologically active polymers the so-called biopolymers
  • biopolymers biologically active polymers
  • 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 propionate provides much wanted rapid relief of the pruritus. Therapy with only is Mometasone propionate recommended for severe eczematic eruptions to provide instant relief to patients from itching and burning.
  • compositions comprising a combination of Fusidic Acid and corticosteroid such as Mometasone propionate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection.
  • the inventors of WO 2009063493 apparently surprisingly found that antibiotic action of Fusidic Acid and the anti-inflammatory effect of corticosteroid, such as Mometasone propionate both play important roles in reducing S.
  • WO 2009063493 also apparently surprisingly found that antibiotic action of Fusidic Acid and the antiinflammatory effect of a corticosteroid such as Mometasone propionate, 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.
  • a corticosteroid such as Mometasone propionate
  • 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.
  • the present invention relates to topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Mometasone propionate 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
  • EP1787652 relates to a composition with antifungal properties, against foot fungus.
  • the invention comprises the use of Melaleuca Alternifolia essential oil in combination with at least one component chosen from the group consisting of Terbinafine Hydrochloride, benzoic acid and sodium benzoate.
  • EP1787652 claims novelty on the assertion that the composition according to this invention has an improved antifungal effect and can be used for both preventive and therapeutic applications.
  • the composition comprises 2 to 8% by weight of Melaleuca Alternifolia essential oil and 0.5 to 1% by weight of a benzoate compound relative to the total composition. At this concentration an optimum level is achieved between antifungal activity and economic use of Melaleuca Alternifolia essential oil and benzoate compound.
  • US 20020009422 relates to a tanning product that treat tinea versicolor and promote tanning.
  • the product includes the active ingredients tolnaftate and Terbinafine Hydrochloride.
  • US 20020009422 claims novelty on the assertion that the product manages to overcome few problem faced by conventionally used therapeutic like unpleasant smell, dry and rough skin caused by the conventional treatment.
  • the applicant has devices a system for treating tinea versicolor which consists of three systems; a body wash having a mixture of a shampoo, an exfoliate and tolnaftate cream; a tanning lotion and anti-fungal topical having mixture of a lotion, a tanning bronzer and a Terbinafine Hydrochloride; and body spray having a mixture of a liquid tan enhancing body spray and tolnaftate cream.
  • US 4911932 describe a skin care composition having improved effectiveness in preventing and treating acute inflammatory skin conditions.
  • the composition consists of Terbinafine Hydrochloride and zinc oxide.
  • US 4911932 claims novelty on the assertion that the formulation is an improved skin care compositions, which can be used for the prevention and treatment of diaper rash.
  • CN 1931164 deals with the nanometer Terbinafine Hydrochloride emulsion medicine, which consists of surfactant, oil, Terbinafine Hydrochloride and distilled water.
  • US 5,461,068 pertains to improved formulations for topical treatment of fungal diseases, and more particularly to solutions of imidazole derivatives such as
  • the Terbinafine Hydrochloride of sufficient strength and stability for pharmaceutical use can accommodate a therapeutically significant concentration of the antifungal agents; thereby increasing the stability of the antifungal agents in solution for extended periods of time.
  • the solvent system comprises a primary carboxylic acid, a polar solvent, a solubilizer, a non-ionic or amphoteric surfactant, and water, in which imidazole derivatives can be dissolved.
  • cream base matrix as a functional element of the cream rather than a mere carrier for the main APIs
  • biopolymers Contain biologically active polymers (the so-called biopolymers) without compromising the stability of the formulations. If the right biopolymer is not selected the stability of the formulations could be affected.
  • the present invention is directed to a medicinal composition for treating skin inflammations, fungal/bacterial skin infections and related wounds, and also other skin wounds including those caused by burns.
  • the cream also causes skin rejuvenation through an epithelisation process.
  • the cream comprises:
  • APIs Active Pharmaceutical Ingredients
  • Fusidic Acid that has been generated in situ from Sodium Fusidate, Hydrocortisone acetate & Terbinafine Hydrochloride
  • a cream base containing primary and secondary emulsifiers, waxy materials, co- solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants
  • the active ingredients namely Chitosan, Hydrocortisone acetate, Terbinafine Hydrochloride and Fusidic Acid, are incorporated in cream base for use in treating skin inflammations, fungal/ bacterial skin infections with allergy & itching, & wounds on human skin involving contacting human skin with the above-identified composition.
  • the invention also discloses a process to make the medicinal cream containing Fusidic Acid which is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic Acid under oxygen-free environment created using inert gas, preferably nitrogen, and Chitosan.
  • the cream produced by the process of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional creams containing Fusidic Acid.
  • the cream produced by the process of the present invention contains Fusidic Acid as the API that has been formed in situ from Sodium Fusidate, Hydrocortisone acetate& Terbinafine Hydrochloride in a cream base comprising a preservative, an acid, a co-solvent, an emulsifier and a waxy material along with water, preferably purified water.
  • the cream produced by the process of the present invention further optionally contains an ingredient selected from a group comprising, a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • Creams containing Fusidic Acid that are made using Sodium Fusidate as starting API along with Hydrocortisone acetate as a steroid, and Terbinafine Hydrochloride as antifungal are not commercially available.
  • Sodium Fusidate is not considered to be inherently more stable as an API than Fusidic Acid.
  • Creams containing Chitosan and Fusidic Acid which has been created in situ from Sodium Fusidate, Hydrocortisone acetate as a steroid, and Terbinafine
  • fusidic acid has very labile trans, sys, trans arrangement of these rings which forces ring B into a boat conformation.
  • fusidic acid readily undergoes acid mediated dehydration of C-l l hydroxy group to generate a C9-C11 double bond which on further isomerization followed by oxidization in the presence of oxygen leads to a mixture of biologically inactive fusidic acid derivatives.
  • carboxylic acid functional group present in the fusidic acid facilitates the above process more readily upon storage.
  • carboxylic acid promoted decomposition is not feasible.
  • sodium fusidate has superior solid-state stability when compared to fusidic acid. This discovery of the inventor has also been corroborated through stability assessment of sodium fusidate and fusidic acid.
  • Tables 1 and 2 also show the comparison between the stability of the Fusidic Acid and Sodium Fusidate as raw APIs.
  • the study was carried out using an in-house HPLC method developed by the applicant, which the applicant believes is a true stability-indicating method as opposed to the titration method suggested in British Pharmacopoeia (BP). This is because the BP method does not differentiate between the intact API and the degraded form.
  • BP British Pharmacopoeia
  • a dermaceutical cream that uses Sodium Fusidate would exploit the benefit of the fact that Sodium Fusidate is more stable than Fusidic Acid and it would also provide a cream formulation, which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic Acid.
  • the applicant therefore surprisingly discovered that in order to achieve greater stability of the API in a dermaceutical cream, Sodium Fusidate rather than Fusidic Acid may be used as the starting API during the cream's manufacture. Using Sodium Fusidate as starting material eliminates the drawback associated with the manufacture and storage of existing Fusidic Acid creams.
  • the applicant has also discovered that the Fusidic Acid cream prepared using Sodium Fusidate as the starting API and Hydrocortisone acetate as a steroid and Terbinafine Hydrochloride as an antifungal showed good chemical stability and efficacy.
  • the application discloses a process of making a cream containing a biopolymer - Chitosan, Hydrocortisone acetate as a steroid, and Terbinafine Hydrochloride as an antifungal, and Fusidic Acid (the API) that has been prepared using Sodium Fusidate as the starting API, in which Fusidic Acid forms in-situ under totally oxygen-free environment created using inert gas, preferably nitrogen, by slow addition of an acid, into a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic Acid regenerates as an extremely fine dispersion when added to a final cream base, thereby resulting in a finely and homogeneously dis
  • 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, Hydrocortisone acetate as a steroid, and Terbinafine Hydrochloride as an antifungal in a cream base comprising a preservative, an acid, a co-solvent, an emulsifier and a waxy material along with water, preferably purified water.
  • the active compounds Sodium Fusidate, Hydrocortisone acetate & Terbinafine Hydrochloride 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, skin inflammations and fungal skin infections.
  • the active compounds Sodium Fusidate, Hydrocortisone acetate & Terbinafine Hydrochloride require a base component to be used in the pharmaceutical composition that uses the compound, since the compound cannot, by themselves, be deposited directly on to human skin due to their harshness.
  • the base component usually contains a biopolymer, primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, purified water and the like.
  • the cream base of the cream made using the process of the present invention optionally further comprises an ingredient selected from a group comprising a buffering agent, an anti oxidant, a chelating agent, and a humectant, or any combination thereof.
  • the present invention provides a process to make a novel cream that has been produced using Sodium Fusidate as the starting raw material, and which cream contains Fusidic Acid of high therapeutic efficacy and of chemical stability that is generally superior to the commercially available creams containing Fusidic Acid.
  • the Fusidic Acid cream made using the process of the present invention has been manufactured in a totally oxygen free environment under purging with inert gas and applying vacuum, the inert gas being preferably nitrogen. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic Acid and to which Hydrocortisone acetate as a steroid, and Terbinafine Hydrochloride, as an antifungal is added.
  • the cream of the present invention is used in the treatment of bacterial skin infections fungal 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.
  • biopolymers biologically active polymers
  • Incorporation of a functionally bioactive excipient polymer in cream matrix while retaining the functional stability of the API in a single dose format of dermaceutical cream involves resolution of problems specific to the physical stability of cream matrix.
  • suitable topical antibacterial agents include, but are not limited to Sodium Fusidate, Neomycin Sulphate, Calcium Mupirocin, Gentamycin, Silver Sulphadiazine, Ciprofloxacin, Framycetin Sulphate, Quinidochlor, Povidone-Iodine, Sisomicin, Nitrofural and the like.
  • Corticosteroids examples include, but are not limited to Hydrocortisone acetate, Dexamethasone Acetate, Betamethasone Valerate, Fluticasone Propionate, Mometasone Furoate, Hydrocortisone Acetate, Clobetasol Propionate, Beclomethasone Dipropionate, Betamethasone Dipropionate and the like.
  • Antifungals include, but are not limited to Terbinafine Hydrochloride, Oxiconazole Nitrate, Clotrimazole Miconazole Nitrate, Ketoconazole, 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. It's known properties include accelerated blood clotting. However, a person skilled in the art that Chitosan's behaviour with a pharmaceutical active ingredient such as an antibacterial or antifungal agent needs to be treated with caution does not know it. It is known to have film forming, mucoadhesive and viscosity-increasing properties and it has been used as a binder and disintegrating agent in tablet formulations.
  • 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 lkdal to 5000kdal.
  • Chitosan is discussed in the US Pharmacopoeia forum with regard to its functional excipient category and has been published in the official monographs - (USP 34) NF 29. Since Chitosan is basically a polymer, it is available in various grades depending upon the molecular weight. The various grades of Chitosan include Chitosan long chain, Chitosan medium chain & Chitosan short chain. The grades long, medium & short chain directly corresponds to the molecular weight of the Chitosan.
  • the long chain grade has a molecular weight in the range of 500,000- 5,000,000 Da
  • the medium chain grade has a molecular weight in the range of 1,00,000-2,000,000 Da
  • the short chain grade has a molecular weight in the range of 50,000-1,000,000 Da.
  • the molecular weight of the Chitosan plays an important role in the formulation. Higher molecular weight Chitosan imparts a higher viscosity to the system and lower molecular weight Chitosan imparts a lower viscosity to the system. However the medium chain grade Chitosan delivered an optimum level of viscosity to the formulation. Since the dosage form is a cream, appropriate levels of viscosity is required to achieve a good spreadability over the skin.
  • the inventors finalized the Chitosan medium chain grade for the present invention since it imparted the required rheologic properties to the cream without compromising the therapeutic activity of the actives, ie Sodium Fusidate, Hydrocortisone acetate & Terbinafine Hydrochloride, as the starting actives and Chitosan.
  • the concentration of Chitosan medium chain grade was carefully arrived based on several in house trials and Preclinical animal studies for efficacy.
  • Topical anti-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 Terbinafine Hydrochloride, Oxiconazole Nitrate, Ketoconazole, Miconazole nitrate, etc.
  • Fungal infections are generally manifested with itching at the site.
  • Anti-fungals act by altering the permeability of the fungal membrane by inhibiting the synthesis of sterols Terbinafine Hydrochloride
  • Terbinafine Hydrochloride is an antifungal agent. Chemically, Terbinafine hydrochloride is (E)-N-(6, 6-dimethyl-2-hepten-4-ynyl)-N-methyl-l- naphthalenemethanamine hydrochloride. The compound has the empirical formula C 2 iH 26 ClN, a molecular weight of 327.90.
  • Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations terbinafine is fungicidal against dermatophytes, molds and certain dimorphic fungi. The activity against yeasts is fungicidal or fungistatic, depending on the species.
  • Terbinafine interferes specifically with fungal sterol biosynthesis by inhibition of squalene epoxidase in the fungal cell membrane. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death.
  • the enzyme squalene epoxidase is not linked to the cytochrome P450 system; hence terbinafine does not influence the metabolism of hormones or other drugs.
  • the drug concentrates rapidly in skin, hair and nails at levels associated with fungicidal activity. The cream has a rapid onset of action and can be effective with a short duration of treatment. Indications and Clinical Uses:
  • Topical terbinafine is indicated in the treatment of fungal infections of the skin caused by dermatophytes such as Trichophyton, as well as yeast infections of the skin, principally those caused by the genus Candida (e.g., Candida albicans).
  • the cream is also indicated in the treatment of pityriasis (tinea) versicolor due to P. orbiculare (also known as M. furfur).
  • Topical corticosteroids are a powerful tool for treating skin diseases.
  • Corticosteroids include drugs such as Hydrocortisone acetate, Dexamethasone Acetate, 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. Topical corticosteroids are classified by their potency, ranging from weak to extremely potent.
  • Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.
  • Hydrocortisone is a member of synthetic steroids used as anti-inflammatory and antipruritic agent. It's chemical name is Pregn-4-ene-3,20-dione, 11,17,21- trihydroxy-, (11 ⁇ )-. Its molecular formula is C21H30O5 and molecular weight 362.47. Hydrocortisone Acetate is a white to off-white crystalline powder insoluble in water and slightly soluble in alcohol and in chloroform. It is a low potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of
  • Hydrocortisone Acetate is a low potency synthetic corticosteroid with anti inflammatory, antipruritic, and vasoconstrictive properties. Hydrocortisone Acetate depresses formation, release, and activity of endogenous mediators of inflammation, including prostaglandins, kinins, histamine, liposomal enzymes, and complement system; modifies body's immune response.
  • Hydrocortisone Acetate has been shown to have a wide range of inhibitory effects on multiple cell types (e.g. mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (e.g. histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response.
  • mediators e.g. histamine, eicosanoids, leukotrienes, and cytokines
  • Mechanism Of Action They enter cells where they combine with steroid receptors in cytoplasm and then the combination enters nucleus where it controls synthesis of protein, including enzymes that regulate vital cell activities over a wide range of metabolic functions including all aspects of inflammation formation of a protein that inhibits the enzyme phospholipase A 2 which is needed to allow the supply of arachidonic acid.
  • Arachidonic acid is essential for the formation of inflammatory mediators. They also act on cell membranes to alter ion permeability. They also modify the production of neurohormones.
  • Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses.
  • topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
  • Hydrocortisone Acetate is a low potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses.
  • Topical Anti-bacterials are intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance Staphylococcus Aureus (MRSA) etc.
  • Anti-bacterials act by inhibiting cell wall synthesis by combining with bacterial ribosomes and interfering with mRNA ribosome combination.
  • anti-bacterials induce ribosomes to manufacture peptide chains with wrong amino acids, which ultimately destroy the bacterial cell.
  • Sodium Fusidate belongs to the group of medicines known as antibiotics.
  • 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 C3i H 4 7Na06.
  • the chemical name is 3 ⁇ , 29- ⁇ -8 ⁇ , 9B, 13 ⁇ , 14B-dammara- 17(20) [10,21-cis], 24- dien-21-oic acid 16-acetate, sodium salt. It is a white colour crystalline powder soluble in one part of water at 20 °C.
  • Sodium Fusidate inhibits bacterial protein synthesis by interfering with amino acid transfer from aminoacyl-sRNA to protein on the ribosomes.
  • Sodium Fusidate may be bacteriostatic or bactericidal depending on inoculum size.
  • Mammalian cells are much less susceptible to inhibition of protein synthesis by Sodium Fusidate than sensitive bacterial cells. These differences are believed to be due primarily to a difference in cell wall permeability.
  • 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 topical preparation used for application on the skin.
  • 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 (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.
  • ointment bases 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. 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 Chitosan Cream with antibacterial agent - Sodium Fusidate, Hydrocortisone acetate as a steroid, Terbinafine Hydrochloride as an antifungal of the present invention is from about 3 to 6.
  • ointments that are commercially available are greasy and cosmetically non elegant.
  • the penetration of skin is slow.
  • 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.
  • Topical Sodium Fusidate & Terbinafine Hydrochloride have profound efficacy in primary & secondary bacterial/fungal skin infections of varied etiology due to their antibacterial/antifungal properties.
  • a drawback of the monotherapy with any topical antibacterial/antifungal has been the relatively slow onset of the effect.
  • Fusidic Acid along with Hydrocortisone acetate and Terbinafine Hydrochloride& Chitosan in a formulation, the properties of antibacterial, antifungal, and anti-inflammatory agents as well as Chitosan are optimized.
  • Chitosan is film forming, biocompatible, non-allergenic material it helps in protecting the skin by acting as a barrier. It further controls the superficial bleeding caused by scratching and also arrests the mobility of pathogens due to its cationic charge.
  • Chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments.
  • the combination of Chitosan with Sodium Fusidate, Hydrocortisone acetate, and Terbinafine Hydrochloride 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 straightforward process of mere addition.
  • the inventor has found that the compatibility of the functional excipient such as Chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product.
  • the inventors have found that well known excipients such as Xanthan Gum and carbomer, which have been variously used as stabilizing agents, cannot be used in combination with functional biopolymers such as Chitosan.
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy Materials, and Emulsifiers etc. Polymers are used as gelling agents, suspending agents, viscosity builders, release modifiers, diluents, etc. Surfactants are used as wetting agents, emulsifiers, solubilising agents release enhancers, etc.
  • polymers & surfactants may or may not possess ionic charge. They may be anionic or cationic or non-ionic in nature. If anionic excipients are included in the formulation they interact with cationic formulation excipients and produce products which are not homogenous, aesthetically not appealing and give rise to unwanted by products, possible allergens, impurities, toxic substances etc due to incompatibility. 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.
  • the inventors carefully screened the excipients which included the polymers and surfactants for developing a formulation. A thorough study was performed after screening the short listed excipients. The possible interactions between the excipients were given much focus and detailed experiments were done.
  • Fusidic Acid provides relief against bacterial infections
  • Hydrocortisone acetate provides relief against skin inflammations
  • Terbinaflne Hydrochloride provides relief against fungal infections
  • the aspects such as like skin protection, bleeding at the site, mobility of pathogens from one site to another, etc are not addressed so far in a single dose therapy that includes Fusidic Acid generated in situ from Sodium Fusidate.
  • This present invention with its single-dose application fills this gap by incorporating Chitosan and tapping the required benefits of skin protection (by way of film forming property), stopping the bleeding (by way of blood clotting property) and immobilization of pathogenic microbes (due to its cationic electrostatic property).
  • Therapeutic value addition by incorporation of a functional excipient in the form of a Chitosan, which is a biopolymer in the cream matrix is an integrated sub-set of the following functional attributes of the biopolymer:
  • the present invention with its single-dose therapy reduces the overall treatment time of a serious skin disorder significantly.
  • Preferred embodiment no. 1 A medicinal cream for topical treatment of bacterial skin infections, fungal skin infections, inflammations and for related wound healing including burns wound, wherein said cream comprises an antibacterial agent, Sodium Fusidate, an antifungal agent Terbinafine Hydrochloride, a corticosteroid Hydrocortisone acetate and a biopolymer provided in a cream base, said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co-solvent, an acid, and water, preferably purified water.
  • said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co-solvent, an acid, and water, preferably purified water.
  • Embodiment no. 1 A medicinal cream as disclosed in the preferred embodiment no 1, wherein said cream further comprising any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.
  • Embodiment no. 2 A novel dermaceutical cream as disclosed in the preferred embodiment no 1 and the embodiment no. 1 , wherein
  • said Fusidic Acid is present in an amount from about 0.1% (w/w) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w), and more preferably about 2.00 % (w/w), and in which the amount of said Sodium Fusidate used to form in situ said Fusidic Acid is in the range between about 0.1% (w/w) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w) and more preferably about 2.08 % (w/w), and
  • the topical corticosteroid is from about 0.001% (w/w) to about 5% (w/w) , preferably from about 0.01%(w/w) to about 1.5% (w/w) and most preferably about 1.00% (w/w) , of Hydrocortisone acetate , and,
  • said antifungal is added from about 0.5%(w/w) to about 5.0%(w/w) , preferably from about 0.5%(w/w) to about 3.0% (w/w) , and most preferably about 1.0%(w/w)
  • said antifungal preferably being Terbinafine Hydrochloride
  • - said biopolymer is in the form of Chitosan, added in an amount between about 0.01% and about 1% (w/w) , preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.1% w/w, said chitosan being of the molecular weight between lkdal and 5000kDal,
  • said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like and added in an amount from about 1% (w/w) to 20% (w/w); said waxy materials is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 30% (w/w); said co-solvent is selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400, Isopropyl Myristate and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w); said acid is selected from a group comprising HCl, H 2 SO 4 , HNO 3 , Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w)
  • Embodiment no.3 A medicinal cream as disclosed in the preferred embodiment no 1 and embodiment 2 further comprising a buffering agent which is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.001% (w/w) to 2.00% (w/w).
  • a buffering agent which is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.001% (w/w) to 2.00% (w/w).
  • Embodiment no. 4 A medicinal cream as disclosed in the preferred embodiment no 1 and embodiments 2 and 3 further comprising an antioxidant which is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, and added in an amount from about 0.001% (w/w) to 1 % (w/w).
  • 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 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 medicinal cream as disclosed in the preferred embodiment no 1, and embodiments nos. 2 to 5 further comprising a humectant which is selected from a group comprising Glycerin, Sorbitol, Propylene Glycol and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w).
  • Embodiment no. 7 A novel dermaceutical cream as described in the preferred embodiment 1 and embodiments nos.
  • 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 The preferred embodiment of the invention 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:
  • waxy materials selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, either singly or any combination thereof, in an amount between 5% (w/w) and 30% (w/w), preferably 15%
  • a primary emulsifier preferably in the form of a non ionic surfactant, selected from a group comprising Cetostearyl alcohol, Cetomacrogol- 1000, either singly or any combination thereof, wherein Cetostearyl alcohol is added in an amount between 1% (w/w) and 20% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), and Cetomacrogol-1000 is added in an amount between 0.1% (w/w) and 5% (w/w), preferably 1% (w/w), more preferably 0.5% (w/w), and optionally a secondary emulsifier selected from a group comprising Polysorbate-80, Span- 80 and the like, preferably Polysorbate-80, in an amount between 1% (w/w) and 5%(w/w) , preferably l%(w/w) to 3%(w/w),more preferably 2% w/w and mixing the mixture thoroughly
  • a secondary emulsifier selected
  • a co-solvent selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like, either singly or any combination thereof, in an amount between 5% (w/w) and 50% (w/w), preferably 30% (w/w),more preferably 23% (w/w), preferably propylene glycol, subjecting the contents of said API-vessel to inert gas flushing, said inert gas being preferably nitrogen, and adding Sodium Fusidate to the mixture, said Sodium Fusidate added in an amount between 0.1% (w/w) and about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w) and more preferably about 2.08 % (w/w), and dissolving said 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
  • an acid selected from a group comprising acids such as HC1, H 2 SO 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably 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),
  • a preservative preferably Benzyl alcohol in an amount between 0.05% (w/w) and about 2% (w/w), preferably from about 0.5% (w/w) to about 2% (w/w) and more preferably about 1 % (w/w), and adding propylene glycol in an amount between 1% (w/w) to 10% (w/w), preferably 5% (w/w), more preferably 4% (w/w) and dissolving Terbinafine Hydrochloride in it by continuous mixing to form a solution , said Terbinafine Hydrochloride added in an amount between 0.5% (w/w) and about 5% (w/w), preferably from about 0.5% (w/w) to about 3% (w/w) and more preferably about 1 % (w/w),
  • step g transferring the contents of said first API- vessel of step g to the mixing vessel of step e 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,
  • a biopolymer-mixing vessel adding an acid, selected from a group comprising acids such as HC1, H 2 SO 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Lactic acid from about 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.05% (w/w), and purified water from about 0.1% (w/w) to 10% (w/w), preferably 8% (w/w), more preferably 5% (w/w) to form a mixture and dissolving a biopolymer, preferably Chitosan in an amount between about 0.01% w/w and about 1% w/w, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.1% w/w, said chitosan being of the molecular weight between lkDal and 5000 kDal,
  • step n transferring the contents of the biopolymer-mixing vessel of step m to the mixing vessel of step e 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,
  • step e cooling the contents of the mixing vessel of step e to 30 °C to 37 °C using circulation of cooled water from a cooling tower at 8 °C to 15 °C into the jacket of mixing vessel,
  • Embodiment No. 11 In an embodiment of the present invention, the co-solvent of step f 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 10, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, from about 5% (w/w) to 50% (w/w), preferably 35% (w/w), more preferably 30% (w/w).
  • Embodiment No. 12 In another embodiment of the present invention the process described in embodiment no. 11 further incorporates adding a chelating agent, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, from about 0.05% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 0.1% (w/w).
  • a chelating agent selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, from about 0.05% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 0.1% (w/w).
  • Embodiment No. 13 In yet another embodiment of the present invention the process described in embodiments no.
  • 11 and 12 further incorporate a buffering agent after the step of adding chelating agent selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.001% (w/w) to 2.00% (w/w), preferably 1% (w/w), more preferably 0.5% (w/w).
  • chelating agent selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.001% (w/w) to 2.00% (w/w), preferably 1% (w/w), more preferably 0.5% (w/w).
  • Embodiment No. 14 In a further embodiment of the present invention the process described in embodiments no. 11 to 13 further incorporate an anti oxidant in the step f of embodiment 10 selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001% (w/w) to 1% (w/w), preferably 0.1% (w/w), more preferably 0.01% (w/w).
  • Embodiment No. 15 Yet another process of making the composition as per the said earlier preferred embodiments & embodiments is disclosed, said process comprises the steps of:
  • heating purified water in the range from 20% (w/w) to 75% (w/w), preferably 30% (w/w) to 50% (w/w), more preferably 25% (w/w) to 40% (w/w) in a water-phase vessel to 70 0 C to 80 0 C,
  • step b adding to said water-phase vessel of step a) a chelating agent, or buffering agent , or a humectant added in combination thereof, wherein said chelating agent is preferably Disodium edetate, added in an amount preferably between 0.05 %(w/w) and 1 %(w/w), preferably 0.5%(w/w), more preferably
  • said buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount preferably 0.001% (w/w) to 2.00% (w/w), preferably 1.0% (w/w), more preferably 0.5% (w/w) and said humectant is preferably Propylene Glycol, added in an amount preferably 5% (w/w) to 50% (w/w), preferably 35% (w/w), more preferably 30% (w/w),
  • step b mixing the mixture of said water-phase vessel of step b using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 70°C to 80°C, d. adding to an oil-phase vessel an emulsifying wax, preferably Cetostearyl alcohol, in an amount preferably between l%(w/w) and 20 %(w/w), preferably 15 %(w/w), more preferably 12.5 %(w/w) and a waxy material, preferably white soft paraffin, in an amount preferably between 5% (w/w) and 30 %(w/w), preferably 15 %(w/w), more preferably 12.5 %(w/w), and melting them by heating to 70 0 C to 80 0 C,
  • an emulsifying wax preferably Cetostearyl alcohol
  • a non ionic surfactant or emulsifier in an amount between l%(w/w) to 5 %(w/w), preferably l%(w/w) to 3% (w/w), more preferably 2 %(w/w), of Polysorbate 80 and in an amount between 0.1%(w/w) to 5 %(w/w), preferably l%(w/w), more preferably 0.5 %(w/w),of Cetomacrogol 1000 and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at
  • 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 50% (w/w), preferably 30% (w/w), more preferably 23% (w/w), and optionally adding and dissolving an antioxidant, selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, added in an amount preferably between 0.001% (w/w) and 1 % (w/w), preferably 0.1 % (w/w), more preferably 0.01 % (w/w) Butylated Hydroxy Toluene in it by continuous mixing,
  • said inert gas preferably being nitrogen and adding Sodium Fusidate to the mixture and dissolving it in the mixture, said Sodium Fusidate being added in an amount between 0.1% (w/w) and about 25% (w/w), preferably between 0.5% (w/w) and about 5% (w/w) and more preferably about 2.08 % (w/w),
  • an acid selected from a group comprising acids such as HCL, H 2 SO 4 , HNO 3 , lactic acid and the like, either singly or any combination thereof, preferably Nitric acid in an amount preferably between 0.005% (w/w) and 0.5 % (w/w), preferably 0.3 % (w/w), more preferably 0.25% (w/w),
  • a preservative preferably Benzyl alcohol in an amount between 0.05% (w/w) and about 2% (w/w), preferably from about 0.5% (w/w) to about 2% (w/w) and more preferably about 1 % (w/w), and adding propylene glycol in an amount between 1% (w/w) to 10% (w/w), preferably 5% (w/w), more preferably 4% (w/w) and dissolving Terbinafine Hydrochloride in it by continuous mixing to form a Solution, said Terbinafine Hydrochloride added in an amount between 0.5% (w/w) and about 5% (w/w), preferably from about 0.5 % (w/w) to about 3% (w/w) and more preferably about 1 % (w/w),
  • a biopolymer-mixing vessel adding an acid, selected from a group comprising acids such as HC1, H 2 S0 4 , HNO 3 , Lactic acid and the like, either singly or any combination thereof, preferably Lactic acid from about 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.05% (w/w), and purified water from about 0.1% (w/w) to 10% (w/w), preferably 8% (w/w), more preferably 5% (w/w) to form a mixture and dissolving the said biopolymer, Chitosan in an amount between about 0.01%(w/w) and about l%(w/w) by weight, preferably from about 0.01% (w/w) to
  • step p transferring the contents of the biopolymer mixture of step p 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,
  • the co-solvent of step i also serve as a humectant.
  • an additional humectant may be added, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, from about 5% (w/w) to 50% (w/w), preferably 35% (w/w), more preferably 30% (w/w).
  • a method of treating primary & secondary bacterial & fungal skin infections and inflammations comprising applying of a cream containing at least one corticosteroid such as Hydrocortisone acetate, one antifungal Terbinafine Hydrochloride 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.
  • a cream containing at least one corticosteroid such as Hydrocortisone acetate, one antifungal Terbinafine Hydrochloride and Fusidic Acid which is made in situ under oxygen-free environment using Sodium Fusidate
  • 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
  • Embodiment no. 17 A method of treating primary & secondary bacterial & fungal skin infections and inflammations said method comprising applying of a cream as described in the preferred embodiment 1 and any of embodiments 1 to 9.
  • the cream obtained using the process of the present invention is homogenous and white to off white in colour and viscous in consistency.
  • the pH of the product made using the process of the present invention is from about 3 to 6.
  • Sodium Fusidate ointments that are commercially available are greasy and cosmetically non elegant.
  • the active drug It is essential that the active drug penetrate 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.
  • Particle size analysis was carried out on the cream made using the process of the present invention and on some commercially available product samples (samples A, C, D, F, G, and K). An optical microscope by Carl Zeiss (Axio Star Plus 2x to lOOx magnification) was used for this purpose. Maximum and minimum particle sizes, mean particle size and standard deviation and the coefficient of variation were assessed. Table 8: Particle size analysis
  • the particle size distribution analysis results indicated in table 8 clearly indicate the presence of Fusidic Acid of fine particle size in the product of the present invention, the size that is advantageously much reduced than the conventional products.
  • the maximum particle size observed for fusidic acid of the present invention is less than 6 ⁇
  • the maximum particle size observed for existing creams varies between 19 ⁇ to 40 ⁇ , with a majority of them having the maximum particle size between 30 ⁇ and 40 ⁇ .
  • the average size of the fusidic acid particles in the present invention has been found to be less than 3 ⁇ whereas that for the existing creams varies between 14 ⁇ to 19 ⁇ .
  • the minimum particle size observed was approx. 0.84 ⁇ whereas the minimum particle size observed for existing creams ranged between 5 ⁇ and 10 ⁇ .
  • the cream of the present invention is therefore physically distinct from any of the existing creams and easily distinguishable. This is attributed to the fact that the instant product is made using Sodium Fusidate using in situ conversion of Sodium Fusidate to Fusidic Acid in a finely dispersed form. All of the measured parameters are better than those found for the commercially available creams containing Fusidic Acid. This is another clear advantage of the product disclosed herein over the commercially available products.
  • the reduced particle size of the fusidic acid of the present invention is of particular significance as it has been achieved without compromising the stability of fusidic acid.
  • products such as those disclosed in WO2007087806 by Leo Pharma have employed mechanical means such as mortar and pestle to mechanically grind fusidic acid for adding to a cream base.
  • WO2007087806 is silent on the particle size achieved, it will be known to a person skilled in the art that its particle size of fusidic acid cannot be finer than that of the present invention.
  • the product of the present invention is efficacious due to the pronounced antibacterial activity of the regenerated Fusidic Acid, antifungal activity of the Terbinafine Hydrochloride, anti-inflammatory activity of the Hydrocortisone acetate , which are available in reduced particle size than the conventional products, and in a finely dispersed form.
  • the inventor has screened different co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fusidate in one of above co-solvents varying from about 5% (w/w) to 50% (w/w) under inert gas purging and under vacuum and converted to Fusidic Acid in-situ by adding an acid such as HC1, H 2 S0 4 , HN0 3 , Lactic acid and the like from about 0.005% (w/w) to about 0.5% (w/w) under stirring and obtained Fusidic Acid in more stabilized and solution form, which makes our final product in a cream base which easily penetrates the skin and highly efficacious, and also highly derma compatible by having a pH of about 3.0 to about 6.0.
  • co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 & the like and dissolved the Sodium Fus
  • the stability of the product is confirmed by the stability studies performed for 6 months as per ICH guidelines and a comparison of stress studies done for in-house product with those on samples of commercially available comparable products.
  • API-stability experiments were carried out (see tables 10 - 12) using the product of the present invention and products currently commercially available. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the API over a period of time. Tests were also carried out to assess the stability by subjecting the product to stress studies such as autoclave test and oxydative degradation test. Further, in vitro antimicrobial zone of inhibition studies and preclinical studies such as blood clotting studies & burns wound healing studies were also carried out over a period of time.
  • Each gram of product of the present invention used for the tests contained Sodium Fusidate as the starting raw material in the amount required to produce approximately 2% (w/w) Fusidic Acid, 1.00% (w/w) Hydrocortisone acetate & 1.00%(w/w) Terbinafine Hydrochloride 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. It was packaged in an aluminium collapsible tube and each gram of the product contained 20.8 mg of Sodium Fusidate (in conformance with BP), which is equivalent to 20 mg of Fusidic Acid (BP conformant) and appropriate amount of steroids and antifungals as mentioned below.
  • Composition Fusidic Acid 2.0% (equivalent of Sodium Fusidate 2.08% w/w) + Hydrocortisone acetate (1.00%w/w) + Terbinafine Hydrochloride (1.00%w/w) + Chitosan 0.1% (w/w) Cream
  • PRODUCT Sodium Fusidate + Hydrocortisone acetate + Terbinafine
  • Measured parameter pH Limits of measured parameter: 5.0-6.5
  • product of the present invention is quite stable at ambient conditions and also at elevated temperature & humid conditions of storage. This is a major advantage over the currently available Fusidic Acid creams.
  • the stability of the product is further ascertained by the shelf-life prediction of the formulation using arrhenius plot of degradation employing Nova-LIMS software.
  • the antimicrobial/antibacterial activity of the product is confirmed by the in vitro Zone of Inhibition studies for the product. The results obtained clearly indicate the statistical significance.
  • the cream is applied after thorough cleansing and drying the affected area. Sufficient cream should be applied to cover the affected skin and surrounding area. The cream should be applied two - four times a day depending upon the skin conditions for the full treatment period, even though symptoms may have improved.
  • A. Wound Contraction Excision wound healing activity of the cream of the present invention was determined through animal testing. Cutting away full thickness of the skin inflicted an excision wound 2.5 cm in diameter. 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).
  • B. Period Of Epithelisation Epithelisation of the wound occurred within shorter number of days using the cream of the present invention as compared to the days taken for epithelisation using the conventional cream. Therefore one benefit of the cream of the present invention is that it facilitates significantly faster epithelisation of the skin than a control (untreated wound).
  • Blood Clotting time was observed in both groups of animals, untreated control group and the test group of animals treated with the product of the present invention. Statistically significant decrease in the blood clotting time in treated group animals was observed when compared with that of the control group animals. The mean percent reduction of 50-60% was observed for the blood clotting time using the product of the present invention.
  • the therapeutic efficacy of topically applied cream of the present invention is due to the pronounced antibacterial / antifungal activity of the Sodium Fusidate & Terbinafine Hydrochloride against the organisms responsible for skin infections, pronounced anti-inflammatory activity of the Hydrocortisone acetate against inflammations, the unique ability of actives to penetrate intact skin and wound healing & soothing properties of Chitosan.
  • the cream of the present invention incorporates a skin-friendly biopolymer in the form of Chitosan provides enhanced therapeutic outcomes. This is evident from the reduced blood clotting time, increased epithelial effect, and faster relief from infection and inflammation and wound contraction.
  • the cream of the present invention incorporates a biopolymer without compromising the stability of the cream matrix and without adversely affecting the functioning of known active pharmaceutical ingredients. This has been achieved through a careful selection of functional excipients to bypass undesirable aspects of physio-chemical compatibility/stability and bio-release.
  • the cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations.
  • 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 / fungal skin infections, inflammations and wound healing involving contacting human skin with the above-disclosed composition.

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Abstract

La présente invention concerne une composition médicamenteuse permettant de traiter des inflammations cutanées, des infections cutanées fongiques/bactériennes et des plaies associées, ainsi que d'autres plaies cutanées comprenant celles causées par des brûlures. Ladite crème induit également une réjuvénation cutanée par le biais d'un processus d'épithélisation. Ladite crème comprend du chitosane, de l'acétate d'hydrocortisone, du chlorhydrate de terbinafine et de l'acide fusidique. L'invention concerne également un procédé de préparation de ladite crème médicamenteuse contenant de l'acide fusidique préparé in situ avec du fusidate de sodium comme matière première de départ, lequel fusidate de sodium est transformé en acide fusidique dans un environnement exempt d'oxygène créé à l'aide d'un gaz inerte, de préférence de l'azote, et du chitosane. La crème produite selon le procédé présente une meilleure stabilité à la conservation et une taille particulaire de la substance pharmaceutique active plus fine que les crèmes classiques contenant de l'acide fusidique. La crème produite selon le procédé contient de l'acide fusidique comme substance pharmaceutique active, lequel acide fusidique est produit in situ à partir de fusidate de sodium, de l'acétate d'hydrocortisone et du chlorhydrate de terbinafine, dans une base de crème renfermant un conservateur, un acide, un co-solvant, un émulsifiant et un matériau cireux, ainsi que de l'eau, de préférence de l'eau purifiée.
PCT/IB2011/053407 2010-08-17 2011-08-01 Crème médicamenteuse à base d'acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d'hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant WO2012023082A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2017091167A1 (fr) 2015-11-28 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. Composition pharmaceutique topique comprenant de l'acide fusidique, de l'isoconazole, du dexpanthénol et de l'hydrocortisone
WO2019058268A1 (fr) * 2017-09-19 2019-03-28 Omnipharm Developments Limited Formulation anti-infectieuse topique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017091167A1 (fr) 2015-11-28 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. Composition pharmaceutique topique comprenant de l'acide fusidique, de l'isoconazole, du dexpanthénol et de l'hydrocortisone
WO2019058268A1 (fr) * 2017-09-19 2019-03-28 Omnipharm Developments Limited Formulation anti-infectieuse topique

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