WO2011101826A1 - Crème médicinale contenant de l'acide fusidique fabriquée à l'aide de fusidate de sodium et incorporant un biopolymère, de la terbinafine et de la dexaméthasone et son procédé de fabrication - Google Patents

Crème médicinale contenant de l'acide fusidique fabriquée à l'aide de fusidate de sodium et incorporant un biopolymère, de la terbinafine et de la dexaméthasone et son procédé de fabrication Download PDF

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WO2011101826A1
WO2011101826A1 PCT/IB2011/050714 IB2011050714W WO2011101826A1 WO 2011101826 A1 WO2011101826 A1 WO 2011101826A1 IB 2011050714 W IB2011050714 W IB 2011050714W WO 2011101826 A1 WO2011101826 A1 WO 2011101826A1
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amount
vessel
cream
added
mixture
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PCT/IB2011/050714
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English (en)
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Balkrishnana Selvaraj
Sankar Haridas
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Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Balkrishnana Selvaraj
Sankar Haridas
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Publication of WO2011101826A1 publication Critical patent/WO2011101826A1/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
    • A61K31/13—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to primary and secondary bacterial skin infections, skin inflammations, fungal skin infections and wounds including burn wounds.
  • a cream incorporating Fusidic Acid and a biopolymer in the 10 form of Chitosan, a corticosteroid in the form of Dexamethasone Acetate, and an antifungal agent in the form of Terbinafine Hydrochloride, and the process of making it and using it in treating these infections, inflammations and wounds.
  • the Fusidic Acid in the said cream has been created in situ using Sodium Fusidate as the starting Active Pharmaceutical Ingredient (API).
  • Topical and systemic bacterial infection treatment 20 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 and a biopolymer such as Chitosan, a corticosteroid such as Dexamethasone Acetate, an antifungal agent such as Terbinafine Hydrochloride and the like.
  • Fusidic Acid in fine powder form is used as source API.
  • the small particle size enhances its dermal contact by providing a large specific surface area and penetration, and provides a smooth feel on application to skin.
  • a serious shortcoming of the fine size of Fusidic Acid particles is that it presents an enormous surface area for contact and reaction with molecular Oxygen during manufacture, handling, and processing of the cream. This has serious implications to its chemical stability and results in rapid reduction in potency of the API (Fusidic Acid) in the final cream formulation.
  • Stabilization of medicaments containing Fusidic Acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include: • replacing Oxygen in pharmaceutical containers with inert gases such as Nitrogen, Carbon dioxide, Helium and the like
  • compositions There are several treatments available to treat skin disorders caused by bacteria or fungi. Typically, such compositions use steroids, antibacterial agents or antifungal agents, (or a fixed dose combination of these) and focus on these pharmaceutically active ingredients.
  • the composition of such formulations is such as to enhance their physical/chemical/bio-release profile.
  • the current approaches of skin treatment can be broadly categorized into two stages, a. healing b. restoration of skin to pre-ailment state.
  • the healing part comprises elimination, to the best possible extent, of the root cause of the disorder. This may be elimination of bacteria or fungi causing the infection through a suitable treatment of antibacterial or antifungal agents or reducing the inflammation through steroid treatment. While this treatment is under way, the ongoing compromised condition of the skin continues to be susceptible to secondary infections which can be of quite serious nature. In the case of scratched or wounded skin, it is important for blood clotting to occur quickly as it reduces chances of secondary infections.
  • the focus of such treatments, which are administered through creams, lotions, ointments is on the action of active pharmaceutical ingredients. Cream bases or ointment bases are merely viewed as carriers to take APIs to the sites of disorder.
  • Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcome of the main APIs is enhanced.
  • biopolymers biologically active polymers
  • Fusidic Acid has been used in cream form.
  • the PCT application WO 2009063493 discloses a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Mometasone furoate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin.
  • topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Mometasone furoate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection.
  • WO 2009063493 also apparently surprisingly found that antibiotic action of Fusidic Acid and the anti-inflammatory effect of a corticosteroid such as Halobetasol, both play important roles in prevention of secondary bacterial infections in patients with non-infected dermatoses and in treatment of infected steroid responsive dermatoses such as secondarily infected dermatoses including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • infected steroid responsive dermatoses such as secondarily infected dermatitis including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • CCD corticosteroid responsive dermatoses
  • the invention disclosed in WO 2009063493 relates to a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Mometasone furoate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin.
  • the present invention also relates to topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Mometasone furoate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection
  • 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.
  • PCT/GB2007/004373 claims novelty on the assertion that the pharmaceutical composition according to the invention possesses ability of inhibit methicillin resistant Staphylococcus species.
  • the composition described in the invention by the applicant is use for orally 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.
  • US 6,899,897 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 use for the treatment of vaginal infection.
  • US 6,537,970 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 describes a topical composition for medical, veterinarian or dental use containing active antimycotic ingredient like, clotrimazole, ketoconazole, micanazole, 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.
  • US 6,080,744 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.
  • US 5,023,251 discloses a oil in water cream comprising hydrocortisone diester, oil in water emulsifier based on polyoxyethylene fatty acid esters and fatty alcohols, stearyl alcohol, white Vaseline, benzyl alcohol and water.
  • US 5,023,251 claims novelty on the basis that the ointments with no water or very low water are creams and are not always satisfactory in respect of absorption of the active ingredient, while the claimed invention provide an O/W cream which contains a hydrocortisone diester and which ensures satisfactory storage stability and high absorption of the active ingredient through the skin.
  • the composition is used for the treatment of eczemas, dermatitis, psoriasis and inflammations.
  • US 5,961,997 disclose antipruritic composition
  • the composition preferably further comprises lidocaine and pramoxine and more preferably further comprise lidocaine, pramoxine and Hydrocortisone Acetate .
  • the composition relieves itching in patients suffering from a variety of dermatoses or pruritis.
  • US 5,961,997 claims novelty on the basis that the pharmaceutical composition contains effective concentrations of relevant chemicals, while helping in avoiding components which causes allergenic, irritating, acne-causing, comedogenic, irritant dermatitis, photosensitivity, or allergic contact sensitization and yet is aesthetically pleasing.
  • the antipruritic composition of the invention is oil-free, fragrance-free, lanolin-free and free of formaldehyde-releasing preservatives
  • US 6,352,691 disclose a therapeutic after-shave care lotion comprising Aloe Vera gel, Vitamin C (Ascorbic acid), Vitamin E (tocopherol), and Hydrocortisone Acetate .
  • US 6,352,691 claims novelty on the assertion that the produce will provides effective relief from discomforts associated with shaving, immediate relief of irritation symptoms upon application, initiates repair of damaged skin, shall eliminate the necessity for tedious long term treatment to relieve shaving symptoms and discomforts, help in combating pseudofolliculitis, shall decrease the intensity of the natural inflammatory response caused by shaving and moisturize and nourishes the damaged skin
  • US 2002111298 relates to a moisturizing skin ointment composition consisting of polymyxin B Sulfate, bacitracin zinc, neomycin, Hydrocortisone Acetate and white petrolatum.
  • hydrocortisone present in the composition alleviates problems associated with itching of dry skin because the ointment penetrates the dermis almost immediately, the moisturizing properties of petrolatum allows the full benefit of the antibiotic products and hydrocortisone to remain on/in the skin through several washings thereby alleviating the need to reapply several times a day.
  • US 6,767,534 deals with a post hair removal skin lotion composition for use in reducing inflammation and irritation of skin immediately following hair removal by shaving, waxing, tweezing, electrolysis, or use of depilatory products, and for repairing skin damage resulting from these methods.
  • the composition comprises deionized water, Aloe vera gel, soybean oil, alpha lipoic acid, stearic acid, glyceryl monostearate, propylene glycol, lauramide DEA, vitamin E (tocopherol), Hydrocortisone Acetate , vitamin C (ascorbic acid), carbomer, hydroxymethylcellulose, methylparaben, propylparaben, and polyquaternium-15.
  • the composition claims novelty over the existing prior art on the assumption that the current composition is more suitable for the prevention and treatment of skin damage caused by shaving and other processes used for hair removal. It also claims to provide an effective treatment for pseudofolliculitis and to prevent long-term damage to the skin.
  • cream base 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.
  • Another object of the present invention is to provide a medicinal cream that is effective in treatment of skin inflammations, bacterial/fungal skin infections, wounds including burn wounds.
  • Figure 1 Non-homogeneous nature of creams containing Chitosan with non- compatible excipient such as carbomer.
  • 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:
  • Active Pharmaceutical Ingredients in the form of Fusidic Acid that has been generated in situ from Sodium Fusidate, Dexamethasone 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, Dexamethasone 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, Dexamethasone Acetate and 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 is made using Sodium Fusidate as starting API is not 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 along with Dexamethasone Acetate, as a steroid, and Terbinafine Hydrochloride as antifungal are not commercially available.
  • Sodium Fusidate as an API is significantly more stable than Fusidic Acid and that Fusidic Acid deteriorates more rapidly than Sodium Fusidate.
  • a look at the chemical structures of sodium fusidate and fusidic acid reveals some interesting facts.
  • 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.
  • a dermaceutical cream that uses Sodium Fusidate would exploit the benefit of the fact that Sodium Fusidate is more stable than Fusidic Acid and it would also provide a cream formulation which is far superior in its application qualities than an ointment. It would thus fill an existing need for a cream that has better stability than currently available creams containing Fusidic Acid.
  • Sodium Fusidate rather than Fusidic Acid may be used as the starting API during the cream's manufacture.
  • Using Sodium Fusidate as starting material eliminates the drawback associated with the manufacture and storage of existing Fusidic Acid creams.
  • the application discloses a process of making a cream containing a biopolymer - Chitosan, Dexamethasone 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 dispersed Fusidic Acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen created using inert gas, preferably nitrogen.
  • the cream made using the process of the present invention contains Fusidic Acid as the API that has been formed in situ from Sodium Fusidate, a biopolymer - Chitosan, Dexamethasone 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, Dexamethasone 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, Dexamethasone 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 Dexamethasone Acetate as a steroid, and Terbinafine Hydrochloride as an antifungal are added.
  • the cream of the present invention is used in the treatment of bacterial skin infections fungal infections and inflammations. From the study of the prior art several lacking aspects of the existing topical treatment formulations in the field of prescription medications are evident. The prior art does not teach or suggest that:
  • 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
  • biopolymers biologically active polymers
  • - Incorporation of a functionally bio-active excipient polymer in cream matrix while retaining the functional stability of the API in a single dose format of dermaceutical cream involves resolution of problems specific to the physical stability of cream matrix.
  • topical antibacterial agents examples 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 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, Miconazole Nitrate, Ketoconazole, Clotrimazole and the like.
  • Suitable biopolymer examples include, but are not limited to Chitosan and the like. Chitosan
  • 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 It's known properties include accelerated blood clotting. However, it is not known to a person skilled in the art that Chitosan' s behavior with a pharmaceutical active ingredient such as an antibacterial or antifungal agent needs to be treated with caution. 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. It 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. 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, Dexamethasone 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, Ketoconazole, Miconazole nitrate, Terbinafine 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 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 C21H25N, HC1 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.
  • 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
  • Topical corticosteroids are a powerful tool for treating skin diseases.
  • Corticosteroids include drugs such as Dexamethasone Acetate, Betamethasone dipropionate, Beclomethasone dipropionate, , Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Diflorasone diacetate, Prednicarbate, Hydrocortisone Acetate etc.
  • drugs such as Dexamethasone Acetate, Betamethasone dipropionate, Beclomethasone dipropionate, , Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Flutica
  • 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.
  • Dexamethasone Acetate is a low to moderately potent synthetic adrenal corticosteroid with anti-inflammatory and immunosuppressive properties. In addition to binding to specific nuclear steroid receptors, dexamethasone also interferes with NF-kB activation and apoptotic pathways. Dexamethasone Acetate is chemically 9-fluoro-l l D, 17- dihydroxy-16D-methyl-3,20-dioxopregna-l,4-dien-21-yl acetate. The molecular formula and weight of Dexamethasone Acetate are C 24 H 31 FO 6 and 434.5 respectively.
  • Dexamethasone Acetate is a white or almost white, crystalline powder, practically insoluble in water, freely soluble in acetone and in alcohol, slightly soluble in methylene chloride. Dexamethasone Acetate shows polymorphism Pharmacology And Mechanism Of Action
  • Dexamethasone and its derivatives dexamethasone sodium phosphate and Dexamethasone Acetate, are synthetic glucocorticoids are used for their antiinflammatory or immunosuppressive properties.
  • Dexamethasone is used alone to manage cerebral edema and with tobramycin to treat corticosteroid-responsive inflammatory ocular conditions.
  • Dexamethasone is a glucocorticoid agonist. Unbound dexamethasone crosses cell membranes and binds with high affinity to specific cytoplasmic receptors.
  • dexamethasone results in a modification of transcription and, hence, protein synthesis in order to achieve inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, suppression of humoral immune responses, and reduction in edema or scar tissue.
  • the anti-inflammatory actions of dexamethasone are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.
  • 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.
  • Topical Dexamethasone Acetate 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 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. It is used to treat bacterial infections, such as infections of the joints and bones by killing or stopping the growth of the bacteria responsible.
  • the molecular formula of Sodium Fusidate is C3i H 47 Na0 6 .
  • the chemical name is 3 ⁇ , ⁇ , 16B-Trihydroxy 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.
  • Sodium Fusidate is virtually inactive against gram-negative bacteria.
  • the differences in activity against gram-negative and gram-positive organisms are believed to be due to a difference in cell wall permeability.
  • 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.
  • 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 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.
  • 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
  • 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 topical that have a pH value close to that of skin of a young adult.
  • 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, Dexamethasone 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 active drug penetrates the skin for the optimum bio-dermal efficacy.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in colloidal or molecular dispersed state for the product being highly efficacious form. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug.
  • the product of the present invention is highly efficacious due to the pronounced antibacterial & wound healing activity of the active ingredients, which are available in ultra micro-size, colloidal form, which enhances skin penetration.
  • 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.
  • Chitosan 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, Dexamethasone 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 straight forward process of mere addition.
  • the inventor has found that the compatibility of the functional excipient such as Chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product.
  • the inventors have found that well known excipients such as Xanthan Gum and carbomer which have been variously used as stabilizing agents, cannot be used in combination with functional biopolymers such as Chitosan.
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy Materials, and Emulsifiers etc. Polymers are used as gelling agents, suspending agents, viscosity builders, release modifiers, diluents, etc. Surfactants are used as wetting agents, emulsifiers; solubilising agents release enhancers, etc.
  • polymers & surfactants may or may not possess ionic charge. They may be anionic or cationic or non-ionic in nature. If anionic excipients are included in the formulation they interact with cationic formulation excipients and produce products which are not homogenous, aesthetically not appealing and give rise to unwanted by products, possible allergens, impurities, toxic substances etc due to incompatibility. 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
  • Dexamethasone Acetate provides relief against skin inflammations
  • Terbinafine 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 Dexamethasone Acetate and a biopolymer provided in a cream base, said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co- solvent, an acid, and water, preferably purified water.
  • Embodiment no. 1 A medicinal cream as disclosed in the preferred embodiment no 1 , wherein said cream further comprising any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.
  • Embodiment no. 2 A medicinal cream as disclosed in the preferred embodiment no 1 and the embodiment no. 1, wherein
  • said Fusidic Acid is present in an amount from about 0.1% (w/w) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w), and more preferably about 2.00 % (w/w), and in which the amount of said Sodium Fusidate used to form in situ said Fusidic Acid is in the range between about 0.1% (w/w) to about 25% (w/w), preferably from about 0.5% (w/w) to about 5% (w/w) and more preferably about 2.08 % (w/w), and
  • said topical corticosteroid is added from about 0.001% to about 5% by weight, preferably from about 0.01% to about 1.00% by weight, and most preferably from about 0.1 % by weight, and further wherein said corticosteroid is Dexamethasone Acetate , and - said antifungal is added from about 0.5% to about 3.0% by weight, preferably from about 0.5% to about 2.0% by weight, and most preferably about 1.0% by weight; said antifungal preferably being Terbinafine Hydrochloride, 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 0.1% w/w, the molecular weight of said chitosan being 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 HC1, 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) to
  • 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).
  • 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).
  • Embodiment no. 5 A medicinal cream as disclosed in the preferred embodiment no 1 and 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, 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 medicinal cream as described in the preferred embodiment 1 and embodiments nos. 1 to 6 wherein Sodium Fusidate is converted in-situ under totally oxygen free environment by slow addition of an acid, into Fusidic Acid of a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic Acid regenerates into an extremely finely dispersed form when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic Acid in the final cream; all operations of converting Sodium Fusidate into Fusidic Acid carried out preferably in an environment free of atmospheric oxygen.
  • Embodiment no. 8 A medicinal cream as described in the preferred embodiment 1 and embodiment's 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 medicinal cream as described in the preferred embodiment 1 and embodiments no. 7 and 8 wherein said oxygen-free environment comprises a gaseous environment formed of inert gas selected from a group comprising carbon dioxide, nitrogen, helium and the like.
  • Preferred embodiment 2 discloses a process to make a dermaceutical cream containing Fusidic Acid, said process comprising the step of using Sodium Fusidate as the raw API and converting it in situ into Fusidic Acid under oxygen- free environment in a cream base.
  • Embodiment No. 10 In an embodiment of the present invention the process of making the composition is disclosed, wherein the step of converting the Sodium Fusidate in situ into Fusidic Acid of the preferred embodiment no. 2 comprises the steps of:
  • 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 ° C to 80 ° C,
  • a preservative selected from a group comprising Benzyl alcohol, Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, and the like, either singly or any combination thereof, in an amount between 0.5% (w/w) and 1.5% (w/w), preferably 1.2% (w/w),more preferably 1.00% (w/w)Benzyl alcohol.
  • 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% (w/w), more preferablyl2.5% (w/w), to an oil-phase vessel and melting said wax by heating to 70 ° C to 80 ° C,
  • 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), more preferably 2% (w/w), and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature
  • 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 19% (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 Sodium Fusidate in the mixture,
  • an acid selected from a group comprising acids such as HNO 3 , 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), adding in a second API-vessel propylene glycol in an amount between 1% (w/w) to 10% (w/w), preferably 5% (w/w), more preferably 3% (w/w), dispersing Dexamethasone Acetate in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill and dissolving Dexamethasone Acetate in it by continuous mixing, said Dexamethasone Acetate added in an amount between 0.001% (w/w) and about 5% (w/w), preferably
  • a third API-vessel propylene glycol in an amount between 1% (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 10% (w/w) and dispersing Terbinafine Hydrochloride in it by continuous mixing to form a dispersion, followed by passing said dispersion through a colloid mill, said Terbinafine Hydrochloride added in an amount between 0.5% (w/w) and about 3% (w/w), preferably from about 0.5% (w/w) to about 2% (w/w) and more preferably about 1 % (w/w),
  • step g transferring the contents of said first API- vessel of step i to the mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • a biopolymer-mixing vessel adding an acid, selected from a group comprising acids such as HC1, H2S0 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, the molecular weight of said chitosan being between lkDal and 5000 kDal,
  • step p transferring the contents of the biopolymer-mixing vessel of step o 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,
  • step g cooling the contents of the mixing vessel of step g 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 h of the embodiment no. 10 above also serves as a humectant. However, in another embodiment of the invention, an additional humectant may be added, in the step a of embodiment 7, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, from about 5% (w/w) to 50% (w/w), preferably 5% (w/w) to 35% (w/w), more preferably 32% (w/w).
  • 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 5% (w/w) to 35% (w/w), more preferably 32% (w/w).
  • Embodiment No. 12 In another embodiment of the present invention the process described in embodiment no. 11 further incorporates adding a chelating agent, after the step of adding a preservative, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, from about 0.05% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a chelating agent after the step of adding a preservative, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, from about 0.05% (w/w) to 1% (w/w), preferably 0.5% (w/w), more preferably 0.1 % (w/w).
  • a chelating agent after the step of adding a preservative, selected from a group comprising Disodium EDTA and the like, either singly or any combination thereof, from about 0.05% (w/w) to 1% (w/w),
  • 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 1.00% (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 1.00% (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 oxidants in the step h of embodiment 10 selected from a group comprising Butylated Hydroxy Toluene, Butylated Hydroxy Anisole and the like from about 0.001% (w/w) to 1% (w/w), preferably 0.1% (w/w), more preferably 0.01% (w/w).
  • an anti oxidants in the step h of embodiment 10 selected from a group comprising Butylated Hydroxy Toluene, Butylated Hydroxy Anisole 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 ° C to 80 ° C,
  • a preservative selected from a group comprising Benzyl alcohol, Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, and the like, either singly or any combination thereof, added in an amount between 0.5% (w/w) and 1.5% (w/w), preferably 1.2% (w/w), more preferably 1.00% (w/w), the preferred preservative being Benzyl alcohol, adding to said water-phase vessel of step b a chelating agent, or buffering agent , or a humectants added in combination thereof, wherein said chelating agent is preferably Disodium edetate, added in an amount between 0.05 %(w/w) and 1 %(w/w), preferably 0.5%(w/w),more preferably 0.1%(w/w), said buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount preferably 0.001% (w/w) to 2.00%
  • an oil-phase vessel preferably Cetostearyl alcohol, in an amount 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 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°C to 80°C, adding to said oil phase vessel a non ionic surfactant or emulsifiers, preferably 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 ionic surfactant or emulsifiers, preferably Cetomacrogol-1000 is added in an amount between 0.1% (w/w) and 5% (w/w), preferably 1% (
  • 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 19% (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,
  • step j adjusting the pH of the mixture in said first API-vessel of step j to below 2 by using 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),
  • 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),
  • step h transferring the contents of said first API-vessel of step k to said mixing vessel of step h with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas preferably being nitrogen,
  • 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 to form a 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% and about 1% by weight, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.1% w/w, molecular weight of said chitosan being between lkDal and 5000kDal,
  • step r transferring the contents of the biopolymer mixture of step q to the mixing vessel of step h with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen, s. cooling the contents of said mixing vessel of step h to 30 0 C to 37 0 C using circulation of cooled water from cooling tower at H 0 C to 15 0 C into the jacket of mixing vessel,
  • the co-solvent of step i also serves as a humectant.
  • an additional humectant may be added, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, from about 5% (w/w) to 50% (w/w), preferably 5% (w/w) to 35% (w/w), more preferably 32% (w/w).
  • a method of treating primary & secondary bacterial & fungal skin infections and inflammations comprising applying of a cream containing at least one corticosteroid Dexamethasone 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.
  • 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. It is essential that the active drug penetrates the skin for the optimum bio-dermal efficacy.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in a finely dispersed form for the product to be being efficacious. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug.
  • 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.
  • 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 25 ⁇ 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. 0.66 ⁇ 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 Dexamethasone 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 HN0 3 , HC1, H 2 S0 4 , 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 Fusidate
  • 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 oxidative degradation test. Further, in vitro antimicrobial zone of inhibition studies and preclinical studies such as blood clotting studies & burns wound healing studies were also carried out over a period of time.
  • Each gram of product of the present invention used for the tests contained Sodium Fusidate as the starting raw material in the amount required to produce approximately 2% (w/w) Fusidic Acid, 0.1% (w/w) Dexamethasone Acetate & l%(w/w) Terbinafine Hydrochloride in the finished product.
  • the product used for the Stability Studies tests contained approximately 10% extra API (average).
  • the product of the present invention used for studies contained Fusidic Acid cream prepared using Sodium Fusidate as starting material.
  • composition Fusidic Acid 2% (equivalent of Sodium Fusidate 2.08% w/w) + Dexamethasone Acetate (0.1% w/w) + Terbinafine Hydrochloride (l%w/w) + Chitosan 0.1% (w/w) Cream
  • PRODUCT Sodium Fusidate + Dexamethasone Acetate + Terbinafine Hydrochloride Cream
  • Composition i) Sodium Fusidate IP equivalent to Fusidic Acid IP 2.0 % ii) Dexamethasone Acetate IP 0.1 % iii) Terbinafine HC1 BP 1.0 %
  • product of the present invention is quite stable at ambient conditions and also at elevated temperature & humid conditions of storage. This is a major advantage over the currently available Fusidic Acid creams.
  • the stability of the product is further ascertained by the shelf-life prediction of the formulation using Arrhenius plot of degradation employing Nova-LIMS software.
  • the 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.
  • Excision wound healing activity of the cream of the present invention was determined through animal testing. An excision wound 2.5 cm in diameter was inflicted by cutting away full thickness of the skin. The amount of contraction of the wound observed over a period indicated that the cream of present invention provides significantly improved wound contraction than a control (untreated wound).
  • one benefit of the cream of the present invention is that it facilitates significantly faster epithelisation of the skin than a control (untreated wound).
  • Blood clotting time was observed in both groups of animals, untreated control group and the test group of animals treated with the product of the present invention. Statistically significant decrease in the blood clotting time in treated group animals was observed when compared with that of the control group animals. The mean percent reduction of 60 - 70% was observed for the blood clotting time using the product of the present invention.
  • the 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.
  • the cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations.
  • the novel cream of the present invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage - hence will go a long way in achieving these social objectives.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur une crème dermaceutique contenant de l'acétate de dexaméthasone comme corticostéroïde, un agent antifongique sous la forme de chlorhydrate de terbinafine et un agent antibactérien sous la forme d'acide fusidique, ledit acide fusidique étant formé in situ à partir de fusidate de sodium comme matière première de départ, le fusidate de sodium étant converti en acide fusidique dans un environnement exempt d'oxygène. La crème de la présente invention a une plus grande stabilité sur sa durée de conservation et une plus fine taille des particules du principe pharmaceutique actif (API) que les crèmes classiques contenant de l'acide fusidique. La crème de la présente invention contient de l'acide fusidique comme API qui a été formé in situ à partir de fusidate de sodium, de l'acétate de dexaméthasone et du chlorhydrate de terbinafine, dans une base de crème comprenant un conservateur, un acide, un cosolvant, des émulsifiants, et une matière cireuse conjointement avec de l'eau, de préférence de l'eau purifiée.
PCT/IB2011/050714 2010-02-22 2011-02-22 Crème médicinale contenant de l'acide fusidique fabriquée à l'aide de fusidate de sodium et incorporant un biopolymère, de la terbinafine et de la dexaméthasone et son procédé de fabrication WO2011101826A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012017383A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de béclométhasone, et du chlorhydrate de terbinafine et procédé de fabrication de celle-ci
WO2012017371A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du propionate de clobétasol, du chlorhydrate de terbinafine et son procédé de fabrication
WO2012017370A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de bétaméthasone, du chlorhydrate de terbinafine, et procédé de fabrication de celle-ci

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012017383A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de béclométhasone, et du chlorhydrate de terbinafine et procédé de fabrication de celle-ci
WO2012017371A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique fabriquée en utilisant du fusidate de sodium et en incorporant un biopolymère, du propionate de clobétasol, du chlorhydrate de terbinafine et son procédé de fabrication
WO2012017370A1 (fr) * 2010-08-02 2012-02-09 Sulur Subramaniam Vanangamudi Crème médicinale à l'acide fusidique obtenue en utilisant du fusidate de sodium et incorporant un biopolymère, du dipropionate de bétaméthasone, du chlorhydrate de terbinafine, et procédé de fabrication de celle-ci

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