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WO2011101828A1 - Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère et de la bétaméthasone, et procédé de réalisation associé - Google Patents

Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère et de la bétaméthasone, et procédé de réalisation associé Download PDF

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Publication number
WO2011101828A1
WO2011101828A1 PCT/IB2011/050716 IB2011050716W WO2011101828A1 WO 2011101828 A1 WO2011101828 A1 WO 2011101828A1 IB 2011050716 W IB2011050716 W IB 2011050716W WO 2011101828 A1 WO2011101828 A1 WO 2011101828A1
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amount
cream
vessel
added
mixture
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WO2011101828A8 (fr
Inventor
Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kausik Ghosh
Sankar Haridas
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Priority to PH1/2012/501666A priority Critical patent/PH12012501666A1/en
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Publication of WO2011101828A8 publication Critical patent/WO2011101828A8/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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 and wounds including burn wounds.
  • the Fusidic Acid and a biopolymer in the form of chitosan
  • a corticosteroid in the form of Betamethasone Dipropionate
  • 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 20 comprise an antibiotic/antibacterial such as Fusidic Acid, corticosteroid such as
  • Betamethasone Dipropionate and a biopolymer such as chitosan and the like are examples of biopolymer such as chitosan and the like.
  • Fusidic Acid in fine powder form is used as source API.
  • the small particle size enhances its dermal contact by providing a large specific surface area and penetration, and provides a smooth feel on application to skin.
  • a serious shortcoming of the fine size of Fusidic Acid particles is that it presents an enormous surface area for contact and reaction with molecular Oxygen during manufacture, handling, and processing of the cream. This has serious implications to its chemical stability and results in rapid reduction in potency of the API (Fusidic Acid) in the final cream formulation.
  • Sodium Fusidate is known to have been used to make dermaceutical medicaments for topical application.
  • these are in the form of ointment rather than cream.
  • Drawbacks of ointments over creams are well known and it's generally preferable to use creams rather than ointments for topical application.
  • Skin disorders can be broadly categorized as those arising from bacterial forms or fungi.
  • Antifungal or antibacterial compositions are traditionally applied as lotions, creams or ointments. Furthermore in many instances, it is difficult to ascertain whether the skin condition is due to a bacterial agent or a fungus.
  • Antibacterial 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.
  • There are several treatments available to treat skin disorders caused by bacteria Typically, such compositions use steroids, antibacterial 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 conventionally available treatments do not focus on skin healing or rejuvenation; normally these two aspects are left to heal naturally.
  • the word healing as related to compromised skin conditions are not only about prevention, control, elimination of the source cause such as bacteria 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.
  • 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 Betamethasone Dipropionate 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.
  • compositions comprising a combination of Fusidic Acid and corticosteroid such as Betamethasone Dipropionate 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 Betamethasone Dipropionate both play important roles in reducing S.
  • 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.
  • the present invention relates to topical pharmaceutical compositions comprising a combination of Fusidic Acid and corticosteroid such as Betamethasone
  • Dipropionate 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 Betamethasone Dipropionate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection
  • EP2092935 relates to aerosolized formulations for the treatment of asthma that contain mometasone furoate and formoterol fumarate and processes for preparing same.
  • the formulation is substantially free of CFC's and has utility in metered dose pressurized inhalers (MDI's).
  • MDI's metered dose pressurized inhalers
  • the formulation comprises effective amount Betamethasone Dipropionate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3, -heptaflouopropane, additionally it consist of dry powder surfactant.
  • EP2092935 claims novelty on the assertion that the aerosol suspension formulation is non-toxic, substantially free of CFC's, has improved stability, it is also easily manufacturable and is substantially free of a carrier and excipients.
  • the applicant has also disclosed a process for the production of the formulation wherein dry powder of the active agents and the surfactant is mixed together and filled into a metered dose inhaler canister, followed by crimping the canister with a metering valve, and filling it with nonchlorofiuorocarbon propellant.
  • PCT/IN2008/000577 provides a treatment of inflammatory dermatoses associated with secondary bacterial infections using a combination therapy of a topical antibiotic and a topical steroid.
  • the composition comprises a combination of Fusidic Acid and corticosteroid Betamethasone Dipropionate.
  • the application further discloses yet another formulation comprising Fusidic Acid and corticosteroid such as halobetasol propionate useful in treatment of infected steroid responsive dermatoses.
  • PCT/IN2008/000577 claims novelty on the assertion that the applicant had found a combination which is very effective for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • the applicant has disclosed 2 formulations of which the first formulation consists of a) 1% w/w - 5%w/w of Fusidic Acid; b) 0.05% w/w to 2%w/w of Betamethasone Dipropionate; and c) a pharmaceutically acceptable carrier and the second formulation comprises a) 1 % w/w - 5% w/w of Fusidic Acid; and b) 0.01 % to 2% w/w of Halobetasol propionate; and c) a pharmaceutically acceptable carrier.
  • the first composition is effective in the treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, allergic contact dermatitis, psoriasis and atopic dermatitis with secondary bacterial infections of skin while the second is useful for the treatment of steroid responsive dermatoses such as secondarily infected dermatoses including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
  • the formulation is available in the forms include hydrous or anhydrous semisolids such as creams, gels, ointments and lotions.
  • WO2008126076 discloses a topical cream composition comprising low dose Betamethasone Dipropionate for the treatment of corticosteroid responsive dermatoses.
  • the composition can be safely applied over large surface areas of the skin (including areas with wrinkles and/or hair), and can be used for extended periods of time (e.g., greater than 3 weeks) without any adverse effects.
  • the cream composition of the present invention is apparently safe for the use of babies and infants under 2 years old.
  • cream base matrix as a functional element of the cream rather than a mere carrier for the main APIs
  • Another object of the present invention is to provide a medicinal cream that is effective in treatment of skin inflammations, bacterial skin infections, wounds including burn wounds.
  • Figure 1 Non-homogeneous nature of creams containing chitosan with non- compatible excipient such as carbomer
  • the present invention is directed to a medicinal composition for treating skin inflammations, bacterial skin infections and related wounds, and also other skin wounds including those caused by burns.
  • the cream also causes skin rejuvenation through an epithelisation process.
  • the cream comprises:
  • a cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants.
  • 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 & Betamethasone Dipropionate 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 humectants, or any combination thereof.
  • 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 & Betamethasone Dipropionate is not commercially available.
  • 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.
  • Fusidate (rather than Fusidic Acid) as the starting raw material.
  • Sodium Fusidate has been used in dermaceutical applications, it has not been possible to make creams that use Sodium Fusidate. This is because of the inherent alkalinity of Sodium Fusidate (pH 7.5 to 9), which means it cannot be used in a cream form therefore all products manufactured using Sodium Fusidate as starting material are ointments.
  • a dermaceutical cream that uses Sodium Fusidate 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 -
  • Fusidic Acid (the API) that has been prepared using Sodium Fusidate as the starting API, in which Fusidic Acid forms in-situ under totally oxygen-free environment created using inert gas, preferably nitrogen, by slow addition of an acid, into a molecular dispersion form (due to the presence of a co-solvent) at the intermediate stage, and which Fusidic Acid regenerates as an extremely fine dispersion when added to a final cream base, thereby resulting in a finely and homogeneously dispersed Fusidic Acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen created using inert gas, preferably nitrogen.
  • the cream made using the process of the present invention contains Fusidic Acid as the API that has been formed in situ from Sodium Fusidate, a biopolymer - Chitosan, and Betamethasone Dipropionate as a steroid, in a cream base comprising a preservative, an acid, a co-solvent, an emulsifier and a waxy material along with water, preferably purified water.
  • the active compounds Sodium Fusidate & Betamethasone Dipropionate which may be employed in the process of the present invention as starting APIs are well known in the art of treating bacterial primary & secondary bacterial skin infections, and skin inflammations.
  • the active compounds Sodium Fusidate & Betamethasone Dipropionate 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 humectants, 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 Betamethasone Dipropionate as a steroid, is added.
  • the cream of the present invention is used in the treatment of bacterial skin 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
  • 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.
  • 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
  • Betamethasone Dipropionate Betamethasone Valerate, Fluticasone Propionate,
  • Mometasone Furoate Dexamethasone Acetate, Hydrocortisone Acetate,
  • Clobetasol Propionate Clobetasol Propionate, Beclomethasone Dipropionate, and the like.
  • suitable biopolymer 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. 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.
  • 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, i.e. Sodium Fusidate, &
  • Betamethasone Dipropionate as the starting actives and chitosan.
  • concentration of chitosan medium chain grade was carefully arrived based on several in house trials and Preclinical animal studies for efficacy.
  • Topical corticosteroids are a powerful tool for treating skin diseases.
  • Corticosteroids include drugs such as Betamethasone Dipropionate, Beclomethasone dipropionate, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate, etc.
  • drugs such as Betamethasone Dipropionate, Beclomethasone dipropionate, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate,
  • Topical corticosteroids are classified by their potency, ranging from weak to extremely potent. They include weak potent steroids, moderate potent steroids, potent steroids, very potent steroids and extremely potent steroids.
  • the high potency steroids include Betamethasone Dipropionate, Betamethasone Valerate, Diflorasone Diacetate, Clobetasol Propionate, Halobetasol Propionate, Desoximetasone, Diflorasone Diacetate, Fluocinonide, Mometasone Furoate, Triamcinolone Acetonide, etc.
  • Low potency topical steroids include Desonide, Fluocinolone acetate, and Hydrocortisone acetate, etc.
  • Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.
  • Betamethasone Dipropionate is a synthetic adrenocorticosteroid and an analog of prednisolone, which has high corticosteroid activity and slight mineral-corticoid activity. Betamethasone Dipropionate is the 17, 21-dipropionate ester of betamethasone.
  • Betamethasone Dipropionate is 9-Fluoro-l l ⁇ , 17, 21 -trihydroxy- ⁇ -methylpregna-l, 4-diene-3, 20-dione 17, 21-dipropionate, with the empirical formula C28H37F07, a molecular weight of 504.6.
  • corticosteroids are a class of compounds comprising steroid hormones, secreted by the adrenal cortex and their synthetic analogs. In pharmacologic doses corticosteroids are used primarily for their anti-inflammatory and/or immunosuppressive effects.
  • Topical corticosteroids such as Betamethasone Dipropionate
  • Betamethasone Dipropionate are effective in the treatment of corticosteroid-responsive dermatoses primarily because of their anti- inflammatory, antipruritic, and vasoconstrictive actions.
  • the physiologic, pharmacologic, and clinical effects of the corticosteroids are well known, the exact mechanisms of their actions in each disease are uncertain.
  • 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.
  • 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 Anti-bacterial is intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance Staphylococcus Aureus (MRSA) etc.
  • Anti-bacterial act by inhibiting cell wall synthesis by combining with bacterial ribosomes and interfering with mRNA ribosome combination.
  • Sodium Fusidate belongs to the group of medicines known as antibiotics.
  • the molecular formula of Sodium Fusidate is C31 hUyNaOe.
  • the chemical name is 3 ⁇ , 11 ⁇ , 166-Trihydroxy 29- ⁇ -8 ⁇ , 9 ⁇ , 13 ⁇ , 146-dammara-17(20) [10, 21-cis], 24-dien-21-oic acid 16-acetate, sodium salt. It is a white color 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 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.
  • the pH of the Chitosan Cream with Betamethasone Dipropionate and Sodium Fusidate 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. 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 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).
  • the product of the present invention is highly efficacious due to the pronounced anti-inflammatory & wound healing activity of the active ingredients, which are available in ultra micro-size, colloidal form, which enhances skin penetration. Rationale for the Use of Betamethasone Dipropionate, Sodium Fusidate, and Chitosan Combination
  • Topical Sodium Fusidate have profound efficacy in primary & secondary bacterial skin infections of varied etiology due to its antibacterial properties.
  • a drawback of the monotherapy with any topical antibacterial has been the relatively slow onset of the effect.
  • Fusidic Acid along with Betamethasone Dipropionate & chitosan in a formulation, the properties of antibacterial and anti-inflammatory agents as well as chitosan are optimized.
  • chitosan is film forming, biocompatible, non- allergenic material it helps in protecting the skin by acting as a barrier. It further controls the superficial bleeding caused by scratching and also arrests the mobility of pathogens due to its cationic charge.
  • the properties of Sodium Fusidate, Betamethasone Dipropionate, and chitosan's skin regenerative aspects are well exploited in the present invention and the maximum therapeutic benefit is passed on to the patient thereby aiding in faster healing. This ensures that the patient would benefit for the treatment of skin inflammations, wounds, burns with bacterial infections.
  • chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments.
  • Another inventive aspect of the present invention is that the addition of a functional excipient in the cream base is not a straight forward process of mere addition.
  • the inventor has found that the compatibility of the functional excipient such as chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product.
  • the inventors have found that well known excipients such as Xanthan Gum and carbomer which have been variously used as stabilizing agents, cannot be used in combination with functional biopolymers such as chitosan.
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy 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.
  • Betamethasone Dipropionate (see tables 3 - 7 ) containing Xanthan Gum &
  • Fusidic Acid provides relief against bacterial infections
  • Betamethasone Dipropionate provides relief against skin inflammations.
  • the aspects such as like skin protection, bleeding at the site, mobility of pathogens from one site to another, etc are not addressed so far in a single dose therapy that includes Fusidic Acid generated in situ from Sodium Fusidate.
  • This present invention with its single-dose application fills this gap by incorporating chitosan and tapping the required benefits of skin protection (by way of film forming property), stopping the bleeding (by way of blood clotting property) and immobilization of pathogenic microbes (due to its cationic electrostatic property).
  • Therapeutic value addition by incorporation of a functional excipient in the form of a chitosan which is a biopolymer in the cream matrix is an integrated sub-set of the following functional attributes of the biopolymer: formation of a micro -film on the skin surface,
  • the unique innovative formulation of the present invention takes care of the skin conditions by treating them along with controlling the superficial bleeding at the site. It is well understood that if the superficial bleeding is left untreated, it will lead to secondary microbial infections.
  • the present invention advantageously provides a solution to this unmet need.
  • Preferred embodiment no. 1 A medicinal cream for topical treatment of bacterial skin infections, inflammations and for related wound healing including burns wound, wherein said cream comprises an antibacterial agent, Sodium Fusidate, a corticosteroid Betamethasone Dipropionate 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 humectants, 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
  • said corticosteroid is added from about 0.001% to about 2.5% by weight, preferably from about 0.005% to about 1.00% by weight, and most preferably from about 0.05% by weight, and further wherein said corticosteroid is Betamethasone Dipropionate, 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, Cetomacrogo 1-1000, 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 , FINC , Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w) to
  • said preservative is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 0.5% (w/w); said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 25% (w/w) to 50% (w/w), more preferably 25% (w/w) to 40% (w/w), preferably purified water.
  • 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 1.00% (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 1.00% (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).
  • Embodiment no.6 A medicinal cream as disclosed in the preferred embodiment no 1 , and embodiments nos. 2 to 5 further comprising a humectants 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 25% (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,
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), more preferably Benzoic acid, c.
  • 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 preferably! 2.5% (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, Cetomacrogo 1-1000, 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 Cetomacrogo 1-1000 is added in an amount between 0.1 % (w/w) and 5% (w/w), preferably 1.0% (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 and 5% w/w, more preferably 2% w/w and mixing the mixture thoroughly, preferably using an agitator, at 10 to 50 RPM while maintaining the temperature of the mixture at 70 0 C to
  • 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 13% (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 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
  • Betamethasone Dipropionate added in an amount between 0.001 % (w/w) and about 2.5% (w/w), preferably from about 0.005 (w/w) to about 1.0% (w/w) and more preferably about 0.05 % (w/w),
  • step k 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, H 2 SO 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 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 5000kDal, n.
  • an acid selected from a group compris
  • step m transferring the contents of the biopolymer-mixing vessel of step m to the mixing vessel of step g with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under inert gas flushing and under vacuum of minus 1000 to minus 300 mm of mercury, said inert gas being preferably nitrogen,
  • 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,
  • step h of the embodiment no. 10 above also serves as humectants.
  • an additional humectants 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, to form a from about 5% (w/w) to 50% (w/w), preferably 30% (w/w), more preferably 26% (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 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 1.0% (w/w), preferably 0.05% (w/w), more preferably 0.5% (w/w).
  • a buffering agent selected from 0.001 % (w/w) to 1.0% (w/w), preferably 0.05% (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 Anisole, Butylated Hydroxy Toluene and the like from about 0.001 % (w/w) to 1.0% (w/w), preferably 0.1% (w/w), more preferably 0.01 % (w/w).
  • an anti oxidants in the step h of embodiment 10 selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.001 % (w/w) to 1.0% (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 25% (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,
  • a preservative selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, either singly or any combination thereof, added in an amount between 0.05% (w/w) and 0.5% (w/w), preferably 0.3% (w/w), more preferably 0.2% (w/w), the preferred preservative being Benzoic acid
  • said buffering agent is preferably Di Sodium Hydrogen Ortho Phosphate, added in an amount preferably 0.001 % (w/w/w
  • a non ionic surfactant or emulsifier in an amount preferably between 1% (w/w) and 5%(w/w), more preferably 2% (w/w) of Polysorbate 80% and in an amount between 0.1 % (w/w) and 5% (w/w), preferably 1.0% (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 70 0 C to 80 ° C,
  • 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 HC1, 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 HC1, 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),
  • Betamethasone Dipropionate added in an amount between 0.001 % (w/w) and about 2.5% (w/w), preferably from about 0.005% (w/w) to 1.0% (w/w) and more preferably about 0.05 % (w/w), m.
  • 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,
  • n. transferring the contents of the said second API-vessel of step 1 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 vacuum, preferably of a magnitude between minus 1000 and minus 300 mm of mercury, o. in 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 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
  • step o transferring the contents of the biopolymer mixture of step o 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,
  • step i also serve as humectants.
  • an additional humectants may be added, selected from a group comprising Glycerin, Sorbitol, Propylene glycol and the like, either singly or any combination thereof, to form a from about 5% (w/w) to 50% (w/w), more preferably 26% (w/w).
  • a method of treating primary & secondary bacterial skin infections and inflammations comprising applying of a cream containing at least one corticosteroid Betamethasone Dipropionate, and Fusidic Acid which is made in situ under oxygen-free environment using Sodium Fusidate, wherein said cream comprises Fusidic Acid made using Sodium Fusidate, a cream base containing a preservative, primary and secondary emulsifiers, waxy materials, co-solvents, acids, and water.
  • Embodiment no. 17 A method of treating primary & secondary bacterial skin infections and inflammations said method comprising applying of a cream as described in the preferred embodiment 1 and any of embodiments 1 to 9.
  • the cream obtained using the process of the present invention is homogenous and white to off white in color 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 5 ⁇
  • 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 approximately 2.5 ⁇ whereas that for the existing creams varies between 14 ⁇ to 19 ⁇ .
  • the minimum particle size observed was approx. 0.47 ⁇ 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, anti- inflammatory activity of the Betamethasone Dipropionate which is 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, H2SO4, HNO3, 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 in one
  • 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, & 0.05% (w/w) Betamethasone Dipropionate 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 aluminum 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 as mentioned below.
  • composition Fusidic Acid 2.0% (equivalent of Sodium Fusidate 2.08% w/w) + Betamethasone Di ro ionate (0.05 %w/w) + Chitosan 0.1 % (w/w) Cream
  • PRODUCT Sodium Fusidate + Betamethasone Dipropionate Cream
  • composition i) Sodium Fusidate IP equivalent to Fusidic Acid IP 2.0 % ii) Betamethasone Dipropionate USP 0.05 % Table 10: Description Test, Batch No. STD-01
  • Measured parameter pH Limits of measured parameter: 3.5-5.5
  • 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 cream is applied after thorough cleansing and drying the affected area. Sufficient cream should be applied to cover the affected skin and surrounding area. The cream should be applied two - four times a day depending upon the skin conditions for the full treatment period, even though symptoms may have improved.
  • Excision wound healing activity of the cream of the present invention was determined through animal testing. An excision wound 2.5 cm in diameter was inflicted by cutting away full thickness of the skin. The amount of contraction of the wound observed over a period indicated that the cream of present invention provides significantly improved wound contraction than a control (untreated wound).
  • one benefit of the cream of the present invention is that it facilitates significantly faster epithelisation of the skin than a control(untreated wound).
  • Blood clotting time was observed in both groups of animals, untreated control group and the test group of animals treated with the product of the present invention. Statistically significant decrease in the blood clotting time in treated group animals was observed when compared with that of the control group animals. The mean percent reduction of 55-65% was observed for the blood clotting time using the product of the present invention.
  • the therapeutic efficacy of topically applied cream of the present invention is due to the pronounced antibacterial activity of the Sodium Fusidate against the organisms responsible for skin infections, pronounced anti-inflammatory activity of the
  • Betamethasone Dipropionate against inflammations the unique ability of actives to penetrate intact skin and wound healing & soothing properties of chitosan. It is further evident that the ability of the cream of the present invention to achieve statistically significant level of epithelisation as well as wound contraction is surprisingly greater than the currently available therapies.
  • 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 physico- chemical compatibility/stability and bio-release.
  • the cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations. 4.
  • the novel cream of the present invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage - hence will go a long way in achieving these social objectives.

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Abstract

La présente invention concerne une crème dermaceutique contenant du dipropionate de bétaméthasone en tant que corticostéroïde, et un agent antibactérien sous la forme d'acide fusidique, ledit acide fusidique étant formé in situ à partir de fusidate de sodium en tant que produit brut de départ, et ledit fusidate de sodium étant converti en acide fusidique dans un environnement exempt d'oxygène. La crème de la présente invention possède une meilleure stabilité de conservation, et une taille de particule de principe actif plus fine, que les crèmes classiques qui contiennent de l'acide fusidique. La crème de la présente invention contient de l'acide fusidique en tant que principe actif qui a été formé in situ à partir de fusidate de sodium, et du dipropionate de bétaméthasone, dans une base de crème qui comprend un conservateur, un acide, un co-solvant, des émulsifiants et un matériau cireux avec de l'eau, de préférence de l'eau purifiée.
PCT/IB2011/050716 2010-02-22 2011-02-22 Crème médicinale d'acide fusidique faite au moyen de fusidate de sodium et incorporant un biopolymère et de la bétaméthasone, et procédé de réalisation associé Ceased WO2011101828A1 (fr)

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PH1/2012/501666A PH12012501666A1 (en) 2010-02-22 2011-02-22 A medicinal fusidic acid cream made using sodium fusidate and incorporating a biopolymer, a corticosteroid - betamethasone dipropionate, and a process to make it

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IN58MU2010 2010-02-22
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WO2011101828A1 true WO2011101828A1 (fr) 2011-08-25
WO2011101828A8 WO2011101828A8 (fr) 2013-02-21

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FR3039399A1 (fr) * 2015-07-31 2017-02-03 Int Drug Licensing Creme pour l'admnistration de steroides et son procede de preparation

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FR3039399A1 (fr) * 2015-07-31 2017-02-03 Int Drug Licensing Creme pour l'admnistration de steroides et son procede de preparation

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