MXPA06010641A - Novel compositions for topical delivery - Google Patents

Abstract

Pharmaceutical composition for topical administration comprising of at least one active ingredient, its salts, esters, hydrates or derivatives;a gelator system consisting of a fiend of surfactants, a solvent system comprising at least one oily component;an aqueous phase;optionally containing one or more stabilizing agent;and other pharmaceutically acceptable excipients;and process for preparing such compositions are provided. Also provided is a method for the management/treatment of fungal, bacterial or microbial infections, inflammations, autoimmune conditions, or hormonal disorders which comprises administering a pharmaceutically effective amount of such pharmaceutical composition to a subject in need of such treatment. The compositions of the present invention are non-greasy and easily water washable, and provides an enhanced localization of hydrophobic and/or amphiphilic active ingredients on the skin.

Description

NOVEDOS COMPOSITIONS FOR TOPICAL SUPPLY FIELD OF THE INVENTION The present invention relates to topical pharmaceutical compositions, methods for preparing said compositions, and method for the management of microbial and / or fungal infections of the skin layers, inflammations, autoimmune conditions or hormonal disorders using said compositions. Preferably, the present invention relates to topical compositions comprising the active ingredient (s) either (s) alone or in combination, which are highly effective in the management of microbial infections and / or fungal from the upper layers of the skin, particularly epidermis and dermis, autoimmune conditions, or hormonal disorders.

BACKGROUND OF THE INVENTION Many topical formulations, especially those comprising antifungal, antibacterial or antimicrobial drugs, immunomodulators, or steroids exist in the literature but most of them suffer from drawbacks such as instability, poor retention on the surface of the skin, lack of aesthetic appeal, and difficulty in removing the surface of the skin.

Terbinafine hydrochloride is a synthetic allylamine derivative useful as a topical antifungal agent. Terbinafine hydrochloride exerts its antifungal effect by inhibiting squalene epoxidase, a key enzyme in sterol biosynthesis in fungi. This action results in a deficiency in ergosterol and a corresponding accumulation of sterol within the fungal cell. Terbinafine has been described in the US patent. No. 4,755,538, which reports a number of methods for the preparation thereof. Several articles have been published which emphasize the pharmaceutical properties of terbinafine: see Petranyl, G. et al: Science. 1984, 24, 1239; Stutz A. et al, J. Med. Chem., 1984, 27, 1539. Topical formulations comprising immunosuppressive drugs such as cyclosporin, tacrolimus, etc. and steroids such as testosterone, etc. which are highly absorbed, have an acceptable aesthetic appeal, and are docile to patients in terms of easy use and removal of the surface of the skin, have difficulty in developing, especially due to the large size of the drug molecule or poor absorption through the skin. Tacrolimus is an immunosuppressant of macrolides produced by Streptomyces species. Cyclosporin is an immunosuppressive agent of a cyclic polypeptide consisting of 11 amino acids. It is produced as a metabolite by the fungal species Beauveria nlyea. No topical composition comprising cyclosporin is available in the market.

The patent of E.U.A. No. 6,383,471 describes compositions and method for improved delivery of ionizable hydrophobic therapeutics. However, these compositions do not require a combination of surfactants as an essential feature of the invention. Also, there is no indication of gelation ie, a formation of especially a structured gel of oily components used in the mixture of surfactants for the topical delivery of drugs. The patent of E.U.A. Nos. 6,451, 339, 6294192 and 6,309,663 disclose pharmaceutical formulations for administration of a hydrophobic lipid regulating agent, comprising a therapeutically effective amount of the lipid regulating agent and a carrier, wherein the carrier is formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. These compositions use a mixture of surfactants; said compositions after dilution with an aqueous solvent form a clear aqueous dispersion of the surfactants containing the therapeutic agent. However, these compositions are not related to the gelling properties of the solvent using mixtures of surfactants nor are they for topical use. The patent of E.U.A. No 6, 455,592 describes the use of penetration agents in dermatological compositions for the treatment of onychomycosis, and corresponding compositions with a pharmaceutically effective amount of terbinafine hydrochloride, a solvent medium comprising water, and at least one C2-C8 alkanol of straight or branched chain and a hydrophilic penetrating agent. The patent of E.U.A. No. 6,309,663 claims the triglyceride-free pharmaceutical compositions for improved absorption of a hydrophilic therapeutic agent comprising hydrophilic and hydrophobic surfactants. The patent of E.U.A. No. 6,761, 903 discloses a pharmaceutical composition comprising a carrier comprising a triglyceride and at least two surfactants, at least one of the surfactants being hydrophilic; and a therapeutically effective amount of a polysaccharide drug, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in a ratio of aqueous medium to carrier of about 100: 1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 to 400 nm. However, none of the patents describe compositions comprising a gelling system, which consists of a mixture of surfactants, a solvent system comprising at least one oil component; an aqueous phase; optionally containing one or more stabilizing agents; and other pharmaceutically acceptable excipients; wherein the mixture of surfactants act as gelling agents of the oil component present in the solvent system and lead to the formation of a highly structured gelled composition which provides a uniform and localized release in the skin of the active ingredient. The patent of E.U.A. No. 5,446,070 describes compositions and methods for topical administration of pharmaceutically active agents.

However, this is a bioadhesive composition for topical application and contains essentially no lipophilic solvents and / or surfactants. The patent of E.U.A. No. 5,593,680 discloses cosmetic or dermopharmaceutical compositions in the form of modified aqueous gels by the addition of expanded microspheres. The patent of E.U.A. No. 5,660,839 and 5,993,083 discloses a non-tacky, non-greasy composition comprising at least one fatty substance and an amount of deformable hollow particles effective to prevent the greasy and / or sticky feeling otherwise attributable to at least one fatty substance, said deformable hollow particles comprise a copolymer of vinylidene chloride, acrylonitrile and a (meth) acrylic comonomer. The patent of E.U.A. No. 5,665,386 describes the use of essential oils to increase the bioavailability of oral pharmaceutical compounds but does not disclose the use of a specific mixture of surfactants to cause the gelling of said oils. The patent of E.U.A. Nos. 5,681, 849 and 5,856,355 describe topical pharmaceutical compositions comprising terbinafine in free base form or in an acid addition salt form, water, a lower alkanol, and a water-miscible or water-soluble nonionic surfactant, in where no anionic surfactant is present and wherein said composition is an emulsion or lotion gel, which further comprises an oil phase and a thickener. However, this invention does not relate to the use of surfactant mixtures for the gelation of solvents as a carrier for hydrophobic drugs. The patent of E.U.A. No. 5,385,907 describes an ointment consisting essentially of a tricyclic compound such as tacrolimus, solubilizing agent and / or absorption promoter selected from the group consisting of a lower alkanediol, a lower alkylene carbonate, an alkane dicarboxylic ester, an glycerin, superior alkane carboxylic acid, a higher alkene carboxylic glycerin ester, an upper alkane carboxylic alkyl ester, a higher unsaturated alcohol and an azacycloalkane, and an ointment base selected from the group consisting of oil and fat bases. However, said preparations are oily and adhere to the skin, and are not easily removed after washing with water. The patent of E.U.A. No. 6,022,852 discloses a pharmaceutical preparation comprising cyclosporin A, polyethylene glycol 1000 tocopherol succinate, and optionally an emulsifier, with the exception of a vegetable oil or fat. The patent of E.U.A. No. 6,113,921 relates to the pharmaceutical composition for topical or transdermal improved effect, comprising drops on the sub-micron size scale of a water-insoluble drug in an aqueous dispersion system, wherein the drops consist essentially of about 0.5 to 30% of a first component of an oily liquid comprising the drug, about 0.1 to 10% of a second component of an emulsifier and about 0.05 to 5% of a third component of a nonionic surfactant, in where the second and third components are different. The patent of E.U.A. No. 5,891, 846 claims an oil-in-water emulsion composition containing cyclosporin comprising cyclosporin, a polyalkyl ester of a polycarboxylic acid in the form of a liquid at room temperature, at least one oil component, a surface active agent and crotamiton. The patent of E.U.A. No. 5,807,820 discloses a topical pharmaceutical composition for dermal administration comprising cyclosporin, a mono- or poly-unsaturated fatty alcohol of C-? 2-24 and dermally acceptable topical carriers or diluents. The patent of E.U.A. No. 5,504,068 describes a topical preparation comprising cyclosporin; an organic solvent; and a skin penetration enhancer, said skin penetration enhancer being at least one element selected from the group consisting of alkanolamines and monovalent alcohol esters of myristic acid, adipic acid and sebasic acid. None of the literature available in the art discloses compositions comprising a therapeutic agent (s) and a mixture of surfactants to produce gelation of the solvent component (s) containing the agent (s). ) therapeutic (s) as essential ingredients, which can lead to localized and highly effective topical preparations for prolonged duration of activity. Preferably, there is still an unfulfilled need to develop highly effective topical compositions for the management of antimicrobial, antifungal, autoimmune, or hormonal disorders that may produce the desired effects for prolonged periods with minimal systemic absorption thus avoiding undue drug toxicity. .

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide a pharmaceutical composition for topical administration that provides an improved location of the ingredient comprising at least one active ingredient, its salts, esters, hydrates or derivatives; a gelling system consisting of a mixture of surfactants, a solvent system comprising at least one oil component; an aqueous phase comprising one or more stabilizing agents; and optionally other pharmaceutically acceptable excipients; wherein the mixture of surfactants act as gelling agents of the oil component present in the solvent system forming a three-dimensional network that immobilizes the characterized solvent system so that the gelled oil phase of surfactant can accommodate the aqueous phase without changing the micro-environment of lipids and the gel architecture of the composition. It is also an object of the present invention to provide a method for the preparation of a pharmaceutical composition for topical administration that provides an improved location of the active ingredient comprising at least one active ingredient, its salts, esters, hydrates or derivatives; a gelling system consisting of a mixture of surfactants, a solvent system comprising at least one oil component; an aqueous phase comprising one or more stabilizing agents; and optionally other pharmaceutically acceptable excipients; wherein the mixture of surfactants act as gelling agents of the oil component present in the solvent system forming a three-dimensional network that immobilizes the solvent system characterized in that the gelled oil phase of surfactant can accommodate the aqueous phase without changing the lipid microenvironment and the gel architecture of the composition, which comprises the following steps: i. preparation of the oil phase comprising the gelling system, ii. incorporate the active ingredient in the oil phase, iii. Preparation of the aqueous phase comprising the stabilizer, iv. Mix the oil phase and the aqueous phase with continuous agitation to obtain the desired composition. It is a further object of the present invention to provide a method for the treatment of fungal, bacterial or microbial infections, inflammations, autoimmune conditions or hormonal disorders comprising administering a pharmaceutically effective amount of said pharmaceutical composition to a subject in need of such treatment. The compositions of the present invention provide an improved location of the hydrophobic and / or amphiphilic active ingredients for the management of microbial and / or fungal infections of the skin, or for the treatment of autoimmune or hormonal disorders. It is even another object of the present invention to provide pharmaceutical compositions that are easily washable in water and essentially non-greasy for topical administration.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition for topical administration which provides an improved location of the active ingredient comprising at least one active ingredient, its salts, esters, hydrates or derivatives; a gelling system consisting of a mixture of surfactants, and a solvent system comprising at least one oil component; an aqueous phase comprising one or more stabilizing agents; and optionally other pharmaceutically acceptable excipients. The mixture of surfactants present in the pharmaceutical compositions of the present invention acts as gelling agents of the oil component present in the solvent system forming a three-dimensional network that immobilizes the solvent system characterized in that the gelled oil phase of surfactant can accommodate the phase aqueous without changing the lipid microenvironment and the gel architecture of the composition.

The pharmaceutical compositions of the present invention are preferably a topical gelled system with a lipid rich microenvironment, but easily washable in water. In an essential embodiment, the present invention overcomes the problems related to the location of the drug in the upper layers of the skin by providing a single lipid microenvironment based on a gelifier. The term "gelling" as used herein refers to the gelation of the oily component by the mixture of surfactants used in the composition of the present invention which leads to the formation of a highly structured system. The present invention provides pharmaceutical compositions comprising a hydrophobic or amphiphilic active ingredient, selected but not limited to a group comprising antifungals such as terbinafine, butenafine, griseofulvin, and the like; antibacterials such as sertaconazole, minocycline, and the like; immunomodulators such as cyclosporin, tacrolimus, and the like; steroids such as testosterone, hydrocortisone, and the like, analgesics, anti-inflammatory agents such as nimesulide, diclofenac, ibuprofen, naproxen, and the like; keratinizing agents such as salicylic acid, antimicrobials, skin sensitizing or nourishing agents, anti-psoriatic and anti-eczema drugs, used alone or in combination thereof. In a preferred embodiment of the present invention, the active ingredient is terbinafine, tacrolimus, cyclosporin, testosterone, hydrocortisone, or salts, esters, hydrates or derivatives thereof.

In one embodiment, the pharmaceutical composition of the present invention comprises a gelling system consisting of a mixture of surfactants comprising at least two surfactants wherein at least one is a hydrophilic surfactant having a higher HLB value than or equal to around 10; and a lipophilic surfactant having an HLB value of less than about 10. The lipophilic surfactant component is present in an amount sufficient to achieve the required concentration ratio of the surfactant mixture to produce the gelation of one or more components oil present in the solvent system. In another embodiment, the gelling system is present in an amount of from about 5% to about 50% by weight of the total weight of the composition. The hydrophilic surfactant of the gelling system of the present invention is selected but not limited to the group comprising polyoxyethylene alkyl ethers; polyoxyethylene sorbitan fatty acid esters known as polysorbates; polyoxyethylene alkylphenols; fatty acid esters of polyethylene glycol; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols; polyoxyethylene vegetable oils; hydrogenated polyoxyethylene vegetable oils; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of fatty acids; laurylmacrogolglycerides, or mixtures thereof. The lipophilic surfactant of the present invention is selected but not limited to the group consisting of fatty acids; sorbitan fatty acid esters; esters of acetylated glycerol fatty acid; esters of lower alcohol fatty acids; transesterification products of fatty acids; glycerides, vegetable oils, hydrogenated vegetable oils, triglycerides and polyalkylene glycols; sterols and sterol derivatives; fatty acid esters of pentaerythritol and polyalkylene glycol ethers; monoglycerides and acetylated, for example mono- and di-acetylated monoglycerides; or mixtures thereof. Preferably, the gelling system of the present invention consists of a mixture of surfactants comprising a lipophilic surfactant which is a sorbitan fatty acid ester selected from a group comprising sorbitan monolaurate (SPAN® 20), sorbitan monopalmitate ( SPAN® 40), sorbitan monooleate (SPAN® 60) and sorbitan monostearate (SPAN® 80); and a hydrophilic surfactant which is a polyoxyethylene sorbitan fatty acid ester selected from a group comprising polyoxyethylene sorbitan monolaurate (TWEEN® 20), polyoxyethylene sorbitan monopalmitate (TWEEN® 40), polyoxyethylene sorbitan monooleate (TWEEN® 60) , and polyoxyethylene sorbitan monostearate (TWEEN® 80). More preferably, the lipophilic surfactant is SPAN® 80 and the hydrophilic surfactant is TWEEN® 80.

In one embodiment of the present invention, the ratio of hydrophilic surfactant to lipophilic surfactant is from about 1: 20 to about 20: 1. The solvent system of the present invention comprises at least one oil component, and one or more components selected from a group comprising but not limited to lipophilic solvents and hydrophilic solvents such as methanol, ethanol, isopropanol, triethyl citrate, citrate of acetylbutyl, or triacetin, ethylene glycol, propylene glycol, glycerol, polyethylene glycol and polyethylene glycol esters. The oily components of the solvent system are selected but not limited to natural oils, mono-, di or triglyceride esters of oils selected from a group consisting of medium chain triglycerides, oleic acid, ethyl oleate, ethyl caprylate, ethyl butyrate, isopropyl myristate, soybean oil, canola oil or its mono- and diglycerides, aluminum monostearate, aluminum distearate, aluminum tristearate, microcrystalline wax, petroleum wax and mixtures, used either alone or in combination with them. Preferably, at least one oily component of the solvent system is a medium chain triglyceride. In another embodiment of the pharmaceutical composition of the present invention, the aqueous phase comprises water, aliphatic or aromatic alcohols, glycerols or mixtures thereof. The lipophilic solvents include triethyl citrate, acetylbutyl citrate or triacetin, triglyceride selected but not limited to the group comprising vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures used either alone or in combination therewith. The hydrophilic solvents are selected but not limited to a group consisting of water, glycols, for example propylene glycol, butylene glycol, hexylene glycol, ethylene glycol, and polyethylene glycols; and mixtures, used either alone or in combination with them. In one embodiment of the present invention, the solvent system comprises at least one oil component (s) and / or at least one lipophilic solvent (s), and optionally hydrophilic solvent (s) (s). ); said composition may further contain from 1% to 30% by weight of the aqueous phase relative to the total weight of the composition. In one embodiment, the composition of the present invention optionally comprises a stabilizing agent (s), wherein the stabilizing agent is a natural, synthetic or semi-synthetic polymer that acts as a structure former and stabilizer in optical formulations which oscillates from an emulsion, cream, lotion or gel in its consistency and architecture. The stabilizing agent (s) useful in the present invention is selected from a group of natural and synthetic polymers and carbohydrates such as chitosan, alginates, carrageenan, cellulose derivatives, pectin, starch, xanthan gum, albumin, alginate, gelatin, acacia, cellulose dextran, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, colloidal silicon dioxide, hyaluronic acid, carboxyethylcellulose, carboxymethylcellulose, poloxamer (polyethylene-propylene glycol copolymer), carbopol (carbomer), acrylic acid-based polymers and derivatives thereof. Preferably the stabilizing agent of the present invention is a poloxamer. In yet another embodiment, the stabilizer is added either in the oil phase, or in the aqueous phase or is added as an aqueous solution to about a concentration ranging from 0.1% to 20% of the total weight of the composition. In one embodiment of the present invention, the other pharmaceutically acceptable excipients are selected but not limited to the group comprising preservatives, formulation aids, antioxidants diluents, pH adjusting agents, pH regulating agents, tonicity modifiers, colorants, and the like or mixtures thereof. In one embodiment of the present invention, the preservative and antioxidants are selected from a group comprising parabens such as sodium methylparaben, sodium propylparaben, benzalkonium chloride, benzyl alcohol, sodium metabisulfite, butylated hydroxytoluene, butylated hydroxyanisole, sulfur, and the like or mixtures thereof. In one embodiment of the present invention, the formulation aid can be selected from the group comprising a poloxamer, carbopol, cellulose polymers, acrylic acid-based polymer and the like, and mixtures thereof. In one embodiment of the present invention, the formulation aid can be selected from a group comprising citric acid, tartaric acid, and the like. In one embodiment, the compositions of the present invention are in the form of a cream, gel, jelly, lotion, ointment, topical solution or the like, preferably in the form of a cream or gel. In another embodiment, the compositions of the present invention serve for highly localized topical administration for hydrophobic and / or amphiphilic active ingredients, including but not limited to antibacterials, antifungals, antiparasites, antifungals, antibiotics, anti-inflammatories, analgesics (narcotic and non-narcotic). , antiseptics, disinfectants, antipsoriatics, anti-eczema, anti-aging, anti-statin, anti-pruritic, keratolytic, anti-seborrheic, glucocorticoid, steroid, immunomodulators, muscle relaxants, anti-viral, anesthetic, antiallergic, or its salts , esters, hydrates or derivatives as used either alone or in combination thereof. In even a further embodiment, the analgesic and / or antiinflammatory agent selected but not limited to a group comprising, nimesulide, acetaminophen, acetanilide, acetylsalicylates, acetylsalicylic acid, alminoprofen, aspirin, benoxaprofen, carbamazepine, diflunisai, enfenamic acid, etodolac, fenoprofen , flufenamic acid, flurbiprofen, diclofenac, ibufenac, piroxicam, indomethacin, indoprofen, ketoprofen, ketorolac, microprofen, morpholine salicylate, naproxen, phenacetin, phenyl salicylate, quinine salicylate, salicylamide, salicylic acid, salicylates and their derivatives, tenoxicam, tolfenamic acid, tramadol, etc., or their salts, esters, hydrates or derivatives thereof. Surprisingly, the inventors of the present have found that compositions comprising a combination of a lipophilic or hydrophilic surfactant can gel a combination of oily and lipophilic solvents (collectively referred to as "solvent system") and incorporate a sufficient amount of aqueous phase without changing lipid microenvironment and gel architecture. The use of these compositions results in an improved location of the hydrophobic and / or amphiphilic active ingredients essentially for the treatment of microbial and / or fungal infections of the skin layers, or autoimmune or hormonal disorders. In the present invention, the gelling components (combination of surfactants) provide gelation of the solvent system and thus form a three-dimensional network. This is due to the fact that surfactant molecules have a tendency to interact in a solvent environment that leads to the formation of aggregates. These are also related to another through contact points, and in this way the three-dimensional networks are established, which immobilize the solvent system and act as a gel. The addition of aqueous components generally does not break these tubular and toroid structures and in addition, the stabilizing agent (s) emulsifies the access oil, which has not been gelled during the gelation process. This also provides a cosmetic appearance to the composition. further, this highly lipophilic microenvironment in interaction with skin lipids aims to form a deposit within the skin layers through which trapped hydrophobic drug can be released over a prolonged period in a localized area. In a preferred embodiment, the therapeutic agent (s) present in the pharmaceutical compositions of the invention have about 0.1% about 10% by weight, based on the total weight of the pharmaceutical composition. In yet another embodiment, the present invention provides a method for the preparation of a pharmaceutical composition for topical administration that provides an improved location of the active ingredient comprising at least one active ingredient, its salts, esters, hydrates or derivatives; a gelling system consisting of a mixture of surfactants, a solvent system comprising at least one oil component; an aqueous phase comprising one or more stabilizing agents; and optionally other pharmaceutically acceptable excipients; wherein the mixture of surfactants act as gelling agents of the oil component present in the solvent system forming a three-dimensional network that immobilizes the solvent system characterized in that the gelled oil phase of surfactant can accommodate the aqueous phase without changing the microenvironment of lipids and a gel architecture of the composition. In another embodiment, the method of preparing compositions of the present invention comprises preparing an oil phase by mixing the ingredients under temperature and stirring followed by incorporation of the active ingredient (s) with stirring; preparation of an aqueous phase by mixing the ingredients under temperature and agitation; and mixing the oil phase and the aqueous phase under temperature and stirring to obtain the desired product. The present invention also provides methods for the management / treatment of fungal, bacterial or microbial infections, inflammations, autoimmune conditions, or hormonal disorders comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a pharmaceutical composition as described in I presented. In order to illustrate the embodiments of the present invention, the following examples are provided. However, these examples are not intended to limit the scope of the invention.

EXAMPLES EXAMPLE 1 No. of Ingredients Amount m. (mg / g) 1. Terbinalin hydrochloride 10.00 2. Sorbitan monostearate 195.00 3. Polysorbate 20 21.50 4. Medium chain triglyceride 41.85 5. Aqueous poloxamer 188 solution (7% w / w) 34.00 6. Benzyl alcohol 10.00 7 Sodium metabisulfite 5.00 8. Purified water in. to 1.00 g The topical formulation was prepared as follows Preset heavy amounts of sorbitan monostearate, polysorbate 20, medium chain triglyceride and benzyl alcohol were taken. The contents were heated with continuous stirring in a water bath at constant temperature while maintaining the temperature of the mass at 60-65 ° C. Terbinafine hydrochloride was added in the melt while it was stirred until a homogeneous mixture was achieved. An aqueous phase is prepared. A predetermined heavy amount of poloxamer 188 was mixed with purified water (7% w / w). To this was added sodium metabisulfite in prescribed amount. The mixture was stirred and subsequently heated while maintaining the temperature of the mass at 60-65 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and the volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous agitation to obtain the desired product.

EXAMPLE 2 No. of Ingredients Amount m. (mg / g) 1. Terbinafine hydrochloride 10.00 2. Sorbitan monostearate 195.00 3. Polysorbate 20 21.50 4. Medium chain triglyceride 318.50 5. Aqueous carbopol 971 P solution (2% w / w) 250.00 6. Benzyl alcohol 10.00 7. Sodium metabisulfite 5.00 8. Triethanolamine 100.00 9. Purified water in. to 1.00 g The topical formulation was prepared in the following manner. Pre-determined heavy amounts of monostearate of sorbitan, polysorbate 20, medium chain triglyceride and benzyl alcohol were taken. The contents were heated with continuous stirring to a constant temperature water bath while maintaining the temperature of the mass at 60-65 ° C. Terbinafine hydrochloride was added to the melt, while stirring until a homogeneous mixture was obtained. An aqueous phase was prepared. A predetermined heavy amount of Carbopol 971 P and triethanolamine was mixed with purified water (2% w / w). To this was added sodium metabisulfite in prescribed amount and the mixture was stirred while maintaining the dough temperature at 60-65 ° C. The oil phase and the aqueous phase are maintained at 60-65 ° C and the volume of the aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired product.

EXAMPLE 3 No. and Ingredients Quantity m- (mg / g) 1. Butenafin hydrochloride 10.00 2. Sorbitan monostearate 195.00 3. Polysorbate 20 21.50 4. Medium chain triglyceride 318.50 5. Aqueous sodium alginate solution (2% w / w ) 250.00 6. Benzyl alcohol 10.00 7. Sodium metabisulphite 5.00 8. Triethanolamine 100.00 9. Purified water in. to 1.00 g The topical formulation was prepared in the following manner. The predetermined heavy amounts of sorbitan monostearate, polysorbate 20, medium chain triglyceride and benzyl alcohol were taken. The contents were heated with continuous agitation in a bath of water at constant temperature while maintaining the temperature of the dough at 60-65 ° C. Butenafine hydrochloride was added to the melt, while stirring until a homogeneous mixture was obtained. An aqueous phase was prepared. A predetermined heavy amount of sodium alginate and triethanolamine was mixed with purified water (2% w / w). To this was added sodium metabisulfite in prescribed amount and the mixture was stirred while maintaining the dough temperature at 60-65 ° C. The oil phase and the aqueous phase are maintained at 60-65 ° C and the volume of the aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired product.

EXAMPLE 4 No. or / and Ingredients Amount # 77. (mg / g) 1. Terbinafine hydrochloride 10.00 2. Glyceryl monostearate 195.00 3. Polysorbate 20 21.50 4. Medium chain triglyceride 318.50 5. Aqueous sodium alginate solution (2% w / w) 250.00 6. Benzyl alcohol 10.00 7. Sodium metabisulfite 5.00 8. Triethanolamine 100.00 9. Purified water in. to 1.00 g The topical formulation was prepared in the following manner. The predetermined heavy amounts of glyceryl monostearate, polysorbate 20, medium chain triglyceride and benzyl alcohol are they took The contents were heated with continuous stirring in a constant temperature water bath while maintaining the temperature of the mass at 60-65 ° C. Terbinafine hydrochloride was added in the melt, while stirring until a homogeneous mixture was obtained. An aqueous phase was prepared. A predetermined heavy amount of sodium alginate and triethanolamine is mixed with purified water (2% w / w). To this was added metabisulfite from sodium in prescribed amount and the mixture was stirred while maintaining the dough temperature at 60-65 ° C. The oil phase and the aqueous phase are maintained at 60-65 ° C and the volume of the aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired product.

EXAMPLE 5 No. of Ingredients Amount m. (mg / g) 1. Terbinafine hydrochloride 10.00 2. Glyceryl monostearate 19.50 3. Polysorbate 20 21.50 4. Isopropyl myristate 318.50 5. Aqueous poloxamer 188 solution (10% 0.250 P / P) 6. Benzyl alcohol 10.00 7. Sodium metabisulfite 5.00 8. Triethanolamine 100.00 9. Purified water in. to 1.00 g The topical formulation was prepared in the following manner. The predetermined heavy amounts of glyceryl monostearate, polysorbate 20, isopropyl myristate and benzyl alcohol were taken.

The contents were heated with continuous stirring in a water bath at constant temperature while maintaining the temperature of the mass at 60-65 ° C. Terbinafine hydrochloride was added to the melt, while stirring until a homogeneous mixture was obtained. An aqueous phase was prepared. A predetermined heavy amount of poloxamer 188 and triethanolamine is mixed with purified water (10% w / w). To this was added sodium metabisulfite in prescribed amount and the mixture was stirred while maintaining the dough temperature at 60-65 ° C. The oil phase and the aqueous phase are maintained at 60-65 ° C and the volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired product.

EXAMPLE 6 No. of Ingredients Amount m. (mg / g) 1. Terbinafine hydrochloride 10.00 2. Sorbitan monostearate 250.00 3. Polysorbate 20 25.00 4. Medium chain triglyceride 250.00 5. Isopropyl myristate 255.00 6. Propylene glycol 200.00 7. Benzyl alcohol 10.00 The topical formulation was prepared in the following manner.

The predetermined heavy amounts of sorbitan monostearate, polysorbate 20, medium chain triglyceride, propylene glycol, isopropyl myristate and benzyl alcohol were taken. The contents were heated with continuous stirring in a water bath at constant temperature while maintaining the temperature of the mass at 60-65 ° C. Terbinafine hydrochloride was added in the melt, while stirring until a homogeneous mixture was obtained.

The whitish cream-colored formulation thus obtained can be stored in a hermetically sealed HDPE container.

EXAMPLE 7 No. of Ingredients Amount m. (mg / g) 1. Terbinafine hydrochloride 10.00 2. Sorbitan monostearate 250.00 3. Polysorbate 20 25.00 4. Medium chain triglyceride 250.00 5. Propylene glycol 75.00 6. Chitosan 40.00 7. Citric acid 90.00 8. Benzyl alcohol 10.00 9. Water purified 250.00 The topical formulation was prepared in the following manner.

An oil phase was prepared first. The predetermined heavy amounts of sorbitan monostearate, polysorbate 20, medium chain triglyceride, propylene glycol and benzyl alcohol were taken; the liquid ingredients were passed through a nylon cloth and transferred to a S.S. with shirt. The solid ingredients were added to the contents of the S.S. and they mixed. This mixture was heated with continuous stirring by circulating hot water on the shirt while maintained the temperature of the dough at 60-65 ° C. Terbinafine hydrochloride is added in the previous merger, while stirring until achieving a homogeneous mixture. An aqueous phase was then prepared. The predetermined heavy amounts of chitosan and citric acid were mixed with sufficient purified water and the mixture was heated with continuous stirring while maintaining the temperature of the mass at 60-65 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and the volume of the aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired formulation.

EXAMPLE 8 No. of Ingredients Amount m. (mg / g) 1. Terbinafine hydrochloride 10.00 2. Nimesulide 10.00 3. Glyceryl monostearate 250.00 4. Polysorbate 20 50.00 5. Propylene glycol 320.00 6. Isopropyl myristate 350.00 7. Benzyl alcohol 10.00 The topical formulation was prepared in the following manner. The predetermined heavy amounts of glyceryl monostearate, polysorbate 20, isopropyl myristate, propylene glycol and benzyl alcohol were taken. The contents were heated with continuous agitation while maintaining the temperature of the dough at 60-65 ° C. They added terbinafine hydrochloride and nimesulide in the melt, while stirring until a homogeneous mixture was obtained. The whitening cream-like formulation obtained was stored in a hermetically sealed HDPE container.

EXAMPLE 9 No. of Ingredients Quantity (mg / g) m. 1. Clotrimazole 10.00 2. Polyethylene glycol distearate 250.00 3. Polysorbate 20 25.00 4. Mineral oil 250.00 5. Cytosan 40.00 6. Citric acid 80.00 7. Benzyl alcohol 10.00 8. Purified water 335.00 The topical formulation was prepared in the following manner. First an oil phase was prepared. Amounts were taken predetermined weights of polyethylene glycol distearate, polysorbate 20, medium chain triglyceride, mineral oil and benzyl alcohol; the liquid ingredients were passed through a nylon cloth and transferred to a S.S jacketed container. The solid ingredients were added to the contents of the S.S container and mixed. This mixture is heated with continuous agitation by circulating hot water in the shirt, same time that the temperature of the dough was maintained at 60-65 ° C. HE I added clotrimazole in the previous melted mixture, while still stirring until a homogeneous mixture was achieved. Then an aqueous phase was prepared. Predetermined heavy amounts of cytosan and citric acid were mixed with enough purified water and the mixture was heated with continued stirring while maintaining the temperature of the dough at 60-65 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to get the desired product.

EXAMPLE 10 No. of Ingredients Amount M. (mg / g) 1. Miconazole 20.00 2. Gentamicin sulphate 10.00 3. Polyethylene glycol distearate 250.00 4. Polysorbate 20 25.00 5. Isopropyl myristate 250.00 6. Citosan 40.00 7. Citric acid 80.00 8. Alcohol Benzyl 10.00 9. Purified water 315.00 The topical formulation was prepared in the following manner. An oil phase was prepared first. Determined heavy amounts of polyethylene glycol distearate, polysorbate 20, isopropyl myristate and benzyl alcohol were taken; the liquid ingredients were passed through a nylon cloth and transferred to a S.S container with shirt. The solid ingredients were added to the contents of the container S.S and mixed. This mixture was heated with continuous stirring making circulate hot water in the shirt while maintaining the temperature of the dough at 60-65 ° C. Miconazole and gentamicin were added in the above melt mixture while stirring until a homogeneous mixture was obtained. An aqueous phase was prepared. Predetermined heavy amounts of cytosan and citric acid were mixed with enough water purified and the mixture was heated with continued stirring while maintaining the mass temperature at 60-65 ° C. The phase was maintained oil and the aqueous phase at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with stirring Continue to obtain the desired product.

EXAMPLE 11 No. of Ingredients Amount M. (mg / g) 1. Sertaconazole 10.00 2. Sorbitan monostearate 250.00 3. Polysorbate 20 25.00 4. Medium chain triglyceride 250.00 5. Propylene glycol 75.00 6. Cytosan 40.00 7. Citric acid 90.00 8. Benzyl alcohol 10.00 9. Water purified 250.00 The topical formulation was prepared in the following manner. First an oil phase was prepared. Amounts were taken weight samples of sorbitan monostearate, polysorbate 20, medium chain triglyceride, propylene glycol and benzyl alcohol. The liquid ingredients were passed through a nylon cloth and transferred to a S.S container with a shirt. The solid ingredients were added to the contents of the S.S container and mixed. This mixture was heated with continuous stirring by circulating hot water in the jacket while maintaining the mass temperature at 60-65 ° C. Sertaconazole was added to the above molten mixture while stirring until a homogeneous mixture was obtained. Then an aqueous phase was prepared. HE mixed predetermined heavy amounts of cytosan and citric acid with a sufficient purified water and the mixture was heated with stirring continues to same time that the temperature of the dough was maintained at 60-65 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired product.

EXAMPLE 12 No. of Ingredients Amount M. (mg / g) 1. Terbinalin hydrochloride 10.00 2. Methanol 20.00 3. Medium chain triglyceride (Crodamol GTC / C) 412.50 4. Sorbitan monostearate (SPAN-60) 195.00 . Polyoxyethylene sorbitan monolaurate (polysorbate 20) 21.50 6. Butylated hydroxytoluene (BHT) 0.90 7. Butylated hydroxyanisole (BHA) 0.01 8. Poloxamer 118 26.80 9. Triethanolamine 0.75 10. Benzyl alcohol 10.00 11. Purified water in. to 1.00 g The topical formulation was prepared in the following manner. First an oil phase was prepared. Amounts were taken predetermined weighings of sorbitan monostearate, polysorbate 20, medium chain triglyceride, butylated hydroxytoluene and butylated hydroxyanisole; the liquid ingredients were passed through a nylon cloth and transferred to a jacketed S.S container. The solid ingredients were added to the contents of the S.S container and mixed. This mixture was heated with continuous stirring by circulating hot water in the jacket while maintaining the temperature of the dough at 50-55 ° C. Terbinafine hydrochloride was dissolved in methanol and added to the above molten mixture, while stirring until a homogeneous mixture was obtained. Then an aqueous phase was prepared. Predetermined heavy amounts of poloxamer and triethanolamine were mixed with sufficient purified water and benzyl alcohol was added, and the mixture was heated with continuous stirring while maintaining the temperature of the mass at 50-55 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired formulation.

EXAMPLE 13 No. of Ingredients Amount M. (mg / g) 1. Terbinalin hydrochloride 10.00 2. Methanol 20.00 3. Medium chain triglyceride (Crodamol GTC / C) 412.50 4. Sorbitan monostearate (SPAN-60) 195.00 . Polyoxyethylene sorbitan monolaurate (polysorbate 20) 21.50 6. Butylated hydroxytoluene (BHT) 0.90 7. Butylated hydroxyanisole (BHA) 0.01 8. Poloxamer 118 26.80 9. Triethanolamine 0.75 10. Methylparaben sodium 1.80 11. Propylparaben sodium 0.20 12. Propylene glycol 10.00 13. Purified water c. n. to 1.00 g The topical formulation was prepared in the following manner. First an oil phase was prepared. Preset heavy amounts of sorbitan monostearate, polysorbate 20, medium chain triglyceride, sodium propylparaben, butylated hydroxytoluene were taken. butylated hydroxyanisole; the liquid ingredients were passed through a nylon cloth and transferred to a S.S. with shirt. The solid ingredients were added to the contents of the S.S. and they mixed. This mixture was heated with continuous stirring by circulating hot water in the jacket while maintaining the temperature of the dough at 50-55 ° C. Terbinafine hydrochloride was dissolved in methanol and added to the previous melted mixture, at the same time that it was stirred until obtaining a homogeneous mixture. Then an aqueous phase was prepared. Predetermined heavy amounts of poloxamer and methyl paraben sodium were mixed with enough purified water and propylene glycol was added and the mixture was added. heated with enough purified water and added propylene glycol and the mixture heated with continuous agitation at the same time that the dough temperature at 50-55 ° C. The oil phase and the phase were maintained aqueous at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring followed by the addition of benzyl alcohol to obtain the desired formulation.

EXAMPLE 14 No. of Ingredients Amount NI .. (mg / g) 1. Tacrolimus 0.30 2. Methanol 20.00 3. Medium chain triglyceride (Crodamol GTC / C) 422.20 4. Sorbitan monostearate (SPAN-60) 195.00 5. Polyoxyethylene sorbitan monolaurate 21.50 (polysorbate 20 ) 6. Butylated hydroxytoluene (BHT) 0.90 7. Butylated hydroxyanisole (BHA) 0.01 8. Poloxamer 118 26.80 9. Triethanolamine 0.75 10. Benzyl alcohol 10.00 11. Purified water c. n. to 1.00 g The topical formulation was prepared as follows: First an oil phase was prepared. Amounts were taken predetermined weighings of sorbitan monostearate, polysorbate 20, medium chain triglyceride, butylated hydroxytoluene and butylated hydroxyanisole; the liquid ingredients were passed through a nylon cloth and transferred to a S.S. with shirt. The solid ingredients were added to the contents of the S.S. and they mixed. This mixture was heated with continuous stirring by circulating hot water in the jacket while maintaining the temperature of the dough at 50-55 ° C. Tacrolimus was dissolved in methanol and added to the above melt while stirring to a homogenous mixture. Then an aqueous phase was prepared. Predetermined heavy amounts of poloxamer and triethanolamine were mixed with sufficient purified water and benzyl alcohol was added and the mixture was heated with continuous stirring while maintaining the temperature of the mass at 50-55 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired formulation.

EXAMPLE 15 No. of Ingredients Quantity M. (mg / g) 1. Tacrolimus 1.00 2. Ethanol 20.00 3. Medium chain triglyceride (Crodamol GTC / C) 399.00 4. Sorbitan monostearate (SPAN-60) 195.00 5. Polyoxyethylene sorbitan monolaurate 21.40 (Polysorbate 20) 6. Butylated hydroxytoluene (BHT) 0.90 7. Butylated hydroxyanisole (BHA) 0.01 8. Poloxamer 118 23.00 9. Methylparaben sodium 1.80 10. Propylparaben sodium 0.20 11. Propylene glycol 51.40 12. Tartaric alcohol 1.00 13. Purified water c . n. to 1.00 g The topical formulation was prepared in the following manner. First an oil phase was prepared. Preset heavy amounts of sorbitan monostearate, polysorbate 20, medium chain triglyceride, sodium propylparaben, butylated hydroxytoluene and butylated hydroxyanisole were taken; the liquid ingredients were passed through a cloth nylon and transferred to a S.S. with shirt. The ingredients solids were added to the contents of the S.S. and they mixed. This mixture was heated with continuous stirring by circulating hot water in the jacket while maintaining the temperature of the dough at 50-55 ° C. Tacrolimus was dissolved in methanol and added to the molten mixture before, while stirring until obtaining a homogeneous mixture.

Then an aqueous phase was prepared. Predetermined heavy amounts of poloxamer and methylparaben sodium were mixed with sufficient purified water and propylene glycol was added, and the mixture was heated with continuous stirring while maintaining the temperature of the mass at 50-55 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and added a volume of aqueous phase to the oil phase maintaining the temperature similar (60-65 ° C) with continuous agitation followed by the addition of alcohol benzyl to obtain the desired formulation.

EXAMPLE 16 No. of Ingredients Quantity M. (mg / g) 1. Ciclosporin 50.00 2. Methanol 20.00 3. Medium chain triglyceride (Crodamol GTC / C) 372.50 4. Sorbitan monostearate (SPAN-60) 195.00 5. Polyoxyethylene sorbitan monolaurate 21.50 (Polysorbate 20) 6. Butylated hydroxytoluene (BHT) 0.90 7. Butylated hydroxyanisole (BHA) 0.01 8. Poloxamer 118 26.80 9. Triethanolamine 0.75 10. Benzyl alcohol 10.00 11. Purified water n. to 1.00 g The topical formulation was prepared in the following manner.

First an oil phase was prepared. Amounts were taken weight samples of sorbitan monostearate, polysorbate 20, medium chain triglyceride, butylated hydroxytoluene and butylated hydroxyanisole; the liquid ingredients were passed through a nylon cloth and transferred to a S.S. with shirt. The solid ingredients were added to the contents of the S.S. and they mixed. This mixture was heated with continuous stirring by circulating hot water in the jacket, while maintaining the temperature of the dough at 50-55 ° C. Cyclosporin was dissolved in methanol and added to the above melt, while stirring further until a homogeneous mixture was obtained. Then an aqueous phase was prepared. Predetermined heavy amounts of poloxamer and triethanolamine were mixed with sufficient purified water and benzyl alcohol was added and the mixture was heated with continuous stirring while maintaining the temperature of the mass at 50-55 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and a volume of aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring to obtain the desired formulation.

EXAMPLE 17 No. of Ingredients Amount M. (mg / g) 1. Ciclosporin 80.00 2 Ethanol 20.00 3 Medium chain triglyceride (Crodamol GTC / C 320.0 4 Sorbitan monostearate (SPA? -60) 195.00 Polyoxyethylene sorbitan monolaurate 5 21.40 (Polysorvate 20) 6 Butylated hydrozatoluene ( BHT) 0.90 7 Butylated hydrosianisol (BHA) 23.00 8 Poloxamemer 18 23.00 9 Methylparaben sodium 1.80 10 Peopilparaben sodium 0.20 11 Propylene glycol 51.40 12 Tortoric acid 1.00 13 Purified water cn to 100 g The topical formulation was prepared in the following manner.

First an oil phase was prepared. Preset heavy amounts of sorbitan monostearate, polysorvate 20, medium chain triglyceride, propyl paraben sodium, butylated hydroxytoluene and butylated hydroxyanisole were taken; the liquid ingredients were passed through a cloth nylon and transferred to a S.S. with shirt, the solid ingredients were added to the contents of the S.S. and they mixed. This mixture was heated with continuous stirring by circulating hot water in the shirt, while maintaining the temperature of the dough at 50-55 ° C. Cyclosporin was dissolved in methanol and added to the previous melt mixture, at the same time that it was agitated until achieving a homogeneous mixture. Then an aqueous phase was prepared. Predetermined heavy amounts of poloxamer and methylparaben sodium were mixed with sufficient purified water and propylene glycol was added and the mixture was heated with continuous stirring while maintaining the temperature of the mass at 50-55 ° C. The oil phase and the aqueous phase were maintained at 60-65 ° C and a volume of the aqueous phase was added to the oil phase maintaining the similar temperature (60-65 ° C) with continuous stirring followed by the addition of benzyl alcohol for get the desired formulation.

Dermopharmacokinetic study The dermatopharmacokinetic (DPK) studies in the present invention are used to mimic clinical dome assays of documentation of the bioavailability and equivalence of topical products of the drug. For the therapeutic class of antifungal drugs, the corneo state itself is the site of action. For example, in fungal infections of the skin, the fungi reside in the stratum corneum and therefore the measurement of the DPK in an antifungal drug in the stratum corneum represents the direct measurement of the concentration of the drug at the site of action. No better bioequivalence assay for this class of compounds can be predicted than the direct assay of the target tissue. The "strip cut" method that is used is capable of demonstrating the differences in the location in the stratum corneum (SC) of said invention over competing products. This is determined by applying different compositions of said invention to the surface of the skin during a specified exposure time, adhesive films are placed on the treated skin and removed again after a certain time of application, and the analysis of the amount located in the stratum corneum using a validated analytical method to measure the location index in the stratum corneum by area of unit of applied area. The dermatofarmacokinetic study (DPK) was studied to determine the comparative efficacy of the topical formulations of Terbinalfina HCl of the innovative product (Lamisil®, referred to herein as INV) and Panacea Bistec Ltd. (DDR-FRD-F1, in the present it is referred to as PBL). The composition described in Example 2 above has been coded as DDR-FRD-F1 and is used for said study. The assay values of the compositions used for the study were as follows: (Lamisil® contained 0.099 mg of Terbinafine HCl per mg of the cream formulation and DDR-FRD-F1 (encoded for example 2) contained 0.090 mg of Terbinafine. HCl per mg of cream formulation The strip cutting experiment was carried out following the guideline of US FDA (Guidance for inndustry: Topical dermatoiogical drug product NDAs and ANDAs-invitro bioequivalence, in Vitro relay and associated studies). of the test in the mentioned study was the following: first the hair of the experimental animal (guinea pig) is removed by epilation (preferably) and then the animals are exposed in a conditioned room maintained at 20 ° with 60% RH This condition has to be maintained during the experimental period.The dorsal side of the guinea pigs (2X235 cm2) is marked on the left and right dorsal sites. to simultaneously carry out the control to check the reading of the baseline. Approximately 65.0 to 125.0 mg of the formulations (1% topical creams ie 100.0 mg formulations containing 1 mg of the active drug, terbinafine hydrochloride) were applied to the stratum corneum of five guinea pigs (N = 5 denoted as N1, N2, N3, N4 and N5). A non-occlusive protective barrier is placed to cover the application area (non-occlusive aluminum foil is used). After 15 minutes the excess formulation is removed from the application site by lightly cleaning three times with a cotton swab. The initial and final weight of the cotton swab was measured to precisely monitor the amount applied per square meter of the skin. After appropriate time intervals, the samples were collected after cutting into strips using adhesive tape. The Transpore ™ tape (model 1527-1, 2.5 cm2 surface area, 3M) was used as adhesive tape. The adhesive tape was applied using uniform pressure and was removed at different time intervals using a constant release force. The duration of the study was 24 hours at the following intervals: 0.5, 1.0, .3.0, 6.0, 12.0 and 24.0 hours. Tweezers with rounded tips were used to apply the individual adhesive tape with a constant pressure, each time by the same researcher. Both the test and reference products are applied on the same site to counterbalance the variation between the subjects. The procedure was repeated at each site at the designated time points. The drug was extracted from eight cuts in combined strips and the concentration was determined using a validated analytical method. The first two cuts were removed in strips and were not included in the validation of the analytical method (to accommodate the contamination of the residual product). Eight other cuts were taken in strips and sampled for each interval, and analyzed using a validated estimation method for Terbinafine hydrochloride. Samples from strips were stored in a 10 ml polypropylene tube with 7.0 ml at 80:20 v / v acetonitrile and TEA (0.72 mM) at pH 2.5, and subjected to shaking for 16 hours. In case of delay, the samples were stored at -70 ° C until they were processed. The supernatant was passed through a 0.45 μm filter and subjected to a validated HPLC analytical method. The results of the study are expressed as a concentration of the drug (nmol) calculated to be in the stratum corneum (SC) per cm2 of the area applied (ie, the calculation for 100 nmol per cm2 of the applied cream). The results of the study are presented in tables 1 to 3 and in figure 1, as mentioned below. Table 1: Calculation of the location of the drug of the inventor's formulation (PBL) in the corneous stratum Table 2: Calculation of the location of the drug of the innovative formulation (INV) in the stratum corneum Table 3: Comparative efficacy of the formulation of the Inventor (PBL) on the innovative formulation (INV) of the dermatofarmacokinetic studies (DPK) Figure 1: Comparative profile of the dermatofarmacocinetic (DPK) of the inventor's formulation (PBL) and the innovative formulation (INV) The results of the Dermatofarmacokinetic study showed a significant increase in the location of Terbinafina HCl in the skin (stratum corneum), and therefore improved the effectiveness of the composition of the present invention on the innovative product (Lamisil®).

TABLE 1 Calculation of the location of the drug of the inventor's formulation (PBL) in the stratum corneum TABLE 2 Calculation of the location of the drug of the innovative formulation (INV) in the stratum corneum TABLE 3 Comparative efficacy of the inventor's formulation (PBL) on the innovative formulation (INV) from dermatofarmacokinetic studies (DPK) Location Codes in SC (nmol / cnX) after 100.0 nmol / cnX applied dose application N1 N2 * N3 * N4 * N5 * INNOVATIVE PRODUCT (LAMISIL '"") INV-0.5 5,832 7,364 7,615 18.02 6,541 INV-1.0 6,650 4,238 5,238 9,341 8,064 INV-3.0 13,912 8,576 6,113 6,233 6,573 INV-6.0 4,151 4,807 3,023 7,042 4,672 INV-12.0 5,150 3,541 0,789 3,993 3,272 INV-24.0 1,993 2,188 0.296 2,152 1,861 PRODUCT OF THE INVENTOR / PBL PRODUCT (DDR-FRD-F1) PBL-0.5 6.964 14.322 7.247 20.571 9.435 PBL-1.0 3,629 2,833 13,397 8.8307 6,539 PBL-3.0 15,849 15,755 3,613 12,181 11,701 PBL-6.0 3,381 4,155 3,078 12,802 8,667 PBL-12.0 4,025 4,579 3,559 7.0115 2,531 PBL-24.0 2,509 6,617 3,485 4,011 2,653 * Number of animals (N = 5, guinea pigs) that were used in the study denoted as N1, N2, N3, N4 and N5 0.5, 1.0, 3.0, 6.0, 12.0 & 24.0 denotes the time intervals in hours.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. A composition for topical administration comprising an improved location of the active ingredient, comprising at least one active ingredient, its salts, esters, hydrates or derivatives; a gelling system consisting of a mixture of surfactants, a solvent system comprising at least one oleaginous component; an aqueous phase comprising one or more stabilizing agents; and optionally other pharmaceutically acceptable excipients; wherein the mixture of surfactants acts as a gelling agent of the oleaginous component that is present in the absorbent system, forming a three-dimensional network that immobilizes the solvent system, characterized in that the gelled oleaginous phase of the surfactant can be accommodated to the aqueous phase without changing the lipid microenvironment and the gel architecture of the composition.

2. The pharmaceutical composition according to claim 1, further characterized in that the active ingredient has a hydrophobic or amphiphilic nature.

3. The pharmaceutical composition according to claim 1, further characterized in that the active ingredient is selected from the group comprising antifungal, antibacterial, immunomodulatory, steroid, analgesic, anti-inflammatory, keratinizing agents, antimicrobial, nutrient or sensitizing agents. of the skin, anti-psoriatic agents and anti-eczema, which are used alone or in combination thereof.

4. The pharmaceutical composition according to claim 3, further characterized in that the active ingredient is terbinafine, its salts, esters, hydrates or derivatives thereof.

5. The pharmaceutical composition according to claim 3, further characterized in that the active ingredient is a immunomodulator that is selected from tacrolimus or cyclosporin, or salts, esters, hydrates or derivatives thereof.

6. The pharmaceutical composition according to claim 3, further characterized in that the active ingredient is a steroid selected from testosterone or hydrocortisone or salts, esters, hydrates or derivatives thereof.

7. The pharmaceutical composition according to claims 1 to 6, further characterized in that the gelling system consists of a mixture of surfactants comprising at least two surfactants, wherein at least one is a hydrophilic surfactant having a surface-active agent. HLB value greater than or equal to approximately 10; and a lipophilic surfactant having an HLB value of less than about 10, said lipophilic surfactant component is present in an amount sufficient to achieve the required concentration ratio of the surfactant mixture to achieve the gelation of one or more oleaginous components that are present in the solvent system.

8. The pharmaceutical composition according to claims 1 to 7, further characterized in that the gelling system consists of a mixture of surfactants comprising at least two surfactants, wherein the two surfactants are nonionic.

9. The pharmaceutical composition according to claims 1 to 8, further characterized in that the gelling system is present in an amount of about 5% to about 50% by weight of the total weight of the composition.

10. The pharmaceutical composition according to claims 1 to 9, further characterized in that the hydrophilic surfactant is selected from the group comprising polyoxyethylene sorbitan fatty acid esters, sodium docusate, succinylated monoglycerides, lauryl sulfates, taurocholates, caprylates , caprates, oleates, poloxamer, or mixtures thereof.

11. The pharmaceutical composition according to claims 1 to 9, further characterized in that the lipophilic surfactant is selected from the group comprising sorbitan fatty acid esters, polyoxyethylene alkyl ethers, fatty acid esters, polyoxyethylene glycerides, transesterified vegetable oils, hydrogenated polyoxyethylene vegetable oils, or mixtures thereof.

12. The pharmaceutical composition according to claims 1 to 9, further characterized in that the gelling system consists of a mixture of surfactants comprising a lipophilic surfactant which is a sorbitan fatty acid ester selected from a group comprising monolaurate of sorbitan, sorbitan monopalmitate, sorbitan monooleate and sorbitan monostearate; and a hydrophilic surfactant which is a polyoxyethylene sorbitan fatty acid ester selected from the group comprising polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, and polyoxyethylene sorbitan monostearate.

13. The pharmaceutical composition according to claims 7 to 12, further characterized in that the ratio of the hydrophilic surfactant to the lipophilic surfactant is approximately 1: 20 to about 20: 1.

14. The pharmaceutical composition according to claim 1, further characterized in that the solvent system comprises at least one oleaginous component, and one or more other components selected from the group comprising methanol, ethanol, isopropanol, triethyl citrate, citrate of acetylbutyl or triacetin; other hydrophilic solvents selected from the group comprising ethylene glycol, propylene glycol, glycerol, polyethylene glycol, and polyethylene glycol esters.

15. - The pharmaceutical composition according to claim 14, further characterized in that the at least one oleaginous component of the solvent system is selected from the group comprising natural oils, mineral oil, mono-, di- or triglyceride esters of oils selected from the group consisting of medium chain triglycerides, oleic acid, ethyl oleate, ethyl acrylate, ethyl butyrate, isopropyl myristate, soybean oil, canola oil or its mono and diglycerides, aluminum monostearate, aluminum distearate, tristearate aluminum, microcrystalline wax, petroleum wax and mixtures, used alone or in combination with them.

16. The pharmaceutical composition according to claims 14 and 15, further characterized in that the at least one oleaginous component of the solvent system is a medium chain triglyceride.

17. The pharmaceutical composition according to claim 1, further characterized in that the aqueous phase comprises water, aliphatic or aromatic alcohols, glycols, or mixtures thereof.

18. The pharmaceutical composition according to claim 1, further characterized in that the stabilizing agent is a natural, synthetic or semi-synthetic polymer that acts as a forming and stabilizing structure in topical formulations ranging from an emulsion, cream, lotion or gel in its consistency and architecture, which are selected from a group comprising chitosan, poloxamer, cellulose polymers, gums and alginates.

19. The pharmaceutical composition according to claim 18, further characterized in that the stabilizing agent is poloxamer.

20. The pharmaceutical composition according to claims 18 and 19, further characterized in that the stabilizer is added either in the oil phase or in the aqueous phase, or is added as an aqueous solution in a concentration ranging up to approximately 0.1. % to 20% of the total weight of the composition.

21. The pharmaceutical composition according to claim 1, further characterized in that the other pharmaceutically acceptable excipients are selected from the group comprising preservatives, formulation aids, antioxidants, diluents, pH adjusting agents, pH regulating agents, tonicity modifiers. , dyes, and the like, or mixtures thereof

22. A process for the preparation of a pharmaceutical composition according to claim 1, comprising the following steps: i) the preparation of the oleaginous phase comprises a gelling system; ii) incorporating the active ingredient (s) in the oil phase; iii) the aqueous phase preparation comprises stabilizer; V) Mix the oil phase and the aqueous phase with continuous stirring to obtain the desired composition.

23. - The use of a composition as claimed in claim 1, for the preparation of a medicament for the treatment of fungal, bacterial or microbial infections, inflammations, autoimmune conditions or hormonal disorders.