Title of Invention	COMPOSITION FOR THE EFFECTIVE TREATMENT OF MYCOSES
Abstract	A antimycotic composition comprising Terbibafine as an active agent in the from of an acidic-additive salt, a thickener, a solubilizer and target additives.

Full Text

THE PATENTS ACT 1970 COMPLETE / PROVISIONAL SPECIFICATION SECTION 10 -PReBtteT-PATCNT TOR THE COMPOSITION FOR THE EFFECTIVE TREATMENT OF MYCOSES CIPLA LIMITED MUMBAI CENTRAL MUMBAI - 400 008 AN INDIAN COMPANY INCORPORATED UNDER THE INDIAN COMPANIES ACT, 1956 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED This invention relates to a medical composition and. the use, thereof. More. particularly, it relates to a composition for topical application, in the form of a cream for the effective treatment of mycoses. The invention is a formulation of a pharmaceutical composition which consists as an active ingredient, terbinafine (I) given in the specification in the following form, % : (I) an acidic ~ additive salt = 1%; water 50-75%, thickeners and solubilizers. The formulation also contains non-ionic surfactants in the quantity whereby the mass ratio of compound I : the surfactant is equal to 1: (3-18). The surfactants are polyoxyethylene ether of fatty alcohol"s, glyceryl mono stearate and block polymer of polyethylene glycol and polypropylene glycol (Poloxamer). The composition will be a cream used for topical application. Terbinafine is solubilized with the help of propylene glycol and non-ionic surfactants. This is then included in an oil-in-water emulsion, where the aqueous phase constitutes 50-75%. Though Terbinafine is very active both in local and peroral administration, in the real practice, only the local application in the form of a cream is widely used, in which the medicine is maintained as dissolved in propylene glycol and non-ionic surfactant. Moreover, the cream technology is conventional. The local application mode in the form of the composition according to this invention is desirable, because of the following advantages: 1. The drug is more readily and completely released from the cream, and it rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum. Also high concentrations are achieved in hair follicles, hair and sebum-rich skin. 2. The cream has an elegant appearance with easy spreadibility. The above-mentioned advantages can be obtained by solubilizing the drug in the aqueous system with the help of non-ionic surfactants. Use of the acidic salt form is desirable, being the preferable example for embodying this invention, for in this case the drug solubility in the aqueous medium can be improved as compared to it"s free base. In a broad embodiment, the formulation consists of the compound in the form of a salt in combination with conventional solubilisers and waxes (thickeners) (white soft paraffin and cetostearyl alcohol) typical fillers for creams. According to the method proposed by this invention, an oil-in-water emulsion system is provided, wherein salt is dissolved in the aqueous phase. In another embodiment of the invention, it has been found that the precipitate of the salt in aqueous phase can be avoided through use of suitable solubilizers, e.g. a non-ionic surfactant. As the solubilizers preferably desired are those that are dissolved in, or mixed with water, compatible with the drug substance and additional fillers present in a given formulation. The solubilizers used in the invention are compatible with the skin , and other fillers of the composition. No irritation has been felt on usage of the composition. The following solubilizers are particularly suitable for the formulatioh:- a). "Cremophor RH 40", saponification number - approximately 50,-60, acid number "Cremophor RH 60", saponification number - approximately 40-50, acid number "Cremophor EL", having the molecular mass (determined by steam osmometry) approximately 1630, saponification number - approximately 65-70, acid number - approximately 2, iodine number - approximately 28-32; n2^ - approximately 1.471. "Nikkol". For example, "Nikkol HCO-60" is a product of reaction of the hydrogenized castor oil with ethylene oxide, exhibiting the following characteristics; acid number - 0.3; saponification number - 47.4; hydrdxyl number - 42.5; pH (5%) - 4.6; coloring index registered by APHA - 40; melting point - 36.0°C, freezing point 32.4°C; content of H2O(5, KF) - 0.03. b). Polyoxyethylene ethers of sorbitan and fatty acids, or polysorbates, for example of the type that is commercially available as "Tween" and "Armotan" , inclusive of such products as: "Tween 20: - polyoxyethylene(20)sorbitanemonolaurate; "Tween 40: - polyoxyethylene(20)sorbitanemonopalmitate; "Tween 60: - polyoxyethylene(20)sorbitanemonostearate; "Tween 65: - polyoxyethylene(20)sorbitanetristearate; "Tween 80: - polyoxyethylene(20)sorbitanemonooleate; "Tween 85: - polyoxyethylene(20)sorbitanetrioleate; "Tween 21: - polyoxyethylene(20)sorbitanemonolaurate; "Tween 61: - polyoxyethylene(2Q)sorbitanemonostearate; "Tween 81: - polyoxyethylene(20)sorbitanemonooleate. c). Polyoxyethylene ethers of fatty acids, for example polyoxyethylene ethers of stearic acid of the type that is commercially available as "Myrf ; as well as polyoxyethylene ethers of fatty acids that are commercially available as "Cetiol HE". d). Polyoxyethylene and polyoxypropyiene copolymers, for example of the type commercially available as "Pluronic" and "Emkalyx" and "Lutrols". "Lutrol" grades are poloxamers in an extensive line of block polymers. Poloxamer 188 ("Lutrol F68") is a block polymer consisting of 81% of polyethylene glycol and 19% of propylene glycol. It has an average molecular weight of 8,600. "Lutrol F68" is primarily intended as an emulsifier, solubilizer and stabilizer in liquid orals, topical and parenteral drugs and also used for enhancing bio¬availability of insoluble drugs. Poloxamer 407 ("Lutrol F127") is a block polymer consisting of 73% of polyethylene glycol and 27% of polypropylene glycol with an average molecular weight of 12,000. The main applications of Lutrol F127 are as a thickener in creams, as a solubilizer for insoluble drugs and as a stabilizer in topical applications. e). Polyoxypropyiene ethers of fatty alcohols, for example polyoxyethylene ether of stearyl, oleoyl ether and cetyl ether, for example of the type that is commercially available as "Brij" e.g., "Brij 78" and "Brij 96", and also "Cetamacrogol 1000". The preferable solubilizers are those that are cited in items c,d,and e, the most-preferable being Polyoxyethylene and polyoxypropylene copolymers eg., "Lutrols". The formulation has conventional thickener additives. The constituents that are suitable for this purpose, for example, are: a), polymethaacrylates. b). cellulose derivatives, including, for example, ethyl- propyl-, methyl- and hydroxypropyf cellulose. c). white soft paraffin, cetostearyl alcohol, glyceryl monostearate. Quantity of these constituents is sufficient when it reaches (in percent of the total weight of a composition) 20%, mostly - to 10%. The most acceptable are. quantities from approximately 0.5 to approximately 15%, for example (by weight of the entire composition). The preferable thickeners are those cited in item c. The appearance and the consistency of the final formulation can be easily regulated by changing the proportion of the thickener in the formulation. The formulation also includes emollients like : a), dimethicone and liquid paraffin b). triglycerides of capric and caprilic acid , eg., Myritol ®. Concentrations generally range from 5-15% w/w. The preferable emollients are those cited in item a. These emollients give good spreadibility and elegant appearance. The so obtained emulsion has good cosmetic properties and uniform distribution over the skin. In yet another embodiment of the present invention, emulsion can be produced using a method comprising the steps dissolving a compound (I) in the form of an acidic salt in propylene glycol and non-ionic surfactants, the oily phase being emulsified with a relevant aqueous phase, and then introduced into the solution of compound (I) in the form of acidic salt. In yet another embodiment, the composition can comprise additional ingredients . as well, for example: - complex agents, for example diamine tetracetate (disodium salt); preservatives like benzyl alcohol. The composition according to this invention can also comprise conventional additives intended to adjust pH value so that the same will be of the value acceptable in terms of treatment of the skin, eg., triethanolamine. Formula (I) and Examples: Formula (I) Qty (%w/w) 1.0 5.0 5.25 3.0 4.0 10.0 7.0 1.0 5.0 0.1 10.0 0.25 q.s. Ingredients 1. Terbinafine hydrochloride 2. Cetostearyl alcohol IP 3. Cetomacrogol 1000 BP 4. Self emulsifying Glyceryl monostearate IP 5. Dimethicone 100 cps 6. Poloxamer USP (Lutrol F 127) 7. Light liquid paraffin IP 8. Benzyl alcohol IP 9. White soft paraffin IP 10.Disodium edetate IP 11.Propylene glycol IP 12.Triethano!amine IP 13.Purified water IP q.s. Formula (II) Ingredients Qty (%w/w) 1. Terbinafine hydrochloride 1.0 2. Cetostearyl alcohol IP 3.0 3. Cetomacrogol 1000 BP 3.0 4. Self emulsifying Glyceryl monostearate IP 2.0 5. Dimethicone 100 cps 3.0 6. Poloxamer USP (Lutrol F 127) 8.0 7. Light liquid paraffin IP 6.0 8. Benzyl alcohol IP 1.0 9. White soft paraffin IP 4.0 10.Disodium edetate IP 0.1 11 .Propylene glycol IP 15.0 12.Triethanolamine IP 0.25 13.Purified water IP q.s. q.s. Formula (111) Ingredients 1. Terbinafine hydrochloride 2. Cetostearyl alcohol IP 3. Cetomacrogol 1000 BP 4. Self emulsifying Glyceryl monostearate IP 5. Dimethicone 100 cps 6. Poloxamer USP (Lutroi F 127) 7. Light liquid paraffin IP 8. Benzyl alcohol IP 9. White soft paraffin IP l0.Disodium edetate IP 11.Propylene glycol IP 12.Triethanolamine IP 13.Purified water IP q.s. Qty (%w/w) 1.0 6.5 6.5 3.5 4.5 15.0 8.5 1.0 5.5 0.1 10.0 0.25 q.s. Formula (IV) Ingredients Qty (%w/w) 1. Terbinafine hydrochloride 1.0 2. Cetostearyl alcohol IP 3.0 3. Cetomacrogol 1000 BP 3.0 4. Self emulsifying Glyceryl monostearate IP 2.0 5. Dimethicone 100 cps 3.0 6. Poloxamer USP (Lutroi F 68) 8.0 7. Light liquid paraffin IP 6.0 8. Benzyl alcohol IP 1.0 9. White soft paraffin IP 4.0 10.Disodium edetate IP 0.1 11 .Propylene glycol IP 15.0 12.Triethanolamine IP 0.25 13.Purified water IP q.s. q.s. We Claim, 248/BOM/1999 1 .An antimycotic oil-in-water emulsion /composition in the form of acidic -additive salt comprising terbinafine in the range f 0.1 to 1% , water 50 to 75% oil phase 10 to 40%, non ionic surfactants 5 to 15%, thickner, solubiliser, additives, and emollients, 2. A composition as claimed in claim 1, wherein the surfactants selcted from ether of fatty aclcohols, 3. A composition as claimed in claim 1, whre in the thickners are selected from the paraffin, cetosterayl alcohol, 4. A composition as claimed in claim 1, wherein an emollients used is dimethicone and liquid paraffin, 5. A composition as claimed in claim 1, wherein an preservatives is benzyl alcohol, 6. A composition as claimed in claim 1, wherein chelating is agent is diamine tetracetate, 7. An antimycotic oil-in-water emulsion /composition such as here in described weth reference to an accompanying example,

Documents:

248-bom-1999-cancelled pages(16-10-2007).pdf

248-bom-1999-claims(granted)-(16-10-2007).doc

248-bom-1999-claims(granted)-(16-10-2007).pdf

248-bom-1999-correspondence(16-10-2007).pdf

248-bom-1999-correspondence(ipo)-(19-10-2006).pdf

248-bom-1999-form 18(29-12-2005).pdf

248-bom-1999-form 1a(01-04-1999).pdf

248-bom-1999-form 2(granted)-(16-10-2007).doc

248-bom-1999-form 2(granted)-(16-10-2007).pdf

248-bom-1999-genral power of attorney(01-04-1999).pdf

248-bom-1999-genral power of attorney(11-07-2001).pdf