Patent EA-002881-B1 (EA)
Title: Crystallographically stable amorphous cephalosporin compositions and process for producing the same
Inventor: ONODERA MASSAHIRO
IPC: C07D501/24
Filed: 1999-01-07
Abstract: 1. An orally administrable, powdery composition consisting of amorphous Cefditoren pivoxil or orthorombic crystalline Cefditoren pivoxil as an active ingredient and a water soluable substance, characterized in that a said yellow-colored powdery composition consists essentially of the solid particles each formed of the homogeneous mixture of (i) the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, with (ii) the water-soluble high-molecular additive which is either such a pharmaceutically acceptable, water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol, that the water-soluble high-molecular additive (ii) contained in the above-mentioned solid particles is present in said particles in a proportion of 0.5 % SIMILAR 5 % based on the weight of the Cefditoren pivoxil substance, that said particles fuse at a temperature of 120 degree C or higher, but do not show any definite melting point, that the amorphous substance of Cefditoren pivoxil (i) contained in said particles does not show any peak of the angle of diffraction in a X-ray powder diffractometry chart of said particles but exhibits in its infrared absorption spectrum (as measured by pelleted potassium bromide method) a substantially broader peak of absorption at a wave number of 1750 cm<-1>, as compared with the sharp peak of absorption exhibited by the orthorhombic crystalline substance of Cefditoren pivoxil at a wave number of 1750 cm<-1> in the infrared absorption spectrum, and that the amorphous substance of Cefditoren pivoxil (i) contained in said particles can be dissolved in an acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg/ml of Cefditoren pivoxil at 37 degree C and has a crystallographical stability such that said amorphous Cefditoren pivoxil substance does not involve crystallization when stored at 40 degree C for 4 months in a sealed container under dry conditions. 2. A composition as claimed in Claim 1, which consists essentially of particles each formed of a homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose or polyvinylpyrrolidone blended as the water-soluble high-molecular additive which is present in an amount of 1 % ( 3 % based on the weight of Cefditoren pivoxil. 3. An orally administrable powdery composition consisting essentially of particles which each substantially comprise mixtures of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with water-soluble high-molecular additive or additives, and which particles have a uniform, internal texture within each particle, characterized in that a yellow-colored powdery composition consists essentially of the particles each substantially comprising a mixture of (i) the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl) ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, with (ii) a first, water-soluble high-molecular additive which is either such a pharmaceutically acceptable, water-solubilized derivative of cellulose as chosen from hydroxy-propylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol, that the central portion or core portion of the respective particles which is lying under the surface layer of said respective particles is formed only from a homogeneous mixture of (i) the amorphous substance of Cefditoren pivoxil with (ii) the above-mentioned first, water-soluble high-molecular additive, but the surface layer of said particles is formed from a homogeneous mixture of (i) the amorphous substance of Cefditoren pivoxil with (ii) the first water-soluble high-molecular additive and also with (iii) such a second, water-soluble high-molecular additive which is additionally incorporated, which is made of a substance different from the above-mentioned first water-soluble high-molecular additive present just in the central portion or core portion of said particles lying under said surface layer of the particle, and which second, water-soluble high-molecular additive is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone, that both the first water-soluble high-molecular additive (ii) and the second water-soluble high-molecular additive (iii) are present in a total proportion of them of 0.5 % ( 5 % based on the weight of the Cefditoren pivoxil substance contained in said particles, that said particles fuse at a temperature of 120 degree C or higher, but do not show any definite melting point, that the amorphous substance of Cefditoren pivoxil (i) contained in said particles does not show any peak of the angle of diffraction in a powder X-ray diffractometry chart of said particles but exhibits in its infrared absorption spectrum (as measured by pelleted potassium bromide method) a substantially broader peak of absorption at a wave number of 1750 cm<-1>, as compared with the sharp peak of absorption exhibited by the orthorhombic crystalline substance of Cefditoren pivoxil at a wave number of 1750 cm<-1> in the infrared absorption spectrum, and that the amorphous substance of Cefditoren pivoxil (i) contained in said particles can be dissolved in an acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg/ml of Cefditoren pivoxil at 37 degree C and has a crystallographical stability such that said amorphous Cefditoren pivoxil substance does not involve crystallization when stored at 40 degree C for 4 months in a sealed container under dry conditions. 4. A composition as claimed in Claim 3, wherein the central portion or core portion of the respective particles which is lying under the surface layer of the respective particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropylmethyl cellulose, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropylmethyl cellulose and also with hydroxypropyl cellulose or methyl cellulose. 5. A composition as claimed in Claim 3, wherein the central portion or core portion of the respective particles which is lying under the surface layer of the respective particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropyl cellulose, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropyl cellulose and also with hydroxypropylmethyl cellulose or methyl cellulose. 6. A composition as claimed in Claim 3, wherein the central portion or core portion of the respective particles which is lying under the surface layer of the particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with methyl cellulose, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with methyl cellulose and also with hydroxypropylmethyl cellulose or hydroxypropyl cellulose. 7. A composition as claimed in Claim 3, wherein the central portion or core portion of the respective particles which is lying under the surface layer of the particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with polyvinylpyrrolidone, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with polyvinylpyrrolidone and also with hydroxypropylmethyl cellulose or hydroxypropyl cellulose or methyl cellulose. 8. A process for the preparation of a yellow-colored powdery composition consisting essentially of particles which each are formed of a homogeneous mixture of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with a water-soluble high-molecular additive, and which particles have a uniform, internal texture within each particle, characterized in that the process comprises a step of dissolving an orthorhombic crystalline substance of Cefditoren pivoxil, namely 7-[(Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, in an acidic aqueous solution which is containing a water-soluble high-molecular additive made of either such a water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol as dissolved at a concentration of 0.05 % to 1 % (weight/weight basis), and which acidic aqueous solution is containing also hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0.1N ( 12N of the acid, so that the amount of Cefditoren pivoxil dissolved in