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AssigneeMeiji Seika Kaisha, Ltd.
InventorsMasahiro Onodera, Masamichi Sukegawa, Kiyoshi Yasui, Tatsuo Watanabe, Toyomi Sato, Yasushi Murai, Katsuharu Iinuma
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Processes are provided for the preparation of orally administrable, yellow and powdery compositions essentially consisting of particles composed of a homogeneous mixture of an amorphous Cefditoren pivoxil substance with a water soluble high-molecular additive. These compositions can be produced by dissolving crystalline Cefditoren pivoxil substance and the water-soluble high-molecular additive in an aqueous solution of an acid, then neutralizing the resultant solution, to co-precipitate the product, and drying the thus precipitated product, followed by recovering the product in the form of the above-mentioned particles.
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 weight 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 in an acidic aqueous solution which contains a water-soluble high-molecular weight additive made of either a water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose and 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 dissolved at a concentration of 0.05% to 1% (weight/weight basis), and said acidic aqueous solution also contains 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 said acidic aqueous solution is in the range of 10 times to 130 times based on the entire weight of said water-soluble high-molecular weight additive contained in said acidic aqueous solution, resulting in an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular weight additive and the acid dissolved therein, a step of subsequently neutralizing the acidic aqueous solution by adding slowly thereto an aqueous solution selected from the group consisting of an aqueous solution of sodium or potassium hydroxide, an aqueous solution of sodium or potassium hydrogen carbonate, an aqueous solution of sodium or potassium carbonate and an aqueous solution of ammonium hydroxide, singly or in combination, while maintaining said acidic aqueous solution at a temperature of 10° C. or below under stirring, and with the amount of said basic sodium or potassium compound or ammonium hydroxide to be added to said acidic aqueous solution being so adjusted that the resulting reaction solution after the neutralization has a pH value of 6.5˜7.1, and a step of continuing during the neutralization reaction the stirring of the aqueous solution containing Cefditoren pivoxil at a temperature of 10° C. or below, to bring about co-precipitation of Cefditoren pivoxil and the water-soluble high-molecular weight additive simultaneously from the aqueous solution, a step of collecting by filtration or centrifugation, the deposited precipitate from the resulting neutralization reaction mixture, a step of washing the collected precipitate with an aqueous solution of a water-soluble high-molecular weight additive made of the same substance as that of the first-mentioned water-soluble high-molecular weight additive and containing said additive dissolved in said solution at a concentration of 0.5%˜10% (weight/weight basis), while at least a portion of said water-soluble high-molecular weight additive used in the washing aqueous solution is transferred from the washing aqueous solution of the water-soluble high-molecular weight additive onto the surfaces of the particles of said precipitate, and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of the particles each formed of the homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with the above-mentioned water-soluble high-molecular weight additive present in a proportion of 0.5%˜5% based on the weight of the Cefditoren pivoxil substance.
A process for the preparation of a yellow-colored powdery composition consisting essentially of particles which each comprise mixtures of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with water-soluble high-molecular weight additive or additives, wherein said particles have a uniform, internal texture within each particle, characterized in that the process comprises a step of dissolving an orthorhombic substance of Cefditoren pivoxil in an acidic aqueous solution which contains a first water-soluble high-molecular weight additive made of either a water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose and 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 dissolved at a concentration of 0.05%˜1% (weight/weight basis) and wherein said acidic aqueous solution also contains 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 said acidic aqueous solution is in a range of 10 times to 130 times based on the whole weight of said first water-soluble high-molecular weight additive contained in said acidic aqueous solution, resulting in an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular weight additive and the acid dissolved therein, a step of subsequently neutralizing the said acidic aqueous solution, by adding slowly thereto an aqueous solution selected from the group consisting of an aqueous solution of sodium or potassium hydroxide, an aqueous solution of sodium or potassium hydrogen carbonate and an aqueous solution of sodium or potassium carbonate, singly or in combination, or by adding slowly thereto an aqueous solution of ammonium hydroxide, while maintaining said acidic aqueous solution at a temperature of 10° C. or below under stirring, and with the amount of the basic sodium or potassium compound or ammonium hydroxide to be added to said acidic aqueous solution adjusted so that the reaction solution after the neutralization has a pH value of 6.5˜7.1, a step of continuing during the neutralization reaction the stirring of the aqueous solution containing Cefditoren pivoxil at a temperature of 10° C. or below, to bring about co-precipitation of Cefditoren pivoxil and the first water-soluble high-molecular weight additive simultaneously from the aqueous solution, a step of collecting by filtration or centrifugation the precipitate from the resulting neutralization reaction mixture, a step of washing the collected precipitate with an aqueous solution which contains a second, water-soluble high-molecular weight additive made of a substance different from the above-mentioned first, water-soluble high-molecular weight additive contained in said acidic aqueous solution containing Cefditoren pivoxil, and which aqueous solution is containing said second high molecular weight additive dissolved therein at a concentration of 0.5%˜10% (weight/weight basis), while at least a portion of said second water-soluble high-molecular weight additive used in the washing aqueous solution is transferred from the washing aqueous solution of the second water-soluble high-molecular weight additive onto the surfaces of the particles of the precipitate, and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of such particles which each contain Cefditoren pivoxil, and of which the central portion or core portion of each particle is formed only from a homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with the first water-soluble high-molecular weight additive present in a proportion of 0.5%˜5% based on the weight of said Cefditoren pivoxil substance, and of which the surface layer of each particle is formed from a homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with said first water-soluble high-molecular weight additive and also with said second water-soluble high-molecular weight additive.
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