Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-07
2002-01-29
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S202000, C514S208000, C514S960000
Reexamination Certificate
active
06342493
ABSTRACT:
TECHNICAL FIELD
This invention relates to an orally administrable and powdery composition consisting essentially of a number of particles each comprising a crystallographically stable and amorphous cephalosporin. More specifically, this invention relates to a novel, orally administrable and powdery composition consisting essentially of particles which each have a uniform internal texture within each particle and each are formed from a homogeneous mixture of an amorphous and water-soluble substance of 7-[(Z)-2-(2-aminothiazol-4-yl) -2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl) ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, that is, Cefditoren pivoxil (a generic name), with a water-soluble, high-molecular additive, for example, a water-solubilized derivative of cellulose. This invention further relates to processes for the preparation of the novel, orally administrable and powdery composition as above-mentioned.
BACKGROUND ART
The cephem compound known under the generic name “Cefditoren” is the compound which is represented by the following formula (A)
and which compound was at first named as 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer) (refer to Japanese Patent Publication Hei 3-64503 specification, U.S. Pat. No.4,839,350 and European Patent No.0175610 specification).
Cefditoren pivaloyloxymethyl ester is a pro-drug known under the generic name “Cefditoren pivoxil” and is the compound represented by the following formula (B)
Cefditoren pivoxil is also known in the name of “(−)-(6R,7R) -7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester” and is described on page 317 of the literature “Merck Index”, the 12th Edition to be a pale yellow-colored powdery substancemelting at 127~129° C. Another chemical name of the compound “Cefditoren pivoxil” is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.
Cefditoren pivoxil, when orally administered, can be well absorbed by the digestive tracts, within which Cefditoren pivoxil is hydrolyzed into Cefditoren. It is known that Cefditoren is an antibiotic substance possessing an extremely broad antibacterial spectrum but a low toxicity and Cefditoren is very excellently useful for the therapeutic treatment and prevention of diseases which are caused by gram-positive and gram-negative bacteria. At present, Cefditoren pivoxil is widely utilized as an orally administrable pro-drug for the therapy.
We, the present inventors, had made investigations with the intention of obtaining a highly pure product of Cefditoren pivoxil, and as a result, we already succeeded in obtaining Cefditoren pivoxil in the form of an orthorhombic crystalline substance (at a purity of: 97~98%) of a melting point of 206~215.7° C. (with decomposition), by adopting a certain particular process (refer to International Open-Laying Publication No. W098/12200 of PCT application No. PCT/JP97/03340, issued on Mar. 26, 1998). This orthorhombic crystalline substance of Cefditoren pivoxil shows such advantages that it has a high purity, a high thermal stability and a high storage-stability under high-humidity conditions, but still it shows such disadvantage that it itself is not so suitable for the purpose of oral administrations due to its poor solubility in water.
DISCLOSURE OF INVENTION
In general, for such medicinal compounds which are sparingly soluble in water, it is well known that the solubility or the dissolution speed of the sparingly water-soluble compounds in water can exert a great influence on the absorption in vivo of said compounds. Thus, many reports were presented on how to improve the water-solubility of such medicinal compounds which are sparingly soluble in water. One of the reported proposals is a method in which a medicinal compound sparingly soluble in water is converted into an amorphous substance, thus to improve the solubility of the compound in water. It is known that an amorphous substance generally has a higher solubility in water, as compared with that of the corresponding crystalline substance. It is therefore expectable that if the orthorhombic crystalline substance of Cefditoren pivoxil sparingly soluble in water is converted into an amorphous substance which is; of a higher solubility in water, there may be afforded such a water-soluble and highly pure product of Cefditoren pivoxil which is capable of exhibiting its therapeutic efficacy to a full extent.
We have therefore further prosecuted diligently our investigations in order to solve the problem of converting the crystalline Cefditoren pivoxil into an amorphous substance having a higher water-solubility. As a result, we have now found that there can successfully be prepared an orally administrable, yellow-colored powdery composition consisting essentially of such particles which each have a uniform internal texture or tissue within each particle and which each are formed from a homogeneous mixture of the amorphous Cefditoren pivoxil substance having a high water-solubility and a high thermal stability, with a water-soluble high-molecular additive, when use is made of such a process which comprises dissolving a crystalline Cefditoren pivoxil in an acidic aqueous solution containing a water-soluble high-molecular additive, for example, a water-solubilized derivative of cellulose and an acid dissolved therein, thereby to form an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular additive and the acid dissolved therein, then slowly adding to the resultant acidic aqueous solution an aqueous solution of an inorganic base to neutralize said acidic aqueous solution to a neutral or a substantially neutral pH value, with co-precipitating Cefditoren pivoxil and said water-soluble high-molecular additive simultaneously from said aqueous solution during the neutralization operation, then washing the deposited precipitate with an aqueous solution of the water-soluble high-molecular additive, drying the washed precipitate, and recovering the resulting particulate product so dried. This invention has been established on the basis of these findings mentioned above.
Thus, according to a first aspect of this invention, there is provided an orally administrable, yellow-colored powdery composition consisting essentially of solid 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 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%~5% based on the weight of the Cefditoren pivoxil substance, that said particles fuse at a temperature of 1
Iinuma Katsuharu
Murai Yasushi
Onodera Masahiro
Sato Toyomi
Sukegawa Masamichi
Jagoe Donna
Krass Frederick
Larson & Taylor PLC
Meiji Seika Kaisha Ltd.
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