Particulate preparation containing a flourracil derivative and h

Details Particulate preparation containing a flourracil derivative and h Particulate preparation containing a flourracil derivative and h

1992-03-16

1994-05-31

Webman, Edward

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424488, 424487, 424497, 424451, 424456, 424464, A61K 914, A61K 4738

Patent

active

053167732

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates to a solid preparation.


DISCLOSURE OF THE INVENTION

It is known that 3-[3-(6-Benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5- fluorouracil (hereinafter referred to as "BOF-A2") is converted, after administration in vivo, into 1-ethoxymethyl-5-fluorouracil (hereinafter referred to as "EM-FU") and 3-cyano-2,6-dihydropyridine (hereinafter referred to as "CNDP") by chemical hydrolysis and enzymolysis, EM-FU being gradually converted into 5-fluorouracil, CNDP working as a metabolic inhibitor and showing continuous and strong anti-cancer activity.
Because of the slight solubility of BOF-A2 in water, rapid absorption of BOF-A2 from the alimentary canal can not be expected.
In general, as means to enhance elution of an active ingredient with slight solubility, exemplified are (1) converting the active ingredient into a soluble derivative and using the derivative, (2) adding a solubilizer, such as surface active agents and the like in preparing the preparation. However, these means do not produce a satisfactory result in the case of BOF-A2.More specifically, in the case of BOF-A2, BOF-A2 has a relatively high molecular weight and is easily hydrolyzed so that it is extremely difficult to improve the solubility of BOF-A2 by introducing hydrophilic groups. Further, in preparation containing added surface active agents, such as polysorbate 80, sodium lauryl sulfate, stearic acid polyoxyl 40 and the like generally used as a solubilizer, the elution improvement effect of the solubilyzer is small and impractical.
The inventors conducted research to improve the solubility of BOF-A2 conditions and accomplished the present invention.
Thus, the present invention relates to a solid preparation characterized in that dissolving BOF-A2 and a water-soluble polymer in an organic solvent completely and preparing a preparation of amorphous powder obtained by removing the organic solvent.
As the water-soluble polymer used in the invention, previously known polymers can be widely used, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methacrylic acid copolymer and the like can be exemplified. In the polymers, hydroxypropylmethylcellulose and hydroxypropylcellulose are preferable in view of absorbability, hydroxypropylmethylcellulose is particularly preferable in view of preservation stability.
The hydroxypropylmethylcellulose used in the invention has 19 to 30% of methoxy groups and 4 to 12% of hydroxypropyl groups, and a viscosity of 3 to 30000 cps (2% water solution, 20.degree. C.) preferably 3 to 4000 cps.
In the invention, as the organic solvent, all of known solvents can be used as long as they are capable of dissolving a water-soluble polymer completely, more specifically lower alcohols, such as methanol, ethanol, isopropanol and the like, ketones, such as acetone, methylethylketone and the like, halogenated hydrocarbon(s), such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like or a mixture thereof can be exemplified. Further, purified water can be added into these solvents, if necessary. Of the organic solvents, lower alcohols and halogenated hydrocarbon(s) are preferable in view of solubility and subsequent removal, a mixed solvent of dichloromethane with methanol or ethanol is particularly preferable.
When producing the solid preparation of the invention, first of all, BOF-A2 and a water-soluble polymer are completely dissolved in the above organic solvent. Although the mixing proportion of BOF-A2 and a water-soluble polymer is not limited, the former is normally used at least 0.01 times as much as the amount of the latter by weight, preferably about 0.05 to about 3 times, in particular, preferably about 0.05 to about 1 times. When the mixing proportion of the water-soluble polymer to BOF-A2 is too low, the mixture are not likely to become amorphous, when the mixing proportion is too high, the stability of BOF-A2 become worse.
In the present invention, amorphous powder is then obtained by r

REFERENCES:
patent: 4127647 (1978-11-01), Sato et al.
patent: 4343789 (1982-08-01), Kawata et al.
patent: 4404183 (1983-09-01), Kawata et al.
patent: 4412986 (1983-11-01), Kawata et al.
patent: 4673564 (1987-06-01), Kawata et al.
patent: 4983609 (1991-01-01), Fujii
patent: 5126145 (1992-06-01), Evanstad et al.

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