Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1993-10-15
1997-04-29
Hulina, Amy
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424494, 424497, A61K 914
Patent
active
056246870
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a pH-independent quick-dissolution solid preparation containing as a principal agent a drug which is otherwise rapidly depressed in solubility with pH elevation.
BACKGROUND ART
A quick-dissolution solid preparation is designed to achieve a rapid rise in the blood concentration of a drug administered orally in expectation of the immediate action of the drug. Therefore, in designing a quick-dissolution solid preparation, the disintegration of pharmaceutical per se, solubility and bioavailability of the drug are important considerations.
However, a drug which is sharply depressed in solubility with pH elevation is generally less efficiently absorbed in the stomach than in the intestinal tract even if it is highly disintegrable and is soluble in the gastric juice and, therefore, has the disadvantage of low bioavailability. Another disadvantage of such a drug is that it can hardly exhibit its expected efficacy in patients with achlorhydria or gastric hypoacidity.
For the purpose of enhancing the solubility of a hardly soluble drug, it is known to disperse the drug in substantially amorphous state in an inert carrier such as polyvinylpyrrolidone to thereby provide a solid solution (also known as solid dispersion) [cf. Chiou. W. L., Riegelman, S: J. Pharm. Sci., 60, 1281 (1971) and JP-A-54-2316 (the term "JP-A" as used herein means an unexamined published Japanese patent application)].
It is also known, for improving the absorption of nifedipine which is a hardly soluble drug, to coat fine beads of a water-soluble pharmaceutical additive substance with a solid solution consisting of nifedipine and polyvinylpyrrolidone (JP-A-57-85316).
It is also disclosed in JP-A-56-110612 that a preparation prepared by mixing a hardly soluble drug with a base, such as polyvinylpyrrolidone, with or without addition of a surfactant or the like, granulating the resulting composition by the fluidized-bed granulating method, and compression-molding the resulting granules is excellent in disintegration, rate of absorption, and rapidity of dissolution. In this process, anhydrous calcium hydrogenphosphate, among others, is used as the core material for fluidized-bed granulation.
However, Yakugaku Zasshi 104(5), 485-489 (1984) reports that when the hardly soluble drug nifedipine is made into a solid solution using an enteric coating base such as hydroxypropylcellulose phthalate or methacrylic acid-methyl methacrylate copolymer and coating is carried out, the rate of dissolution in JP (Japanese Pharmacopoeia) Test Solution 1 is suppressed and it is, therefore, generally acknowledged that as long as an enteric base is employed, coating with a solid solution of a hardly soluble drug may not easily provide a quick-dissolution solid preparation.
DISCLOSURE OF INVENTION
In the above state of the art, the inventors of the present invention conducted extensive studies to develop a pH-independent quick-dissolution solid preparation for N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenza mide, inclusive of its salt, which is depressed in solubility with pH elevation, and found surprisingly that a solid preparation prepared from granules prepared by coating fine particulate cores with a solid solution consisting of the same compound and a definite amount of an enteric base is excellent in dissolution even under low pH conditions without undergoing change in solubility even when the pH is increased, thus offering a remarkably improved bioavailability as a whole. The present invention was accomplished based on this finding.
The present invention relates, therefore, to a solid preparation comprising granules each comprises a fine particulate core and a drug layer coated on said fine particulate core, said drug layer comprising
(1) an enteric base and
(2) a pH-dependent hardly soluble drug which is depressed in solubility with pH elevation object of the invention is to provide such a preparation.
One of the outstanding features of the present invention is as follows. Enteric bases
REFERENCES:
patent: 4101651 (1978-07-01), Kobayashi et al.
patent: 4673564 (1987-06-01), Kawata et al.
patent: 5026560 (1991-06-01), Makino et al.
patent: 5213811 (1993-05-01), Frisbee et al.
patent: 5223268 (1993-06-01), Stetsko et al.
patent: 5300304 (1994-04-01), Sheth et al.
Hasumi Shunji
Nishizono Yasuhiro
Ohmura Tadayoshi
Yamazaki Shigeru
Yano Katsuhiko
Hulina Amy
Yamanouchi Pharmaceutical Co. Ltd.
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