Encapsulated medicine

Details Encapsulated medicine Encapsulated medicine

1996-01-02

1997-11-04

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

424461, 424464, A61K 948, A61K 3144

Patent

active

056837160

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to an encapsulated pharmaceutical composition comprising a practically insoluble compound or a salt thereof and an intracapsular fluid, and/or a surfactant and/or cellulose derivative and finds application in the medical field.


BACKGROUND ART

Being very poorly soluble in water, the so-called practically insoluble compounds are generally absorbed only sparingly on oral administration in a crystalline or finely divided powder form and much research has been undertaken for improving their absorption. As typically disclosed in Japanese Patent Application Kokai H-5-17356, there is known a hard capsule containing a liquid composition comprising nifedipine, which is a practically insoluble compound, polyethylene glycol and polyvinylpyrrolidone. In this prior art invention, polyvinylpyrrolidone is added for improving the solubility of the drug in water.
Heretofore, various absorption-improving agents for practically insoluble compounds have been explored for the purpose of preventing precipitation of such practically insoluble compounds or increasing their solubility in the gastrointestinal tract. However, the technologies so far proposed at times fail to provide for satisfactory improvements in absorption and the advent of new absorption-improving agents for practically insoluble compounds has been awaited.


DISCLOSURE OF INVENTION

The inventors of this invention explored a quite new pharmaceutical approach by which the process of precipitation after release of contents of a capsule comprising a practically insoluble compound can be controlled to provide microcrystals in situ and found that a capsule comprising a practically insoluble compound or a salt thereof and an intracapsular fluid, and/or a surfactant and/or cellulose derivative provides for high bioavailability of the compound after oral administration. This invention has been developed on the basis of the above finding.
The practically insoluble compound for use in this invention is a compound having an extremely low solubility in water and, as such, showing poorly oral absorption kinetics. As examples of the compound, nilvadipine, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-methylsulfonylphenyl)pyrazole, and 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)pyrazole can be mentioned.
The intracapsular fluid for use in this invention is a fluid which is conventionally used in soft capsules and, as such, includes polyhydric alcohols such as polyethylene glycol, propylene glycol, butylene glycol, polypropylene glycol, glycerol, polyglycerol, etc. and oils/fats such as fatty acid glycerol esters, sesame oil, soybean oil and so on.
Of them, polyhydric alcohols are preferred and polyethylene glycol is more recommendable, and polyethylene glycol 400 is the most advantageous.
The surfactant for use in this invention includes nonionic surfactants which are conventionally used in the art. Preferred are polyalcohol ester surfactants and the most useful is polyoxyl stearate.
The cellulose derivative for use in this invention includes hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and carboxymethylcellulose, among other derivatives. Of them, the preferred is hydroxypropylcellulose, the more recommendable is a medium-or low-degree-of-polymerization hydroxypropylcellulose, and the most advantageous is a low-degree-of-polymerization hydroxypropylcellulose.
The pharmaceutical dosage form of this invention may, where necessary, contain those common additives which are conventionally used in pharmaceutical practice (e.g. corrigents, perfumes, etc.). The optimal dosage form is a soft capsule or a hard capsule.
The process for producing the dosage form of this invention employing a practically insoluble compound or a salt thereof and an intracapsular fluid, and/or a surfactant and/or cellulose derivative is now described in detail.
The pharmaceutical dosage form of this invention can be manufactured by mixing a practically insoluble compound or a salt thereof, with an intracapsular fluid, and

REFERENCES:
patent: 5340591 (1994-08-01), Nakano et al.

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