Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-09-25
1992-02-25
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
424475, 424479, 424457, 424466, 424486, 424488, 424501, A61K 3141, A61K 4726, A61K 4738, A61K 916
Patent
active
050911910
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to pharmaceutical compositions with improved dissolution property of sodium 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate or its optical isomer or its hydrate which is useful as a thromboxane synthetase-inhibiting medicine.
BACKGROUND ART
In the specification of U.S. Pat. No. 4661603, it is disclosed that sodium 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate or its optical isomer or its hydrate (hereinafter referred to generally as "the Compound" including the corresponding hydrate) is useful as a thromboxane synthetase-inhibitor in a therapeutic medicament for diseases such as thrombosis and asthma, and can be formed into oral preparations such as tablets or into injections. In said U.S. Patent, there are also disclosed pharmaceutical formulation examples containing lactose, starch, fine crystalline cellulose, talc and magnesium stearate as the carriers or excipients.
Since the Compound is a sodium salt in the carboxyl group moiety, its solubility is lowered under weakly acid to neutral conditions (in the range of about pH 3 to about pH 7) as shown in FIG. 1. Therefore, pharmaceutical compositions obtained by such a conventional means as described in the above-mentioned U.S. Patent specification, for example, by adding lactose, corn starch and the like to the Compound, granulating the mixture, adding talc, magnesium stearate and the like thereto and compressing for forming, have a pretty inferior dissolution property in the weakly acid dissolution test medium, e.g. 0.1 M acetate buffer solution (pH 4.0). This is a reflection of the property of the Compound per se, as shown in FIG. 2.
It is widely known that when a compound having such dissolution property which depends on the pH of the dissolution test medium or a pharmaceutical composition thereof is administered to a human, the pH in the stomach influences the absorption rate and the like.
On the other hand, it is also well known that the pH in the stomach of aged people quite frequently ranges from weakly acid area to neutral area. Thus, in view of the fact that patients to be treated with the Compound are often aged people, pharmaceutical improvement of the preparations is strongly demanded.
Accordingly, in order to assure uniform pharmaceutical effects to the patients, there has been desired the development of a pharmaceutical composition wherein the dissolution of the Compound is free from any dependency on the pH of the digestive tract including the stomach. That is, it is required to obtain a pharmaceutical composition with improved pH-dependent dissolution property of the Compound by adding additives in combination, which do not exhibit any particular pharmacological actions by themselves and are harmless.
In general, as the methods for improving dissolution of sparingly-soluble medicaments, there are known (1) a method of finely-powdering, (2) a method of forming a molecular compound (3) a method of forming a solid dispersion (4) a method of converting into a soluble derivative and the like.
Since the Compound is in the form of a sodium salt, even if it was treated by a known method belonging to the abovementioned (1), the corresponding free acid was produced through chemical reaction when added to a weakly acid solution. Thus, there was not found any dissolution-improving effect by the method.
According to the methods belonging to the above methods (2) and (3), no effect can be expected unless the additives are added in a not less than 3 to 4 times larger amount relative to the amount of the bulk of the Compound. Thus, they pose problems when put to practical use in view of the clinical dosage of the Compound. Furthermore, the above method (4) cannot be adopted in case where it is required to use the Compound per se.
DISCLOSURE OF THE INVENTION
The object of this invention is to provide pharmaceutical compositions with improved dissolution of the Compound.
This invention relates to a pharmaceutical composition of sodium 4-[c-hydroxy-5-(1-imidazoly
REFERENCES:
patent: 4661603 (1987-04-01), Tsuruda et al.
patent: 4737506 (1988-04-01), Shimizu et al.
Kino Shigemi
Oda Minoru
Ogawa Kenji
Shiotsuki Takako
Page Thurman K.
Webman E. J.
Yoshitomi Pharmaceutical Industries Ltd.
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