Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-25
2001-12-04
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S572000, C514S033000, C514S025000, C424S466000, C424S465000, C424S468000, C424S474000
Reexamination Certificate
active
06326360
ABSTRACT:
This is a 371 application of PCT/JP99/01157 filed Mar. 10, 1999.
TECHNICAL FIELD
The present invention relates to an oral pharmaceutical preparation for glycyrrhizin (which is also called glycyrrhizic acid or glycyrrhizinic acid; referred herein to as “glycyrrhizin”) having the good property of being well absorbed from the digestive tract. More particularly, the present invention relates to an effervescent enteric pharmaceutical preparation thereof.
BACKGROUND ART
Glycyrrhizin is a pharmaceutically active ingredient which is appreciated as a therapeutic agent for hepatic diseases and for allergy, and a medically essential drug due to its excellent improving action for hepatic functions, especially in the therapy of chronic hepatic diseases. At present, two kinds of clinically used glycyrrhizin-containing preparations, i.e., injection preparations and oral tablets, are available. In view of efficacy, the use of injection preparations is overwhelming. In the case of tablets, it has been reported that glycyrrhizin is quickly decomposed into glycyrrhetinic acid in the stomach, that transfer of unchanged glycyrrhizin having a high pharmacological activity into blood is hardly observed and accordingly that its effect is far poor as compared with injection preparations (Minophagen Medical Review, Extra Issue No.30, page 1 (1993)).
However, in the case of injection preparations, a dosage level for each administration is as high as 40-100 ml. It compels pain to the patient and, moreover, causes a lot of burden including hospitalization for long time or necessity of visiting the hospital for injection every day or several days a week to the patient in the case of chronic hepatic diseases requiring a therapy for a long period. Therefore, the use of suppositories or oral preparations as substitutes for injection preparations has been proposed where the improvement of absorption is attempted.
For instance, there have been proposals for suppositories, such as a suppository where a conventionally known base such as Witepsol H-15 is used (JP, 1-294619, A (1989)), a suppository where at least one kind of nonionic surface-active agents or medium-chain fatty acids is admixed as an absorption enhancer (JP, 4-261117, A (1992)) and a suppository where a nonionic surface-active agent is admixed, as an absorption enhancer, with an oleaginous base (JP, 5-97680, A (1993)). For oral preparations with an object of improvement in absorption, the following has been proposed: a preparation where fatty acid glyceride is admixed followed by coating with an enteric film (JP, 3-255037, A (1991)) and a preparation where glycyrrhizin is made into a fat emulsion, a mixture with a conjugated lipid, or dry powders thereof (JP, 6-192107, A (1994)).
However, those conventional preparations have disadvantages as described hereinbelow.
For the above-mentioned suppositories, it takes a long therapeutic term to treat chronic hepatic diseases as mentioned already, and the use of suppositories for a long period therefore compels a considerable burden on the patient although it will not be so much as in the case of injection preparations.
Further, for the above-mentioned oral preparations, the prior art example as disclosed in JP, 3-255037, A (1991) is discussed because the prior art oral preparation is administered to rats intraduodenally instead of orally in which glycyrrhizin is merely dispersed in a fatty acid glyceride mixture and consequently the concentration of glycyrrhizin in blood is measured whereby there are no data which scientifically and clearly support the oral efficacy of the disclosed preparation.
For the next prior art example as disclosed in JP, 6-192107, A (1994), a fat emulsion or conjugated lipid mixture of glycyrrhizin is prepared therein. Unlike solid preparations such as tablets, however, such a liquid preparation inherently has an anxiety of stability and its handling is also inconvenient. Even if such an emulsified preparation is dried and made into powders, steps for manufacturing such a preparation are quite complicated.
As such, at the level of the conventional art, it is difficult to prepare an oral preparation of glycyrrhizin causing little burden to patients and having the excellent property of being well absorbed from the digestive tract.
DISCLOSURE OF THE INVENTION
Under such circumstances, the present inventors have carried out an intensive study for the manufacture of oral glycyrrhizin preparations manufacturable by a simple, convenient method and exerting the property of being excellently well absorbed from the digestive tract. As a result, the present inventors have found that such problems can be solved when an oral preparation is made into an enteric form wherein glycyrrhizin is admixed with not only an absorption enhancer but also an effervescent agent. Based on their further investigation, they have succeeded in completing the present invention.
Thus, the present invention provides:
(1) an oral pharmaceutical preparation comprising glycyrrhizin or a pharmaceutically acceptable salt thereof, an absorption enhancer and an effervescent agent;
(2) the oral pharmaceutical preparation according to the above (1), which is enteric;
(3) the preparation according to the above (1) or (2), wherein the absorption enhancer is a C
6
to C
20
fatty acid or a salt thereof;
(4) the preparation according to the above (1) or (2), wherein the absorption enhancer is a medium-chain fatty acid or a salt thereof;
(5) the preparation according to the above (1) or (2), wherein the absorption enhancer is capric acid or a salt thereof;
(6) the preparation according to the above (1) or (2), wherein the absorption enhancer is a medium-chain fatty acid glyceride; and
(7) the preparation according to the above (1) or (2), wherein the effervescent agent consists of sodium hydrogen carbonate and citric acid or tartaric acid.
In another aspect, the present invention provides:
(8) the preparation according to the above (1) or (2), wherein the absorption enhancer is an alkyl ester of fatty acid;
(9) the preparation according to the above (1) or (2), wherein the absorption enhancer is a nonionic surface-active agent;
(10) the preparation according to the above (1) or (2), wherein the absorption enhancer is a bile acid salt;
(11) the preparation according to the above (1) or (2), wherein the absorption enhancer is a nonsteroidal anti-inflammatory agent;
(12) the preparation according to any of the above (1) to (3), wherein the absorption enhancer is selected from the group consisting of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid and linolenic acid as well as sodium salts, potassium salts and calcium salts thereof;
(13) the preparation according to any of the above (1) to (4), wherein the absorption enhancer is a C
6
to C
12
fatty acid or a salt thereof;
(14) the preparation according to any of the above (1) to (4) and (13), wherein the absorption enhancer is selected from the group consisting of caproic acid, caprylic acid, capric acid and lauric acid as well as sodium salts, potassium salts and calcium salts thereof;
(15) the preparation according to any of the above (1), (2) or (6), wherein the absorption enhancer is selected from the group consisting of mono-, di- and/or tri-glycerides of C
6
to C
12
fatty acids;
(16) the preparation according to any of the above (1), (2), (6) or (15), wherein the absorption enhancer is selected from the group consisting of mono-, di- and/or tri-glycerides of a compound selected from the group consisting of caproic acid, caprylic acid, capric acid and lauric acid;
(17) the preparation according to any of the above (1) to (6) and (8) to (16), wherein the effervescent agent is a substance which has a property of, when the administered preparation is dissolved or disintegrated in the digestive tract, producing a gaseous substance such as carbon dioxide gas to disperse the drug, etc.;
(18) the preparation according to any of the above (1) to (6) and (8) to (17), wherein the effervescen
Kanazawa Hashime
Sasaki Kazuhiro
Shimizu Kenji
Sugimoto Tetsuya
Fay Zohreh
Grelan Pharmaceuticals Co., Ltd.
Kwon Brian-Yong
Wenderoth , Lind & Ponack, L.L.P.
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