Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1995-12-01
1999-01-26
Azpuru, Carlos
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424451, 424464, 514182, A61F 202, A61K 948, A61K 920, A61K 3156
Patent
active
058635505
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of international application PCT JP94/00282, filed Feb. 23, 1994.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a cholestasis ameliorant containing tauroursodeoxycholic acid as the active ingredient. Tauroursodeoxycholic acid is a taurine conjugate of ursodeoxycholic acid represented by the following structural formula. ##STR1##
2. Background Information
Cholestasis is a pathological condition where the choleresis, which is one of the important functions of the liver, is suppressed and the bile flow from the liver through the bile duct to the duodenum is reduced, resulting in congestion of biliary components, and it is categorized into extrahepatic obstructive jaundice, which is caused by an apparent mechanical obstruction such as tumor or gallstones, and intrahepatic cholestasis, which occurs with no macroscopically noticeable site of obstruction. Intrahepatic cholestasis is further classified into acute type due to drug-induced hepatitis or viral hepatitis, chronic type represented by primary biliary cirrhosis (PBC), recurrent type occurring familially or during pregnancy and the like and the main clinical symptoms common to all types of intrahepatic cholestasis are severe jaundice and persistent itching.
Steroid and phenobarbital preparations are currently used for the treatment of intrahepatic cholestasis, showing a certain level of, but often insufficient, efficacy.
In patients with obstructive jaundice, biliary drainage techniques such as percutaneous transhepatic cholangio drainage (PTCD), whose purpose is external biliary drainage, are performed but there are quite a few cases where jaundice takes a chronic course because of insufficient biliary drainage.
Since it has recently been reported in Japan and other countries that ursodeoxycholic acid preparations have very high efficacy against intrahepatic cholestasis, development of injectable ursodeoxycholic acid preparations has been hoped for.
However, the solubility of ursodeoxycholic acid is very low and, if it is prepared in an injectable form, the injection would have shortcomings such as causing angialgia because of high pH value.
Therefore, a related substance that is soluble in water and is easy to be prepared into injectable preparations at near-neutral pH has been searched for.
SUMMARY OF THE INVENTION
In the course of research on the effects of ursodeoxycholic acid on various derivatives of bile acids in patients with liver diseases, the present inventors had found that tauroursodeoxycholic acid has ameliorative effect against cholestasis and better solubility in water as compared with ursodeoxycholic acid and that it may be easily prepared into injectable preparations.
According to the present invention, cholestasis ameliorant containing tauroursodeoxycholic acid as the active ingredient are provided.
Tauroursodeoxycholic acid used in the present invention may be a pharmaceutically acceptable salt thereof, and can be produced from ursodeoxycholic acid by the application of well known manufacturing processes of taurine-conjugated bile acids. For instance, it can be produced by reacting an alkyl chlorocarbonate with ursodeoxycholic acid in a nonhydrating solvent in the presence of a basic catalyst and then reacting taurine in an alkaline solution with this solution.
DETAILED DESCRIPTION OF THE INVENTION
An extra external-biliary fistula was developed in female SD rats under anesthesia and, after bile collection for 30 minutes, estradiol-17.beta.-D-glucuronide (E-17-G) was administered via their femoral veins as a single dose of 10 .mu. mole/kg. Immediately after the administration, tauroursodeoxycholic acid was continuously administered over two hours via the femoral veins at a rate of 0.6 .mu. mole/min/100 g body weight, and the bile flow was measured serially.
Tauroursodeoxycholic acid inhibited the reduction of the bile flow induced by E-17-G at a rate of 0.3 .mu. mole/min/100 g body weight or higher, and this inhibi
REFERENCES:
patent: 5260074 (1993-11-01), Sipos
patent: 5500421 (1996-03-01), Parenti
Kitani et al., "Tauroursodeoxycholate prevents taurocholate induced cholestasis", Life Sci., 30(6):515-523 (1982).
Hayakawa et al., "Effect of bile acid on cholestasis induced by 17.alpha ethinylestradiol", Chem. Abstr. 108(9):(1988).
Schoelmerich et al., "Taurohyocholate, taurocholate, and tauroursocholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver", Res. Exp. Med. 190(2):121-129 (1990).
Schoelmerich et al., "Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver", J. Hepatol. 10(3):280-283 (1990).
Zhao et al., "Effects of bile salt supplementation on biliary secretion in estrogen-treated rats", Chem. Abstr. 113(21):189102 (1990).
Yokote M., "Effect of bile acids on experimental intrahepatic cholestasis of the rat", Teikyo Igaku Zasshi 13(2):137-150 (1990).
Abernathy et al., "Drug-induced cholestasis in the perfused rat liver and its reversal by taroursodeoxycholate: an ultrastructural study", Proc, Soc. Exp. Biol. Med., 199(1):54-58 (1992).
Utili et al., "Effect of bile salt infusion on chlorpromazine-induced cholestasis in the isolated perfused rat liver", Proc. Soc. Exp. Biol. Med., 199(1):49-53 (1992).
Minagawa et al., "Cholestasis induced by lithocholate glucuronide. A study with congenital jauniced rats and effects of ursodeoxycholate conjugates", Chem Abstr. 117(15):148401 (1992).
Nakai et al., "Microtubule-independent choleresis and anticholestatic action of cholchicine-treated rat liver", Biochem. J. 288(2):613-617 (1992).
Heuman et al., "Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts: in vivo studies in the rat", Gastroenterology 100(1):201-211 (1991).
Koiso Kumiko
Maeda Minoru
Sekido Shozaburo
Azpuru Carlos
Tokyo Tanabe Company Limited
LandOfFree
Cholestasis ameliorant does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cholestasis ameliorant, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cholestasis ameliorant will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1448189