Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-02-24
2001-06-26
Jones, Dwayne C. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S169000
Reexamination Certificate
active
06251884
ABSTRACT:
BACKGROUND OF THE INVENTION
3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid (“Ursodeoxycholic acid” or “UDCA”) has been used clinically for more than two decades, initially proving effective for the treatment of patients with cholelithiasis and more recently showing promise in the treatment of patients with cholestatic liver diseases. It is well established that oral administration of UDCA leads to a significant improvement in serum liver enzymes, and based on results from long-term clinical trials, the consensus opinion is that UDCA is beneficial for the treatment of early-stage primary biliary cirrhosis. In addition, clinical trials have shown that UDCA is beneficial in improving clinical and biochemical indices of hepatic function in patients with sclerosing cholangitis, cystic fibrosis and chronic hepatitis.
Despite the promising effects shown by UDCA in liver diseases, the exact mechanism of its action remains unclear. Early speculation suggested that a shift in the hydrophobic/hydrophilic balance of the biliary bile acid pool was an important determinant of its effectiveness, but recent data do not totally support this contention; and the improvement in liver function is almost certainly the result of a marked hypercholeresis induced by UDCA, which facilitates the biliary excretion of potentially more toxic bile acids or other endogenous agents.
In studies focussing on the metabolism of UDCA in patients with a variety of liver diseases, the appearance of substantial amounts of the C-3 sulfate ester of UDCA in the urine has been consistently observed, and this specific metabolite has proven to be a useful marker for UDCA compliance. In addition, animal studies have suggested that sulfation of bile acids may represent an important metabolic pathway for preventing cholestasis and limiting hepatocellular damage.
The cytotoxic or membrane-damaging effect of a bile acid is related to its physicochemical properties. Hydrophobic bile acids are markedly more membrane damaging than hydrophilic bile acids, and relative indices of cytotoxicity have been established based on the retention volume of the bile acid in reverse-phase high-pressure liquid chromatography systems or from partition coefficients in octanol/water. It is paradoxical that the human liver synthesizes chenodeoxycholic acid, a hydrophobic molecule that is intrinsically hepatotoxic, as one of its primary bile acids; in cholestasis, the hepatic accumulation of this bile acid may initiate, contribute to, or exacerbate liver damage. In contrast, UDCA, the 7&bgr;-epimer of chenodeoxycholic acid, is highly hydrophilic and has been shown to counteract the membrane-damaging effects of hydrophobic bile acids. This is one rationale for the therapeutic use of UDCA in the treatment of a variety of liver diseases. After the oral or intravenous administration of UDCA, this bile acid is efficiently biotransformed in the liver, mainly by conjugation. Negligible concentrations and proportions of unconjugated UDCA are consequently found in human bile, even after the administration of relatively high doses.
UDCA also may have a therapeutic role beyond its use in the treatment of various liver diseases. In this respect, data are emerging from animal models of colonic carcinogenesis that suggest a protective role for UDCA.
However, actual delivery of UDCA to the colon is problematic, in that, at the usual therapeutic doses administered orally (10-15 mg/kg body weight/day), UDCA is relatively well absorbed from the intestine and efficiently biotransformed in the liver mainly by conjugation. As a consequence, it is extremely difficult to deliver effective amounts of UDCA specifically to the colon.
Therefore, given this limitation of delivery to the colon, it would be extremely beneficial to have a compound, composition or method in which UDCA may be effectively delivered to the colon. It also would be desirable to have a compound, composition or method which may be used to deliver UDCA effectively to other portions of the gastrointestinal tract. In addition, it would be advantageous to have a compound, composition or method for use in effectively inhibiting or treating an inflammatory disorder of the gastrointestinal tract or liver.
SUMMARY OF THE INVENTION
One aspect of this invention is directed to a pharmacologically acceptable composition including a sulfate of 3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid (Ursodeoxycholic acid or “UDCA”) and a pharmacologically acceptable carrier. In a preferred composition, the sulfate is UDCA-3-sulfate, UDCA-7-sulfate, UDCA-3,7-disulfate, glyco-UDCA-3-sulfate, glyco-UDCA-7-sulfate, glyco-UDCA-3,7-disulfate, tauro-UDCA-3-sulfate, tauro-UDCA-7-sulfate, tauro-UDCA-3,7-disulfate or a combinations thereof.
Another aspect of the invention concerns a method of delivering UDCA to a mammal to inhibit or treat a disorder, which includes administering a sulfate of UDCA to the mammal in an amount sufficient to inhibit or treat the disorder. For example, a UDCA sulfate may be used to advantage in inhibiting or treating an inflammatory condition of the gastrointestinal tract, such as colon cancer, rectum cancer, a neoplasm of the colon, a neoplasm of the rectum, carcinogenesis of the colon, carcinogenesis of the rectum, ulcerative colitis, an adenomatous polyp, familial polyposis and the like. A sulfate of UDCA also may be administered to inhibit or treat an inflammatory disorder of the liver. A UDCA sulfate may be used to improve serum biochemistries of liver disease or liver function, to increase bile flow or to decrease binary secretion of phospholipid or cholesterol.
In yet a further aspect, the invention is directed to a method of maintaining an isolated organ by perfusing the organ with a sulfate of UDCA.
This invention offers several benefits and advantages over the prior art. For example, therapeutically effective quantities of UDCA may be delivered to the colon and other portions of the gastrointestinal tract for inhibition or treatment of inflammatory disorders, such as colon cancer and the like. In addition, sulfates of UDCA may be used effectively to inhibit or treat liver disease or improve liver function. These and other benefits and advantages will become readily apparent to one of ordinary skill in the art upon review of the following detailed description of the invention.
REFERENCES:
patent: 4565811 (1986-01-01), Di Schiena
patent: 5460812 (1995-10-01), Sipos
patent: 0117570 (1984-09-01), None
Hcaplus, DN 124:193196, Rodrigues et al., Gastroenterology, 109(6), 1835-44, 1995.*
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Czygan, P., et al.,Chenodeoxycholic acid but not ursodeoxycholic acid enhances colonic carcinogenesis in the rat, Falk Symposium 33, pp. 393-395, 1982.
Earnest, D. L., et al.,Chemoprevention of Azoxymethane-induced Colonic Carcinogenesis by Supplemental Dietary Ursodeoxycholic Acid, Cancer Research, pp. 5071-5074, Oct. 1, 1994.
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Franzone, J. S., et al.,Farmacocinetica e metabolism epatico dell′acido ursulcolico (forma solubile dell′UDCA) nel ratto, Boll. Chim. Farm. vol. 126, No. 7 1987, pp. 289-293, XP000644487.
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Rigas, B., et al., Abstract,Ursodeoxycholic Acid and Piroxicam Up-Regulate MHC Antigen Expression in Rat Coloncytes During Colon Cancer Development, Gastrointestinal Oncology, A433, Apr. 1994.
Roda, A., et al.,Improved Intestinal Absorption of an Enteric-Coated Sodium Ursodeoxycholate Formulation, Pharmaceutical Research, vol. 11, No. 5, May 1994, pp. 642-647, XP000645
Children's Hospital Medical Center
Delacroix-Muirheid C.
Jones Dwayne C.
Wood Herron & Evans L.L.P.
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