IMPROVED INTESTINAL-ABSORPTION OF AN ENTERIC-COATED SODIUM URSODEOXYCHOLATE FORMULATION

A new enteric-coated formulation of sodium ursodeoxycholate was prepar ed and administered to man. The barrier film disintegrates and release s the drug only at pH greater than or equal to 5.5. The sodium salt of glycoursodeoxycholate was also prepared and encapsulated like ursodeo xycholate. Serum levels of ursodeoxycholate and glycoursodeoxycholate were measured by specific enzyme immunoassay after oral administration of their sodium salts in an enteric-coated formulation at equimolar d oses of 475 and 540 mg. The same subjects also received in separate ex periments ursodeoxycholic acid, sodium ursodeoxycholate, and glycourso deoxycholic acid in gelatin capsules. The mean area under the curve (m u mol/L.hr) following administration of enteric-coated sodium ursodeox ycholate (45 +/- 8) was significantly higher than that of either ursod eoxycholic acid (26 +/- 5; P < 0.01) or sodium ursodeoxycholate (25 +/ - 6; P < 0.001) administered in a conventional gelatin capsule. No dif ferences were found when glycoursodeoxycholic acid was administered as an enteric-coated sodium salt or in acid form in gelatin capsules. Ur sodeoxycholic was administered at a dose of 10 mu mol/min/kg over 1 hr to bile fistula rats both intraduodenally (i.d.) and intravenously (i .v.). The experiment included administration of the sodium salt in sol ution and the acid as a suspension. A similar experiment was performed with glycoursodeoxycholic acid. The ratio of the amount recovered fro m bile in the i.d. to that in the i.v. experiment is almost 1 for the sodium salt of ursodeoxycholate in solution, while it drops to 0.55 fo r ursodeoxycholic acid. No differences were found between i.v. and i.d . administration when glycoursodeoxycholic acid was administered in ac id form and as a soluble sodium salt. The results in rats point out th at the limiting factor for ursodeoxycholic acid intestinal absorption is its poor solubility and the high pH (8.4) it requires for micellar solubilization. On the other hand, glycoursodeoxycholic acid is well a bsorbed either in acid form or as a sodium salt because of its higher solubility at lower pH (6.4). The new enteric-coated sodium ursodeoxyc holate formulation resulted in complete solubilization and increased a bsorption.