Bile Acid Sequestrants Based on Cationic Dextran Hydrogel Microspheres. 2. Influence of the Length of Alkyl Substituents at the Amino Groups of the Sorbents on the Sorption of Bile Salts

• Published in: Journal of pharmaceutical sciences 2001-06, Vol.90 (6), p.681-689
• Main Authors: Nichifor, Marieta, Zhu, X.X., Baille, Wilms, Cristea, Doina, Carpov, Adrian
• Format: Article
• Language: English
• Subjects: Alkylation; Amination; bile acids; Bile Acids and Salts - metabolism; Binding, Competitive; Biological and medical sciences; Cholestyramine Resin - metabolism; dextran polymers; Dextrans - chemical synthesis; Dextrans - chemistry; Dextrans - metabolism; General pharmacology; Humans; Hydrogels - chemical synthesis; Hydrogels - chemistry; Hydrogels - metabolism; hydrophobic interactions; hypercholesterolemia; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; quaternary ammonium groups
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.1024

Cationic dextran hydrogel microspheres with pendant quaternary ammonium groups having alkyl substituents (C2–C12) at quaternary nitrogen were synthesized. The in vitro sorption of sodium salts of four bile acids (glycocholic, cholic, taurocholic, and deoxycholic acids) with these hydrogels was studied as a function of substituent alkyl chain length and bile acid hydrophobicity. Sorption experiments were performed in phosphate buffer solutions (pH 7.4) containing one bile salt (individual sorption) or mixtures of several bile salts (competitive sorption). Parameters for individual sorption were calculated taking into consideration the stoichiometric and cooperative binding of bile salts to oppositely charged polymer hydrogels. The results show that the increase in the length of the alkyl chain of the substituent leads to an increase in both ionization constant K0 and overall stability constant of binding K, but decreases the cooperativity parameter u. The competitive sorption studies indicate that the hydrogels display a good affinity for both dihydroxylic and trihydroxylic bile salts. The molar ratio of maximum amounts bound for the two types of bile acid is 2 to 1, which is much lower than those reported for other cationic polymers recommended as bile acid sequestrants. The binding constants for the sorption of bile salts by some dextran hydrogels are 20–30 times higher than those obtained for cholestyramine under similar sorption conditions. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:681–689, 2001