Release characteristics of a short‐chain fatty acid, n‐butyric acid, from its β‐cyclodextrin ester conjugate in rat biological media

Abstract

6A‐O‐(n‐Butanoyl)‐β‐cyclodextrin was prepared and its hydrolysis behavior in aqueous solutions and in rat intestinal fluids was investigated. Furthermore, the enzymatic hydrolyses of the n‐butyric acid–β‐cyclodextrin conjugate using α‐amylase and esterase were studied to gain insight into the release behavior of n‐butyric acid from the conjugate. The hydrolysis of the conjugate proceeded according to a first‐order kinetics in aqueous solution, and gave a V‐shaped pH profile, indicating a specific acid‐base‐catalyzed hydrolysis at acidic and neutral‐alkaline regions, respectively. The half‐lives (t1/2) of the conjugate at pH 4.4, 6.8, and 7.4 at 37 °C were ∼580, 43, and 6 days, respectively, indicating that the conjugate is stable in aqueous solution. No appreciable release of n‐butyric acid from the conjugate was observed in the stomach and small intestinal contents of rats, or in the small and large intestinal homogenates of rats. On the other hand, a fast disappearance of the conjugate and an appearance of n‐butyric acid were observed in the cecal and colonic contents of rats. The t1/2 values of the disappearance were ∼4, 1, and 6 h in 10 and 15% cecal contents and 10% colonic contents, respectively, and the appearance of n‐butyric acid after 6 h was ∼10% in the 15% cecal contents. Aspergillus oryzae α‐amylase hydrolyzed the conjugate to small saccharide conjugates, such as the triose and maltose conjugates, but there was no appreciable release of n‐butyric acid. The conjugate was less susceptible to carboxylic esterase (from porcine live), thus releasing no appreciable amounts of n‐butyric acid. On the other hand, a fast release of n‐butyric acid was observed when the esterase was employed after amylase hydrolysis, suggesting that two types of enzymes, sugar‐degrading and ester‐hydrolyzing enzymes, are necessary for the release of n‐butyric acid from the conjugate in large intestinal contents. © 2000 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1486–1495, 2000