O-carboxymethyl-O-ethylcyclomaltoheptaose as a delayed-release-type drug carrier: improvement of the oral bioavailability of diltiazem in the dog.

The utility of O-carboxymethyl-O-ethylcyclomaltoheptose (carboxymethyl-ethyl-beta-cyclodextrin, CME-beta CD) as a delayed-release-type drug carrier was investigated in vitro and in vivo, using diltiazem hydrochloride as a model drug. The aqueous solubility of CME-beta CD showed a marked dependency on pH, because of the ionization of the carboxyl group (pKa 3.75). The formation of an inclusion complex between diltiazem and CME-beta CD in aqueous solution and in the solid state was assessed by a solubility method and by X-ray diffractometry, respectively. The rate of release of the drug from the compressed tablet containing the complex was significantly retarded in solutions at low pH and increased with increase in pH, and this was reflected in the blood levels in the dog after the oral administration. The results suggested that the use of CME-beta CD could improve the oral bioavailability of diltiazem and release the drug preferentially in the intestinal fluid but only slightly in the gastric fluid.