Biodegradable polymeric prodrugs of antihypertensive agents

Biodegradable polymeric prodrugs of antihypertensive agents were developed by covalently binding minoxidil, clonidine, prazosin, and CGS 16617 to poly(alpha-amino acids) via labile linkages. The amide bond was used to link minoxidil and clonidine onto poly(glutamic acid), while the carbamate linkage was used to couple prazosin and CGS 16617 to poly(hydroxypropyl glutamine) (PHPG) or copolymer of hydroxypropyl glutamine and leucine [P(HPG/LEU)]. In vitro release studies were performed in isotonic phosphate buffered saline (pH 7.4) to investigate the factors that influence the release rate. It was shown that the release rate of antihypertensive agents from the polymeric prodrug was dependent on particle size, drug water solubility, and drug loading. Zero order release of minoxidil and prazosin was achieved in "in vitro" studies. In vivo experiments were performed with New Zealand White rabbits and Sprague-Dawley rats by subcutaneously injecting PHPg-prazosin carbamate particles in order to study the blood plasma levels of prazosin and tissue biocompatibility. Following an initial burst, a nearly constant prazosin plasma concentration profile above 2 ng/mL was maintained for 10 days. Histological studies were performed on the injection sites of PHPG-prazosin carbamate particles in rats. The significant histological findings were the focal inflammation and the formation of the fibrous capsule around the injection site. Hence, it is concluded that the biodegradable injectable PHPG-prazosin carbamate polymeric prodrug system is biocompatible.