Polymeric materials as carriers for drugs in controlled drug delivery systems have been recognized as a new mode of limited drug administration for a number of years. However, in most such systems, the polymer serves as a mechanical barrier through which the drug must diffuse or as a degradable device in which the drug is physically entrapped and is released as the device degrades. This proposal involves systems in which model drugs are covalently bonded to biodegradable poly-Alpha-amino acids which serve as chemical carriers wherein drug is released by chemical or enzymatic hydrolysis. The potential efficacy of such compounds has been demonstrated in this laboratory using norethindrone chemically bonded to poly(L-glutamic acid) either directly or through appropriate spacer groups. The major studies in this proposal involve: 1) synthesis of homopolymers of L-glutamic acid or aspartic acid and copolymers of these agents with L-leucine 2) chemical incorporation into the molecule appropriate spacer groups attached to the free carboxyls of glutamic or aspartic acids 3) chemical attachment of model antihypertensive drugs to the spacer group via selected biologically labile bonds 4) in vitro studies on the release of drug in various fluids such as buffers, plasma, etc., and identification of the fragments from these hydrolyses 5) preparation of dosage forms which could be used subsequently to evaluate in vivo release characteristics and 6) preliminary in vivo release study to establish the criteria for extensive pharmacological study. This application is aimed toward the development of controlled delivery antihypertensives which can be subcutaneously injected to minimize side effects and maximize efficacy of the existing antihypertensives.
