Modified polypeptides containing gamma-benzyl glutamic acid as drug delivery platforms.
We previously reported the development of diffusion-controlled biodegradable polypeptides for drug delivery purposes. In this paper, we describe the synthesis of three modified polypeptides that contain gamma-benzyl glutamic acid as the common structural backbone. The properties of these polymers were characterized with regard to their potential application as drug delivery platforms. Procainamide hydrochloride, a hydrophilic drug, and protamine sulfate, a low molecular weight protein, were used as model drugs for examining release rate profiles from these polymers. The homopolymer of poly(gamma-benzyl-L-glutamic acid), PBLG, showed a highly helical configuration and a moderate release rate of procainamide. Modification of structural attributes by random copolymerization of the D- and L- isomers of gamma-benzyl glutamic acid produced poly(gamma-benzyl-D,L-glutamic acid), PBDLG, which displayed a significantly slower release of procainamide when compared to PBLG. The modification of polymer bulk hydrophobicity by copolymerization of PBLG (A) with poly(ethylene glycol) (B) yielded an ABA triblock copolymer exhibiting much faster release rates for both procainamide and protamine than those demonstrated by the other two polymers. Using this triblock copolymer, protamine release rates ranging from 2 weeks to approximately 2 months were obtained by simply varying the polymer processing conditions and protein particle size. A nearly complete release of protein was obtained from the triblock copolymer blends and this occurred without reliance upon degradation of the polymer backbone. Fickian diffusion-controlled release mechanisms were implied for release of procainamide and protamine from these polypeptide formulations based on the linear relationship displayed between cumulative drug release and the square root of time.
Markland
P
P
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Amidon
G L
GL
Yang
V C
VC
D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D010455:Peptides / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D011342:Procainamide / Q000493:pharmacokinetics*; D011479:Protamines / Q000493:pharmacokinetics*; D013997:Time Factors
D003692:Delayed-Action Preparations; D010455:Peptides; D011479:Protamines; D011099:Polyglutamic Acid; D011342:Procainamide