Perivascular delivery of heparin for the reduction of smooth muscle cell proliferation after endothelial injury

• Published in: Journal of controlled release 1999-06, Vol.60 (1), p.129-142
• Main Authors: Teomim, D., Fishbien, I., Golomb, G., Orloff, L., Mayberg, M., Domb, A.J.
• Format: Article
• Language: English
• Subjects: Animals; Anticoagulants - administration & dosage; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cell Division - drug effects; Controlled release; Drug Delivery Systems; Endothelium, Vascular - physiology; General pharmacology; Heparin; Heparin - administration & dosage; Heparin - pharmacology; Medical sciences; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - pathology; Perivascular delivery; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyanhydride; Polymers - administration & dosage; Rats; Restenosis
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(99)00071-1

Thin flexible sheets composed of poly(lactic acid) (PLA) laminated polyanhydride, poly(erucic acid dimer-sebacic anhydride) (P(EAD-SA)), loaded with heparin were evaluated in vitro and in vivo. PLA was used for coating the polyanhydride to improve the release profile and improve the strength of the films. Heparin was released constantly for 20 days from PLA-coated 2% loaded P(EAD-SA). The uncoated film of P(EAD-SA) released heparin for only 4 days. The localized delivery of heparin around the carotid artery was investigated by implanting polymer loaded with [ 3H]heparin around the carotid artery of rats and the heparin release and tissue distribution was monitored. The maximum heparin concentration in the artery exposed to the drug was on day 4 for the P(EAD-SA) uncoated device (fast releasing system) and day 11 for the coated devices. The control artery, the uncovered segments of the artery, and the surrounding tissue contained negligible amounts of radioactivity. These data confirm that heparin was delivered locally without systemic exposure. Two independent animal studies were conducted to evaluate the effectiveness of these heparin-releasing devices. In both studies the balloon catheter injury in a rat model was used. After inflicting an injury to the common carotid, a matrix oriented with its long axis along the artery was placed under the injured portion of the vessel. In both studies the treated rats showed a very thin layer of neointima where the control group showed a significant reduction of the artery internal diameter with SMC neointima ratio greater than 1.