SIMVASTATIN INCORPORATED PERIVASCULAR POLYMERIC CONTROLLED DRUG DELIVERY SYSTEM FOR THE INHIBITION OF VASCULAR WALL INTIMAL HYPERPLASIA (2007)

Dialysis access graft failure is a major complication in providing care to patients on hemodialysis therapy.The failure rates have been reported as high as 80% at one year for this procedure.The major cause of failure is intimal hyperplasia.Intimal hyperplasia is an exaggeration of the normal vascular wall healing response to injury resulting from the migration and proliferation of medial smooth muscle cells.To mitigate this disease condition, we developed a perivascular polymeric controlled drug delivery device which we hypothesized when applied locally, would be effective in preventing intimal hyperplasia by enabling a sustained release of the therapeutic agent to the anastamotic site.This novel polymeric device, named PolyRing, is a composite system consisting of poly (DL-lactide-co-glycolide) microspheres embedded in a poly (ethylene glycol) hydrogel.The drug for the treatment of intimal hyperplasia is encapsulated within the poly (DL-lactide-co-glycolide) microspheres.The device is snapped into place around the vessel to deliver the drug.This work focuses on evaluating the feasibility of releasing the drug Simvastatin from the device to provide localized, site specific, sustained drug delivery for the prevention of intimal hyperplasia in vascular tissue.Simvastatin, obtained in a pro-drug form, when hydrolyzed to its active form, Simvastatin Acid, acts as a potent competitive inhibitor of the 3-Hydroxy-3-methylglutaryl coenzyme A reductase.The inhibition of this enzyme suppresses the mevalonate pathway and thereby prevents the proliferation of smooth muscle cells.As the focus is on controlled localized iv delivery, we hypothesize the need of using the active form as against the lactone form.Therefore, we fabricated Simvastatin and Simvastatin Acid loaded poly (DL-lactide-coglycolide) microspheres using oil-water and water-oil-water techniques respectively.The oil-water emulsion resulted in smooth surfaced microspheres (determined by Scanning Electron Microscopy) with a particle size of approximately 50m (determined by dynamic light scattering), a yield range of 65-85 % and a drug loading efficiency of approximately 81%.The water-oil-water emulsion for simvastatin acid produced microparticles with a yield in the range of 60-70 % and a loading efficiency of approximately 7%.The Simvastatin Acid loaded microspheres had a smooth surface morphology with a particle size in the range of 2-25 microns.PolyRings were characterized by environmental scanning electron microscopy and revealed a uniform distribution of the drug-loaded microspheres in the poly (ethylene glycol) hydrogel matrix.The cell culture study to compare the efficacy of the two forms of the drug in inhibiting smooth muscle cell proliferation indicated that the inhibitory effect of Simvastatin Acid was significantly higher than that of Simvastatin.The release of Simvastatin Acid from the device lasted for about 70 days.Further, the Simvastatin Acid loaded device successfully inhibited the proliferation of smooth muscle cells in culture.Therefore, we conclude that the device, PolyRing, has been successfully modified for the controlled delivery of statins to inhibit intimal hyperplasia.v DEDICATION This thesis is dedicated to god and my parents vi