Vipul Dave

Polymers for Drug Eluting Stents

Currently approved drug eluting stents (DES) consist of a metallic scaffold and an elutable drug dispersed in a polymer matrix that conformally surrounds the struts. These primarily biostable polymers bind the drug to the stent and modulate the elution of the drug into the arterial tissue. This chapter summarizes the key requirements for polymers used in the DES, including physical properties, stability, compatibility with drugs, biocompatibility with vascular tissue and control of drug release. An in-depth analysis of polymer structure, coating design, drug-polymer morphology and drug elution profile is provided for the four currently marketed DES: CYPHER(®) Sirolimus-eluting Coronary Stent, Taxus(®) / Taxus(®) Liberte(®), XIENCE V(™) / Promus(®) and Endeavor Resolute(®). A new generation of DES is being developed using bioabsorbable polymers which degrade over time and leave behind a bare metal stent. This includes the RES TECHNOLOGY™ platform employed in the NEVO™ Sirolimus-eluting Coronary Stent which is explored with respect to polymer composition, degradation profile and drug release kinetics.

Microstructure and drug-release studies of sirolimus-containing poly(lactide-co-glycolide) films

Sirolimus-containing poly(lactide-co-glycolide) (PLGA) films were prepared by solution casting and removing the residual solvent, 1,4-dioxane, by liquid and supercritical carbon dioxide (CO(2) ) extraction. The effect of lactide:glycolide ratio, stereochemistry of PLGA, and extraction condition (i.e., temperature and pressure) on the polymer and drug morphologies was studied using wide-angle X-ray scattering and differential scanning calorimetry. The polymer and drug crystallinity increased after liquid and supercritical CO(2) extraction, and the level of drug crystallinity within the film depended on the extraction conditions. Generally, higher levels of drug crystallinity were observed in the films with amorphous polymer matrices, and the drug crystallinity increased with temperature and pressure of the extraction conditions. In vitro drug elution from these films was studied using a USP 4 apparatus. Polymer crystallinity was found to be the determining factor for drug release, whereby films with higher polymer crystallinity eluted less drug compared to films with amorphous polymer matrices.

Morphological and degradation studies of sirolimus‐containing poly(lactide‐co‐glycolide) discs

The effect of residual solvent and copolymer ratio on the in vitro degradation and drug release behavior of a bioabsorbable polymer/drug system was investigated in an effort to understand and develop the use of these excipients for controlled drug delivery devices. Sirolimus-containing poly(lactide-co-glycolide) (PLGA) discs were fabricated by a solution-casting method using dimethyl sulfoxide (DMSO) as the solvent. The residual DMSO was removed from a set of discs by supercritical carbon dioxide extraction, and reflections of crystalline sirolimus were observed in the wide-angle X-ray scattering profile observed after extraction. A correlation was not observed between the extent of drug crystallization and extraction conditions and copolymer ratio. Mass loss, molecular weight, and sirolimus release were monitored during an in vitro study of the oven-dried neat PLGA, sirolimus-containing PLGA, and extracted sirolimus-containing PLGA discs during 56 days. The sirolimus-containing PLGA discs with residual DMSO exhibited a faster sirolimus release rate compared to the extracted discs. The residual DMSO facilitated release of sirolimus. The discs that contained PLGA with higher glycolide content, particularly 50% glycolide, degraded faster and exhibited faster sirolimus release.

Properties of nylon 12 balloons after thermal and liquid carbon dioxide treatments

Critical design attributes of angioplasty balloons include the following: tear resistance, high burst pressures, controlled compliance, and high fatigue. Balloons must have tear resistance and high burst pressures because a calcified stenosis can be hard and nominal pressures of up to 16 atm can be used to expand the balloon. The inflated balloon diameter must be a function of the inflation pressure, thus compliance is predictable and controlled. Reliable compliance is necessary to prevent damage to vessel walls, which may be caused by over-inflation. Balloons are often inflated multiple times in a clinical setting and they must be highly resistant to fatigue. These design attributes are dependent on the mechanical properties and polymer morphology of the balloon. The effects of residual stresses on shrinkage, crystallite orientation, balloon compliance, and mechanical properties were studied for angioplasty nylon 12 balloons. Residual stresses of these balloons were relieved by oven heat treatment and liquid CO2 exposure. Residual stresses were measured by quantifying shrinkage at 80 °C of excised balloon samples using a dynamic mechanical analyzer. Shrinkage was lower after oven heat treatment and liquid CO2 exposure compared to the as-received balloons, in the axial and radial directions. As-received, oven heat treated, and liquid CO2-exposed balloon samples exhibited similar thermal properties (T(g), T(m), X(t)). Crystallite orientation was not observed in the balloon cylindrical body using X-ray scattering and polarized light microscopy, which may be due to balloon fabrication conditions. Significant differences were not observed between the stress-strain curves, balloon compliance, and average burst pressures of the as-received, oven heat treated, and liquid CO2-exposed balloons.

Endothelial Cell Attachment and Proliferation Studies on Modified Metal Stent Surfaces

Flat coupons prepared from cobalt chromium alloy (CoCr) were modified using different methods (low energy excimer laser processing, electron beam irradiation, and immobilized covalently-bound heparin coating). Human coronary artery endothelial cell (HCAEC) attachment and growth kinetics were investigated on unmodified and modified metal surfaces. Results showed that HCAEC attach to unmodified CoCr coupons and surface-modified CoCr coupons. No change in cell number was observed when cells were grown on CoCr coupons and heparin coated coupons throughout the 72h study period. A decrease in cell number was observed for excimer treated coupons. HCAEC seeding on CoCr stents indicated that cells attached and proliferated on the stents over a ten day study period. This research showed that physical modifications did not improve cell proliferation. Very few non-viable cells were observed for unmodified and surface bound heparin coupons, and cells attached to the surface up to 72h. This shows that heparin can be coated on a stent surface to provide anti-thrombotic properties without any negative effect on cell attachment and proliferation. In vitro screening method of testing endothelial cell attachment and proliferation on modified metal stent surfaces can be used to gain insight for developing next generation drug eluting stents with improved endothelialization behavior.