The SYNERGY biodegradable polymer everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety study.

AIMS: SYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly-lactide-co-glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent. METHODS AND RESULTS: SYNERGY stents were implanted in arteries of domestic swine. Devices were explanted at predetermined time points (up to 120 days) and the extent of PLGA coating or everolimus remaining on the stents was quantified. Everolimus levels in the arterial tissue were also evaluated. A pathological analysis on coronary arteries of single and overlapping stents was performed at time points between 5 and 270 days. PLGA bioabsorption began immediately after implantation, and drug release was essentially complete by 90 days; PLGA absorption was substantially complete by 120 days (>90% of polymer was absorbed) leaving a bare metal SYNERGY stent. Vascular response was similar among SYNERGY and control stents (bare metal, polymer-only, and 3× polymer-only). Mild increases in para-strut fibrin were seen for SYNERGY at an early time point with no significant differences in all other morphological and morphometric parameters through 270 days or endothelial function (eNOS immunostaining) at 90 or 180 days. Inflammation was predominantly minimal to mild for all device types. CONCLUSION: In a swine model, everolimus was released by 90 days and PLGA bioabsorption was complete shortly thereafter. The SYNERGY stent and its biodegradable polymer, even at a 3× safety margin, demonstrated vascular compatibility similar to bare metal stent controls.

Investigation of the cytotoxicity and insulin transport of acrylic-based copolymer protein delivery systems in contact with Caco-2 cultures.

Microparticles or nanospheres of hydrogels of crosslinked poly(methacrylic acid) grafted with poly(ethylene glycol) as well as crosslinked poly(acrylic acid) grafted with poly(ethylene glycol) were prepared for use as oral insulin delivery carriers. The copolymer carriers were synthesized by precipitation/dispersion polymerization that led to gel nanospheres or by bulk polymerization and subsequent size reduction of thin films to obtain gel microparticles. The cytotoxicity of these copolymers was investigated in contact with Caco-2 cell cultures using a metabolic assay to measure the effect of the presence of copolymers on the cell viability. The copolymers were found to exhibit no cytotoxic effect on the cell cultures. Insulin-loaded formulations were also tested for cytotoxicity and insulin transport studies across cell monolayers. The copolymers were shown to open the tight junctions between cells, increasing the available area for diffusion across the cell monolayer, and thus increasing the permeability of insulin across the monolayer.

Development of acrylic-based copolymers for oral insulin delivery.

We developed nanospheres of crosslinked networks of methacrylic acid grafted with poly(ethylene glycol), and acrylic acid grafted with poly(ethylene glycol) nanospheres for use as oral insulin delivery devices. The copolymer nanospheres were synthesized via free-radical precipitation/dispersion. The average particle diameter of the copolymer gel nanospheres at various physiologically relevant pH values was characterized using photon correlation spectroscopy. Their size increased dramatically as the surrounding pH rose above the pK(a) of the network. The nanospheres ranged in diameters from 200 nm at pH of 2.0 to 2 microm at pH around 6.0. Insulin was loaded into the copolymers at levels of 9.33 and 9.54 mg per 140 mg solid sample, by partitioning from concentrated insulin solutions. In vitro studies were performed to study the passage of the insulin-loaded copolymer samples in the gastrointestinal tract. Insulin was entrapped at low pH (pH=3.0) but released at more neutral pH (pH=7.0). Animal studies were performed to investigate the abilities of insulin-loaded copolymer samples to influence the serum glucose levels of rats. In studies with diabetic rats, the serum glucose level was lower than control values for the animals that received the insulin-loaded copolymers and lasted for at least 6 h. The insulin loaded copolymer nanospheres caused a significant reduction of serum glucose with respect to that of a control animal.