A poly(styrene-b-isobutylene-b-styrene) (SIBS) triblock polymer is employed as the polymer drug carrier for the TAXUS Express2 Paclitaxel-Eluting Coronary Stent system (Boston Scientific Corp.). It has been shown that the release of paclitaxel (PTx) from SIBS can be modulated by modification of either drug-loading ratio or altering the triblock morphology by blending. In the present work, results toward achieving release modulation of PTx by chemical modification of the styrenic portion (using hydroxystyrene or its acetylated version) of the SIBS polymer system are reported. The synthesis of the precursor poly[(p-tert-butyldimethylsilyloxystyrene)]-b-isobutylene-b-[(p-tert-butyldimethylsilyloxystyrene] triblock copolymers was accomplished by living sequential block copolymerization of isobutylene (IB) and p-(tert-butyldimethylsiloxy)styrene (TBDMS) utilizing the capping-tuning technique in a one-pot procedure in methylcyclohexane/CH3Cl at -80 degrees C. This procedure involved the living cationic polymerization of IB with the 5-tert-butyl-1,3-bis(1-chloro-1-methylethyl)benzene/TiCl4 initiating system and capping of living difunctional polyisobutylene (PIB) chain ends with 1,1-ditolylethylene (DTE) followed by addition of titanium(IV) isopropoxide (Ti(OIp)4) to lower the Lewis acidity before the introduction of TBDMS. Deprotection of the product with tetrabutylammonium fluoride yielded poly(hydroxystyrene-b-isobutylene-b-hydroxystyrene), which was quantitatively acetylated to obtain the acetylated derivative. The hydroxystyrene and acetoxystyrene triblock copolymers have acceptable mechanical properties for use as drug delivery coatings for coronary stent applications. It was concluded that the hydrophilic nature of the endblocks and polarity effects on the drug/polymer miscibility lead to enhanced release of PTx from these polymers. The drug-polymer miscibility was confirmed by differential scanning calorimetry and atomic force microscopy evaluations.

Polyisobutylene (PIB)-based block copolymers have attracted significant interest as biomaterials. Poly(styrene-b-isobutylene-b-styrene) (SIBS) has been shown to be vascularly compatible and, when loaded with paclitaxel (PTx) and coated on a coronary stent, has the ability to deliver the drug directly to arterial walls. Modulation of drug release from this polymer has been achieved by varying the drug/polymer ratio, by blending SIBS with other polymers, and by derivatizing the styrene end blocks to vary the hydrophilicity of the copolymer. In this paper, results are reported on the synthesis, physical properties, and drug elution profile of PIB-based block copolymers containing methacrylate end blocks. The preparation of PIB-poly(alkyl methacrylate) block copolymers has been accomplished by a new synthetic methodology using living cationic and anionic polymerization techniques. 1,1-Diphenylethylene end-functionalized PIB was prepared from the reaction of living PIB and 1,4-bis(1-phenylethenyl)benzene, followed by the methylation of the resulting diphenyl carbenium ion with dimethylzinc (Zn(CH(3))(2)). PIB-DPE was quantitatively metalated with n-butyllithium in tetrahydrofuran, and the resulting macroinitiator could initiate the polymerization of methacrylate monomers, yielding block copolymers with high blocking efficiency. Poly(methyl methacrylate-b-isobutylene-b-methyl methacrylate) (PMMA-b-PIB-b-PMMA) and poly(hydroxyethyl methacrylate-b-isobutylene-b-hydroxyethyl methacrylate) (PHEMA-b-PIB-b-PHEMA) triblock copolymers were synthesized and used as drug delivery matrixes for coatings on coronary stents. The PMMA-b-PIB-b-PMMA/PTx system displayed zero-order drug release, while stents coated with PHEMA-b-PIB-b-PHEMA/PTx formulations exhibited a significant initial burst release of PTx. Physical characterization using atomic force microscopy and differential scanning calorimetry of the formulated PMMA-b-PIB-b-PMMA coating matrix indicated the partial miscibility of PTx with the PMMA microphase of the matrix.

The TAXUS Express 2 Paclitaxel Eluting Coronary Stent System employs a coating consisting of the thermoplastic elastomer, poly(styrene-b-isobutylene-b-styrene; SIBS), selected for its drug-eluting characteristics, vascular compatibility, mechanical properties, and biostability. This study was conducted to evaluate the impact of different SIBS (17-51 mole % styrene) compositions on mechanical properties, chemical stability, and vascular compatibility. Mechanical property (stress-strain measurements) and stability studies were conducted on polymer films with five different styrene contents (17, 24, 32, 39, and 51 mole %). The ultimate tensile strength did not change significantly with composition, but the elongation at break decreased with increased styrene content. A pulsatile fatigue test further confirmed the mechanical stability of SIBS up to 39 mole % styrene. The vascular compatibility of five different SIBS compositions was assessed using SIBS-only coated stents, in the coronary and carotid arteries in a porcine model study. The stability of the vessel wall, rate/degree of endothelialization, inflammation, and thrombus at timepoints from 30 to 180 days were evaluated. The results confirm vascular compatibility over the range of 17-51 mole % styrene.

Acrylate-based block copolymers, synthesized by atom transfer radical polymerization (ATRP) processes, were evaluated as drug delivery matrices for the controlled release of paclitaxel from coronary stents. The polymers were multiblock copolymers consisting of poly(butyl acrylate) or poly(lauryl acrylate) soft blocks and hard blocks composed of poly(methyl methacrylate), poly(isobornyl acrylate), or poly(styrene) homo- or copolymers. Depending on the ratio of hard to soft blocks in the copolymers, coating formulations were produced that possessed variable elastomeric properties, resulting in stent coatings that maintained their integrity when assessed by scanning electron microscopy (SEM) imaging of overexpanded stents. In vitro paclitaxel release kinetics from coronary stents coated with these copolymers typically showed an early burst followed by sustained release behavior, which permitted the elution of the majority of the paclitaxel over a 10-day time period. It was determined that neither the nature of the polyacrylate (n-butyl or lauryl) nor that of the hard block appeared to affect the release kinetics of paclitaxel at a loading of 25% drug by weight, whereas some effects were observed at lower drug loading levels. Differential scanning calorimetry (DSC) analysis indicated that the paclitaxel was at least partially miscible with the poly(n-butyl acrylate) phase of those block copolymers. The copolymers were also evaluated for sterilization stability by exposing both the copolymer alone and copolymer/paclitaxel coated stents to e-beam radiation at doses of 1-3 times the nominal dose used for medical device sterilization (25 kGy). It was found that the copolymers containing blocks bearing quaternary carbons within the polymer backbone were less stable to the radiation and showed a decrease in molecular weight as determined by gel-permeation chromatography. Conversely, those without quaternary carbons showed no significant change in molecular weight when exposed to 3 times the standard radiation dose. There was no significant change in drug release profile from any of the acrylate-based copolymers after exposure to 75 kGy of e-beam radiation, and this was attributed to the inherent radiation stability of the poly(n-butyl acrylate) center block.