Background Drug-coated balloons are increasingly utilized for peripheral vascular disease and yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used Paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined Zotarolimus pharmacokinetics. Methods and results Animal studies, bench-top experiments and computational modeling were integrated to quantify arterial distribution after Zotarolimus-coated balloon (ZCB) use. Drug diffusivity and binding parameters for use in computational modeling were estimated from kinetics of Zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like Paclitaxel, Zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with Zotarolimus concentration decreasing with transmural depth as opposed to multiple peaks displayed by Paclitaxel. Drug release kinetics was measured by inflating ZCBs in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion but binding determined drug retention. Conclusions Large bolus of Zotarolimus releases during balloon inflation, some of which pervades the tissue and a fraction of the remaining drug adheres to the tissue-lumen interface. As a result, duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.

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Drug‐eluting stents (DES) are a preferred treatment modality for occlusive coronary artery disease. First‐generation DES have demonstrated high levels of efficacy. However, concerns have been raised over late thrombotic events. XIENCE V™ everolimus‐eluting coronary stent is a second‐generation DES designed to be more deliverable and safe, while maintaining efficacy in a broad patient population compared with first‐generation DES. 1 − 3 As a drug/device combination product, the overall performance of a DES is determined by its components and how well they are integrated. XIENCE V utilizes the MULTI‐LINK VISION® stent, the antiproliferative drug everolimus, a fluorinated polymer drug carrier, poly(vinylidene fluoride‐co‐hexafluoropropylene) (PVDF‐HFP), and a stent‐specific delivery system. A DES coating must fulfill the multiple goals of biocompatibility, controlled drug release and maintenance of the coating durability through stent crimping, and expansion in vivo. The XIENCE V coating utilizes a two‐layer coating system composed of an acrylate primer and a fluorinated copolymer drug reservoir. Fluorinated polymers have a long history of use in permanent vascular implant applications. The XIENCE V fluorinated copolymer offers in vivo biocompatibility combined with excellent chemical stability and high purity. Described in this article are the design rationale and polymer selection criteria. The hemocompatibility and biocompatibility of the fluorinated polymer coating are discussed. Characterization results on drug release control, possible drug release mechanism, coating integrity, coating uniformity, and fatigue resistance are also presented.

The polymers poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly(n-butyl methacrylate) (PBMA) are employed in manufacturing the XIENCE family of coronary stents. PBMA serves as a primer and adheres to both the stent and the drug coating. PVDF-HFP is employed in the drug matrix layer to hold the drug everolimus on the stent and control its release. Chemical stability of the polymers of XIENCE stents in the in-vivo environment was evaluated by pyrolysis-gas chromatography with mass spectrometry (Py-GC/MS) detection. For this evaluation, XIENCE stents explanted from porcine coronary arteries and from human coronary artery specimens at autopsy after 2-4 and 5-7 years of implantation, respectively, were compared to freshly manufactured XIENCE stents (controls). The comparison of pyrograms of explanted stent samples and controls showed identical fragmentation fingerprints of polymers, indicating that PVDF-HFP and PBMA maintained their chemical integrity after multiple years of XIENCE coronary stent implantation. The findings of the present study demonstrate the chemical stability of PVDF-HFP and PBMA polymers of the XIENCE family of coronary stents in the in-vivo environment, and constitute a further proof of the suitability of PVDF-HFP as a drug carrier for the drug eluting stent applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1721-1729, 2018.

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