Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug

Abstract

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-powder electrostatic process. The AC-SES demonstrated enhanced drug stability under simulated use conditions and consistent drug delivery balanced with coating erosion in a porcine coronary implant model. The initial drug burst was eliminated and drug release was sustained after implantation. The coating was absorbed within 90 days. Following implantation into porcine coronary arteries the AC-SES coating is distributed in the surrounding intimal tissue over the course of several weeks. Computational modeling of drug delivery characteristics demonstrates how distributed coating optimizes the load of drug immediately around each stent strut and extends drug delivery between stent struts. The result was a highly efficient arterial uptake of drug with superior performance to a clinical bare metal stent (BMS). Neointimal thickness (0.17±0.07 mm vs. 0.28±0.11 mm) and area percent stenosis (22±9% vs. 35±12%) were significantly reduced (p<0.05) by the AC-SES compared to the BMS 30 days after stent implantation in an overlap configuration in porcine coronary arteries. Inflammation was significantly reduced in the AC-SES compared to the BMS at both 30 and 90 days after implantation. Biocompatible, rapidly absorbable stent coatings enable the matching of drug release with coating erosion and provide for the controlled migration of coating material into tissue to reduce vicissitudes in drug tissue levels, optimizing efficacy and reducing potential toxicity.

Fig. 1

Scaled schematic representation of the 2D computational domain of a tissue embedded strut pair apposed to the internal elastic lamina (IEL). Depicted here is the baseline case of conformable strut-adherent coating. Notations: t - time since stent implantation; n - unit normal; c - concentration of free drug, b_NS and b_REC - concentrations of, respectively, non specific- (NS) and receptor- (REC) bound drug; b_NS,max and b_REC,max - concentrations of NS binding sites and receptors; $k_{on}^{\text{NS}}$ and $k_{on}^{\text{REC}}$- respective binding on-rate constants, $K_d^{NS}$ and $K_d^{\mathit{REC}}$- respective equilibrium dissociation constants; D – drug diffusion coefficient in arterial tissue (for parameter values see Table S2, Supplemental Materials).

Fig. 2

Sequential addition of PLGA and micronized sirolimus is followed by sintering that fuses the layers into a smooth, conformal stent coating.

Fig. 3

AC-SES stents were incubated in a flow loop for up to 14 days and imaged through the clear silastic tubing with dark field microscopy. Coating spread is seen as a broadening of the white areas surrounding the stent struts. Bars represents 500 μm.

Fig. 4

Data from preclinical studies evaluating AC-SES after 30 day implant in the porcine coronary implant model. The square-shaped clear spaces represent the stent strut (S) location though the actual strut was lost during processing of the histology slides. In each panel, distinct, irregularly shaped clear spaces (B, D: black arrows) represent areas previously occupied by coating that has been lost during processing. Coating can be seen to have spread into the surrounding neointima either close to the strut (A, B) or relatively distant (C, D). Bars represent 200 μm (A, C) and 75 μm (B, D).

Fig. 5

Modeling of drug delivery characteristics based on the assumptions that the coating moves lateral relative to the stent strut, that both struts have the same amount of coating migration and that (in this example) approximately 30 % of the coating migrates. All color schemes are uniform (0–1 for bound receptors; 0–40 ng/mg for deposited drug). “Conformal” refers to strut-adherent coating and the numbers 35, 100 and 350 represent relative distances from the stent strut.

Fig. 6

After 90 days implantation, the coating is largely absorbed as is evidenced by the resolution of clear areas representing space-occupying coating. Bars represent 100 μm.

Fig. 7

Drug release was shown to be complete within 45 – 60 days after stent implantation into porcine coronary arteries. The average daily release rate amounts to approximately 3 μg of sirolimus from a 3.0 × 15 mm stent. Arterial levels of drug were quantified from arterial tissue surrounding the stented segment. Each data point represents the average from quantification of six stents. Data are presented as ± standard error.

Fig. 8

Comparison of AC-SES with BMS at 30 and 90 days after implant under conditions of single or overlapping (OLP) stent configurations. Inflammation was scored as described in Table 1. Neointimal thickness was calculated by subtracting the lumen diameter from the internal elastic lamina diameter and dividing by two. Data are presented as ± standard error.

Fig. 9

Day 30 AC-SES (A) Vision BMS (B) Overlap. Bars represent 1 mm.