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Coating and Pharmacokinetic Evaluation of Air Spray Coated Drug Coated Balloons.

ABSTRACT: Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti-proliferative drugs, such as paclitaxel. Excipients thus play a vital role in the design and function of DCB, however methods to coat balloons with excipients and anti-proliferative drugs remain unknown. The goal of this study was to thus develop an approach to coat and evaluate DCB for various excipients. An air sprayer method was developed to deposit paclitaxel and various excipients onto non-coated commercially available angioplasty balloons. The coating of the angioplasty balloons was evaluated for drug deposition and coating efficiency using high performance liquid chromatography tandem mass spectrometry. Drug transfer and retention of the coated angioplasty balloons into arterial segments were evaluated ex vivo using harvested pig arteries in a pulsatile flow bioreactor. The air sprayer method successfully delivered varying excipients including bovine serum albumin (BSA), urea and iohexol. The air spray method was configured to coat four angioplasty balloons simultaneously with paclitaxel and iohexol with an average paclitaxel load of 4.0?±?0.70 µg/mm2. The intra-day (within) and inter-day (between) coating precisions, defined as relative standard deviation (RSD), was 17.2 and 15.5%, respectively. Ex vivo deployment of iohexol-paclitaxel DCB yielded an arterial paclitaxel concentration of 123.4?±?44.68 ng/mg (n?=?3) at 1 h, 126.7?±?25.27 ng/mg (n?=?3) at 1 day, and 12.9?±?12.88 ng/mg (n?=?3) at 7 days. This work provides proof-of-concept of a quick, inexpensive approach to coat commercially available angioplasty balloons with paclitaxel and various excipients.

SUBMITTER: Turner EA

PROVIDER: S-EPMC5990435 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Project description:Paclitaxel coated balloons (PCBs) are a promising non-implantable alternative to drug-eluting stents, whereby drug is delivered to the arterial wall in solid form as a semi-continuous solid coating or as micro drug depots. To date, it has been impossible to predict or even infer local tissue dosing levels and persistence, making it difficult to compare in vivo performance of different devices in healthy animals or to extrapolate such data to diseased human arteries. Here we derive and analyze a coupled reaction diffusion model that accounts for coating dissolution and tissue distribution, and predicts the concentration of dissolved drug in the tissue during and post dissolution. Time scale analysis and numerical simulations based on estimated diffusion coefficients in healthy animal and diseased human arteries both imply that dissolution of crystalline paclitaxel coating is mass transfer coefficient-limited, and can therefore be solved for independently of the tissue transport equations. Specifically, coating retention is predicted to follow piecewise linear kinetics, reflecting the differential and faster dissolution of lumenal versus tissue-embedded coating owing to a disparity in convective forces. This prediction is consistent with published data on a range of PCBs and allowed for the estimation of the associated dissolution rate-constants and the maximal soluble drug concentration in the tissue during coating dissolution. Maximal soluble drug concentration in the tissue scales as the product of the solubility and ratio of the dissolution and diffusion rate-constants. Thus, coatings characterized by micromolar solubilities give rise to nanomolar soluble concentrations in healthy animal arteries and ~0.1 micromolar in calcified atherosclerotic arteries owing to slower tissue diffusion. During dissolution, retention in porcine iliofemoral arteries is predicted to be dominated by solid coating, whereas post dissolution it is dominated by receptor-bound drug (3.7 ng receptors/g tissue). Paclitaxel coating dissolution and dosing kinetics can now be modeled based upon accepted principles of surface dissolution and tissue transport to provide insights into the dependence of clinical efficacy on device properties and the interplay of lesion complexity and procedural parameters.

Project description:Background/objectivesDrug-coated balloon therapy for diseased superficial femoral arteries remains controversial. Despite its clinical relevance, only a few computational studies based on simplistic two-dimensional models have been proposed to investigate this endovascular therapy to date. This work addresses the aforementioned limitation by analyzing the drug transport and kinetics occurring during drug-coated balloon deployment in a three-dimensional geometry.MethodsAn idealized three-dimensional model of a superficial femoral artery presenting with a calcific plaque and treated with a drug-coated balloon was created to perform transient mass transport simulations. To account for the transport of drug (i.e. paclitaxel) released by the device, a diffusion-reaction equation was implemented by describing the drug bound to specific intracellular receptors through a non-linear, reversible reaction. The following features concerning procedural aspects, pathologies and modelling assumptions were investigated: (i) balloon application time (60-180 seconds); (ii) vessel wall composition (healthy vs. calcified wall); (iii) sequential balloon application; and (iv) drug wash-out by the blood stream vs. coating retention, modeled as exponential decay.ResultsThe balloon inflation time impacted both the free and specifically-bound drug concentrations in the vessel wall. The vessel wall composition highly affected the drug concentrations. In particular, the specifically-bound drug concentration was four orders of magnitude lower in the calcific compared with healthy vessel wall portions, primarily as a result of reduced drug diffusion. The sequential application of two drug-coated balloons led to modest differences (~15%) in drug concentration immediately after inflation, which became negligible within 10 minutes. The retention of the balloon coating increased the drug concentration in the vessel wall fourfold.ConclusionsThe overall findings suggest that paclitaxel kinetics may be affected not only by the geometrical and compositional features of the vessel treated with the drug-coated balloon, but also by balloon design characteristics and procedural aspects that should be carefully considered.

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Coating and Pharmacokinetic Evaluation of Air Spray Coated Drug Coated Balloons.

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