Arterial diseases, characterized by their chronic and progressive nature, are hallmarked by the atherosclerotic occlusion of vascular arteries, a primary cause of cardiovascular mortality and compromised limb functionality [1]. On a global scale, over 200 million individuals are afflicted by peripheral arterial disease (PAD) [2,3], while 17.9 million succumb to coronary artery disease (CAD) annually [4]. DES are the prevailing standard in targeted therapeutic strategies for the management and treatment of life-threatening arterial pathologies. FDA-approved stents for the amelioration of peripheral artery disease are paclitaxel-eluting Zilver® (without polymeric coating) from Cook Medical LLC and ELUVIA™ from Boston Scientific Corporation, coated with non-biodegradable polymers, poly (styrene-b-isobutylene-b-styrene) and poly (butyl methacrylate) (PBMA)–poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP). These stents are reliant on anticancer drugs like paclitaxel, a known cytotoxic agent that facilitates apoptotic processes even in the therapeutic dosage range, to prevent restenosis [5]. However, the utilization of non-biodegradable, synthetic polymers in DES can result in local tissue inflammation, hypersensitivity reactions, delayed vascular healing, late-stage thrombosis, in-stent restenosis, and the eventual surgical requirement for removal of accumulated polymer within the body [[6], [7], [8]]. Moreover, CE (Conformité Européenne) approved limus drug eluting coronary stents with biodegradable polymers such as Cypher® (Cordis, USA), Supralimus® and Supraflex™ (Sahajanand Medical Technologies Pvt. Ltd., India), MiStent SES® (Micell Technologies, Durham, SC) and all other available stents are emerging alternatives over conventional stents owing to their ability to attenuate the rate of in-stent restenosis (ISR). Nonetheless, the challenges are still not abolished, even in the current modernistic stent era [9,10]. As the coatings employed for both peripheral and coronary stents are predominantly layer-by-layer assembled drug and polymer based films, they exhibit limitations in regulating drug release and demonstrating efficient drug permeation within arterial tissues [11,12].

There is no DES coated with drug loaded biodegradable micro and nanoparticles (particulate systems/particulates) approved by the FDA for clinical application due to technological challenges affecting precise stent coatings for drug delivery leading to significant inconsistencies in drug release from inter- and intra-batch coating processes [13]. Hence, ensuring prolonged drug delivery from DES is pivotal in combating in-stent restenosis effectively. Despite advancements in medical science and technological innovations, these limitations highlight a critical research gap, an unmet need for safer therapeutic agents, and the development of requisite drug delivery systems tailored to address arterial diseases.

The incorporation of drug-loaded biodegradable particulate systems introduces a promising avenue for augmenting existing stent technologies. To address the existing challenges, various particulate systems, such as 2-aminochromone-PLGA nanoparticles [14], lipid-polymer nanohybrids of SRL and bivalirudin [15], SRL -PLGA nanoparticles [16], PLGA microparticles [17,18] and microcrystalline SRL with PLGA coatings [19], have exhibited potentials in DES delivery by emphasizing drug release kinetics, enhanced cellular uptake, and prolonged tissue residence time. The use of safer therapeutic agents and targeted drug delivery with prolonged drug action is imperative to address arterial diseases. So far, no investigation has explored the application of SRL (PLGA) 85:15 micro- or nano-particulate coatings on stents in arterial diseases, especially through a comprehensive assessment using the quality by design (QbD) approach.

This study presents a systematic QbD approach to address intra- and inter-batch variability in the coating process for SRL embedded PLGA particulate systems on stents. Considering the adverse effects of paclitaxel, the current research project proposes the use of a Mammalian Target of Rapamycin (mTOR) inhibitor, SRL, for targeted delivery. mTOR inhibitors are cytostatic drugs with a wider therapeutic range as compared to cytotoxic drugs [5]. Our previous research on coronary intervention utilizing nanoparticle eluting stents has shown prolonged drug release and an improved SRL nanoparticle penetration into the arterial wall. Moreover, these nanoparticles have demonstrated superior efficacy in inhibiting smooth muscle cell growth and enhanced cellular uptake, including entry into the cell nucleus [15,16].

The current study aims to study the effects of spray coating parameters on various critical quality attributes (CQAs), including coating mass transfer efficiency, coating uniformity, drug elution rate, drug content, and coating time, for DES coated with drug-loaded biodegradable polymeric micro- and nano-particles.