Control of drug release kinetics from hot-melt extruded drug-loaded polycaprolactone matrices

Drug-eluting polymeric structures are widely used in medical applications where sustained local drug delivery is desired [1]. Potential applications include the management of inflammations subsequent to tissue incision or suture injury and wound dressings that release anti-inflammatory or anti-infectious drugs over a defined period [2,3]. With spatiotemporal control of the release, these agents can protect the tissue injury site from further inflammation or infection and promote tissue regeneration, thereby minimizing the risks of off-target side effects and drug resistance due to excessive systemic exposure to the drug.

A drug of interest in wound management is the non-steroidal anti-inflammatory drug (NSAID) meloxicam, a relatively selective cyclooxygenase (COX)-2 inhibitor, which reduces the synthesis of lipid inflammatory mediators [4,5]. Meloxicam is indicated for the treatment of rheumatoid arthritis [6], osteoarthritis [7], ankylosing spondylitis [8], joint pain [9], and post-surgical inflammation [10]. Meloxicam is also expected to prevent biofilm formation on implanted devices or post-surgical wound dressings [11] and provide opioid-sparing postoperative analgesia [12,13]. For these purposes, a two-week sustained meloxicam delivery is desirable because most subacute inflammations and biofilm formations are likely to occur during this period [[14], [15], [16], [17]]; moreover, the extended use of an NSAID may interfere with wound healing [18].

Sustained local delivery of meloxicam may be accomplished by its encapsulation in biocompatible polymers, which can be fabricated into implants, fibers, or particles. Commonly used polymers include poly(lactic-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), and polycaprolactone (PCL). These polymers control the drug release by serving as a diffusion barrier, where the barrier function may change with time as they swell and/or degrade. Previously, it was demonstrated that PCL was most appropriate for the sustained delivery of meloxicam among these polymers [19]. In that study, meloxicam was mixed with PCL and extruded through a hot-melt extruder to form a cylindrical matrix with the drug embedded in the polymer as solid clusters. Since the PCL matrix did not degrade within the time scale of interest, the drug release rate was dependent on the dissolution of drug clusters by the infiltrating fluid, followed by the diffusion of dissolved drug molecules through the polymer matrix. The drug content in the matrix played a major role in controlling the drug release rate, as the dissolving drug clusters generated fluid channels to facilitate additional fluid influx as well as drug dissolution and transport. Therefore, a higher drug content, and thereby a better-connected channel network, resulted in a faster drug release. Accordingly, a PCL matrix loaded with 65 wt% meloxicam completed the drug release in two weeks [19], which is the target period for applications in post-surgical wound management [20].

However, when the dose and dimension/geometry of the dosage forms are constrained by the type of applications (such as surgical staples and wound dressing), it is not feasible to control the drug release rate by the drug loading content alone. In this case, an alternative approach is needed to control the drug release rate. Therefore, we sought to control the drug release rate, independent of the drug content, by employing a sustained porogen, which dissolves in the PCL matrices over time and generates evolving pores in the PCL matrices to facilitate drug release.

In this study, the meloxicam-loaded PCL matrices were produced by a hot melt extruder in the shape of a thin cylinder with a dimension relevant to medical applications, such as surgical staples, sutures, and injectable implants. First, the effect of cylinder diameter size on the in vitro drug release profiles was investigated. High-resolution micro-computed tomography (HR μCT) and artificial intelligence (AI) image analysis were used to simulate drug release kinetics and understand the drug release process. Different salts were screened as porogens to facilitate drug release control. The salt-containing meloxicam/PCL matrices were characterized by solid-state analysis and multiple imaging techniques to investigate the drug state and the role of salt in the drug release control. The results of this study demonstrate the feasibility of tuning the drug release by salt porogens and the utility of imaging analysis in understanding the drug release process.