(M1330-03-15) Control of Drug Release Kinetics from Hot-Melt Extruded Drug/Polycaprolactone Matrices

Purpose: Anti-inflammatory drugs can reduce inflammatory responses following surgery and prevent biofouling of implantable devices. Controlling the kinetics of drug release is critical because excessive anti-inflammatory drugs may interfere with wound healing. For preventing the development of chronic inflammation, 14 days are known to be the optimal duration [1]. We have previously shown that meloxicam release can be controlled by adjusting the drug content in a polymer matrix [2]. However, when the geometry and dose are dictated by the size of surgical wound or the dimension of implants, there is little room for adjusting the drug content. Therefore, we aim to develop a formulation strategy to facilitate sustained/controlled meloxicam release given the constraints in geometry and dose.

Methods: Meloxicam and poly(ε-caprolactone) (PCL, Purasorb PC 17) mixtures were extruded through a die with a diameter of 2 or 0.5 mm on HAAKE miniCTW Extruder, with or without Mg(OH)2. Meloxicam content was 30 wt% (M30/PCL) or 65 wt% (M65/PCL). Mg(OH)₂ content was varied from 20 to 50 wt.% of the total weight, keeping the meloxicam content fixed at 30 wt% (designated as M30Mg#/PCL, with # indicating the Mg(OH)₂ content). In vitro drug release kinetics were evaluated in phosphate-buffered saline with 0.1% Tween80 (PBST). Micro computed tomography (microCT) or X-ray microscopy (XRM) was performed on the matrices before and/or after 14-day release to locate drug, pores, and the polymer. Additionally, scanning electron microscopy (SEM) was performed on Mg(OH)₂-containing matrices after 14-day release. XRM images of M30/PCL and M65/PCL matrices completing 14-day drug release were classified by Artificial Intelligence (AI) analytics to quantify drug release percentages. Drug release profiles were simulated from the imaging data, with the assumption that pores in 14-day structure represent the drug network in fresh matrices (before drug release).

Results: We investigated the effect of the dimension of meloxicam-loaded polycaprolactone (PCL) matrices on drug release kinetics and tested the utility of Mg(OH)₂, a slowly dissolving salt, in controlling the drug release. The drug release rate from the meloxicam-loaded PCL matrices with a smaller diameter was relatively slow (Figure 1a), suggesting that different geometry may have changed the surface area per volume, thus the release rate. The XRM imaging (Figure 1b) and image-based simulation (Figure 1c) showed surface depletion of drug and a non-zero order drug release kinetics consistent with in vitro measurement, which indicate diffusion-controlled drug release. The fraction of meloxicam release from the meloxicam-loaded PCL HME matrices (D = 0.5 mm) increased with Mg(OH)₂ amount at the fixed drug content (Figure 2a). The microCT analysis of fresh matrices showed that the salt was distributed throughout the matrices (Figure 2b), which would have dissolved over time and generated pores to accelerate the drug release. Though the salt constituted significant fractions of the matrices, the structure was grossly intact after 14-day drug release, according to SEM (Figure 3).

Conclusion: Mg(OH)₂ combined with the PCL/meloxicam matrix allows for flexible control of drug release kinetics despite the constraints in geometry and dose. The release control strategy may be applied to developing drug-eluting devices with a fixed geometry, such as surgical staple, post-surgical dressing, and stents.

References: (1) H.P. Sandoval, et al., Clinical ophthalmology (Auckland, NZ), 1 (2007) 367.
(2) Y.C. Chen, et al., Journal of Controlled Release, 342 (2022): 189-200.

Acknowledgments: This research was funded by Eli Lilly and Company. The authors thank Drs. Coralie A. Richard, Monica R. Swinney, and Sarena D. Horava for their contributions to the conception and design of the study.

Figure 1. (a) In vitro release of meloxicam from matrices in two dimensions. (b) Morphology of M30/PCL and M65/PCL with diameter 0.5 mm before (microCT) and after (XRM) drug release by day 14. (c) XRM image-based simulation of drug release from M65/PCL.



Figure 2. (a) In vitro release of meloxicam from M30/PCL matrices with 20, 35, 40, and 50 wt.% of Mg(OH)2. (b) MicroCT analysis before drug release of M30/PCL matrices with 20 (i), 35 (ii), and 50 (iii) wt.% salts.



Figure 3. SEM imaging after drug release of M30/PCL matrices with 20%, 35%, and 50% of porogen, Mg(OH)2.