Interplay between solid state properties and tissue-associated release of acetylsalicylic acid from PLGA microneedles across in vitro, ex vivo and in silico models

Abstract

Despite the fact that acetylsalicylic acid (ASA) remains clinically important for inflammatory conditions, conventional oral administration is hampered by gastrointestinal adverse effects and variable systemic exposure. Whilst polymeric microneedles (MNs) enable transdermal delivery as an alternative to oral delivery through bypassing the stratum corneum; how drug solid-state behaviour affects the release kinetics of sustained-release MN systems has yet to be thoroughly elucidated. Herein, ASA-loaded poly (lactic-co-glycolic acid) (PLGA) MNs were developed to examine how retained but altered ASA crystallinity within the PLGA matrices contributes to release across in vitro, ex vivo and in silico models. 10*10 arrays of pyramidal PLGA MNs with a needle length of 600 µm were produced via micromoulding. Parent ASA stability studies showed near-quantitative recovery following fabrication-like exposure (98.0 ± 3.11%). Because the MNs were not only able to penetrate Parafilm M® and dermatomed porcine skin under a 32 N application force, but also withstand whole-patch compression at the exact same insertion force, the fabricated MN patches were deemed mechanically robust enough for application-relevant insertion into the skin under tested conditions. Whilst PXRD showed that ASA loaded into PLGA MNs retained crystalline features, albeit attenuated, DSC demonstrated that ASA-PLGA MNs exhibited a broadened, lower-temperature ASA-associated endotherm. As such, it was inferred that ASA solid-state behaviour had been altered within the polymer matrix. In contrast to apparent ex vivo release, which reached near completion by 168 h, in vitro ASA release was slower and incomplete, with drug release plateauing at approximately 60% by 504 h. These differences suggest that retained but altered ASA crystallinity may contribute to sustained release by limiting the rate at which ASA dissolves and diffuses from the PLGA matrix under static in vitro conditions. However, when MNs are in constant contact ex vivo, hydration of the PLGA matrix, in consort with tissue-associated diffusion and partitioning may promote continued removal of dissolved ASA from the polymer-skin interface, thereby accelerating apparent release. Taken together, this work identifies ASA solid-state behaviour as one formulation variable that interacts with the release environment to shape release from PLGA MNs. Furthermore, an exploratory in silico model simulating a potential ASA pharmacokinetic profile based on empirically obtained release profiles sets the foundation for future in vivo investigation.