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

This study developed acetylsalicylic acid-loaded poly(lactic-co-glycolic acid) microneedle patches and investigated how drug solid-state properties interact with the polymer matrix and tissue environment to influence transdermal release. The authors fabricated 10 × 10 arrays of 600 µm pyramidal PLGA microneedles containing acetylsalicylic acid, or ASA, by solvent casting and micromoulding. Mechanical and insertion testing demonstrated that the patches could penetrate multilayer Parafilm and 300–400 µm dermatomed porcine skin under a 32 N application force while maintaining comparable compression behaviour to blank PLGA microneedles. PXRD and DSC showed that ASA retained crystalline features after incorporation into PLGA but exhibited substantially reduced diffraction intensity and a broadened, lower-temperature thermal transition, indicating altered and heterogeneous solid-state behaviour rather than complete amorphization. Drug-loading analysis showed an efficiency of 80.6 ± 10.5% and approximately 30.0 ± 3.79 mg ASA per patch. In vitro release in PBS was biphasic and incomplete, reaching approximately 60% after 504 hours and fitting best to the Korsmeyer-Peppas model, consistent primarily with diffusion-controlled release. In contrast, ex vivo release from microneedles applied to porcine skin approached 100% by 168 hours and was best described by a first-order model, suggesting that tissue-associated hydration, diffusion, partitioning, and matrix changes accelerated apparent drug release. An exploratory in silico pharmacokinetic model was also developed to simulate ASA and salicylic acid distribution across skin and systemic compartments. Overall, the study shows that PLGA microneedle performance depends not only on mechanical integrity and insertion capability but also on interactions among drug crystallinity, polymer structure, and the local tissue release environment.