Triple-layered core-shell microneedle patch for sustained analgesic delivery and chondroprotection in osteoarthritis

Osteoarthritis (OA) is a prevalent chronic condition characterized by persistent pain, necessitating sustained therapeutic interventions to manage symptoms effectively. In this study, we introduce a novel core-shell microneedle system for sustained release, termed Microneedle-based Integrated Release with Advanced Composite Layered Efficacy (MIRACLE). The design is a triple-layered microneedle (MN) patch engineered for the prolonged management of OA-associated pain. The patch consists of a 15 × 15 array within a 1 cm² area, featuring a specialized three-level architecture. One core-layer of the MIRACLE is designed to provide sustained controlled release of multiple pain drugs. One sub-shell layer is designed to prevent premature burst release (over-dosing) of the encapsulated payloads and an outermost layer is designed to ensure sufficient mechanical strength for skin penetration regardless of the core-layer drug formulation which is often tuned to obtain different sustained release profiles. Within an hour of application, an integrated effervescent layer (between the needle tips and backing layer) is rapidly dissolved and facilitates implantation of the MNs into the skin. Subsequently, the system provides a controlled, co-delivery of Bupivacaine (BUP) and Meloxicam (MEL), which act synergistically to provide sustained anesthetic and anti-inflammatory effects for up to 10 days (for comparison, the only commercial long-acting Zynrelef™ drug for post-operational pain only has up to 3-day acting period) in OA rat models. Besides the analgesic efficacy, the MIRACLE system demonstrated a significant capacity to mitigate articular cartilage degradation. This multi-layered MNs platform could represent an excellent strategy for not only the treatment of chronic osteoarthritis pain but also the management of other types of neuromusculoskeletal pains, offering a significant and broad impact on modern medicine.