Transdermal ropivacaine delivery via hydrogel-forming microneedles: A pain-free alternative for local anaesthesia

Surgical procedures in critical care settings are often associated with prolonged postoperative pain, which remains a significant clinical challenge. Conventional analgesic strategies typically rely on injection-based delivery, which is invasive, requires trained personnel, and carries risks such as infection and tissue damage. To address these limitations, this study developed a minimally invasive transdermal delivery system for the local anaesthetic ropivacaine (ROP) using hydrogel-forming microneedles (HFMNs) combined with drug reservoir tablets. Two HFMN formulations were prepared using Gantrez^® S-97 (MN1) and PVA-PVP (MN2), each paired with reservoirs fabricated by direct compression (DCT) or lyophilisation (LYO). Insertion capability study demonstrated that MN2 exhibited superior skin penetration compared with MN1. In vitro permeation studies showed that MN2-DCT achieved the highest transdermal delivery of ROP (> 12 mg across dermatomed porcine skin). However, when both permeated and deposited drug (within skin and HFMNs) were considered, LYO reservoirs paired with either MN1 or MN2 resulted in higher total drug delivery over 24 h. This is attributed to the porous structure of LYO tablets, which enhances fluid uptake and rapid dissolution. The retained drug within the skin and HFMN matrix may serve as a depot for sustained release. In vivo evaluation in a postoperative pain mouse model demonstrated that MN2-LYO provided rapid and sustained analgesia, achieving > 50% maximum possible effect (%MPE) within 1 h and maintaining efficacy for up to 72 h, whereas MN1-LYO showed limited analgesic response. Furthermore, both MN1-LYO and MN2-LYO significantly reduced inflammatory cytokines (IL-6 and TNF-α), with the greatest reduction observed for MN2-LYO (~ 50% decrease compared with negative control and subcutaneous ROP groups). Overall, these findings highlight the potential of HFMN-based delivery systems combined with LYO reservoirs as a minimally invasive, patient-friendly alternative to injectable anaesthetics for prolonged postoperative pain management.