Fabrication and Preclinical Evaluation of Hyaluronic Acid/Aminoclay Nanocomposite Microneedles for Noninvasive Delivery of Semaglutide in Anti-Obesity Therapy

Introduction: Injectable formulations are common for protein-based therapeutics. However, non-injectable formulations are crucial for improving patient compliance. This study aims to develop hyaluronic acid/aminoclay-based dissolving microneedles as a noninvasive delivery system for semaglutide in the treatment of obesity. Methods: The core nanocomplex (Sema-AC) was formed by combining semaglutide (Sema) with aminoclay (AC) via electrostatic interaction. This nanocomplex was then mixed with hyaluronic acid (HA) of varying molecular weights and poured into a reverse polydimethylsiloxane (PDMS) mold to create dissolving microneedles (MNs). Various in vitro and in vivo studies were performed to evaluate the physicochemical properties and therapeutic efficacy of the MNs. Results: Among the developed MNs, Sema-AC/HA10 demonstrated a mechanical strength of 0.37 ± 0.020 N/needle and retained stable physicochemical and morphological properties at 25°C during storage. Encapsulated Sema retained its conformational stability within the MNs. Sema-AC/HA10 dissolved rapidly upon skin insertion, enabling efficient transdermal drug absorption. The MNs containing Sema-AC nanocomplex significantly enhanced the systemic drug exposure compared to the MN loaded with the free drug. Consequently, Sema-AC/HA10 demonstrated in vivo efficacy comparable to that of subcutaneous Sema injection in type 2 diabetic rats, significantly reducing blood glucose, HbA1c, total cholesterol, triglycerides, food intake, water consumption, and body weight”. Conclusion: These findings suggest that Sema-AC/HA10 is an effective transdermal delivery system for semaglutide.