Design of Electrostatic Nanocomplex of Semaglutide with Protamine and Zinc for Subcutaneous Prolonged Delivery

The aim of this study was to design a poorly water-soluble electrostatic nanocomplex of semaglutide (SMG) with protamine sulfate (PS) and zinc ions (Zn) for prolonged subcutaneous delivery. Complexation of SMG with the cationic peptide PS increased the lipophilicity (logP) proportionally from -4.7 to 0.3, particularly in the presence of Zn. The optimized nanocomplex exhibited spherical morphology, an amorphous state, a particle size of 196.0 nm, and a zeta potential of -45.7 mV. In an in vitro dissolution test under sink conditions, native SMG showed rapid drug release with 98% dissolution within 24 h. In contrast, the nanocomplexes showed markedly delayed release, with a concentration-dependent relationship between PS/Zn contents and SMG release rate, exhibiting 19% drug release over 7 days in the optimized formula. These findings suggest that the proposed nanocomplex is a promising system for long-acting injectable delivery of SMG, potentially enhancing patient compliance in patients with obesity or type 2 diabetes.