Injectable CS‐SH/SF‐GMA Hydrogel– PCL Microsphere Composite for Sustained Progesterone Delivery

ABSTRACT

Surgical sterilization causes irreversible damage to reproductive organs, whereas hormone‐based estrus suppression requires frequent administration. Although polymeric microspheres can extend drug release, maintaining microsphere incorporation within injectable systems remains challenging. An injectable composite drug delivery system was developed by integrating progesterone‐loaded poly(ε‐caprolactone) (PCL) microspheres with a fast‐gelling hydrogel matrix. Progesterone‐loaded microspheres were prepared using an oil‐in‐water (O/W) emulsion–solvent evaporation method, and formulation parameters were optimized to achieve high encapsulation efficiency. A CS‐SH/SF‐GMA hydrogel system was constructed to incorporate microspheres within the hydrogel matrix, with sodium β‐glycerophosphate (β‐GP) added to modulate gelation behavior and hydrogel properties. The optimized microspheres exhibited an encapsulation efficiency of 90.45% and a drug loading capacity of 18.23%. The composite hydrogel gelled within 1 min, remained injectable through a 22G needle, and enabled uniform microsphere incorporation. Compared with free microspheres, the hydrogel–microsphere system sustained progesterone release for up to 45 days under in vitro conditions. β‐GP‐modified hydrogels containing 30 and 60 mg microspheres reduced cumulative drug release by 9.28% and 5.18%, respectively. Hemolysis rates were below 5%, and NIH3T3 cell viability remained close to 100%, indicating favorable hemocompatibility and cytocompatibility. Overall, this platform integrates hydrogel formation, microsphere incorporation, and sustained progesterone release, providing a potential strategy for controlled progesterone delivery. Further in vivo studies are required to evaluate pharmacokinetics and biological performance.