Hydroxyethyl starch surface-modified semi-solid lipid microparticles for sustained intramuscular delivery of progesterone with improved local tolerability

Repeated intramuscular administration of progesterone (PRG) oily injections often causes macrophage-mediated injection-site reactions and pain, limiting patient compliance during long-term therapy. Herein, a PRG-loaded hydroxyethyl starch-coated semi-solid lipid microparticle system (HES-SLM) was developed for low-irritant sustained intramuscular delivery. Oleic acid-grafted HES was synthesized as an emulsifier, and HES-SLM was prepared by melt emulsification using glyceryl monostearate/medium-chain triglycerides as the lipid core, with PEG-SLM as a control. HES-SLM exhibited a uniform spherical morphology, a D 50 of 34.36 ± 0.42 μm, low burst release within 2 h (4.17 ± 0.98%), and sustained release for 13 days. Compared with PEG-SLM, HES-SLM significantly reduced macrophage infiltration, inflammatory cytokine expression, collagen deposition, and profibrotic responses at the injection site, thereby improving the local release microenvironment and facilitating PRG transport into systemic circulation. Consequently, HES-SLM markedly increased PRG exposure, with an AUC 0–t of 3649.113 ± 1066.590 ng·mL −1 ·h versus 1751.285 ± 357.668 ng·mL −1 ·h for PEG-SLM. In immature female rats, HES-SLM also achieved efficacy comparable to marketed PRG oily injection and reduced inflammatory factors and Nav1.8 expression, indicating reduced injection-site pain. This study provides a surface-modified microparticle strategy for sustained, low-irritant intramuscular PRG delivery with reduced dosing frequency.