Injectable and biodegradable thermosensitive hydrogels loaded with PHBHHx nanoparticles for the sustained and controlled release of insulin

Biodegradable PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) nanoparticles containing insulin phospholipid complex were loaded in chitosan-based thermosensitive hydrogels for long-term sustained and controlled delivery of insulin. The injectable hydrogels, prepared by adding β-glycerophosphate disodium salt (GP) solution to chitosan (CS) solution under stirring, showed a rapid solution-to-gel transition at 37 °C, a porous structure and a comparative degradation and swelling rate in vitro. In the in vitro release studies, only 19.11% of total insulin was released from the nanoparticle-loaded hydrogel (NP-CS/GP) within 31 days. However, 96.41% of total insulin was released from the free insulin-loaded hydrogel (INS-CS/GP) within 16 days. Most importantly, the hypoglycemic effect of NP-CS/GP following subcutaneous injection in diabetic rats lasted for >5 days, much longer than the effect caused by INS-CS/GP or other long-acting insulin formulations. The pharmacological availability of NP-CS/GP relative to INS-CS/GP was 379.85%, indicating that the bioavailability of insulin was significantly enhanced by NP-CS/GP gels. Therefore, biodegradable and thermosensitive NP-CS/GP gels have great potential for use in novel ultralong-acting insulin injections. In addition, the NP-loaded hydrogel system also paves the way for long-term delivery of other proteins and peptides.