Aqueous remote loading of model cationic peptides in uncapped poly(lactide-co-glycolide) microspheres for long-term controlled release

Remote loading microencapsulation of peptides into polymer microspheres without organic solvent represents a promising alternative to develop long-acting release depots relative to conventional encapsulation methods. Here, we formulated drug-free microspheres from two kinds of uncapped poly(lactide-co-glycolides) (PLGAs), i.e., ring-opening polymerized Expansorb ® DLG 50-2A (50/50, 11.2 kDa) and Expansorb ® DLG 75-2A (75/25, 9.0 kDa), and evaluated their potential capacity to remote-load and control the release of two model peptides, leuprolide and octreotide. Degradation and erosion kinetics, release mechanism, and storage stability was also assessed. As control formulations, peptide was loaded in the same PLGA 75/25 polymer by the conventional double emulsion-solvent evaporation method (W/O/W) and remote loaded in polycondensation poly(lactic-co-glycolic acid) 75/25 (Wako 7515, 14.3 kDa). Loading content of 6.7%–8.9% w/w (~ 67%–89% encapsulation efficiency (EE)) was attained for octreotide, and that of 9.5% w/w loading (~ 95% EE) was observed for leuprolide, by the remote loading paradigm. Octreotide and leuprolide were both slowly and continuously released in vitro from the remote-loaded Expansorb ® DLG 75-2A MPs for over 56 days, which was highly similar to that observed from traditionally-loaded formulations by W/O/W (8.8% loading, 52.8% EE). The faster release kinetics was observed for the faster degrading PLGA 50/50 remote-loaded Expansorb ® DLG 50-2A MPs relative to microspheres from the PLGA 75/25 Expansorb ® DLG 75-2A. Despite slight differences in degradation kinetics, the release mechanism of octreotide from the Expansorb ® microspheres, whether remote loaded or by W/O/W, was identical as determined by release vs. mass loss curves. Octreotide acylation was also minimal (< ~ 10%) for this polymer. Finally, drug-free Expansorb ® DLG 75-2A MPs displayed excellent storage stability over 3 months. Overall, this work offers support for the use of ring-opening Expansorb ® PLGA-based microspheres to remote load peptides to create simple and effective long-acting release depots. Graphical Abstract