Optimized aqueous remote loading of leuprolide into PLGA microspheres achieved ~9.8% drug loading with continuous month-long release and low initial burst, with a theoretical framework to predict and improve encapsulation efficiency.
1-month releaseLeuprolide-loaded PLGA microspheres released drug continuously over one month with low initial burst after optimized aqueous remote loading
What the researchers found
Aqueous remote loading of leuprolide into PLGA-COOH microspheres achieved ~9.8% drug loading with initial encapsulation efficiency of ~38%. Optimization revealed that high microsphere concentrations (180-240 mg/mL) strongly improved encapsulation efficiency, with quasi-equilibrium reached within 8 hours. Porosity (controlled by inner water phase volume, 0-350 μL) ranged from 38-60%, with minimal initial burst at low porosity. Drug loading and EE were not strongly affected above 50% porosity.
A theoretical framework was derived showing that encapsulation efficiency depends on binding strength/capacity, polymer water content, and initial polymer concentration, while loading additionally depends on peptide/polymer mass ratio.
Why it matters
Long-acting injectable peptide formulations are critical for patient compliance — monthly injections are far more manageable than daily ones. This work improves the manufacturing process for loading peptide drugs into microspheres, potentially making production more efficient and enabling new long-acting formulations for other therapeutic peptides that are currently limited to short-acting injections.
How the study worked
Preformed 50/50 PLGA-COOH microspheres were loaded with leuprolide acetate in 0.1 M HEPES buffer (pH 7.4). Parameters optimized included microsphere concentration in loading solution, duration of loading, inner water phase volume, and porosity. In vitro release was assessed over 1 month. A quasi-equilibrium absorption model was developed to predict encapsulation efficiency and loading.
What this study cannot tell us
The study focused on leuprolide as a model peptide; other peptides with different charge, size, or solubility may behave differently. Only in vitro release was assessed — in vivo pharmacokinetics were not studied. The theoretical model assumes quasi-equilibrium binding, which may not hold for all peptide-polymer combinations. Scale-up from laboratory conditions to commercial manufacturing was not addressed.
How to read the evidence
This is a pharmaceutical formulation study with rigorous in vitro characterization and theoretical modeling. The work provides strong evidence for the loading process optimization but lacks in vivo validation of the resulting formulation.
When this study was published
Published in 2025, this study advances the state of the art in peptide microsphere formulation technology.
The bigger picture
As peptide therapeutics proliferate (GLP-1 agonists, antimicrobial peptides, hormone analogs), the need for sophisticated controlled-release formulations grows. This study advances the fundamental understanding of how peptides interact with PLGA polymers and provides a generalizable framework that could accelerate development of long-acting formulations for the next generation of peptide drugs.
Questions still open
- Can this remote loading approach be applied to larger or more hydrophobic therapeutic peptides?
- How does the in vitro release profile translate to in vivo pharmacokinetics and therapeutic levels?
- Could this framework enable development of long-acting formulations for peptide drugs currently limited to daily injections?
Common questions
What is leuprolide and why does it need slow-release formulation?
What is 'remote loading' and why is it better?
Read the original research
Optimization of aqueous remote loading of leuprolide in poly(lactic-co-glycolic acid) microspheres.
International journal of pharmaceutics, 685, 126206
Citation
Giles, Morgan B; Walker, Jennifer; Schwendeman, Steven P. (2025). Optimization of aqueous remote loading of leuprolide in poly(lactic-co-glycolic acid) microspheres.. International journal of pharmaceutics, 685, 126206. https://doi.org/10.1016/j.ijpharm.2025.126206