Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres

J Control Release. 2019 Aug 28:308:1-13. doi: 10.1016/j.jconrel.2019.07.013. Epub 2019 Jul 10.


Peptide loaded PLGA microsphere products are more complex in terms of manufacturing, drug release characteristics as well as release mechanism compared to small molecule loaded PLGA microsphere products. This is due to the complex structure of peptides, their hydrophilicity, charged state, large size and potential for instability. Moreover, therapeutic peptides are highly potent and therefore, any unintended change in the microsphere release profile may lead to undesirable side effects and toxicity. Accordingly, the objectives of the present work were: 1) to evaluate the impact of minor manufacturing changes on the quality and performance of peptide microspheres; and 2) to investigate the feasibility of developing Level A in vitro-in vivo correlations (IVIVCs) for peptide microspheres. Compositionally equivalent leuprolide acetate (LA) microspheres prepared with minor manufacturing changes (solvent system/homogenization speed) showed significant differences in their physicochemical properties (such as pore size, total porosity, particle size and surface distribution of peptide on the prepared microspheres). This, in turn, resulted in significant alteration in the release characteristics. Peptide-polymer interaction, in vitro degradation and microsphere morphology studies were conducted to facilitate understanding of the differences in the drug release characteristics. A rabbit model was used to determine the pharmacokinetic profiles of all the prepared formulations. The obtained in vivo release profiles showed the same rank order as the in vitro release profiles but with low burst release and overall faster in vivo release rates. The low in vivo burst release is considered to be due to the masking effect of the absorption phase from the intramuscular site, and this complicated the development of an IVIVC. Despite these challenges, an affirmative Level A IVIVC over the entire release profile was successfully developed in a rabbit model for peptide microspheres for the first time. The developed IVIVC was also predictive of the RLD product, Lupron Depot®. This work highlights the feasibility of developing IVIVCs for complex parenteral drug products such as peptide microspheres. In conclusion, these results indicate the sensitivity of peptide release, and hence, the safety and efficacy of highly potent peptide microspheres, to minor manufacturing changes. Accordingly, development of IVIVCs for such complex drug products is highly desirable.

Keywords: Compositionally equivalent; In vitro-in vivo correlation (IVIVC); Leuprolide acetate; PLGA; Peptide microspheres; Release testing.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chemistry, Pharmaceutical / methods
  • Delayed-Action Preparations
  • Drug Carriers / chemistry
  • Drug Liberation
  • Leuprolide / administration & dosage*
  • Leuprolide / chemistry
  • Leuprolide / pharmacokinetics
  • Male
  • Microspheres*
  • Particle Size
  • Peptides / administration & dosage*
  • Peptides / chemistry
  • Peptides / pharmacokinetics
  • Polylactic Acid-Polyglycolic Acid Copolymer / chemistry*
  • Porosity
  • Rabbits


  • Delayed-Action Preparations
  • Drug Carriers
  • Peptides
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Leuprolide