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Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres.
J Control Release 2019; 308:1-13JC

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Connecticut, CT 06269, USA.Department of Pharmaceutical Sciences, University of Connecticut, CT 06269, USA.Department of Pharmaceutical Sciences, University of Connecticut, CT 06269, USA.Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA.Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA.Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA.Department of Pharmaceutical Sciences, University of Connecticut, CT 06269, USA. Electronic address: d.burgess@uconn.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31301338

Citation

Andhariya, Janki V., et al. "Development of Level a in Vitro-in Vivo Correlations for Peptide Loaded PLGA Microspheres." Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 308, 2019, pp. 1-13.
Andhariya JV, Jog R, Shen J, et al. Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres. J Control Release. 2019;308:1-13.
Andhariya, J. V., Jog, R., Shen, J., Choi, S., Wang, Y., Zou, Y., & Burgess, D. J. (2019). Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres. Journal of Controlled Release : Official Journal of the Controlled Release Society, 308, pp. 1-13. doi:10.1016/j.jconrel.2019.07.013.
Andhariya JV, et al. Development of Level a in Vitro-in Vivo Correlations for Peptide Loaded PLGA Microspheres. J Control Release. 2019 Aug 28;308:1-13. PubMed PMID: 31301338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres. AU - Andhariya,Janki V, AU - Jog,Rajan, AU - Shen,Jie, AU - Choi,Stephanie, AU - Wang,Yan, AU - Zou,Yuan, AU - Burgess,Diane J, Y1 - 2019/07/10/ PY - 2019/03/20/received PY - 2019/06/29/revised PY - 2019/07/09/accepted PY - 2019/7/14/pubmed PY - 2019/7/14/medline PY - 2019/7/14/entrez KW - Compositionally equivalent KW - In vitro-in vivo correlation (IVIVC) KW - Leuprolide acetate KW - PLGA KW - Peptide microspheres KW - Release testing SP - 1 EP - 13 JF - Journal of controlled release : official journal of the Controlled Release Society JO - J Control Release VL - 308 N2 - 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. SN - 1873-4995 UR - https://www.unboundmedicine.com/medline/citation/31301338/Development_of_Level_A_in_vitro-in_vivo_correlations_for_peptide_loaded_PLGA_microspheres L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-3659(19)30400-6 DB - PRIME DP - Unbound Medicine ER -