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FY2015 Regulatory Science Research Report: Long-Acting Injectable Formulations

Introduction

Long-acting injectable formulations include biodegradable injectable microspheres and in-situ gelling implants.  Compendial in vitro release methods for these complex formulations are not well developed, and demonstration of BE for these products can be challenging.

Research

Currently, two research grants have been awarded to explore biorelevant IVIVCs for biodegradable injectable poly lactide-co-glycolide (PLGA) microspheres and another two grants have been awarded to investigate dissolution methods for PLGA microsphere and implant drug products. As in vivo studies for long-acting injectable products may sometimes be difficult to conduct, having a better understanding of the key factors which impact IVIVCs may aid in the development of future recommendations including in vitro approaches. Dissolution measurements are useful for evaluating the effect of manufacturing differences and assessing performance characteristics of a sustained release dosage form. Studies are currently underway to develop dissolution methods and evaluate their capability to detect manufacturing differences and predict in vivo performance of long-acting injectable formulations.

One of the ongoing collaborative research projects involves the study of IVIVC for risperidone microspheres in which test products are similar in composition to the approved formulation of risperodone. Analysis of critical physicochemical properties showed that risperidone microspheres that are similarly composed are very sensitive to manufacturing differences. An in vitro release test using USP apparatus 4 demonstrated excellent discriminatory ability and may also have the potential to predict the in vivo performance of these microspheres.  

Figure 7. Comparison of risperidone microspheres to those of approved risperidone formulation.

Figure 7. Comparison of risperidone microspheres to those of approved risperidone formulation

(A) Approved Risperidone formulation in comparison to (B, C): two risperidone microspheres prepared with different manufacturing processes

Figure 8. Plasma profiles of Risperidone microspheres compared to an approved formulation of risperidone

Figure 8. Plasma profiles of Risperidone microspheres compared to an approved formulation of risperidone

The figures above show the in vitro release and in vivo plasma profile of two Risperidone microspheres prepared with different manufacturing processes in comparison to approved risperidone formulation.

ORS staff facilitating research in this area

  • Stephanie Choi, Yan Wang, Yuan Zou

Projects and Collaborators

  • In vitro-In vivo Correlations of Parenteral Microsphere Drug Products
    • Site PI: Diane Burgess
    • Grant #: 1U01FD004931-01
  • Dissolution Methods for Parenteral Sustained Release Implant Drug Products
    • Site PI: Diane Burgess
    • Grant #: 1U01FD005169-01
  • In vitro-In vivo correlations of parenteral microsphere drug products
    • Site PI: Steven Schwendeman
    • Grant #: 1U01FD005014-01
  • Development of hydrogel-based in vitro dissolution apparatus for microparticle formulations
    • Site PI: Haesun Park
    • Grant #: 1U01FD005168-01

Publications and Presentations

  • Development of an in vitro release testing method for porous PLGA microspheres. Jie Shen, Wen Qu, Stephanie Choi, Yan Wang, Diane J Burgess. AAPS San Diego, CA (November 2-6, 2014) 
  • In vitro and in vivo performance testing of risperidone microspheres.  Jie Shen, Wen Qu, Stephanie Choi, Yan Wang, Diane J Burgess. AAPS San Diego, CA (November 2-6, 2014) 
  • In vitro-In vivo correlation of risperidone microspheres. Jie Shen, Namita Tipnis, Stephanie Choi, Wen Qu, Yan Wang, Diane J Burgess. Controlled Release Society Annual Meeting, Edinburgh, Scotland (July 26-29, 2015)
  • A Reproducible Accelerated In Vitro Release Testing Method for PLGA Microspheres. Jie Shen, Kyulim Lee, Stephanie Choi, Wen Qu, Yan Wang, and Diane J. Burgess. International Journal of Pharmaceutics (Submitted)
  • In Vitro-In Vivo Correlation of Parenteral Risperidone Polymeric Microspheres. Jie Shen, Stephanie Choi, Wen Qu, Yan Wang, and Diane J. Burgess. Journal of Controlled Release (In Press)
  • Cage Implant System to Evaluate Mechanisms of in vivo PLGA Microsphere Release for IVIVC Model Development. Amy C. Doty,  Yan Wang,  Stephanie Choi,  Wen Qu,  Robert Lionberger,  Meihua R. Feng,  Anna S. Schwendeman,  Steven P. Schwendeman. In Vivo Predictive Dissolution Conference at the University of Michigan College of Pharmacy. 2014
  • Cage implant system to evaluate mechanisms of in vivo PLGA microsphere drug release for IVIVC model replacement. AC Doty, Y Wang, S Choi, W Qu, R Lionberger, MR Reng, AS Schwendeman, SP Schwendeman. AAPS San Diego, CA (November 2-6, 2014)
  • A cage implant system for assessing in vivo controlled release performanceof long-acting release PLGA depots. Amy C. Doty, Keiji Hirota, Karl Olsen, Rose Ackermann, Rose Feng, Wen Qu, Yan Wang, Stephanie Choi, Anna Schwendeman, and Steven P. Schwendeman. NIPTE Research Conference, Rockville, MD (April 30-May 1, 2015)
  • A cage implant system for assessing in vivo controlled release performance of PLGA microspheres. Amy C. Doty, Keiji Hirota, Karl Olsen, Rose Ackermann, Rose Feng, Wen Qu, Yan Wang, Stephanie Choi, Anna Schwendeman, and Steven P. Schwendeman. Pharmaceutical Graduate Student Research Meeting 2015
  • A cage implant system for assessing in vivo controlled release performanceof long-acting release PLGA depots. Amy C. Doty, Keiji Hirota, Karl Olsen, Rose Ackermann, Rose Feng, Wen Qu, Yan Wang, Stephanie Choi, Anna Schwendeman, and Steven P. Schwendeman. The 9th International Symposium on Intelligent Drug Delivery Systems at Korea Institute of Science and Technology 2015
  • A Cage Implant System for Assessing in vivo Controlled Release Performance of Long-acting Release PLGA Microspheres. Amy C Doty, Keiji Hirota, Rose Ackermann, Karl Olsen, Rose Feng, Wen Qu, Yan Wang, Stephanie Choi, Anna Schwendeman, Steven P Schwendeman. AAPS Orlando, FL (October 25-29, 2015)
  • Characterizing Release Mechanisms of Leuprolide-Loaded PLGA Microparticles for IVIVC Development. K. Hirota, A. Doty, R. Ackermann, K. Olsen, M. Feng, Y. Wang, S. Choi, W. Qu, A. Schwendeman, S. Schwendeman. AAPS Orlando, FL (October 25-29, 2015)
  • Mechanistic Analysis of Triamcinolone Acetonide Release from PLGA Microspheres as a Function of Varying In vitro Release Conditions. Amy C. Doty, Ying Zhang, David G. Weinstein, Yan Wang, Stephanie Choi, Wen Qu, Sachin Mittal, Steven P. Schwendeman. (Submitted to Molecular Pharmaceutics)
  • A Protocol for Assay of Poly(lactide-co-glycolide) in Clinical Products. John Garner, Sarah Skidmore, Haesun Park, Kinam Park, Stephanie Choi, Yan Wang. International Journal of Pharmaceutics (In Press)

Outcomes

  • Revision of Product-Specific Recommendation on Risperidone Intramuscular Injection
  • Revision of Product-Specific Recommendation on Naltrexone Suspension, Extended Release Intramuscular Injection

 

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