Date of Completion

4-25-2019

Embargo Period

4-24-2021

Keywords

PLGA, microspheres, IVIVC, Naltrexone, Leuprolide Acetate, Manufacturing processes

Major Advisor

Dr. Diane J. Burgess

Associate Advisor

Dr. Jie Shen

Associate Advisor

Dr. Stephanie Choi

Associate Advisor

Dr. Bodhisatva Chaudhuri

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

This work focuses on development of IVIVCs for variety of Q1/Q2 equivalent parenteral PLGA microspheres with different physicochemical and release characteristics to: 1) achieve a comprehensive understanding of impact of minor manufacturing changes on the physicochemical properties of the microspheres and their relationship with in vitro and in vivo performance; 2) establish Level A IVIVCs; and 3) determine whether release characteristic differences between microspheres can affect the development and predictability of IVIVCs for a variety of microsphere drug products.

Naltrexone and leuprolide acetate (LA) were chosen as the small molecule and peptide microsphere model drug product, respectively. Significant differences were observed in the physicochemical properties (such as particle size, porosity, and morphology) and release characteristics (such as rate and duration) of the compositionally equivalent naltrexone and LA microspheres formulations prepared with minor manufacturing changes. In addition, significant differences in the in vitro burst release and the impact of pore diameter/structure on the release rate were observed for the prepared peptide microsphere formulations. An accelerated in vitro release testing method using modified USP apparatus 4 was developed as a quality control tool for naltrexone microspheres.

The in vivo release profiles of microspheres obtained using a rabbit model were deconvoluted using the Loo-Riegelman method, and compared with the respective in vitro release profiles. The in vivo release profiles showed the same rank order as the in vitro release profiles but with overall faster in vivo release rates. In addition, LA microspheres had significantly low in vivo burst release, which is considered to be due to the masking effect of the absorption phase from the intramuscular site, and this was shown to complicate the development of an IVIVC. Despite these challenges, affirmative Level A IVIVCs were successfully developed for both microsphere products.

Moreover, Level A IVIVCs, with the ability to predict various types of burst release were developed for the compositionally equivalent risperidone and LA microspheres. It was observed that IVIVCs developed using formulations with less variation in burst release had better predictability and vice-versa.

This work provides a comprehensive understanding of developing IVIVCs for complex parenteral drug products such as microspheres.

Development of In Vitro-In Vivo Correlation of Q/1Q2 Equivalent Parenteral Microsphere Drug Products

May 12th 2019

Janki Andhariya

B.Pharm, L.M.College of Pharmacy, Gujarat University, India

M.Pharm, Nirma University, India

Ph.D. University of Connecticut

Directed by: Professor Diane J. Burgess

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