Purpose: The objective of the present study was to understand the effect of differences in the burst release % of compositionally equivalent PLGA microspheres on the modeling and predictability of in vitro-in vivo correlation (IVIVC).
Methods: Risperidone (LA) was chosen as a model drug and PLGA polymer (molecular weight: ~90 KD) was used to prepare microspheres. Different process parameters (e.g. solvent system/ratio and sieving procedure) were investigated in order to obtain compositionally equivalent risperidone microspheres with manufacturing differences. Critical quality attributes (e.g. drug loading, particle size, size distribution and morphology) of the prepared microspheres were determined. Furthermore, in vitro release profiles of the prepared microspheres were investigated using a previously developed USP apparatus 4 method in order to study differences in the burst release phase. In vivo release testing was conducted using a rabbit model and collected plasma samples were analysed using LC-MS. The in vivo plasma concentration vs time profiles were deconvoluted using the Loo-Riegelman method and used to establish IVIVCs. The developed IVIVCs were validated by determination of % prediction error (PE) using WinNonlin 6.4, PK/PD software.
Results: Despite the use of different solvent systems, all the microsphere formulations prepared using different manufacturing processes had similar drug loading (36%, w/w) and all were spherical in shape, but had significant differences in particle size and porosity. This may be a result of differences in the emulsification method (homogenization (Homo) vs vortexing), differences in microsphere solidification due to differences in polymer solubility in the different solvent systems used, or a result of differences in solvent evaporation or any combination of these factors. In addition, differences in the solvent system used may affect drug solubility and hence, the homogeneity of drug distribution in the microspheres, i.e. on the surface or evenly distributed throughout the bulk1. Accordingly, all the microsphere formulations prepared with manufacturing differences showed different in vitro release profiles with variable burst release percentages and lag phase (Figure 1). The developed USP apparatus 4 in vitro release testing method was able to discriminate variations in the burst release phase of the risperidone microsphere formulations. The in vivo release profiles were also different, but with relatively faster release rates compared to the respective in vitro release profiles (Figure 2). Different combinations of the microsphere formulations were used to establish IVIVCs between the fraction released in vitro and the fraction absorbed in vivo. However, not all the combinations of formulations resulted in IVIVCs with good prediction of the burst release phase. This is because burst release is difficult to control and its extent also varies under in vitro and in vivo conditions. However, the IVIVCs developed using combinations of formulations with similar (or less variable) burst release phase (i.e. Formulations F1, F2 and F3 for higher burst release and Formulations F4, F5 and F6 for lower burst release) showed better correlation and predictability compared to other combinations of the formulations. It should be noted that in order to develop the IVIVCs, a time scaling factor was used for the higher burst release formulations, while a time shifting factor was used for the lower burst release formulations. The % PE of the developed IVIVC was acceptable (<10% for Cmax and AUC)) as per the U.S. FDA guideline2.
Conclusion: The burst release phase of risperidone microspheres appeared to be sensitive to manufacturing changes such as the solvent system. The developed USP apparatus 4 in vitro release testing method was capable of discriminating variations in the burst release phase of the risperidone microsphere formulations prepared with manufacturing differences. An affirmative level A IVIVC was established between fraction released in vitro and fraction absorbed in vivo for the formulations with similar burst release characteristics using a rabbit model. This indicates that the developed USP Apparatus 4 based in vitro release testing method has the potential to be used as a biorelevant method.
Jie Shen– Assistant Professor, University of Rhode Island, kingston, Rhode Island
Yuan Zou– Staff Fellow, United States Food and Drug Administration
Yan Wang– Staff Fellow, United States Food and Drug Administration
Stephanie Choi– Chemist, US Food and Drug Administration, Maryland
Diane Burgess– Distinguished Professor of Pharmaceutics, University of Connecticut, Storrs, Connecticut