Formulation and optimization of Paliperidone palmitate biodegradable injectable microspheres using Box-Behnken design

Abstract

The objective of study was to formulate and optimize poly lactic-co-glycolic acid based long-acting injectable microspheres of Paliperidone palmitate (PP) using Box- Behnken design for treatment of schizophrenia. The oral bioavailability of PP is 28%, it necessitates the formulation of PP in injectable dosage form. In this study, PP microspheres were manufactured using oil in water (O/W) emulsion solvent evaporation technique. Box-Behnken design was selected to study effect of independent variables (X) on dependent variables (Y). Independent variables in this study were drug: polymer ratio (X1), homogenization speed (X2), rate of addition (X3). While mean particle size (Y1), drug loading (Y2), entrapment efficiency (Y3), burst release (Y4) and drug release on day 21 (Y5) were considered as dependent variables. The statistical evaluation of data was performed by using Design Expert software. Size of formulated microspheres was studied using laser diffraction technique. The shape of particles was determined using digital microscope and scanning electron microscopy (SEM). Drug release was studied using controlled temperature shaking water bath apparatus. Fourier transforms infrared spectroscopy (FTIR) and differential scanning calorimetric (DSC) study was carried out to detect any incompatibility. Nuclear magnetic resonance (NMR) techniques were used to characterize end cap and monomer ratio in developed microspheres. The prepared PP microspheres exhibited smooth surface and spherical shape. Box-Behnken design was employed for optimization of microspheres. Mean particle size of prepared PP microspheres was found to be in between 12 ± 3.7 μm and 152 ± 3.4 μm. Drug loading in prepared microspheres was found in between 19.4 ± 0.2% to 46.5 ± 0.7%. Entrapment efficiency of prepared microspheres was obtained between 58.6 ± 0.8% and 96.8 ± 1.4%. Drug release from PP microspheres was observed as near zero order. The observed and predicted values of all responses were in close agreement with each other. End cap analysis and molar ratio of Lactic acid: Glycolic acid for formulated microspheres was found to be ester end cap and ∼75:25 respectively. The optimized PP microspheres were capable of releasing drug in vitro up to 28 days. The optimized novel PP injectable microspheres are having profound advantages over conventional oral drug delivery systems in treatment of schizophrenia.