Formulation Development and Characterization of Multiparticulate System for Oral Fixed Dose Combination Therpay

Abstract

The aim of present work was to develop Fixed Dose Combination (FDC) using Multiparticulate Drug Delivery Systems. For this purpose, an already approved FDC containing Naproxen (NAP) and Esomeprazole magnesium (EMT) was taken as reference. The reference product is a tablet, approved by different regulatory authorities but not by DCGI. For the formulation development of FDC, different multiparticulate approaches were employed. The developed FDC was compared with reference FDC for release profiles of NAP and EMT. In case of Naproxen, pellets and minitablets were explored as multiparticulate approach and the formulations were optimized using application of Quality by Design (QbD). The optimized NAP pellets and minitablets formulations were compared for release profiles of NAP with reference product. Minitablets formulation of NAP showed promising results in terms of release profile and hence was selected as core formulation. Over the core formulation, delayed release coating was applied through Wurster Processing and was further optimized. Further, over optimized delayed release coated NAP minitablets, a barrier layer was applied to avoid direct contact of delayed release polymer with EMT formulation. In case of EMT, granules and pellets were explored as multiparticulate formulations. The formulations were developed based on QbD approach and optimized. Both the formulations were compared with each other for stability of EMT in formulation. Pellets formulations exhibited intact stability of EMT as compared to granules. The release of EMT from pellets was optimized on basis of release of EMT from reference product. Both optimized NAP and EMT formulations were filled in capsule dosage form depending on the dose of individual drugs. The combined formulation was studied for release of NAP and EMT in different dissolution media and was compared with reference product. The study was extended by performing the stability of combined dosage forms at long term and accelerated conditions using different type of capsule shell and packaging material. The stability samples were studied for stability of EMT and NAP in combined formulation and release profiles of NAP and EMT. Further, the in-vivo performance of NAP and EMT was also estimated using Wagner-Nelson Method and found in good agreement with in-vivo studies. The present study revealed that the developed FDC was simpler in manufacturing as compared to reference product, exhibited equivalence and hence can be an effective formulation in treating GI ulcer induced due to exposure to NSAIDs and increase patient compliance.