Development of Novel Drug Delivery Systems for the Management of NSAID induced Gastroenteropathy: A Quality by Design (QbD) Approach

Abstract

Management of Nonsteroidal anti-inflammatory drugs (NSAID)-induced gastroenteropathy has emerged as an important medico-socioeconomic problem. There are no approved therapeutic agents to prevent NSAID-induced enteropathic damage and its exacerbation by proton pump inhibitors (PPIs; viz. pantoprazole sodium, PTZ). Hence, the primary objective of the present study was to develop the novel formulations of quercetin (QCT) and PTZ to prevent NSAID-induced gastroenteropathic damage and exacerbation of enteropathic damage caused by PTZ. However, since these novel formulations were required to be tested in an animal model, hence; a clinically simulated rat model for NSAID-induced gastroenteropathy was developed. Using this model, the anti-gastroenteropathic potential of QCT was proven against NSAID-induced gastroenteropathy and exacerbation of enteropathic damage caused by PTZ. Further, sodium alginate based systematically optimized multiple-unit gastroretentive drug delivery system (GRDDS) of QCT and enteric coated formulation of PTZ were developed using quality by design (QbD) approach. A 33 Box–Behnken design (BBD) was employed for optimizing the formulations. Optimized formulation of QCT prevented the NSAID-induced gastroenteropathic lesions at reduced dose levels (25 mg kg-1) compared to non-formulated QCT (50 mg kg-1) and enteric coated formulation of PTZ did not exacerbate the NSAID-induced enteropathic damage. While, co-administration of QbD-enabled novel formulations of QCT (25 mg kg-1) and PTZ (4 mg kg-1) prevented the NSAID-induced gastroenteropathic damage successfully. Oral toxicity study (28 days) of the optimized formulations of QCT and PTZ established the safety of these NDDS in healthy male wistar rats. Further, it can be inferred from toxicity study that PTZ/PTZ loaded microparticles and QCT/QCT loaded microparticles up to and inclusive of 16 mg Kg-1 and 100 mg Kg-1 body weight twice daily respectively was tolerated by the rats up to 28 days. Based on these findings, it can be concluded that ALG based QbD-enabled novel formulations of QCT and PTZ offer an interesting approach for the efficient management of NSAID-induced gastroenteropathic damage and PPI-related exacerbation of NSAID enteropathy.