Enhancing Glycemic Control through QbD-Optimized Bilayer Tablet with Saxagliptin and Metformin for Type 2 Diabetes Treatment

Abstract

In the realm of healthcare, the age-related scourge of mortality finds a significant relationship with diabetes mellitus (DM), notably the insidious type 2 diabetes (T2DM). This study focuses on age-related mortality, primarily associated with diabetes mellitus (DM), particularly type 2 diabetes (T2DM). The pathogenesis of T2DM involves insulin resistance, pancreatic beta-cell dysfunction, incretin deficit, and gastrointestinal incretin resistance. To address these factors and enhance treatment efficacy, a combination of medications is often required. The oral hypoglycemic drug Saxagliptin, inhibiting dipeptidyl peptidase-4 (DPP-4), was added to Metformin to improve glycemic control. Quality by Design (QbD) was employed as a systematic, scientific, risk-based, and proactive approach to develop an optimized bilayer tablet containing Saxagliptin and Metformin. The study involved preformulation studies to assess compatibility, a validated RP-HPLC technique for quantitative analysis, and QbD in four steps to design the bilayer tablet. Physicochemical properties were evaluated in accelerated conditions, confirming compatibility. RP-HPLC analysis demonstrated accuracy, linearity, precision, and specificity. QbD steps included defining Critical Quality Attributes (CQAs), creating a Quality Target Product Profile (QTPP), optimizing layers, and preparing the final bilayer tablet. CQAs such as flow property, content uniformity, and drug release were crucial. Optimization involved risk assessment, Taguchi design, and Box-Behnken design. For the immediate-release layer, key variables were kneading time, lubrication time, and magnesium stearate. The sustained-release layer optimization considered HPMC level, compritol level, and MS level. The design space was established based on dissolution criteria. The bilayer tablet was formed by compressing optimized layers. Dissolution studies revealed drug release patterns fitting Korsmeyer-Peppas model, indicating Fickian and super case II transport for Saxagliptin and Metformin, respectively. Comparisons with commercial tablets showed similar dissolution profiles. Stability analysis over six months demonstrated minimal changes, complying with ICH requirements.