Rational design and DoE based prediction model for levodopa gastroretentive systems based on hot-melt tube extrusion

The presented study focuses on the development of a floating gastroretentive drug delivery system (GRDDS) for Levodopa, utilizing a design of experiment (DoE) approach to predict and optimize drug release profiles over an 8-hour period. Due to Levodopa's narrow absorption window in the upper gastrointestinal tract, achieving steady release and consistent gastroretention is crucial for maintaining constant therapeutic plasma levels in Parkinson's disease patients. By combining the polymers Eudragit® RS (EuRS) and E PO (EPO), drug release was effectively modulated. For the DoE, 21 Levodopa formulations, including immediate and extended-release variants, were extruded into hollow tubes and sealed with 3D-printed PLA plugs. Dissolution behavior was characterized using a Weibull fit alongside a time-point parametrization method to generate input variables for the DoE. All formulations exhibited immediate buoyancy and no alteration in crystallinity after extrusion as shown by XRPD results. A "sweet spot" was identified within the formulation space – containing 50-59% Levodopa, 23-28% EuRS, and 15-19% EPO – where formulations achieved a burst release of less than 20% within the first hour and approximately 70% drug release over 8 hours. The DoE’s predictive capability was validated using three confirmation points inside and two outside the design space, resulting in an optimized GRDDS formulation comprising 50% Levodopa, 30% EuRS, and 19.5% EPO with dimensions comparable to capsule size 1 holding approximately 250 mg Lev and an extended drug release of 8 h.