DOE-Guided Development of a Varied Drug Release Cup-Shaped Bilayer Tablet: Delayed-Release Naproxen Sodium and Immediate-Release Misoprostol

AbstractLong-term administration of Naproxen Sodium, a potent non-steroidal anti-inflammatory drug (NSAID), isfrequently associated with dose-dependent gastrointestinal ulceration, a significant clinical challenge. To mitigate thisadverse effect and enhance patient safety, a novel fixed-dose combination tablet was formulated to providesequential, site-specific release of Naproxen Sodium, and the gastro-protective drug, Misoprostol. The abovecombination is not available commercially and can be used to prevent the side effects of Naproxen Sodium. However,Naproxen Sodium in combination with Esomeprazole (proton pump inhibitor) is available emphasizing the need forthe protection from deleterious effects of Naproxen Sodium on gastric mucosa. Therefore, a fixed dose combinationof Naproxen Sodium and misoprostol is proposed and selected for design, development & evaluation of combinationproduct with varied release profile. This was achieved through a unique cup-shaped bilayer novel design, wherein anenteric-coated Naproxen Sodium core is in the lower part of the bilayer tablet and upper layer is placebo followed byenteric coating and film coating to design unique cup shaped bilayer tablet. Misoprostol was placed on the concave shaped cup and dried. The formulation of the Naproxen Sodium core was systematically optimized using a three-factor, two-level factorial Design of Experiments (DoE), which identified the concentration of the super-disintegrant (Croscarmellose sodium) as the most critical variable influencing dissolution. The final scale up batchesdemonstrated effective gastro-resistance, releasing less than 10% of Naproxen Sodium in acidic media over twohours. Subsequent dissolution testing in pH 6.8 media for Naproxen Sodium and water for Misoprostol confirmedthat the release profiles for both drugs were statistically similar to their respective individual marketed products. Thecalculated similarity factors (f2) were 69.37 for the delayed-release Naproxen Sodium component and 88.07 for theimmediate-release Misoprostol component. This successful application of Quality by Design principles to a novelbilayer tablet design validates its potential as a platform technology for complex, multi-drug release systems.