Self‐Microemulsifying Drug Delivery System: Liquid‐Filled Gelatin Capsules of Atorvastatin and Ezetimibe

Atorvastatin (ATV) and ezetimibe (EZE) are BCS Class II drugs with low oral bioavailability (14% and 35%, respectively) attributed to poor aqueous solubility and extensive first‐pass metabolism. Although the two drugs act synergistically to lower cholesterol, their combination into a single delivery system is complicated by differing physicochemical properties. This study aimed to develop and characterize a self‐microemulsifying drug delivery system (SMEDDS) coloaded with ATV and EZE, encapsulated in an Empo Caps LP + size 00 capsule, to improve their dissolution and permeability. Pseudoternary phase diagrams were constructed to identify microemulsion regions, and candidate formulations were screened by droplet size, polydispersity index, refractive index, and viscosity. Four formulations (ME#22, ME#26, ME#31, and ME#35) met the physical acceptance criteria, including a polydispersity index (PDI) within its theoretically valid 0–1 range; a fifth trial (ME#12) was excluded on this basis. Formula 31—containing 14.96% triacetin, 39.89% Tween 80%, and 19.94% PEG 400 (oil:surfactant/cosurfactant ratio 2:8; surfactant:cosurfactant ratio 2:1)—showed the highest drug loading (ATV 3.95 ± 0.35 mg/mL; EZE 3.04 ± 0.06 mg/mL), a droplet size of 74.15 ± 1.68 nm, PDI of 0.34 ± 0.02, refractive index of 1.372, and viscosity of 310 ± 9.58 cP, with assay values of 104.6% (ATV) and 104.9% (EZE). This formulation demonstrated faster in vitro dissolution than the commercial reference product (Atozet) across all tested media and significantly greater ex vivo intestinal permeability than plain drug suspension ( p < 0.05 from 90 min onward). In conclusion, an ATV‐/EZE‐loaded SMEDDS encapsulated in an Empo Caps LP + size 00 capsule was successfully developed and showed improved in vitro dissolution and ex vivo permeability relative to the marketed product, supporting its potential as an alternative oral delivery strategy for this drug combination.