A Study on the Formulation and Optimization of Nanostructured Lipid Carriers for Bempedoic Acid with Improved Biorelevant Intestinal Solubilization

Bempedoic acid is an ATP-citrate lyase inhibitor used to reduce low-density lipoprotein cholesterol; however, its poor aqueous solubility under acidic conditions and pH-dependent dissolution may limit gastrointestinal drug availability. This study aimed to develop and optimize an aqueous nanostructured lipid carrier (NLC) dispersion to improve bempedoic acid release and biorelevant intestinal solubilization. Pre-formulation screening evaluated drug solubility in solid and liquid lipids, lipid–aqueous partitioning, drug–excipient compatibility, and surfactant emulsification. Precirol® ATO 5 and Capryol® 90 were selected as the solid and liquid lipid components, respectively, at an 80:20 ratio; Tween® 80 and Poloxamer 188 were selected as the stabilizer system. NLCs were prepared by hot homogenization followed by probe ultrasonication. The optimized dispersion exhibited a particle size of 145.8 ± 4.9 nm, polydispersity index (PDI) of 0.21 ± 0.02, zeta potential of −24.7 ± 1.5 mV, entrapment efficiency of 86.3 ± 2.4%, drug loading of 4.6 ± 0.3%, and drug content of 98.9 ± 1.7%. In pH-shift release testing, cumulative release at 24 h was 79.3 ± 3.1% for NLCs compared with 28.7 ± 2.2% for plain drug suspension. Release data were best fitted by the Korsmeyer–Peppas model (R² = 0.989; n = 0.52). During pH-stat lipolysis, 67.9 ± 3.4% of the drug remained in the micellar/aqueous fraction for NLCs compared with 24.6 ± 2.8% for suspension. The dispersion maintained its quality more effectively at 4°C than at 25°C over 30 days, whereas accelerated storage produced particle growth and PDI increase. The findings demonstrate improved in vitro release and digestion-phase solubilization; in vivo pharmacokinetic confirmation remains necessary.