Acalabrutinib loaded nanostructured lipid carriers to improve the oral delivery of the drug: Optimization, physicochemical characterization, in vivo pharmacokinetics and lymphatic uptake studies

Nanostructured lipid carriers (NLCs) offer a promising solution for improving the delivery of lipophilic drugs by enhancing solubility, bioavailability, and targeting, though optimizing their physicochemical properties, such as particle size and drug loading, remains challenging. Traditional one-factor-at-a-time methods fail to account for complex interactions among variables, so this study employs a design of experiments approach to optimize NLCs for oral delivery of acalabrutinib, using a 2⁵⁻¹ fractional factorial design for screening followed by a circumscribed central composite design for optimization. The optimized NLCs exhibited spherical morphology with a mean particle size of 249.3 ± 9.1 nm with PDI of 0.349 ± 0.036, 10.69 ± 0.51 % loading and 77.51 ± 3.72 % entrapment efficiency. The in vitro release of acalabrutinib from the NLCs followed square root kinetics with 100 % drug release at the end of 48 h in pH 7.2. The formulation exhibited stable particle size and entrapment efficiency with minimum deviations when stored at 5 °C for 6 months. Oral pharmacokinetic studies showed that NLCs nanosuspension enhanced C_max and AUC_0-tlast by 2.17- and 4.35-folds (p < 0.001) compared to conventional suspension. Additionally, NLCs sustained plasma drug concentrations longer, with an MRT_0-tlast of 6.97 h vs. 3.61 ± 0.19 h for the conventional suspension. Inhibiting the lymphatic flow reduced the AUC_0-tlast by 44.14 %, highlighting the significant role played by lymphatic transport in the oral absorption NLCs. This study underscores the potential of the developed NLCs as an effective platform for oral delivery of acalabrutinib.