Oral linalool-based nanoemulsion of acalabrutinib for ameliorating its oral bioavailability and in vitro anticancer potential in T lymphoblast cell lines

Acalabrutinib (ACL) was approved in the United States in the year of 2017 and 2019 for the treatment of chronic lymphocytic leukemia (CLL) and relapsed mantle cell lymphoma (MCL). Low-energy method was employed to curate nanoemulsion (NE) for which various components were screened through solubility study and optimization was done through a pseudo-ternary phase diagram. The NE was evaluated for its droplet size, polydispersity index (PDI), transmittance, morphology, rheology, robustness to dilution, the effect of pH, storage stability, and ex vivo permeation study. The optimized ACL-NE demonstrated an appropriate droplet size (94.35 ± 0.3 nm), PDI (0.27 ± 0.03), and an entrapment efficiency of 67.38 ± 2.69%. It showed non-Newtonian (shear thinning behavior) due to reduced viscosity with an increasing shear rate. The apparent permeability was 3.09-fold higher for ACL-NE than ACL suspension. An in vitro drug release study depicted a higher release of ACL (71.10 ± 10.99%) from the optimized NE in a sustained fashion than the suspension (49.01 ± 1.65%). A dose-dependent cytotoxicity was observed in MOLT-4 and HH-cell lines where the IC50 values of ACL were 5.62- and 16.49-fold reduced when encapsulated in oil globules for the respective cell lines. Blank-NE did cause a reduction in cellular toxicity at higher doses. A 7.31- and 5.1-fold increase in C_max and bioavailability was noted between ACL suspension and ACL-NE.

Graphical abstract