Solid Self Nano-Emulsifying Drug Delivery System of Dasatinib: Optimization, In-vitro, Ex-vivo and In-vivo assessment

Abstract

Aim: Dasatinib (DST) is an oral tyrosine kinase inhibitor with poor aqueous solubility. To outwit this issue, a solid self-nano emulsifying drug delivery system (S-SNEDDS) of DST was formulated.

Methods: I-optimal mixture design was used for optimization of DST-loaded SNEDDS using Linalool, Cremophor RH40 and Transcutol P. S-SNEDDS underwent physicochemical characterization, in-vitro release and ex-vivo permeation, cell-based assays and pharmacokinetic study.

Results: DST-S-SNEDDS showed globule size and PDI of 141.53 ± 5.371 nm and 0.282 ± 0.020, respectively. DST-S-SNEDDS revealed significantly lower IC₅₀ (1.825 μg/mL) than free DST (7.298 μg/mL) in MDA-MB-231. In-vivo pharmacokinetic study revealed 1.94-fold increment in AUC_0-t for the DST-S-SNEDDS group than free DST.

Conclusion: S-SNEDDS could be promising approach for improving bioavailability and efficacy of DST.

Introduction

DST, being a BCS class II molecule, possesses several challenges, such as low aqueous solubility and low bioavailability.
SNEDDS remains an ideal and robust dosage form for delivery and improving the stability of hydrophobic cargos.

Optimization & characterization of DST-S-SNEDDS

DST was screened for its solubility in various oils, surfactants and co-surfactants followed by the emulsification potential. Linalool, Cremophor RH 40 and Transcutol P were selected for further optimization using the mixture design.
DST-L-SNEDDS showed an optimized droplet size of 26.99 ± 0.62 nm and a percent transmittance of 99%. Further, to improve the stability of liquid SNEDDS, DST-L-SNEDDS was lyophilized with different inert solid carriers such as Neusilin^® US2, Neusilin^® UFL2 and Aerosil^® 200. Aerosil^® 200 resulted in a desirable globule size of 141.53 ± 5.371 nm and a PDI of 0.282 ± 0.020 after reconstitution. Thus, it was selected for further characterization.
The developed solid SNEDDS were free-flowing powders that showed complete adsorption of DST-L-SNEDDS over its surface under a scanning electron microscope. DSC analysis revealed the complete disappearance of the DST peak in DST-S-SNEDDS, indicating complete solubilization of DST.
In-vitro release and dissolution studies demonstrated significantly higher DST release from DST-S-SNEDDS. This could be attributed to the solubilized form of DST in lipids.
Similar observations were noted in gut permeation studies. DST-S-SNEDDS showed higher permeation compared with free DST.
In-vitro anti-cancer efficacy was studied in the MDA-MB-231 cell line, which showed a 3.29-fold reduction in IC₅₀ value and significantly higher cellular uptake.
DST-S-SNEDDS further resulted in an improvement in bioavailability by 1.96-fold and a more than fourfold increase in C_max. compared with free DST.

Conclusion

Thus, DST-S-SNEDDS showed an enhanced dissolution profile and higher permeation compared with free DST. The enhanced anticancer activity and internalization in MDA-MB231 were also observed with DST-S-SNEDDS. Further, improved bioavailability was also observed with DST-S-SNEDDS. These enhanced properties could be attributed to the nano-sized globules of DST-S-SNEDDS and the improved solubility of DST.