Enhancing oral bioavailability of dasatinib via supersaturable SNEDDS: Investigation of precipitation inhibition and IVIVC through in-vitro lipolysis-permeation model

Abstract

Dasatinib (DASA), a potent second-generation multitarget kinase inhibitor marketed as Sprycel® (Tablet), is limited by poor oral bioavailability (14–24 %) and dose-related gastrointestinal side effects. A supersaturable self-nanoemulsifying drug delivery system (su-SNEDDS) designed to enhance DASA’s solubility, sustain supersaturation, and improve oral bioavailability. The su-SNEDDS formulation comprises DASA, an oil, surfactant, co-surfactant, and polyvinylpyrrolidone (PVP) K30 as a precipitation inhibitor (PI).

Highlights

Su-SNEDDS maintained ∼ 13.5-fold higher aqueous drug concentrations than DASA suspension.

The formulation having monodisperse nanometric size, were stable in GIT and dilution.

In-vitro lipolysis-permeation showed enhanced drug solubilization and permeation.

Su-SNEDDS exhibited significantly higher permeation and Caco-2 uptake than others.

A linear correlation (R² = 0.9042) was established between in- vitro and in-vivo outcomes.

This innovative system demonstrated exceptional stability in gastrointestinal fluids and robustness against dilution, maintaining significantly elevated drug concentrations in the aqueous milieu. su-SNEDDS achieved ∼ 13.5-fold and 2-fold higher aqueous drug concentrations than DASA suspension and SNEDDS without PI, respectively, after 60 min of digestion. This improvement is attributed to the inhibition of crystal growth by PVP K30. In-vitro lipolysis-permeation and Caco-2 cell assays revealed significantly enhanced drug permeation with su-SNEDDS compared to DASA suspension and SNEDDS without PI. In-vivo pharmacokinetic studies further demonstrated ∼ 1.9-fold and 2.7-fold higher AUC compared to SNEDDS without PI and drug suspension, respectively.

A linear correlation (R² = 0.9042) was established between the AUC data obtained from in–vitro vs in-vivo study. These findings underscore the potential of su-SNEDDS to significantly enhance DASA’s solubility, permeation and oral bioavailability, presenting a substantial advancement in pharmaceutical drug delivery systems. Moreover, in-vitro lipolysis-permeation could be promising tool to predict the in-vivo fate of the oral SNEDDS formulations.

Materials

Dasatinib (anhydrous) was received as a gift sample from Cipla, India. Maisine TM, Capryol® 90, Labrafil®M 1944 CS and Transcutol® HP were obtained as gift samples from Gattefosse, France. Capmul® MCM C8, Acconon CCG, Maisine was generous free sample from Abitec. Oleic was procured from Sigma Aldrich, Germany. HPLC and other solvents i.e. Ethyl acetate, acetonitrile and methanol were procured from Fischer Scientific.

Other excipients mentioned in the study: PVP K30

Dharshini Mageshvaran, Sheetal Yadav, Vivek Yadav, Kaushik Kuche, Oly Katari, Sanyog Jain, Enhancing oral bioavailability of dasatinib via supersaturable SNEDDS: Investigation of precipitation inhibition and IVIVC through in-vitro lipolysis-permeation model, International Journal of Pharmaceutics, Volume 668, 2025, 125007, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125007.