DoE-guided comparison of SNEDDS, solid dispersion, and polymeric nanoparticles for enhancing apparent epithelial transport and oral exposure of sorafenib

Abstract

Sorafenib is an orally administered multikinase inhibitor whose clinical utility is limited by extremely low aqueous solubility and poor oral bioavailability. Although sorafenib is generally considered dissolution-limited, its oral absorption may also be affected by formulation-dependent epithelial transport behavior.

In this study, three nanotechnology-based oral delivery platforms—self-nanoemulsifying drug delivery systems (SNEDDS), spray-dried solid dispersions (SD), and polymeric nanoparticles (PN)—were developed and directly compared using a unified design of experiments (DoE)-guided optimization framework.

Component selection was guided by solubility screening, and each platform was optimized to improve colloidal or solid-state performance. The optimized formulations—solidified SNEDDS (S-SNEDDS), SD, and lyophilized PN—were characterized by PXRD and DSC, indicating a marked reduction in detectable sorafenib crystallinity. All formulations increased apparent solubility in aqueous, pH-adjusted, and biorelevant media, with S-SNEDDS showing the greatest enhancement.

In Caco-2 monolayers, S-SNEDDS achieved the highest apparent permeability, showing a 13.4-fold increase over raw sorafenib. In beagle dogs, S-SNEDDS also produced the highest systemic exposure, with a C_max of 2,948.23 ± 530.68 ng/mL and an AUC_0–48h of 30,958 ± 2,092 ng·h/mL, corresponding to a 6.2-fold AUC increase. The rank order of in vivo exposure aligned more closely with Caco-2 permeability than with apparent solubility alone. These findings suggest that formulation architecture influences sorafenib absorption through combined effects on luminal solubilization and epithelial transport-related behavior.

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Materials

Sorafenib tosylate was kindly provided by Hanmi Pharmaceutical Co., Ltd. (Seoul, South Korea). Unless otherwise specified, sorafenib referred to throughout this study denotes sorafenib tosylate, the clinically approved salt form of sorafenib used in Nexavar®. Lipid-based excipients including Labrasol®, Lauroglycol® 90, Capryol® 90, Maisine® CC, Labrafac® PG, Labrafac® Lipophile WL 1349, Transcutol® P, Tefose® 63, Labrafil® M 1944 CS, Labrafil® M 2125 CS, and Labrafil® M 2130 CS were obtained by Gattefosse.

Taek Kwan Kwon, Chan Hui Park, Ho Taek Im, Jung Hyun Cho, DoE-guided comparison of SNEDDS, solid dispersion, and polymeric nanoparticles for enhancing apparent epithelial transport and oral exposure of sorafenib, Journal of Pharmaceutical Sciences, 2026, 104467, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2026.104467.

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