Enhanced oral bioavailability of valsartan in rats using a supersaturable self-microemulsifying drug delivery system with P-glycoprotein inhibitors

Abstract

Valsartan (VST) is a poorly water-soluble drug and a P-glycoprotein (P-gp) substrate. To enhance the dissolution and oral absorption of VST, a novel supersaturable self-microemulsifying drug delivery system (Su-SMEDDS) was formulated. Based on the previously reported Su-SMEDDS composed of Capmul^® MCM (oil), Tween^® 20 (T20; surfactant), Transcutol^® P (cosurfactant), and Poloxamer 407 (supersaturating agent), P-gp inhibitory surfactants including Tween^® 80 (T80) and Cremophor^® EL (CR) were newly introduced to replace T20. All Su-SMEDDS formulations had a droplet size of <200 nm and showed rapid (>90% within 5 min) and pH-independent dissolution characteristics. The effective permeability coefficient (P_eff) in rat jejunum was obtained using an in situ single-pass intestinal perfusion study: P_eff values of Su-SMEDDS-T20, Su-SMEDDS-T80, and Su-SMEDDS-CR were 2.3, 4.1, and 3.4 times greater, respectively, than that of the VST solution. After oral administration of various formulations to rats (equivalent dose of VST 10 mg/kg), plasma drug levels were measured by liquid chromatography-tandem mass spectrometry. The relative bioavailabilities of Su-SMEDDS-T20, Su-SMEDDS-T80, and Su-SMEDDS-CR were 262%, 470%, and 458%, respectively, compared with the VST suspension. Thus, we propose that the Su-SMEDDS-T80 formulation is a good candidate for improving the oral absorption of poorly water-soluble and P-gp substrate drugs such as VST.

Graphical Abstract

Keywords:

• Valsartan
• supersaturable self-microemulsifying drug delivery system (Su-SMEDDS)
• P-glycoprotein (P-gp)
• dissolution
• single-pass intestinal perfusion
• bioavailability
• pharmacokinetics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Advanced Technology Center program (10051950) funded by the Ministry of Trade, Industry, & Energy (MOTIE, KOREA). This work was also supported in part by the Chung-Ang University Graduate Research Scholarship in 2018.