期刊
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
卷 25, 期 2, 页码 178-186出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/10837450.2019.1683749
关键词
Valsartan; supersaturable self-microemulsifying drug delivery system (Su-SMEDDS); P-glycoprotein (P-gp); dissolution; single-pass intestinal perfusion; bioavailability; pharmacokinetics
资金
- Advanced Technology Center program - Ministry of Trade, Industry, & Energy (MOTIE, KOREA) [10051950]
- Chung-Ang University
- Korea Evaluation Institute of Industrial Technology (KEIT) [10051950] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 (R) MCM (oil), Tween (R) 20 (T20; surfactant), Transcutol (R) P (cosurfactant), and Poloxamer 407 (supersaturating agent), P-gp inhibitory surfactants including Tween (R) 80 (T80) and Cremophor (R) 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.
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