Search

To enhance the dissolution and oral bioavailability of telmisartan (TMS), a poorly water-soluble anti-hypertensive drug, a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) was developed. Amorphous alkalinized TMS (AAT) was formulated into a SMEDDS, composed of Capmul® MCM (oil), Cremophor® RH40 (surfactant), and tetraglycol (co-surfactant). Although the SMEDDS was rapidly dissolved (>80% within 5 min) in a limited condition (500 mL, pH 6.8), drug precipitation was observed over time, resulting in a decrease in dissolution levels. The precipitation was due to drug recrystallization, as determined by differential scanning calorimetry and powder X-ray diffraction analyses. Several polymers, including Soluplus® (SOL), were screened as precipitation inhibitors; ultimately, SuSMEDDS-SOL was prepared by admixing SOL and the SMEDDS at a 5:100 (w/w) ratio. SuSMEDDS-SOL was superior in terms of dissolution efficiency (>90% over 2 h) and dissolution-retaining time (no precipitation over 2 h). An in vivo pharmacokinetic study in rats revealed that the oral bioavailability of SuSMEDDS-SOL was 4.8-, 1.3-, and 1.2-fold greater than those of the TMS suspension, AAT solution, and SMEDDS, respectively. Therefore, SuSMEDDS-SOL is a promising candidate to enhance the dissolution and oral bioavailability of TMS. [ABSTRACT FROM AUTHOR]

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 (Peff) in rat jejunum was obtained using an in situ single-pass intestinal perfusion study: Peff 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. [ABSTRACT FROM AUTHOR]

To improve the dissolution and oral bioavailability of valsartan (VST), we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMED) composed of Capmul® MCM (oil), Tween® 80 (surfactant), Transcutol® P (cosurfactant), and Poloxamer 407 (precipitation inhibitor) but encountered a stability problem (Transcutol® P-induced weight loss in storage) after solidification. In the present study, replacing Transcutol® P with Gelucire® 44/14 resulted in a novel SuSMED formulation, wherein the total amount of surfactant/cosurfactant was less than that of the previous formulation. Solidified SuSMED (S-SuSMED) granules were prepared by blending VST-containing SuSMED with selective solid carriers, L-HPC and Florite® PS-10, wherein VST existed in an amorphous state. S-SuSMED tablets fabricated by direct compression with additional excipients were sufficiently stable in terms of drug content and impurity changes after 6 months of storage at accelerated conditions (40 ± 2 °C and 75 ± 5% relative humidity). Consequently, enhanced dissolution was obtained (pH 1.2, 2 h): 6-fold for S-SuSMED granules against raw VST; 2.3-fold for S-SuSMED tablets against Diovan® (reference tablet). S-SuSMED tablets increased oral bioavailability in rats (10 mg/kg VST dose): approximately 177–198% versus raw VST and Diovan®. Therefore, VST-loaded S-SuSMED formulations might be good candidates for practical development in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]