Abstract

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul® MCM (13.2 mg), Tween® 80 (59.2 mg), Transcutol® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite® PS-10 (119.1 mg) and Vivapur® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

CONCLUSIONS

Novel formulations of VST-loaded S-SuSMEDDS granules and tablets were successfully developed using D-optimal mixture design and 3-LFD, respectively, resulting in percentage prediction errors of <10%. SuSMEDDS composed of VST, Capmul® MCM, Tween® 80, Transcutol® P, and Poloxamer 407 was efficiently solidified with Florite® PS-10 and Vivapur® 105, and the resultant granules showed good flow properties and rapid drug dissolution. By introducing CS as a superdisintegrant, S-SuSMEDDS tablets were successfully formulated, resulting in fast disintegration and high dissolution efficiency. In PK studies in rats, the RBA of the optimized granules was 107% and 222% of the values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we suggest that the optimized S-SuSMEDDS formulations offer great potential for developing solid dosage forms, with improved oral absorption of poorly water-soluble drugs such as VST.