Optimization of lipid materials in the formulation of S-carvedilol self-microemulsifying drug-delivery systems

Abstract

Objectives

The blocking effect of S-carvedilol (S-CAR) on the beta-adrenoceptor is about 100 times stronger than that of the right-handed conformation. However, further development is restricted because of its poor bioavailability caused by its low solubility and high first-pass effect. In the study, S-CAR self-microemulsifying drug-delivery systems (SMEDDSs) were established, and the effects of different lipid materials on the absorption and metabolism of S-CAR were investigated.

Methods

Six kinds of lipid materials with different chemical structures including oleic acid, glycerol monooleate, glycerol trioleate, oleoyl macrogol-6 glycerides, soybean lecithin, and α-tocopherol were selected to be the oil phase. The S-CAR SMEDDSs were prepared by the same ratio. In vitro characteristics, in vitro release, in situ intestine absorption, and bile excretion, as well as the in vivo characteristic of relative bioavailability, were determined.

Key findings

The lipid structure significantly affected physical characteristics, the absorption and excretion rates of S-CAR SMEDDSs. The findings of rat-intestine perfusion experiments showed that the S-CAR SMEDDSs decreased the bile-excretion rate of S-CAR. Compared with the S-CAR group, the oleic acid and soybean lecithin groups decreased the bile excretion to 32% and 45%, respectively. Pharmacokinetic studies showed that the AUCs of these two groups were about 1.9 and 1.7 times more than that of the S-CAR group, and the mean retention time was extended.

Conclusion

The SMEDDS using ionic lipids (oleic acid or soybean lecithin) as oil phase can increase the oral bioavailability of S-CAR by increasing the solubility and reducing the first-pass effect.

Keywords:

• S-carvedilol
• self-microemulsifying drug-delivery system
• lipid
• solubility
• first-pass effect
• bioavailability

Disclosure statement

The authors confirm that this article content has no conflict of interest.

Additional information

Funding

This work was supported by National Natural Science Foundation of China under Grant No. 81973268; Natural Science Foundation of Guangdong Province under Grant No. 2016A030313562; Guangdong Major S&T Projects about New Drug Innovation under Grant No. 2019B020202002; Youth Foundation of Zhejiang Academy of Medical Sciences under Grant No. C12006Q04.