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. 2019 Dec;26(1):63-69.
doi: 10.1080/10717544.2018.1556360.

Stereoselectivity evaluation of chiral chitosan microspheres delivery system containing rac-KET in vitro and in vivo

Li-Na Yin  1 , Ya-Wen Zhang  1 , Wen-Hai Huang  1 , Sheng-Hao Wang  1 , Gao-Li Zheng  1
Affiliations

Stereoselectivity evaluation of chiral chitosan microspheres delivery system containing rac-KET in vitro and in vivo

Li-Na Yin et al. Drug Deliv. 2019 Dec.

Abstract

The influence of chiral excipient D-chitosan (CS) on the stereoselective release of racemic ketoprofen (rac-KET) microspheres has been investigated in comparison to those microspheres containing individual enantiomers in vitro and in vivo. Stereoselectivity was observed in vitro release test, with R-KET release slightly higher than that of S-KET, especially in 3% rac-KET loading microspheres. Stereoselectivity is dependent on the content of chiral excipient and pH of release medium. A molecular docking study between CS and KET enantiomers further revealed that S-KET has a stronger interaction with CS compared to R-KET. Moreover, the plasma concentration of KET enantiomers in rats shows substantial differences, as the plasma levels of S-KET were higher than those of R-KET. Plasma levels of enantiomers from the R-KET microspheres had similar stereoselectivity as rac-KET microspheres. The S/R ratio of rac-KET microspheres was significantly lower than that of rac-KET suspension (regular-release formulation) (p<.05), and the differences is 3-5 fold. Besides, rates of R-KET converted to S-KET exhibited differences between rac-KET microspheres and suspension. Similar results were also found between R-KET microspheres and suspension. All investigations suggest that the chitosan interacting preferentially with S-KET to R-KET significantly affect the stereoselective pharmacokinetics of rac-KET from chitosan microspheres in rats.

Keywords: Stereoselective release; chiral excipient; chitosan; ketoprofen; molecular docking study; stereoselective pharmacokinetics.

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Figures

Figure 1.
Figure 1.
S-KET and R-KET plasma level after single subcutaneous injection of rac-KET suspension and microspheres at a dose of 40 mg/kg in rats. Each point represents the mean ± SD (n = 5).
Figure 2.
Figure 2.
S-KET and R-KET plasma level after single subcutaneous injection of R-KET suspension and microspheres at a dose of 40 mg/kg in rats. Each point represents the mean ± SD (n = 5).
Figure 3.
Figure 3.
S-KET plasma level after single subcutaneous injection of S-KET suspension and microspheres at a dose of 40 mg/kg in rats. Each point represents the mean ± SD (n = 5).
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