Development And Evaluation Of STVNa/STV-1 Novel Oral Drug Delivery Systems

Although isosteviol(STV-1)has been significantly confirmed bioactive,it is barely watersoluble,hardly absorbed by organism and has shorter half-life,so that the clinical application of STV-1 is subject to certain restrictions.The present study designed that water-soluble isosteviol sodium(STVNa)was prepared to conventional tablets and matrix sustained-release tablets(SR tablets)and insoluble STV-1 was prepared to polymeric micelles as a result of the development of the drug delivery technology for increasing the solubility of STV-1 and extending the residence time of STV-1 in vivo.Furthermore,the two formulations of tablets were evaluated for in vitro and vivo release while the polymer micelles for in vitro release.Details are following:STVNa conventional tablets and SR tablets were prepared,both of which appearance,hardness and friability were eligible.STVNa SR tablets were proved sustained-release by comparing the in vitro release results of the two formulations.And the in vitro release curve of STVNa from SR tablets fit Higuichi model.In addition,the results fitting Ritger-Peppas model showed that the release behavior of STVNa from SR tablets did not follow Fick's diffusion but cooperation of drug diffusion and matrix erosion.UPLC-MS/MS method for quantitative analysis of STV-1 in dog plasma which is rapid and sensitive with good selectivity and LLOQ of 2.000 ng/mL was established.Accuracy and precision of the method is qualified,both the recoveries of STV-1 and IS were precise and reproducible,and the concentration of STV-1 in dog plasma in the range of 2.000 ~ 1000 ng/mL fit linear well.Applying the above established method to PK study for measuring STV-1 in dog plasma(oral STVNa conventional tablets and SR tablets),the fitting results by twocompartment model showed the Cmax of STV-1 from SR tablets was apparently lower than that from conventional tablets,and STV-1 from SR tablets could maintain stable in vivo till 8 h;the T1/2 extended about 94%;the AUC0~t was close;the relative bioavailability was 112.9%;the MRTs were respectively 6.96 ± 2.5 h and 9.66 ± 1.1 h.Thus,to some extent,STVNa SR tablets could release STVNa slowly and extend its residence time in vivo.STV-1 micelles with high encapsulation efficiency and drug loading,small and uniform particle size,good stability and significant in vitro sustained release effect were successfully prepared.By investigating the influences of different weight ratios of drug and polymeric materials on pharmaceutics characteristics of STV-1 micelles,the optimum weight ratio was from 50 wt.% to 80 wt.%.The comparison of STV-1 in vitro release behaviors from suspension and micelles described that micelles could not only take effect to long-acting release,but also improve the solubility of STV-1.And the in vitro release curve of STV-1 from micelles fit Firstorder model in certain release time.In addition,the results fitting Ritger-Peppas model showed that the release behavior of STV-1 from micelles followed Fick's diffusion.