| Objective:The aim of preparation of teniposide solid lipid nanoparticles?SLN?was to prepare a more safe and effective oral administration agent.The appearance,particle size and stability of teniposide SLN dispersion system were studied to establish the quality standard of teniposide SLN.Methods:1.A HPLC method was established for the determination of teniposide in vitro.The physicochemical properties such as solubility and oil-water distribution coefficientof teniposide were investigated.2.The blank SLN,was prepared by different methods and the preparation process was optimized.Single factor test and orthogonal test were used to optimize the prescription of teniposide SLN.3.The particle morphology of teniposide SLN was observed by transmission electron microscope;The particle size distribution and potential of teniposide SLN were determined by Zeta potential particle size analyzer;The average entrapment efficiency and drug loading were determined by glucose gel microcolumn method;In vitro release test was performed by dialysis.The stability of teniposide was investigated by high temperature test and long-term stability test.4.To establish a method for in vivo analysis of UPLC-MS/MS teniposide.The plasma concentration of teniposide in rats was determined by oral administration of teniposide SLN and the control drug.The plasma concentration-time curve of teniposide was drawn.Results:1.In this paper,a HPLC quantitative analysis method with good reproducibility and accurate results was established,which can be used to evaluate the quality of teniposide SLN.The physicochemical properties showed that teniposide was poor in water solubility and highly fat soluble.2.The ultrasonic dispersion method was used as the preparation method,and the preparation technology was as follows:the colostrum should be stirred at 80?for 15minutes,and the colostrums were treated with 400W ultrasound for 4min in a cell grinder.The optimum prescription was determined by orthogonal test:teniposide 25mg,glycerol monostearate 500mg,soybean lecithin 1000mg,Poloxamer 188 800mg dissolved in 80mL water to make teniposide SLN of 50mL.3.The quality evaluation and preliminary stability of teniposide were studied.The results showed that the shape of SLN particles was round and the particle size of teniposide was normal distribution in 50120nm.The mean particle size was 90.43±13.06 nm,the mean Zeta potential was-32.45±7.36 mV,the mean entrapment efficiency was 84.68±0.76%,and the average drug loading was 0.91±0.01%.The cumulative release of teniposide at 24h in pH6.8 and was 81.18%and 69.25%,respectively,and the vitro release was in accordance with the Weibull kinetic model;The average pH was 6.71±0.16.The entrapment efficiency and drug loading amount of teniposide SLN decreased significantly after 10 days'storage at high temperature,and remained unstable at room temperature for 3 months,but there was no significant change in entrapment efficiency and drug loading at 4?for 3 months.4.A method for quantitative analysis of UPLC-MS/MS teniposide in vivo was established with strong specificity,high sensitivity and good repeatability.The maximum peak concentrations of SLN and control drugs were 557ng·mL-1and 125ng·mL-1,respectively.The AUC of TS-SLN was 7.83 times higher than that of the control.The peak time was 2h and 0.5h,respectively.Conclusion:The results of high temperature test and long-term stability test show that the SLN of teniposide is unstable and easy to leak under high temperature,and the stability is good at4?for 3 months.In vitro release results showed that teniposide SLN was effective in simulated gastrointestinal environment.The results of pharmacokinetics showed that teniposide SLN had a certain sustained release effect compared with teniposide dimethyl sulfoxide solution,and could improve the bioavailability of teniposide.In conclusion,the preparation of teniposide SLN is stable and the oral bioavailability is improved.It is a promising drug delivery preparation for teniposide. |
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