Preparation And Pharmacodynamics Of Sirolimus New Drug Preparations

As the works of organ transplant developed,it became more important to exploit an immunosuppressive agent with high efficiency and low toxicity. Sirolimus^[1] was a novel antirejection drug with potent immunosuppressive a ctivity, which might potentially be used as a widespread drug for renal thans plant patients^[2].In October,1999, Sirolimus was firstly come into the Amecric an market named Rapamune by American Home Products^[3].Afterwards,it entere d into Britain ,Germany, Danmark,Norway,Sweden,Switzerland market at the t ime of March,2000.The major dosage form of sirolimus appeared in foreign c ountries was oral suspension, with sirolimus concentration at 1mg · mL^-1,and i ncluded two standards(60 mL, 150 mL,respectively).The sirolimus oral suspen sion with 1 year of validity had to sealed to avoid light and stored at 4-8℃, moreover,it was hard to quantification when the patients administrated orally. Therefore,the sirolimus nanocrystal was developed by Elan in 2002.Briefly,the sirolimus was added to the solution with Poloxamer contained ,the suspensio n was then milled by ball mill at the condition of 50% critical rate for 5 da ys, the obtained nanocrystal appeared below 400 nm in diameter.Compared with sirolimus oral suspension,the bioavailability of nanocrystal increased about1 fold.The results suggested that the nano-technology was in great value forwater poor soluble drugs preparation.In present study,the sirolimus nanoparticles were prepared by High press ure homogenisation.The optimized parameters,such as the type of surfactant, t he ritio of organic phase,the parameter of homogenisation process ,were chos en for producing nanoparticles .As a result,the size of nanoparticles was 191.5nm,and the zeta potential was -12.2 mv. By adding appropriate freeze-dryin g cryoprotectant to the nanoparticles suspension, the sirolimus nanoparticles p owders was obtained by low temperature freeze-drying technology .The result ant powders could be re-dispersed rapidly when mixed with water and form fine nanoparticles suspension as well.Finally,the sirolimus nanoparticles tabletswere prepared by direct press technology with optimized formulation and tec hnics.The quality evaluation results revealed that the sirolimus preparation obt ained in this study,not only had even sub-dosage,but also showed elevated sta bility and could be preserved at room temperature.To get the information of sirolimus nanoparticles tablets in vivo,the powd ers of sirolimus nanoparticles tablets were given orally to rat.Compared with liquid-liquid extraction ,a novel, reversed-phase high-performance liquid chrom atographic (HPLC) method was described for the analysis of sirolimus in wh ole blood with solid-phase extraction.The method was rapid,sensitive,accurate, specific,precise ,and linear over a range of 2.5⁶0 ngmL^.The lower limit ofquantification(LOD) was 2 ng-mL"1. The assay did not show interference pea ks from whole blood with sirolimus drug.In contrast to sirolimus oral suspens ion , the sirolimus nanoparticles obtained by nano-technology showed increase d absorption velocity when they were given orally to rat.In addition, the areaunder the concentration-time curve (AUC) of sirolimus nanoparticles was hi gher than that of sirolimus oral suspension with the same dosage.Obviously,th ese results indicate that the relative bioavailability of sirolimus nanoparticles was improved .