介质研磨法制备他达拉非纳米混悬液研究

目的:采用介质研磨法制备他达拉非纳米混悬液,以提高他达拉非的溶出度和生物利用度。方法:以粒径、多分散指数(PDI)、Zeta电位和物理稳定性为评价指标,优化处方和工艺参数;采用扫描电镜(SEM)、X-射线粉末衍射法(XRPD)、差示扫描量热法(DSC)对样品进行表征,HPLC法测定他达拉非纳米混悬液体外溶出度,UPLC-MS/MS法检测大鼠中他达拉非的血药浓度。结果:他达拉非纳米混悬液最优处方为他达拉非质量分数2%、HPC 1%和SDS 0.1%;最优工艺为粒径0.1 mm氧化锆珠,转速3 000 r·min^-1,研磨时间30 min。制备的他达拉非纳米混悬液PDI为0.173±0.013,Zeta电位为(－22.6±0.4) mV,纳米颗粒为棒状结晶,粒径为(218.2±1.3) nm,分布均匀,晶型稳定;体外溶出度10 min内达到99%,大鼠体内生物利用度为原料药的4.01倍,在室温条件下放置6个月稳定性良好。结论:介质研磨法制备他达拉非纳米混悬液方法简单,产品稳定性好,能显著提高他达拉非溶出度和生物利用度。

Preparation of tadalafil nanosuspension by wet media milling

OBJECTIVE To prepare tadalafil nanosuspension by wet media milling to enhance the dissolution and bioavailability.METHODS The particle size, polydispersity index (PDI), Zeta potential and physical stability were adopted to screen the optimal formulation and method. The optimized nanosuspension was characterized by scanning electron microscope (SEM), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The dissolution profile of tadalafil nanosuspension was investigated by HPLC, and the plasma concentration of tadalafil in rats were determined by UPLC-MS/MS.RESULTS The optimal formulation of tadalafil nanosuspension contained tadalafil 2%, HPC 1% and SDS 0.1%. The optimal method included zirconia beads size of 0.1 mm, grinding time of 30 min and stirrer speed of 3 000 r·min^-1. The average PDI of tadalafil nanosuspension was 0.173±0.013, and the average Zeta potential was (-22.6±0.4) mV. The nanoparticles were rod-like crystals with the average particle size of (218.2±1.3) nm, which were uniform in distribution and had no change in crystalline state. Accumulative dissolution of tadalafil nanosuspension was 99% within 10 min. The bioavailability of tadalafil nanosuspension was 4.01 times higher than that of the bulk drug. Tadalafil nanosuspension remained stable after stored at room temperature for 6 months.CONCLUSION The preparation method and formulation of tadalafil nanosuspension are simple. Tadalafil nanosuspension shows good stability, fast dissolution and high bioavailability.