【作者】 刘文；

【导师】 孙伯旺；

【作者基本信息】 东南大学 ， 化学工程（专业学位）， 2021， 硕士

【摘要】 纳米混悬剂技术是解决药物难溶性问题最重要的手段之一,本课题以难溶性药物二丙酸倍他米松为原料,制备了二丙酸倍他米松纳米混悬剂,以提升二丙酸倍他米松的饱和溶解度、释放速率与药效,提高二丙酸倍他米松的相对生物利用度,减少刺激性和毒副作用。在处方前研究中,利用差示扫描量热法,X射线法粉末衍射法,傅里叶红外色谱,对药物活性成分,辅料,药物活性成分-辅料混合物进行了测定,确认了二丙酸倍他米松与所选择的辅料经物理混合后没有产生任何化学反应,因而本配方是一个稳定的制剂配方。通过实验建立了测定二丙酸倍他米松含量的高效液相色谱测定法。本课题研究了二丙酸倍他米松纳米混悬剂的配方和制备工艺,选择了微波辅助下的反溶剂沉淀法作为制备方法,通过调整转速、滴加时间、微波功率等工艺参数,优化了制备工艺。通过冷冻干燥法,对二丙酸倍他米松进行了固态化,延长了纳米混悬剂的有效保存时间。利用实验设计(Do E)的方法进行了处方筛选和用量优化,以纳米晶的粒径、ζ电位、多分散系数作为主要评价指标,确定了二丙酸倍他米松纳米混悬剂的最佳处方组成。在最佳配方与工艺参数下,再次制备了二丙酸倍他米松纳米混悬剂用于接下来的表征和测试。用扫描电镜对二丙酸倍他米松纳米晶的形态进行了表征,结果表明,二丙酸倍他米松纳米晶为规则矩形,边缘齐整,形貌均一,分布均匀,粒径约400 nm。使用激光粒度仪与Zeta电位仪测得二丙酸倍他米松纳米混悬剂的平均粒径为372.28 nm,PDI为0.2922,ζ电位为-25.08 m V。采用振动台法对二丙酸倍他米松纳米晶溶解度进行了测试。结果表明,二丙酸倍他米松纳米晶在水中的饱和溶解度约为原料药粉末的4倍。体外溶出度实验证明,二丙酸倍他米松纳米混悬剂在PBS溶液中快速释放,在60分钟内迅速溶解了约99.94%的二丙酸倍他米松,而未经加工的二丙酸倍他米松粉末则释放缓慢。我们根据ICH指导原则对制备的二丙酸倍他米松纳米混悬剂进行了加速稳定性研究,结果表明储存两个月后,二丙酸倍他米松纳米混悬剂的平均粒径仅上升到412.48 nm,并且API剩余率为99.3%。同时,我们也探索了微流体技术应用于制备二丙酸倍他米松纳米混悬剂的可能,以期望通过微流体技术提升混合效率来进一步提升二丙酸倍他米松纳米混悬剂的制备效率与产品性能的均一性,我们根据制备过程的需要设计了一种微通道撞击流反应器,并研究了反应器的微观混合性能。通过控制变量法对二丙酸倍他米松纳米混悬剂制备过程中的3个关键工艺参数进行了考察,确定了最佳的工艺参数。结果表明,经过操作条件与工艺参数的优化,微通道撞击流反应器展现出良好的微观混合效率,有效提升了产品制备的连续性、均一性。更多还原

【Abstract】 Nanocrystal technology is one of the most important means to solve the problem of drug insoluble.In this project,betamethasone dipropionate nanosuspension was prepared from the insoluble drug betamethasone dipropionate,in order to improve the saturated solubility,release rate and drug efficacy of betamethasone dipropionate,and improve the relative bioavailability of betamethasone dipropionate,Reduce irritation and side effects.In the pre-prescription study,the active ingredients,excipients and the mixture of active ingredients and excipients were determined by differential scanning calorimetry,X-ray diffraction and Fourier infrared chromatography.It was confirmed that there was no chemical reaction between betamethasone dipropionate and the selected excipients after physical mixing.Therefore,this formulation is a stable formulation.A HPLC method for the determination of betamethasone propionate was established.In this project,the formulation and preparation process of betamethasone dipropionate nanosuspension were studied.The microwave-assisted antisolvent precipitation method was selected as the preparation method.The preparation process was optimized by adjusting the speed,dropping time,microwave power and other process parameters.Betamethasone dipropionate was solidified by freeze-drying method,which extended the effective storage time of the nano suspension.Design of experiment(DOE)was used to optimize the formulation and dosage of betamethasone dipropionate nanosuspension ζ potential and polydispersity coefficient were used as the main evaluation indexes to determine the optimal formulation of nano suspension.Under the optimal formulation and process parameters,betamethasone dipropionate nanosuspension was prepared again for the next characterization and testing.The morphology of betamethasone dipropionate nanocrystals was characterized by scanning electron microscope(SEM).The results showed that betamethasone dipropionate nanocrystals were regular rectangle with neat edges,uniform morphology and uniform distribution,and the particle size was about 400 nm.The average particle size of betamethasone dipropionate nanosuspension were 372.28 nm and PDI was 0.2922,respectively,ζ potential was-25.08 m V.The saturated solubility of betamethasone dipropionate nanocrystals was compared with that of API by shaking table method.The results show that the saturated solubility of betamethasone dipropionate nanocrystals in water is about 4 times higher than that of betamethasone dipropionate powder.In vitro dissolution test showed that betamethasone dipropionate nanosuspension was rapidly released in PBS solution,and about99.94% of betamethasone dipropionate was rapidly dissolved in 60 minutes,while the unprocessed betamethasone dipropionate powder was slowly released.According to ICH guidelines,the accelerated stability of betamethasone dipropionate nanosuspension was studied.The results showed that the average particle size of betamethasone dipropionate nanosuspension only increased to412.48 nm after storage for two months,and the API residual rate was 99.3%.At the same time,we also explored the possibility of applying microfluidic technology to the preparation of betamethasone dipropionate nanosuspension,in order to improve the preparation efficiency and product performance uniformity of betamethasone dipropionate nanosuspension by improving the mixing efficiency through microfluidic technology,The micromixing performance of the reactor was also studied.The results show that the microchannel impinging stream reactor shows good micromixing efficiency through the optimization of operation conditions and process parameters.Three key process parameters in the preparation of betamethasone dipropionate nanosuspension were investigated by variable control method,and the best process parameters were determined.更多还原