泊沙康唑亚微乳制剂的制备及其质量研究

发布时间：2018-10-18 06:38

【摘要】：泊沙康唑是第二代三唑类抗真菌药物,抗菌谱广,不良反应较小,而且对接合菌病、镰刀菌病和球孢子菌病等真菌疾病有效。但由于泊沙康唑在水、油中均难溶,很大程度上限制了其在临床上的应用。目前上市的泊沙康唑注射液采用环糊精包合来提高药物溶解度,制备工艺较复杂。本实验将泊沙康唑制备为磷脂复合物后再进一步制备为亚微乳,有效解决了药物溶解度的问题,且得到的泊沙康唑注射剂稳定性好、制备工艺简单易行。本实验首先建立了泊沙康唑原料药以及亚微乳中泊沙康唑的含量测定方法。其次,以泊沙康唑的含量为评价指标,在单因素考察的基础上通过正交试验优化泊沙康唑磷脂复合物处方及制备工艺。然后进一步制备泊沙康唑亚微乳,以包封率为评价指标,在单因素考察基础上进行正交试验优化,最终确定最优处方及工艺。为了提高本产品产业化可行性,根据国内外亚微乳制剂的研究情况,本实验尝试以一种新的载药方式制备泊沙康唑亚微乳,即利用SolEmuls?技术,以直接载药的方式制备泊沙康唑亚微乳。按上述相同的考察方式,筛选直接载药泊沙康唑亚微乳的最优处方及制备工艺。两种方式制备的泊沙康唑亚微乳的理化性质如下,以磷脂复合物形式制备的泊沙康唑亚微乳剂,其pH约为7.01,平均粒径为0.186μm,Zeta电位为-33.12m V,含量为98.12%,包封率为91.41%,渗透压为302mOsmol/L;而直接载药方式制备的泊沙康唑亚微乳的pH约为7.03,平均粒径为0.225μm,Zeta电位为-30.86mV,含量为96.72%,包封率为84.70%,渗透压为314mOsmol/L。分别考察上述两种方法制备的泊沙康唑亚微乳稳定性,实验结果表明其对高温敏感,应置于阴凉处保存,在初步稳定性试验中放样3个月,其理化性质均符合质量要求,且以泊沙康唑磷脂复合物为载体的亚微乳的稳定性比直接载药制备的泊沙康唑亚微乳更好。综上所述,本实验成功的以磷脂复合物形式制备了泊沙康唑亚微乳剂,所制备的亚微乳质量较好,工艺简单。而直接载药制得的泊沙康唑亚微乳,其含量及包封率还有待提升,值得进一步开发研究。
[Abstract]:Posaconazole is a second generation triazole antifungal drug with wide antimicrobial spectrum and less adverse reactions. It is also effective against fungal diseases such as conjugate disease, Fusarium disease and globocystis. However, the insolubility of posaconazole in water and oil limits its clinical application to a great extent. Cyclodextrin inclusion was used to improve the solubility of posaconazole injection. In this experiment, posaconazole was prepared as phospholipid complex and then further prepared as sub-microemulsion, which effectively solved the problem of drug solubility. The obtained posaconazole injection was stable and the preparation process was simple and feasible. In this experiment, a method for the determination of posaconazole in bulk drug and submicron emulsion was established. Secondly, the formulation and preparation process of posaconazole phospholipid complex were optimized by orthogonal test on the basis of single factor investigation with the content of posaconazole as the evaluation index. Then the posaconazole microemulsion was further prepared. The encapsulation efficiency was taken as the evaluation index and the orthogonal experiment was carried out on the basis of single factor investigation to determine the optimal formulation and process. In order to improve the feasibility of industrialization of the product, according to the research situation of submicroemulsion at home and abroad, this experiment attempts to prepare posaconazole microemulsion by a new drug loading method, that is, using SolEmuls? Technology for preparation of posaconazole microemulsion by direct drug loading. According to the same investigation method above, the optimum formulation and preparation technology of posaconazole microemulsion with direct drug loading were selected. The physicochemical properties of posaconazole microemulsion prepared by two methods are as follows: posaconazole microemulsion prepared in the form of phospholipid complex. The pH was about 7.01, the average particle size was -33.12mV, the entrapment efficiency was 91.41m, the osmotic pressure was 302mOsmoll / L, the pH of posaconazole microemulsion was about 7.03, the average particle size was -30.86mV, the entrapment efficiency was 84.70m, the osmotic pressure was 314mOsmolL / L, the average particle size was -30.86mV, the entrapment efficiency was 84.70mV, and the osmotic pressure was 314mOsmolL / L. The stability of posaconazole microemulsion prepared by the two methods mentioned above was investigated. The results showed that the emulsion was sensitive to high temperature and should be kept in the shade. The physicochemical properties of the microemulsion were in accordance with the quality requirements during the initial stability test for 3 months. The stability of submicroemulsion with posaconazole phospholipid complex as carrier was better than that of posaconazole microemulsion prepared by direct drug loading. In conclusion, posaconazole microemulsion was successfully prepared in the form of phospholipid complex. However, the content and encapsulation efficiency of posaconazole microemulsion prepared by direct drug loading need to be improved, which is worthy of further study.
【学位授予单位】：成都学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

【参考文献】