【摘要】：泊沙康唑是第二代三唑類抗真菌藥物,抗菌譜廣,不良反應(yīng)較小,而且對接合菌病、鐮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、油中均難溶,很大程度上限制了其在臨床上的應(yīng)用。目前上市的泊沙康唑注射液采用環(huán)糊精包合來提高藥物溶解度,制備工藝較復(fù)雜。本實驗將泊沙康唑制備為磷脂復(fù)合物后再進(jìn)一步制備為亞微乳,有效解決了藥物溶解度的問題,且得到的泊沙康唑注射劑穩(wěn)定性好、制備工藝簡單易行。本實驗首先建立了泊沙康唑原料藥以及亞微乳中泊沙康唑的含量測定方法。其次,以泊沙康唑的含量為評價指標(biāo),在單因素考察的基礎(chǔ)上通過正交試驗優(yōu)化泊沙康唑磷脂復(fù)合物處方及制備工藝。然后進(jìn)一步制備泊沙康唑亞微乳,以包封率為評價指標(biāo),在單因素考察基礎(chǔ)上進(jìn)行正交試驗優(yōu)化,最終確定最優(yōu)處方及工藝。為了提高本產(chǎn)品產(chǎn)業(yè)化可行性,根據(jù)國內(nèi)外亞微乳制劑的研究情況,本實驗嘗試以一種新的載藥方式制備泊沙康唑亞微乳,即利用SolEmuls?技術(shù),以直接載藥的方式制備泊沙康唑亞微乳。按上述相同的考察方式,篩選直接載藥泊沙康唑亞微乳的最優(yōu)處方及制備工藝。兩種方式制備的泊沙康唑亞微乳的理化性質(zhì)如下,以磷脂復(fù)合物形式制備的泊沙康唑亞微乳劑,其pH約為7.01,平均粒徑為0.186μm,Zeta電位為-33.12m V,含量為98.12%,包封率為91.41%,滲透壓為302mOsmol/L;而直接載藥方式制備的泊沙康唑亞微乳的pH約為7.03,平均粒徑為0.225μm,Zeta電位為-30.86mV,含量為96.72%,包封率為84.70%,滲透壓為314mOsmol/L。分別考察上述兩種方法制備的泊沙康唑亞微乳穩(wěn)定性,實驗結(jié)果表明其對高溫敏感,應(yīng)置于陰涼處保存,在初步穩(wěn)定性試驗中放樣3個月,其理化性質(zhì)均符合質(zhì)量要求,且以泊沙康唑磷脂復(fù)合物為載體的亞微乳的穩(wěn)定性比直接載藥制備的泊沙康唑亞微乳更好。綜上所述,本實驗成功的以磷脂復(fù)合物形式制備了泊沙康唑亞微乳劑,所制備的亞微乳質(zhì)量較好,工藝簡單。而直接載藥制得的泊沙康唑亞微乳,其含量及包封率還有待提升,值得進(jìn)一步開發(fā)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.
【學(xué)位授予單位】：成都學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943

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