本文選題：姜黃素 + 負電荷�。� 參考：《北京中醫(yī)藥大學》2017年碩士論文

【摘要】：目的:利用結腸炎癥部位陽離子蛋白表達增高,結腸炎癥部位帶正電的特點,構建負電荷的姜黃素炎癥靶向自微乳給藥系統(tǒng)(NC-CUR-SMEDDS)。對自微乳進行初步質量評價,并對自微乳的體外靶向性和體內藥效學進行探討,為炎癥靶向制劑的開發(fā)提供新思路,為實現潰瘍性結腸炎的炎癥靶向治療提供理論和數據基礎。方法:在前期姜黃素自微乳(CUR-SMEDDS)的研究基礎上,以姜黃素為模型藥物,以乳劑的粒徑、Zeta電位、包封率和載藥量為評價指標,通過單因素試驗篩選電荷調節(jié)劑的最佳用量,制備NC-CUR-SMEDDS。通過觀察微乳外觀和微觀形態(tài)并測定其粒徑、Zeta電位、包封率及載藥量對其進行質量評價。并采用5%葡聚糖硫酸鈉(DSS)造成BALB/c小鼠急性潰瘍性結腸炎模型,通過間接體內(ex vivo)實驗、小動物在體熒光檢測技術考察自微乳在炎癥部位的黏附情況,評價其體外炎癥靶向效果。同時,采用保留灌腸的給藥方式,將藥物直接靶向于結腸部位,以5-氨基水楊酸(5-ASA)為陽性對照藥,非炎癥靶向自微乳(CUR-SMEDDS)作為對照組,以疾病活動指數評分(DAI)、結腸長度、結腸黏膜組織病理學評分、結腸組織中丙二醛(MDA)含量、髓過氧化物酶(MPO)活性、白細胞介素-6(IL-6)和腫瘤壞死因子-α(TNF-α)的含量為評價指標,評價NC-CUR-SMEDDS體內靶向治療效果。結果:以丁二酸二辛酯磺酸鈉為最佳電荷調節(jié)劑,單因素實驗篩選得到NC-CUR-SMEDDS的最優(yōu)處方:聚氧乙烯氫化蓖麻油RH40(CremophorRH40):二乙二醇單乙基醚HP(Transcutol HP):丙二醇單辛酸酯90(Capryol 90):丁二酸二辛酯磺酸鈉(Docusate Sodium)=6:3:1:0.4,所形成的微乳 Zeta 電位可以達到-43.43±0.29mV,外觀澄清、透明,粒徑分布均勻,平均粒徑為(14.08±0.082)nm,姜黃素載藥量為37.98 mg·g-1,包封率為99.22%。間接體內(ex vivo)黏附實驗結果表明,NC-CUR-SMEDDS(Zeta電位為-43.43±0.29mV)在DSS誘導小鼠UC模型結腸炎癥部位體現出良好的炎癥靶向作用,熒光半定量結果顯示,NC-CUR-SMEDDS在炎癥部位的吸附是正常組織部位的2.8倍,具有顯著性差異(P0.0001);同時,NC-CUR-SMEDDS與CUR-SMEDDS(Zeta電位為-6.28±0.86mV)相比,NC-CUR-SMEDDS在炎癥部位吸附較多,是CUR-SMEDDS的1.5倍(P0.01),體現出很好的炎癥靶向作用。通過保留灌腸結腸定向給藥,NC-CUR-SMEDDS對DSS誘導的小鼠UC模型具有明顯的改善作用,能夠減輕小鼠的臨床癥狀,包括精神活動狀態(tài)、便血、體重等。同時,NC-CUR-SMEDDS對于小鼠結腸組織充血、水腫、潰瘍等癥狀具有不同程度的緩解作用,病理組織學檢查結果顯示,NC-CUR-SMEDDS組炎癥細胞浸潤減少,隱窩結構相對完整,杯狀細胞存在較多。生化指標檢測結果顯示NC-CUR-SMEDDS顯著降低小鼠結腸組織中MPO的活性以及MDA、TNF-α和IL-6的含量,治療作用與陽性對照組接近。結論:本課題通過改變粒子表面電性,構建的姜黃素負電荷自微乳給藥系統(tǒng)包封率高,粒徑分布均勻,實現了姜黃素自微乳在結腸炎癥部位的特異性靶向,增加姜黃素在潰瘍性結腸炎炎性細胞表面的藥物濃度,為炎癥靶向制劑系統(tǒng)提供了新思路和新方法。
[Abstract]:Objective: using increased colitis site cationic protein expression, characteristics of colitis parts of positive, negative charge of construction inflammation targeted curcumin self microemulsifying drug delivery system (NC-CUR-SMEDDS). The preliminary evaluation of the quality of self microemulsion, and the in vitro self microemulsion and pharmacodynamics in vivo to explore, for targeting inflammation preparation The development of new ideas, and to provide theoretical foundation for the realization of the target data of inflammation of ulcerative colitis treatment. Methods: in the early stage of curcumin self microemulsion (CUR-SMEDDS) based on the research, using curcumin as a model drug, the emulsion particle size, Zeta potential, entrapment efficiency and drug loading as evaluation index, adjusted by the single factor screening test charge The best dosage of agent, the preparation of NC-CUR-SMEDDS. by observing the appearance and microstructure of microemulsion and determine the particle size, Zeta potential, encapsulation efficiency and drug loading to evaluate its quality. And the use of 5% dextran sulfate sodium (DSS) caused by acute ulcerative colitis in mice model of BALB/c (ex, vivo) by ex vivo experiments, small animal in vivo fluorescence detection Investigation of self microemulsion at sites of inflammation adhesion, inflammation and evaluate its in vitro targeting effect. At the same time, the retention enema administration, the drug directly targeted to the colon, with 5- amino salicylic acid (5-ASA) as a positive control medicine, non inflammatory target self microemulsion (CUR-SMEDDS) as the control group, the disease activity index (DAI),. The length of intestine, colon mucosa pathological study score, malondialdehyde (MDA) content in colon tissue, myeloperoxidase (MPO) activity of interleukin -6 (IL-6) and tumor necrosis factor alpha (TNF- alpha) content as the evaluation index, evaluation of NC-CUR-SMEDDS targeting therapy in vivo. Results: two succinic acid ester is the best sodium charge regulator, single The experimental factors screened the optimal prescription of NC-CUR-SMEDDS: Cremophor RH40 (CremophorRH40): diethylene glycol monoethyl ether HP (Transcutol HP): propylene glycol monocaprylate 90 (Capryol 90) two: succinic acid octyl sulfonic acid sodium (Docusate Sodium) =6:3:1: 0.4, Zeta potential microemulsion formed can reach -43.43 + 0.29mV. The appearance of Weicheng Clear, transparent, uniform particle size distribution and average particle size (14.08 + 0.082) nm, curcumin loading was 37.98 Mg - g-1, the encapsulation rate of 99.22%. (ex vivo) ex vivo adhesion experiment results show that NC-CUR-SMEDDS (Zeta potential of -43.43 + 0.29mV) in DSS induced colitis in mice UC model of parts good inflammation targeting, semi quantitative fluorescence The amount of results showed that the adsorption of NC-CUR-SMEDDS at the site of inflammation is 2.8 times of normal tissues, with a significant difference (P0.0001); at the same time, NC-CUR-SMEDDS and CUR-SMEDDS (Zeta potential of -6.28 + 0.86mV) compared to NC-CUR-SMEDDS at the site of inflammation absorb more, is 1.5 times that of CUR-SMEDDS (P0.01), reflecting the good target of inflammation through to. Retention enema colon targeted delivery, NC-CUR-SMEDDS has obvious effect on mouse UC model induced by DSS, can alleviate clinical symptoms in mice, including mental activity, stool, weight and so on. At the same time, NC-CUR-SMEDDS in colon tissue of mice with hyperemia, edema, ulcers and other symptoms have different degrees of ease, histopathology Test results show that the decrease of NC-CUR-SMEDDS group inflammatory cell infiltration and crypt structure is relatively complete, there are many goblet cells. Biochemical test results showed that the NC-CUR-SMEDDS decreased significantly in mice colonic tissue MPO activity and MDA content of TNF- alpha and IL-6, the treatment effect and the positive control group. Conclusion: according to the change of particle Sub surface electricity, negative charge of curcumin self microemulsifying drug delivery system with high encapsulation efficiency, uniform particle size distribution, the specific target of curcumin self microemulsion in colitis parts to increase drug concentration, the effect of curcumin on ulcerative colonic inflammatory cell surface, inflammatory target provides new ideas and new methods to the preparation system.
【學位授予單位】：北京中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R283.6

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