本文選題：貝伐單抗 + 膜聯(lián)蛋白A5脂質體�。� 參考：《新鄉(xiāng)醫(yī)學院》2017年碩士論文

【摘要】：背景目前,新生血管性眼病的發(fā)病率不斷上升。貝伐單抗是一種治療新生血管性眼病的單克隆抗體藥物。由于各種眼部屏障的存在,局部點眼治療無法在眼內到達有效濃度。目前臨床上采用玻璃體注射此類藥物來治療眼內新生血管性疾病。但多次玻璃體注射可能產生一些嚴重并發(fā)癥。近來研究發(fā)現(xiàn),采用膜聯(lián)蛋白A5脂質體作為載體可以使貝伐單抗穿過角膜的能力有較大的提高,具有成為對眼內新生血管性疾病進行無創(chuàng)性治療方法的潛力。因此,對貝伐單抗膜聯(lián)蛋白A5脂質體滴眼液在兔眼的藥物代謝動力學進行研究將會對臨床治療眼內新生血管性疾病能夠提供幫助。目的為減少眼部并發(fā)癥,提高藥物局部應用的眼內通透性,本研究通過制備一種新型貝伐單抗膜聯(lián)蛋白A5脂質體滴眼液,通過對實驗動物進行局部點眼,對其眼部藥動學進行研究,為臨床治療視網(wǎng)膜脈絡新生血管性疾病提供實驗基礎與理論依據(jù)。方法1.制備藥品:貝伐單抗來自購買的成品。貝伐單抗脂質體由脂質體微泡和貝伐單抗采用雙水化法制成。貝伐單抗膜聯(lián)蛋白A5脂質體由貝伐單抗脂質體加酶聯(lián)蛋白A5于攪拌器上低速旋轉制成。2.實驗動物分組:105只健康無眼病的新西蘭大白兔,不分雌雄,隨機數(shù)字表法分為實驗組、對照組1、對照組2,每組35只,每組再隨機分為7個亞組,每個亞組5只,分別對應給藥后的7個時間點(5min、15min、30min、1h、2h、4h、8h)。3.給藥及樣品采集:實驗組新西蘭大白兔單眼接受貝伐單抗膜聯(lián)蛋白A5脂質體局部點眼50μL;對照組1新西蘭大白兔單眼接受貝伐單抗脂質體局部點眼50μL;對照組2新西蘭大白兔單眼接受貝伐單抗局部點眼50μL。各組分別在給藥后預定時間點處死動物,摘取眼球,取房水及玻璃體、視網(wǎng)膜脈絡膜標本,備用。4.獲取藥代動力學參數(shù)及統(tǒng)計學分析:酶聯(lián)免疫吸附法計算各樣本濃度值。應用DAS 2.1.1軟件計算各個藥物代謝動力學參數(shù),擬合曲線。應用SPSS 19.0軟件進行統(tǒng)計分析,采用方差分析和LSD檢驗對數(shù)據(jù)進行統(tǒng)計學分析。結果1.各組實驗數(shù)據(jù)證明貝伐單抗膜聯(lián)蛋白A5脂質體在各個已測時間點的濃度明顯高于對照組1和對照組2(P0.05)。2.實驗組視網(wǎng)膜脈絡膜組織中的貝伐單抗?jié)舛雀哂隗w外貝伐單抗對hVEGF的IC50。結論貝伐單抗膜聯(lián)蛋白A5脂質體有望成為治療新生血管性眼病的新劑型,通過局部點眼的方式給藥從而避免眼內注射,減少并發(fā)癥。
[Abstract]:Background at present, the incidence of neovascular ophthalmopathy is increasing. Bevacizumab is a monoclonal antibody drug for the treatment of neovascular ophthalmopathy. Due to the presence of various eye barriers, local eye therapy cannot reach the effective concentration in the eye. At present, vitreous injection is used to treat intraocular neovascularization. But multiple vitreous injections can lead to serious complications. Recently, it has been found that the ability of bevacizumab to penetrate the cornea can be improved by using A5 liposome as carrier, and it has the potential to be a non-invasive therapy for intraocular neovascularization. Therefore, the study of pharmacokinetics of bevacizumab A5 liposome eye drops in rabbit eyes will be helpful for the clinical treatment of intraocular neovascularization. Objective to reduce the ocular complications and improve the intraocular permeability of the drug, we prepared a new type of bevacizumab membrane binding protein A 5 liposome eye drops, and made a local eye spot on the experimental animals by the preparation of a new type of bevacizumab A5 liposome eye drops. The study of ocular pharmacokinetics provides experimental and theoretical basis for the clinical treatment of retinal choroidal neovascularization. Method 1. Preparation of drugs: bevacizumab comes from the finished product purchased. The bevacizumab liposome was prepared by double hydration of liposome microbubbles and bevacizumab. The bevacizumab membrane linked protein A5 liposome was prepared from bevacizumab liposome and enzyme linked protein A5 by rotating at low speed on the agitator. The experimental animals were divided into 10 groups: 105 healthy New Zealand white rabbits without eye disease, male and female, randomly divided into experimental group, control group 1, control group 2, each group 35. Each group was randomly divided into 7 subgroups, 5 in each subgroup. The results showed that 7 time points after administration were 5 min ~ 15 min ~ 30 min ~ (-1) ~ 1 h ~ (-1) ~ 2 h ~ (-1) ~ 4 h ~ (8) h ~ (-1) ~ 8 h ~ (-1) ~ (3). Administration and sample collection: the experimental group New Zealand white rabbits received bevacizumab A5 liposome 50 渭 L locally; the control group 1 New Zealand white rabbit single eye received bevacizumab liposome 50 渭 L; control group 2 The local point of bevacizumab was 50 渭 L in single eye of blue white rabbit. The animals in each group were killed at a predetermined time point after administration, eyeball was removed, aqueous humor and vitreous body, retinal choroid specimen were taken, reserve. 4. The pharmacokinetic parameters and statistical analysis were obtained: enzyme linked immunosorbent assay (Elisa) was used to calculate the concentration of each sample. DAS 2.1.1 software was used to calculate the pharmacokinetic parameters and fit the curve. SPSS 19.0 software was used for statistical analysis, and ANOVA and LSD test were used for statistical analysis. Result 1. The experimental data showed that the concentration of bevacizumab A5 liposome at each time point was significantly higher than that of control group 1 and control group 2 (P0.05 路2). The concentration of bevacizumab in retinal choroid tissue of experimental group was higher than that of in vitro bevacizumab on hVEGF. Conclusion the bevacizumab A5 liposome is expected to be a new dosage form for the treatment of neovascular ophthalmopathy, which can avoid intraocular injection and reduce complications.
【學位授予單位】：新鄉(xiāng)醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R77

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