本文選題：鬼臼毒素 + 納米脂質(zhì)載體��； 參考：《南方醫(yī)科大學(xué)》2017年碩士論文

【摘要】：研究背景鬼臼毒素(podophyllotoxin,POD)是從足葉草及八角蓮的根莖中提取的一種具有顯著抗病毒和抗腫瘤作用的天然活性木脂素。1990年WHO將鬼臼毒素酊劑(podophyllotoxin tincture,POD-T)外用作為治療生殖器疣的一線治療方案。然而,POD-T對生殖道黏膜刺激性大,使宮頸局部組織感染風(fēng)險增加,且容易被吸收中毒,故不適合用于女性宮頸尖銳濕疣(condyloma acuminatum,CA)的治療。20世紀以來,納米脂質(zhì)載體作為納米制劑新劑型已廣泛應(yīng)用于臨床研究,在生殖道黏膜給藥中具有較好的應(yīng)用前景。研究目的自制0.5%POD-NLC并檢測其理化特性。建立西藏小型豬宮頸給藥模型,以POD-酊劑為對照組,探討其對小型豬宮頸黏膜的刺激性及系統(tǒng)毒性,進一步評價其安全性。材料與方法1、采用改良乳化蒸發(fā)-低溫固化法,自制0.5%POD-NLC�？疾�0.5%POD-NLC外觀、粒徑、包封率及微觀形態(tài)。2、選用不同劑量0.5%POD-NLC作為實驗組,0.5%POD-T作陽性對照,觀察宮頸黏膜的肉眼及病理改變;LUMINEX檢測各實驗組中宮頸分泌物IL-1β、IL-6、IL-8 的濃度。3、選用0.5%POD-NLC及不同濃度POD-T(0.5%,1%,2%),分別于小型豬宮頸給藥2h,4h,6h,8h,10h后檢測宮頸分泌物、宮頸黏膜組織POD濃度,評估0.5%POD-NLC的體內(nèi)代謝規(guī)律。4、將不同劑量藥物經(jīng)小型豬宮頸黏膜給藥,分別檢測給藥后2h、4h、6h、8h、10h血藥濃度,分析0.5%POD-NLC經(jīng)小型豬宮頸黏膜給藥后血液中POD濃度變化,評估系統(tǒng)安全性。5、經(jīng)宮頸黏膜給藥后予小型豬前腔靜脈取血,采用全自動生化儀測定各類生化指標;全自動血細胞分析儀測定各類血細胞數(shù)及血紅蛋白含量,評估POD-NLC經(jīng)小型豬宮頸黏膜給藥后其血液生理生化指標改變。6、采用SPSS20.0(PASW)進行數(shù)據(jù)統(tǒng)計、描述與分析,數(shù)據(jù)以X±S表示。P0.05代表組間比較具有統(tǒng)計學(xué)差異。結(jié)果與分析1、成功制備0.5%POD-NLC,外觀為質(zhì)地均勻半透明膠狀乳劑。馬爾文型粒徑分析儀檢測POD-NLC粒徑為178.5±20nm,包封率為(75.7±0.44)%,電鏡掃描分析儀顯示POD-NLC呈規(guī)則圓形及類圓形,分布均勻一致。2、小型豬宮頸黏膜刺激性評分結(jié)果顯示,POD-T組總分值顯著高于同等劑量POD-NLC組,差異具有統(tǒng)計學(xué)意義(p=0.001)。POD-NLC大劑量組總分值顯著高于POD-NLC小劑量組,而生理鹽水(NS)組總分值較POD-NLC小劑量組略低,無顯著差異(p=0.092)。小型豬宮頸分泌物各因子濃度檢測結(jié)果提示,POD-NLC小劑量組IL-1β、IL-6、IL-8濃度顯著低于POD-NLC大劑量組(p0.01),而與NS組相比無明顯差異(p0.05)。POD-T組各因子濃度較POD-NLC大劑量組升高,差異具有統(tǒng)計學(xué)意義(p0.05)。3、在相同給藥時間內(nèi),0.5%POD-NLC組宮頸黏液中POD濃度均高于0.5%POD-T組(p0.05)。0.5%POD-T組宮頸黏膜組織中藥物濃度最高峰值出現(xiàn)在給藥后4h,隨后快速下降。給藥1Oh內(nèi),0.5%POD-NLC組黏膜中藥物濃度呈緩慢持續(xù)升高,未見明顯峰值;至給藥10h,0.5%POD-NLC組黏膜組織中藥物濃度開始高于0.5%POD-T組。4、宮頸給藥1ml時,0.5%POD-NLC組未能測及POD血藥濃度;0.5%POD-T組血藥濃度最高峰值出現(xiàn)在給藥后4h,并于給藥后10h內(nèi)呈低濃度持續(xù)出現(xiàn)。宮頸給藥2ml時,0.5%POD-T組血藥濃度顯著高于0.5%POD-NLC組,差異具有顯著意義(P0.05),0.5%POD-NLC組血藥濃度變化平緩,未見明顯峰值,給藥10h后血藥濃度未能測及。5、小型豬經(jīng)POD-NLC、POD-T宮頸黏膜給藥后,ALT、AST平均測定值均較給藥前略高,但差異無統(tǒng)計學(xué)意義(p0.05)。各劑量組給藥后白細胞測定值均較給藥略高,但差異無統(tǒng)計學(xué)意義(p0.05)。0.5%POD-NLC(2ml)經(jīng)小型豬宮頸黏膜給藥后,未見明顯系統(tǒng)毒性。結(jié)論本研究證實自制POD-NLC具有粒徑小、穩(wěn)定性好、包封率高等特點。POD-NLC經(jīng)小型豬宮頸給藥后局部刺激性小,同時可長時間滯留于宮頸分泌物中,并于宮頸黏膜組織中持續(xù)緩慢釋藥;常規(guī)治療劑量POD-NLC對宮頸黏膜刺激性小,且經(jīng)黏膜吸收量少,具有較好的系統(tǒng)安全性。
[Abstract]:Background podophyllotoxin (POD) is a natural active lignan, extracted from the rhizomes of podocyte and octagonal lotus, is a first-line treatment for the treatment of genital warts by using podophyllotoxin tincture (POD-T) as a first-line treatment for genital warts by.1990 WHO, which has a significant antiviral and anti-tumor effect. The mucosal irritation of the mucous membrane is large, the risk of local tissue infection of the cervix increases, and it is easily absorbed and poisoned, so it is not suitable for the treatment of condyloma acuminatum (CA) in the female cervix of the cervix for.20 century. The nano lipid carrier has been widely used in clinical research as a new dosage form of nanoscale preparation. The purpose of this study was to study the physical and chemical properties of the self-made 0.5%POD-NLC and to establish the physical and chemical properties of the cervix in Tibet miniature pigs. With the POD- tincture as the control group, the irritation and systemic toxicity of the cervix on the cervix mucosa of the miniature pig was discussed. The material and method 1, the modified emulsification evaporation low temperature curing method and the self-made 0.5%POD-NLC. were used. The 0.5%POD-NLC appearance, particle size, encapsulation rate and Micromorphology.2 were investigated, and different doses of 0.5%POD-NLC were selected as the experimental group, and 0.5%POD-T was used as the positive control to observe the naked eye and pathological changes of the cervical mucosa; LUMINEX was used to detect the IL-1 beta, IL-6, IL-8 concentration.3 in the experimental groups, and 0.5%POD-NLC and POD-T (0.5%, 1%, 2%), respectively, respectively. 2H, 4h, 6h, 8h, 10h were given to the cervix of a small pig to detect the cervical secretion and the concentration of POD in the cervical mucosa of the cervix, and to evaluate the metabolism of 0.5%POD-NLC in the body,.4. The drug was given at different doses of the cervix of the cervix of the small pig. The concentration of 2h, 4h, 6h, 8h, and the concentration of the blood were measured. Degree changes, evaluate the safety of the system.5. After the cervix mucosa was administered to the small pig's anterior vena cava, all kinds of biochemical indexes were measured by an automatic biochemical analyzer. The total number of blood cells and hemoglobin content were measured by the automatic blood cell analyzer. The blood physiological and biochemical indexes of POD-NLC after the administration of the cervix mucous membrane of the small pigs were changed.6. SPSS20.0 (PASW) data statistics, description and analysis, the data is X + S to indicate that.P0.05 represents a statistical difference between groups. Results and analysis 1, a successful preparation of 0.5%POD-NLC, the appearance of a homogeneous semitransparent gelatinous emulsion. The Malvin particle size analyzer is 178.5 + 20nm, the encapsulation rate is (75.7 + 0.44)%, SEM scanning The analyzer showed that POD-NLC was round and round, and the distribution of.2 was uniform and uniform. The results of cervical mucosa irritation of small pigs showed that the total score of POD-T group was significantly higher than that of the same dose POD-NLC group. The difference was statistically significant (p=0.001) the total score of.POD-NLC large dose group was significantly higher than that of the POD-NLC small dose group, while the total score of the normal saline (NS) group was significantly higher than that of the POD-NLC group. Compared with the POD-NLC small dose group, there was no significant difference (p=0.092). The results showed that the concentration of IL-1 beta, IL-6 and IL-8 in the POD-NLC small dose group was significantly lower than the POD-NLC large dose group (P0.01), but there was no significant difference between the NS group and the NS group (P0.05).POD-T group (P0.05).POD-T group. Statistical significance (P0.05).3, in the same time of administration, the concentration of POD in the cervical mucus in group 0.5%POD-NLC was higher than that in group 0.5%POD-T (P0.05) the highest concentration of drug concentration in the cervical mucous tissue of group.0.5%POD-T was found after the administration of 4h, and then decreased rapidly. In the drug 1Oh, the drug concentration in the mucous membrane of the 0.5%POD-NLC group increased slowly and continuously, and no obvious peak was found. When the drug was given 10h, the drug concentration in the 0.5%POD-NLC group began to be higher than that of the 0.5%POD-T group.4, and when the cervix was given 1ml, the 0.5%POD-NLC group failed to measure the concentration of POD; the highest peak value of the serum concentration in 0.5%POD-T group appeared at 4h after the administration, and the low concentration of the 10h was low in 10h after administration. The concentration of the blood drug in the 0.5%POD-T group was significant when the cervix was administered 2ml. Higher than 0.5%POD-NLC group, the difference was significant (P0.05), the blood drug concentration in group 0.5%POD-NLC was slow and no obvious peak, and the concentration of blood drug after 10h was not measured and.5 was not measured. After POD-NLC, POD-T cervix mucosa was given, ALT and AST mean values were slightly higher than those before administration, but the difference was not statistically significant (P0.05). The value of leucocyte was slightly higher than that of the drug, but the difference was not statistically significant (P0.05).0.5%POD-NLC (2ml) had no obvious systemic toxicity after the small pig cervix mucous membrane. Conclusion this study confirmed that the self-made POD-NLC has small size, good stability and high encapsulation efficiency, and.POD-NLC has a small local irritation after the administration of the cervix of a small pig, and it can be long at the same time. Time was delayed in cervix secretion and sustained slow release in cervical mucosa. The routine treatment dose of POD-NLC was less irritant to cervical mucosa and less mucosal absorption, and had better system safety.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.33

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