本文選題：2-甲氧基雌二醇 + 2-ME可吸入微粒��； 參考：《鄭州大學(xué)》2014年碩士論文

【摘要】：2-甲氧基雌二醇(2-Methoxyestradiol,2-ME)是雌二醇的內(nèi)源性代謝產(chǎn)物，藥理活性研究表明其對多種癌細(xì)胞都有較好的作用效果，具有廣譜抗腫瘤作用。本實驗室之前對其口服制劑和注射劑進(jìn)行了廣泛研究，發(fā)現(xiàn)其口服吸收無規(guī)律，生物利用度低，注射劑在體內(nèi)代謝快，半衰期短，不能長時間維持有效的血藥濃度。因此積極探索其他的給藥方式，改變上述劑型所存在的缺點是極其必要的。干粉吸入劑是通過肺部給藥的制劑，其可避免肝臟的首過效應(yīng)，提高藥物的生物利用度，藥物在肺部的吸收起效亦較快，且能實現(xiàn)肺部靶向給藥，更有利于肺部疾病的治療。因此，本實驗擬將2-ME制成干粉吸入劑，探討其用于肺部給藥的可行性，為肺部腫瘤的治療開辟新劑型。 本文首先建立了2-ME干粉吸入劑的體外HPLC分析方法，經(jīng)方法學(xué)考察知，該分析方法的專屬性強(qiáng)，日內(nèi)、日間精密度分別為0.99%、1.06%，平均回收率為100.18%，均符合應(yīng)用HPLC分析法的規(guī)定，2-ME在0.2～40μg·ml-1的濃度范圍內(nèi)，濃度與峰面積的線性關(guān)系良好，所得回歸方程及相關(guān)系數(shù)分別為A=6×107C+106，r=0.9999，因此該方法適用于2-ME體外含量的測定分析。 其次，鑒于肺部可吸入微粒粒徑的最佳條件為1～5μm范圍內(nèi)，本實驗采用控制結(jié)晶法先制備了2-ME的可吸入微粒。通過對所制備微粒的外觀形態(tài)、粒徑大小及穩(wěn)定性的考察，篩選出2-ME微粒制備的最佳處方和工藝條件，分別為：2-ME為2.5mg·ml-1，泊洛沙姆為5mg·ml-1，轉(zhuǎn)速為1200r·min-1，無水乙醇與水的比例為1:3。用上述方法制備出2-ME微粒溶液后，再通過離心、再分散和冷凍干燥制備出2-ME可吸入微粒。 第三，以溶解性、粉末形態(tài)、引濕性、粒徑及其分布、水分含量、休止角、霧化特性、排空率及體外沉積性等粉體理化性質(zhì)及霧化特性為評價指標(biāo)，對2-ME干粉吸入劑制備的處方和工藝條件進(jìn)行研究，得到了2-ME干粉吸入劑制備的最優(yōu)處方和最佳制備工藝，分別為：①處方，2-ME與乳糖和亮氨酸的比為2:1:1，泊洛沙姆用量為其余三者用量的2%，然后將藥物和各輔料配制成一定濃度的混懸溶液，進(jìn)行噴霧干燥；②制備工藝，進(jìn)口溫度140℃，霧化進(jìn)氣量為470L·h-1，抽真空度為80%，供液速度為240ml·h-1，溶液濃度為1%。 第四，，測定了按最優(yōu)條件制備的干粉吸入劑的各項評價指標(biāo)，由實驗結(jié)果知，本品載體溶解性好，能迅速釋放出2-ME可吸入微粒；空氣動力學(xué)徑為2.72μm，適合肺部吸入給藥；有引濕性，水分含量為2.224±0.73%；外觀形態(tài)不規(guī)則，休止角為42.36°±1.42°，流動性稍差；霧化特性為B級，排空率90%，有效部位沉積量30%，均符合吸入給藥的要求。 第五，通過建立動物吸入給藥模型，對2-ME干粉吸入劑在大鼠體內(nèi)的初步藥代動力學(xué)和釋放行為進(jìn)行了考察。由實驗結(jié)果知2-ME干粉吸入劑在大鼠體內(nèi)的代謝為一室模型，分布半衰期(t1/2ka)為0.6±0.22h，消除半衰期(t1/2ke)為3.49±1.26h，AUC0-12h為2.95±1.24μg·ml-1·h，釋放行為符合Higuchi釋放模型，r=0.9945。 最后，對2-ME干粉吸入劑肺部給藥的安全性進(jìn)行了初步評價，知2-ME干粉吸入劑對肺部具有一定的刺激性，但無嚴(yán)重刺激性及成纖維細(xì)胞增生現(xiàn)象，表明2-ME干粉吸入劑的生物相容性和安全性能夠滿足肺部給藥的要求。
[Abstract]:2- methoxy estradiol (2-Methoxyestradiol, 2-ME) is an endogenous metabolite of estradiol. The pharmacological activity studies show that it has a good effect on various cancer cells and has broad spectrum antitumor effect. Before this laboratory, the oral preparation and injection were extensively studied, and its oral absorption was irregular and bioavailability was found. Low, the injection is fast in metabolism in the body, short half life and can not maintain effective blood concentration for a long time. Therefore, it is extremely necessary to actively explore other ways of administration and change the shortcomings of the above dosage forms. Dry powder inhalant is a preparation through the lung, which can avoid the first over effect of the liver, improve the bioavailability of the drug, and improve the bioavailability of the drug. The absorption of the substance in the lungs is also faster, and it can achieve the lung target drug delivery, which is more conducive to the treatment of lung disease. Therefore, this experiment is to make 2-ME into dry powder inhalant, to explore the feasibility of its use in lung administration, and to open up a new dosage form for the treatment of lung tumor.
In this paper, the method of HPLC analysis in vitro for 2-ME dry powder inhalant is first established. It is known by the jurisprudence that the analysis method has a strong specificity. The day interval is 0.99%, 1.06%, and the average recovery is 100.18%. It is in line with the application of HPLC analysis. 2-ME is in the concentration range of 0.2 ~ 40 mu g. The concentration and peak area are linear. The regression equation and correlation coefficient were A=6 * 107C+106 and r=0.9999 respectively, so the method is suitable for the determination and analysis of 2-ME in vitro.
Secondly, in view of the optimum condition of the inhalable particle size of the lung to be within the range of 1~5 m, this experiment uses the controlled crystallization method to prepare the inhalable particles of 2-ME first. Through the investigation of the appearance, size and stability of the prepared particles, the best formulation and technological conditions for the preparation of 2-ME particles are selected: 2-ME is 2.5mg. Ml, respectively. -1, mooring Losham is 5mg ml-1, the rotational speed is 1200R. Min-1, and the proportion of ethanol and water is 1:3.. The 2-ME particle solution is prepared by the method above, and then the 2-ME inhalable particles are prepared by centrifugation, re dispersion and freeze drying.
Third, on the basis of solubility, powder morphology, wettability, particle size and distribution, moisture content, repose angle, atomization characteristics, the physicochemical properties and atomization characteristics of powders, such as emptying rate and extracorporeal deposition, the formulation and technological conditions of the preparation of 2-ME dry powder inhalers were studied, and the best prescription and the best preparation for the preparation of 2-ME dry powder inhalers were obtained. The best preparation techniques are as follows: (1) the ratio of 2-ME to lactose and leucine is 2:1:1, and the dosage of poloxamer is 2% of the remaining three. Then the drug and the auxiliary materials are prepared into a certain concentration of suspension solution and spray drying; the preparation process is 140, the inlet temperature is 470L. H-1 and the vacuum degree is 80%. The degree is 240ml. H-1, and the solution concentration is 1%.
Fourth, the evaluation indexes of dry powder inhalers prepared on the optimal conditions were measured. The results were known by the experimental results that the carrier was good in solubility and could release 2-ME inhalable particles quickly; the aerodynamic diameter was 2.72 m, suitable for lung inhalation; it was wet, the moisture content was 2.224 + 0.73%, the appearance was irregular and the rest angle was 42.36 The degree of fluidity is slightly worse than the 1.42 degree, the atomization characteristic is B grade, the emptying rate is 90%, and the effective part deposition amount is 30%, which all accord with the requirement of inhalation.
Fifth, the preliminary pharmacokinetics and release behavior of 2-ME dry powder inhalants in rats were investigated by establishing an animal inhalation drug delivery model. The experimental results showed that the metabolism of 2-ME dry powder inhalants in rats was a one chamber model, the distributed half life (t1/2ka) was 0.6 + 0.22h, and the elimination half life (t1/2ke) was 3.49 + 1.26h, AUC0-12h was 2.95 + 1.24 g ml-1 h, the release behavior accords with Higuchi release model, r=0.9945.
Finally, the safety of 2-ME dry powder inhalers was evaluated preliminarily. It was known that 2-ME dry powder inhalers have a certain irritation to the lungs, but there is no serious irritation and fibroblast proliferation. It shows that the biocompatibility and safety of 2-ME dry powder inhalant can be full of the requirements of lung administration.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

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