發(fā)布時間：2018-06-23 13:09

  本文選題：支氣管鏡 + 肺結核�。� 參考：《河北大學》2013年碩士論文

【摘要】：耐藥結核病的產(chǎn)生給結核病的治療帶來了新的難題，使常規(guī)的治療手段很難達到滿意的治療效果。支氣管鏡介入治療是一種可直視病灶局部的靶向治療方式，其投遞藥物多為口服或靜脈真溶液藥物或凝膠藥物，雖然靶向性強、藥物劑量控制準確,但是藥物的緩釋效果差，肺內的呼吸擠壓還會阻礙凝膠藥物向遠端注入，影響治療效果。因此本課題選擇水溶性藥物環(huán)丙沙星作為研究對象，開發(fā)其緩釋微粒，作為支氣管鏡介入治療用專屬藥物。 本研究以殼聚糖作為藥物載體，環(huán)丙沙星作為研究藥物，應用乳化交聯(lián)法制備環(huán)丙沙星殼聚糖微球，并對其粒徑、粒徑分布、載藥量、包封率、通透性、降解度、肺部滯留性，緩釋性，安全性等方面進行評價，進而評估其經(jīng)支氣管鏡介入給藥的可行性，以期達到抗結核藥物環(huán)丙沙星肺部緩慢持續(xù)釋放，減少給藥次數(shù)，提高患者順應性的目的。 第一部分：環(huán)丙沙星殼聚糖微球的制備及體外釋放初步研究 制備支氣管鏡介入治療用環(huán)丙沙星緩釋微球，并通過考察環(huán)丙沙星殼聚糖微球多種影響因素，并對其表征及理化性質進行評價，篩選出適合支氣管鏡介入治療用處方工藝。以戊二醛作為交聯(lián)劑，采用乳化交聯(lián)法制備環(huán)丙沙星殼聚糖緩釋微球，，正交實驗設計篩選處方工藝，并應用掃描電鏡、激光粒度儀、UV等檢測手段對其形態(tài)、粒徑、載藥量、包封率及恒溫條件下體外釋放度等指標進行測定。制備的環(huán)丙沙星殼聚糖微球球型完整，球體光滑，粒度分布均勻符合正態(tài)性分布，80%以上的微球粒徑大小120-160μm，平均粒徑（142.31±7.85）μm，平均載藥量（14.20±0.61）%，平均包封率（56.43±1.31）%。該微球能順利通過7號針頭，可經(jīng)支氣管鏡介入導管順暢注射。在恒溫條件下，殼聚糖微球緩釋時間可達到48h，較明顯的延緩了水溶性藥物的釋放時間。 第二部分：環(huán)丙沙星殼聚糖多重交聯(lián)微球的制備及體外評價 為了更有效的延緩環(huán)丙沙星藥物的釋放時間，選取非離子型表面活性劑乙基纖維素作為輔料，制備環(huán)丙沙星殼聚糖-乙基纖維素多重交聯(lián)微球。采用乳化交聯(lián)法制備多重交聯(lián)微球，以體外釋放度作為主要參考指標，通過正交實驗結果優(yōu)化處方，綜合考察該處方工藝制備的多重交聯(lián)微球，對其體外釋放度、體外降解度等情況進行評價。對處方條件下制備的殼聚糖緩釋微球的形態(tài)、粒徑分布、Zeta電位等指標進行檢測，評定該多重交聯(lián)微球的表征。制備3批殼聚糖載藥微球，呈肉眼顆粒狀，光鏡觀察球型圓整，黏連較少，電鏡觀察球體表面光滑，但存在少量褶皺；粒度分布均勻，平均粒徑（142.31±7.85）μm，平均Zeta電位值為（51.68±2.3）mV；在恒溫條件下，多重交聯(lián)微球緩釋時間可達到144h，較普通殼聚糖微球表現(xiàn)出更出色的緩釋效果，更加明顯的延緩了水溶性藥物的釋放時間，為接下來的體內實驗提供了研究依據(jù)，更進一步的達到了支氣管鏡介入給藥后靶向緩釋的研究目的。 第三部分：緩釋系統(tǒng)體內生物相容性及安全性的初步研究 綜合考察該處方工藝制備的載藥微球，需對其藥效學、藥動學及毒理學指標進行評價。通過兔肺內注入載藥微球，考察2周內不同組別兔體溫、進食、活動性等方面的變化，發(fā)現(xiàn)兔沒有表現(xiàn)出明顯的熱源反應及表觀生理性變化，較空白組無顯著性差異；通過兔肺內注射自制的載藥微球，考察其肺局部組織病理學變化及肺內滯留性，研究發(fā)現(xiàn)載藥微球表現(xiàn)出很好的肺內滯留性，雖然體內降解實驗中，28天載藥微球未見完全降解，但兔呼吸正常，肺內支氣管粘膜各層結構清晰可見，形態(tài)正常，肺泡結構完整，無間隙紅細胞增多、肺泡間隔增厚等病理學改變。該方法制備的載藥微球具有較出色的生物相容性及體內安全性，具有進一步開發(fā)支氣管鏡介入用專屬緩釋藥物的可行性和必要性。
[Abstract]:The present invention relates to a targeting therapeutic method for treating tuberculosis , which has the advantages of strong targeting property and accurate drug dosage control , but the slow release effect of the drug is poor , and the slow release effect of the drug is affected .

Chitosan was used as the drug carrier , ciprofloxacin was used as the study drug , and its particle size , particle size distribution , drug loading , encapsulation efficiency , permeability , degradability , lung retention , sustained release and safety were evaluated .

The first part : preparation of ciprofloxacin chitosan microspheres and preliminary study on in vitro release

The microspheres were prepared by using glutaraldehyde as cross - linking agent . The microspheres were prepared by using glutaraldehyde as cross - linking agent . The microspheres were prepared by emulsion crosslinking method . The average particle size ( 14.20 鹵 0.61 ) % , the average particle size ( 142.31 鹵 7.85 ) 渭m , the average particle size ( 14.20 鹵 0.61 ) % , the average entrapment efficiency ( 56.43 鹵 1.31 ) % .

The second part : preparation and in vitro evaluation of ciprofloxacin chitosan multiple cross - linked microspheres

In order to delay the release time of ciprofloxacin drugs more effectively , the non - ionic surfactant ethyl cellulose was selected as the auxiliary material to prepare the ciprofloxacin chitosan - ethyl cellulose multiple cross - linked microspheres .
The average particle size distribution was ( 142.31 鹵 7.85 ) 渭m and the average zeta potential was ( 51.68 鹵 2.3 ) mV .
Under the constant temperature condition , the sustained - release time of the multiple cross - linked microspheres can reach 144h , the chitosan microspheres show better sustained - release effect , the release time of the water - soluble drug is obviously delayed , the research basis is provided for the following in vivo experiments , and further , the research purpose of targeting sustained release after the interventional administration of the bronchoscopic mirror is achieved .

The third part : preliminary study on biocompatibility and safety of sustained - release system

The pharmacodynamics , pharmacokinetics and toxicological indexes of the drug - loaded microspheres prepared by the prescription were evaluated . The changes of body temperature , feeding and activity of different groups in rabbits were investigated by injecting drug - loaded microspheres into the lung of rabbits .
The pathological changes of lung and the retention of lung were investigated by injection of self - made drug - loaded microspheres in rabbit lung . The results showed that the drug - carrying microspheres showed good intrapulmonary retention . Although the drug - loaded microspheres were not completely degraded in 28 - day drug - loaded microspheres , the structure of the lung was normal , the alveolar structure was intact , no gap erythrocytes were increased , and the thickening of alveolar septum was changed . The drug - loaded microspheres prepared by the method have excellent biocompatibility and in vivo safety , and have the feasibility and the necessity of further developing the sustained - release drug for the interventional therapy of the bronchoscopic mirror .
【學位授予單位】：河北大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R521;R96

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