本文關(guān)鍵詞： 莫西沙星 透明質(zhì)酸 脂質(zhì)體 凝膠 緩釋 肺靶向給藥 支氣管鏡　出處：《黑龍江中醫(yī)藥大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：[目的]建立適用于經(jīng)纖維支氣管鏡肺部介入給藥治療的緩釋藥物載體,旨在提高藥物在肺部的滯留性,實現(xiàn)藥物的緩慢、持續(xù)釋放,以減少給藥次數(shù),提高患者順應(yīng)性,提高臨床治愈率。本研究以莫西沙星為模型藥物,采用硫酸銨梯度法結(jié)合高壓均質(zhì)法制備莫西沙星脂質(zhì)體,再以透明質(zhì)酸為凝膠載體,制備得到適用于經(jīng)支氣管鏡肺部介入治療的莫西沙星脂質(zhì)體凝膠復(fù)合制劑,并對含藥脂質(zhì)體及含藥脂質(zhì)體凝膠復(fù)合制劑的制備工藝、表征特性、體外釋放行為、動物肺部應(yīng)用的安全性及動物體內(nèi)藥代動力學(xué)進(jìn)行評價和考察。 [方法]建立高效液相色譜法分析莫西沙星的含量；本研究將硫酸銨梯度法與高壓均質(zhì)法相結(jié)合制備莫西沙星脂質(zhì)體,以脂質(zhì)體粒徑及其分布和包封率、載藥量為考察指標(biāo),優(yōu)化處方和工藝,確定最佳制備工藝。將脂質(zhì)體溶液置于25℃環(huán)境保存,分別于放置1天、7天、30天、60天后取樣,考察其包封率和粒徑變化；以能否順利通過6F左冠狀動脈造影導(dǎo)管為考察指標(biāo),確定脂質(zhì)體凝膠復(fù)合制劑中透明質(zhì)酸用量,以制備通針性良好適用于經(jīng)纖維支氣管鏡肺部介入給藥的制劑；采用動態(tài)膜透析技術(shù)考察莫西沙星脂質(zhì)體及其脂質(zhì)體凝膠復(fù)合制劑的體外釋藥行為;對新西蘭白兔及比格犬模型進(jìn)行一般情況觀察和一定時間的肺組織病理切片觀察,以對莫西沙星脂質(zhì)體凝膠復(fù)合制劑肺內(nèi)應(yīng)用的可行性和安全性做出初步評價。對健康新西蘭白兔單次肺部介入給予莫西沙星脂質(zhì)體凝膠復(fù)合制劑,采用HPLC法測定莫西沙星在新西蘭白兔體內(nèi)的血藥濃度及肺組織藥物濃度,采用DAS2.1軟件處理血液及肺組織中藥物濃度數(shù)據(jù),SPSS19.0軟件對主要藥動學(xué)參數(shù)進(jìn)行統(tǒng)計學(xué)分析。 [結(jié)果]確定莫西沙星脂質(zhì)體最佳制備工藝為：水化介質(zhì)硫酸銨質(zhì)量濃度70mg/mL、磷脂質(zhì)量濃度50mg/m L、空白脂質(zhì)體粒徑120nm左右、透析時間5h、藥脂比(質(zhì)量比)2：3、孵育溫度40℃、孵育時間30min；以最佳工藝制備得到的莫西沙星脂質(zhì)體平均粒徑為(143±3.98)nm.,PDI為0.102,粒徑分布屬正態(tài)分布,平均包封率為(74.56±3.21)%,平均載藥量為(25.96±1.11)%；體外室溫放置穩(wěn)定性良好,60天內(nèi)包封率與粒徑幾乎無變化；透明質(zhì)酸終濃度為1.75%時,制劑可以順利通過6F左冠狀動脈造影導(dǎo)管,既擁有良好的通針性,又能夠提高制劑黏附性延長藥物在病灶的滯留時間；以優(yōu)化處方工藝制備的莫西沙星脂質(zhì)體及其脂質(zhì)體凝膠復(fù)合制劑的體外釋放行為基本一致,釋放分為三個階段,在釋放初期約有25%的突釋(基本上來自脂質(zhì)體或脂質(zhì)體凝膠中的未包封的游離莫西沙星),在第24小時釋放出約60%的藥量,之后釋放基本達(dá)到平衡進(jìn)入平臺期；莫西沙星脂質(zhì)體凝膠復(fù)合制劑肺內(nèi)應(yīng)用后可生物降解吸收,對試驗動物的正常呼吸功能無影響,不刺激支氣管粘膜,不會造成肺組織病理性改變,初步證實其具有良好的可行性和安全性。莫西沙星脂質(zhì)體凝膠在血液中的藥物濃度大致在局部注藥4h左右達(dá)峰,峰值為1.48μg/ml,在局部注藥24h后下降到0.2μg/ml,t1/2β為28.6h。在注藥局部肺組織中的藥物濃度降低明顯緩慢,t1/2β為32.3h,同時在局部注藥144h后依然維持在最低抑菌濃度0.25μg/ml以上。 [結(jié)論]采用硫酸銨梯度法結(jié)合高壓均質(zhì)法制備的莫西沙星脂質(zhì)體形態(tài)規(guī)整,粒徑均一,包封率與載藥量較高,具有良好的緩釋特征,穩(wěn)定性良好,并且明顯改變了莫西沙星的藥動學(xué)行為,減緩其釋放與消除。同時脂質(zhì)體凝膠復(fù)合制劑生物安全性良好,采用經(jīng)支氣管鏡肺部介入給藥顯著提高了藥物在肺組織中的含量,延長肺部滯留時間,提高藥效。
[Abstract]:[Objective] to establish a drug carrier in transbronchial lung interventional treatment, in order to improve drug retention in the lungs, the drug is slow, sustained release, in order to reduce the frequency of administration, improve the compliance of patients, improve the clinical cure rate. In this study, moxifloxacin as model drug, preparation of moxifloxacin lipid the combination of high pressure homogenization method using ammonium sulfate gradient method with hyaluronic acid gel carrier, prepared for transbronchial lung involvement of moxifloxacin liposome gel preparation for treating compound, and preparation process of drug containing liposomes and liposome gel composite preparation characterization and in vitro release behavior, application animal pulmonary safety and animal pharmacokinetics and evaluated.
[Methods] analysis of moxifloxacin to establish a high performance liquid chromatography content; this study will prepare moxifloxacin liposome ammonium sulfate gradient method and high pressure homogenization method combined with liposome particle size and its distribution and encapsulation efficiency, drug loading as investigation index, optimization of prescription and technology, determine the best preparation process of the lipid. Precursor solution in 25 C environment preservation, were placed for 1 days, 7 days, 30 days, 60 days after the sampling, the encapsulation rate and diameter change; the indexes can pass the 6F left coronary artery catheter for determination of liposome gel compound preparation of hyaluronic acid dosage, to prepare a pass the needle suitable for transbronchial lung involvement in drug preparation; using the dynamic membrane dialysis technology study of moxifloxacin liposome and liposomal gel composite preparations in vitro release behavior of New Zealand white rabbit and beagle dogs; a model To observe the pathological section of lung tissue was observed and a certain time, the feasibility and safety of moxifloxacin liposome gel compound lung application to make a preliminary evaluation of single lung in healthy New Zealand rabbits were treated with moxifloxacin liposome gel preparation, determination of moxifloxacin in drug concentration and blood concentration of lung tissue in rabbits with HPLC method, using the concentration data of blood and lung in DAS2.1 software, SPSS19.0 software on the main pharmacokinetic parameters were statistically analyzed.
[results] determine moxifloxacin liposome preparation technology: hydration medium ammonium sulphate concentration 70mg/mL, phospholipid concentration 50mg/m L blank liposomes particle size of about 120nm, dialysis time 5h, drug lipid ratio (mass ratio) 2:3, incubation temperature is 40 degrees centigrade, the incubation time of 30min with the best process; the prepared moxifloxacin liposome average particle size (143 + 3.98) nm., PDI is 0.102, the particle size distribution is a normal distribution, the average encapsulation rate was (74.56 + 3.21)%, the average drug loading was (25.96 + 1.11)%; in vitro at room temperature for 60 days with good stability, encapsulation efficiency with almost no change in particle size; hyaluronic acid concentration is 1.75%, agents can smoothly through the 6F catheter in the left coronary artery, which has good syringeability, but also can improve the adhesion of preparation can prolong the drug retention time in the lesions; to optimize the moxifloxacin liposome preparation process and Liposome gel composite preparations in vitro release behavior is consistent, the release is divided into three stages, the initial release of about 25% of the burst release (basically from liposome or liposomal gel in the non encapsulated free release, moxifloxacin) about 60% of the dose in twenty-fourth hours after the release of balance into the platform; biodegradation absorption of moxifloxacin liposome gel lung compound application, not affect the normal respiratory function of the experimental animal, does not stimulate the bronchial mucosa, will not cause the pathological changes of lung tissue, preliminary confirmed that a good feasibility and safety. The drug concentration in the blood of moxifloxacin liposome gel roughly in the local injection 4H reached the peak, the peak is 1.48 g/ml, decreased to 0.2 g/ml in the local after 24h injection, t1/2 beta 28.6h. injection of local lung tissue in drug concentration decreased significantly slow, T1/2 beta was 32.3h and remained at the minimum inhibitory concentration of 0.25 g/ml after local injection of 144H.
[Conclusion] combined with moxifloxacin liposomes prepared by high pressure homogenization with regular shape with the ammonium sulfate gradient method, uniform particle size, entrapment efficiency and high drug loading, with sustained release characteristics, good stability, and significantly alters the pharmacokinetics of moxifloxacin, slow release and elimination. At the same time liposome gel compound preparation good biological safety, by transbronchial lung interventional administration significantly increased the content of the drug in the lung tissue, prolong the retention time of the lungs, improve the efficacy.

【學(xué)位授予單位】：黑龍江中醫(yī)藥大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R96

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本文編號：1480395