莫西沙星脂质体凝胶肺部靶向介入给药缓释系统的研究

发布时间：2018-02-01 00:20

本文关键词： 莫西沙星透明质酸脂质体凝胶缓释肺靶向给药支气管镜　出处：《黑龙江中医药大学》2014年硕士论文　论文类型：学位论文

【摘要】：[目的]建立适用于经纤维支气管镜肺部介入给药治疗的缓释药物载体,旨在提高药物在肺部的滞留性,实现药物的缓慢、持续释放,以减少给药次数,提高患者顺应性,提高临床治愈率。本研究以莫西沙星为模型药物,采用硫酸铵梯度法结合高压均质法制备莫西沙星脂质体,再以透明质酸为凝胶载体,制备得到适用于经支气管镜肺部介入治疗的莫西沙星脂质体凝胶复合制剂,并对含药脂质体及含药脂质体凝胶复合制剂的制备工艺、表征特性、体外释放行为、动物肺部应用的安全性及动物体内药代动力学进行评价和考察。 [方法]建立高效液相色谱法分析莫西沙星的含量；本研究将硫酸铵梯度法与高压均质法相结合制备莫西沙星脂质体,以脂质体粒径及其分布和包封率、载药量为考察指标,优化处方和工艺,确定最佳制备工艺。将脂质体溶液置于25℃环境保存,分别于放置1天、7天、30天、60天后取样,考察其包封率和粒径变化；以能否顺利通过6F左冠状动脉造影导管为考察指标,确定脂质体凝胶复合制剂中透明质酸用量,以制备通针性良好适用于经纤维支气管镜肺部介入给药的制剂；采用动态膜透析技术考察莫西沙星脂质体及其脂质体凝胶复合制剂的体外释药行为;对新西兰白兔及比格犬模型进行一般情况观察和一定时间的肺组织病理切片观察,以对莫西沙星脂质体凝胶复合制剂肺内应用的可行性和安全性做出初步评价。对健康新西兰白兔单次肺部介入给予莫西沙星脂质体凝胶复合制剂,采用HPLC法测定莫西沙星在新西兰白兔体内的血药浓度及肺组织药物浓度,采用DAS2.1软件处理血液及肺组织中药物浓度数据,SPSS19.0软件对主要药动学参数进行统计学分析。 [结果]确定莫西沙星脂质体最佳制备工艺为：水化介质硫酸铵质量浓度70mg/mL、磷脂质量浓度50mg/m L、空白脂质体粒径120nm左右、透析时间5h、药脂比(质量比)2：3、孵育温度40℃、孵育时间30min；以最佳工艺制备得到的莫西沙星脂质体平均粒径为(143±3.98)nm.,PDI为0.102,粒径分布属正态分布,平均包封率为(74.56±3.21)%,平均载药量为(25.96±1.11)%；体外室温放置稳定性良好,60天内包封率与粒径几乎无变化；透明质酸终浓度为1.75%时,制剂可以顺利通过6F左冠状动脉造影导管,既拥有良好的通针性,又能够提高制剂黏附性延长药物在病灶的滞留时间；以优化处方工艺制备的莫西沙星脂质体及其脂质体凝胶复合制剂的体外释放行为基本一致,释放分为三个阶段,在释放初期约有25%的突释(基本上来自脂质体或脂质体凝胶中的未包封的游离莫西沙星),在第24小时释放出约60%的药量,之后释放基本达到平衡进入平台期；莫西沙星脂质体凝胶复合制剂肺内应用后可生物降解吸收,对试验动物的正常呼吸功能无影响,不刺激支气管粘膜,不会造成肺组织病理性改变,初步证实其具有良好的可行性和安全性。莫西沙星脂质体凝胶在血液中的药物浓度大致在局部注药4h左右达峰,峰值为1.48μg/ml,在局部注药24h后下降到0.2μg/ml,t1/2β为28.6h。在注药局部肺组织中的药物浓度降低明显缓慢,t1/2β为32.3h,同时在局部注药144h后依然维持在最低抑菌浓度0.25μg/ml以上。 [结论]采用硫酸铵梯度法结合高压均质法制备的莫西沙星脂质体形态规整,粒径均一,包封率与载药量较高,具有良好的缓释特征,稳定性良好,并且明显改变了莫西沙星的药动学行为,减缓其释放与消除。同时脂质体凝胶复合制剂生物安全性良好,采用经支气管镜肺部介入给药显著提高了药物在肺组织中的含量,延长肺部滞留时间,提高药效。
[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.

【学位授予单位】：黑龙江中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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