【作者】 陈桂良；

【导师】 侯惠民；

【作者基本信息】 上海医药工业研究院 ， 药剂学， 2006， 博士

【摘要】 本文选择了以水为介质的水雾剂（Aqueous aerosol，AA）为研究课题，进行了系统的研究；同时为解决气雾剂中禁用氯氟烷烃类化合物（氟利昂，CFC）的问题，提供了新的思路。 采用普通定量雾化器和超声波雾化器雾化以水为介质的溶液。选择了水溶性药物硫酸沙丁胺醇（SBT）和盐酸左氧氟沙星（LOF）、水不溶性药物丙酸倍氯米松（BDP）为模型，采用水直接溶解、微乳技术或乙醇溶解的方法制成了水雾剂，进行了大鼠经鼻、Beagle犬经口的吸入试验，并与市售的气雾剂、粉雾剂进行了比较。 建立了HPLC荧光检测法测定大鼠肺中SBT、LOF药物量，方法简单快速、定量限分别为0.1μg／ml和0.05μg／ml；建立LC-MS／MS法测定大鼠血浆及Beagle犬血浆中SBT浓度，以特布他林为内标，方法专属性强、灵敏度高，定量限分别为0.10ng／ml和0.05ng／ml；建立了LC-MS／MS方法检测Beagle犬血浆中BDP的活性代谢产物17-BMP的浓度，采用BDP为对照，解决了BDP在体内浓度低无法检测的困难，定量限为0.1ng／ml，为水雾剂的Beagle犬体内药动学研究提供了手段。 设计并制造了大鼠经鼻、Beagle犬经口吸入的动物给药装置，利用了储雾罐原理的动物经鼻给药装置，动物经口吸入粉雾剂的给药装置尚未见报道。本研究自制了超声波雾化器供使用。 采用飞行时间气动学微粒粒径测定法（TOF法）和多级液体撞击取样器法（MLI法）分别测定了超声波雾化药物溶液的雾粒约为10μm，二种方法的测定结果基本一致。采用激光衍射气雾粒度测定法（LD法）测定了普通定量雾化器雾化水雾剂的雾粒约为50μm，其中有部分小于10μm的微粒；使用TOF法也证明了普通定量雾化器的雾粒中有一部分小于20μm的微粒。 大鼠经鼻吸入SBT气雾剂和LOF超声波雾化剂肺部药物量符合Weibull分布模式，在实验条件下，药物量随时间变化的方程式分别为： LnLn[100／(100-M_lung)]=1.622Lnt-5.525 和 LnLn[100／(100-M_lung]=-4.531+1.146Lnt 大鼠经鼻吸入SBT气雾剂的药动学参数分别为：T_5min为33.38ng／ml，T_max为0.25h，C_max为302.7 ng／ml，t_1／2为3.97h；Beagle犬经口吸入SBT气雾剂的药动学参数分别为：T_5min为0.175ng／ml，T_max为2h，C_max为0.98ng／ml，t_1／2为3.56h；结果提示，经鼻吸入达峰时间较快。更多还原

【Abstract】 Aqueous aerosol （AA） has been investigated and been used as target of our research. It also provides a new way to solve the problem of the prohibition of chlorofluorocarbon （CFC） used in aerosol.The aqueous drug solution was atomized using a metered jet nebulizer and ultrasonic AA to be inhaled via nose or mouth by animals. The water soluble salbutamol sulfate （SBT） and levofloxacin hydrochloride （LOF） and insoluble beclomethasone dipropionate （BDP） were used as the models. The SBT and LOF solution, BDP micro-emulsion and BDP ethanol（?）solution were used in the study. The laboratory investigations were carried out by nasal inhalation by rats and oral inhalation by Beagle dogs in comparison with the CFC metered-dose inhaler（MDI） and dry powder inhaler（DPI）.The HPLC methods with fluorescence detection for determination of the concentration of SBT or LOF in lung of rats were established. The methods are sensitive with the LOQ of 0.10 μg/ml and 0.05μg/ml, respectively. The LC-MS/MS methods for determining the concentration of SBT in rat plasma and in Beagle dog plasma were established using terbutaline as internal standard with LOQ of 0.10 ng/ml and 0.05ng/ml, respectively. The LC-MS/MS method for determining the concentration of 17- beclomethasone monopropionate（17-BMP） in Beagle dog plasma were established for BDP pharmacokinetics test using BDP as the reference. The LOQ is 0.10 ng/ml.The apparatus were designed and made for nasal inhalation and oral inhalation. The later apparatus has not been reported yet in literature. The ultrasonic AAs were made for research.Both time-of-flight aerodynamic particle size analyzer （TOF method） and multiple-stage liquid impinger （MLI method） were used to evaluate particle size generated from ultrasonic AA to give the similar result of the average particle size of about 10 μm. The most particles produced from metered jet nebulizer, measured by laser diffraction method（LD method）, were about 50μm, and some below 10 μm, and when the TOF method was used, some less than 20μm.By inhalation of the aerosols generated from SBT MDI and from ultrasonic AA of LOF solution, the amount of drug deposited in the lung of rats accorded with the Weibull equation. The equations in the experiments were:LnLn[100/(100-M_lung)]= 1.622Ln t-5.525andLnLn[100/(100-M_lung)] = -4.531 + 1.146 Ln t, respectively.The pharmacokinetic parameters in rats after nasal inhalation of SBT MDI were T_5min 33.38更多还原