尼莫地平自微乳处方优化及其体内外评价
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摘要
目的:尼莫地平是临床常用的二氢吡啶类钙拮抗剂,但其水溶性差,首过效应明显,生物利用度仅为4.8%～8.8%。自微乳制剂是提高药物生物利用度、减少不良反应的新型制剂,其能够显著提高药物的溶出度,可通过淋巴循环进入血液,从而避免首过效应。本研究根据自乳化原理,设计优化尼莫地平自微乳制剂处方,可望提高尼莫地平的生物利用度,为研制各方面性能优良的尼莫地平自微乳制剂奠定基础。
方法:(1)通过溶解度测定选择尼莫地平自微乳制剂的辅料;采用差示扫描量热分析,观察药物与辅料之间以及辅料之间的相互作用;按照处方设计制备21个处方的自乳化液,对其进行体外评价,包括目测、乳化效率、粒径分布、吸光度和溶出度等实验,并在透射电镜下观察,综合考虑确定最优处方。(2)分离大鼠全段小肠,由断口注入冰生理盐水,充分洗净肠腔后用充有混合气体(95%O2,5%CO2)的Krebs氏液清洗1~2次,然后用玻棒将肠管粘膜面向外翻转,将肠段一端结扎,由另一端注入Krebs氏液2mL,然后封闭成双侧均为盲端的肠囊备用。将肠囊置于通有混合气体(95%O2,5%CO2)的Krebs氏液中(37℃),转桨转速50 r?min-1,在0min时分别加入含尼莫地平10、20、40mg的自微乳,孵育30、60、90、120、240min,取出肠囊。用Krebs氏液清洗2~3次,电子天平称重,以每克小肠组织加入5mL生理盐水的标准定量加入生理盐水,匀浆器制备匀浆,采用HPLC方法检测匀浆液中尼莫地平的含量。将大鼠小肠取出后按照上、中、下段各取10cm,同上法制备肠囊,在如上中剂量时考察不同肠段在120min时的吸收情况。以小肠组织中蛋白含量为参照,以小肠组织中尼莫地平含量为指标,观察尼莫地平自微乳制剂和尼莫地平普通片在大鼠小肠的吸收情况。(3)大鼠分别灌胃给予尼莫地平普通片混悬液和尼莫地平自微乳制剂,剂量均为12.5mg/kg,给药后分别在0,15,30,60,90,120,180,240,480,720min时大鼠眼眶静脉丛取血,并设置尼莫地平静脉注射组,剂量为1.25mg/kg,给药后分别在0,5,10,20,40,60,120,180,240,480,720min时大鼠眼眶静脉丛采集血液标本,样本经过提取后HPLC测定其中尼莫地平浓度,得到血药浓度-时间数据,采用DAS2.1.1版药动学分析软件对血药浓度-时间数据进行分析并计算主要药代动力学参数。
结果:(1)最优处方为尼莫地平、油酸乙酯、聚氧乙烯氢化蓖麻油-35和单辛酸甘油酯的质量百分数分别为3.5%、40%、40%和16.5%。在0.1mol ?L-1稀盐酸中轻微搅拌,该处方能够在1min内迅速乳化,目测澄清,略显淡蓝色乳光,激光粒径分布测定得到粒径均值为58.6nm的水包油型乳滴,在0.1mol ?L-1稀盐酸中的溶出度在1min时即达到了84.3%,且在实验室条件下避光放置3个月性质保持稳定。(2)建立了检测大鼠小肠匀浆中尼莫地平含量的高效液相方法,采用C18柱(250 x 4.6 mm, 5μm, phenomenex)为分析柱,柱温25℃;流动相组成为乙腈:水=70:30(v/v),检测波长350nm;流速1mL? min-1 ;进样量20μL。尼莫地平标准曲线回归方程为Y=5.9968X+0.0415,r=0.9995,线性范围为0.02~1.0mg·L-1。与尼莫地平普通片相比,尼莫地平自微乳制剂显著提高了孵育后药物在小肠组织中的浓度,且呈剂量依赖性关系,孵育至60min时基本达到饱和。尼莫地平自微乳在大鼠小肠全段均有吸收,吸收量随上、中、下肠段递减,在尼莫地平自微乳制剂剂量为20mg时,尼莫地平在上、中、下肠段的吸收量分别为0.0281±0.0036,0.0240±0.0031,0.0218±0.0026μg/100μg蛋白。(3)建立了检测大鼠血浆中尼莫地平含量的高效液相方法,采用C18柱(250 x 4.6 mm, 5μm, phenomenex)为分析柱,柱温25℃;流动相组成为乙腈:水=70:30(v/v),检测波长350nm;流速1mL? min-1;进样量20μL。尼莫地平标准曲线回归方程为Y=2.2872X+0.1645,r=0.9991,线性范围为0.02~1.0mg·L-1。尼莫地平普通片和尼莫地平自微乳的Cmax分别为0.101±0.018mg·L-1和0.147±0.085mg·L-1 , AUC分别为9.674±1.674mg·min·L-1和19.620±7.275mg·min·L-1,MRT分别为71.784±2.739min和199.636±62.382min,达峰时间无差异。尼莫地平自微乳制剂的绝对生物利用度为9.84%,以尼莫地平市售普通片剂为参比制剂,尼莫地平自微乳制剂的相对生物利用度为202.8%。
结论:(1)本研究设计优化的尼莫地平制剂为自微乳化制剂。(2)外翻肠囊实验和大鼠体内的药动学实验结果均表明,本研究设计优化的尼莫地平自微乳制剂能够显著提高尼莫地平的吸收,其有可能成为一种有应用前景的口服尼莫地平自微乳制剂。
Objective: Nimodipine is one of dihydropyridines frequently used in clinic. Because of the poor water-solubility and obvious first pass effect, its bioavailability is only 4.8%～8.8%. Self-microemulsifying drug delivery system (SMEDDS) is a new preparation which could improve bioavailability and reduce adverse effect. SMEDDS could increase the dissolution of drug greatly and send the drug into blood by lymph circulation avoiding first pass effect. Based on the theory of SEDDS, we optimized the formulation of self-microemulsifying drug delivery system (SMEDDS) of nimodipine in order to improve the bioavailability and provide scientific basis for preparing SMEDDS of nimodipine.
Methods: (1) The solubility of nimodipine in each adjuvant was tested firstly. Then the interaction between all the adjuvants and nimodipine was determined by differential scanning calorimetry (DSC). The designed and prepared 21 formulations of SEDDS were evaluated in vitro to optimize formulation according to the observation, emulsifying efficiency, particle diameter distribution, UV absorbance, dissolution and transmission electron microscope. In view of all the factors mentioned above, the optimized formulation was obtained. (2) After separated the whole intestine of rats, the intestine was affluxed with ice-cold physiological saline from the incision of intestine in order to clean the enteric cavity, and then affluxed with Krebs-Ringer solution saturated by mixed gas (95%O2,5%CO2)for one or two times. The intestine which was tied in one end was everted by a glass stick and filled with 2mL Krebs-Ringer solution from the other end that was tied later. The everted intestinal sac was put into a dissolution cup within 200mL Krebs-Ringer solution saturated by mixed gas (95%O2,5%CO2) and stired with the rotation rate of 50 r?min-1. SMEDDS contained 10, 20 or 40mg nimodipine and conventional tablet contained 20mg nimodipine were added at 0min respectively. After incubated for 30min, 60min, 90min, 120min or 240min, they were taken out, flushed with Krebs-Ringer solution for two or three times and weighed. 5mL physiological saline solution was added for every gram of intestine. Then the everted intestinal sac was homogenized by a homogenizer. The concentration of nimodipine in the homogenate was analyzed by HPLC. The superior, middle and inferior intestinal segments of approximately 10 cm in length were prepared just like the whole intestine we did before. The everted intestinal sac and SMEDDS contained 20mg nimodipine was added to the medium of 200mL Krebs-Ringer solution and incubated for 120min. By analyzing the concentration of nimodipine in the homogenate of intestine and the concentration of protein in the homogenate of intestine, we compared the absorption of nimodipine of SMEDDS and the conventional tablets in the whole intestine. In this way, the difference of absorption of nimodipine in the optimized formulation between different parts of intestine was studied. (3) The suspension of nimodipine conventional tablets and SMEDDS were orally administrated to two groups of rats with the dose of 12.5mg/kg respectively. The blood samples were drawn from the orbital vein of rats at 0,15,30,60,90,120,180,240,480,and 720min. As for the group of administrating by vein, the dose was 1.25mg/kg. The blood samples were also drawn from the orbital vein of rats at 0,5,10,20,40,60,120,180 , 240 , 480 and 720min. After dealing with all the samples, the concentration of nimodipine in the samples was analyzed by HPLC to get the concentration-time data. Then the main kinetic parameters were calculated by the DAS 2.1.1 software.
Results:(1) The ratios(%) of nimodipine, ethyl oleate, Cremophor EL, and GMC in the optimized formulation were 3.5%, 40%, 40% and 16.5% respectively. The optimized formulation was able to emulsify rapidly under gentle agitation within 1min in the 0.1mol ?L-1 HCl. And the average droplet size was 58.6nm. The dissolution of the optimized formulation in the medium of 0.1mol ?L-1 HCl was 84.3% after 1 min. The optimized formulation could keep stable after three monthes in the lab environment protected from light. (2) The detecting method of nimodipine in the homogenate of rat intestine by HPLC was set up. The chromatographic column was C18 analytical column(250 x 4.6 mm, 5μm, phenomenex). The column temperature was maintained at 25℃. The mobile phase consisted of 70% acetonitrile and 30% water. The flow rate was 1mL? min-1 with detection wavelength at 350nm. Injection volume was 20μL. The regression equation of standard curve was: Y=5.9968X+0.0415,r=0.9995. The linear range was 0.02~1.0mg?L-1. By analyzing the concentration of nimodipine in the homogenate of intestine and the concentration of protein in the homogenate of intestine, we found that the concentration of homogenate of intestine was much higher in the three groups of SMEDDS than that of in the group of conventional tablets. And the three groups of SMEDDS were dose-dependent. The concentration kept balance until 60min. Nimodipine of SMEDDS could be absorbed in the entire intestine, however, the absorption decreased progressly from superior to inferior. When incubated in SMEDDS contained 20mg nimodipine, the content of nimodipine in every 100μg protein were 0.0281±0.0036μg , 0.0240±0.0031μg ,0.0218±0.0026μg for superior, middle and inferior intestine. (3) The detecting method of nimodipine in the plasma of rats by HPLC was set up. The chromatographic column was C18 analytical column(250 x 4.6 mm, 5μm, phenomenex). The column temperature was maintained at 25℃. The mobile phase consisted of 70% acetonitrile and 30% water. The flow rate was 1mL? min-1 with detection wavelength at 350nm. Injection volume was 20μL. The regression equation of standard curve was: Y=2.2872X+0.1645,r=0.9991,The linear range was 0.02~1.0mg?L-1. Main pharmacokinetics parameters of conventional tablets group and SMEDDS group were as following: Cmax were 0.101±0.018 mg?L-1 and 0.147±0.085 mg?L-1; AUC were 9.674±1.674mg·min·L-1 and 19.620±7.275mg·min·L-1; MRT were 71.784±2.739 min and 199.636±62.382 min, Tmax was almost the same. The absolute bioavailability of SMEDDS was 9.84%. Comparing with the conventional tablets, relative bioavailability of SMEDDS was 202.8%.
Conclusion: (1) The optimized formulation is SMEDDS of nimodipine. (2)Both the results of everted intestinal sac in vitro and pharmacokinetics study in vivo of rats showed that the optimized formulation of SMEDDS could enhance the absorption of nimodipine which indicated that the optimized formulation of SMEDDS might have a promising future.
方法:(1)通过溶解度测定选择尼莫地平自微乳制剂的辅料;采用差示扫描量热分析,观察药物与辅料之间以及辅料之间的相互作用;按照处方设计制备21个处方的自乳化液,对其进行体外评价,包括目测、乳化效率、粒径分布、吸光度和溶出度等实验,并在透射电镜下观察,综合考虑确定最优处方。(2)分离大鼠全段小肠,由断口注入冰生理盐水,充分洗净肠腔后用充有混合气体(95%O2,5%CO2)的Krebs氏液清洗1~2次,然后用玻棒将肠管粘膜面向外翻转,将肠段一端结扎,由另一端注入Krebs氏液2mL,然后封闭成双侧均为盲端的肠囊备用。将肠囊置于通有混合气体(95%O2,5%CO2)的Krebs氏液中(37℃),转桨转速50 r?min-1,在0min时分别加入含尼莫地平10、20、40mg的自微乳,孵育30、60、90、120、240min,取出肠囊。用Krebs氏液清洗2~3次,电子天平称重,以每克小肠组织加入5mL生理盐水的标准定量加入生理盐水,匀浆器制备匀浆,采用HPLC方法检测匀浆液中尼莫地平的含量。将大鼠小肠取出后按照上、中、下段各取10cm,同上法制备肠囊,在如上中剂量时考察不同肠段在120min时的吸收情况。以小肠组织中蛋白含量为参照,以小肠组织中尼莫地平含量为指标,观察尼莫地平自微乳制剂和尼莫地平普通片在大鼠小肠的吸收情况。(3)大鼠分别灌胃给予尼莫地平普通片混悬液和尼莫地平自微乳制剂,剂量均为12.5mg/kg,给药后分别在0,15,30,60,90,120,180,240,480,720min时大鼠眼眶静脉丛取血,并设置尼莫地平静脉注射组,剂量为1.25mg/kg,给药后分别在0,5,10,20,40,60,120,180,240,480,720min时大鼠眼眶静脉丛采集血液标本,样本经过提取后HPLC测定其中尼莫地平浓度,得到血药浓度-时间数据,采用DAS2.1.1版药动学分析软件对血药浓度-时间数据进行分析并计算主要药代动力学参数。
结果:(1)最优处方为尼莫地平、油酸乙酯、聚氧乙烯氢化蓖麻油-35和单辛酸甘油酯的质量百分数分别为3.5%、40%、40%和16.5%。在0.1mol ?L-1稀盐酸中轻微搅拌,该处方能够在1min内迅速乳化,目测澄清,略显淡蓝色乳光,激光粒径分布测定得到粒径均值为58.6nm的水包油型乳滴,在0.1mol ?L-1稀盐酸中的溶出度在1min时即达到了84.3%,且在实验室条件下避光放置3个月性质保持稳定。(2)建立了检测大鼠小肠匀浆中尼莫地平含量的高效液相方法,采用C18柱(250 x 4.6 mm, 5μm, phenomenex)为分析柱,柱温25℃;流动相组成为乙腈:水=70:30(v/v),检测波长350nm;流速1mL? min-1 ;进样量20μL。尼莫地平标准曲线回归方程为Y=5.9968X+0.0415,r=0.9995,线性范围为0.02~1.0mg·L-1。与尼莫地平普通片相比,尼莫地平自微乳制剂显著提高了孵育后药物在小肠组织中的浓度,且呈剂量依赖性关系,孵育至60min时基本达到饱和。尼莫地平自微乳在大鼠小肠全段均有吸收,吸收量随上、中、下肠段递减,在尼莫地平自微乳制剂剂量为20mg时,尼莫地平在上、中、下肠段的吸收量分别为0.0281±0.0036,0.0240±0.0031,0.0218±0.0026μg/100μg蛋白。(3)建立了检测大鼠血浆中尼莫地平含量的高效液相方法,采用C18柱(250 x 4.6 mm, 5μm, phenomenex)为分析柱,柱温25℃;流动相组成为乙腈:水=70:30(v/v),检测波长350nm;流速1mL? min-1;进样量20μL。尼莫地平标准曲线回归方程为Y=2.2872X+0.1645,r=0.9991,线性范围为0.02~1.0mg·L-1。尼莫地平普通片和尼莫地平自微乳的Cmax分别为0.101±0.018mg·L-1和0.147±0.085mg·L-1 , AUC分别为9.674±1.674mg·min·L-1和19.620±7.275mg·min·L-1,MRT分别为71.784±2.739min和199.636±62.382min,达峰时间无差异。尼莫地平自微乳制剂的绝对生物利用度为9.84%,以尼莫地平市售普通片剂为参比制剂,尼莫地平自微乳制剂的相对生物利用度为202.8%。
结论:(1)本研究设计优化的尼莫地平制剂为自微乳化制剂。(2)外翻肠囊实验和大鼠体内的药动学实验结果均表明,本研究设计优化的尼莫地平自微乳制剂能够显著提高尼莫地平的吸收,其有可能成为一种有应用前景的口服尼莫地平自微乳制剂。
Objective: Nimodipine is one of dihydropyridines frequently used in clinic. Because of the poor water-solubility and obvious first pass effect, its bioavailability is only 4.8%～8.8%. Self-microemulsifying drug delivery system (SMEDDS) is a new preparation which could improve bioavailability and reduce adverse effect. SMEDDS could increase the dissolution of drug greatly and send the drug into blood by lymph circulation avoiding first pass effect. Based on the theory of SEDDS, we optimized the formulation of self-microemulsifying drug delivery system (SMEDDS) of nimodipine in order to improve the bioavailability and provide scientific basis for preparing SMEDDS of nimodipine.
Methods: (1) The solubility of nimodipine in each adjuvant was tested firstly. Then the interaction between all the adjuvants and nimodipine was determined by differential scanning calorimetry (DSC). The designed and prepared 21 formulations of SEDDS were evaluated in vitro to optimize formulation according to the observation, emulsifying efficiency, particle diameter distribution, UV absorbance, dissolution and transmission electron microscope. In view of all the factors mentioned above, the optimized formulation was obtained. (2) After separated the whole intestine of rats, the intestine was affluxed with ice-cold physiological saline from the incision of intestine in order to clean the enteric cavity, and then affluxed with Krebs-Ringer solution saturated by mixed gas (95%O2,5%CO2)for one or two times. The intestine which was tied in one end was everted by a glass stick and filled with 2mL Krebs-Ringer solution from the other end that was tied later. The everted intestinal sac was put into a dissolution cup within 200mL Krebs-Ringer solution saturated by mixed gas (95%O2,5%CO2) and stired with the rotation rate of 50 r?min-1. SMEDDS contained 10, 20 or 40mg nimodipine and conventional tablet contained 20mg nimodipine were added at 0min respectively. After incubated for 30min, 60min, 90min, 120min or 240min, they were taken out, flushed with Krebs-Ringer solution for two or three times and weighed. 5mL physiological saline solution was added for every gram of intestine. Then the everted intestinal sac was homogenized by a homogenizer. The concentration of nimodipine in the homogenate was analyzed by HPLC. The superior, middle and inferior intestinal segments of approximately 10 cm in length were prepared just like the whole intestine we did before. The everted intestinal sac and SMEDDS contained 20mg nimodipine was added to the medium of 200mL Krebs-Ringer solution and incubated for 120min. By analyzing the concentration of nimodipine in the homogenate of intestine and the concentration of protein in the homogenate of intestine, we compared the absorption of nimodipine of SMEDDS and the conventional tablets in the whole intestine. In this way, the difference of absorption of nimodipine in the optimized formulation between different parts of intestine was studied. (3) The suspension of nimodipine conventional tablets and SMEDDS were orally administrated to two groups of rats with the dose of 12.5mg/kg respectively. The blood samples were drawn from the orbital vein of rats at 0,15,30,60,90,120,180,240,480,and 720min. As for the group of administrating by vein, the dose was 1.25mg/kg. The blood samples were also drawn from the orbital vein of rats at 0,5,10,20,40,60,120,180 , 240 , 480 and 720min. After dealing with all the samples, the concentration of nimodipine in the samples was analyzed by HPLC to get the concentration-time data. Then the main kinetic parameters were calculated by the DAS 2.1.1 software.
Results:(1) The ratios(%) of nimodipine, ethyl oleate, Cremophor EL, and GMC in the optimized formulation were 3.5%, 40%, 40% and 16.5% respectively. The optimized formulation was able to emulsify rapidly under gentle agitation within 1min in the 0.1mol ?L-1 HCl. And the average droplet size was 58.6nm. The dissolution of the optimized formulation in the medium of 0.1mol ?L-1 HCl was 84.3% after 1 min. The optimized formulation could keep stable after three monthes in the lab environment protected from light. (2) The detecting method of nimodipine in the homogenate of rat intestine by HPLC was set up. The chromatographic column was C18 analytical column(250 x 4.6 mm, 5μm, phenomenex). The column temperature was maintained at 25℃. The mobile phase consisted of 70% acetonitrile and 30% water. The flow rate was 1mL? min-1 with detection wavelength at 350nm. Injection volume was 20μL. The regression equation of standard curve was: Y=5.9968X+0.0415,r=0.9995. The linear range was 0.02~1.0mg?L-1. By analyzing the concentration of nimodipine in the homogenate of intestine and the concentration of protein in the homogenate of intestine, we found that the concentration of homogenate of intestine was much higher in the three groups of SMEDDS than that of in the group of conventional tablets. And the three groups of SMEDDS were dose-dependent. The concentration kept balance until 60min. Nimodipine of SMEDDS could be absorbed in the entire intestine, however, the absorption decreased progressly from superior to inferior. When incubated in SMEDDS contained 20mg nimodipine, the content of nimodipine in every 100μg protein were 0.0281±0.0036μg , 0.0240±0.0031μg ,0.0218±0.0026μg for superior, middle and inferior intestine. (3) The detecting method of nimodipine in the plasma of rats by HPLC was set up. The chromatographic column was C18 analytical column(250 x 4.6 mm, 5μm, phenomenex). The column temperature was maintained at 25℃. The mobile phase consisted of 70% acetonitrile and 30% water. The flow rate was 1mL? min-1 with detection wavelength at 350nm. Injection volume was 20μL. The regression equation of standard curve was: Y=2.2872X+0.1645,r=0.9991,The linear range was 0.02~1.0mg?L-1. Main pharmacokinetics parameters of conventional tablets group and SMEDDS group were as following: Cmax were 0.101±0.018 mg?L-1 and 0.147±0.085 mg?L-1; AUC were 9.674±1.674mg·min·L-1 and 19.620±7.275mg·min·L-1; MRT were 71.784±2.739 min and 199.636±62.382 min, Tmax was almost the same. The absolute bioavailability of SMEDDS was 9.84%. Comparing with the conventional tablets, relative bioavailability of SMEDDS was 202.8%.
Conclusion: (1) The optimized formulation is SMEDDS of nimodipine. (2)Both the results of everted intestinal sac in vitro and pharmacokinetics study in vivo of rats showed that the optimized formulation of SMEDDS could enhance the absorption of nimodipine which indicated that the optimized formulation of SMEDDS might have a promising future.
引文
1. Shah NH, Carvajal MT, Patel CI. Self-emulsifying drug delivery systems(SEDDS) with polyglycolyzed glycerides for improving vitro dissolution and oral aborption of lipophilic drugs [J]. Int J Pharm, 1994, 106(1):15-23.
2. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects [J].Pharm Res, 1995, 12(11):l561-l572.
3. Crison United States Patent,5993858(1999).
4. B T Gattefosse. The use of self-emulsifying systems as a means of improving drug delivery [J]. Int J Pharm, 1993, 86: 21-31.
5. Pouyon CW.Formulation of Self-emulsifying drug delivery systems [J]. Adv.Drug Delivery Rev, l997,25(4): 47-58.
6. Gershanik T.Benita S.Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Bio. 2000, 50(2):l79- 188.
7. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects[J]. Pharm Res, 1995, 12 (11): 1561-1572.
8. Amemiya T, Mizuno S, Yuasa H. Development of emulsion type new vehicle for soft gelatin capsule. I. Selection of surfactants for development of new vehicle and its physicochemical properties. Chem Pharm Bull, 1998, 46(2):309-313.
9. Bachynsky MO, Shah NH, Patel CI. Factors affecting the efficiency of aself-emulsifying oral delivery system. Drug Dev. Ind. Pharm. 1997, 23(8): 809-816.
10. Ping Li, Anasuya Ghosh, Robert F. Wagner. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions[J] . Int J Pharm, 2005, 288(1):27-34.
11.纪海英,张钧寿.尼群地平胶囊自乳化释药系统处方优化研究[J].中国药科大学学报,2004,35(3): 211-214.
12. Gershanik T, Benzeno S, Benita S. Interaction of a self-emulsifying lipid drug delivery system with the everted rat intestinal mucosa as a function of droplet size and surface charge [J]. Pharm Res, 1998, 15 (6): 863-869.
13. Pouton,CW.Formulation of self-emulsifying drug delivery system[J].Adv Drug Deliv Rev, 1997, 235:47-58.
14.陈宗淇,戴闽光.胶体化学[M].北京:高等教育出版社,1984, 342-345.
15. Schechter RS.Microemulsions and Releated Systems[M].New York:Marcel Dekker,1998:1-200.
16. Craig DQM,Barker SA,Banning D.An investigation into mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy[J].Int J Pharm,1995,114(1):103-113.
17. Nazzal H,Smalyn KH.Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone: mechanism and progress of emulsion formation [J].Int J Pharm,2002,235:247-265.
18.Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems [J]. Euro J Pharma Sci, 2000,11(2): 93-98.
19. Florence AT. The oral absorption of micro-and nano-particulates: neither exceptional nor unusual[J]. Pharm Res,1997,14(3):259-266.
20. Charman S A,Charman W N, Rogge MC.Self-emulsifying drug delivery systems:formulation and biopharmaceutic evaluation of an investigatinal lipophilic compound[J].Pharm Ras,l992, 9(1):87-93.
21. Serajuddin AT,Sheen PC,Mufson D.Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water- soluble drug from solid dispersion[J]. Pharm Sci, 1998,77(5):414-417.
22. Pouton CW. Effect of the inclusion of a model drug on the performation of self emulsifying formulation [J]. J Pharm Pharmacal, 1985, 37(1): 1-11.
23. Gershanik T,Benita S.Positively charged self-emulsifying oil formulation for improving oral bioavailability of progesterone[J].Pharm Dev and Tech,l996, l(2):l47-l57.
24.李莉,王中彦,莫凤奎.自乳化药物传递系统的研究概况.药学专论, 2005, 14(2):25-27.
25.何仲贵,崔升森.葛根黄酮自微乳化软胶囊及其制备方法,中国CN1457795A[P]2003-l1-26.
26.何仲贵,唐景玲.银杏叶提取物自微乳化软胶囊及其制备方法,中国CN1457796A[P]2003-l1-26.
27.李国栋.中药挥发油自乳化释药系统:中国,CNl366877[P]2002-09-04.
28. Sami Nazzal, Mansoor A. Khan. Controlled Release of a Self-Emulsifying Formulation from a Tablet Dosage Form: Stability Assessment and Optimization of Some Processing Parameters[J]. Int J Pharm,2006,315(1-2):110-121.
29. Jian You, Fu-de Cui. Study of the preparation of sustained-release microspheres containing zedoary turmeric oil by the emulsion–solvent-diffusion method and evaluation of the self-emulsification and bioavailability of the oil[J]. Colloids Surf , 2006 (48) 35–41.
30.涂秋榕,朱颖,朱家璧.尼莫地平自微乳化液的处方研究[J].中国药学杂志,2005,40(1):43-46.
31. Ehab I. Taha, Saleh Al-Saidan, Mansoor A. Khana. Preparation and in vitro characterization of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate [J]. Int J Pharm, 2004,285(1-2):109-119.
32. Pouton CW. Formulation of self-emulsifying delivery systems [J]. Adv Drug Deliv Rev, 1997, 25(4): 47-58.
33.刘华,李三鸣,袁悦.酮洛芬自乳化制剂处方及化学稳定性研究[J].沈阳药科大学学报, 2005, 22(1): 5-14.
34. Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs [J]. Eur J Pharm Bio, 2000, 50(2):179- 188.
35. Bachynsky MO, Shah NH, Patel CI. Factors affecting the effecting the efficiency of a self-emulsifying oral delivery system [J]. Drug Dev Ind. Pharm, 1997, 23(8):809-816.
36. Ling Wang, Xuehua Jiang, Weijuan Xu. Complexation of tanshinone IIA with 2-hydroxypropyl-β-cyclodextrin: Effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats[J]. Int J Pharm, 2007, 341(1-2): 58-67.
37. D. Suresh, K. Srinivasan. Studies on the in vitro absorption of spice principles– Curcumin, capsaicin and piperine in rat intestines[J]. Food Chem. Toxicol, 2007(45) 1437-1442.
38. M.F. Mahomoodally, A. Gurib-Fakim, A.H. Subratty. Effect of exogenous ATP on Momordica charantia Linn. (Cucurbitaceae) induced inhibition ofd-glucose, l-tyrosine and fluid transport across rat everted intestinal sacs in vitro[J]. J. Ethnopharmacol , 2007 (110) 257–263.
39. Pradeep Sharma, Singh Chawla, Ramesh Panchagnula. Analytical method for monitoring concentrations of cyclosporin and lovastatin in vitro in an everted rat intestinal sac absorption model [J]. J. Chromatogr. B, 2002, (768)349–359.
40. L. Barthe, M. Bessouet, G. Houin, The improved everted gut sac: a simple method to study intestinal P-glycoprotein[J]. Int J Pharm, 1998 ,(173) 255–258.
41.李文浩何应. 5-氟尿嘧啶口服微乳的制备及其大鼠肠吸收作用研究[J].中国药房. 2008, 19(7): 501-503.
42.王梅高晓黎.齐墩果酸新型前体脂质体大鼠小肠吸收实验研究[J].新疆医科大学学报. 2007, 30(2): 122-124.
43.张学农,唐丽华.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志. 2005, 24(4): 294-298.
44.戴幼琴,张瑜.尼莫地平纳米脂质微粒大鼠体内药动学及生物利用度研究[J].中国药学杂志. 2007, 42(24): 1885-1887.
45.刘晓兰,陈钰瑛.尼莫地平在大鼠体内的药物代谢动力学研究[J].中国医学杂志. 2007, 5(7): 3-5.
46. Christian H?cht, Alberto Lazarowski. Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model[J]. Neuroscience Letters, 2007 (413)168–172.
47. Qizhi Zhang, Xinguo Jiang, Wenming Jiang. Preparation of nimodipine- loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain[J]. Int J Pharm, 2004 (275)85–96.
48. Muck W, Breuel H.P, Kuhlmann. The influence of age on thepharmacokinetics of nimodipine. J. Clin. Pharmacol. 1996(34) 293–298.
49. Gao Z.G., Choi H.G., Shin H.J. Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A[J]. Int J Pharm, 1998,161 (1): 75-86.
50. Shui-Mei Khoo, Andrew J. Humberstone. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine[J]. Int J Pharm, 1998 (167) 155–164.
51. P.Chris de Smidt, Miguel A. Campanero. Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: contribution of emulsification versus digestibility[J]. Int J Pharm, 2004 (270) 109–118.
2. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects [J].Pharm Res, 1995, 12(11):l561-l572.
3. Crison United States Patent,5993858(1999).
4. B T Gattefosse. The use of self-emulsifying systems as a means of improving drug delivery [J]. Int J Pharm, 1993, 86: 21-31.
5. Pouyon CW.Formulation of Self-emulsifying drug delivery systems [J]. Adv.Drug Delivery Rev, l997,25(4): 47-58.
6. Gershanik T.Benita S.Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Bio. 2000, 50(2):l79- 188.
7. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects[J]. Pharm Res, 1995, 12 (11): 1561-1572.
8. Amemiya T, Mizuno S, Yuasa H. Development of emulsion type new vehicle for soft gelatin capsule. I. Selection of surfactants for development of new vehicle and its physicochemical properties. Chem Pharm Bull, 1998, 46(2):309-313.
9. Bachynsky MO, Shah NH, Patel CI. Factors affecting the efficiency of aself-emulsifying oral delivery system. Drug Dev. Ind. Pharm. 1997, 23(8): 809-816.
10. Ping Li, Anasuya Ghosh, Robert F. Wagner. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions[J] . Int J Pharm, 2005, 288(1):27-34.
11.纪海英,张钧寿.尼群地平胶囊自乳化释药系统处方优化研究[J].中国药科大学学报,2004,35(3): 211-214.
12. Gershanik T, Benzeno S, Benita S. Interaction of a self-emulsifying lipid drug delivery system with the everted rat intestinal mucosa as a function of droplet size and surface charge [J]. Pharm Res, 1998, 15 (6): 863-869.
13. Pouton,CW.Formulation of self-emulsifying drug delivery system[J].Adv Drug Deliv Rev, 1997, 235:47-58.
14.陈宗淇,戴闽光.胶体化学[M].北京:高等教育出版社,1984, 342-345.
15. Schechter RS.Microemulsions and Releated Systems[M].New York:Marcel Dekker,1998:1-200.
16. Craig DQM,Barker SA,Banning D.An investigation into mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy[J].Int J Pharm,1995,114(1):103-113.
17. Nazzal H,Smalyn KH.Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone: mechanism and progress of emulsion formation [J].Int J Pharm,2002,235:247-265.
18.Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems [J]. Euro J Pharma Sci, 2000,11(2): 93-98.
19. Florence AT. The oral absorption of micro-and nano-particulates: neither exceptional nor unusual[J]. Pharm Res,1997,14(3):259-266.
20. Charman S A,Charman W N, Rogge MC.Self-emulsifying drug delivery systems:formulation and biopharmaceutic evaluation of an investigatinal lipophilic compound[J].Pharm Ras,l992, 9(1):87-93.
21. Serajuddin AT,Sheen PC,Mufson D.Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water- soluble drug from solid dispersion[J]. Pharm Sci, 1998,77(5):414-417.
22. Pouton CW. Effect of the inclusion of a model drug on the performation of self emulsifying formulation [J]. J Pharm Pharmacal, 1985, 37(1): 1-11.
23. Gershanik T,Benita S.Positively charged self-emulsifying oil formulation for improving oral bioavailability of progesterone[J].Pharm Dev and Tech,l996, l(2):l47-l57.
24.李莉,王中彦,莫凤奎.自乳化药物传递系统的研究概况.药学专论, 2005, 14(2):25-27.
25.何仲贵,崔升森.葛根黄酮自微乳化软胶囊及其制备方法,中国CN1457795A[P]2003-l1-26.
26.何仲贵,唐景玲.银杏叶提取物自微乳化软胶囊及其制备方法,中国CN1457796A[P]2003-l1-26.
27.李国栋.中药挥发油自乳化释药系统:中国,CNl366877[P]2002-09-04.
28. Sami Nazzal, Mansoor A. Khan. Controlled Release of a Self-Emulsifying Formulation from a Tablet Dosage Form: Stability Assessment and Optimization of Some Processing Parameters[J]. Int J Pharm,2006,315(1-2):110-121.
29. Jian You, Fu-de Cui. Study of the preparation of sustained-release microspheres containing zedoary turmeric oil by the emulsion–solvent-diffusion method and evaluation of the self-emulsification and bioavailability of the oil[J]. Colloids Surf , 2006 (48) 35–41.
30.涂秋榕,朱颖,朱家璧.尼莫地平自微乳化液的处方研究[J].中国药学杂志,2005,40(1):43-46.
31. Ehab I. Taha, Saleh Al-Saidan, Mansoor A. Khana. Preparation and in vitro characterization of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate [J]. Int J Pharm, 2004,285(1-2):109-119.
32. Pouton CW. Formulation of self-emulsifying delivery systems [J]. Adv Drug Deliv Rev, 1997, 25(4): 47-58.
33.刘华,李三鸣,袁悦.酮洛芬自乳化制剂处方及化学稳定性研究[J].沈阳药科大学学报, 2005, 22(1): 5-14.
34. Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs [J]. Eur J Pharm Bio, 2000, 50(2):179- 188.
35. Bachynsky MO, Shah NH, Patel CI. Factors affecting the effecting the efficiency of a self-emulsifying oral delivery system [J]. Drug Dev Ind. Pharm, 1997, 23(8):809-816.
36. Ling Wang, Xuehua Jiang, Weijuan Xu. Complexation of tanshinone IIA with 2-hydroxypropyl-β-cyclodextrin: Effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats[J]. Int J Pharm, 2007, 341(1-2): 58-67.
37. D. Suresh, K. Srinivasan. Studies on the in vitro absorption of spice principles– Curcumin, capsaicin and piperine in rat intestines[J]. Food Chem. Toxicol, 2007(45) 1437-1442.
38. M.F. Mahomoodally, A. Gurib-Fakim, A.H. Subratty. Effect of exogenous ATP on Momordica charantia Linn. (Cucurbitaceae) induced inhibition ofd-glucose, l-tyrosine and fluid transport across rat everted intestinal sacs in vitro[J]. J. Ethnopharmacol , 2007 (110) 257–263.
39. Pradeep Sharma, Singh Chawla, Ramesh Panchagnula. Analytical method for monitoring concentrations of cyclosporin and lovastatin in vitro in an everted rat intestinal sac absorption model [J]. J. Chromatogr. B, 2002, (768)349–359.
40. L. Barthe, M. Bessouet, G. Houin, The improved everted gut sac: a simple method to study intestinal P-glycoprotein[J]. Int J Pharm, 1998 ,(173) 255–258.
41.李文浩何应. 5-氟尿嘧啶口服微乳的制备及其大鼠肠吸收作用研究[J].中国药房. 2008, 19(7): 501-503.
42.王梅高晓黎.齐墩果酸新型前体脂质体大鼠小肠吸收实验研究[J].新疆医科大学学报. 2007, 30(2): 122-124.
43.张学农,唐丽华.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志. 2005, 24(4): 294-298.
44.戴幼琴,张瑜.尼莫地平纳米脂质微粒大鼠体内药动学及生物利用度研究[J].中国药学杂志. 2007, 42(24): 1885-1887.
45.刘晓兰,陈钰瑛.尼莫地平在大鼠体内的药物代谢动力学研究[J].中国医学杂志. 2007, 5(7): 3-5.
46. Christian H?cht, Alberto Lazarowski. Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model[J]. Neuroscience Letters, 2007 (413)168–172.
47. Qizhi Zhang, Xinguo Jiang, Wenming Jiang. Preparation of nimodipine- loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain[J]. Int J Pharm, 2004 (275)85–96.
48. Muck W, Breuel H.P, Kuhlmann. The influence of age on thepharmacokinetics of nimodipine. J. Clin. Pharmacol. 1996(34) 293–298.
49. Gao Z.G., Choi H.G., Shin H.J. Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A[J]. Int J Pharm, 1998,161 (1): 75-86.
50. Shui-Mei Khoo, Andrew J. Humberstone. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine[J]. Int J Pharm, 1998 (167) 155–164.
51. P.Chris de Smidt, Miguel A. Campanero. Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: contribution of emulsification versus digestibility[J]. Int J Pharm, 2004 (270) 109–118.