环孢素A-羟丙甲纤维素酞酸酯纳米粒的大鼠相对生物利用度

目的制备环孢素A-HPMCP(两种型号HP50与HP55)纳米粒，并与新山地明(Neoral)进行大鼠相对生物利用度与药物动力学行为的比较。方法以溶剂-非溶剂法制备CyA-HP50 NP与CyA-HP55 NP，用HPLC法测定其相对生物利用度，并用3P97程序计算药代动力学参数。结果3种制剂的血药浓度-时间数据均以2室模型拟合最佳。与Neoral相比，CyA-HP50 NP与CyA-HP55 NP的相对生物利用度分别为82.3%和119.6%，均无显著性差异；CyA-HP50 NP与CyA-HP55 NP的K₁₀均较小(P<0.05)，说明药物消除较慢。与CyA-HP50 NP相比，CyA-HP55 NP的相对生物利用度为145.3%，有显著性差异(P<0.01)。结论CyA-HPMCP NP 制备方法简便，生物利用度高，可望开发为一种新的制剂。     

环孢素A pH敏感性纳米粒的制备与大鼠口服药代动力学

目的研究环孢素A(CyA) pH敏感性纳米粒的制备工艺与口服药代动力学性质。方法采用改良的乳化-溶剂扩散技术(QESD)制备CyA pH敏感性纳米粒；经大鼠灌胃给药，HPLC法测定全血药物浓度，计算口服相对生物利用度。结果经3P87程序拟合，确定CyA在大鼠体内的药代动力学过程为二室模型；与Neoral微乳相比，CyA-E100，CyA-L100，CyA-L100-55和CyA-S100纳米粒的相对生物利用度分别为94.8%，115.2%，113.6%和132.5%。结论经统计分析，CyA-S100纳米粒可以显著改善CyA的生物利用度(P<0.05)，而CyA-L100-55纳米粒，CyA-L100纳米粒和CyA-E100纳米粒与Neoral微乳相比无显著性差异。实验结果表明,pH敏感性纳米粒有望成为促进蛋白、多肽类药物及难溶性药物口服吸收的有效载体。     

盐酸阿霉素聚乳酸纳米粒的制备及大鼠体内药动学研究

目的 优化盐酸阿霉素聚乳酸纳米粒（DOX-PLA-NPs）的制备工艺,并对其理化性质、体外释放及大鼠体内药动学进行研究。方法 采用改良的复乳-溶剂挥发法制备DOX-PLA-NPs,正交设计优化其处方工艺,对其纳米粒形态、粒径、Zeta电位、包封率与载药量进行测定。以DOX原药为对照组,考察DOX-PLA-NPs的体外释药特性及大鼠尾静脉给药后的体内药动学参数。结果 DOX-PLA-NPs外观圆整,平均粒径为（125.67±3.80） nm、Zeta电位为（-35.97±1.58） mV、包封率和载药量分别为（81.23±1.46）%,（10.29±0.63）%。体外释放结果显示,DOX经纳米粒包裹后,具明显的缓释作用。DOX原药和纳米粒的体内药动学过程均符合开放式二室模型,t_1/2β分别为（1.15±0.175） h、（6.43±2.12） h,CL分别为（174.76±47.22） h·L^-1、（30.68±11.86） h·L^-1,AUC_0→t分别为（6.01±1.61）μg·h·L^-1、（36.04±13.72）μg·h·L^-1。结论 制备的盐酸阿霉素聚乳酸纳米粒粒径较小、包封率较高,具明显的缓释作用,并能提高药物的生物利用度。     

克林沙星在大鼠体内的药代动力学和生物利用度

目的　研究克林沙星在大鼠体内的药动学和生物利用度。方法　HPLC法测定大鼠ig和iv克林沙星后的血药浓度,计算药动学参数和生物利用度。色谱柱为C₁₈柱(5μm),流动相为乙腈-0.05mol·L^-1柠檬酸三乙胺液(pH2.5)(20∶80),流速为1.0mL·min^-1,检测波长300nm。结果　克林沙星0.1-20μg·mL^-1呈良好线性关系,在大鼠体内的药动学过程符合一室模型,大鼠ig50和100mg·kg^-1后,C_max和AUC均与剂量呈正比,T_1/2与剂量无关;绝对生物利用度(F)为42%。结论　克林沙星50-100mg·kg^-1的吸收和消除呈一级动力学特征,在大鼠体内的生物利用度低。     

替硝唑片在健康人体的药代动力学和相对生物利用度

目的 研究替硝唑片在健康人体的药代动力学和相对生物利用度。方法 采用高效液相色谱法测定20名健康男性志愿者,随机交叉单剂量口服替硝唑片1g后血浆中的药物浓度,计算药代动力学参数和相对生物利用度,并进行生物等效性评价。结果 受试和参比替硝唑片的t_1/2分别为(13.98±1.55)h、(13.80±0.93)h,t_max分别为(2.1±1.0)h、(2.3±0.9)h,c_max分别为(18.60±2.27)mg·L^-1、(18.47±3.14)mg·L^-1,AUC_0-τ分别为(368.49±44.08)mg·L^-1·h^-1、(353.86±40.99)mg·L^-1·h^-1。受试制剂于参比制剂的人体相对生物利用度为104.9±13.4%。结论 两种制剂的药代动力学参数相近,具有生物等效性。     

双烟酸姜黄素酯纳米粒与双烟酸姜黄素酯体内转运动力学特性研究

目的 提高双烟酸姜黄素酯的生物利用度，考察双烟酸姜黄素酯是否代谢为姜黄素。方法 以新西兰家兔为试验对象，采用口服给予双烟酸姜黄素酯纳米粒与双烟酸姜黄素酯原料药后，在不同时间点采血，HPLC测定血中双烟酸姜黄素酯、姜黄素等成分含量，计算体内药物转运动力学参数AUC，比较两者的差别。结果 采用统计矩法中的零阶矩法计算AUC，原料药的AUC平均值为（354.835±8.660）μg·L^-1·h，而纳米粒的AUC平均值为（883.335±16.37）μg·L^-1·h。纳米粒的AUC是原料药AUC的2.486倍。可知纳米粒与原料药相比显著提高了生物利用度；血中未检测到姜黄素。结论 双烟酸姜黄素酯制成纳米粒可显著提高双烟酸姜黄素酯的生物利用度；双烟酸姜黄素酯在体内没有代谢为姜黄素。     

溴泰君(W198)在大鼠和比格狗体内的药代动力学

目的研究溴泰君(W198)在大鼠和比格狗的药代动力学。方法采用HPLC紫外检测方法测定大鼠及比格狗注射W198后血清药物浓度。结果大鼠iv W198 10,20和40 mg·kg^-1 3个剂量的T_1/2β分别为6.60,7.36和6.77 h,AUC_0-24h分别为3.797,7.371和15.192 mg·h·L^-1,V_d分别为7.14,4.33和4.13 L·kg^-1,CL分别为2.83,2.60和2.71 L·(kg·h)^-1。大鼠im W198 20 mg·kg^-1后T_1/2β为11.61 h,AUC_0-24h为4.191 mg·h·L^-1,im的生物利用度为56.9%。比格狗iv W198 5 mg·kg^-1,T_1/2β为11.72 h,AUC_0-24h为12.646 mg·h·L^-1,V_d为0.70 L·kg^-1,CL为0.46 L·(kg·h)^-1。W198与人血浆蛋白的结合率平均为78.0%。结论W198 im的T_1/2β比iv的略长,其生物利用度为56.9%。在10～40 mg·kg^-1剂量内的吸收呈现一级动力学特征。     

汉黄芩素固体脂质纳米粒在大鼠体内的药动学及组织分布

摘 要 目的:研究汉黄芩素固体脂质纳米粒在大鼠体内的药动学及组织分布情况。方法: 大鼠随机分成汉黄芩素注射液组和汉黄芩素固体脂质纳米粒组,分别于给药后不同时间采血测定汉黄芩素含量,并测定两组大鼠心、肝、脾、肺、肾中汉黄芩素含量,计算靶向效率以评价其在大鼠体内的组织分布及靶向性。结果:汉黄芩素固体脂质纳米粒在大鼠体内的药动学模型符合二室模型,主要药动学参数为：t_1/2α=（0.551 0±0.124 7）h, t_1/2β=(14.589 1±1.563 8)h, CL=(0.006 4±0.001 4) ml·h·Kg^-1, AUC_0→∞=(125.76±9.5728) mg·h·L^-1,其在肝脏、脾脏、心脏、肺脏及肾脏的靶向效率分别为2.003、1.789、0.634、0.707、0.259。结论:与汉黄芩素溶液相比,汉黄芩素固体脂质纳米粒能提高对肝脏、脾脏的趋向性,有利于提高其治疗作用。     

头孢克肟颗粒在健康受试者体内的生物利用度及其药代动力学

目的 研究头孢克肟颗粒在健康人体内的药代动力学及相对生物利用度。方法 20名健康男性志愿者随机交叉单剂量口服200mg头孢克肟及参比制剂;采用HPLC法测定血药浓度。结果 受试及参比制剂药动学参数分别为C_max(3.15±0.82)和(3.17±0.84)mg·L^-1,t_max(4.6±0.7)和(5.1±0.5)h,t_1/2(4.64±1.44)和(4.18±1.09)h,AUC_0～t(28.54±8.68)和(27.81±8.38)h·mg·L^-1,MRT(8.90±2.03)和(8.78±0.99)。经统计分析,两种制剂的药物动力学参数均无显著性差异;头孢克肟颗粒的相对生物利用度为(103.4±14.7)%。结论 两种制剂具有生物等效性。     

紫杉醇PLGA纳米粒大鼠生物利用度的测定

目的制备紫杉醇PLGA纳米粒,以紫杉醇注射液为参比制剂,进行生物利用度考察。方法以乳化-溶剂挥发法制备紫杉醇纳米粒,用HPLC法测定全血中的药物浓度,计算紫杉醇纳米粒的生物利用度。结果紫杉醇纳米粒外观圆整,平均粒径为99.0nm,Zeta电位58.3mV,平均包封率为56.77%,载药量为7.10%。大鼠口服给药后,紫杉醇纳米粒的绝对生物利用度达到19.5%。结论纳米载药系统的制备有利于促进紫杉醇的吸收,提高了其口服生物利用度。     

pH-sensitive nanoparticles for improving the oral bioavailability of cyclosporine A

The purpose of this work was to improve the oral bioavailability of cyclosporine A (CyA) by preparation the CyA-pH sensitive nanoparticles. The CyA-pH sensitive nanoparticles were prepared by using poly(methacrylic acid and methacrylate) copolymer. The characterization and the dispersion state of CyA at the surface or inside the polymeric matrices of the nanoparticles were investigated. The in vitro release studies were conducted by ultracentrifuge method. The bioavailability of CyA from nanoparticles and Neoral microemulsion was assessed in Sprague–Dawley (SD) rats at a dose of 15 mg/kg. The particle size of the nanoparticles was within the range from 37.4 ± 5.6 to 106.7 ± 14.8 nm. The drug entrapped efficiency was very high (from 90.9 to 99.9%) and in all cases the drug was amorphous or molecularly dispersed within the nanoparticles polymeric matrices. In vitro release experiments revealed that the nanoparticles exhibited perfect pH-dependant release profiles. The relative bioavailability of CyA was markedly increased by 32.5% for CyA-S100 nanoparticles (P < 0.05), and by 15.2% and 13.6% for CyA-L100-55 and CyA-L100 nanoparticles respectively, while it was decreased by 5.2% from CyA-E100 nanoparticles when compared with the Neoral microemulsion. With these results, the potential of pH-sensitive nanoparticles for the oral delivery of CyA was confirmed.     

环孢素A硬脂酸纳米球的实验研究

目的：探讨硬脂酸纳米球作为新型药物载体的可能性。方法：制备了硬脂酸纳米球(SA-NP),用电镜考察其形态,测定了各种理化特性;以环孢素A(CYA)为模型药物,制备了环孢素A硬脂酸纳米球(CYA-SA-NP);对其进行了红外光谱测定和差示扫描量热分析;建立了测定CYA-SA-NP和血中CYA的HPLC法。以市售CYA微乳型口服液为对照,测定了口服CYA-SA-NP在大鼠体内的药代动力学参数和相对生物利用度。结果：CYA-SA-NP的平均粒径为316.6nm,CYA的平均包封率为88.39%,CYA和硬脂酸之间无化学反应发生;CYA-SA-NP的相对生物利用度接近80%,而且达峰时间较晚,具有明显的缓释效果。结论：硬脂酸纳米球将可能成为一种新型的药物载体。     

Oral evaluation in rabbits of cyclosporin-loaded Eudragit RS or RL nanoparticles

The hydrophobic cyclic undecapeptide cyclosporin A (CyA) used in the prevention of graft rejection and in the treatment of autoimmune diseases was encapsulated by nanoprecipitation within non-biodegradable polymeric nanoparticles. The effect of polymers (Eudragit RS or RL) and additives within the alcoholic phase (fatty acid esters and polyoxyethylated castor oil) on the size, zeta potential and the encapsulation efficiency of the nanoparticles was investigated. The mean diameter of the various CyA nanoparticles ranged from 170 to 310 nm. The size as well as the zeta potential increased by adding fatty acid ester and polyoxyethylated castor oil within the organic phase. No significant differences in surface potential were observed for all formulations tested. Probably due to the very low water solubility of the drug, high encapsulation efficiencies were observed in a range from 70 to 85%. The oral absorption of CyA from these polymeric nanoparticles was studied in rabbits and compared to that of Neoral capsule. Based on comparison of the area under the blood concentration-time curve values, the relative bioavailability of CyA from each nanoparticulate formulation ranged from 20 to 35%.     

环孢素A纳米粒在小鼠体内的药动学及组织分布

目的:研究环孢素A纳米粒(CyA-NP)在小鼠体内组织分布,并与市售新山地明微乳制剂(Neoral)的组织分布特征进行比较。方法:取小鼠120只,随机分为20组,每组6只,前10组小鼠按25mg·kg-1的剂量灌胃给予Neoral溶液,后10组灌胃给予等剂量的CyA-NP溶液,于给药后不同时间摘眼球取血及制备各组织样品,各样品中的药物采用液-液萃取法提取,建立高效液相色谱(HPLC)法测定血液及各组织中不同时间的药物浓度,以各组织药动学参数和靶向参数为评价指标,对2种制剂在小鼠体内的分布特征和靶向性进行评价。结果:血药浓度测定方法的回收率均大于72%,日内、日间精密度良好;2种制剂在小鼠体内均符合口服吸收二室模型;与Neoral比较,CyA-NP给药后CyA在血液及各组织中药物浓度较快达到峰值,相对生物利用度为162.5%;在体内药物浓度分布趋势为肝>心>肾>脾>肺,在肝中无蓄积。结论:与Neoral比较,CyA-NP体内分布迅速,组织分布广泛,促进了药物口服吸收,改变了CyA在体内的组织分布,有助于提高临床用药水平,对局部脏器移植有更好的疗效。     

Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A

In this study, cyclosporin-A (Cy-A) a highly lipophilic, poorly absorbable drug can be prepared easily and reproducibly as positively and negatively charged nanoparticles with the aim of improving its bioavailability and reducing its inter- and intra-individual variability. The nanoparticles were prepared by emulsification solvent diffusion method, using lecithin and poloxamer 188 as emulsifiers, and chitosan HCl, gelatin-A or sodium glycocholate (SGC) as charge inducing agents. The prepared nanoparticles were evaluated with respect to particle size, zeta potential, drug content and encapsulation efficiency. The bioavailability Cy-A from nanoparticles in comparison with the currently available Cy-A microemulsion (Neoral) were assessed in beagle dogs. The results obtained revealed that, it was possible to prepare Cy-A as nanoparticles with size range of 104-148 nm. Chitosan HCl and gelatin-A nanoparticles exhibited +31.2 and +23.1 mV zeta potential, respectively; while SGC-nanoparticles exhibited -41.6 mV zeta potential. The in vivo results showed that, chitosan-nanoparticles gave the highest C(max) (2762.8 ng/ml) of Cy-A after 2.17 h (T(max)), while SGC-nanoparticles gave the lowest one (1202.4 ng/ml after 4.0 h). Furthermore, AUC(0-24) of Cy-A from chitosan-nanoparticles was markedly increased by about 2.6-fold when compared with SGC-nanoparticles and increased by about 1.8-fold when compared with the reference Neoral microemulsion. However, in case of gelatin-nanoparticles the AUC(0-24) of Cy-A increased by about 1.8 and 1.2-fold when compared with SGC-nanoparticles and the reference Neoral microemulsion, respectively. The relative bioavailability of Cy-A from chitosan-nanoparticles was increased by about 73%, and by about 18% from gelatin nanoparticles, while it was decreased by about 36% from SGC-nanoparticles.     

聚乙二醇-聚十六烷基氰丙烯酸酯聚合物及其纳米粒的制备

聚乙二醇氰乙酸酯和十六烷基氰乙酸酯聚合得到两亲性的标题聚合物,通过IR、1HNMR及凝胶渗透色谱法等确证结构.将此聚合物用溶剂-非溶剂法所制得的纳米粒粒径为100～400nm,分布均匀.     

口服胰岛素羧甲基壳聚糖纳米粒的制备及评价

目的:研制一种生物利用度高且具有缓释作用的口服胰岛素制剂。方法:通过钙离子交联制备羧甲基壳聚糖纳米粒,采用正交试验优化纳米粒制备条件,以透射电镜观察纳米粒形态,激光粒度分析仪测定粒度,高效液相色谱法测定纳米粒包封率和载药量,并对胰岛素的体外释放性能进行考察。结果:优化工艺制备的纳米粒外观形态圆整,平均粒径为(256.1±11.2)nm,包封率为(45±0.41)%,载药量为(17.2±0.33)%,药理相对生物利用度为14.71%。结论:口服载胰岛素羧甲基壳聚糖纳米粒具有降血糖作用和显著的缓释作用,药理相对生物利用度高。     

Bioavailability of Sandimmun® versus Sandimmun Neoral®: a meta-analysis of published studies

For the past 25 years, cyclosporine A (CyA) has played a pivotal role in transplant immunosuppressant therapy. From the availability of the 2 primary marketed formulations (Sandimmun? and Sandimmun Neoral?, Novartis), confusion has existed with regard to whether these two formulations are bioequivalent. Due to the underlying clinical relevance of this information, we therefore conducted a meta-analysis of all available comparative pharmacokinetic studies to assess whether the two different CyA formulations, Sandimmun? and Sandimmun Neoral?, can be considered bioequivalent. All clinical studies that compared the bioavailability of the 2 formulations in organ transplant recipients were considered for analysis. We searched computerised databases (Embase/Excerpta Medica and Medline/PubMed) from their inception to May 2010. Only studies with AUC values determined at 12 hours were considered for analysis. Relative bioavailability was calculated with 90 percent confidence intervals (CI) for Sandimmun? (test substance) versus Sandimmun Neoral? (reference substance) according to Schuirmann?s Two One-Sided Tests Procedure and the Classical Shortest CI. Homogeneity of data was tested using the Χ(2) test. Fifteen studies were considered for meta-analysis and none of these studies reported AUC values in the 80-125 percent range required for the bioequivalence of two formulations. The overall bioavailability for Sandimmun? versus the microemulsion formulation Sandimmun Neoral? was 76 percent, with upper CI limits lower than 80 percent in some cases. Mean AUC values for Sandimmun? were significantly lower than those for Sandimmun Neoral? (p<0.01). This study demonstrates that the 2 main cyclosporine formulations, Sandimmun? and Sandimmun Neoral?, cannot be considered bioequivalent.