番茄红素脂质体的体外释放及大鼠体内药代动力学和抗氧化功能

利用旋转薄膜-超声法制备了番茄红素脂质体并研究其体外释放，大鼠体内药代动力学和对机体抗氧化能力的影响。用液相色谱法测定大鼠体内的番茄红素含量，所得数据进行3P97程序处理，得到各主要药代动力学参数；配制人工胃液和肠液，比较番茄红素油和番茄红素脂质体的体外释放效果；番茄红素油和番茄红素脂质体灌胃后，用试剂盒测定大鼠血清和肝组织匀浆中的超氧化物歧化酶活性、丙二醛、总抗氧化能力、过氧化氢酶及谷胱甘肽过氧化酶的含量。结果显示，脂质体体外释放呈肠溶性；番茄红素油及番茄红素脂质体的T_max分别为4.45和7.45 h；C_max为0.473和0.654 μg·mL^-1；AUC分别为12.38和21.67 μg·h·mL^-1。抗氧化指标测定结果表明：番茄红素脂质体比番茄红素油显著地提高机体内抗氧化酶的活力，抑制脂质过氧化。     

灯盏花素在家犬体内的药代动力学

目的建立高效液相色谱法测定家犬血浆中灯盏花素主要有效成分灯盏乙素的浓度,研究灯盏花素在家犬体内的药代动力学。方法用高效液相色谱法测定6只家犬iv灯盏花素(以灯盏乙素计为120 mg/只)后不同时间血浆中灯盏乙素的浓度,绘制药-时曲线,计算药代动力学参数。结果灯盏乙素的药-时曲线符合三室模型,其T_1/2 γ,T_1/2α和T_1/2β分别为(1.1±0.8) min,(7.0±2.8) min和(52±29) min;Vc为(880±508) mL;CL为(190±54) mL·min^-1;AUC_0-90和AUC_0-∞分别为(574±134) mg·min·L^-1和(599±132) mg·min·L^-1。结论灯盏花素家犬iv给药后,血浆中灯盏乙素浓度迅速下降,提示制剂开发的剂型选择、临床给药方法或给药间隔时间的确定都应该考虑其T_1/2。     

泻心汤黄酮类成分在大鼠体内的药代动力学研究

研究泻心汤中黄酮类成分在大鼠体内药代动力学规律。大鼠灌胃给予泻心汤12 g·kg^-1，给药前及给药后不同时间采集血样或尿样，HPLC法测定黄酮类成分浓度，血药浓度-时间数据和尿药排泄量-时间数据用DAS软件进行动力学分析。采用大鼠肾匀浆温孵法，进行黄芩苷的体外代谢研究。结果显示,黄芩苷、汉黄芩苷血药浓度迅速达峰，药时曲线呈现双峰现象，消除T_1/2均为6 h左右；黄芩苷、汉黄芩苷、黄芩素、汉黄芩素在尿中均有排泄，尿中排泄量占给药量均<10%，尿排泄T_1/2在6～8 h；大鼠肾匀浆可将黄芩苷代谢生成黄芩素，酶动力学参数V_max＝702 nmol·min^-1·g^-1(protein)，K_m＝135 μmol·L^-1。可见，泻心汤中黄酮类成分可迅速吸收进入体内；黄芩苷、汉黄芩苷、黄芩素、汉黄芩素均可从尿排泄，但尿药排泄量较少；肾脏可将黄芩苷代谢成黄芩素。     

水飞蓟宾磷脂复合物的制备与大鼠生物利用度的研究

目的制备水飞蓟宾磷脂复合物并对其理化性质进行考察，比较水飞蓟宾磷脂复合物与水飞蓟宾原料在大鼠体内的生物利用度。方法以丙酮为溶剂，加入水飞蓟宾和大豆磷脂，充分搅拌至澄清，真空干燥即得黄白色固体；用DSC，UV，IR等方法测定水飞蓟宾磷脂复合物的理化性质；两组大鼠分别灌胃给予水飞蓟宾磷脂复合物和水飞蓟宾原料后，用RP-HPLC法测定不同时间血浆中总的和游离的水飞蓟宾的浓度，通过3P97程序计算药代动力学参数。结果研究表明水飞蓟宾磷脂复合物是以非共价键结合，而不是新的化合物；水飞蓟宾磷脂复合物明显改善了水飞蓟宾在水中及正辛醇中的溶解性能；大鼠灌胃给予水飞蓟宾磷脂复合物，体内吸收符合一级吸收一室模型，血浆中游离药物和总的药物浓度的T_max分别为10 min和2 h；C_max分别为0.11和1.08 μg·mL^-1；T_1/2分别为2.18和3.84 h；AUC_0～∞分别为1.71和12.94 μg·mL^-1·h，而给予水飞蓟宾原料，大鼠体内吸收的浓度在检测限以下，不能测定。结论水飞蓟宾磷脂复合物与水飞蓟宾原料相比亲脂性显著增加，从而增强了水飞蓟宾在胃肠道中的吸收，提高了水飞蓟宾的口服生物利用度。     

吹扫捕集-气相色谱-质谱联用测定试验犬体内全氟丙烷血药浓度

目的建立对一种新型的包裹全氟丙烷气体的白蛋白微囊超声造影剂静脉给药后直接测定全氟丙烷血药浓度的方法，研究全氟丙烷在试验犬体内的药代动力学行为。方法试验犬麻醉后静脉给药，给药剂量0.6 mL·kg^-1，取全血样品，直接进样。应用Tekmar 3000吹扫捕集-气相色谱质谱组合分析仪对全氟丙烷血药浓度进行定量分析，用非室模型计算药代动力学参数。结果全氟丙烷测定的线性范围为0.016 8-4.03 mg·L^-1。主要药代动力学参数平均滞留时间(MRT)为(63±5) s,T_1/2为(44±4) s,T_max为30 s,C_max为(2.20±0.20) mg·L^-1,AUC_0-∞为(96±11) mg·s·L^-1。结论该法简便、快速、灵敏度好、精密度高。可用于包裹氟碳类气体的微囊类超声造影剂的药代动力学研究     

家犬单剂量和多剂量口服阿昔莫司缓释制剂的药代动力学和生物等效性研究

目的研究阿昔莫司缓释片在家犬体内单剂量和多剂量的药代动力学和生物等效性。方法测定6只家犬单剂量和多剂量口服缓释片和普通胶囊后的血药浓度。结果阿昔莫司的药-时曲线符合非隔室模型。单剂量给药后，缓释片和普通胶囊的AUC分别为(158±30)和(147±37) μg·h·mL^-1；T_max分别为(4.3±0.8)和(2.6±1.3) h；C_max分别为(29±6)和(42±10) μg·mL^-1；T_1/2分别为(2.3±0.7)和(1.60±0.10) h；MRT分别为(6.0±0.8)和(3.9±0.7) h；F_r为(108±16)%。多剂量给药后，缓释片和普通胶囊的AUC分别为(209±23)和(195±26) μg·h·mL^-1；T_max分别为(6.3±0.8)和(3.4±1.5) h；C_max分别为(27±4)和(36±5) μg·mL^-1；Cmin分别为(2.2±1.0)和(0.20±0.20) μg·mL^-1；C_av分别为(8.7±1.0)和(8.1±1.1) μg·mL^-1；FI分别为(293±73)%和(448±91)%；F_r为(114±19)%。结论单剂量实验的双单侧检验结果表明：缓释片和普通胶囊生物等效；缓释片具有良好的缓释效果。多剂量实验结果表明：缓释片和普通胶囊生物等效；缓释片的波动系数优于普通胶囊。     

复方丹参pH依赖型延迟释药微丸在家犬体内的药效动力学

目的制备复方丹参pH依赖型延迟释药微丸填充胶囊并进行家犬体内药效动力学研究。方法分别用HPMC，Eudragit L-30D-55，Eudragit L100/S100 (1∶6)包衣制备pH依赖型延迟释药微丸，测定体外释放曲线，并用血清药理学方法进行家犬体内的药效动力学研究。结果制备了复方丹参pH依赖型延迟释药微丸，体外溶出曲线呈pH依赖特征。单剂量给药后自制速释片R的药效动力学参数T_max为0.58 h，E_max为34.63%，延迟释药胶囊T1和T2的T_max分别延长至2.42和3.17 h，E_max分别降低至13.57%和14.52%，相对生物利用度分别为99.3%和133.6%。多剂量给药后自制速释片R波动度DF 7.32，延迟释药胶囊T1和T2的波动度DF 3.40和3.03。结论复方丹参pH依赖型延迟释药胶囊体外释放具有pH依赖特征，体内具有明显的延迟释药作用，多剂量达到稳态时，药效动力学波动系数低于普通片。     

盐酸曲马多微球缓释片的制备及药动学研究

目的 探讨盐酸曲马多微球缓释片的制备方法,并对微球缓释片在家犬体内药动学进行研究。方法 以乙基纤维素作为包裹材料,运用喷雾干燥法制备盐酸曲马多缓释微球,直接压片得到盐酸曲马多微球缓释片。对微球缓释片和市售缓释片进行家犬体内单剂量给药实验,建立高效液相分析方法。结果 HPLC显示方法精密度、回收率、专属性都符合要求。市售缓释片和微球缓释片的药动学参数C_max分别为(322±16)ng·mL^-1和(346±11)ng·mL^-1;T_max分别为(2.5±0.3)h和(1.5±0.4)h;t_1/2分别为(4.31±0.84)h和(4.95±0.79)h,AUC_0→t分别为(2 940.8±32.1)ng·h·mL^-1和(3 560.9±18.6)ng·h·mL^-1,相对生物利用度为121.09%,不同释放时间点,盐酸曲马多微球缓释片的体内吸收与体外释放都具有良好的相关性。结论 盐酸曲马多微球缓释片具有缓释效果。     

十名志愿者口服维拉帕米缓释片药代动力学和心电图研究

对10名男性受试者单剂量po240mgVer缓释片药代动力学及心电图变化进行研究。血药浓度—时间数据用零级吸收过程的一室模型拟合,其药代动力学参数:T_max5.9±1.6h;C_max118.9±37.2μg·L^-1;T₁ 5.4±1.5h;k₀30.5±17.5μg·L^-1·h^-1;T_1/210.8±4.9h。PR间期延长有显著意义,血药浓度与PR间期变化满足S 型模型,其药效学参数:EC₅₀ 64.6±16.9μg·L^-1; E_max54±11ms;s 1.68±0.66。     

间硝苯地平在Beagle犬体内的药代动力学

目的用反相高效液相色谱法研究间硝苯地平(m-nifedipine，m-Nif)在Beagle犬体内的药代动力学特征。方法正交设计优化色谱分离条件，Beagle犬分别iv给予m-Nif 0.288 mg·kg^-1和ig m-Nif 1.152，3.456，10.370 mg·kg^-1。用反相高效液相色谱法分析血浆中原型药物浓度，血浆药物浓度-时间数据用3P97药代动力学软件分析。结果Beagle犬iv m-Nif，其体内过程符合二室模型，T_1/2β为116.8 min；ig给予m-Nif 后在Beagle犬体内的代谢符合一室模型，其中低剂量(1.152 mg·kg^-1)组C_max为20 μg·L^-1， T_1/2(k_e)为147 min；中剂量(3.456 mg·kg^-1)组C_max为36 μg·L^-1，T_1/2(k_e) 为122 min；高剂量(10.37 mg·kg^-1)组C_max为69 μg·L^-1，T_1/2(k_e)为144 min。结论Beagle犬ig和iv m-Nif 后，血浆中药物消除迅速，口服绝对生物利用度较低。     

三七总皂苷肠溶微囊的药代动力学及体内外相关性

目的:考察三七总皂苷(panax notoginseng saponins,PNS)肠溶微囊在Beagle犬体内的释药行为及其体内外相关性研究。方法:采用双周期交叉试验设计,6只健康Beagle犬口服市售血栓通胶囊或自制PNS肠溶微囊(胶囊型)后,用HPLC法测定血药浓度,计算两制剂的药代动力学参数,进行生物利用度比较,并对体外累积释放度和体内累积吸收百分率进行线性回归。结果:自制PNS肠溶微囊对市售血栓通胶囊的相对生物利用度为三七皂苷R1(R1)313.63%,人参皂苷Rb1(Rb1)314.35%,人参皂苷Rg1(Rg1)202.03%,上述3成分在体内的平均滞留时间均延长,R1,Rb1和Rg1的体内外相关系数分别为0.866 4,0.958 0和0.719 2。结论:自制PNS肠溶微囊与市售血栓通胶囊相比生物利用度更高,Rb1体内外相关性较好,可用一定的体外释放条件进行体内行为的预测,R1和Rg1体内外相关性较差。     

吡哌酸缓释微囊的体外溶出特性考察

考察了不同主药含量、不同粒径的吡哌酸缓释微囊的药物溶出特性及在不同pH介质中的溶出行为,探讨了微囊中吡哌酸含量对微囊结构、半数测出时间T_(50)及药物渗透性的影响与因不同pH介质中由于药物溶解度不同而引起的溶出行为的改变。证实了微囊释药符合Higuchi方程,其结构与药物含量有关,药物渗透性及T_(50)~(1/2)与药物含量存在线性相关性,药物溶出因微囊粒径减小、药物于介质中溶解度增加而增加。     

全反式维甲酸自乳化给药系统的体内外评价

目的研究全反式维甲酸(RA)自乳化释药系统的自乳化能力及在比格犬体内的药代动力学。方法通过测定不同时间粒子的散射光强度来评价自乳化速度，光学显微镜下观察乳化后形成乳剂粒径的大小及分布情况；采用HPLC法测定比格犬血浆药物浓度，与市售胶囊比较，考察RA自乳化制剂体外溶出行为及体内药代动力学。结果体系在10 min内已基本乳化完全，通过光学显微镜观察，乳化后乳剂粒子大多数在3 μm以下。与市售胶囊剂相比：以水为溶出介质，维甲酸自乳化制剂15 min可以溶出80%以上，而市售胶囊溶出不到5%。比格犬体内药代动力学研究结果表明：与市售胶囊剂相比，自乳化制剂达峰时间提前，Tmax=1.25 h,而市售胶囊 Tmax=2 h；AUC0-∞提高了67%。结论自乳化制剂可以显著提高RA的体外溶出及体内吸收。     

Assessment of bioavailability of experimental controlled release microcapsules of nifedipine

Experimental controlled release nifedipine microcapsules composed of ethylcellulose and eudragit RL were explored for the assessment of bioavailability on rabbit. The pharmacokinetic parameters were compared between the formulations and with the pure drug material. A statistically significant difference between the formulations was noticed in the parameters, K, T1/2, AUC (0-->infinity), MRT and bioavailability but not in Vd, Cmax and Tmax and in each case a highly significant difference was observed with reference drug material. Controlled release absorption profiles in vivo were observed from the experimental microcapsules as revealed by the Wagner-Nelson method. The absorption lag time, absorption rate constant, and absorption half life were calculated by using the back projection method of residuals. A good correlation demonstrated between in vivo absorption and in vitro release data for both the products merits specific attention. There was no loss in bioavailability of the experimental ethylcellulose microcapsule (drug content 75.8%), even though nifedipine undergoes extensive first pass metabolism.     

Technology to obtain sustained release characteristics of drugs after delivered to the colon

To determine the necessary technology by which sustained drug release is obtained after drug is delivered to the colon, two kinds of microcapsules were prepared and were filled in a pressure-controlled colon delivery capsule (PCDC). As a model drug 5-aminosalicylic acid (5-ASA) was used, because the target site of 5-ASA is the entire large intestine. 5-ASA was microencapsulated using a water-insoluble polymer, ethylcellulose (EC) or with pH-sensitive polymers, Eudragit L-100 or S-100 and encased in PCDC. The particle size of these microcapsules was around 800 microns and the loading efficiencies of 5-ASA were approximately 90%. In vitro dissolution tests were performed with the prepared microcapsules. The release rate of 5-ASA from the microcapsules was significantly prolonged as compared to 5-ASA powder, although there were no significant differences in the release rates between these microcapsules. By incorporating the 5-ASA microcapsules into PCDC, sustained release PCDCs for colon delivery were prepared and in vivo evaluation was performed using beagle dogs. As a fast release colon delivery system, PCDCs were prepared with 5-ASA powder suspended in suppository base. After oral administration of the test preparations to beagle dogs, plasma 5-ASA concentrations were measured and sustained release characteristics of 5-ASA from the test preparations were evaluated from the plasma 5-ASA concentration-time profiles. The first appearance time of 5-ASA into the systemic circulation after oral administration were 3 h for all the colon delivery preparations and it was thought that these test preparations were delivered to the colon. Both EC microcapsules and Eudragit S-100/RS-100 microcapsules in PCDC showed longer the mean residence time MRT, 8.2 +/- 0.6 h and 8.7 +/- 0.9 h, than Eudragit L-100/RS-100 microcapsules in PCDC where the MRT was 6.6 +/- 0.2 h. Since PCDCs containing 5-ASA powder exhibited a MRT of 7.0 +/- 1.0 h, these two types of preparations have suggested sustained release characteristics.     

Retarded dissolution of ibuprofen in gelatin microcapsule by cross-linking with glutaradehyde

Ibuprofen-loaded gelatin microcapsule, a solid form of microcapsules simultaneously containing ethanol and ibuprofen in water-soluble gelatin shell was previously reported to improve the dissolution of drug. In this study, to retard the initial high dissolution of ibuprofen from gelatin microcapsule, the ibuprofen-loaded cross-linked gelatin microcapsule was prepared by treating an ibuprofen-loaded gelatin microcapsule with glutaraldehyde and its dissolution was evaluated compared to ibuprofen powder and gelatin microcapsule. The ibuprofen-loaded cross-linked microcapsule treated with glutaraldehyde for 10 and 60 sec gave significantly higher dissolution rates than did ibuprofen powder. Furthermore, the dissolution rate of ibuprofen from the cross-linked microcapsule treated for 10 sec was similar to that from gelatin microcapsule. However, the dissolution rate of ibuprofen from the cross-linked microcapsule treated for 60 sec decreased significantly compared to gelatin microcapsule, suggesting that the treatment of gelatin microcapsule with glutaraldehyde for 60 sec could cross-link the gelatin microcapsule. Furthermore, the cross-linking of gelatin microcapsule markedly retarded the release rate of ibuprofen in pH 1.2 simulated gastric fluid compared to gelatin microcapsule. However, the cross-linking of gelatin microcapsule with glutaraldehyde hardly changed the size of gelatin microcapsules, ethanol and ibuprofen contents encapsulated in gelatin microcapsule. Thus, the ibuprofen-loaded cross-linked gelatin microcapsule could retard the initial high dissolution of poorly water-soluble ibuprofen.     

Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability

The effects of the core to colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a √t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer, smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.     

Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability

The effects of the core toi colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a square root t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.     

正交实验设计优化岩白菜素微囊的制备工艺

目的优化岩白菜素微囊的制备工艺,并对制备的岩白菜素微囊进行质量评价。方法以明胶为囊材,单凝聚法制备岩白菜素微囊,通过正交实验设计优化其制备工艺,并对包封率、载药量、平均粒径、体外溶出率进行研究。结果明胶制备岩白菜素微囊的最佳工艺条件为:明胶质量分数为6%,囊心囊材质量比为1∶2,搅拌速度为750r·min^-1。此最佳工艺制备的岩白菜素微囊包封率为75.90%,载药量为23.09%,体外溶出度测定30min为28.6%,12h累计释放达到90%以上。结论以最佳工艺条件制备岩白菜素微囊工艺稳定,包封率高,同时体外释放实验表明,该微囊具有较好的缓释作用。