非诺贝特缓释微球片体内外相关性评价

目的：用脱卷积法进行自制非诺贝特缓释微球片体内外相关性的评价。方法：以市售微粒化非诺贝特胶囊剂的大鼠体内血药浓度数据为权函数，根据自制非诺贝特缓释微球片制剂大鼠体内血药浓度数据，采用脱卷积法，将不同时间点的体内吸收分数与体外累计释放百分数做线性回归，考察体内外相关性。结果：采用脱卷积法计算体外累计释放百分数和体内吸收分数相关系数较好（r=0．9225），相关性方程为Y=0．4642R＋42．044。结论：脱卷积法适用于非诺贝特缓释微球片的体内外相关性研究。     

右旋酮洛芬氨丁三醇速释缓释双层片在Beagle犬体内的药物动力学及生物等效性

目的考察右旋酮洛芬氨丁三醇速释缓释双层片与普通制剂在Beagle犬体内的药物动力学特征和生物等效性。方法以自制的右旋酮洛芬氨丁三醇速释缓释双层片作为受试制剂,上市制剂"葵拉兰"作为参比制剂,采用UPLC-MS/MS联用技术,测定受试制剂与参比制剂在Beagle犬体内的血药浓度经时过程,数据经DAS2.0软件处理分析获得药物动力学参数,对AUC0-t、AUC0-∞、ρmax及tmax的对数值进行方差分析、双单侧t检验、非参数检验等统计学处理,评价双层片与普通制剂的生物等效性,利用Loo-Rigelman法评价其体内外相关性。结果与参比制剂相比,受试制剂的ρmax降低,tmax有所延长,体内外相关性中r=0.986 6。结论右旋酮洛芬氨丁三醇速释缓释双层片较参比制剂具有速释和缓释特征,体内吸收与体外释放具有良好的相关性。     

盐酸氨溴索缓释片体内外相关性研究

目的考察盐酸氨溴索缓释片体外释放度与体内吸收的相关性。方法应用释放度测定法研究盐酸氨溴索缓释片体外释药行为 ,采用HPLC法测定盐酸氨溴索缓释制剂在家犬体内的血药浓度 ,按照Wagner Nelson公式计算药物的吸收分数。 结果 3种自制盐酸氨溴索缓释片与参比制剂生物等效 ,以药物累积吸收百分数 f(t)与相应时刻的体外累积释放百分数F(t)建立的一元线性回归方程 ,参比制剂与 3种自制制剂的体内外相关系数分别为 0 969、0 979、0 970和 0 983。结论盐酸氨溴索缓释片的体外释放度与体内吸收具有显著的相关性。     

普萘洛尔药物树脂缓释混悬剂在Beagle犬体内的药动学

目的考察普萘洛尔药物树脂缓释混悬剂在Beagle犬体内的缓释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犬口服市售缓释胶囊或自制缓释混悬剂后,用HPLC法测定血药浓度,计算2制剂的药动学参数,进行生物利用度比较,用不同的体外释放量对体内吸收量进行线性拟和。结果自制缓释混悬剂的药动学参数计算结果为AUC_(0-24)(1031±s 63)μg·h·L~(-1),c_(max)(87±4)μg·L~(-1),t_(max)(6.5±1.2)h,市售缓释胶囊的计算结果相应为AUC_(0-24)(989±99)μg·h·L~(-1),c_(max)(85±3)μg·L~(-1),t_(max)(7.2±0.7)h,2制剂的3项药动学参数没有显著差异(P>0.05),自制缓释混悬剂对市售缓释胶囊的平均相对生物利用度为(106±9)%,以0.5mol·L~(-1) NaCl溶液中所得体外溶出数据与体内吸收量相关性较好(r=0.937 7)。结论普萘洛尔药物树脂缓释混悬剂在Beagle犬体内达到明显的缓释效果,与参比制剂相比具生物等效性,可用一定的体外释放条件进行体内行为的预测。     

硝苯地平控释胶囊在Beagle犬体内的药动学研究

目的评价自制硝苯地平(NF)控释胶囊在Beagle犬体内的药动学,并对其体内外相关性进行研究。方法 6只健康Beagle犬随机分成2组,分别单剂量服用实验制剂(硝苯地平控释胶囊)和参比制剂(拜新同渗透泵片)各30 mg,一周后交叉给药。采用HPLC法,以尼群地平(NT)为内标测定犬给药后不同时间的血药浓度,用以估算药动学参数和相对生物利用度。结果实验制剂与参比制剂的主要药动学参数分别为:Cmax(21.79±8.11)、(21.99±3.97)ng·mL-1;tmax(8.32±1.51)、(9.31±1.02)h;AUC0^t(337.42±84.44)、(348.65±56.25)ng·h·mL-1;t1/2(9.27±1.75)、(8.96±1.73)h;相对生物利用度为(96.8±7.34)%;体内外相关性r=0.944。结论自制硝苯地平控释胶囊具有明显的控释特性,体内外相关性良好。     

尼群地平微丸家犬体内药动学研究

目的研究自制尼群地平速释、缓释微丸在家犬体内的药物动力学,并进行相对生物利用度评价。方法分别以尼群地平国产片和日本片为参比制剂,采用高效液相色谱法测定4个制剂的家犬体内血浆药物浓度并绘制平均血药浓度-时间曲线,计算药动学参数并进行方差分析,同时对自制制剂的生物利用度进行了评价。结果尼群地平速释微丸、缓释微丸、国产片和日本片的Tmax依次为0.92±0.14、5.0、1.83±0.29和1.08±0.38h;Cmax依次为187.01±21.23、85.25±13.80、88.31±8.65和160.22±24.34ng.mL-1;AUC0~t依次为665.54±109.07、606.47±130.68、472.44±89.44和659.16±100.05 ng.h.mL-1。以国产片为参比制剂时,自制速释微丸和缓释微丸的相对生物利用度分别为146.92%和135.92%;以日本片为参比制剂时,速释微丸和缓释微丸的相对生物利用度分别为101.04%和91.63%。结论自制速释微丸接近同类产品国外制剂,优于国内制剂;缓释微丸体内作用时间延长,但生物利用度偏低,需进一步改进处方或工艺。     

氯氮平漂浮缓释胶囊体内外相关性评价

目的建立氯氮平漂浮缓释胶囊体内外相关性评价模型 ,评价体内外相关性。方法利用Wanger Nelson方法和卷积模型分别评价氯氮平漂浮缓释胶囊体内外相关性。通过反卷积方法由体外释放数据得到了氯氮平漂浮缓释胶囊的体内输入函数。利用基本卷积模型和扩展卷积模型预测了氯氮平漂浮缓释胶囊体内血药浓度峰值 (Cmax)和血药浓度 时间曲线下面积值 (AUC)。结果Wanger Nelson方法的相关系数为0 9798;反卷积方法得到的体内输入值与体外释药量相关性良好 ,相关系数为 0 996。扩展卷积模型预测的Cmax和AUC值与实验值误差 <6 % ;而基本卷积模型预测值误差 >2 8%。结论氯氮平漂浮缓释胶囊体内外相关性良好。应用扩展的卷积模型能很好的预测氯氮平体内血药浓度 ,预测的体内情况可用来指导处方筛选     

灯盏花素固体分散体缓释胶囊的制备及犬体内外相关性研究

以乙基纤维素为载体，制备难溶性药物灯盏花素（1）的固体分散体。粉碎后制成1含量为60mg的胶囊，考察其体外释放度和犬体内吸收情况。用删．C测定血药浓度，并进行体内外相关性研究。结果表明，胶囊的体外释药行为用Higuchi方程拟合较好，在犬体内有明显的缓释效果，体内外相关系数为0．9808。     

尼群地平缓释胶囊在家犬体内的药动学与相对生物利用度

目的研究尼群地平缓释胶囊在家犬体内的药代动力学与相对生物利用度。方法用高效液相色谱法测定了 6条健康家犬口服尼群地平缓释胶囊 (受试制剂 )和尼群地平普通片 (参比制剂 )后不同时间点血浆中尼群地平的浓度 ,绘制血药浓度 -时间曲线 ,计算药代动力学参数及相对生物利用度。结果受试犬口服含尼群地平 4 0mg的受试制剂和参比制剂后 ,血浆中尼群地平的tmax分别为 (6 1 7± 1 60 )和 (1 4 6± 0 5 1 )h;cmax分别为 (3 4 3 8± 1 2 2 6)和 (45 6 5± 1 0 7 4 )nmol L ;用梯形法计算 ,AUC0～t分别为 (1 93 0 1± 1 0 0 5 1 0 6)和 (1 790 8± 94 2 8)nmol·h L。以AUC计算 ,与参比制剂相比 ,受试制剂中尼群地平的相对生物利用度平均为 (1 1 0 5 9± 2 3 60 ) %。将AUC0～t经对数转换后进行方差分析 ,结果表明 ,受试制剂与参比制剂相比 ,除个体间外 ,周期间与制剂间无显著性差异 (P >0 0 5 ) ,受试制剂AUC0～t的 90 %置信区间为参比制剂的 88 5 4 %～ 1 3 1 93 %。结论尼群地平缓释胶囊与国外普通片相比 ,在犬体内具有更长的作用时间 ,且相对生物利用度相近     

盐酸二甲双胍缓释微丸在犬体内的药动学与体内外相关性研究

目的:研究盐酸二甲双胍(MH)缓释微丸在犬体内的药动学及生物利用度。方法:将6只犬随机均分为2组,分别灌胃受试制剂MH缓释微丸和参比制剂MH片,给药剂量为24.5 mg/kg,1周后交叉实验。分别于给药前和给药后0.5、1、1.5、2、3、4、5、6、8、10、13、24、36 h取血,采用高效液相色谱法测定血药浓度,3p97软件计算药动学参数,并考察其体内外相关性。结果:受试制剂的药-时曲线符合单室模型,受试制剂与参比制剂的tmax分别为(5.88±0.41)、(2.34±0.17)h,t1/2分别为(4.35±0.67)、(2.01±0.30)h,cmax分别为(4.99±0.67)、(7.09±1.83)μg/ml,AUC0-24 h分别为(52.41±7.45)、(48.13±5.51)μg·h/ml,受试制剂相对生物利用度为108.9%;体外释药与体内吸收数据的相关系数r=0.785 8。结论:MH缓释微丸具有缓释特征,体外释药与体内吸收具有一定的相关性。     

尼群地平缓释微球的制备及其体内外相关性的研究

目的制备具有固体分散体结构的尼群地平缓释微球 ,并筛选具有良好体内外相关性的释放介质。方法采用球晶造粒法制备尼群地平缓释微球 ,考察微球的粒径、载药量、包封率及释放行为 ,并根据 6只试验犬体内药物动力学试验结果 ,将不同时间的吸收分数与不同释放介质的相应时间点的体外累积释放百分数作线性回归 ,筛选具有良好体内外相关性的释放介质。结果制备的微球的粒径随搅拌速度的增加而减少 ,包封率均在 96 80 %以上 ,药物从微球中的释放速度随处方中固体分散体载体量的增加而增加 ,随阻滞剂量的增加而减小。以 1 7 4mmol L十二烷基硫酸钠为释放介质时 ,体外累积释放百分数与体内吸收分数相关系数较好 (r =0 985 1 ) ,方程为Fa =1 64 5 8ft-2 7 64 2。结论该方法较适用于难溶性药物制备缓释微球。以 1 7 4mmol L十二烷基硫酸钠水溶液为释放介质可作为控制微球内在质量的标准     

Release and absorption characteristics of chlorphenesin carbamate sustained-release formulations: In vitro-in vivo and in vivo dog-human correlations

The bioavailability of chlorphenesin carbamate (CPC) in sustained-release (SR) formulations exhibiting different in vitro release characteristics in dogs and humans was examined using formulations tested previously in the in vitro dissolution method. The human-dog correlation of the bioavailability of SR formulations was examined under fasting conditions. Pharmacokinetic analysis using the Wagner-Nelson procedure revealed sustained-release absorption characteristics for the SR formulations, with the exception of the immediate-release (IR) formulation as control in dogs and humans. For each of the SR formulations tested, regression analysis results of the percentage of CPC absorbed in human against that in dogs, at corresponding times, indicated a high correlation. Moreover, the correlation of the dissolution rates and bioavailabilities of these formulations in humans was also examined. Although the in vitro CPC release profiles from the SR formulations were smooth and controlled, they were too rapid when compared with the in vivo human data. However, the rank order was exactly the same between in vivo and in vitro data, and a good relationship was found after time scaling of the release data. These data imply that the release characteristics of CPC after changing of the formulations could be evaluated using the in vitro dissolution method or dogs as an animal model in place of human studies.     

Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations

The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50?rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1?h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed.     

阿昔莫司缓释片的体外释放度与犬体内吸收相关性

目的:研究阿昔莫司缓释片的体外释放度与其在家犬体内吸收的相关性。方法:以水为溶出介质,测定阿昔莫司缓释片的体外释放度。采用高效液相色谱法测定家犬单剂量口服阿昔莫司胶囊和缓释片后的血药浓度,用非隔室模型对阿昔莫司的体内过程进行拟合,以反卷积分法求算积分方程中的输入函数。以输入函数与同时间点体外累积释放度回归求得相关系数并与相关系数临界值进行比较。结果:以累积释放度Y与输入函数R建立的回归方程为:Y=18.118R+35.717(r=0.9309),相关系数临界值r4,0.05=0.811,r>r4,0.05,表明回归方程显著。结论:自制阿昔莫司缓释片体内外相关性良好。     

萘哌地尔缓释胶囊的体外释放与体内吸收相关性研究

目的 :研究萘哌地尔缓释胶囊的体外释放与其在家犬体内吸收的相关性 ,考察体外释放条件设计的合理性。方法 :以人工胃液为溶出介质 ,测定两种萘哌地尔缓释胶囊的体外释放度 ;单剂量给予家犬萘哌地尔缓释胶囊200mg 后测定血药浓度变化 ,用3p97药动学程序对萘哌地尔体内过程进行拟合 ,根据拟合结果计算不同时间点萘哌地尔缓释胶囊在家犬体内的吸收分数 ;以反卷积分法求算积分方程中的输入函数。以体内吸收分数或输入函数与同时间点体外累积释放度回归 ,求得相关系数并与相关系数临界值进行比较。结果 :采用模型拟合计算的吸收分数法、反卷积分法计算所得的两种萘哌地尔缓释胶囊的体外释放与体内吸收回归的相关系数均大于相关系数临界值 ,制剂的体外释放与体内吸收的相关性良好。结论 :模型拟合计算吸收分数与反卷积分法用于萘哌地尔缓释胶囊体内外相关性研究 ,方法简单可行。研究结果为萘哌地尔缓释制剂的快速处方筛选、体外释放条件的合理设计及缓释制剂的快速评价提供了理论依据     

Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations

The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50?rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1?h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed.     

缓释制剂的体内外相关性试验及检验

目的：探讨缓释制剂体内外相关试验方法。方法：以植入用缓释依托泊苷为例，根据体内及体外预试验数据，求算对应时间点关联系数K，按中华人民共和国药典要求作对应时间点的点对点相关试验及检验。结果：成功进行植入用缓释依托泊苷的体内外相关试验并实现相关。结论：此法为长效缓释制剂提供了一种体内外相关试验的参考方法。     

三七总皂苷缓释片的释放性能及体内外相关性研究

目的评价三七总皂苷缓释片的体外释放特性、体内药物动力学及体内外相关性。方法以磷酸盐缓冲液为释放介质,考察三七总皂苷缓释片的体外释放特性。以6只Beagle犬为实验动物,测定口服给予缓释片后血药浓度的变化,计算药代动力学参数,并对体外累积释放度和体内累积吸收百分率进行回归,考察其体内外相关性。结果三七总皂苷缓释片体外药物释放具有明显的缓释特性;与普通片相比,在Beagle犬体内的达峰时间延长,峰浓度降低,平均滞留时间延长,也具有明显的缓释特性。结论制得的三七总皂苷缓释片达到了缓慢释放药物的目的,并且其体内外参数间有明显的相关性。