两种托芬那酸注射液在犬体内的生物等效性研究
发布时间：2018-08-29 16:17
【摘要】：托芬那酸是一种应用广泛的非甾体抗炎药(NSAID),具有较强的抗炎作用,在人医临床主要用于治疗关节炎和偏头疼,以及痛风、滑囊炎和痛经等疾病。在兽医临床不仅被用于狗、猫缓解骨关节相关的炎症和疼痛,还用于犬、牛等家畜上呼吸道疾病的辅助治疗,具有非常广阔的应用前景。本研究在建立犬血浆中托芬那酸含量测定的HPLC方法基础上,通过对国产托芬那酸注射液受试品和进口参比品在犬体内的药代动力学特征研究,获得相关药动学参数并进行生物等效性分析,以确定国产托芬那酸注射液仿制品和原研药是否具有临床可替代性1、犬血浆中托芬那酸含量HPLC测定法犬血浆中托芬那酸采用乙腈提取净化,采用高效液相色谱紫外检测器检测,色谱柱为ZORBAX Eclipse Plus C18(250×4.6 mm,5 μm);流动相为甲醇-乙腈-0.05M 醋酸钠(pH 4.6)(36.5:36.5:27,V/V/V);流速:0.7mL/min;波长..290 nm;柱温:35。C;进样量20 μL。托芬那酸血浆浓度在0.025～10.0 μg/mL范围内线性关系良好(R20.999),最低检测限和定量限分别为0.025 μg/mL和0.05 μg/mL;空白血浆中托芬那酸添加样品在0.05、1和5μg/mL时回收率均在85%以上。本文规定了犬血浆中特芬那酸的提取和净化方法,适用于犬血浆中托芬那酸含量的测定。2、两种托芬那酸注射液在健康犬体内的生物等效性研究20头成年体重一致的健康比格犬随机分为两组,每组10头(公母各半),采用交叉试验设计。第一阶段1-10号犬单剂量(0.1 mL/kgbw)肌内注射托芬那酸注射液受试品,11-20号犬单剂量(0.1 mL/kgbw)肌内注射托芬那酸注射液参比品;第二阶段1-10号犬单剂量(0.1 mL/kgbw)肌内注射托芬那酸注射液参比品,11-20号犬单剂量(0.1 mL/kgbw)肌内注射托芬那酸注射液受试品。两阶段给药间隔期为2周,给药后按预定时间采集血样。血浆中托芬那酸含量采用经验证的HPLC测定方法检测。实测血药浓度-时间数据采用药代参数计算软件是WINNONLIN 6.3版药动学分析软件拟合药代动力学参数,采用《人体生物利用度数据处理通用程序》(BAPP)软件检验受试品和参比品的生物等效性。单剂量(0.1 mL/kgbw)肌内注射托芬那酸参比品注射液后,托芬那酸的平均消除半衰期(T1/2)为14.52 h,平均达峰时间(Tmax)和峰值浓度(Cmax)分别为0.3h和5.38 μg/mL,平均曲线下面积(AUC0-t、AUC0-∝)分别为 12.28μg·h·mL-1 和 13.85μg·h·mL-1,平均滞留时间(MRT)为13.58 h。单剂量(0.1 mL/kgbw)肌内注射托芬那酸受试品注射液后,托芬那酸的平均消除半衰期(T1/2)为13.53h,达峰时间(Tmax)和峰值浓度(Cmax)分别为 0.2 h 和 5.12 μg/mL,平均曲线下面积(AUC0-t、AUC0-∞)分别为12.1 μg.h.mL-和 13.38μg·h.mL-1,平均滞留时间(MRT)为13.43 h,相对生物利用度(F)为101.7%。统计学分析显示,托芬那酸注射液受试品和参比品的AUC0-t、AUC0-∞、Cmax、Tmax均无显著性差异,(p0.05)。受试品与参比品的Cmax对数转换后比值的90%置信区间为86.61%～115.34%;受试品与参比品AUC0-t对数转换后比值的90%置信区间为90.12%～108.31%。结果表明,托芬那酸注射液肌内注射吸收迅速,托芬那酸注射液受试品与参比品生物等效,临床上可相互替代。
[Abstract]:Tofenac acid is a widely used non-steroidal anti-inflammatory drug (NSAID) with strong anti-inflammatory effect. It is mainly used in the treatment of arthritis and migraine headache, gout, bursitis and dysmenorrhea. It is not only used in veterinary clinic to alleviate bone and joint-related inflammation and pain in dogs and cats, but also used to breathe in dogs and cattle. Based on the establishment of an HPLC method for the determination of tofenamic acid in dog plasma, the pharmacokinetic parameters of domestic and imported tofenamic acid injection in dogs were obtained and bioequivalence analysis was performed. To determine the clinical substitutability of domestic tofenac acid injection and the original drug. 1. Determination of tofenac acid in dog plasma by HPLC. Tofenac acid in dog plasma was extracted and purified by acetonitrile and detected by high performance liquid chromatography with ultraviolet detector. The column was ZORBAX Eclipse Plus C18 (250 *4.6 mm, 5 micron); the mobile phase was A. Alcohol-acetonitrile-0.05M sodium acetate (pH 4.6) (36.5:36.5:27, V/V/V); Flow rate: 0.7mL/min; Wavelength..290 nm; Column temperature: 35.C; Sample size: 20 ugL. Tofenamic acid plasma concentration in the range of 0.025-10.0ug/mL linear relationship (R20.999), the minimum detection limit and the quantitative limit are 0.025 ug/mL and 0.05 ug/mL respectively; Tofenamic acid in blank plasma added samples. The recoveries of terfenamic acid in dog plasma were all above 85% at 0.05, 1 and 5 ug/mL. The method of extracting and purifying terfenamic acid from dog plasma was established. It was suitable for the determination of tofenac acid in dog plasma. 2. Bioequivalence of two kinds of tofenac acid injection in healthy dogs A cross-over trial was conducted in 10 dogs (male and female half) in each group. In the first stage, a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscularly into the muscles of dogs 1-10, a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscularly into the muscles of dogs 11-20, a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscularly into the muscles of dogs 1-10, and a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscular A single-dose (0.1 mL/kg bw) intramuscular injection of tofenamic acid was administered in dogs 1-20. The interval of two-stage administration was 2 weeks. Blood samples were collected at a predetermined time after administration. The pharmacokinetic parameters were fitted by the analytical software, and the bioequivalence of the test and reference materials was tested by BAPP software. The mean elimination half-life (T1/2) of tofenamic acid was 14.52 h and the mean peak time (Tmax) was 14.52 h after intramuscular injection of tofenamic acid reference material at a single dose of 0.1 mL/kg bw. The mean area under curve (AUC 0-t, AUC 0-_) was 12.28 ug.h.mL-1 and 13.85 ug.h.mL-1, respectively, and the mean retention time (MRT) was 13.58 H. The mean elimination half-life (T1/2) of tofenamic acid was 13.53 h after intramuscular injection of tofenamic acid at a single dose (0.1 mL/kg bw). Time (Tmax) and peak concentration (Cmax) were 0.2 h and 5.12 ug/mL, respectively. AUC 0-t, AUC 0-infinity were 12.1 ug.h.mL-1 and 13.38 ug.h.mL-1, respectively. Mean retention time (MRT) was 13.43 h, and relative bioavailability (F) was 101.7%. Statistical analysis showed that the AUC 0-t, AUC 0-t, C 10-infinity, C.38 ug. There was no significant difference between Max and Tmax (p0.05). The 90% confidence interval of the logarithmic conversion ratio of Cmax was 86.61% ~ 115.34%, and the 90% confidence interval of the logarithmic conversion ratio of AUC0-t was 90.12% ~ 108.31%. The results showed that the intramuscular injection of tofenamic acid absorbed rapidly and the tofenamic acid injection was tested. The product is bioequivalent to reference product and can be substituted clinically.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S859.7
本文编号：2211735
[Abstract]:Tofenac acid is a widely used non-steroidal anti-inflammatory drug (NSAID) with strong anti-inflammatory effect. It is mainly used in the treatment of arthritis and migraine headache, gout, bursitis and dysmenorrhea. It is not only used in veterinary clinic to alleviate bone and joint-related inflammation and pain in dogs and cats, but also used to breathe in dogs and cattle. Based on the establishment of an HPLC method for the determination of tofenamic acid in dog plasma, the pharmacokinetic parameters of domestic and imported tofenamic acid injection in dogs were obtained and bioequivalence analysis was performed. To determine the clinical substitutability of domestic tofenac acid injection and the original drug. 1. Determination of tofenac acid in dog plasma by HPLC. Tofenac acid in dog plasma was extracted and purified by acetonitrile and detected by high performance liquid chromatography with ultraviolet detector. The column was ZORBAX Eclipse Plus C18 (250 *4.6 mm, 5 micron); the mobile phase was A. Alcohol-acetonitrile-0.05M sodium acetate (pH 4.6) (36.5:36.5:27, V/V/V); Flow rate: 0.7mL/min; Wavelength..290 nm; Column temperature: 35.C; Sample size: 20 ugL. Tofenamic acid plasma concentration in the range of 0.025-10.0ug/mL linear relationship (R20.999), the minimum detection limit and the quantitative limit are 0.025 ug/mL and 0.05 ug/mL respectively; Tofenamic acid in blank plasma added samples. The recoveries of terfenamic acid in dog plasma were all above 85% at 0.05, 1 and 5 ug/mL. The method of extracting and purifying terfenamic acid from dog plasma was established. It was suitable for the determination of tofenac acid in dog plasma. 2. Bioequivalence of two kinds of tofenac acid injection in healthy dogs A cross-over trial was conducted in 10 dogs (male and female half) in each group. In the first stage, a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscularly into the muscles of dogs 1-10, a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscularly into the muscles of dogs 11-20, a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscularly into the muscles of dogs 1-10, and a single dose (0.1 mL/kg bw) of tofenamic acid injection was injected intramuscular A single-dose (0.1 mL/kg bw) intramuscular injection of tofenamic acid was administered in dogs 1-20. The interval of two-stage administration was 2 weeks. Blood samples were collected at a predetermined time after administration. The pharmacokinetic parameters were fitted by the analytical software, and the bioequivalence of the test and reference materials was tested by BAPP software. The mean elimination half-life (T1/2) of tofenamic acid was 14.52 h and the mean peak time (Tmax) was 14.52 h after intramuscular injection of tofenamic acid reference material at a single dose of 0.1 mL/kg bw. The mean area under curve (AUC 0-t, AUC 0-_) was 12.28 ug.h.mL-1 and 13.85 ug.h.mL-1, respectively, and the mean retention time (MRT) was 13.58 H. The mean elimination half-life (T1/2) of tofenamic acid was 13.53 h after intramuscular injection of tofenamic acid at a single dose (0.1 mL/kg bw). Time (Tmax) and peak concentration (Cmax) were 0.2 h and 5.12 ug/mL, respectively. AUC 0-t, AUC 0-infinity were 12.1 ug.h.mL-1 and 13.38 ug.h.mL-1, respectively. Mean retention time (MRT) was 13.43 h, and relative bioavailability (F) was 101.7%. Statistical analysis showed that the AUC 0-t, AUC 0-t, C 10-infinity, C.38 ug. There was no significant difference between Max and Tmax (p0.05). The 90% confidence interval of the logarithmic conversion ratio of Cmax was 86.61% ~ 115.34%, and the 90% confidence interval of the logarithmic conversion ratio of AUC0-t was 90.12% ~ 108.31%. The results showed that the intramuscular injection of tofenamic acid absorbed rapidly and the tofenamic acid injection was tested. The product is bioequivalent to reference product and can be substituted clinically.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S859.7
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