兩種托芬那酸注射液在犬體內(nèi)的生物等效性研究
發(fā)布時(shí)間：2018-08-29 16:17
【摘要】：托芬那酸是一種應(yīng)用廣泛的非甾體抗炎藥(NSAID),具有較強(qiáng)的抗炎作用,在人醫(yī)臨床主要用于治療關(guān)節(jié)炎和偏頭疼,以及痛風(fēng)、滑囊炎和痛經(jīng)等疾病。在獸醫(yī)臨床不僅被用于狗、貓緩解骨關(guān)節(jié)相關(guān)的炎癥和疼痛,還用于犬、牛等家畜上呼吸道疾病的輔助治療,具有非常廣闊的應(yīng)用前景。本研究在建立犬血漿中托芬那酸含量測(cè)定的HPLC方法基礎(chǔ)上,通過(guò)對(duì)國(guó)產(chǎn)托芬那酸注射液受試品和進(jìn)口參比品在犬體內(nèi)的藥代動(dòng)力學(xué)特征研究,獲得相關(guān)藥動(dòng)學(xué)參數(shù)并進(jìn)行生物等效性分析,以確定國(guó)產(chǎn)托芬那酸注射液仿制品和原研藥是否具有臨床可替代性1、犬血漿中托芬那酸含量HPLC測(cè)定法犬血漿中托芬那酸采用乙腈提取凈化,采用高效液相色譜紫外檢測(cè)器檢測(cè),色譜柱為ZORBAX Eclipse Plus C18(250×4.6 mm,5 μm);流動(dòng)相為甲醇-乙腈-0.05M 醋酸鈉(pH 4.6)(36.5:36.5:27,V/V/V);流速:0.7mL/min;波長(zhǎng)..290 nm;柱溫:35。C;進(jìn)樣量20 μL。托芬那酸血漿濃度在0.025～10.0 μg/mL范圍內(nèi)線性關(guān)系良好(R20.999),最低檢測(cè)限和定量限分別為0.025 μg/mL和0.05 μg/mL;空白血漿中托芬那酸添加樣品在0.05、1和5μg/mL時(shí)回收率均在85%以上。本文規(guī)定了犬血漿中特芬那酸的提取和凈化方法,適用于犬血漿中托芬那酸含量的測(cè)定。2、兩種托芬那酸注射液在健康犬體內(nèi)的生物等效性研究20頭成年體重一致的健康比格犬隨機(jī)分為兩組,每組10頭(公母各半),采用交叉試驗(yàn)設(shè)計(jì)。第一階段1-10號(hào)犬單劑量(0.1 mL/kgbw)肌內(nèi)注射托芬那酸注射液受試品,11-20號(hào)犬單劑量(0.1 mL/kgbw)肌內(nèi)注射托芬那酸注射液參比品;第二階段1-10號(hào)犬單劑量(0.1 mL/kgbw)肌內(nèi)注射托芬那酸注射液參比品,11-20號(hào)犬單劑量(0.1 mL/kgbw)肌內(nèi)注射托芬那酸注射液受試品。兩階段給藥間隔期為2周,給藥后按預(yù)定時(shí)間采集血樣。血漿中托芬那酸含量采用經(jīng)驗(yàn)證的HPLC測(cè)定方法檢測(cè)。實(shí)測(cè)血藥濃度-時(shí)間數(shù)據(jù)采用藥代參數(shù)計(jì)算軟件是WINNONLIN 6.3版藥動(dòng)學(xué)分析軟件擬合藥代動(dòng)力學(xué)參數(shù),采用《人體生物利用度數(shù)據(jù)處理通用程序》(BAPP)軟件檢驗(yàn)受試品和參比品的生物等效性。單劑量(0.1 mL/kgbw)肌內(nèi)注射托芬那酸參比品注射液后,托芬那酸的平均消除半衰期(T1/2)為14.52 h,平均達(dá)峰時(shí)間(Tmax)和峰值濃度(Cmax)分別為0.3h和5.38 μg/mL,平均曲線下面積(AUC0-t、AUC0-∝)分別為 12.28μg·h·mL-1 和 13.85μg·h·mL-1,平均滯留時(shí)間(MRT)為13.58 h。單劑量(0.1 mL/kgbw)肌內(nèi)注射托芬那酸受試品注射液后,托芬那酸的平均消除半衰期(T1/2)為13.53h,達(dá)峰時(shí)間(Tmax)和峰值濃度(Cmax)分別為 0.2 h 和 5.12 μg/mL,平均曲線下面積(AUC0-t、AUC0-∞)分別為12.1 μg.h.mL-和 13.38μg·h.mL-1,平均滯留時(shí)間(MRT)為13.43 h,相對(duì)生物利用度(F)為101.7%。統(tǒng)計(jì)學(xué)分析顯示,托芬那酸注射液受試品和參比品的AUC0-t、AUC0-∞、Cmax、Tmax均無(wú)顯著性差異,(p0.05)。受試品與參比品的Cmax對(duì)數(shù)轉(zhuǎn)換后比值的90%置信區(qū)間為86.61%～115.34%;受試品與參比品AUC0-t對(duì)數(shù)轉(zhuǎn)換后比值的90%置信區(qū)間為90.12%～108.31%。結(jié)果表明,托芬那酸注射液肌內(nèi)注射吸收迅速,托芬那酸注射液受試品與參比品生物等效,臨床上可相互替代。
[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.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：S859.7
本文編號(hào)：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.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：S859.7
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