吲哚美辛贴片的质量研究
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摘要
本论文建立了高效液相色谱法测定吲哚美辛贴片的含量和有关物质。采用碟上桨法测定贴片的体外释放度,并利用SPSS软件估算相应的体外释放参数,确定药物体外释放特征。在此基础上,通过体内药动学参数计算,进一步研究了吲哚美辛贴片的体内外相关性。
1.高效液相色谱法测定吲哚美辛贴片含量和有关物质方法的研究
色谱条件:C18柱(150 mm×4.6 mm ID,5μm),以甲醇∶水∶磷酸(600∶400∶1,v/v/v)为流动相,流速:1.0 mL·min~(-1),柱温:40℃,检测波长为228 nm。吲哚美辛的线性范围分别为10～200μg·mL~(-1)和0.5～10μg·mL~(-1),最低可定量限为0.5 ng,平均回收率为99.6%,精密度良好,适用于吲哚美辛贴片含量及有关物质的测定。
2.吲哚美辛贴片体外释放度及体内外相关性研究
采用碟上桨装置,水900 ml为溶出介质,转速为每分钟100转,色谱条件同含量测定项下。吲哚美辛的线性范围为1.0～20μg·mL~(-1),平均回收率为99.5%。利用SPSS软件拟合体外释放数据,选取多个模型进行计算,结果符合一级速率方程,R~2值为0.9268。将体外释放数据带入方程,计算T50、Td等释放参数,结果满意。通过测定大鼠血药浓度,计算主要药动学参数,房室模型为一室模型一级吸收,R~2值为0.9832,采用Wagner-Nelson法计算各时间点体内药物累积吸收百分数,以24h内体内药物累积吸收百分率(Fa)为因变量,以对应体外累积溶出百分率(Fd)为自变量,进行回归。测定结果的回归方程及回归系数通过显著性检验(P <0.01),表明Fa与Fd具有显著相关性。
To establish a method to determine the content and related substances of indomethacin patch by HPLC. The trap-paddle method was used to determine the dissolution of patch. We used the SPSS software to calculate the dissolution parameter and studied the character of vitro dissolution. Then research on the correlation between dissolution rate in vitro and absorption rate in vivo was continued by calculating the pharmacokinetic parameter.
Section one: the research on the determination of indomethacin patch’s content and related substances.
Liquid chromatography was performed on a C18 column(150×4.6 mm,5μm), the mobile phase consisted of methanol, water and phosphoric acid (600:400:1,v/v/v), used a flow rate of 1.0 mL·min~(-1) at 40℃column temperature, and the detection wavelength was 228 nm. The linear concentration ranges of indomethacin were 10～200μg·mL~(-1) and 0.5～10μg·mL~(-1), respectively. The lower limit of quantification of indomethacin was 0.5 ng and the average recovery was 99.6%. The method precision was good and the method could be used for determining the content and the related substances of indomethacin patch.
Section two: the research on the vitro dissolution and the correlation between dissolution rate in vitro and absorption rate in vivo. We used the trap-paddle apparatus, and 900 ml water as the sovent with a rotation speed of 100 rpm, the assay’s chromatographic condition was used. The linear concentration ranges of indomethacin was 1.0～20μg·mL~(-1), and the average recovery was 99.5%. The SPSS software was used to fit dissolution data with several models. The results was consistent with first lever equation, and the R2 was 0.9268. Then calculated the dissolution parameters (T50, Td), the results was satisfaction. At last, we determined the indomethacin concentration in rat skin and calculated main pharmacokinetic parameters which as follows: Compartment number=1, Weight=1, R2=0.9832. Calculated the Fraction absorption at different times with the Wagner-Nelson method. There was a significant relationship between absorption in vivo and dissolution in vitro (P<0.01).
1.高效液相色谱法测定吲哚美辛贴片含量和有关物质方法的研究
色谱条件:C18柱(150 mm×4.6 mm ID,5μm),以甲醇∶水∶磷酸(600∶400∶1,v/v/v)为流动相,流速:1.0 mL·min~(-1),柱温:40℃,检测波长为228 nm。吲哚美辛的线性范围分别为10～200μg·mL~(-1)和0.5～10μg·mL~(-1),最低可定量限为0.5 ng,平均回收率为99.6%,精密度良好,适用于吲哚美辛贴片含量及有关物质的测定。
2.吲哚美辛贴片体外释放度及体内外相关性研究
采用碟上桨装置,水900 ml为溶出介质,转速为每分钟100转,色谱条件同含量测定项下。吲哚美辛的线性范围为1.0～20μg·mL~(-1),平均回收率为99.5%。利用SPSS软件拟合体外释放数据,选取多个模型进行计算,结果符合一级速率方程,R~2值为0.9268。将体外释放数据带入方程,计算T50、Td等释放参数,结果满意。通过测定大鼠血药浓度,计算主要药动学参数,房室模型为一室模型一级吸收,R~2值为0.9832,采用Wagner-Nelson法计算各时间点体内药物累积吸收百分数,以24h内体内药物累积吸收百分率(Fa)为因变量,以对应体外累积溶出百分率(Fd)为自变量,进行回归。测定结果的回归方程及回归系数通过显著性检验(P <0.01),表明Fa与Fd具有显著相关性。
To establish a method to determine the content and related substances of indomethacin patch by HPLC. The trap-paddle method was used to determine the dissolution of patch. We used the SPSS software to calculate the dissolution parameter and studied the character of vitro dissolution. Then research on the correlation between dissolution rate in vitro and absorption rate in vivo was continued by calculating the pharmacokinetic parameter.
Section one: the research on the determination of indomethacin patch’s content and related substances.
Liquid chromatography was performed on a C18 column(150×4.6 mm,5μm), the mobile phase consisted of methanol, water and phosphoric acid (600:400:1,v/v/v), used a flow rate of 1.0 mL·min~(-1) at 40℃column temperature, and the detection wavelength was 228 nm. The linear concentration ranges of indomethacin were 10～200μg·mL~(-1) and 0.5～10μg·mL~(-1), respectively. The lower limit of quantification of indomethacin was 0.5 ng and the average recovery was 99.6%. The method precision was good and the method could be used for determining the content and the related substances of indomethacin patch.
Section two: the research on the vitro dissolution and the correlation between dissolution rate in vitro and absorption rate in vivo. We used the trap-paddle apparatus, and 900 ml water as the sovent with a rotation speed of 100 rpm, the assay’s chromatographic condition was used. The linear concentration ranges of indomethacin was 1.0～20μg·mL~(-1), and the average recovery was 99.5%. The SPSS software was used to fit dissolution data with several models. The results was consistent with first lever equation, and the R2 was 0.9268. Then calculated the dissolution parameters (T50, Td), the results was satisfaction. At last, we determined the indomethacin concentration in rat skin and calculated main pharmacokinetic parameters which as follows: Compartment number=1, Weight=1, R2=0.9832. Calculated the Fraction absorption at different times with the Wagner-Nelson method. There was a significant relationship between absorption in vivo and dissolution in vitro (P<0.01).
引文
[1]杨莉,透皮贴剂的研究进展与临床应用,继续医学教育,2006,20(28):82-85
[2] Radbruch L,Elsner F.Clinical experience with transdermal fentanyl for the treatment of cancer pain in Germany[J].Keio J Med,2004,53 (1):23—29
[3] Mazieres B.Topical ketoprofen patch[J].Drugs R D,2005,6(6):337-344
[4] A rgoff CE,Galer BS,Jensen MP,et a1.Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states, assessment with the Neuropathic Pain Scale[J].Curr Med Res Opin,2004,20(2):21—28
[5] Burioka N,Miyata M,Endo M,et a1.Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy [J].Chronobiol Int,2005,22 (2):383—390
[6] Sobue S,Sekiguchi K,Kikkawa H,et a1.Effect of application sites and multiple doses on nicotine pharmacokinetics in healthy male Japanese smokers following application of the transdermal nicotine patch [J].J Clin Pharmacol,2005,45 (12):1391—1399
[7]徐美华,消炎痛抗肿瘤作用实验与临床研究进展[J],国外医学、生理、病理科学与临床分册,2000,20(3):240—243
[8] Alino SF,Irarrizaga A,Alfaro J,et al.Antimetastic effects of lipo- some entrapped indomethacin [J].Life Science,1991,48(2):149
[9]邓意辉,李焕秋,张瑞香,等,吲哚美辛脂质体注射液的制备、含量测定及稳定性[J],沈阳药科大学学报,1996,13(2):79—81
[10]石如,杨蓓蕾,王君英,等.,吲哚美辛检对晚期癌痛154例的镇痛疗效[J],中国新药与临床杂志,1998,17(5):291—292
[11]孙丽平,段玉龙,侯俊卿,等,吲哚美辛肿瘤生物治疗中的应用[J],中国肿瘤临床与康复,1998,5(4):66
[12]荣根娣,刘来顺,吲哚美辛在儿科临床的新用途[J],医药导报,1995,14 (1):43
[13]刘昌官,李恕香,刘晓瑷,等,吲哚美辛宫内节育器的主要药效学研究[J],生殖与避孕,2000,20(3):165-171
[14]许成岩,侯宁,苏应宽,等,宫内用吲哚美辛缓释系统的研制[J],中国医药工业杂志,1998,29(12):552-553
[15]刘景梅,三种含铜宫内节育器的临床应用[J],临床医学,1999,19(7):31-32
[16]刘乃清,吴汉青,消炎痛的临床新用[J],华西药学杂志,1997,12(4):278
[17]李雪,傅少颖,周景杰,闭角型青光眼发作应用消炎痛的临床观察[J],哈尔滨医科大学学报,2000,34(2):137-138
[18]韩光伟,梁敦,吲哚美辛滴眼液的制备与临床应用[J],中国现代应用药学杂志,1999,16(4):73
[19]《中国药典》2005年版2部:254~257
[20] BP2008
[21] Ph.Eur5.0:1794~1795
[22] USP31:2396~2402
[23] JP15:772~775
[24] Skelly JP,Gonzalez MA.FDA update dissolution testing:simple tool-important contribution.Eur J Pharm Biopham,1994,39(5):222
[25] Gonzalez MA.FDA update GDAC notes partly:in vitro dissolution with immediate release solid oral products. Eur J Pharm Biopharm,1994,40(2):101
[26] LIU Y Z,ZHENG R H.To simpllify and dispose pharmacokinetics mathematics models [J], J Chin Pharm,1996,31(4):248–249
[2] Radbruch L,Elsner F.Clinical experience with transdermal fentanyl for the treatment of cancer pain in Germany[J].Keio J Med,2004,53 (1):23—29
[3] Mazieres B.Topical ketoprofen patch[J].Drugs R D,2005,6(6):337-344
[4] A rgoff CE,Galer BS,Jensen MP,et a1.Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states, assessment with the Neuropathic Pain Scale[J].Curr Med Res Opin,2004,20(2):21—28
[5] Burioka N,Miyata M,Endo M,et a1.Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy [J].Chronobiol Int,2005,22 (2):383—390
[6] Sobue S,Sekiguchi K,Kikkawa H,et a1.Effect of application sites and multiple doses on nicotine pharmacokinetics in healthy male Japanese smokers following application of the transdermal nicotine patch [J].J Clin Pharmacol,2005,45 (12):1391—1399
[7]徐美华,消炎痛抗肿瘤作用实验与临床研究进展[J],国外医学、生理、病理科学与临床分册,2000,20(3):240—243
[8] Alino SF,Irarrizaga A,Alfaro J,et al.Antimetastic effects of lipo- some entrapped indomethacin [J].Life Science,1991,48(2):149
[9]邓意辉,李焕秋,张瑞香,等,吲哚美辛脂质体注射液的制备、含量测定及稳定性[J],沈阳药科大学学报,1996,13(2):79—81
[10]石如,杨蓓蕾,王君英,等.,吲哚美辛检对晚期癌痛154例的镇痛疗效[J],中国新药与临床杂志,1998,17(5):291—292
[11]孙丽平,段玉龙,侯俊卿,等,吲哚美辛肿瘤生物治疗中的应用[J],中国肿瘤临床与康复,1998,5(4):66
[12]荣根娣,刘来顺,吲哚美辛在儿科临床的新用途[J],医药导报,1995,14 (1):43
[13]刘昌官,李恕香,刘晓瑷,等,吲哚美辛宫内节育器的主要药效学研究[J],生殖与避孕,2000,20(3):165-171
[14]许成岩,侯宁,苏应宽,等,宫内用吲哚美辛缓释系统的研制[J],中国医药工业杂志,1998,29(12):552-553
[15]刘景梅,三种含铜宫内节育器的临床应用[J],临床医学,1999,19(7):31-32
[16]刘乃清,吴汉青,消炎痛的临床新用[J],华西药学杂志,1997,12(4):278
[17]李雪,傅少颖,周景杰,闭角型青光眼发作应用消炎痛的临床观察[J],哈尔滨医科大学学报,2000,34(2):137-138
[18]韩光伟,梁敦,吲哚美辛滴眼液的制备与临床应用[J],中国现代应用药学杂志,1999,16(4):73
[19]《中国药典》2005年版2部:254~257
[20] BP2008
[21] Ph.Eur5.0:1794~1795
[22] USP31:2396~2402
[23] JP15:772~775
[24] Skelly JP,Gonzalez MA.FDA update dissolution testing:simple tool-important contribution.Eur J Pharm Biopham,1994,39(5):222
[25] Gonzalez MA.FDA update GDAC notes partly:in vitro dissolution with immediate release solid oral products. Eur J Pharm Biopharm,1994,40(2):101
[26] LIU Y Z,ZHENG R H.To simpllify and dispose pharmacokinetics mathematics models [J], J Chin Pharm,1996,31(4):248–249