吲哚美辛亚微乳胶药动学及体内外相关性研究
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摘要
目的研究吲哚美辛(indomethacin,IMC)亚微乳胶在兔体内的药动学,评价其生物利用度和经皮渗透性行为的体内外相关性。方法采用改良Franz扩散池法,以SD大鼠腹部皮肤进行体外经皮渗透性实验。以家兔为实验动物,两侧腹部去毛涂抹亚微乳胶或市售普通乳膏10 g(相当于IMC 100 mg),不同时间点心脏取血,用高效液相色谱法测定IMC的血药浓度。采用反卷积分法对体外经皮渗透数据和体内药动学数据进行体内外相关性研究。结果 IMC亚微乳胶体外24 h累积经皮渗透量是市售IMC普通乳膏的2倍;经皮给药后,与市售IMC普通乳膏相比,IMC亚微乳胶的T_(max)、C_(max)、T_(1/2)均无显著性差异;AUC_(0-24)和AUC_(0-∞)均为市售IMC普通乳膏的2倍。IMC亚微乳胶体内外相关性系数r=0.930。结论与市售IMC普通乳膏相比,IMC亚微乳胶能够增加IMC渗透入血量,提高IMC的相对生物利用度,且其体内外经皮渗透行为具有良好的体内外相关性。
OBJECTIVE To study the pharmacokinetics of indomethacin(IMC) submicron emulsion gel in rabbits and evaluate its bioavailability and correlation between in vivo and in vitro transdermal penetration. METHODS A modified Franz diffusion cell method was used to test the transdermal penetration of IMC submicron emulsion gel on SD rat abdominal skin. A single dose of 10 g(equivalent to IMC 100 mg) submicron emulsion gel or commercial IMC cream was laid on abdominal skin of rabbit on both sides for an area of 40 cm~2. Blood samples were collected from heart at predetermined time points and plasma concentration was determined by HPLC-UV. Deconvolution method was used to study the correlation between in vitro transdermal penetration data and in vivo pharmacokinetic data. RESULTS The cumulative transdermal permeation amount of IMC submicron emulsion gel in vitro for 24 h was twice that of the commercial IMC cream. Compared with the commercial IMC cream, the T_(max), C_(max), T_(1/2) had no significant differences, the AUC_(0-24) and AUC_(0-∞) of IMC submicron emulsion gel was about twice that of the commercial indomethacin cream. The in vitro and in vivo correlation coefficient of IMC submicron emulsion gel was 0.930. CONCLUSION Compared with the commercial IMC cream, IMC submicron emulsion gel can increase the amount of IMC penetrated into blood, improve the bioavailability of IMC, and the correlation between in vivo and in vitro transdermal penetration is good.
OBJECTIVE To study the pharmacokinetics of indomethacin(IMC) submicron emulsion gel in rabbits and evaluate its bioavailability and correlation between in vivo and in vitro transdermal penetration. METHODS A modified Franz diffusion cell method was used to test the transdermal penetration of IMC submicron emulsion gel on SD rat abdominal skin. A single dose of 10 g(equivalent to IMC 100 mg) submicron emulsion gel or commercial IMC cream was laid on abdominal skin of rabbit on both sides for an area of 40 cm~2. Blood samples were collected from heart at predetermined time points and plasma concentration was determined by HPLC-UV. Deconvolution method was used to study the correlation between in vitro transdermal penetration data and in vivo pharmacokinetic data. RESULTS The cumulative transdermal permeation amount of IMC submicron emulsion gel in vitro for 24 h was twice that of the commercial IMC cream. Compared with the commercial IMC cream, the T_(max), C_(max), T_(1/2) had no significant differences, the AUC_(0-24) and AUC_(0-∞) of IMC submicron emulsion gel was about twice that of the commercial indomethacin cream. The in vitro and in vivo correlation coefficient of IMC submicron emulsion gel was 0.930. CONCLUSION Compared with the commercial IMC cream, IMC submicron emulsion gel can increase the amount of IMC penetrated into blood, improve the bioavailability of IMC, and the correlation between in vivo and in vitro transdermal penetration is good.
引文
[1]FAN C,ZHANG M H,WANG C X.Mechanism of action of non-steroidal analgesic anti-inflammatory drugs[J].Chin JHosp Pharm(中国医院药学杂志),2003,23(2):107-108.
[2]ZHANG X J.Indomethacin new use and indomethacin external use in the treatment of pruritus:China,1543947[P].20030904.
[3]YOU S Z.Indomethacin clinical adverse reaction and prevention[J].J Mod Med Health(现代医药卫生),2007,23(9):1330-1331.
[4]ROSTOM A,DUBE C,Dube,WELLS G A,et al.Prevention of NSAID-induced gastroduodenal ulcers[J].Cochrane Database Syst Rev,2002,4(1):101-103.
[5]ZUO J,DU L,LI M,et al.Transdermal enhancement effect and mechanism of iontophoresis for non-steroidal anti-inflammatory drugs[J].Int J Pharm,2014,466(1/2):76-82.
[6]ELLEITHY E S,IBRAHIM H K,SOROUR R M.In vitro and in vivo evaluation of indomethacin nanoemulsion as a transdermal delivery system[J].Drug Deliv,2015,22(8):1010-1017.
[7]EI MAGHRABY G M,ARAFA M F,OSMAN M A.Microemulsion for simultaneous transdermal delivery of benzocaine and indomethacin:in vitro and in vivo evaluation[J].Drug Dev Ind Pharm,2014,40(12):1637-1644.
[8]KWASIGROCH B,ESCRIBANO E,MORAN M D C,et al.Oil-in-water nanoemulsions are suitable for carrying hydrophobic compounds:Indomethacin as a model of anti-inflammatory drug[J].Int J Pharm,2016,515(1-2):749-756.
[9]MCCLEMENTS D J.Nanoemulsions versus microemulsions:terminology,differences,and similarities[J].Soft Matter,2012,8(6):1719-1729
[10]ZHAO Y J,YAO Y,DING Y F,et al.Determination of IMC-submicron emulsion gel content by HPLC and evaluation of the drug transdermal permeation in vitro[J].Chin J Mod Appl Pharm(中国现代应用药学),2009,26(11):921-924.
[11]SCHWARZ J,WEISSPAPIR M,FRIEDMAN D.Enhanced transdermal delivery of diazepam by submicron emulsion(sme)creams[J].Pharm Res,1995,12(5):687-692.
[12]GOOSEN C,PLESSIS J D,MüLLER D G,et al.Correlation between physicochemical characteristics,pharmacokinetic properties and transdermal absorption of NSAID’s[J].Int J Pharm,1998,163(1/2):203-209.
[13]EL-LEITHY E S,IBRAHIM H K,SOROUR R M.In vitro and in vivo evaluation of indomethacin nanoemulsion as a transdermal delivery system[J].Drug Deliv,2015,22(8):1010-1017.
[14]MOHAMMED D,MATTS P J,HADGRAFT J,et al.In vitro-in vivo correlation in skin permeation[J].Pharm Res,2014,31(2):394-400.
[15]MARGOLSKEE A,DARWICH A S,GALETIN A,et al.Deconvolution and IVIVC:Exploring the role of rate-limiting conditions[J].AAPS J,2016,18(2):321-332.
[16]KESISOGLOU F,XIA B,AGRAWAL N G.Comparison of deconvolution-based and absorption modeling IVIVC for extended release formulations of a BCS III drug development candidate[J].AAPS J,2015,17(6):1492-1500.2018-03-14
[2]ZHANG X J.Indomethacin new use and indomethacin external use in the treatment of pruritus:China,1543947[P].20030904.
[3]YOU S Z.Indomethacin clinical adverse reaction and prevention[J].J Mod Med Health(现代医药卫生),2007,23(9):1330-1331.
[4]ROSTOM A,DUBE C,Dube,WELLS G A,et al.Prevention of NSAID-induced gastroduodenal ulcers[J].Cochrane Database Syst Rev,2002,4(1):101-103.
[5]ZUO J,DU L,LI M,et al.Transdermal enhancement effect and mechanism of iontophoresis for non-steroidal anti-inflammatory drugs[J].Int J Pharm,2014,466(1/2):76-82.
[6]ELLEITHY E S,IBRAHIM H K,SOROUR R M.In vitro and in vivo evaluation of indomethacin nanoemulsion as a transdermal delivery system[J].Drug Deliv,2015,22(8):1010-1017.
[7]EI MAGHRABY G M,ARAFA M F,OSMAN M A.Microemulsion for simultaneous transdermal delivery of benzocaine and indomethacin:in vitro and in vivo evaluation[J].Drug Dev Ind Pharm,2014,40(12):1637-1644.
[8]KWASIGROCH B,ESCRIBANO E,MORAN M D C,et al.Oil-in-water nanoemulsions are suitable for carrying hydrophobic compounds:Indomethacin as a model of anti-inflammatory drug[J].Int J Pharm,2016,515(1-2):749-756.
[9]MCCLEMENTS D J.Nanoemulsions versus microemulsions:terminology,differences,and similarities[J].Soft Matter,2012,8(6):1719-1729
[10]ZHAO Y J,YAO Y,DING Y F,et al.Determination of IMC-submicron emulsion gel content by HPLC and evaluation of the drug transdermal permeation in vitro[J].Chin J Mod Appl Pharm(中国现代应用药学),2009,26(11):921-924.
[11]SCHWARZ J,WEISSPAPIR M,FRIEDMAN D.Enhanced transdermal delivery of diazepam by submicron emulsion(sme)creams[J].Pharm Res,1995,12(5):687-692.
[12]GOOSEN C,PLESSIS J D,MüLLER D G,et al.Correlation between physicochemical characteristics,pharmacokinetic properties and transdermal absorption of NSAID’s[J].Int J Pharm,1998,163(1/2):203-209.
[13]EL-LEITHY E S,IBRAHIM H K,SOROUR R M.In vitro and in vivo evaluation of indomethacin nanoemulsion as a transdermal delivery system[J].Drug Deliv,2015,22(8):1010-1017.
[14]MOHAMMED D,MATTS P J,HADGRAFT J,et al.In vitro-in vivo correlation in skin permeation[J].Pharm Res,2014,31(2):394-400.
[15]MARGOLSKEE A,DARWICH A S,GALETIN A,et al.Deconvolution and IVIVC:Exploring the role of rate-limiting conditions[J].AAPS J,2016,18(2):321-332.
[16]KESISOGLOU F,XIA B,AGRAWAL N G.Comparison of deconvolution-based and absorption modeling IVIVC for extended release formulations of a BCS III drug development candidate[J].AAPS J,2015,17(6):1492-1500.2018-03-14