乙醇对盐酸二甲双胍缓释片体内外释药特性的影响
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摘要
目的研究乙醇对盐酸二甲双胍缓释片体内外释药特性的影响。方法分别考察盐酸二甲双胍缓释片自制制剂及市售制剂Glucophage XR在水、体积分数5%、20%、40%乙醇中的释放和溶胀,并采用相似因子法评价释放的相似性,再基于体外结果,选择水和体外释放产生显著性差异的乙醇浓度进行自制片及Glucophage XR的Beagle犬体内释药影响试验。结果随着乙醇浓度的升高,自制缓释片及Glucophage XR在溶胀过程中凝胶层形成均变慢且溶媒渗入较少,两制剂的体外释放均逐渐降低,且二者在体积分数40%乙醇中释放与水中相比均产生了较显著的差异(f2 <50),但二者在相同介质中的释放均有较好的相似性; Beagle犬体内试验表明,两制剂给体积分数40%乙醇组前期释放与体外一致均明显降低,而后期释放出现了一定的升高,但整体释放与给水组相比无统计学差异,且自制片与Glucophage XR各组间主要药动学参数经统计学分析均无显著性差异。结论乙醇对自制盐酸二甲双胍缓释片及Glucophage XR的体内外释药特性的影响均一致;高浓度乙醇对盐酸二甲双胍缓释片的体外释药特性有较显著的影响,但对其体内的总体释放特性无显著性影响。
OBJECTIVE To investigate the effects of alcohol on release characteristics of metformin hydrochloride extendedrelease tablets in vitro and in vivo. METHODS The release behaviors and swelling of self-made metformin hydrochloride extended-release tablets and commercial products Glucophage XR in different release media including water,5% alcohol,20% alcohol and 40% alcohol were investigated and similar factor method was used to evaluate the similarity of release. Based on results in vitro,water and the alcoholic medium with significant differences were selected for Beagle dogs experiments to investigate further the effects of alcohol on release characteristics of metformin hydrochloride extended-release tablets in vivo. RESULTS Along with the increase of the alcohol concentration in the release media,both formation rate of the gel layer became slower and the penetration of the solvents became less in the swelling process,only dissolving a small amount of drug,so the release of selfmade tablets and Glucophage XR gradually decreased in vitro. Both release in 40% alcohol produced a significant difference compared with that in water( f2 < 50),but the release of self-made tablets was greatly similar to Glucophage XR in the same media. In vivo studies of Beagle dogs revealed that an initial low release of both preparations was observed in 40% alcohol which was consistent with the vitro,while a certain increase was observed later,but the overall release was not statistically different from that of the water supply group. Moreover,the main pharmacokinetic parameters of the self-made tablets and Glucophage XR between the water-supply group and the 40% alcohol-supply group had no statistical difference. CONCLUSION Alcohol has the same effects on the release characteristics of self-made metformin hydrochloride extended-release tablets and Glucophage XR in vitro and in vivo. High concentration of alcohol has a significant effect on the release characteristics in vitro,but it has no significant effect on the overall release in vivo.
OBJECTIVE To investigate the effects of alcohol on release characteristics of metformin hydrochloride extendedrelease tablets in vitro and in vivo. METHODS The release behaviors and swelling of self-made metformin hydrochloride extended-release tablets and commercial products Glucophage XR in different release media including water,5% alcohol,20% alcohol and 40% alcohol were investigated and similar factor method was used to evaluate the similarity of release. Based on results in vitro,water and the alcoholic medium with significant differences were selected for Beagle dogs experiments to investigate further the effects of alcohol on release characteristics of metformin hydrochloride extended-release tablets in vivo. RESULTS Along with the increase of the alcohol concentration in the release media,both formation rate of the gel layer became slower and the penetration of the solvents became less in the swelling process,only dissolving a small amount of drug,so the release of selfmade tablets and Glucophage XR gradually decreased in vitro. Both release in 40% alcohol produced a significant difference compared with that in water( f2 < 50),but the release of self-made tablets was greatly similar to Glucophage XR in the same media. In vivo studies of Beagle dogs revealed that an initial low release of both preparations was observed in 40% alcohol which was consistent with the vitro,while a certain increase was observed later,but the overall release was not statistically different from that of the water supply group. Moreover,the main pharmacokinetic parameters of the self-made tablets and Glucophage XR between the water-supply group and the 40% alcohol-supply group had no statistical difference. CONCLUSION Alcohol has the same effects on the release characteristics of self-made metformin hydrochloride extended-release tablets and Glucophage XR in vitro and in vivo. High concentration of alcohol has a significant effect on the release characteristics in vitro,but it has no significant effect on the overall release in vivo.
引文
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[7]FDA Alert for Healthcare Professionals(July 2005):Hydromorphonehydrochloride extended-release capsules(marketed as PalladoneTM)[EB/OL].[2018-03-21].http://www.fda.gov/cder/drug/Info Sheets/HCP/hydromorphone HCP.
[8]CENTER FOR DRUG EVALUATION.Technical guidelines for the study of human bioequivalence of chemical drugs with pharmacokinetic parameters as evaluation index[EB/OL].[2015-11-27].http://www.cde.org.cn/zdyz.do?method=large Page&id=227.
[9]DEFRONZO R,FLEMING G A,CHEN K,et al.Metformin-associated lactic acidosis:current perspectives on causes and risk[J].Metabol Clin Exper,2016,65(2):20-29.
[10]KIM M J,HAN J Y,SHIN J Y,et al.Metformin-associated lactic acidosis:predisposing factors and outcome[J].Endocrinol Metabol,2015,30(1):78-83.
[11]RAHIM S A,AL-GHAZAWI M,AL-ZOUBI N.Influence of ethanol on swelling and release behaviors of Carbopol-based tablets[J].Pharm Develop Technol,2013,18(5):1089-1100.
[12]ROBERTS M,CESPI M J,DAYS A,et al.Influence of ethanol on aspirin release form hypromellose matrices[J].Int J Pharm,2007,332(1):31-37.
[2]PALMER D,LEVINA M,FARRELL T P,et al.The influence of hydro-alcoholic media on drug release from polyethylene oxide extended-release matrix tablets[J].Pharm Technol Eur,2011,23(7):16-25.
[3]WALDEN M,NICHOLLS F A,SMITH K J,et al.The effect of ethanol on the release of opioids from oral prolonged-release preparations[J].Drug Develop Ind Pharm,2007,33(10):1101-1111.
[4]WANG B,ZHANG L H,LI Y X,et al.Progress on evaluation methods for release mechanism of hydrophlic Gel natrix sustainedrelease tablets[J].Chin J Pharm(中国医药工业杂志),2009,40(10):782-786.
[5]BLOMDE L,DAILEY G E,JABBOUR S A,et al.Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets:results of a retrospective cohort study[J].Curr Med Res Opin,2004,20(4):565-572.
[6]JI L N,CHEN Y L,GAO L L,et al.Randomized controlled clinical study of metformin hydrochloride extended release tablets in the treatment of type 2 diabetes mellitus[J].J China Prescrip Drug(中国处方药),2006,5(5):64-65.
[7]FDA Alert for Healthcare Professionals(July 2005):Hydromorphonehydrochloride extended-release capsules(marketed as PalladoneTM)[EB/OL].[2018-03-21].http://www.fda.gov/cder/drug/Info Sheets/HCP/hydromorphone HCP.
[8]CENTER FOR DRUG EVALUATION.Technical guidelines for the study of human bioequivalence of chemical drugs with pharmacokinetic parameters as evaluation index[EB/OL].[2015-11-27].http://www.cde.org.cn/zdyz.do?method=large Page&id=227.
[9]DEFRONZO R,FLEMING G A,CHEN K,et al.Metformin-associated lactic acidosis:current perspectives on causes and risk[J].Metabol Clin Exper,2016,65(2):20-29.
[10]KIM M J,HAN J Y,SHIN J Y,et al.Metformin-associated lactic acidosis:predisposing factors and outcome[J].Endocrinol Metabol,2015,30(1):78-83.
[11]RAHIM S A,AL-GHAZAWI M,AL-ZOUBI N.Influence of ethanol on swelling and release behaviors of Carbopol-based tablets[J].Pharm Develop Technol,2013,18(5):1089-1100.
[12]ROBERTS M,CESPI M J,DAYS A,et al.Influence of ethanol on aspirin release form hypromellose matrices[J].Int J Pharm,2007,332(1):31-37.
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