国产盐酸莫西沙星片生物等效性和生物豁免研究

发布时间：2018-03-26 03:25

  本文选题：盐酸莫西沙星　切入点：药代动力学　出处：《锦州医科大学》2017年硕士论文

【摘要】：目的1、研究国产盐酸莫西沙星片(受试制剂)与原研药(参比制剂)的生物等效性。2、研究盐酸莫西沙星普通口服固体制剂仿制药生物豁免的可行性。方法1、建立高效液相色谱—荧光检测法(HPLC-FLD)测定人血浆中莫西沙星浓度,并进行验证;各24名健康中国男性志愿者分别于空腹和餐后口服受试制剂(国内某制药公司研制并生产)和参比制剂(德国Bayer Pharma AG生产),采集血浆样品,并采用已通过验证的HPLC-FLD法测定血浆中莫西沙星的浓度;采用WinNonlin 6.4软件,非房室模型方法计算志愿者口服受试制剂和参比制剂后莫西沙星的药代动力学参数,主要药代动力学参数对数转换后进行方差分析,90%置信区间法评价制剂间生物等效性。2、采用HPLC-FLD法和摇瓶法测定盐酸莫西沙星原料药在pH值1~6.8标准缓冲溶液中的平衡溶解度。通过文献确定莫西沙星渗透性。采用HPLC-FLD法和桨法测定盐酸莫西沙星片受试制剂和参比制剂在溶出介质中的的溶出度。根据盐酸莫西沙星的溶解性、渗透性,本课题中盐酸莫西沙星片受试制剂和参比制剂的溶出度、及人体生物等效性研究结果,结合辅料因素探讨盐酸莫西沙星普通口服固体制剂仿制药生物豁免的可行性。结果1、志愿者空腹口服受试制剂和参比制剂后血浆中的莫西沙星的cmax分别为(4.41±1.18)μg·ml-1和(4.43±1.07)μg·ml-1;tmax分别为(1.16±0.87)h和(1.21±0.98)h;t1/2分别为(13.40±1.47)h和(13.44±1.42)h;auc0-t分别为(47.11±5.81)μg·h·ml-1和(46.89±5.36)μg·h·ml-1;auc0-∞分别为(51.11±6.63)μg·h·ml-1和(50.92±6.26)μg·h·ml-1。志愿者餐后口服受试制剂和参比制剂后血浆中的莫西沙星的cmax分别为(3.37±0.774)μg·ml-1和(3.64±0.771)μg·ml-1;tmax分别为(1.71±0.69)h和(1.88±0.68)h;t1/2分别为(13.40±1.44)h和(13.74±1.31)h;auc0-t分别为(43.39±6.81)μg·h·ml-1和(44.22±6.92)μg·h·ml-1;auc0-∞分别为(47.30±8.06)μg·h·ml-1和(48.42±8.18)μg·h·ml-1。盐酸莫西沙星受试制剂与参比制剂空腹给药试验的相对生物利用度f为(100.51±5.37)%,餐后给药试验的相对生物利用度f为(98.2±4.48)%。经对数转换后,志愿者空腹和餐后条件下口服受试制剂和参比制剂的auc0-t、auc0-∞和cmax几何均数比值(gmr)的90%置信区间均在80.00%~125.00%的范围内。2、盐酸莫西沙星原料药在37±1℃,ph值1~6.8(0.1mol·l-1hcl和ph值为2.0、3.0、4.5、5.1、5.8、6.8的缓冲液)的水溶性介质中最大剂量/溶解度比值(d/s)均小于250ml,具有高溶解性;根据已有文献资料报道,盐酸莫西沙星的绝对生物利用度大于90%,具有高渗透性;在50rpm转速条件下,500ml溶出介质(0.1mol·l-1hcl、ph值4.5缓冲介质、ph值6.8缓冲介质)中,15min内盐酸莫西沙星片受试制剂和参比制剂的溶出度均达到标示量的85%以上;本课题中的盐酸莫西沙星片受试制剂的辅料处方中辅料为固体制剂常用辅料且含量在fda规定的含量范围内,不影响药物的吸收。结论1、在空腹给药与餐后给药两种试验条件下,受试制剂与参比制剂均具有生物等效性。2、盐酸莫西沙星为高溶解性、高渗透性药物,属于BCSⅠ类药物;盐酸莫西沙星片受试制剂和参比制剂均为非常快速溶出的口服固体制剂;盐酸莫西沙星片受试制剂的辅料成分对其生物等效性影响较小;该受试制剂推荐生物豁免。3、其他只含有盐酸莫西沙星单一成分的普通口服固体制剂仿制药上市,如果满足下列要求,可以考虑豁免1)该制剂为快速溶出制剂2)处方中辅料对该制剂的吸收速率和吸收程度无显著影响。
[Abstract]:Objective to study the domestic 1, Moxifloxacin Hydrochloride Tablets (sescs) and original drugs (reference preparation) the bioequivalence study of moxifloxacin hydrochloride.2, common oral solid preparation of generic biological immunity. The feasibility of method 1, the establishment of chromatography with fluorescence detection method of high performance liquid (HPLC-FLD) determination of moxifloxacin in human plasma, and the verification; 24 healthy male volunteers were China in fasting and postprandial oral test preparation (preparation and production of a pharmaceutical company in China) and reference preparation (German Bayer Pharma AG production), the collection of plasma samples, and the concentration in plasma was determined by HPLC-FLD method to verify the moxifloxacin; using WinNonlin 6.4 software non compartmental model, calculation method of tested preparation and reference pharmacokinetic parameters of moxifloxacin preparations after volunteers analyzed, the main pharmacokinetic parameters after logarithmic transformation, 90 % confidence interval method to evaluate the bioequivalence between the preparation of.2, using the HPLC-FLD method and shake flask method to determine the equilibrium solubility of 1~6.8 standard in the buffer solution of pH value in moxifloxacin hydrochloride raw medicine. Through the literature to determine the permeability of moxifloxacin. By using HPLC-FLD method and paddle method was Moxifloxacin Hydrochloride Tablets test and reference preparations in the dissolution medium the dissolution. Based on the solubility and permeability of moxifloxacin hydrochloride, Moxifloxacin Hydrochloride Tablets the test and reference preparations of dissolution, and the bioequivalence study results, combined with the discussion of common excipients of moxifloxacin hydrochloride oral solid preparation of generic biological immunity feasibility. The results of 1 volunteers were given orally by the test preparation and reference preparation of moxifloxacin in the plasma of Cmax were (4.41 + 1.18) g and ml-1 (4.43 + 1.07) g, ml-1; Tmax were (1.16 + 0.87) and H (1.21卤0.98)h;t1/2鍒嗗埆涓，

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