药学学报  2014, Vol. 49 Issue (8): 1155-1161   PDF    
溶出度实验结合计算机模拟技术评价国产阿莫西林胶囊的生物等效性
潘瑞雪1, 高源2, 陈万里2, 李玉兰3, 胡昌勤1     
1. 中国食品药品检定研究院, 北京 100050;
2. 贵州省食品药品检验所, 贵州 贵阳 550000;
3. 深圳市药品检验所, 广东 深圳 518057
摘要:对上市仿制药品生物等效性的再评价是当前的研究热点。生物等效性实验是评价仿制药物治疗效果一致性的理想方法,而基于BCS(biopharmaceutical classification system) 理论的体外溶出度实验是最能替代药物体内生物等效性研究的体外试验方法。本文采用常规的溶出度测定方法和开放式流通池法考察国产阿莫西林胶囊在不同介质中的溶出行为,开放式流通池法更能体现其体内的释放特征。流通池法结果显示,国产阿莫西林胶囊存在两种不同的溶出特性。采用Gastro PlusTM软件模拟药物在体内具有不同释放速率(t85%=15~180 min) 时的体内吸收(Cmax和AUC) 情况,发现释放速率在延长至t85%=45 min时,口服阿莫西林胶囊同口服阿莫西林溶液仍具有生物等效性。具有不同溶出特性的国产阿莫西林胶囊45 min内的累积溶出度均可达到85% 以上,模拟计算也提示其在体内具有生物等效性,提示国产阿莫西林胶囊具有生物等效性。
关键词一致性评价     阿莫西林     生物药剂学分类系统    
Dissolution testing combined with computer simulation technology to evaluate the bioequivalence of domestic amoxicillin capsule
PAN Rui-xue1, GAO Yuan2, CHEN Wan-li2, LI Yu-lan3, HU Chang-qin1     
1. National Institutes for Food and Drug Control, Beijing 100050, China;
2. Guizhou Institutes for Food and Drug Control, Guiyang 550000, China;
3. Shenzhen Institutes for Drug Control, Shenzhen 518057, China
Abstract: Re-evaluation of bioequivalence of generic drugs is one of the key research focus currently. As a means to ensure consistency of the therapeutic effectiveness of drug products, clinical bioequivalence has been widely accepted as a gold standard test. In vitro dissolution testing based on the theory of the BCS is the best alternative to in vivo bioequivalence study. In this article, the conventional dissolution method and flow-through cell method were used to investigate the dissolution profiles of domestic amoxicillin capsules in different dissolution media, and the absorption behavior of the drugs with different release rates (t85%=15-180 min) in the gastrointestinal tract was predicted by Gastro PlusTM. The flow-through cell method was thought better to reflect the release characteristics in vivo, and amoxicillin capsules with regard to the release rates up to 45 min (t85%=45 min) were having a satisfied bioequivalence with the oral solution according to the Cmax and AUC. Although two different dissolution profiles of domestic amoxicillin capsules were found by flow-through cell methods, prediction results revealed that domestic capsules were probably bioequivalent to each other.
Key words: drug re-evaluation     amoxicillin     biopharmaceutical classification system    

药物的生物利用度是固体药物制剂的重要评价指标,生物等效性实验是评价仿制药物治疗效果一致性的理想方法。传统的生物等效性评价依赖于临 床试验结果,体外溶出度实验作为重要的质量控制手段保证后续的上市产品与临床试验样品具有一致性。近年来的研究认为,基于BCS(biopharmaceutical classification system) 理论的体外溶出度实验是最能替代药物生物等效性研究的体外实验方法[ 1 ]。虽然目前完全通过体外溶出度方法预测药物处方在体内的行为仍有诸多难题需要解决[ 2 ],但在建立与体内相关的溶出度方法 (biorelevant in vitro dissolution method)[ 3, 4, 5 ]及其应用方面[ 6, 7, 8 ]均已取得了较大进展。FDA、WHO和EDQM先后出台了相关的指导原则[ 9, 10, 11, 12 ],指导生产企业在新药注册中申请生物豁免 (biowaiver),进而鼓励企业自觉运用QbD (quality by design) 原则,根据体外溶出度实验结果对产品的处方和生产工艺进行持续地改进,不断改进产品的质量[ 1 ]。日本自1998年开始实施“药品品质再评价工程”,利用药品在4种特定溶出介质中的特征溶出曲线,控制不同产品具有相同的生物等效性[ 13 ]。美国FDA也于2004年1月起,在其官方网站上推出了固体制剂溶出曲线数据库[ 14 ]。近年来,通过建立药物制剂的体内外相关性模型预测体内的药动学 (PK) 等参数,可以帮助企业进行制剂的处方优化和医生的合理用药[ 15, 16, 17 ]

阿莫西林 (amoxicillin) 胶囊为速释口服制剂,目前国内有多个批准文号,分属多家生产企业。虽然对上市仿制药品生物等效性的再评价是保证其临床有效性的关键,但国内目前尚未全面启动。本研究利用计算机模拟技术建立预测阿莫西林胶囊体内外相关性模型,通过对其体外溶出特性的全面了解,结合阿莫西林的BCS特性,探讨在体外溶出度实验中具有不同溶出行为的制剂在体内的PBPK等参数,进而评价国产阿莫西林胶囊的生物等效性。

材料与方法

仪器与药品 戴安Ultuimate3000高效液相色谱仪 (四元高压梯度泵,四通道可调紫外及可见光检测器); RCZ-8M 型溶出试验仪 (天津市天大天发科技有限公司); ZKT-7F真空脱气仪 (天津市天大天发科技有限公司); SOTAX CE7 Smart流通池溶出测试仪 (力扬企业有限公司); 岛津UV-2450紫外可见分光光度计; CP225D型电子分析天平 (德国Satorious); Gastro PlusTM软件(Version8.0,SimulationPlus,Inc,USA)。阿莫西林胶囊 (250 mg),91个厂家共91批均为2010年全国评价性抽验样品; 阿莫西林对照品 (批号: 130409201011),含量为85.8%,由中国食品药品检定研究院提供。

溶出介质 介质1: pH 1.0盐酸溶液,介质2: pH 4.5磷酸二氢钾缓冲液,介质3: pH 6.8磷酸二氢钾溶液-氢氧化钠缓冲液和介质4: 水 (pH为6.9 ± 0.1) 经真空脱气仪脱气 (40 ℃,脱气15 min) 后使用。

溶出曲线测定 ① 常规法。参考中国药典2010版转篮法,转速为100 r·min-1。温度 (37 ± 0.5) ℃,采用上述4种溶出介质,在5、10、15、20、30、45、60、90和120 min分别取样5 mL (同时补液5 mL),过滤。采用紫外分光光度法测定样品在介质1中的溶出量,采用HPLC法测定样品在介质2~4中的溶出量。② 流通池法 (开放式)。参考相关文献[ 18,19 ]采用两种设计: 一种是依次通过3种溶出介质 (介质1、介质2和介质3),模拟胃酸较多或空腹状态下人体 的胃肠道环境; 另一种是依次通过两种介质 (介质2和介质3),模拟胃酸较少或饱腹状态下人体的胃肠道环境。

检测方法 ① UV法: 篮法取样后无需稀释,流通池法取样后需稀释5倍,在波长272 nm处测定样品的吸收度,采用标准曲线法计算样品溶液的浓度。② HPLC法: Diamonsil C18柱(250 mm × 4.6 mm,5 μm); 以0.05 mol·L-1磷酸二氢钾溶液 (用2 mol·L-1氢氧化钾溶液调节至pH 5.0)-乙腈 (95∶5) 为流动相; 流速为1 mL·min-1; 检测波长为254 nm,进样量为50 μL。

建立体内外相关性模型 采用Gastro PlusTM软件,依据阿莫西林的理化性质和文献报道的药代参数建立体内外相关性模型,预测口服阿莫西林胶囊的诸药代参数,评价其生物等效性。FDA进行生物 等效性实验时,要求受试者摄入250 mL水[ 9 ],因此将剂量体积设置为250 mL。相对分子质量为365.4,剂量为500 mg,溶解度为3.4 mg·mL-1 [ 20 ]; logP为-0.58[ 20 ]; pKa为2.8/7.2[ 20 ]; 平均沉降时间为900 s; 分散系数为0.75×105 cm2·s-1; 药物颗粒密度为1.2 g·mL-1; 人体Peff为0.46×10-4 cm2/s[ 21 ]; 体重为70 kg; Vc为0.121 L·kg-1 (iv) 0.1 L·kg-1 (po)[ 22 ] ; 总清除率为0.045 (iv) 和0.2 L·h-1·kg-1 (po)[ 20 ]

结果 1 常规溶出曲线分析

测定91个厂家91批阿莫西林胶囊在4种介质中的溶出曲线,按样品在4种介质中的溶出行为对阿莫西林胶囊进行分类,国产阿莫西林胶囊可大致分为3类: 第1类为样品在4种介质中均按适当的速率溶出 (图 1A); 第2类为样品在介质2、3、4中均存在溶出延迟现象,即在开始的5min内,累计溶出率小于15% (图 1B); 第3类为样品在介质2 (pH 4.5) 或介质3 (pH 6.8) 中 (一般是在介质2中) 存在溶出延迟现象 (图 1C)。国产阿莫西林胶囊有约89% 的样品属于第1类,约4.4% 的样品属于第2类,约6.6% 的样品属于第3类。

Figure 1 Typical dissolution types of domestic amoxicillin capsule based on dissolution profiles
2 流通池法测定

选择在常规法中溶出行为不同的样品,进一步比较其在流通池法测定中溶出曲线的差异,进而评估其体内释放行为的差异。第1种设计模拟胃酸较多或空腹状态下药物在人体胃肠道环境中的释放行为,3种介质 (pH 1.0、pH 4.5和pH 6.8) 依次通过流通池,样品在15 min内基本都可以达到溶出平台 (>85%) (图 2A)。第2种设计模拟胃酸较少或饱腹状态下药物在人体 胃肠道环境中的释放行为,两种介质 (pH 4.5和pH 6.8) 依次通过流通池,此时,全部样品的溶出行为可以分为两类: 一类为在约30 min处达到溶出平台 (>85%); 另一类的溶出稍慢,在约45 min处达到溶出平台 (图 2B)。与转篮法结果相比可知,在流通池法中溶出稍慢的样品均为篮法测定中的第2或第3类样品 (在pH 4.5或pH 6.8介质中存在溶出时滞的样品)。

Figure 2 Dissolution profiles of domestic amoxicillin capsules by flow-through cell methods. A: Three kinds of media flow through the cell (0-15 min,pH 1.0; 15-30 min,pH 4.5; 30-120 min,pH 6.8); B: Two kinds of media flow through the cell (0-20 min,pH 4.5; 20-120 min,pH 6.8). No. 1-12 in this diagram stands for samples from 12 different manufacturerss
3 建立体内外相关性模型

利用Gastro PlusTM软件构建阿莫西林胶囊的体内吸收曲线模型。将模型预测的模拟药时曲线同文献中报道的实际药时曲线进行比较,考察模型的准确性。图 3为模型预测的静脉注射阿莫西林500 mg以及口服阿莫西林胶囊500 mg的药时曲线与Arancibia等[ 22 ]实测的药时曲线的比较。Gastro PlusTM软件所 构建的模型的预测结果与实测药时曲线非常相似; 预测曲线接近所有文献实测曲线的平均值 (图略),实测的Cmax和AUC值[ 22, 23, 24, 25, 26, 27, 28, 29, 30 ]均分布在预测值 (Cmax和AUC分别为7.62 μg·mL-1和23.68 μg·h·mL-1) 的80%~125% 内。通常模型预测的Cmax和AUC与实际测定结果的误差在两倍以内,可以认为构建的模型较准确[ 31 ],证明了预测模型的准确性[ 31 ]

Figure 3 Comparison of concentration-time curves of amoxicillin samples in plasma between predicted by the simulation model and detected by the experiments. A: iv; B: po. Blue line represents predicted value,and blue dots represent experiment value[ 22 ]

阿莫西林属于高溶解、低渗透的BCS Ⅲ类药物。

根据阿莫西林的理化性质及药动学参数,Gastro PlusTM软件模拟出阿莫西林在胃肠道的主要吸收部位为空肠,药物一般会在1 h后到达该部位,与文献[ 22, 23, 24, 25, 26, 27, 28, 29, 30 ]中记载的tmax结果基本相符; 口服阿莫西林胶囊500 mg后的体内模拟释放和吸收曲线显示,吸收部位的阿莫西林的量远远高于其吸收量,提示如果在生理条件下药物到达最佳吸收部位前完全溶出,其在胃肠道内释放速率的不同不会引起生物利用度的差异。

采用Gastro PlusTM软件中的群体模拟实验 (population simulation),进一步分析释放速率对阿莫西林胶囊生物等效性的影响[ 32 ]。利用所构建的模型预测不同释放速率下阿莫西林胶囊Cmax和AUC的差异 (图 4)。根据WHO的生物豁免原则[ 11 ],在500人的虚拟人群模拟实验中,以t85% = 15 min时药时曲线的平均Cmax和AUC作为参比,考察满足生物等效性标准时阿莫西林胶囊所能接受的最慢释放速率。模拟实验中,人体生理参数以及药物的理化性质等均设定其在预设值的10% 或20% 误差范围内随机波动。模拟结果显示,无论是以Cmax还是AUC为指标,当阿莫西林胶囊的释放速率为t85% = 45 min时,其均值的90% 置信区间完全在参比均值的80%~125% 内(图 5),可认为其与参比制剂具有生物等效性[ 32 ]

Figure 4 Release rate of the drug from the formulation in the GI tract used in the simulations. Lines represents the release versus time of a release pattern corresponding to 85% release in 15,30,45,60,90,120 and 180 min

Figure 5 Cmax(a) and AUC (b) of amoxicillin predicted by computer simulations. Data reported as mean ± SD 90% confidence interval (CI) of Cmax (a) and AUC (b),the simulation being taken with a release rate corresponding to 85% release in 15 min as comparator. Blue bars represent bioequivalence,and red bars represent outside of bioequivalence criteria,i.e. outside of 80% and 125% of the comparatorn

进一步假设阿莫西林胶囊在体内的释放行为与其在流通池法的溶出行为相似,将不同类型的典型溶出曲线以及样本中的极端溶出曲线 (样品中溶出最快和最慢的样品) 加载到软件中,进行单次模拟实验和群体模拟实验,以评价在流通池法表现出不同溶出特性的阿莫西林口服制剂的生物等效性。单次模拟实验得到的Cmax和AUC值 (表 1) 均表明,各样品在体内的药时曲线非常接近,Cmax和AUC的误差都在6%以内。500虚拟人群体的模拟实验同样得出诸样品具有生物等效性的结论。

Table 1 Simulated Cmax and AUC of amoxicillin capsules with different dissolution profile by flow-through cell methods (single simulation)
讨论

使用常规的溶出度测定法 (篮法) 和开放式流通池法考察阿莫西林胶囊在不同介质中的溶出行为,证明国产阿莫西林胶囊存在不同的溶出特性,提示其在体内可能具有不同的释放特征。阿莫西林胶囊为BCS III药物,Gastro PlusTM软件模拟预测分析显示,阿莫西林胶囊口服后主要在空肠吸收,药物一般要在1 h后才会到达最佳吸收部位; 吸收部位的药物量远远高于其吸收量; 因此,阿莫西林胶囊在体内的释放速率延长至t85% = 45 min时,仍与口服溶液具有生物等效性。以Cmax和AUC值为指标,通过模拟预测,分析国产阿莫西林胶囊在流通池法表现出的溶出特性的差异对其体内吸收的影响,提示国产阿莫西林胶囊在体内具有生物等效性。

Gastro PlusTM软件基于药物的理化性质和人体胃肠道生理特性,模拟口服药物在体内的吸收。它采用高级房室模型 (ACAT模型) 作为吸收模型,生理药代动力学模型 (PBPK模型) 作为处置模型; 根据与机体相关的生理学性质、药物特性和生理模型结构来模拟药物及其制剂的药代动力学和药效动力学行为。目前该软件在建立药物的体内外相关性、进行虚拟生物等效性实验判断生物豁免性等方面均得到了较为广泛的应用[ 33, 34, 35, 36 ]。本研究在对国产阿莫西林胶囊的体内外行为进行了充分考察的基础上,应用该软件模拟具有不同溶出特性的国产阿莫西林胶囊的药动学参数,进而评价其生物等效性,为仿制药物的一致性评价提供了参考。

流通池法提供的流体力学性质与体内相近,且在测试中可模拟人体胃肠道pH等的变化,改变溶液的pH等条件,使测试参数与生理条件相关。大量研究表明,使用流通池法更有助于建立药物的体内外相关性[ 4,33,37 ]。对于阿莫西林胶囊而言,其在采用3种介质的流通池法中的溶出行为与其在pH 1.0介质 (篮法) 中溶出行为类似,提示可以在pH 1.0介质中使用常规法 (篮法) 代替流通池法来模拟阿莫西林胶囊在空腹状况或胃酸较多时的体内溶出行为; 而采用两种介质的流通池法显示,模拟阿莫西林胶囊在饱腹或胃酸较少时的体内溶出行为是更关键的参数,因此,其在常规法pH 4.5介质中的溶出行为更能体现其在体内释放的优劣。

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