纳米类似药何去何从——再议原研药与仿制药的差异

2018-05-31 佚名 肿瘤资讯

近年来,为了提高药品供应保障能力,更好地满足临床用药及公共卫生安全需求,国家多次强调要促进仿制药的研发,认真落实一致性评价。全国合理用药监测办公室的孙忠实教授应邀分享了“再议原研药与仿制药的差异”主题演讲,从纳米药物的视角剖析了纳米类似药物研发面临的机遇与挑战。

近年来,为了提高药品供应保障能力,更好地满足临床用药及公共卫生安全需求,国家多次强调要促进仿制药的研发,认真落实一致性评价。全国合理用药监测办公室的孙忠实教授应邀分享了“再议原研药与仿制药的差异”主题演讲,从纳米药物的视角剖析了纳米类似药物研发面临的机遇与挑战。

仿制药的审评:高标准才有高质量

批准上市的药品分为四大类:原研药、仿制药、派生药(Me-too)和生物类似药。原研药是经全面的药学、药理学和毒理学研究以及临床研究数据证实其安全有效性并首次被批准上市的药品,又叫专利药,一般享有20年专利保护期。而药物专利到期后,其他公司在得到药监局审批后可生产并销售该药的仿制药,其中仿制药的审批需要进行一致性评价。

但是仿制药不可能与原研药完全相同,除了原研药的核心处方工艺保密外,主要原因是国家标准偏低。各国仿制药需满足生物等效性方能获批上市,即仿制药的主要动力学参数(AUC、Cmax)与原研药应无显着差异。然而,不同国家的标准又各不相同。美国FDA规定,仿制药与原研药的曲线下面积(AUC)、峰浓度(Cmax)近似度为80%-125%即为合格。加拿大与欧盟的标准则更高。

表1  各国对仿制药生物等效性的相关要求


*受试与参照药品AUC比值的90%置信区间;

**受试与参照药品Cmax比值的90%置信区间;

由于药物质量的差异(主药晶型、生产工艺、辅料、质控标准等)、药代动力学与生物利用度差异、对照品的规范性(以原研药为金标准)、临床研究有限(多为健康受试者、病例较少、多为单剂量研究),仿制药与原研药的差异往往被掩盖,因此药学等效性和生物等效性并不等于临床等效性。于是,国务院提出《关于改革完善仿制药供应保障及使用政策的意见》强调要促进仿制药研发,细化落实鼓励企业开展一致性评价的政策措施,并重申仿制药需按照与原研药质量和疗效一致的原则受理和审评审批。

纳米药物:新型药物制剂

纳米药物是应用纳米技术标准、直接加工的、用以修复、重构以及操控人体生物系统的药物,具有颗粒小、比表面积大、活性高等特点。纳米药物主要分为两类:纳米分子药物和纳米载体药物,前者是将原料药直接加工制成纳米粒,后者是采用纳米级高分子材料为载体与药物以一定方式结合后制成的药物制剂。纳米药物载体能够延长药物循环时间,减少药物在非靶点组织的积累,并通过被动/主动靶向增加药物在肿瘤靶位点的定位。那么纳米制剂到底只是换了一种载体还是一种新药?由于纳米制剂这一转运载体作为一种有效成分会产生不同的药理学特征、组织分布、适应症、疗效和安全性,因此纳米药物应为一种全新的药物。而纳米药物也由于特殊的物理、化学与生物学特性,其生物安全性备受关注,研发生产获批的门槛也相当高。


其中,白蛋白紫杉醇则是纳米制剂的典型代表。白蛋白结合型紫杉醇选用人体白蛋白作为载体,通过白蛋白在体内的天然转运通路(白蛋白结合受体蛋白和窖蛋白的作用),迅速的组织分布并且更多地聚集在肿瘤组织,而在正常组织分布较少,能够在增加化疗疗效的同时降低毒性。另外白蛋白无免疫原性,相容性与亲和性极强,因此白蛋白纳米微粒相比脂质体纳米微粒,具有无毒性、长期稳定、无抗原性。

2005年白蛋白结合型紫杉醇(Abraxane ?,凯素TM)作为第一个在美国上市的白蛋白为载体的纳米药物被FDA批准。而FDA迄今批准的纳米级化疗药物共5个,白蛋白紫杉醇是唯一获批的白蛋白结合型药物,其他4个均为脂质体药物。白蛋白紫杉醇与传统紫杉相比,不需要传统有机溶剂做载体,具有独特的分子构成、全新的转运机制和优化的药代动力学特性,可大幅提高紫杉醇用量,具有高肿瘤组织分布、高疗效和低毒性。同时,白蛋白紫杉醇的使用非常方便,无需抗过敏预处理,无需特殊输液装置,输液时间大大缩短至30分钟。由于剂型彻底的改变,白蛋白紫杉醇的适应症从乳腺癌逐渐扩展多种肿瘤,是唯一可以治疗胰腺癌的紫杉类药物。


纳米类似药的审评与监管——治疗等效性的挑战

如今纳米药物存在着四大挑战:1. 尚无良好的生产管理规范(GMP);2. 价格昂贵;3. 生产/仿制困难,急需建立完善的临床评价和检测系统;4. 安全问题,包括纳米毒性与免疫原性。因此,必须加强新型纳米药物的研发、加速纳米类似药的跟进,对其质量、安全、效能和风险尽享全面评估。


纳米类似药即纳米药物的仿制药,那么纳米类似药如何进行审评和监管?2007版中国药品注册管理办法中曾提到,仿制药中需要用工艺和标准控制药品质量的,应当进行临床试验,且临床试验病例不少于100对。纳米药物的生产过程非常复杂,往往有很高的专利技术壁垒。目前虽然其仿制药的PE与原研纳米药物的研究相似,但由于仿制药与原研药在生产流程中所存在的任何细微差异,包括生产工艺、原料、反应时间、pH值及温度等,都可能影响其制剂的理化性质。而理化性质必将影响制剂稳定性及药物的正常释放,外壳的组成方式将影响复合物的表观分子量以及整个化合物的稳定性。那么,直接套用化学仿制药的常规质量评价方法是否妥当,有待进一步探讨。因此,纳米类似药作为一种独特的、类似于生物类似药的药物,不仅要做到药学等效性(PE)和生物等效性(BE),还要开展前瞻性的对比临床研究,验证其治疗等效性(TE)。


FDA严格要求,对纳米药物的生产质量和安全性均需进行评估,其中对纳米药物的安全性问题尤其重视。要求中提到,纳米微粒的物理化学性质可影响其生物分布,药物的结合型与游离型都需单独进行评估,同时需要对多种成分的ADME(吸收、分布、代谢及排泄)进行研究,以及长期的安全性研究。另外,白蛋白作为载体的纳米药物可能通过激活体内的免疫原性而引起过敏等不良反应,必须进行相关的毒性研究和检测。

今年4月24日,港交所公布了关于生物科技公司上市的《上市规则》,其中明确了生物仿制药需至少通过一次人体临床试验,且不反对开展第二阶段的临床试验以证明生物等效性。因此,生物类似药包括纳米类似药的临床评估相当重要。国家审评中心强调:一致性评价不能成为“一次性评价”,要加大力度对企业进行各类检查,全面提高仿制药的质量。

专家简介


孙忠实教授

主任药师,曾任海军总医院药剂科主任

国家食品药品监督管理局药品评价中心专家

国家卫计委全国合理用药监测系统专家

国家处方集办公室核心专家

中国非处方药协会专家

国家食品药品监督管理局执业药师培训中心专家等职

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    2018-06-01 drwjr
  3. [GetPortalCommentsPageByObjectIdResponse(id=1704383, encodeId=d35d1e043830a, content=<a href='/topic/show?id=3be83e20383' target=_blank style='color:#2F92EE;'>#原研药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37203, encryptionId=3be83e20383, topicName=原研药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9b9530733134, createdName=shanyongle, createdTime=Wed Aug 08 16:36:00 CST 2018, time=2018-08-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261414, encodeId=a7ac1261414d2, content=<a href='/topic/show?id=b56025592eb' target=_blank style='color:#2F92EE;'>#仿制药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25592, encryptionId=b56025592eb, topicName=仿制药)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Fri Jun 01 16:36:00 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320426, encodeId=c135320426f1, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Fri Jun 01 06:24:51 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320164, encodeId=173532016405, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Thu May 31 06:56:05 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320145, encodeId=5524320145a4, content=了解了解.继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Thu May 31 06:14:16 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320137, encodeId=b07f32013ef5, content=学习.谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyhb9xDeHojCicsdRdyC3XXdGk2ib9yLypZuHN06WeW4HO8WN0GGrgEfvnTX8gsckof05GHOU5OM4Mvx/0, createdBy=9cee1982656, createdName=执着追梦, createdTime=Thu May 31 05:55:13 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320124, encodeId=110532012496, content=学习学习再学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu May 31 05:24:47 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320120, encodeId=a569320120de, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Thu May 31 03:25:00 CST 2018, time=2018-05-31, status=1, ipAttribution=)]
    2018-06-01 深海的鱼

    学习学习学习

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1704383, encodeId=d35d1e043830a, content=<a href='/topic/show?id=3be83e20383' target=_blank style='color:#2F92EE;'>#原研药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37203, encryptionId=3be83e20383, topicName=原研药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9b9530733134, createdName=shanyongle, createdTime=Wed Aug 08 16:36:00 CST 2018, time=2018-08-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261414, encodeId=a7ac1261414d2, content=<a href='/topic/show?id=b56025592eb' target=_blank style='color:#2F92EE;'>#仿制药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25592, encryptionId=b56025592eb, topicName=仿制药)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Fri Jun 01 16:36:00 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320426, encodeId=c135320426f1, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Fri Jun 01 06:24:51 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320164, encodeId=173532016405, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Thu May 31 06:56:05 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320145, encodeId=5524320145a4, content=了解了解.继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Thu May 31 06:14:16 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320137, encodeId=b07f32013ef5, content=学习.谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyhb9xDeHojCicsdRdyC3XXdGk2ib9yLypZuHN06WeW4HO8WN0GGrgEfvnTX8gsckof05GHOU5OM4Mvx/0, createdBy=9cee1982656, createdName=执着追梦, createdTime=Thu May 31 05:55:13 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320124, encodeId=110532012496, content=学习学习再学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu May 31 05:24:47 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320120, encodeId=a569320120de, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Thu May 31 03:25:00 CST 2018, time=2018-05-31, status=1, ipAttribution=)]
    2018-05-31 sunfeifeiyang

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1704383, encodeId=d35d1e043830a, content=<a href='/topic/show?id=3be83e20383' target=_blank style='color:#2F92EE;'>#原研药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37203, encryptionId=3be83e20383, topicName=原研药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9b9530733134, createdName=shanyongle, createdTime=Wed Aug 08 16:36:00 CST 2018, time=2018-08-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261414, encodeId=a7ac1261414d2, content=<a href='/topic/show?id=b56025592eb' target=_blank style='color:#2F92EE;'>#仿制药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25592, encryptionId=b56025592eb, topicName=仿制药)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Fri Jun 01 16:36:00 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320426, encodeId=c135320426f1, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Fri Jun 01 06:24:51 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320164, encodeId=173532016405, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Thu May 31 06:56:05 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320145, encodeId=5524320145a4, content=了解了解.继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Thu May 31 06:14:16 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320137, encodeId=b07f32013ef5, content=学习.谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyhb9xDeHojCicsdRdyC3XXdGk2ib9yLypZuHN06WeW4HO8WN0GGrgEfvnTX8gsckof05GHOU5OM4Mvx/0, createdBy=9cee1982656, createdName=执着追梦, createdTime=Thu May 31 05:55:13 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320124, encodeId=110532012496, content=学习学习再学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu May 31 05:24:47 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320120, encodeId=a569320120de, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Thu May 31 03:25:00 CST 2018, time=2018-05-31, status=1, ipAttribution=)]
    2018-05-31 1dd8c52fm63(暂无匿称)

    了解了解.继续关注

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=1704383, encodeId=d35d1e043830a, content=<a href='/topic/show?id=3be83e20383' target=_blank style='color:#2F92EE;'>#原研药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37203, encryptionId=3be83e20383, topicName=原研药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9b9530733134, createdName=shanyongle, createdTime=Wed Aug 08 16:36:00 CST 2018, time=2018-08-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261414, encodeId=a7ac1261414d2, content=<a href='/topic/show?id=b56025592eb' target=_blank style='color:#2F92EE;'>#仿制药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25592, encryptionId=b56025592eb, topicName=仿制药)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Fri Jun 01 16:36:00 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320426, encodeId=c135320426f1, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Fri Jun 01 06:24:51 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320164, encodeId=173532016405, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Thu May 31 06:56:05 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320145, encodeId=5524320145a4, content=了解了解.继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Thu May 31 06:14:16 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320137, encodeId=b07f32013ef5, content=学习.谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyhb9xDeHojCicsdRdyC3XXdGk2ib9yLypZuHN06WeW4HO8WN0GGrgEfvnTX8gsckof05GHOU5OM4Mvx/0, createdBy=9cee1982656, createdName=执着追梦, createdTime=Thu May 31 05:55:13 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320124, encodeId=110532012496, content=学习学习再学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu May 31 05:24:47 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320120, encodeId=a569320120de, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Thu May 31 03:25:00 CST 2018, time=2018-05-31, status=1, ipAttribution=)]
    2018-05-31 执着追梦

    学习.谢谢分享

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=1704383, encodeId=d35d1e043830a, content=<a href='/topic/show?id=3be83e20383' target=_blank style='color:#2F92EE;'>#原研药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37203, encryptionId=3be83e20383, topicName=原研药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9b9530733134, createdName=shanyongle, createdTime=Wed Aug 08 16:36:00 CST 2018, time=2018-08-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261414, encodeId=a7ac1261414d2, content=<a href='/topic/show?id=b56025592eb' target=_blank style='color:#2F92EE;'>#仿制药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25592, encryptionId=b56025592eb, topicName=仿制药)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Fri Jun 01 16:36:00 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320426, encodeId=c135320426f1, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Fri Jun 01 06:24:51 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320164, encodeId=173532016405, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Thu May 31 06:56:05 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320145, encodeId=5524320145a4, content=了解了解.继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Thu May 31 06:14:16 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320137, encodeId=b07f32013ef5, content=学习.谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyhb9xDeHojCicsdRdyC3XXdGk2ib9yLypZuHN06WeW4HO8WN0GGrgEfvnTX8gsckof05GHOU5OM4Mvx/0, createdBy=9cee1982656, createdName=执着追梦, createdTime=Thu May 31 05:55:13 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320124, encodeId=110532012496, content=学习学习再学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu May 31 05:24:47 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320120, encodeId=a569320120de, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Thu May 31 03:25:00 CST 2018, time=2018-05-31, status=1, ipAttribution=)]
    2018-05-31 yjs木玉

    学习学习再学习

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=1704383, encodeId=d35d1e043830a, content=<a href='/topic/show?id=3be83e20383' target=_blank style='color:#2F92EE;'>#原研药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37203, encryptionId=3be83e20383, topicName=原研药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9b9530733134, createdName=shanyongle, createdTime=Wed Aug 08 16:36:00 CST 2018, time=2018-08-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261414, encodeId=a7ac1261414d2, content=<a href='/topic/show?id=b56025592eb' target=_blank style='color:#2F92EE;'>#仿制药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25592, encryptionId=b56025592eb, topicName=仿制药)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Fri Jun 01 16:36:00 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320426, encodeId=c135320426f1, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Fri Jun 01 06:24:51 CST 2018, time=2018-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320164, encodeId=173532016405, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Thu May 31 06:56:05 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320145, encodeId=5524320145a4, content=了解了解.继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Thu May 31 06:14:16 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320137, encodeId=b07f32013ef5, content=学习.谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyhb9xDeHojCicsdRdyC3XXdGk2ib9yLypZuHN06WeW4HO8WN0GGrgEfvnTX8gsckof05GHOU5OM4Mvx/0, createdBy=9cee1982656, createdName=执着追梦, createdTime=Thu May 31 05:55:13 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320124, encodeId=110532012496, content=学习学习再学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu May 31 05:24:47 CST 2018, time=2018-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=320120, encodeId=a569320120de, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Thu May 31 03:25:00 CST 2018, time=2018-05-31, status=1, ipAttribution=)]
    2018-05-31 wzb521zf

    一起学习学习

    0