恩替卡韦开发报告

恩替卡韦开发 一、基本情况 中文名:恩替卡韦 英文名:Entecavir 化学名:2-氨基-9-[(1S,3S,4S)-4-羟基-3-羟甲基-2-亚甲戊基]-1，9-氢-6-H-嘌呤-6- 酮-水合物。 分子式:CHNO?HO 1215532 分子量:295.3 CAS号:142217-69-4 结构式: 上市剂型:片剂0.5mg 和1mg;分散片0.5mg 和1mg 适应症:本品适用于病毒复制活跃，血清转氨酶ALT持续升高或肝脏组织学显示有活动 性病变的慢性成人乙型肝炎的治疗。 二、选的目的与依据 1、作用机制: 本品为鸟嘌呤核苷类似物，对乙肝病毒(HBV)多聚酶具有抑制作用。它能够通过磷酸化成为具有活性的三磷酸盐，三磷酸盐在细胞内的半衰期为15小时。通过与HBV多聚酶的天然底物三磷酸脱氧鸟嘌呤核苷竞争，恩替卡韦三磷酸盐能抑制病毒多聚酶(逆转录酶)的所有三种活性:(1)HBV多聚酶的启动;(2)前基因组mRNA逆转录负链的形成;(3)HBVDNA正链的合成。恩替卡韦三磷酸盐对HBVDNA多聚酶的抑制常数(Ki)为0.0012μM。恩替卡韦三磷酸盐对细胞的α、β、δDNA多聚酶和线粒体γDNA多聚酶抑制作用较弱，Ki值为18至于160μM。 在细胞试验中发现，拉米夫定耐药的病毒株对恩替卡韦怕显型敏感性降低8至30倍。for computer software engineering GB/T50314-2000 of electrical installations code for construction and acceptance of GBJ232- 92 intelligent building weak design construction figure set GJBT-471 2. system description this times engineering weak design including: hours a Kok information facilities system integrated wiring system (containing room network, communications part) wired TV system information guide and the released system hours II Kok public security system fire automatically alarm system (containing public broadcast part) security technology prevention system security monitoring system out entrance control system car library management system hours three Kok building equipment monitoring system hours four Kok information application system queued station ICU visitation system operation the system monitoring and training system call intercom system hours, five hours Kok Kok intelligent integrated system of information system (1) cabling systems (including computer room network, communication component) computer network systems and voice communications systems Center of information on medical floor computer room located in the engine room. Voice communication system using a local telecommunications operator providing voice service, configuration-independent integrated services digital program-controlled switchboards. Operators providing communications ... If any compatibility requirements, by way of increased access to the Communications Board within the chassis to meet 如果乙肝病毒多聚酶本来就存在对拉米夫定耐药的氨基酸置换(rtL180M和/或rtLM204V/I),再加上rtT184，rtS202或rtM250位点的置换变异，都会造成对恩替卡为的显型敏感受性降低更多(>70倍。)。 2、临床研究: 核苷类药物初治患者:81%的核苷类药物初治病人在口服恩替卡韦0.5mg/天48周后，病毒载量达到1×ULN的患者。 服用本品1.0mg/天，持续48周(12周的双盲给药加上36周的开放期给药),能够非常有效地降低拉米夫定治疗失效患者HBV-DNA水平。基线时ALT水平异常的患者经治疗后，85%患者ALT水平复常。在双盲阶段服用安慰剂的患者转为恩替卡韦开放给药(1.0mg/天，36周)，疗效相同。 3、品种优势 目前被专家公认的乙肝抗病毒药物一共两大类，共五种，分别是干扰素类(普通干扰素、长效干扰素)和核苷类(拉米夫定、阿德福韦、恩替卡韦)。 干扰素-α(普通或聚乙二醇干扰素)的主要优点是不存在耐药，有潜在的免疫介导的抗HBV作用，从而使治疗结束时HBV DNA保持阴性的患者有机会得到持久的病毒学应答以及HBsAg消失。但是频发的副作用和需要皮下注射是干扰素α的主要缺点。 拉米夫定据III期临床研究显示，治疗1年后，从14%,32%的病例中检测到YMDD变异株。另外拉米夫定阻止病毒蛋白的表达作用弱，所以HBeAg转阴率低。 阿德福韦酯具有耐药率较低的优点，并且跟拉米夫定没有交叉耐药，对拉米夫定耐药的病人比较好。但是有一个缺点，它的起效比较慢，对于比较重比较急的病人不太合适。另外，阿德福韦酯有潜在肾毒性作用。 恩替卡韦与原有的核苷类似物比较具有抗病毒作用强、Qi效快副作用小、临床耐药率低的优点，恩替卡韦能够强效抑制HBV,并且具有高耐药基因屏障。恩替卡韦使患者以单药初始治疗并维持长期疗效，摆脱加药换药顾虑。最近公布的恩替卡韦治疗5年的耐药，在核苷初治患者中，治疗5年时对恩替卡韦基因型耐药累积发生率为1.2%;在拉米夫定治疗失效患者中，治疗5年时对恩替卡韦基因型耐药同时有病毒学反弹的累积发生率达43%。 研究发现:新1代核苷类似物恩替卡韦经临床使用后与拉米夫定比较有以下的优点:?恩替卡韦抗病毒治疗具有高效Qi效快的特点，治疗后8周即在HBV DNA 定量上、肝功能for computer software engineering GB/T50314-2000 of electrical installations code for construction and acceptance of GBJ232- 92 intelligent building weak design construction figure set GJBT-471 2. system description this times engineering weak design including: hours a Kok information facilities system integrated wiring system (containing room network, communications part) wired TV system information guide and the released system hours II Kok public security system fire automatically alarm system (containing public broadcast part) security technology prevention system security monitoring system out entrance control system car library management system hours three Kok building equipment monitoring system hours four Kok information application system queued station ICU visitation system operation the system monitoring and training system call intercom system hours, five hours Kok Kok intelligent integrated system of information system (1) cabling systems (including computer room network, communication component) computer network systems and voice communications systems Center of information on medical floor computer room located in the engine room. Voice communication system using a local telecommunications operator providing voice service, configuration-independent integrated services digital program-controlled switchboards. Operators providing communications ... If any compatibility requirements, by way of increased access to the Communications Board within the chassis to meet 上与治疗前及拉米夫丁组差异均有统计学意义(P均 <0.05)。观查到治疗后24周、48周、72周与拉米夫丁组比较差异均有统计学意义(P均 <0.05);?恩替卡韦治疗72周未发现耐药现象，但拉米夫定组72周中已有耐药出现，表现为肝功能较前升高及HBV DNA 再升高1例;?口服方便，治疗过程中患者依从性好，未发现不良反应。专家称，恩替卡韦的抗病毒效力是拉米夫定的300倍。 恩替卡韦的临床疗效优于阿德福韦酯，从09年4月份刚刚结束的欧洲肝病年会上公布的最新研究数据看，与阿德福韦酯相比，恩替卡韦的降病毒能力更快、更强。早至治疗第10天，恩替卡韦降病毒载量的幅度和阿德福韦酯相比有显著的统计学差异;治疗48周时，58,恩替卡韦治疗的患者病毒载量下降到不可检测水平，而阿德福韦酯对照组为19%。同时，现有的乙肝抗病毒药物的耐药数据显示，在核苷初治患者中使用不同的药物，在治疗第4年的耐药发生率分别为:拉米夫定为71,，阿德福韦酯为18,，恩替卡韦低于1,。恩替卡韦能强效抑制HBV且具有较高的耐药屏障，因此可以放心将其用作一线单药治疗。 4、市场情况 我国是被世界公认的“乙肝大国”。在我国，慢性乙型肝炎病毒(HBV)感染的人数约有1.3亿，其中3000万人患有慢性乙肝。根据最新的数据显示，我国每年因肝病死亡的人数接近50万，给社会造成损失高达1000亿元。 鉴于近年核苷类药物在抗乙肝病毒中的出色表现，《中国慢性乙型肝炎防治指南》中已将阿德福韦酯、恩替卡韦和拉米夫定推荐为全国抗乙肝病毒的一线用药，从而促进了抗乙肝病毒药物市场有了快速的发展。据中国药学会统计数据表明，我国重点城市样本医院抗乙肝病毒用药市场2001~2006年的平均增长率超过了30%。葛兰素史克专利药“贺普丁”(拉米夫定)创下了国内医院市场最高年销售近9亿元的辉煌业绩。2006年，阿德福韦酯在22个重点监测统计城市中，已进入18个城市的样本医院，销售额进入前100位用药排名，创下了近7000万元的市场份额，而“贺维力”仅占40%，2个国产品种夺得60%的市场，预计到2010年阿德福韦酯将超过10亿元的市场规模。 恩替卡韦是百时美施贵宝公司自主研发的鸟嘌呤核苷类似物口服药。2005年3月美国FDA批准恩替卡韦上市。恩替卡韦于2005年底通过中国食品与药品监督管理局(SFDA)审批，并于2006年初由中美上海施贵宝制药有限公司在国内上市,年销售势如破竹。 for computer software engineering GB/T50314-2000 of electrical installations code for construction and acceptance of GBJ232- 92 intelligent building weak design construction figure set GJBT-471 2. system description this times engineering weak design including: hours a Kok information facilities system integrated wiring system (containing room network, communications part) wired TV system information guide and the released system hours II Kok public security system fire automatically alarm system (containing public broadcast part) security technology prevention system security monitoring system out entrance control system car library management system hours three Kok building equipment monitoring system hours four Kok information application system queued station ICU visitation system operation the system monitoring and training system call intercom system hours, five hours Kok Kok intelligent integrated system of information system (1) cabling systems (including computer room network, communication component) computer network systems and voice communications systems Center of information on medical floor computer room located in the engine room. Voice communication system using a local telecommunications operator providing voice service, configuration-independent integrated services digital program-controlled switchboards. Operators providing communications ... If any compatibility requirements, by way of increased access to the Communications Board within the chassis to meet 据Datamonitor预测，到2009年其专利到期以前，恩替卡韦在全球7大主要市场的销售额最高将达3亿美元，而2007年1~9月，该药已达到1.76亿美元，比上一年同期增长了274.47%，呈现出高速增长的态势。 2006年，恩替卡韦在样本医院的用药金额已突破2000万元。虽然恩替卡韦在抗乙肝药物市场虽未形成强势，用药金额仅仅占据三大抗乙肝病毒药物市场的16%，但其前景不可低估。从2007年前3季度样本医院用药可以看出，恩替卡韦已成为拉米夫定的替代药物，前3季度，恩替卡韦用药金额已经超过了上一年的购药总额。而2007年上半年。北京诺华制药公司的替比夫定在中国的上市，为将形成四雄争霸的局面埋下伏笔。 在我国每年约100亿元乙肝药品市场总容量中，西药占约30%，中药占约70%。众所周知，对国内抗乙肝市场而言，新品种的进入必然会对老品种构成威胁，形成新的竞争格局。多年来，乙肝抗病毒治疗药物品种匮乏，市场需求量远远未得到满足。因此，新品种的进入将更多地起到满足市场需求，扩大市值的作用。 随着临床应用的不断开展，因为干扰素应用不方便、副作用太大;拉米夫定耐药性差;阿德福韦酯的起效慢、肾脏毒性的缺点，所以会被医生逐渐淘汰，而在研的西药距离临床应用至少还要3—5年，因而可预见恩替卡韦在未来一段时间5---8年内在西药领域独领风骚。国内销售额有望达到17亿元/年。 三、品种相关情况 for computer software engineering GB/T50314-2000 of electrical installations code for construction and acceptance of GBJ232- 92 intelligent building weak design construction figure set GJBT-471 2. system description this times engineering weak design including: hours a Kok information facilities system integrated wiring system (containing room network, communications part) wired TV system information guide and the released system hours II Kok public security system fire automatically alarm system (containing public broadcast part) security technology prevention system security monitoring system out entrance control system car library management system hours three Kok building equipment monitoring system hours four Kok information application system queued station ICU visitation system operation the system monitoring and training system call intercom system hours, five hours Kok Kok intelligent integrated system of information system (1) cabling systems (including computer room network, communication component) computer network systems and voice communications systems Center of information on medical floor computer room located in the engine room. Voice communication system using a local telecommunications operator providing voice service, configuration-independent integrated services digital program-controlled switchboards. Operators providing communications ... If any compatibility requirements, by way of increased access to the Communications Board within the chassis to meet 1、恩替卡韦生产厂家 海南中和药业有限公司已于2009年3月首家拿到恩替卡韦原料药生产批文，并率先获得恩替卡韦分散片及胶囊两个剂型的临床批件;截止2010年5月，江苏正大天晴药业已抢先获得恩替卡韦分散片的批准文号。详情见下表: 药品名称 规格 生产企业 批准文号 批准日期 类型 (商品名) 恩替卡韦 285g/包，1kg/包 Swords Laboratories H20050542 2005-11-18 进口药品 恩替卡韦 2.5kg/包，5kg/包 Swords Laboratories H20050547 2005-11-18 恩替卡韦 原料药 海南中和药业有限公司 H20093354 2009-3-23 恩替卡韦 原料药 江苏正大天晴药业股份有限公司 H20100020 2010-2-10 恩替卡韦片 中美上海施贵宝制药有限公司 1mg H20080798 2008-12-9 恩替卡韦片 中美上海施贵宝制药有限公司 0.5mg H20052237 2005-11-15 (博路定) 国产药品 恩替卡韦分江苏正大天晴药业股份有限公司 0.5mg H20100019 2010-2-10 散片 恩替卡韦分江苏正大天晴药业股份有限公司 1.0mg H20100018 2010-2-10 散片 2、国内受理情况 马来酸恩替卡韦及片剂:江苏正大天晴和北京典范科技有限责任公司以新药4类申请; 恩替卡韦原料药(仿制):28家申报; 恩替卡韦分散片:18家申报; 恩替卡韦胶囊:21家申报 恩替卡韦颗粒:3家申报 恩替卡韦口崩片:1家申报 恩替卡韦片:无人申报。 3、知识产权和行政保护情况 恩替卡韦在国内无行政保护期。2010年10月恩替卡韦化合物专利到期，截止目前，其在国内的专利包括还未授权的已有几十个。 4、药品收载情况(标准未公开) for computer software engineering GB/T50314-2000 of electrical installations code for construction and acceptance of GBJ232- 92 intelligent building weak design construction figure set GJBT-471 2. system description this times engineering weak design including: hours a Kok information facilities system integrated wiring system (containing room network, communications part) wired TV system information guide and the released system hours II Kok public security system fire automatically alarm system (containing public broadcast part) security technology prevention system security monitoring system out entrance control system car library management system hours three Kok building equipment monitoring system hours four Kok information application system queued station ICU visitation system operation the system monitoring and training system call intercom system hours, five hours Kok Kok intelligent integrated system of information system (1) cabling systems (including computer room network, communication component) computer network systems and voice communications systems Center of information on medical floor computer room located in the engine room. Voice communication system using a local telecommunications operator providing voice service, configuration-independent integrated services digital program-controlled switchboards. Operators providing communications ... If any compatibility requirements, by way of increased access to the Communications Board within the chassis to meet 药品名称 标准出处 生产厂 代码 恩替卡韦 进口药品注册标准 施贵宝 JX20050113 恩替卡韦片 药品注册标准 上海施贵宝 YBH33292005 5、社会经济效益 有观点认为( 恩替卡韦上市后相当一段时间内还不能成为治疗乙肝的主流药物，市场前景也没有预测的那样好，原因是其价格较为昂贵。目前在美国市场上恩替卡韦的售价为 20美元/片。同类药物拉米夫定和阿德福韦酯在美国的售价分别为6美元,片和1 8美元,片，因为后者比前者贵了3倍(因而近几年阿德福韦酯在美国及欧洲市场上的表现远不如拉米夫定。事实上，很多外国公司的产品打人中国市场时，其定价都比国外要低，有的低了很多。如葛兰素史克公司生产的拉米夫定( 商品名贺普丁) ，国外售价每片6美元 ，国内产品100 m g x14片一盒包装的每盒234元人民币，每片16.7元人民币。 同为葛兰素史克公司生产的阿德福韦酯( 商品名贺维力)，国外售价每片l 8美元，2005年在中国上市时 10mg x 14片一盒包装的全国统一价格为每盒298元人民币，每片21.29元人民币，比国外要低很多。2005年上市的国产阿德福韦酯价格为每片16元人民币左右。恩替卡韦目前价格为39.2元/片，相信2010年恩替卡韦专利到期，仿制药大量涌现时，我们能在原有工艺及制剂等方面有所改进和创新，开发出具有自主知识产权的新产品，其社会效益和经济效益都将十分可观。 四、结论 恩替卡韦原料药和片剂无新药监测，无行政保护，化合物专利即将到期，国内厂家争相仿制，并申请了众多专利保护，我公司如果规避了重要已受权专利，在原有工艺及制剂等方面有所改进和创新，开发出具有自主知识产权的新产品，其社会效益和经济效益都将十分可观。建议申报恩替卡韦原料药和分散片。 for computer software engineering GB/T50314-2000 of electrical installations code for construction and acceptance of GBJ232- 92 intelligent building weak design construction figure set GJBT-471 2. system description this times engineering weak design including: hours a Kok information facilities system integrated wiring system (containing room network, communications part) wired TV system information guide and the released system hours II Kok public security system fire automatically alarm system (containing public broadcast part) security technology prevention system security monitoring system out entrance control system car library management system hours three Kok building equipment monitoring system hours four Kok information application system queued station ICU visitation system operation the system monitoring and training system call intercom system hours, five hours Kok Kok intelligent integrated system of information system (1) cabling systems (including computer room network, communication component) computer network systems and voice communications systems Center of information on medical floor computer room located in the engine room. Voice communication system using a local telecommunications operator providing voice service, configuration-independent integrated services digital program-controlled switchboards. Operators providing communications ... If any compatibility requirements, by way of increased access to the Communications Board within the chassis to meet