【《关于盐酸那拉曲坦的研究文献综述》8100字】

关于盐酸那拉曲坦的研究文献综述目录TOC\o"1-3"\h\u14308关于盐酸那拉曲坦的研究文献综述 162771.1偏头痛及相关药物研究背景 1296991.2盐酸那拉曲坦结构、理化性质 2222981.2.1盐酸那拉曲坦结构 2174251.2.2盐酸那拉曲坦的理化性质 255421.3盐酸那拉曲坦的药理、毒理、不良反应 215171.3.1药理作用 2150311.3.2毒理作用及不良反应 3116241.4盐酸那拉曲坦的药代动力学 3318271.5盐酸那拉曲坦的剂型 4194671.6盐酸那拉曲坦片的制备 6212941.6.1常用辅料及其性质 661001.6.2片剂制备方法 6176311.7药品质量研究及质量标准概述 7偏头痛及相关药物研究背景偏头痛是一种临床常见的慢性、反复发作性神经系统疾病ADDINEN.CITEADDINEN.CITE.DATA[1,2]。主要表现为发作时一侧或双侧搏动性中至重度头痛，往往伴有恶心、呕吐、畏光、恐声等症状ADDINEN.CITEADDINEN.CITE.DATA[2-4]。在《2016年全球疾病负担研究》（GBD2016）中，偏头痛被列为世界第六大流行性疾病，也是全球第二大致残性疾病(YLDs)ADDINEN.CITEADDINEN.CITE.DATA[5,6]。相关调查发现，中国年偏头痛患病率为9.3%，接近全球平均水平的11%ADDINEN.CITE<EndNote><Cite><Author>Yu</Author><Year>2012</Year><RecNum>147</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[7]</style></DisplayText><record><rec-number>147</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585391829">147</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yu,S.</author><author>Liu,R.</author><author>Zhao,G.</author><author>Yang,X.</author><author>Qiao,X.</author><author>Feng,J.</author><author>Fang,Y.</author><author>Cao,X.</author><author>He,M.</author><author>Steiner,T.</author></authors></contributors><auth-address>DepartmentofNeurology,ChinesePLAGeneralHospital,Beijing,China.yusy1963@126.com</auth-address><titles><title>ThePrevalenceandBurdenofPrimaryHeadachesinChina:APopulation-BasedDoor-to-DoorSurvey</title><secondary-title>Headache</secondary-title></titles><periodical><full-title>Headache</full-title></periodical><pages>582-591</pages><volume>52</volume><number>4</number><edition>2012/05/17</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>China/epidemiology</keyword><keyword>*CostofIllness</keyword><keyword>Female</keyword><keyword>HeadacheDisorders,Primary/*diagnosis/*epidemiology/psychology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>*PopulationSurveillance</keyword><keyword>Prevalence</keyword><keyword>SurveysandQuestionnaires</keyword><keyword>YoungAdult</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1526-4610(Electronic) 0017-8748(Linking)</isbn><accession-num>22590713</accession-num><urls><related-urls><url>/pubmed/22590713</url></related-urls></urls><electronic-resource-num>10.1111/j.1526-4610.2011.02061.x</electronic-resource-num></record></Cite></EndNote>[7]。其发病率、致残率还在逐年升高，不仅妨碍患者的日常生活、降低患者生活品质，还给社会带来沉重的经济负担ADDINEN.CITEADDINEN.CITE.DATAADDINEN.CITE.DATA[8-11]。作为遗传和环境等多因素共同作用的疾病ADDINEN.CITEADDINEN.CITE.DATA[12]，其致病机制复杂且无定论，涉及血管学说、皮质扩散抑制学说、三叉神经血管学说、炎症介质学说、中枢神经系统学说及基因遗传学说等，而目前普遍认为最可能的机制是三叉神经学说ADDINEN.CITEADDINEN.CITE.DATA[8,13,14]。偏头痛的药物治疗分为急性发作期治疗和预防性治疗，前者主要是依靠非甾体抗炎药、曲坦类药物和钙通道拮抗剂等；后者主要是利用三环类抗抑郁剂、β－受体阻滞剂和抗惊厥剂等ADDINEN.CITE<EndNote><Cite><Author>张兵帅</Author><Year>2017</Year><RecNum>69</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[13]</style></DisplayText><record><rec-number>69</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585292439">69</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">张兵帅</style></author><author><styleface="normal"font="default"charset="134"size="100%">李博文</style></author><author><styleface="normal"font="default"charset="134"size="100%">邱智东</style></author><author><styleface="normal"font="default"charset="134"size="100%">董雪莲</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">偏头痛研究进展</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">亚太传统医药</style></secondary-title></titles><periodical><full-title>亚太传统医药</full-title></periodical><pages>43-45</pages><volume>13</volume><number>22</number><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>[13]。自2002年依利曲坦上市至2017年近15年的时间里，抗偏头痛药物的研发暂无突破ADDINEN.CITE<EndNote><Cite><Author>雷诺岛</Author><Year>2017</Year><RecNum>101</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[15]</style></DisplayText><record><rec-number>101</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585319843">101</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="NewspaperArticle">23</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">雷诺岛</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">曲坦类药物国内上市进度</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">医药经济报</style></secondary-title></titles><edition><styleface="normal"font="default"charset="134"size="100%">第</style><styleface="normal"font="default"size="100%">F02</style><styleface="normal"font="default"charset="134"size="100%">版</style></edition><dates><year>2017</year><pub-dates><date>07-17</date></pub-dates></dates><urls></urls></record></Cite></EndNote>[15]，随着人们对偏头痛致病机制研究的逐步深入，发现降钙素基因相关肽（CGRP）在偏头痛的病理生理机制中起着重要作用，并基于此研发了CGRP拮抗剂及抗CGRP的单克隆抗体，目前Gepant类、Ditans类（LasmiditanADDINEN.CITE<EndNote><Cite><Author>夏训明</Author><Year>2019</Year><RecNum>78</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[16]</style></DisplayText><record><rec-number>78</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585292486">78</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">夏训明</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">美国FDA批准Ｒeyvow(lasmiditan)治疗急性偏头痛</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">广东药科大学学报</style></secondary-title></titles><periodical><full-title>广东药科大学学报</full-title></periodical><pages>706</pages><volume>35</volume><number>5</number><dates><year>2019</year></dates><urls></urls></record></Cite></EndNote>[16]）CGRP受体拮抗剂和靶向CGRP的单克隆抗体Erenumab（AIMOVIGTM）、Fremanezumab（Ajovy）、Galcanezumab（EmgalityTM）均已在美国获批上市ADDINEN.CITEADDINEN.CITE.DATA[2,17,18]。曲坦类药物作为目前唯一一类仅针对偏头痛开发的药物，国外多项临床试验的结果均表明，其对急性发作期偏头痛的疗效和耐受性均优于其他药物，是美国头痛协会推荐的应用于治疗急性偏头痛的药物，目前在国内外临床上使用的有：第一代的舒马曲坦及第二代的佐米曲坦、那拉曲坦、利扎曲坦和依利曲坦等ADDINEN.CITEADDINEN.CITE.DATA[15,19,20]。目前，在8个FDA批准的含曲坦类药物中，实现国产化的仅有3个分别是：佐米曲普坦、舒马普坦和利扎曲普坦；进口的仅有AstraZeneca的佐米曲普坦。截至2017年，利扎曲普坦占据了国内近70%的市场，与全球产品结构及市场相比，国内的产品种类较少。然而，由我国近年来曲坦类抗偏头痛药物销售金额的逐年上升不难看出，国人对偏头痛的认知、重视程度及对生活品质的追求也在逐年提高；综合国内曲坦类药物的审评、注册信息，国内曲坦类抗偏头痛药物市场还在起步阶段ADDINEN.CITEADDINEN.CITE.DATA[15,21]。盐酸那拉曲坦结构、理化性质盐酸那拉曲坦结构盐酸那拉曲坦（NaratriptanHydrochloride）的化学名为N-甲基-3-（1-甲基-4-哌啶基）-1H-吲哚-5-乙基磺酰胺盐酸盐，其分子式为：C17H25N3O2S·HCl，分子量为371.93。化学结构式如下图所示：盐酸那拉曲坦的理化性质盐酸那拉曲坦是白色或淡黄色结晶性粉末，无臭，无味；在水中略溶（25℃时的溶解度为35mg/mL），其解离常数（pKa值）约为9.7ADDINEN.CITE<EndNote><Cite><RecNum>87</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[22]</style></DisplayText><record><rec-number>87</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585319604">87</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="WebPage">12</ref-type><contributors></contributors><titles><title>FDA.AMERGE®BioequivalenceReview(s)</title></titles><number>2021-04-02</number><dates><pub-dates><date>1998-02-10</date></pub-dates></dates><urls><related-urls><url>/drugsatfda_docs/nda/98/20763_Amerge_Bioeqr.pdf</url></related-urls></urls></record></Cite></EndNote>[22]；游离碱的LogD7.4为1.3ADDINEN.CITE<EndNote><Cite><Author>Connor</Author><Year>1997</Year><RecNum>289</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[23]</style></DisplayText><record><rec-number>289</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618884378">289</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Connor,H.E.</author><author>Feniuk,W.</author><author>Beattie,D.T.</author><author>North,P.C.</author><author>Oxford,A.W.</author></authors></contributors><titles><title>Naratriptan:Biologicalprofileinanimalmodelsrelevanttomigraine.</title><secondary-title>Cephalalgia</secondary-title></titles><periodical><full-title>Cephalalgia</full-title></periodical><pages>145-152</pages><volume>17</volume><number>3</number><dates><year>1997</year></dates><urls></urls></record></Cite></EndNote>[23]。那拉曲坦属于BDDCS（基于药物体内处置的生物药剂学分类系统）中的3类药物ADDINEN.CITE<EndNote><Cite><Author>Benet</Author><Year>2011</Year><RecNum>238</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[24]</style></DisplayText><record><rec-number>238</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618801292">238</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Benet,L.Z.</author><author>Broccatelli,F.</author><author>Oprea,T.I.</author></authors></contributors><auth-address>DepartmentofBioengineering&TherapeuticSciences,SchoolsofPharmacyandMedicine,UniversityofCaliforniaSanFrancisco,94143-0912,USA.leslie.benet@</auth-address><titles><title>BDDCSappliedtoover900drugs</title><secondary-title>TheAAPSjournal</secondary-title></titles><periodical><full-title>TheAAPSjournal</full-title></periodical><pages>519-547</pages><volume>13</volume><number>4</number><edition>2011/08/06</edition><keywords><keyword>*Biopharmaceutics</keyword><keyword>HydrogenBonding</keyword><keyword>PharmaceuticalPreparations/*classification</keyword><keyword>*Pharmacokinetics</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1550-7416(Electronic) 1550-7416(Linking)</isbn><accession-num>21818695</accession-num><urls><related-urls><url>/pubmed/21818695</url></related-urls></urls><custom2>PMC3231854</custom2><electronic-resource-num>10.1208/s12248-011-9290-9</electronic-resource-num></record></Cite></EndNote>[24]，即高溶解、低代谢。盐酸那拉曲坦的药理、毒理、不良反应药理作用那拉曲坦是一种吲哚衍生物，含有与神经递质5-羟色胺相同的吲哚环，通过计算机模拟分子对接研究发现，那拉曲坦通过TYR359残基能够选择性地与5-HT1B受体结合，同时对5-HT1D受体及其亚型也有很高的亲和力，是高选择性的5-HT1受体激动剂ADDINEN.CITEADDINEN.CITE.DATA[25-27]。那拉曲坦的抗偏头痛作用涉及以下三种不同的药理作用：一是与颅脑血管平滑肌上及动静脉吻合处的5-HT1B和5-HT1D受体结合，使脑血管收缩，进而抑制促炎神经肽的释放；二是作用于神经突触前和神经末梢的5-HT受体，抑制相关促炎神经肽如CGRP和神经肽P物质的释放，减少炎性物质的渗出；三是通过刺激脑干的5-HT1B/1D受体，降低三叉神经-脑血管系统神经元的兴奋性ADDINEN.CITEADDINEN.CITE.DATA[19,25,28]。毒理作用及不良反应（1）致癌作用：在致癌性研究中，小鼠和大鼠分别灌胃给药那拉曲坦104周。在200mg/kg/day给药剂量的小鼠中，无证据表明与那拉曲坦相关的肿瘤增加。在大鼠亚硝酸盐补充饮食研究中，除发现恶性的淋巴细胞性胸腺瘤和胸腺神经节瘤外，其余肿瘤均为良性。一般来说，那拉曲坦几乎无致癌风险ADDINEN.CITE<EndNote><Cite><RecNum>89</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[27,29]</style></DisplayText><record><rec-number>89</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585319608">89</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="WebPage">12</ref-type><contributors></contributors><titles><title>FDA.AMERGE®PharmacologyReview(s)</title></titles><number>2021-04-02</number><dates><pub-dates><date>1998-02-10</date></pub-dates></dates><urls><related-urls><url>/drugsatfda_docs/nda/98/20763_Amerge_Pharmr.pdf</url></related-urls></urls></record></Cite><Cite><RecNum>267</RecNum><record><rec-number>267</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618815227">267</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="WebPage">12</ref-type><contributors></contributors><titles><title>FDA.AMERGE®Label</title></titles><number>2021-04-02</number><dates><pub-dates><date>2016-11-29</date></pub-dates></dates><urls><related-urls><url>/drugsatfda_docs/label/2016/020763s011lbl.pdf</url></related-urls></urls></record></Cite></EndNote>[27,29]。（2）致突变作用：体外基因突变试验表明：那拉曲坦不具有诱变作用，且人淋巴细胞体外实验和小鼠体内微核实验结果均为阴性。根据世卫组织亚硝化试验结果：那拉曲坦可在体外经亚硝酸盐亚硝化形成诱变产物ADDINEN.CITE<EndNote><Cite><RecNum>89</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[27,29]</style></DisplayText><record><rec-number>89</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585319608">89</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="WebPage">12</ref-type><contributors></contributors><titles><title>FDA.AMERGE®PharmacologyReview(s)</title></titles><number>2021-04-02</number><dates><pub-dates><date>1998-02-10</date></pub-dates></dates><urls><related-urls><url>/drugsatfda_docs/nda/98/20763_Amerge_Pharmr.pdf</url></related-urls></urls></record></Cite><Cite><RecNum>267</RecNum><record><rec-number>267</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618815227">267</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="WebPage">12</ref-type><contributors></contributors><titles><title>FDA.AMERGE®Label</title></titles><number>2021-04-02</number><dates><pub-dates><date>2016-11-29</date></pub-dates></dates><urls><related-urls><url>/drugsatfda_docs/label/2016/020763s011lbl.pdf</url></related-urls></urls></record></Cite></EndNote>[27,29]。（3）不良反应及禁忌症：那拉曲坦的中枢神经系统不良反应发生率较低，但对于正在接受选择性5-HT摄取抑制剂(SSRIs)治疗的患者，那拉曲坦可能会引起5-羟色胺类行为副作用ADDINEN.CITE<EndNote><Cite><RecNum>294</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[30]</style></DisplayText><record><rec-number>294</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618923591">294</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>GeoffreyA.Lambert</author></authors></contributors><titles><title>PreclinicalNeuropharmacologyofNaratriptan</title><secondary-title>CNSDrugReviews</secondary-title></titles><periodical><full-title>CNSDrugReviews</full-title></periodical><pages>289–316</pages><volume>11</volume><number>3</number><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>[30]。药物服用过量时最常见的症状是疲劳、嗜睡、高血压、恶心/呕吐、头晕和心动过速。儿童摄入剂量至成人最大单剂量后，没有或仅造成轻度毒性。对于成人，当摄入剂量达最大单剂量的4~6倍时可诱发中度毒性，出现明显的高血压和心绞痛症状ADDINEN.CITE<EndNote><Cite><Author>D</Author><Year>2012</Year><RecNum>286</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[31]</style></DisplayText><record><rec-number>286</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618884170">286</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Prasa,D.</author><author>Reinecke,H.J.</author><author>Rauber-Luethy,C.</author><author>Seidel,C.</author><author>Hoffmann-Walbeck,P.</author><author>Gerber-Zupan,G.</author><author>Faerber,E.</author><author>Stedtler,U.</author><author>Genser,D.</author></authors></contributors><titles><title>OverdoseofSelectiveSerotonin(5HT1)Agonists</title><secondary-title>ClinicalToxicology</secondary-title></titles><periodical><full-title>ClinicalToxicology</full-title></periodical><pages>324</pages><volume>50</volume><number>4</number><section>324</section><dates><year>2012</year></dates><isbn>1556-3650 1556-9519</isbn><urls></urls><electronic-resource-num>10.3109/15563650.2012.669957</electronic-resource-num></record></Cite></EndNote>[31]。研究发现那拉曲坦在母乳中的排泄率似乎不高，其相对婴儿剂量约为5.0%，尽管如此，考虑到那拉曲坦较高的口服生物利用度，婴儿经乳汁接触药物的可能性依旧不可忽视，故处于哺乳期的妇女不推荐使用ADDINEN.CITEADDINEN.CITE.DATA[32]。由于那拉曲坦可能会导致严重的心血管副作用，故患有心脑血管疾病及病史的人群禁止使用。盐酸那拉曲坦的药代动力学ADME研究表明：那拉曲坦吸收良好，口服生物利用度约为70%，男女间存在轻微差异（女性的绝对生物利用度约为75%，男性约为64%）。单次口服2.5mg片剂后，2~3小时内即达峰值浓度（Cmax为12ng/mL），女性的Cmax比男性稍高(约50%)。偏头痛发作时，药物吸收较慢，Tmax延长为3~4小时。1.5mg静脉滴注15分钟后，稳态表观分布体积为170L，在50~1000ng/mL浓度范围内，药物与血浆蛋白非特异性结合，其结合率为28%~31%；那拉曲坦主要经肝脏由多种细胞色素P450酶代谢为非活性的氮氧化物及哌啶酮代谢物，以50%原型和30%代谢产物的形式经肾脏消除，系统清除率为6.6mL/min/kg，平均消除半衰期为6小时ADDINEN.CITEADDINEN.CITE.DATA[22,28,29]。盐酸那拉曲坦的剂型盐酸那拉曲坦是高选择性的5-HT1D/1B受体激动剂，属第2代曲坦类药物，具有生物利用度高、耐受性好、药效作用时间长，病情复发率低等特点，临床疗效较好ADDINEN.CITE<EndNote><Cite><Author>刘宇</Author><Year>2012</Year><RecNum>86</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[28,33]</style></DisplayText><record><rec-number>86</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585292983">86</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">刘宇</style></author><author><styleface="normal"font="default"charset="134"size="100%">刘东</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">治疗偏头痛药物那拉曲坦的药理与临床研究</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">中国新药与临床杂志</style></secondary-title></titles><periodical><full-title>中国新药与临床杂志</full-title></periodical><pages>373-376</pages><volume>31</volume><number>7</number><dates><year>2012</year></dates><urls></urls></record></Cite><Cite><Author>Pini</Author><Year>2004</Year><RecNum>263</RecNum><record><rec-number>263</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618812992">263</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Pini,LuigiA.</author><author>Brovia,Daria</author></authors></contributors><titles><title>Differentcharacteristicsoftriptans</title><secondary-title>TheJournalofHeadacheandPain</secondary-title></titles><periodical><full-title>TheJournalofHeadacheandPain</full-title></periodical><pages>s109-s111</pages><volume>5</volume><number>S2</number><section>s109</section><dates><year>2004</year></dates><isbn>1129-2369 1129-2377</isbn><urls></urls><electronic-resource-num>10.1007/s10194-004-0122-5</electronic-resource-num></record></Cite></EndNote>[28,33]。其主要应用于成人有或无先兆性偏头痛的急性发作期治疗ADDINEN.CITE<EndNote><Cite><RecNum>267</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[29]</style></DisplayText><record><rec-number>267</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618815227">267</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="WebPage">12</ref-type><contributors></contributors><titles><title>FDA.AMERGE®Label</title></titles><number>2021-04-02</number><dates><pub-dates><date>2016-11-29</date></pub-dates></dates><urls><related-urls><url>/drugsatfda_docs/label/2016/020763s011lbl.pdf</url></related-urls></urls></record></Cite></EndNote>[29]，据文献报道，那拉曲坦在预防丛集性头痛及短期预防妇女月经期偏头痛等方面也有较好的疗效ADDINEN.CITEADDINEN.CITE.DATA[34-37]。自英国GlaxoWellcome公司研发的薄膜包衣片于1997年8月在英国首次上市后ADDINEN.CITE<EndNote><Cite><Author>耿娓琴</Author><Year>1999</Year><RecNum>99</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[38]</style></DisplayText><record><rec-number>99</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1585319833">99</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">耿娓琴</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">急性偏头痛治疗药Naratriptan</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">国外医药.合成药.生化药.制剂分册</style></secondary-title></titles><periodical><full-title>国外医药.合成药.生化药.制剂分册</full-title></periodical><pages>19-20</pages><volume>20</volume><number>1</number><dates><year>1999</year></dates><urls></urls></record></Cite></EndNote>[38]，人们又相继对盐酸那拉曲坦及其游离碱的其他剂型进行了开发和研究，包括膜剂、凝胶剂、口分散片、舌下片等ADDINEN.CITE<EndNote><Cite><Author>Kassem</Author><Year>2016</Year><RecNum>260</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[39]</style></DisplayText><record><rec-number>260</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618812960">260</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>AbeerAhmedKassem</author></authors></contributors><titles><title>FormulationApproachesofTriptansforManagementofMigraine</title><secondary-title>CurrentDrugDelivery</secondary-title></titles><periodical><full-title>CurrentDrugDelivery</full-title></periodical><pages>882-898</pages><volume>13</volume><number>6</number><dates><year>2016</year></dates><urls></urls></record></Cite></EndNote>[39]。口服制剂（1）口腔崩解片口腔崩解片又称口腔分散片、速解片、速溶片、多孔片、速溶片，具有良好的患者顺应性ADDINEN.CITE<EndNote><Cite><Author>KshirasagarN*</Author><Year>2013</Year><RecNum>273</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[40]</style></DisplayText><record><rec-number>273</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618820671">273</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>KshirasagarN</author><author>SenthilKK</author><author>SravanKA</author><author>MalveyS</author></authors></contributors><titles><title>FormulationandEvaluationofNaratriptanOrodispersibleTabletsUsingSuperdisintergrantsbyDirectCompressionMethod</title><secondary-title>InternationalJournalforPharmaceuticalResearchScholars</secondary-title></titles><periodical><full-title>InternationalJournalforPharmaceuticalResearchScholars</full-title></periodical><pages>268-278</pages><volume>2</volume><number>2</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>[40]。ULRIKESTANGEADDINEN.CITEADDINEN.CITE.DATA[41]等人以不同粘结剂（羟乙基淀粉、海藻酸钠、甲基纤维素和明胶）对蔗糖溶液进行冷冻干燥，并以不同EudragitR包衣量的萘普生钠颗粒剂进行配方优化，最终确定以羟乙基淀粉为粘结剂，采用冷冻干燥法成功制备了掩味萘普生钠和盐酸那拉曲坦复方口腔崩解片。本品的优势在于，当药品在口腔崩解后，盐酸那拉曲坦能够直接完全溶解，当急性偏头痛发作时，服用此类制剂，盐酸那拉曲坦与非甾体抗炎药可以同时快速释放并通过口腔吸收，明显改善症状。KshirasagarNADDINEN.CITE<EndNote><Cite><Author>KshirasagarN*</Author><Year>2013</Year><RecNum>273</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[40]</style></DisplayText><record><rec-number>273</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618820671">273</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>KshirasagarN</author><author>SenthilKK</author><author>SravanKA</author><author>MalveyS</author></authors></contributors><titles><title>FormulationandEvaluationofNaratriptanOrodispersibleTabletsUsingSuperdisintergrantsbyDirectCompressionMethod</title><secondary-title>InternationalJournalforPharmaceuticalResearchScholars</secondary-title></titles><periodical><full-title>InternationalJournalforPharmaceuticalResearchScholars</full-title></periodical><pages>268-278</pages><volume>2</volume><number>2</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>[40]等人通过筛选超级崩解剂的浓度，最终确定了交联聚维酮(5%)和交联羧甲基纤维素钠(4%)是较好的崩解剂比例，并以粉末直压法成功将甘露醇、一水乳糖、交联羧甲基纤维素钠、交联聚维酮、硬脂酸镁、阿斯巴甜、橙子香精制备成了那拉曲坦口腔崩解片。RenukaS.DeshmukhADDINEN.CITE<EndNote><Cite><Author>Deshmukh</Author><Year>2018</Year><RecNum>274</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[42]</style></DisplayText><record><rec-number>274</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618820678">274</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Deshmukh,RenukaS.</author><author>Bari,M.M.</author><author>Barhate,S.D.</author></authors></contributors><titles><title>FormulationandEvaluationofOrodispersibleTabletofNaratriptanHCl</title><secondary-title>AsianJournalofPharmacyandTechnology</secondary-title></titles><periodical><full-title>AsianJournalofPharmacyandTechnology</full-title></periodical><pages>139-144</pages><volume>8</volume><number>3</number><section>139</section><dates><year>2018</year></dates><isbn>2231-5705 2231-5713</isbn><urls></urls><electronic-resource-num>10.5958/2231-5713.2018.00022.3</electronic-resource-num></record></Cite></EndNote>[42]等人也以交联聚维酮-交联羧甲基纤维素钠为超级崩解剂对口崩片的处方进行筛选，最终确定了处方（盐酸那拉曲坦：2.5mg；MCCPH101：125mg；甘露醇SD-200：100mg；交联羧甲基纤维素钠：5mg；阿斯巴甜：7.5mg；香草香精：5.0mg；硬脂酸镁：1.25mg；滑石粉：2.5mg；Aerosil：1.25mg），并以直接压片法进行制备。SamiaM.OmarADDINEN.CITEADDINEN.CITE.DATA[43]等人采用D-最优混料设计，以明胶(X1)、水解明胶(X2)、甘氨酸(X3)和甘露醇(X4)四种成分为总固体物质。通过测定各组分相对比例对脆性(Y1)、硬度(Y2)和体外崩解时间(Y3)的影响，对处方进行优化。确定处方后进行了体内药动学研究，比较了最佳处方与市售片剂的体内药动学，结果表明，所开发处方的Cmax、AUClast、AUCinf均显著升高，说明该冻干速解片起效更快。（2）舌下片HiralBrahmbhattADDINEN.CITE<EndNote><Cite><Author>HiralBrahmbhatt</Author><Year>2014</Year><RecNum>276</RecNum><DisplayText><styleface="superscript"font="TimesNewRoman">[44]</style></DisplayText><record><rec-number>276</rec-number><foreign-keys><keyapp="EN"db-id="zpwxpz929r0pzqedwsuxtpt25rwxev05a9fe"timestamp="1618820685">276</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>HiralBrahmbhatt</author><author>HardikBrahmbhatt</author><author>KrishnaPatel</author><author>PritiMakwana</author><author>NimishaChauhan</author><author>HiteshJain</author><author>UmeshUpadhyay</author></authors></contributors><titles><title>FORMULATIONANDEVALUATIONOFSUBLINGUALTABLETFORNARATRIPTA</title><secondary-title>JournalofDrugDeliveryandTherapeutics</secondary-title></titles><periodical><full-title>JournalofDrugDeliveryandTherapeutics</full-title></periodical><pages>19-23</pages><volume>4</volume><number>4</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[44]等人在对超级崩解剂进行筛选后用聚合物制备舌下那拉曲坦片，以减少唾液的冲洗作用，为药物的吸收提供足够的时间。并对优化后的处方批次进行了山羊粘膜渗透研究。结果表明，以交联聚维酮与壳聚糖为辅料共同制备的舌下片具有较好的立即释放作用。因此，采用适当的辅料，特别是以壳聚糖为辅料制备的那拉曲坦舌下片不失为一种替代传统制剂的有发展前景的选择。（3）舌下膜剂由于口腔粘膜血供丰富，且能够直接进入体循环，故经口腔粘膜给药适合于易在胃内酸水解或在肝脏内广泛代谢的药物。口腔局部给药的靶点包括颊，舌下，牙周区域，舌头和牙龈。为了使抗偏头痛药物在口腔内易溶，且能绕过首过效应快速起效，NareshKshirasagar等人采用溶剂流延法制备舌下膜，采用低粘度级HPMCE5、HPMCE15、HPMCE50，以不同配比组合成成膜聚合物，PEG400为增塑剂，甘露醇和阿斯巴甜为增甜剂，为了缩短制剂的崩解时间，以羧甲基淀粉钠为崩解剂，以薄荷为冷却剂，对所有膜剂处方(A1-A4、B1-B4、C1-C4和D1-D4)的厚度变化、含量、耐折性、表面pH值、体外崩解进行评价。研究结果表明，HPMCE15是最适合用于制备快速溶出膜的聚合物，根据体外溶出度数据，B1是最有利于药物释放的处方。该研究表明：舌下膜剂很可能成为服务于儿科、老年和一般人群的新型药物剂型ADDINEN.CITE<EndNote><Cite><Author>Kshirasagar*</Author><Y