關(guān)于鹽酸那拉曲坦的研究文獻(xiàn)綜述目錄TOC\o"1-3"\h\u14308關(guān)于鹽酸那拉曲坦的研究文獻(xiàn)綜述 162771.1偏頭痛及相關(guān)藥物研究背景 1296991.2鹽酸那拉曲坦結(jié)構(gòu)、理化性質(zhì) 2222981.2.1鹽酸那拉曲坦結(jié)構(gòu) 2174251.2.2鹽酸那拉曲坦的理化性質(zhì) 255421.3鹽酸那拉曲坦的藥理、毒理、不良反應(yīng) 215171.3.1藥理作用 2150311.3.2毒理作用及不良反應(yīng) 3116241.4鹽酸那拉曲坦的藥代動力學(xué) 3318271.5鹽酸那拉曲坦的劑型 4194671.6鹽酸那拉曲坦片的制備 6212941.6.1常用輔料及其性質(zhì) 661001.6.2片劑制備方法 6176311.7藥品質(zhì)量研究及質(zhì)量標(biāo)準(zhǔn)概述 7偏頭痛及相關(guān)藥物研究背景偏頭痛是一種臨床常見的慢性、反復(fù)發(fā)作性神經(jīng)系統(tǒng)疾病ADDINEN.CITEADDINEN.CITE.DATA[1,2]。主要表現(xiàn)為發(fā)作時一側(cè)或雙側(cè)搏動性中至重度頭痛，往往伴有惡心、嘔吐、畏光、恐聲等癥狀A(yù)DDINEN.CITEADDINEN.CITE.DATA[2-4]。在《2016年全球疾病負(fù)擔(dān)研究》（GBD2016）中，偏頭痛被列為世界第六大流行性疾病，也是全球第二大致殘性疾病(YLDs)ADDINEN.CITEADDINEN.CITE.DATA[5,6]。相關(guān)調(diào)查發(fā)現(xiàn)，中國年偏頭痛患病率為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]。其發(fā)病率、致殘率還在逐年升高，不僅妨礙患者的日常生活、降低患者生活品質(zhì)，還給社會帶來沉重的經(jīng)濟(jì)負(fù)擔(dān)ADDINEN.CITEADDINEN.CITE.DATAADDINEN.CITE.DATA[8-11]。作為遺傳和環(huán)境等多因素共同作用的疾病ADDINEN.CITEADDINEN.CITE.DATA[12]，其致病機(jī)制復(fù)雜且無定論，涉及血管學(xué)說、皮質(zhì)擴(kuò)散抑制學(xué)說、三叉神經(jīng)血管學(xué)說、炎癥介質(zhì)學(xué)說、中樞神經(jīng)系統(tǒng)學(xué)說及基因遺傳學(xué)說等，而目前普遍認(rèn)為最可能的機(jī)制是三叉神經(jīng)學(xué)說ADDINEN.CITEADDINEN.CITE.DATA[8,13,14]。偏頭痛的藥物治療分為急性發(fā)作期治療和預(yù)防性治療，前者主要是依靠非甾體抗炎藥、曲坦類藥物和鈣通道拮抗劑等；后者主要是利用三環(huán)類抗抑郁劑、β－受體阻滯劑和抗驚厥劑等ADDINEN.CITE<EndNote><Cite><Author>張兵帥</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%">張兵帥</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%">邱智東</style></author><author><styleface="normal"font="default"charset="134"size="100%">董雪蓮</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">偏頭痛研究進(jìn)展</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">亞太傳統(tǒng)醫(yī)藥</style></secondary-title></titles><periodical><full-title>亞太傳統(tǒng)醫(yī)藥</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年的時間里，抗偏頭痛藥物的研發(fā)暫無突破ADDINEN.CITE<EndNote><Cite><Author>雷諾島</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%">雷諾島</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">曲坦類藥物國內(nèi)上市進(jìn)度</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">醫(yī)藥經(jīng)濟(jì)報</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]，隨著人們對偏頭痛致病機(jī)制研究的逐步深入，發(fā)現(xiàn)降鈣素基因相關(guān)肽（CGRP）在偏頭痛的病理生理機(jī)制中起著重要作用，并基于此研發(fā)了CGRP拮抗劑及抗CGRP的單克隆抗體，目前Gepant類、Ditans類（LasmiditanADDINEN.CITE<EndNote><Cite><Author>夏訓(xùn)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%">夏訓(xùn)明</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">美國FDA批準(zhǔn)Ｒeyvow(lasmiditan)治療急性偏頭痛</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">廣東藥科大學(xué)學(xué)報</style></secondary-title></titles><periodical><full-title>廣東藥科大學(xué)學(xué)報</full-title></periodical><pages>706</pages><volume>35</volume><number>5</number><dates><year>2019</year></dates><urls></urls></record></Cite></EndNote>[16]）CGRP受體拮抗劑和靶向CGRP的單克隆抗體Erenumab（AIMOVIGTM）、Fremanezumab（Ajovy）、Galcanezumab（EmgalityTM）均已在美國獲批上市ADDINEN.CITEADDINEN.CITE.DATA[2,17,18]。曲坦類藥物作為目前唯一一類僅針對偏頭痛開發(fā)的藥物，國外多項臨床試驗(yàn)的結(jié)果均表明，其對急性發(fā)作期偏頭痛的療效和耐受性均優(yōu)于其他藥物，是美國頭痛協(xié)會推薦的應(yīng)用于治療急性偏頭痛的藥物，目前在國內(nèi)外臨床上使用的有：第一代的舒馬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個FDA批準(zhǔn)的含曲坦類藥物中，實(shí)現(xiàn)國產(chǎn)化的僅有3個分別是：佐米曲普坦、舒馬普坦和利扎曲普坦；進(jìn)口的僅有AstraZeneca的佐米曲普坦。截至2017年，利扎曲普坦占據(jù)了國內(nèi)近70%的市場，與全球產(chǎn)品結(jié)構(gòu)及市場相比，國內(nèi)的產(chǎn)品種類較少。然而，由我國近年來曲坦類抗偏頭痛藥物銷售金額的逐年上升不難看出，國人對偏頭痛的認(rèn)知、重視程度及對生活品質(zhì)的追求也在逐年提高；綜合國內(nèi)曲坦類藥物的審評、注冊信息，國內(nèi)曲坦類抗偏頭痛藥物市場還在起步階段ADDINEN.CITEADDINEN.CITE.DATA[15,21]。鹽酸那拉曲坦結(jié)構(gòu)、理化性質(zhì)鹽酸那拉曲坦結(jié)構(gòu)鹽酸那拉曲坦（NaratriptanHydrochloride）的化學(xué)名為N-甲基-3-（1-甲基-4-哌啶基）-1H-吲哚-5-乙基磺酰胺鹽酸鹽，其分子式為：C17H25N3O2S·HCl，分子量為371.93?；瘜W(xué)結(jié)構(gòu)式如下圖所示：鹽酸那拉曲坦的理化性質(zhì)鹽酸那拉曲坦是白色或淡黃色結(jié)晶性粉末，無臭，無味；在水中略溶（25℃時的溶解度為35mg/mL），其解離常數(shù)（pKa值）約為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]；游離堿的LogD7.4為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]。那拉曲坦屬于BDDCS（基于藥物體內(nèi)處置的生物藥劑學(xué)分類系統(tǒng)）中的3類藥物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、低代謝。鹽酸那拉曲坦的藥理、毒理、不良反應(yīng)藥理作用那拉曲坦是一種吲哚衍生物，含有與神經(jīng)遞質(zhì)5-羥色胺相同的吲哚環(huán)，通過計算機(jī)模擬分子對接研究發(fā)現(xiàn)，那拉曲坦通過TYR359殘基能夠選擇性地與5-HT1B受體結(jié)合，同時對5-HT1D受體及其亞型也有很高的親和力，是高選擇性的5-HT1受體激動劑ADDINEN.CITEADDINEN.CITE.DATA[25-27]。那拉曲坦的抗偏頭痛作用涉及以下三種不同的藥理作用：一是與顱腦血管平滑肌上及動靜脈吻合處的5-HT1B和5-HT1D受體結(jié)合，使腦血管收縮，進(jìn)而抑制促炎神經(jīng)肽的釋放；二是作用于神經(jīng)突觸前和神經(jīng)末梢的5-HT受體，抑制相關(guān)促炎神經(jīng)肽如CGRP和神經(jīng)肽P物質(zhì)的釋放，減少炎性物質(zhì)的滲出；三是通過刺激腦干的5-HT1B/1D受體，降低三叉神經(jīng)-腦血管系統(tǒng)神經(jīng)元的興奮性ADDINEN.CITEADDINEN.CITE.DATA[19,25,28]。毒理作用及不良反應(yīng)（1）致癌作用：在致癌性研究中，小鼠和大鼠分別灌胃給藥那拉曲坦104周。在200mg/kg/day給藥劑量的小鼠中，無證據(jù)表明與那拉曲坦相關(guān)的腫瘤增加。在大鼠亞硝酸鹽補(bǔ)充飲食研究中，除發(fā)現(xiàn)惡性的淋巴細(xì)胞性胸腺瘤和胸腺神經(jīng)節(jié)瘤外，其余腫瘤均為良性。一般來說，那拉曲坦幾乎無致癌風(fēng)險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）致突變作用：體外基因突變試驗(yàn)表明：那拉曲坦不具有誘變作用，且人淋巴細(xì)胞體外實(shí)驗(yàn)和小鼠體內(nèi)微核實(shí)驗(yàn)結(jié)果均為陰性。根據(jù)世衛(wèi)組織亞硝化試驗(yàn)結(jié)果：那拉曲坦可在體外經(jīng)亞硝酸鹽亞硝化形成誘變產(chǎn)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）不良反應(yīng)及禁忌癥：那拉曲坦的中樞神經(jīng)系統(tǒng)不良反應(yīng)發(fā)生率較低，但對于正在接受選擇性5-HT攝取抑制劑(SSRIs)治療的患者，那拉曲坦可能會引起5-羥色胺類行為副作用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]。藥物服用過量時最常見的癥狀是疲勞、嗜睡、高血壓、惡心/嘔吐、頭暈和心動過速。兒童攝入劑量至成人最大單劑量后，沒有或僅造成輕度毒性。對于成人，當(dāng)攝入劑量達(dá)最大單劑量的4~6倍時可誘發(fā)中度毒性，出現(xiàn)明顯的高血壓和心絞痛癥狀A(yù)DDINEN.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]。研究發(fā)現(xiàn)那拉曲坦在母乳中的排泄率似乎不高，其相對嬰兒劑量約為5.0%，盡管如此，考慮到那拉曲坦較高的口服生物利用度，嬰兒經(jīng)乳汁接觸藥物的可能性依舊不可忽視，故處于哺乳期的婦女不推薦使用ADDINEN.CITEADDINEN.CITE.DATA[32]。由于那拉曲坦可能會導(dǎo)致嚴(yán)重的心血管副作用，故患有心腦血管疾病及病史的人群禁止使用。鹽酸那拉曲坦的藥代動力學(xué)ADME研究表明：那拉曲坦吸收良好，口服生物利用度約為70%，男女間存在輕微差異（女性的絕對生物利用度約為75%，男性約為64%）。單次口服2.5mg片劑后，2~3小時內(nèi)即達(dá)峰值濃度（Cmax為12ng/mL），女性的Cmax比男性稍高(約50%)。偏頭痛發(fā)作時，藥物吸收較慢，Tmax延長為3~4小時。1.5mg靜脈滴注15分鐘后，穩(wěn)態(tài)表觀分布體積為170L，在50~1000ng/mL濃度范圍內(nèi)，藥物與血漿蛋白非特異性結(jié)合，其結(jié)合率為28%~31%；那拉曲坦主要經(jīng)肝臟由多種細(xì)胞色素P450酶代謝為非活性的氮氧化物及哌啶酮代謝物，以50%原型和30%代謝產(chǎn)物的形式經(jīng)腎臟消除，系統(tǒng)清除率為6.6mL/min/kg，平均消除半衰期為6小時ADDINEN.CITEADDINEN.CITE.DATA[22,28,29]。鹽酸那拉曲坦的劑型鹽酸那拉曲坦是高選擇性的5-HT1D/1B受體激動劑，屬第2代曲坦類藥物，具有生物利用度高、耐受性好、藥效作用時間長，病情復(fù)發(fā)率低等特點(diǎn)，臨床療效較好ADDINEN.CITE<EndNote><Cite><Author>劉宇</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%">劉宇</style></author><author><styleface="normal"font="default"charset="134"size="100%">劉東</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">治療偏頭痛藥物那拉曲坦的藥理與臨床研究</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">中國新藥與臨床雜志</style></secondary-title></titles><periodical><full-title>中國新藥與臨床雜志</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]。其主要應(yīng)用于成人有或無先兆性偏頭痛的急性發(fā)作期治療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]，據(jù)文獻(xiàn)報道，那拉曲坦在預(yù)防叢集性頭痛及短期預(yù)防婦女月經(jīng)期偏頭痛等方面也有較好的療效ADDINEN.CITEADDINEN.CITE.DATA[34-37]。自英國GlaxoWellcome公司研發(fā)的薄膜包衣片于1997年8月在英國首次上市后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%">急性偏頭痛治療藥Naratriptan</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">國外醫(yī)藥.合成藥.生化藥.制劑分冊</style></secondary-title></titles><periodical><full-title>國外醫(yī)藥.合成藥.生化藥.制劑分冊</full-title></periodical><pages>19-20</pages><volume>20</volume><number>1</number><dates><year>1999</year></dates><urls></urls></record></Cite></EndNote>[38]，人們又相繼對鹽酸那拉曲坦及其游離堿的其他劑型進(jìn)行了開發(fā)和研究，包括膜劑、凝膠劑、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]?？诜苿?）口腔崩解片口腔崩解片又稱口腔分散片、速解片、速溶片、多孔片、速溶片，具有良好的患者順應(yīng)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]等人以不同粘結(jié)劑（羥乙基淀粉、海藻酸鈉、甲基纖維素和明膠）對蔗糖溶液進(jìn)行冷凍干燥，并以不同EudragitR包衣量的萘普生鈉顆粒劑進(jìn)行配方優(yōu)化，最終確定以羥乙基淀粉為粘結(jié)劑，采用冷凍干燥法成功制備了掩味萘普生鈉和鹽酸那拉曲坦復(fù)方口腔崩解片。本品的優(yōu)勢在于，當(dāng)藥品在口腔崩解后，鹽酸那拉曲坦能夠直接完全溶解，當(dāng)急性偏頭痛發(fā)作時，服用此類制劑，鹽酸那拉曲坦與非甾體抗炎藥可以同時快速釋放并通過口腔吸收，明顯改善癥狀。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]等人通過篩選超級崩解劑的濃度，最終確定了交聯(lián)聚維酮(5%)和交聯(lián)羧甲基纖維素鈉(4%)是較好的崩解劑比例，并以粉末直壓法成功將甘露醇、一水乳糖、交聯(lián)羧甲基纖維素鈉、交聯(lián)聚維酮、硬脂酸鎂、阿斯巴甜、橙子香精制備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]等人也以交聯(lián)聚維酮-交聯(lián)羧甲基纖維素鈉為超級崩解劑對口崩片的處方進(jìn)行篩選，最終確定了處方（鹽酸那拉曲坦：2.5mg；MCCPH101：125mg；甘露醇SD-200：100mg；交聯(lián)羧甲基纖維素鈉：5mg；阿斯巴甜：7.5mg；香草香精：5.0mg；硬脂酸鎂：1.25mg；滑石粉：2.5mg；Aerosil：1.25mg），并以直接壓片法進(jìn)行制備。SamiaM.OmarADDINEN.CITEADDINEN.CITE.DATA[43]等人采用D-最優(yōu)混料設(shè)計，以明膠(X1)、水解明膠(X2)、甘氨酸(X3)和甘露醇(X4)四種成分為總固體物質(zhì)。通過測定各組分相對比例對脆性(Y1)、硬度(Y2)和體外崩解時間(Y3)的影響，對處方進(jìn)行優(yōu)化。確定處方后進(jìn)行了體內(nèi)藥動學(xué)研究，比較了最佳處方與市售片劑的體內(nèi)藥動學(xué)，結(jié)果表明，所開發(fā)處方的Cmax、AUClast、AUCinf均顯著升高，說明該凍干速解片起效更快。（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]等人在對超級崩解劑進(jìn)行篩選后用聚合物制備舌下那拉曲坦片，以減少唾液的沖洗作用，為藥物的吸收提供足夠的時間。并對優(yōu)化后的處方批次進(jìn)行了山羊粘膜滲透研究。結(jié)果表明，以交聯(lián)聚維酮與殼聚糖為輔料共同制備的舌下片具有較好的立即釋放作用。因此，采用適當(dāng)?shù)妮o料，特別是以殼聚糖為輔料制備的那拉曲坦舌下片不失為一種替代傳統(tǒng)制劑的有發(fā)展前景的選擇。（3）舌下膜劑由于口腔粘膜血供豐富，且能夠直接進(jìn)入體循環(huán)，故經(jīng)口腔粘膜給藥適合于易在胃內(nèi)酸水解或在肝臟內(nèi)廣泛代謝的藥物?？谇痪植拷o藥的靶點(diǎn)包括頰，舌下，牙周區(qū)域，舌頭和牙齦。為了使抗偏頭痛藥物在口腔內(nèi)易溶，且能繞過首過效應(yīng)快速起效，NareshKshirasagar等人采用溶劑流延法制備舌下膜，采用低粘度級HPMCE5、HPMCE15、HPMCE50，以不同配比組合成成膜聚合物，PEG400為增塑劑，甘露醇和阿斯巴甜為增甜劑，為了縮短制劑的崩解時間，以羧甲基淀粉鈉為崩解劑，以薄荷為冷卻劑，對所有膜劑處方(A1-A4、B1-B4、C1-C4和D1-D4)的厚度變化、含量、耐折性、表面pH值、體外崩解進(jìn)行評價。研究結(jié)果表明，HPMCE15是最適合用于制備快速溶出膜的聚合物，根據(jù)體外溶出度數(shù)據(jù)，B1是最有利于藥物釋放的處方。該研究表明：舌下膜劑很可能成為服務(wù)于兒科、老年和一般人群的新型藥物劑型ADDINEN.CITE<EndNote><Cite><Author>Kshirasagar*</Author><Y