首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1200394151385756528, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200394147019477416, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0125, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1707235200000, receivedDateStr=2024-02-07, revisedDate=1712851200000, revisedDateStr=2024-04-12, acceptedDate=null, acceptedDateStr=null, onlineDate=1764125867935, onlineDateStr=2025-11-26, pubDate=1720713600000, pubDateStr=2024-07-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764125867935, onlineIssueDateStr=2025-11-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764125867935, creator=13701087609, updateTime=1764125867935, updator=13701087609, issue=Issue{id=1200394147019477416, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='7', pageStart='1897', pageEnd='2182', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764125866894, creator=13701087609, updateTime=1764225115484, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200810425920115296, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200394147019477416, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200810425920115297, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200394147019477416, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1970, endPage=1981, ext={EN=ArticleExt(id=1200394151889073020, articleId=1200394151385756528, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Advances in the study of gastrointestinal microneedles for oral delivery of biomacromolecule drugs, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Biomacromolecule drugs have been increasingly used in clinical practice due to their distinct advantages, including precise targeting, small dose, high safety and activity. However, owing to their high molecular weight, strong hydrophilicity, and poor stability in the gastrointestinal tract, the oral bioavailability of the biomacromolecule drugs remains extremely poor. As a novel and innovative technology for active drug delivery, gastrointestinal microneedles hold immense potential in the oral delivery of biomacromolecule drugs because of their low-invasive nature and high permeation enhancement effects. This review primarily summarizes the actuating force, design strategies, fabrication techniques, and applications of gastrointestinal microneedles for the oral delivery of biomacromolecule drugs. Additionally, the challenges and further perspectives in the development this technology are presented, aiming to promote the subsequent research and clinical translation of gastrointestinal microneedles, and to provide a new efficient and safe strategy for oral delivery of biomacromolecule drugs.

, correspAuthors=Ying-hui WEI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jia-wei FENG, Xiao-feng YE, Qi-bin ZHANG, Ying-hui WEI), CN=ArticleExt(id=1200394156788019251, articleId=1200394151385756528, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=胃肠道微针用于生物大分子药物口服递送研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

生物大分子药物因具有高靶向性、剂量小、安全性和生物活性高等独特优势而越来越多地被用于多种疾病的治疗。但同时由于其分子质量大、亲水性强及胃肠道稳定性差等缺点, 加之胃肠道复杂的生理屏障, 导致生物大分子口服生物利用度极低。胃肠道微针作为一种新型主动药物递送技术, 因其能够直接突破胃肠道屏障而实现药物的定位递送、高效吸收而在生物大分子药物口服递送方面具有巨大的潜力。本综述围绕胃肠道微针的驱动及设计策略、制备方法及其口服递送生物大分子药物的应用等方面进行了总结归纳, 并对该技术目前存在的局限性及发展趋势进行了分析, 以促进胃肠道微针的后续研发和临床转化, 为生物大分子的口服给药提供高效、安全的新策略。

, correspAuthors=魏颖慧, authorNote=null, correspAuthorsNote=
*魏颖慧, Tel: 13357178565, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2024, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=ZhaMkRbkESSJayDYCuPwrA==, magXml=TeBrwhhJ9wOIfCIbesFRuQ==, pdfUrl=null, pdf=Qq8zRU4wwEZfuwSGDJ7dcg==, pdfFileSize=5862738, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=mByTqYfKx4GPY1bwAQe0/Q==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=JlMzcG5uFLCcPXAOu4acsw==, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=冯嘉惟, 叶小风, 张奇镔, 魏颖慧)}, authors=[Author(id=1200470895790773229, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1200470895937573884, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470895790773229, language=EN, stringName=Jia-wei FENG, firstName=Jia-wei, middleName=null, lastName=FENG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1200470896055013384, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470895790773229, language=CN, stringName=冯嘉惟, firstName=嘉惟, middleName=null, lastName=冯, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=浙江中医药大学药学院, 浙江 杭州 310000, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1200470895635583961, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, xref=null, ext=[AuthorCompanyExt(id=1200470895648166876, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China), AuthorCompanyExt(id=1200470895664944094, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=浙江中医药大学药学院, 浙江 杭州 310000)])]), Author(id=1200470896164065293, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1200470896403140641, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470896164065293, language=EN, stringName=Xiao-feng YE, firstName=Xiao-feng, middleName=null, lastName=YE, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1200470896554135596, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470896164065293, language=CN, stringName=叶小风, firstName=小风, middleName=null, lastName=叶, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=浙江中医药大学药学院, 浙江 杭州 310000, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1200470895635583961, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, xref=null, ext=[AuthorCompanyExt(id=1200470895648166876, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China), AuthorCompanyExt(id=1200470895664944094, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=浙江中医药大学药学院, 浙江 杭州 310000)])]), Author(id=1200470896713519162, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1200470896893874250, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470896713519162, language=EN, stringName=Qi-bin ZHANG, firstName=Qi-bin, middleName=null, lastName=ZHANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1200470897028091988, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470896713519162, language=CN, stringName=张奇镔, firstName=奇镔, middleName=null, lastName=张, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=浙江中医药大学药学院, 浙江 杭州 310000, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1200470895635583961, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, xref=null, ext=[AuthorCompanyExt(id=1200470895648166876, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China), AuthorCompanyExt(id=1200470895664944094, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=浙江中医药大学药学院, 浙江 杭州 310000)])]), Author(id=1200470897137143904, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=yhw_nn@zcmu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1200470897321693291, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470897137143904, language=EN, stringName=Ying-hui WEI, firstName=Ying-hui, middleName=null, lastName=WEI, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1200470897434939505, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, authorId=1200470897137143904, language=CN, stringName=魏颖慧, firstName=颖慧, middleName=null, lastName=魏, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=浙江中医药大学药学院, 浙江 杭州 310000, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1200470895635583961, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, xref=null, ext=[AuthorCompanyExt(id=1200470895648166876, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China), AuthorCompanyExt(id=1200470895664944094, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=浙江中医药大学药学院, 浙江 杭州 310000)])])], keywords=[Keyword(id=1200470897808232585, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, orderNo=1, keyword=gastrointestinal microneedle), Keyword(id=1200470897971810453, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, orderNo=2, keyword=biomacromolecule), Keyword(id=1200470898097639584, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, orderNo=3, keyword=oral drug delivery), Keyword(id=1200470898273800363, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, orderNo=4, keyword=bioavailability), Keyword(id=1200470898428989622, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, orderNo=1, keyword=胃肠道微针), Keyword(id=1200470898575790277, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, orderNo=2, keyword=生物大分子), Keyword(id=1200470898722590931, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, orderNo=3, keyword=口服递送), Keyword(id=1200470898861002977, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, orderNo=4, keyword=生物利用度)], refs=[Reference(id=1200470902203863473, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=null, journalName=null, refType=null, unstructuredReference=Brayden DJ, Hill TA, Fairlie DP, et al. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches [J]. Adv Drug Deliv Rev, 2020, 157: 2-36., articleTitle=null, refAbstract=null), Reference(id=1200470902333886906, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Cao YX, Rewatkar P, Wang R, et al. Nanocarriers for oral delivery of biologics: small carriers for big payloads [J]. Trends Pharmacol Sci, 2021, 42: 957-972., articleTitle=null, refAbstract=null), Reference(id=1200470902455521732, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=null, journalName=null, refType=null, unstructuredReference=Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery [J]. Int J Pharm, 2017, 532: 555-572., articleTitle=null, refAbstract=null), Reference(id=1200470902593933769, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Azizi A, Kumar A, Diaz-Mitoma F, et al. Enhancing oral vaccine potency by targeting intestinal M cells [J]. PLoS Pathog, 2010, 6: e1001147., articleTitle=null, refAbstract=null), Reference(id=1200470902711374288, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Choonara BF, Choonara YE, Kumar P, et al. A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules [J]. Biotechnol Adv, 2014, 32: 1269-1282., articleTitle=null, refAbstract=null), Reference(id=1200470902874952151, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=Maher S, Geoghegan C, Brayden DJ. Intestinal permeation enhancers to improve oral bioavailability of macromolecules: reasons for low efficacy in humans [J]. Expert Opin Drug Deliv, 2021, 18: 273-300., articleTitle=null, refAbstract=null), Reference(id=1200470903025947102, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Chen GY, Kang WR, Li W, et al. Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies [J]. Theranostics, 2022, 12: 1419-1439., articleTitle=null, refAbstract=null), Reference(id=1200470903168553441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Kirsch K, Hanke U, Weitschies W. An overview of intestinal wafers for oral drug delivery [J]. Eur J Pharm Biopharm, 2017, 114: 135-144., articleTitle=null, refAbstract=null), Reference(id=1200470903348908524, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Jabbari E. Hydrogels for cell delivery [J]. Gels, 2018, 4: 58., articleTitle=null, refAbstract=null), Reference(id=1200470903428600307, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Jiang YX, Jiang Q, Wang D, et al. The applications of ionic liquids in drug delivery [J]. Acta Pharm Sin (药学学报), 2022, 57: 331-342., articleTitle=null, refAbstract=null), Reference(id=1200470903520875001, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Cui ZX, Qin L, Guo S, et al. Design of biotin decorated enterocyte targeting muco-inert nanocomplexes for enhanced oral insulin delivery [J]. Carbohydr Polym, 2021, 261: 117873., articleTitle=null, refAbstract=null), Reference(id=1200470903621538303, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Traverso G, Schoellhammer CM, Schroeder A, et al. Microneedles for drug delivery via the gastrointestinal tract [J]. J Pharm Sci, 2015, 104: 362-367., articleTitle=null, refAbstract=null), Reference(id=1200470903726395908, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Rzhevskiy AS, Singh TRR, Donnelly RF, et al. Microneedles as the technique of drug delivery enhancement in diverse organs and tissues [J]. J Control Release, 2018, 270: 184-202., articleTitle=null, refAbstract=null), Reference(id=1200470903831253513, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=Cummins G. Smart pills for gastrointestinal diagnostics and therapy [J]. Adv Drug Deliv Rev, 2021, 177: 113931., articleTitle=null, refAbstract=null), Reference(id=1200470903919333899, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=null, journalName=null, refType=null, unstructuredReference=Mercado-Perez A, Beyder A. Gut feelings: mechanosensing in the gastrointestinal tract [J]. Nat Rev Gastroenterol Hepatol, 2022, 19: 283-296., articleTitle=null, refAbstract=null), Reference(id=1200470904074523152, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=null, journalName=null, refType=null, unstructuredReference=Huang LB, Li LH, Jiang YJ, et al. Tumbler‐inspired microneedle containing robots: achieving rapid self‐orientation and peristalsis‐resistant adhesion for colonic administration [J]. Adv Funct Mater, 2023, 33: 2304276., articleTitle=null, refAbstract=null), Reference(id=1200470904183575061, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=null, journalName=null, refType=null, unstructuredReference=Gao XZ, Li JC, Li J, et al. Pain-free oral delivery of biologic drugs using intestinal peristalsis–actuated microneedle robots [J]. Sci Adv, 2024, 10: eadj7067., articleTitle=null, refAbstract=null), Reference(id=1200470904305209883, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=null, journalName=null, refType=null, unstructuredReference=Dhalla AK, Al-Shamsie Z, Beraki S, et al. A robotic pill for oral delivery of biotherapeutics: safety, tolerability, and performance in healthy subjects [J]. Drug Deliv Transl Res, 2022, 12: 294-305., articleTitle=null, refAbstract=null), Reference(id=1200470904397484577, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=null, journalName=null, refType=null, unstructuredReference=Abramson A, Caffarel-Salvador E, Khang M, et al. An ingestible self-orienting system for oral delivery of macromolecules [J]. Science, 2019, 363: 611-615., articleTitle=null, refAbstract=null), Reference(id=1200470904493953575, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=null, journalName=null, refType=null, unstructuredReference=Chen W, Wainer J, Ryoo SW, et al. Dynamic omnidirectional adhesive microneedle system for oral macromolecular drug delivery [J]. Sci Adv, 2022, 8: eabk1792., articleTitle=null, refAbstract=null), Reference(id=1200470904623977003, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhang XX, Chen GP, Fu X, et al. Magneto‐responsive microneedle robots for intestinal macromolecule delivery [J]. Adv Mater, 2021, 33: e2104932., articleTitle=null, refAbstract=null), Reference(id=1200470904745611827, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=null, journalName=null, refType=null, unstructuredReference=Lee J, Lee H, Kwon SH, et al. Active delivery of multi-layer drug-loaded microneedle patches using magnetically driven capsule [J]. Med Eng Phys, 2020, 85: 87-96., articleTitle=null, refAbstract=null), Reference(id=1200470904888218169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=null, journalName=null, refType=null, unstructuredReference=Abramson A, Caffarel-Salvador E, Soares V, et al. A luminal unfolding microneedle injector for oral delivery of macromolecules [J]. Nat Med, 2019, 25: 1512-1518., articleTitle=null, refAbstract=null), Reference(id=1200470904988881472, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=null, journalName=null, refType=null, unstructuredReference=Abramson A, Frederiksen MR, Vegge A, et al. Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors [J]. Nat Biotechnol, 2022, 40: 103-109., articleTitle=null, refAbstract=null), Reference(id=1200470905114710594, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=null, journalName=null, refType=null, unstructuredReference=Makvandi P, Maleki A, Shabani M, et al. Bioinspired microneedle patches: biomimetic designs, fabrication, and biomedical applications [J]. Matter, 2022, 5: 390-429., articleTitle=null, refAbstract=null), Reference(id=1200470905265705547, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=null, journalName=null, refType=null, unstructuredReference=Mbituyimana B, Ma GR, Shi ZJ, et al. Polymer-based microneedle composites for enhanced non-transdermal drug delivery [J]. Appl Mater Today, 2022, 29: 101659., articleTitle=null, refAbstract=null), Reference(id=1200470905399923279, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[27], rfOrder=26, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang M, Hu LZ, Xu CJ. Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing [J]. Lab Chip, 2017, 17: 1373-1387., articleTitle=null, refAbstract=null), Reference(id=1200470905513169491, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[28], rfOrder=27, authorNames=null, journalName=null, refType=null, unstructuredReference=Lyu S, Dong ZF, Xu XX, et al. Going below and beyond the surface: microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration [J]. Bioact Mater, 2023, 27: 303-326., articleTitle=null, refAbstract=null), Reference(id=1200470905601249881, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=null, journalName=null, refType=null, unstructuredReference=Caudill C, Perry JL, Iliadis K, et al. Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity [J]. Proc Natl Acad Sci U S A, 2021, 118: e2102595118., articleTitle=null, refAbstract=null), Reference(id=1200470905685135964, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=null, journalName=null, refType=null, unstructuredReference=Ahadian S, Finbloom JA, Mofidfar M, et al. Micro and nanoscale technologies in oral drug delivery [J]. Adv Drug Deliv Rev, 2020, 157: 37-62., articleTitle=null, refAbstract=null), Reference(id=1200470905794187872, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=null, journalName=null, refType=null, unstructuredReference=Quan HY, Zhang T, Xu H, et al. Photo-curing 3D printing technique and its challenges [J]. Bioact Mater, 2020, 5: 110-115., articleTitle=null, refAbstract=null), Reference(id=1200470905924211300, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=Tarbox TN, Watts AB, Cui ZR, et al. An update on coating/manufacturing techniques of microneedles [J]. Drug Deliv Transl Res, 2018, 8: 1828-1843., articleTitle=null, refAbstract=null), Reference(id=1200470906079400555, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhang XX, Chen GP, Cai LJ, et al. Dip-printed microneedle motors for oral macromolecule delivery [J]. Research (Wash D C), 2022, 2022: 9797482., articleTitle=null, refAbstract=null), Reference(id=1200470906301698673, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=null, journalName=null, refType=null, unstructuredReference=Gupta J, Gupta R, Vanshita. Microneedle technology: an insight into recent advancements and future trends in drug and vaccine delivery [J]. Assay Drug Dev Technol, 2021, 19: 97-114., articleTitle=null, refAbstract=null), Reference(id=1200470906427527794, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[35], rfOrder=34, authorNames=null, journalName=null, refType=null, unstructuredReference=Hossian AKMN, Mackenzie GG, Mattheolabakis G. miRNAs in gastrointestinal diseases: can we effectively deliver RNA-based therapeutics orally? [J]. Nanomedicine(Lond), 2019, 14: 2873-2889., articleTitle=null, refAbstract=null), Reference(id=1200470906570134135, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=null, journalName=null, refType=null, unstructuredReference=Kumari N, Siddhanta K, Panja S, et al. Oral delivery of nucleic acid therapies for local and systemic action [J]. Pharm Res, 2023, 40: 107-122., articleTitle=null, refAbstract=null), Reference(id=1200470906658214522, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[37], rfOrder=36, authorNames=null, journalName=null, refType=null, unstructuredReference=Durán‐Lobato M, Niu ZG, Alonso MJ. Oral delivery of biologics for precision medicine [J]. Adv Mater, 2020, 32: e1901935., articleTitle=null, refAbstract=null), Reference(id=1200470906800820861, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[38], rfOrder=37, authorNames=null, journalName=null, refType=null, unstructuredReference=Hashim M, Korupolu R, Syed B, et al. Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine: a pharmacokinetic and pharmacodynamic study [J]. Pharmacol Res Perspect, 2019, 7: e00522., articleTitle=null, refAbstract=null), Reference(id=1200470906909872769, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[39], rfOrder=38, authorNames=null, journalName=null, refType=null, unstructuredReference=Davies M, Pieber TR, Hartoft-Nielsen ML, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial [J]. JAMA, 2017, 318: 1460-1470., articleTitle=null, refAbstract=null), Reference(id=1200470907056673412, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=null, journalName=null, refType=null, unstructuredReference=Melmed S, Popovic V, Bidlingmaier M, et al. Safety and efficacy of oral octreotide in acromegaly: results of a multileft phase Ⅲ trial [J]. J Clin Endocrinol Metab, 2015, 100: 1699-1708., articleTitle=null, refAbstract=null), Reference(id=1200470907186696840, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[41], rfOrder=40, authorNames=null, journalName=null, refType=null, unstructuredReference=Myers JT, Dasari A, Battiwala A, et al. SAT235 an orally administered robotic pill (RP) reliably and safely delivers the human parathyroid hormone analog hPTH (1-34)(teriparatide) with high bioavailability in healthy human volunteers: a phase 1 study [J]. J Endocr Soc, 2023, 7: bvad114.531., articleTitle=null, refAbstract=null), Reference(id=1200470907258000010, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=null, journalName=null, refType=null, unstructuredReference=Yamaguchi A, Van Dam J, Dhalla AK, et al. Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines [J]. Front Drug Deliv, 2022, 2: 955569., articleTitle=null, refAbstract=null), Reference(id=1200470907341886093, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=null, journalName=null, refType=null, unstructuredReference=Lee J, Sohn SW, Lee H, et al. Open-close mechanism of magnetically actuated capsule for multiple hemostatic microneedle patch delivery [J]. Int J Control Autom Syst, 2022, 20: 2285-2296., articleTitle=null, refAbstract=null), Reference(id=1200470907434160784, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=null, journalName=null, refType=null, unstructuredReference=Jiang XH, Wang N, Liu C, et al. Oral delivery of nucleic acid therapeutics: challenges, strategies, and opportunities [J]. Drug Discov Today, 2023, 28: 103507., articleTitle=null, refAbstract=null), Reference(id=1200470907534824084, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=null, journalName=null, refType=null, unstructuredReference=Abramson A, Kirtane AR, Shi Y, et al. Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections [J]. Matter, 2022, 5: 975-987., articleTitle=null, refAbstract=null), Reference(id=1200470907631293079, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[46], rfOrder=45, authorNames=null, journalName=null, refType=null, unstructuredReference=Kaffash E, Shahbazi MA, Hatami H, et al. An insight into gastrointestinal macromolecule delivery using physical oral devices [J]. Drug Discov Today, 2022, 27: 2309-2321., articleTitle=null, refAbstract=null), Reference(id=1200470907715179161, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[47], rfOrder=46, authorNames=null, journalName=null, refType=null, unstructuredReference=Brayden DJ. The centenary of the discovery of insulin: an update on the quest for oral delivery [J]. Front Drug Deliv, 2021, 1: 726675., articleTitle=null, refAbstract=null), Reference(id=1200470907807453853, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[48], rfOrder=47, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhu QG, Chen ZJ, Paul PK, et al. Oral delivery of proteins and peptides: challenges, status quo and future perspectives [J]. Acta Pharm Sin B, 2021, 11: 2416-2448., articleTitle=null, refAbstract=null), Reference(id=1200470907924894371, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[49], rfOrder=48, authorNames=null, journalName=null, refType=null, unstructuredReference=Yang YX, Zhou RY, Wang YF, et al. Recent advances in oral and transdermal protein delivery systems [J]. Angew Chem Int Ed Engl, 2023, 62: e202214795., articleTitle=null, refAbstract=null), Reference(id=1200470908004586152, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[50], rfOrder=49, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhang ZH, Shang LR. Smart ingestible devices: orally delivering macromolecules and beyond [J]. Matter, 2021, 4: 3379-3381., articleTitle=null, refAbstract=null), Reference(id=1200470908117832367, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[51], rfOrder=50, authorNames=null, journalName=null, refType=null, unstructuredReference=Schoellhammer CM, Langer R, Traverso G. Of microneedles and ultrasound: physical modes of gastrointestinal macromolecule delivery [J]. Tissue Barriers, 2016, 4: e1150235., articleTitle=null, refAbstract=null)], funds=[Fund(id=1200470901914456484, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, awardId=82374047, language=CN, fundingSource=国家自然科学基金资助项目(82374047), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1200470895635583961, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, xref=null, ext=[AuthorCompanyExt(id=1200470895648166876, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China), AuthorCompanyExt(id=1200470895664944094, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, companyId=1200470895635583961, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=浙江中医药大学药学院, 浙江 杭州 310000)])], figs=[ArticleFig(id=1200470899158798582, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=RiM4lsUa74fY2QQvtEZN1A==, figureFileBig=W6sK5yQSXMkKnmVE/avuig==, tableContent=null), ArticleFig(id=1200470899389485319, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 1, caption= Schematic of the microneedle pill. A: Housing of the microneedle pill; B: Endcap and pin of the microneedle pill; C: Design and mechanism of hollow microneedles for intestinal delivery; D: Design and mechanism of solid microneedles for intestinal delivery. Adapted from Ref. 12 with permission. Copyright © 2015 Elsevier , figureFileSmall=RiM4lsUa74fY2QQvtEZN1A==, figureFileBig=W6sK5yQSXMkKnmVE/avuig==, tableContent=null), ArticleFig(id=1200470899553063190, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=g+wcJiH8pJcrWw4SVoLYcw==, figureFileBig=2hK9iI/6TZ6sJi9WCFduHA==, tableContent=null), ArticleFig(id=1200470899683086622, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 2, caption= Design and colonic delivery of the fast self-oriented microneedle containing robots. Adapted from Ref. 16 with permission. Copyright © 2023 Wiley , figureFileSmall=g+wcJiH8pJcrWw4SVoLYcw==, figureFileBig=2hK9iI/6TZ6sJi9WCFduHA==, tableContent=null), ArticleFig(id=1200470899800527142, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=n0dMeDmD0SyqS1pg3e6abw==, figureFileBig=Rg8Wzzbrf4N4EdGAdbnrzw==, tableContent=null), ArticleFig(id=1200470899922161966, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 3, caption= Schematic of expandable microneedle robot. A: The structure of the expandable microneedle robot; B: Schematic of the swelling, penetration, drug release, and disintegration of the expandable microneedle robot through the gastrointestinal tract. Adapted from Ref. 17 with permission. Copyright © 2024 American Association for the Advancement of Science , figureFileSmall=n0dMeDmD0SyqS1pg3e6abw==, figureFileBig=Rg8Wzzbrf4N4EdGAdbnrzw==, tableContent=null), ArticleFig(id=1200470900064768307, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=sTKN2aF512zB05tCQKEXGw==, figureFileBig=dajSxdEmptABRZwA2ZQwTg==, tableContent=null), ArticleFig(id=1200470900224151867, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 4, caption= Schematic of Rani Pill<sup>TM</sup>. A: The structure of Rani Pill<sup>TM</sup>; B: Illustration of penetration and drug delivery of Rani Pill<sup>TM</sup> in the intestine. Adapted from Ref. 18 with permission. Copyright © 2019 Springer Nature , figureFileSmall=sTKN2aF512zB05tCQKEXGw==, figureFileBig=dajSxdEmptABRZwA2ZQwTg==, tableContent=null), ArticleFig(id=1200470900345786690, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=2WptORx1dVPCGzr17Udafg==, figureFileBig=nzEPOJBhhK+E267wiUaXig==, tableContent=null), ArticleFig(id=1200470900484198730, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 5, caption= Schematic of self-orienting millimeter-scale applicator (SOMA). A: The structure of SOMA; B: Illustration of localization and drug delivery of SOMA in the stomach. Adapted from Ref. 19 with permission. Copyright © 2019 American Association for the Advancement of Science , figureFileSmall=2WptORx1dVPCGzr17Udafg==, figureFileBig=nzEPOJBhhK+E267wiUaXig==, tableContent=null), ArticleFig(id=1200470900664553811, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=Ykh6b2F0/rZd1V88max/EA==, figureFileBig=EL7pDNKGlxbpnUl+Z05a1Q==, tableContent=null), ArticleFig(id=1200470900832325979, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 6, caption= Schematic of dynamic omnidirectional adhesive microneedle system (DOAMS). A: The structure of DOAMS; B: Schematic of drug delivery of DOAMS in the stomach. Adapted from Ref. 20 with permission. Copyright © 2022 American Association for the Advancement of Science , figureFileSmall=Ykh6b2F0/rZd1V88max/EA==, figureFileBig=EL7pDNKGlxbpnUl+Z05a1Q==, tableContent=null), ArticleFig(id=1200470901004292456, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=qT086sx1CbTzDP8mCSKV7Q==, figureFileBig=Ey5qHhLhUdFlfSZGHD8fZw==, tableContent=null), ArticleFig(id=1200470901130121584, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 7, caption= Schematic of magneto-responsive microneedle robots (MMR). A: Design and intestinal delivery of MMR; B: Illustration of penetration of MMR driven by magnetic field; C: Illustration of separation of tip–substrate and drug release of tips. Adapted from Ref. 21 with permission. Copyright © 2021 Wiley , figureFileSmall=qT086sx1CbTzDP8mCSKV7Q==, figureFileBig=Ey5qHhLhUdFlfSZGHD8fZw==, tableContent=null), ArticleFig(id=1200470901297893753, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=+3WlhMapMF6K7e44U6qzww==, figureFileBig=7TjGKvWiJyMGJ5de4Xstgg==, tableContent=null), ArticleFig(id=1200470901440500097, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Figure 8, caption= Schematic diagrams of multi-layer drug-loaded MN patch capsule. A: Structure of multi-layer drug-loaded MN patch capsule; B: Multi-layer MN patch attached to a permanent magnet; C: Sequential insertions of multi-layer MN patch; D: Two motion states of the capsule; E: Drug delivery of multi-layer drug-loaded microneedle patch capsule in the intestine. Adapted from Ref. 22 with permission. Copyright © 2022 Elsevier , figureFileSmall=+3WlhMapMF6K7e44U6qzww==, figureFileBig=7TjGKvWiJyMGJ5de4Xstgg==, tableContent=null), ArticleFig(id=1200470901553746311, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Device nameMicroneedle materialFabrication methodSite of actionDrugsPatent No.Ref
Fast self-oriented microneedle containing robotCSRobot: 3D printing; mold filling: micromoldingColonNullZL202210543803.6[16]
Expandable microneedle robot33-vol % PEGDA, 33-wt % PEG, and 1-vol % HMPMicromoldingSmall intestineInsulinNull[17]
Rani PillTMPEGA cylindrical microsyringe fitted into an enteric-coated capsuleSmall intestineInsulin, octreotide, hPTH, human IgGJP6745866B2[18]
Self-orienting millimeter-scale applicatorPEO and hydroxypropyl methylcellulose3D printing (SLA)StomachInsulinUS11541016 B2[19]
Dynamic omnidirectional adhesive microneedle systemOuter layer: Carbopol; inner core: PCLMaster mold: 3D printing; mold filling: micromoldingStomachSemaglutideNull[20]
Magneto-responsive microneedle robotsGelMAMicromoldingSmall intestineInsulinZL202011499405.6[21]
Multi-layer drug-loaded microneedle patchesGelatinMicromoldingSmall intestineChitosanNull[22]
Luminal unfolding microneedle injectorPVPMicromoldingSmall intestineInsulinUS11684315 B2[23]
Liquid-injecting self-orienting millimeter-scale applicatorNovo fine 32G needle3D printing (SLA)StomachAdalimumab, insulin, semaglutide, and epinephrineUS11771829 B2[24]
), ArticleFig(id=1200470901683769747, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200394151385756528, language=CN, label=Table 1, caption=

List of gastrointestinal microneedles for oral delivery of biomacromolecules. CS: Chitosan; PEGDA: Polyethylene glycol diacrylate; PEG: Polyethylene glycol; HMP: 2-Hydroxy-2-methylpropiophenone; PVP: Polyvinyl pyrrolidone; PEO: Polyethyleneoxide; PCL: Polycaprolactone; GelMA: Methacrylated gelalin; SLA: Stereo lithography appearance

, figureFileSmall=null, figureFileBig=null, tableContent=
Device nameMicroneedle materialFabrication methodSite of actionDrugsPatent No.Ref
Fast self-oriented microneedle containing robotCSRobot: 3D printing; mold filling: micromoldingColonNullZL202210543803.6[16]
Expandable microneedle robot33-vol % PEGDA, 33-wt % PEG, and 1-vol % HMPMicromoldingSmall intestineInsulinNull[17]
Rani PillTMPEGA cylindrical microsyringe fitted into an enteric-coated capsuleSmall intestineInsulin, octreotide, hPTH, human IgGJP6745866B2[18]
Self-orienting millimeter-scale applicatorPEO and hydroxypropyl methylcellulose3D printing (SLA)StomachInsulinUS11541016 B2[19]
Dynamic omnidirectional adhesive microneedle systemOuter layer: Carbopol; inner core: PCLMaster mold: 3D printing; mold filling: micromoldingStomachSemaglutideNull[20]
Magneto-responsive microneedle robotsGelMAMicromoldingSmall intestineInsulinZL202011499405.6[21]
Multi-layer drug-loaded microneedle patchesGelatinMicromoldingSmall intestineChitosanNull[22]
Luminal unfolding microneedle injectorPVPMicromoldingSmall intestineInsulinUS11684315 B2[23]
Liquid-injecting self-orienting millimeter-scale applicatorNovo fine 32G needle3D printing (SLA)StomachAdalimumab, insulin, semaglutide, and epinephrineUS11771829 B2[24]
)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, journalRemark=null, publicationField=null, createdTime=1761643429151, updatedTime=1761735768113, createdBy=18614031015, updatedBy=13701087609, firstLetterCn=A, firstLetterEn=A, subjectCode=Life Sciences, subjectName=Life Sciences, subjectCodeEn=Life Sciences, subjectNameEn=null, picCn=BTxjudbJDVO4PqdBR6On6Q==, picEn=c4l1ckL55nWbhl1KrFdWIA==, jcr=null, cjcr=null, exts=[JournalExt(id=1190369346338783397, language=CN, name=药学学报, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1761735768160, updatedTime=1761735768160, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1190369346376532134, language=EN, name=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1761735768169, updatedTime=1761735768169, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1189982191388893191, websiteList=[Website(id=1189982271588340489, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/CN, language=CN, createTime=1761643482348, createBy=18614031015, updateTime=1761643498101, updateBy=18614031015, name=药学学报-中文, tplId=1146099689490845704, title=药学学报, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982873114448678, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=articleTextType, value=kx, createTime=1761643625763, updateTime=1761643625763, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873093477155, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=banner, value=null, createTime=1761643625758, updateTime=1761643625758, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873135420201, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=grayFlag, value=0, createTime=1761643625768, updateTime=1761643625768, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873085088546, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643625756, updateTime=1761643625756, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873152197419, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=minRunFlag, value=0, createTime=1761643625772, updateTime=1761643625772, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873110254373, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic, createTime=1761643625762, updateTime=1761643625762, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873143808810, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=silenceFlag, value=0, createTime=1761643625770, updateTime=1761643625770, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873101865764, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1761643625760, updateTime=1761643625760, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873122837287, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeColor, value=null, createTime=1761643625765, updateTime=1761643625765, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873127031592, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeStyle, value=null, createTime=1761643625766, updateTime=1761643625766, creator=18614031015, updator=18614031015)]), Website(id=1189982271655449355, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/EN, language=EN, createTime=1761643482364, createBy=18614031015, updateTime=1761643514085, updateBy=18614031015, name=药学学报-英文, tplId=1146101810881728533, title=Acta Pharmaceutica Sinica, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982903015633534, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=articleTextType, value=kx, createTime=1761643632892, updateTime=1761643632892, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902990467707, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=banner, value=null, createTime=1761643632886, updateTime=1761643632886, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903036605057, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=grayFlag, value=0, createTime=1761643632897, updateTime=1761643632897, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902982079098, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643632884, updateTime=1761643632884, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903053382275, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=minRunFlag, value=0, createTime=1761643632901, updateTime=1761643632901, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903007244925, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic, createTime=1761643632890, updateTime=1761643632890, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903044993666, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=silenceFlag, value=0, createTime=1761643632899, updateTime=1761643632899, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902998856316, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1761643632888, updateTime=1761643632888, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903019827839, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeColor, value=null, createTime=1761643632893, updateTime=1761643632893, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903028216448, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeStyle, value=null, createTime=1761643632895, updateTime=1761643632895, creator=18614031015, updator=18614031015)])], journalTitle=药学学报, weixinUrl=null, journalUrl=https://www.yxxb.com.cn/aps, iacademicId=null, status=1, seqNo=null, journalTitleEn=Acta Pharmaceutica Sinica, journalPhotoCn=BTxjudbJDVO4PqdBR6On6Q==, journalPhotoEn=c4l1ckL55nWbhl1KrFdWIA==, journalFirstLetter=A, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false), detailUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2024-0125, detailUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/10.16438/j.0513-4870.2024-0125, pdfUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/PDF/10.16438/j.0513-4870.2024-0125, pdfUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/PDF/10.16438/j.0513-4870.2024-0125, aliStartDate=null, aliEndDate=null, collectionFlag=false, citedCount=null, citedUrl=null, reference=null)
收藏切换
胃肠道微针用于生物大分子药物口服递送研究进展
收藏切换
PDF下载
冯嘉惟 , 叶小风 , 张奇镔 , 魏颖慧 *
药学学报 | 综述 2024,59(7): 1970-1981
收起
收藏切换
药学学报 | 综述 2024, 59(7): 1970-1981
胃肠道微针用于生物大分子药物口服递送研究进展
全屏
冯嘉惟, 叶小风, 张奇镔, 魏颖慧*
作者信息
  • 浙江中医药大学药学院, 浙江 杭州 310000

通讯作者:

*魏颖慧, Tel: 13357178565, E-mail:
Advances in the study of gastrointestinal microneedles for oral delivery of biomacromolecule drugs
Jia-wei FENG, Xiao-feng YE, Qi-bin ZHANG, Ying-hui WEI*
Affiliations
  • College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China
出版时间: 2024-07-12 doi: 10.16438/j.0513-4870.2024-0125
文章导航
收藏切换
摘要
收起

生物大分子药物因具有高靶向性、剂量小、安全性和生物活性高等独特优势而越来越多地被用于多种疾病的治疗。但同时由于其分子质量大、亲水性强及胃肠道稳定性差等缺点, 加之胃肠道复杂的生理屏障, 导致生物大分子口服生物利用度极低。胃肠道微针作为一种新型主动药物递送技术, 因其能够直接突破胃肠道屏障而实现药物的定位递送、高效吸收而在生物大分子药物口服递送方面具有巨大的潜力。本综述围绕胃肠道微针的驱动及设计策略、制备方法及其口服递送生物大分子药物的应用等方面进行了总结归纳, 并对该技术目前存在的局限性及发展趋势进行了分析, 以促进胃肠道微针的后续研发和临床转化, 为生物大分子的口服给药提供高效、安全的新策略。

胃肠道微针  /  生物大分子  /  口服递送  /  生物利用度

Biomacromolecule drugs have been increasingly used in clinical practice due to their distinct advantages, including precise targeting, small dose, high safety and activity. However, owing to their high molecular weight, strong hydrophilicity, and poor stability in the gastrointestinal tract, the oral bioavailability of the biomacromolecule drugs remains extremely poor. As a novel and innovative technology for active drug delivery, gastrointestinal microneedles hold immense potential in the oral delivery of biomacromolecule drugs because of their low-invasive nature and high permeation enhancement effects. This review primarily summarizes the actuating force, design strategies, fabrication techniques, and applications of gastrointestinal microneedles for the oral delivery of biomacromolecule drugs. Additionally, the challenges and further perspectives in the development this technology are presented, aiming to promote the subsequent research and clinical translation of gastrointestinal microneedles, and to provide a new efficient and safe strategy for oral delivery of biomacromolecule drugs.

gastrointestinal microneedle  /  biomacromolecule  /  oral drug delivery  /  bioavailability
冯嘉惟, 叶小风, 张奇镔, 魏颖慧. 胃肠道微针用于生物大分子药物口服递送研究进展. 药学学报, 2024 , 59 (7) : 1970 -1981 . DOI: 10.16438/j.0513-4870.2024-0125
Jia-wei FENG, Xiao-feng YE, Qi-bin ZHANG, Ying-hui WEI. Advances in the study of gastrointestinal microneedles for oral delivery of biomacromolecule drugs[J]. Acta Pharmaceutica Sinica, 2024 , 59 (7) : 1970 -1981 . DOI: 10.16438/j.0513-4870.2024-0125
正文
收起
生物大分子药物(多肽、蛋白质、核酸、抗体等) 因具有高度的靶向性、较小的使用剂量、较高的安全性和生物活性等独特优势而越来越多地被用于临床疾病治疗。但生物大分子同时也存在分子质量大、亲水性强及胃肠道稳定性差等缺点, 造成其口服生物利用度极低(通常低于1%)[1], 因此目前其给药方式主要是注射给药。然而, 注射给药存在患者依从性差和潜在不良反应等问题, 因此口服给药因其便捷性和非侵入性通常被视为更理想的给药途径。
生物大分子口服给药屏障主要有胃肠道生化屏障(胃肠道pH和消化酶)[2]、黏液屏障[3]及上皮细胞屏障[4]。为有效克服这些屏障, 目前已发展了多种技术方法以促进生物大分子药物的口服吸收, 如采用酶抑制剂通过抑制相关肽类药物水解酶活性来提高肽类药物的胃肠道稳定性[5]; 采用渗透促进剂或经化学修饰提高药物肠道上皮细胞渗透性[6, 7]; 采用制剂递送技术(如黏附贴片[8]、水凝胶[9]、离子液体[10]、微/纳米载体[11]) 等来提高胃肠道黏附性、延长药物滞留时间或实现定位递送等。但上述方法主要采用间接的方法克服胃肠道内多重屏障而未能直接克服或避开这些屏障。2015年, Traverso等[12]首次提出胃肠道微针的概念并在猪体内进行了实验验证, 证明胃肠道微针能够直接克服胃肠道黏膜和上皮细胞屏障而提高胰岛素的口服生物利用度, 且微针可以安全地通过胃肠道并排出。自此, 因可直接克服胃肠道的多重屏障, 且插入胃肠道后可借助本身微米级传输通路使药物直接入胞[13], 胃肠道微针作为一种新型主动药物递送技术被逐步用于生物大分子药物的口服递送。随着研究的展开和深入, 胃肠道微针得到了进一步的优化和提升, 如通过设计独特的几何形状或增加辅助装置等以实现微针在胃肠道内的准确定向; 开发不同的微针驱动策略以提高其递送药物的效率和精确性。尽管目前尚未有胃肠道微针产品正式上市, 但部分产品已进入I期临床试验阶段[如Rani Therapeutics公司开发的用于胃肠道递送胰岛素、奥曲肽和人甲状旁腺激素类似物hPTH的Rani PillTM (RP) 肠溶微针胶囊], 为验证胃肠道微针在人体内的有效性和安全性及上市应用奠定了坚实的基础, 使胃肠道微针技术在生物大分子药物口服递送方面彰显了巨大的潜力。
本综述主要对胃肠道微针的驱动及设计策略、制备方法、体内外评价及在口服递送生物大分子药物方面的应用进行了总结, 并对该技术目前存在的局限性及发展趋势进行了分析, 以期为胃肠道微针的后续研发和临床转化提供新思路。
1 胃肠道微针体内驱动及设计策略
收起
与经皮给药微针借助手动按压力使微针针尖刺入皮肤不同, 胃肠道微针突破胃肠上皮屏障需要一定的驱动力。鉴于胃肠道蠕动可以产生持续的压缩力, 其本身即可用于微针的体内驱动。为进一步提高微针胃肠道递送药物的效率和精确性, 机械驱动、化学驱动、外场(如磁场) 驱动等策略被开发用于微针的体内驱动。此外, 鉴于胃肠道的复杂结构和动态运动的影响, 胃肠道微针的设计必须考虑如何确保其能够固定于胃肠道并精准地穿透胃肠道屏障而在特定部位递送药物。与经皮给药微针通常由针尖阵列和基底两部分构成不同, 胃肠道微针系统的结构一般较复杂, 通常需要更精密或更智能的设计[14]。
1.1 肠蠕动驱动
人体肠道每分钟径向收缩约10次, 可产生0.18~0.5 N·cm-1的压缩力, 与微针穿透胃肠道屏障所需的力度相当; 即肠道蠕动运动产生的压缩力可推动微针穿透肠壁[15]。因此, 肠蠕动可为胃肠道微针提供自然的驱动力。
基于肠蠕动驱动原理, Traverso等[12]设计了一种新型肠溶微针(图 1)。该装置由具孔的透明丙烯酸制成(图 1A), 针头被插入装置的孔中并突出其表面5 mm (图 1B)。针头表面涂覆pH响应材料, 当药丸到达胃肠道中特定位置时, 首先针头涂层溶解使微针暴露, 进而在胃肠道蠕动的作用下, 空心微针的储药池被压缩并通过针尖释放药物(图 1C); 若是固体微针, 药物则被直接装载于微针中, 微针随着胃肠道蠕动而穿透、释药(图 1D)。
为了提高肠蠕动驱动微针在肠道内定向的准确性, Huang等[16]受到不倒翁启发, 设计了一种低重心、自定向的微针机器人(图 2)。该装置呈流线型, 由主体(包括中空外壳和实心底部)、微针阵列(位于机器人的底部) 和分离层3部分组成。当将微针机器人以任意角度进入结肠后, 由于低重心结构可以使其底部紧贴肠壁从而快速垂直定向到肠道黏膜, 同时在其自身重力和肠道蠕动力的合力作用下微针穿透黏膜并释放药物。随后, 分离层在结肠液中逐渐降解, 使得机器人主体与微针阵列分离, 并排出体外。Gao等[17]受到刺鲀的启发(刺鲀在受到威胁时会迅速吸水膨胀使体形增大, 同时身上的刺会直立起来, 在被吞食后刺伤敌人) 设计了一种可膨胀口服微针机器人(图 3)。该微针机器人主要包括3个部分: 带倒钩的载药微针、可拉伸基底膜(装载微针并抵抗持续的蠕动收缩) 和强吸水性水凝胶颗粒(图 3A)。该微针机器人被封装于肠溶胶囊中, 与肠液接触后, 微针机器人在水凝胶颗粒的作用下会迅速膨胀, 并借助肠道收缩力驱动载药微针刺入肠黏膜; 在肠道松弛过程中, 载药微针尖端可以从微针机器人上分离, 同时借助倒钩固定在肠壁上(图 3B), 随后微针释放药物。分离后的微针机器人主体最终在肠道中分解成碎片并排出体外。
肠蠕动驱动模式无需预先装载动力或依赖外部驱动力, 从而避免了不可生物降解材料(金属弹簧、磁性颗粒等) 的使用。但仅依靠肠蠕动驱动的微针通常可控性较差, 受个体、食物等因素的影响较大, 且肠蠕动驱动微针响应较慢, 会影响微针的刺入速度和准确性。此外, 该类微针不适用于患有严重胃肠运动障碍的特殊群体。
1.2 化学驱动
化学驱动通常借助微针系统装置内部特定化学反应产生的能量或物质变化来驱动胃肠道微针。化学驱动系统设计较简单, 通常不涉及复杂的机械装置, 较易制备。
Rani Therapeutics公司开发出一款Rani PillTM肠溶微针胶囊(图 4)[18], 系将载药微针与气囊相连并折叠于羟丙甲纤维素肠溶胶囊中。气囊内部采用可溶性反应阀将柠檬酸和碳酸氢钠隔开(图 4A)。当该肠溶胶囊进入十二指肠时, 肠溶胶囊壳开始溶解, 使反应阀暴露并溶解于肠液中, 随即导致气囊中的柠檬酸和碳酸氢钠发生反应, 产生二氧化碳气体(CO2) 和压强, 造成气囊膨胀, 继而推动载药微针刺入肠壁并递送药物; 微针溶解并释放药物后, 气囊萎缩, 经肠道蠕动排出体外(图 4B)。
1.3 机械驱动
机械驱动通常借助特定机械装置(如弹簧) 运动产生的力来推动胃肠道微针突破上皮屏障。相较于肠蠕动驱动, 机械驱动的穿透力显著增强, 并且能够相对更准确地控制载药微针在胃肠道内释药。
Abramson等[19]设计了一种机械驱动的自定向微针(self-orienting millimeter-scale applicator, SOMA) 系统(图 5)。该系统结构设计与前述快速自定向微针机器人原理相似, 由加重底部和中空外壳构成。不同之处在于, SOMA装置内装有装载固体胰岛素的微针, 该微针与一个由糖片(蔗糖和异麦芽糖醇) 固定的压缩弹簧相连(图 5A)。SOMA快速完成定位和自我定向后, 糖片会在胃酸中溶解, 触发弹簧弹出从而推动胰岛素微针刺入胃黏膜中并以可控的速度释放胰岛素(图 5B)。
鉴于上述微针系统装置可能会因胃肠道的蠕动、消化液的流动而造成微针的提前脱落, Chen等[20]模仿自然界中刺头蠕虫附着于脊椎动物肠道中的带刺长鼻设计了一款动态全向黏附微针系统(dynamic omnidirectional adhesive microneedle system, DOAMS) (图 6)。该微针系统由弹出装置和两端黏附有微针的药片两部分组成(图 6A)。其中, 微针是一种双层结构, 内层由聚己内酯(polycaprolactone, PCL) 构成, 使微针具有一定的机械强度以穿透组织; 外层由卡波姆构成, 使微针具有黏附性及形变特性。口服后, 在胃内低pH值环境中, 用于压缩弹出装置的黏合材料溶解, 从而触发弹簧伸展将黏附有微针的药片弹出(图 6B), 微针接触胃组织表面, 刺入黏膜层后在组织内会自发膨胀、伸展、形变, 产生“互锁效应”, 这种互锁效应, 即微针膨胀形变产生的机械黏附及外层材料卡波姆与组织形成的水凝胶键化学黏附这两种机制协同作用使得DOAMS附着力显著增强, 使其能够更牢固地附着于组织, 从而使药片能长时间稳定地停留在特定部位。此外, 微针产生的微孔道有助于药物穿透消化道上皮组织, 进入血液循环, 从而有效提高药物的吸收。
机械驱动的胃肠道微针通常被组装于结构复杂的装置中, 尺寸大, 存在消化道梗阻的潜在风险; 且驱动多由不锈钢弹簧实现, 可控性差, 存在一定的胃肠道穿孔的风险。
1.4 外场驱动
外场驱动是利用外部施加的特定类型的力或场来引导微针进行移动、刺入组织而释放药物。由于具有优越的可控性和非侵入性, 外加磁场被广泛用于胃肠道微针的体内驱动。磁场驱动通常通过在微针系统内加入磁性物质, 使其具备磁响应性, 从而能够在外加磁场的作用下实现微针的精确控制和定向移动。磁场驱动能够克服上述化学驱动、机械驱动的一些限制, 如对pH的依赖性导致的可控性差及递送效率不高等问题。磁场驱动可通过调节外部磁场的强度和方向而实现胃肠道微针的靶向递送, 从而提高治疗的精确性和效率。
Zhang等[21]设计了一种磁响应微针机器人(magneto-responsive microneedle robots, MMR) 系统(图 7)。该系统由载药针尖、连接部和磁性基底3部分构成(图 7A)。MMR被装填于肠溶胶囊中, 进入肠道后, 在外部磁场的引导下, MMR的载药针尖首先定向刺入小肠壁(图 7B); 连接部由甲基丙烯酸酯化明胶(methacrylated gelalin, GelMA) 与牛血清白蛋白混合制成, 与消化液接触后会迅速降解, 从而使磁性基底与插入的载药针尖分离并排出体外, 同时载药针尖保留在肠壁持续释放药物(图 7C)。
Lee等[22]设计了一种由外部磁场驱动的多层载药微针贴片胶囊(图 8)。整个系统由三层微针贴片、胶囊体、永磁体和制动器4部分组成(图 8A)。永磁体的一端与微针贴片相连, 另一端与制动器相连以限制永磁体在胶囊中的垂直运动范围; 微针贴片各层之间由聚二甲基硅氧烷(polydimethylsiloxane, PDMS) 连接并使用不同方法处理(图 8B), 由于各层之间黏附性的差异, 多层贴片可以按序分离并分别递送到3个不同病变部位(图 8C)。在外部磁场作用下, 胶囊移动到病变部位后依靠磁场将胶囊调整到垂直于肠壁的位置并将微针贴片从胶囊中推出(图 8D), 插入肠壁并逐次分离(图 8E)。该装置可实现药物在胃肠道内多个病变点的依次递送, 但也存在一定的局限性: 如胃肠分泌液和食物等会削弱微针贴片与胃肠道的黏附力; 胶囊中的微针贴片剂可能会在运动过程中过早暴露于肠液而影响其刺入肠壁递药行为。
2 胃肠道微针的制备及评价
收起
2.1 胃肠道微针制备材料
为减少胃肠道残留, 胃肠道微针阵列多为可溶性微针, 常用聚合物材料制备, 如壳聚糖(chitosan, CS)、聚乙二醇(polyethylene glycol, PEG)、聚乙烯吡咯烷酮(polyvinyl pyrrolidone, PVP)、聚乙烯醇(polyvinyl acetate, PVA)、聚氧乙烯(polyethylene oxide, PEO)、羟丙基甲基纤维素(hydroxypropyl methyl cellulose, HPMC)、PCL、GelMA等(表 1)。此类材料通常具有较高的载药能力、良好的生物安全性和可控的释药速率[25]。胃肠道微针系统中的附加部分通常含有非生物降解材料(弹簧、磁性材料等), 因此, 在进行胃肠道微针系统设计时, 还应确保附加部分在完成药物递送任务后能够安全地排出体外。
2.2 胃肠道微针制备方法
与经皮给药微针相似, 胃肠道微针可采用微机械法(光刻、蚀刻)、微模塑法、液滴吹气法、3D打印法等方法制备[26]。鉴于胃肠道微针形状独特、结构精密、智能, 因此以微模塑法、3D打印或微模塑结合3D打印较为适用。
微模塑法首先采用3D打印、光刻、蚀刻等技术制造出与微针具有相同结构的主模, 然后在主模表面浇铸PDMS预聚物和固化剂混合液固化得到可重复使用的PDMS阴模, 随后借助抽真空或离心力等外力使基质材料与药物混合填充进入模具孔洞, 在促使混合液固化后即可从模具上脱模得到所需的微针[27]。其中模具的填充常用真空、离心、旋涂、雾化喷雾等方法; 在固化阶段可根据所用材料的性能, 采用不同的固化方法, 如溶剂蒸发、光交联、化学交联、熔融凝固、冷冻等[28]。Abramson等[23]将50% PVP和胰岛素混合液填充入PDMS模具, 经3 200 r·min-1离心10 min、室温干燥72 h后制得肠腔展开微针(luminal unfolding microneedle injector, LUMI) 的针尖部分; Chen等[20]向PDMS模具中加入卡波姆溶液, 经离心(2 000 r·min-1, 10 min)、真空处理(45 ℃, 24 h)、加入PCL, 120 ℃真空处理3 h, 即制得DOAMS双层微针; Zhang等[21]将磁响应微针机器人各部分的水凝胶溶液依次加入到PDMS模具中, 再使用真空泵将其压入空腔中, 并逐一使用紫外光(365 nm, 10 W, 30 s) 交联固化来制备微针; Gao等[17]同样将混合液使用超声脱气填充入模具后, 在紫外线灯下光交联10 s以制备可膨胀口服微针机器人的载药微针部分。由于微模塑法简单、廉价且条件较为温和, 目前在胃肠道微针制备中广泛应用。
3D打印法是使用计算机辅助设计软件构建3D模型, 通过逐层添加材料以生成模型[29]。相较于微模塑法, 3D打印法步骤简单, 可以实现微针的一次成型, 且可以灵活设计微针的几何形状和结构, 从而制备复杂结构或定制化微针[30]。但3D打印设备的购置和维护成本也相对较高, 目前在胃肠道微针的制备中一般用于制备主模或较为复杂的机械驱动装置。其中, 光固化成型技术是最早的, 也是目前较为成熟的3D打印技术, 而在胃肠道微针的制备中立体光固化成型(stereolithography apparatus, SLA) 技术最为常用, 这是一种利用紫外激光逐层扫描并固化光敏树脂, 从而层层构建出三维物体的方法[31]。Huang等[16]使用Auto-CAD设计了快速自定向微针机器人主体的3D模型, 并使用生物相容性树脂通过3D打印机逐层立体光固化打印成型; Chen等[20]在DOAMS的制备中采用SolidWorks设计了DOAMS模具(主模) 的3D模型, 并使用光敏树脂(灰色树脂) 通过Form2 3D打印机制备了DOAMS模具; 液体注射SOMA (liquid-injecting self-orienting millimeter-scale applicator, L-SOMA) 顶部的可收缩装置同样也是3D打印制备而得[24]。
此外, 拉伸光刻法也可用于胃肠道微针的制备。拉伸光刻法即通过对黏弹性液体聚合物施加作用力使其产生拉伸变形, 随后采用热固化等方法使其成型而制备特定结构的微针[32]。Zhang等[33]即采用拉伸光刻法制备了独立微针马达, 并研究了拉伸速度和聚合物浓度对微针形态的影响, 发现随着拉伸速度的增加, 微针的长度会显著增长, 但拉伸速度过快会导致水凝胶提前断裂; 在一定范围内增加聚合物的浓度有利于拉伸, 从而有利于形成更长的微针。
2.3 胃肠道微针的体内外评价
与经皮给药微针相似, 胃肠道微针需进行机械性能、生物相容性、载药能力、降解性能、体内外药物释放等方面的评价。但由于胃肠道微针和经皮给药微针所作用的生物组织不同, 胃肠道微针在体外穿透、组织黏附性能及安全性评价等方面具有特殊的要求。
经皮给药微针的长度通常设计为150~1 500 μm, 可穿透皮肤的角质层并将药物递送到表皮或真皮层上部, 而不会深入真皮层损伤神经引起疼痛[34]。而胃肠道微针针尖的长度通常控制在1 mm以内, 穿透力通常控制在5~50 mN之间, 以确保既能有效穿透胃肠道壁又不造成穿孔[23]。同时, 为了防止穿透组织后微针在胃肠道蠕动过程中脱落, 通常需要对其黏附性能进行评价。Chen等[20]通过拉拔试验结果证明了DOAMS与组织间具有较强的黏附力(0.25 N)。Gao等[17]通过实验, 测得每根带倒钩的微针需要6.2 mN的力才能与组织分离, 且该黏附力随着倒钩数量的增加而增加。
在体内安全性评价方面, 由于胃肠道微针装置内通常含有非生物降解材料, 因此需对胃肠道微针肠梗阻风险进行评价, 通常是通过测试胃肠道微针在模拟肠道环境中排出肠道所需的最小推进力, 将其与肠道蠕动力比较, 以确定微针能否安全排出肠道[16]。
3 胃肠道微针递送生物大分子药物的应用
收起
目前胃肠道微针多用于递送蛋白和多肽类药物, 递送抗体类药物、多糖类、核酸类物质的研究相对较少, 可能是由于这些物质的分子质量更大、结构及吸收、转运过程更为复杂。如对于核酸类物质, 口服递送后还需要考虑如何避免核酸被组织和血液中的核酸酶降解、同时逃避免疫系统的识别和清除等问题, 增加了额外的技术挑战[35, 36]。此外, 核酸口服递送领域发展较晚, 研究和临床应用上还有待进一步探索和发展[37]。
3.1 递送蛋白和多肽类药物
Hashim等[38]采用RP胶囊进行了重组人胰岛素(recombinant human insulin, RHI) 在麻醉雌性家猪肠内递送的临床前研究。药代动力学结果显示: RP给药组猪血清胰岛素峰浓度略高于皮下注射给药组, 达峰时间(Tmax) 略短于皮下注射组, 药-时曲线下面积与皮下注射组相似, 表明RP肠内递送RHI速度与皮下注射给药相似, 且相对生物利用度接近100%。正常血糖钳夹试验显示, 给药7 h内, 两组的葡萄糖输注速率接近, 表明RP口服递送RHI降血糖效果与皮下注射给药相等效。Abramson等[19]采用SOMA胶囊进行了胰岛素猪胃内递送的实验研究, 获得了与皮下注射相当的降血糖效果。该团队亦采用LUMI胶囊进行了胰岛素在雌性约克夏猪肠内递送的研究[23]。药代动力学研究结果显示, LUMI组在猪体内递送胰岛素的Tmax (25 min) 远远小于皮下注射给药组(Tmax约为90 min), 表明与皮下注射给药相比, LUMI口服递送胰岛素可更快地发挥作用。同时, LUMI给药和皮下给药血清峰浓度(Cmax) 相似。但LUMI给药并没有提高胰岛素的生物利用度(相对生物利用度约为10%)。因此, 为了提高SOMA和LUMI胶囊的载药量和生物利用度, 该团队又设计了SOMA的新版本——液体注射SOMA (L-SOMA) 并进行了RHI和GLP-1类似物在LYD猪胃内递送的研究[24]。结果表明, L-SOMA给药后RHI的绝对生物利用度为51% ± 16%, 与皮下注射给药(57% ± 8%) 相当; 而L-SOMA递送GLP-1类似物的绝对生物利用度(103% ± 42%) 远高于皮下给药组(78% ± 4%)。此外, 因该装置采用了阶段性、序列控制的多弹簧致动系统从而精密控制了针头刺入和药物注射的先后顺序, 有效避免了针头刺入过程中药物的损失。Gao等[17]采用可膨胀微针机器人进行了重组人胰岛素在巴马小型猪肠内递送的研究。首先比较了微针机器人和皮下注射降血糖效果, 结果表明, 使用微针机器人递送时血糖下降了23.6% ± 10.7%, 与皮下注射下降的30.7% ± 10.4%的效果相当。而药动学结果显示, 微针机器人给药组的相对生物利用度达到23.6%。Zhang等[21]采用磁响应微针(MMR) 系统以糖尿病皮特曼-摩尔(Pitman-Moore) 小型猪为动物模型进行了胰岛素肠内递送的实验研究。结果显示: MMR给药后小型猪的血糖水平可在约2 h内恢复至正常水平; 且给经MMR治疗后的糖尿病小型猪口服葡萄糖后血糖水平变化趋势与健康小型猪相似(先略有升高随后迅速恢复至正常)。此外, 给药24 h后, 经MMR治疗的糖尿病小型猪的血糖水平仍能保持在正常范围内(≈ 5.7 mmol·L-1)。药代动力学结果显示: MMR给药后小型猪体内胰岛素的Tmax为1.5 h左右。实验结果证明MMR可有效经胃肠道递送胰岛素而发挥高效的调节血糖的能力。
Chen等[20]采用DOAMS片剂进行了索马鲁肽在约克夏猪胃内递送的研究。与传统片剂[含索马鲁肽及渗透促进剂8-(2-羟基苯甲酰胺基)辛酸钠, 与皮下注射索马鲁肽相比, 该片剂的生物利用度仅为1.22% ± 0.25%[39]] 相比, DOAMS给药后索马鲁肽在猪体内的吸收率更高, 血清峰浓度约为传统片剂的两倍, 且两者的Tmax无显著差异。此外该研究还比较了饮水量同为15 mL时两种片剂的血药浓度, 结果显示DOAMS组索马鲁肽的血药浓度较传统片剂给药组高出6倍, 表明DOAMS给药受饮水量影响较小, 与组织间的黏附力更强, 口服后可更好地发挥药效。
Rani Therapeutics公司亦采用RP胶囊口服递送奥曲肽[18]。I期临床研究结果显示, RP递送奥曲肽的绝对生物利用度为65%, 远高于口服奥曲肽普通胶囊(绝对生物利用度仅为1%[40])。同时, 受试者在RP膨胀过程中未出现疼痛或不适, 表明球囊的短暂充气和放气不会激活肠道拉伸受体, 研究亦未报告任何严重不良事件。此外, 研究还表明, RP胶囊不受食物效应的影响。该公司也对RP胶囊(RT-102) 递送人甲状旁腺激素类似物hPTH (1-34) (Teriparatide) 进行了I期临床研究[41]。药动学研究表明, 两种规格(20和80 μg) 的RT-102均能有效递送hPTH。与皮下注射相比, RT-102给药后hPTH的血药浓度可以在相对较长时间内维持在较高水平, 且药-时曲线下面积(AUC) 是皮下注射组的3~4倍。RT-102给药20和40 μg, hPTH的Cmax分别为98 ± 10和971 ± 223 pg·mL-1, Tmax分别为68和60 min; 而皮下注射20 μg, Cmax为128 ± 20 pg·mL-1, Tmax为13 min。此外, RT-102可被受试者顺利吞服, 且未出现任何不良反应。该研究为口服RP安全有效递送hPTH (1-34) 提供了有力的临床证据。
3.2 递送抗体类药物
Rani Therapeutics公司采用RP胶囊在雌性比格犬体内递送IgG类单克隆抗体——抗TNFα (GP2017, 阿达木单抗生物类似物) 和抗IL-17A (CJM112)[42]。药动学研究表明, 与皮下注射给药相比, RP胶囊递送GP2017相对生物利用度可达94%; RP递送CJM112绝对生物利用度约为54.2%, 与皮下注射给药(53.8%) 相似。此外, 该两种抗体RP给药后血清峰浓度与皮下注射相似, 且RP给药达峰时间更短。此外, 安全性和耐受性研究表明, 在给药期间或之后, 没有动物表现出疼痛迹象; RP胶囊的未消化成分在96 h内排出体外且未出现大肠或小肠梗阻的现象。
3.3 递送多糖类物质
Lee等[43]研究了装载壳聚糖的多层止血微针贴片胶囊的肠道止血作用。全血凝集试验和血小板黏附试验均表明该微针贴片具有良好的止血效果。此外, 作者还在猪小肠上进行了多层止血微针贴片胶囊的离体试验, 结果显示: 3个病变部位均在止血微针贴片的作用下成功实现止血, 验证了其向肠道多个病变部位递送止血微针贴片的可行性。
3.4 递送核酸类药物
为了克服细胞内外屏障, 防止核酸失活及提高递送效率, 微针递送核酸类药物时, 常与药物递送系统相结合[44]。Abramson等[45]采用SOMA胶囊在雌性约克夏猪体内递送mRNA (mRNA预先采用聚β-氨基酯聚合物纳米粒包裹)。每只猪口服给予3颗SOMA药丸, 每颗药丸含有50 μg编码Cre重组酶的mRNA (Cre重组酶能够使动物表达tdTomato荧光蛋白), 共递送150 μg mRNA (剂量高于现在使用的新冠疫苗中mRNA 30~100 μg的剂量)。蛋白质印迹和免疫组化结果表明, 给药24 h后, Cre已在猪胃内成功表达。
4 结语与展望
收起
近年来, 作为一种新兴的口服给药技术, 胃肠道微针用于生物大分子口服给药研究日益增加, 在降血糖、治疗自身免疫疾病、调节体内激素水平和止血等方面展现出了巨大的潜力。其他新型胃肠道递送系统, 如胃肠溶缓控释制剂、纳米颗粒、脂质体等, 虽然可以提高药物稳定性和控制释放速率, 但通常依赖于胃肠道环境(如pH值变化或酶系统) 释放药物, 且必须克服胃肠道中多重屏障, 从而可能导致药物生物利用度低和药物释放时间、位置的不确定性。与之相比, 胃肠道微针则提供了一种更加直接、高效和精准的生物大分子药物递送方法。并且, 微针在胃肠道内递送药物从最初的仅依靠肠蠕动驱动, 目前已发展出多种驱动方式, 包括机械驱动、化学驱动、外场驱动等, 进一步提高了其递送药物的效率和精确性; 而且为了实现微针在胃肠道内的准确定向, 研究者们进行了一系列创新性设计, 如采用低重心结构、外部磁场引导、增加倒钩部分等。这些改进和创新均进一步拓展了胃肠道微针的生物医药应用。
当然, 胃肠道微针目前仍存在一定的局限性, 如载药量较小, 仅适用于日剂量在微克到几毫克(一般不超过4 mg) 范围内的生物大分子[46]; 其次, 除磁驱动微针外, 其他驱动机制微针通常对pH具有较强的依赖性, 可控性及递送效率欠佳; 再者, 由于患者的个体差异、食物等因素影响, 微针胃肠道递送药物的确切时间难以预测, 因此胃肠道微针不适于递送对时间敏感的药物, 如餐时胰岛素[47]; 此外, 由于胃肠道微针的结构精密, 制备过程较为复杂, 生产成本高, 导致目前的胃肠道微针技术临床转化率较低, 大规模生产和上市面临较大挑战[48], 该技术长期应用的安全性也有待更深入的研究和评估[49]。尽管如此, 胃肠道微针为生物大分子药物口服给药提供了新的策略。未来, 在微针设计方面, 可通过改进微针的几何形状、大小和结构等, 以提高载药量、递送效率和患者的依从性[50]; 也可以通过改进微针的材料(如使用可以提高药物的释放效率和生物相容性的生物可降解材料或纳米材料) 或与纳米载体、渗透促进剂等相结合以设计靶向可控释药、稳定高效的胃肠道微针[51]。同时, 开发具有低成本高效益且简单可控的微针及可工业化的制备技术和设备, 将会推动胃肠道微针的临床转化。因此, 胃肠道微针技术在口服递送生物大分子领域应用前景广阔, 可实现原创性关键技术的突破和整体创新, 推动临床治疗向着更高效、便捷、个性化的方向发展。
作者贡献: 冯嘉惟负责撰写及修改论文; 叶小风、张奇镔负责提供修改意见; 魏颖慧负责指导论文撰写、修改论文并定稿。
利益冲突: 本文所有作者声明不存在利益冲突关系。
基金
收起
  • 国家自然科学基金资助项目(82374047)
文献
收起
参考文献 引证文献
排序方式：
[1]
Brayden DJ, Hill TA, Fairlie DP, et al. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches [J]. Adv Drug Deliv Rev, 2020, 157: 2-36.
[2]
Cao YX, Rewatkar P, Wang R, et al. Nanocarriers for oral delivery of biologics: small carriers for big payloads [J]. Trends Pharmacol Sci, 2021, 42: 957-972.
[3]
Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery [J]. Int J Pharm, 2017, 532: 555-572.
[4]
Azizi A, Kumar A, Diaz-Mitoma F, et al. Enhancing oral vaccine potency by targeting intestinal M cells [J]. PLoS Pathog, 2010, 6: e1001147.
[5]
Choonara BF, Choonara YE, Kumar P, et al. A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules [J]. Biotechnol Adv, 2014, 32: 1269-1282.
[6]
Maher S, Geoghegan C, Brayden DJ. Intestinal permeation enhancers to improve oral bioavailability of macromolecules: reasons for low efficacy in humans [J]. Expert Opin Drug Deliv, 2021, 18: 273-300.
[7]
Chen GY, Kang WR, Li W, et al. Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies [J]. Theranostics, 2022, 12: 1419-1439.
[8]
Kirsch K, Hanke U, Weitschies W. An overview of intestinal wafers for oral drug delivery [J]. Eur J Pharm Biopharm, 2017, 114: 135-144.
[9]
Jabbari E. Hydrogels for cell delivery [J]. Gels, 2018, 4: 58.
[10]
Jiang YX, Jiang Q, Wang D, et al. The applications of ionic liquids in drug delivery [J]. Acta Pharm Sin (药学学报), 2022, 57: 331-342.
[11]
Cui ZX, Qin L, Guo S, et al. Design of biotin decorated enterocyte targeting muco-inert nanocomplexes for enhanced oral insulin delivery [J]. Carbohydr Polym, 2021, 261: 117873.
[12]
Traverso G, Schoellhammer CM, Schroeder A, et al. Microneedles for drug delivery via the gastrointestinal tract [J]. J Pharm Sci, 2015, 104: 362-367.
[13]
Rzhevskiy AS, Singh TRR, Donnelly RF, et al. Microneedles as the technique of drug delivery enhancement in diverse organs and tissues [J]. J Control Release, 2018, 270: 184-202.
[14]
Cummins G. Smart pills for gastrointestinal diagnostics and therapy [J]. Adv Drug Deliv Rev, 2021, 177: 113931.
[15]
Mercado-Perez A, Beyder A. Gut feelings: mechanosensing in the gastrointestinal tract [J]. Nat Rev Gastroenterol Hepatol, 2022, 19: 283-296.
[16]
Huang LB, Li LH, Jiang YJ, et al. Tumbler‐inspired microneedle containing robots: achieving rapid self‐orientation and peristalsis‐resistant adhesion for colonic administration [J]. Adv Funct Mater, 2023, 33: 2304276.
[17]
Gao XZ, Li JC, Li J, et al. Pain-free oral delivery of biologic drugs using intestinal peristalsis–actuated microneedle robots [J]. Sci Adv, 2024, 10: eadj7067.
[18]
Dhalla AK, Al-Shamsie Z, Beraki S, et al. A robotic pill for oral delivery of biotherapeutics: safety, tolerability, and performance in healthy subjects [J]. Drug Deliv Transl Res, 2022, 12: 294-305.
[19]
Abramson A, Caffarel-Salvador E, Khang M, et al. An ingestible self-orienting system for oral delivery of macromolecules [J]. Science, 2019, 363: 611-615.
[20]
Chen W, Wainer J, Ryoo SW, et al. Dynamic omnidirectional adhesive microneedle system for oral macromolecular drug delivery [J]. Sci Adv, 2022, 8: eabk1792.
[21]
Zhang XX, Chen GP, Fu X, et al. Magneto‐responsive microneedle robots for intestinal macromolecule delivery [J]. Adv Mater, 2021, 33: e2104932.
[22]
Lee J, Lee H, Kwon SH, et al. Active delivery of multi-layer drug-loaded microneedle patches using magnetically driven capsule [J]. Med Eng Phys, 2020, 85: 87-96.
[23]
Abramson A, Caffarel-Salvador E, Soares V, et al. A luminal unfolding microneedle injector for oral delivery of macromolecules [J]. Nat Med, 2019, 25: 1512-1518.
[24]
Abramson A, Frederiksen MR, Vegge A, et al. Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors [J]. Nat Biotechnol, 2022, 40: 103-109.
[25]
Makvandi P, Maleki A, Shabani M, et al. Bioinspired microneedle patches: biomimetic designs, fabrication, and biomedical applications [J]. Matter, 2022, 5: 390-429.
[26]
Mbituyimana B, Ma GR, Shi ZJ, et al. Polymer-based microneedle composites for enhanced non-transdermal drug delivery [J]. Appl Mater Today, 2022, 29: 101659.
[27]
Wang M, Hu LZ, Xu CJ. Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing [J]. Lab Chip, 2017, 17: 1373-1387.
[28]
Lyu S, Dong ZF, Xu XX, et al. Going below and beyond the surface: microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration [J]. Bioact Mater, 2023, 27: 303-326.
[29]
Caudill C, Perry JL, Iliadis K, et al. Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity [J]. Proc Natl Acad Sci U S A, 2021, 118: e2102595118.
[30]
Ahadian S, Finbloom JA, Mofidfar M, et al. Micro and nanoscale technologies in oral drug delivery [J]. Adv Drug Deliv Rev, 2020, 157: 37-62.
[31]
Quan HY, Zhang T, Xu H, et al. Photo-curing 3D printing technique and its challenges [J]. Bioact Mater, 2020, 5: 110-115.
[32]
Tarbox TN, Watts AB, Cui ZR, et al. An update on coating/manufacturing techniques of microneedles [J]. Drug Deliv Transl Res, 2018, 8: 1828-1843.
[33]
Zhang XX, Chen GP, Cai LJ, et al. Dip-printed microneedle motors for oral macromolecule delivery [J]. Research (Wash D C), 2022, 2022: 9797482.
[34]
Gupta J, Gupta R, Vanshita. Microneedle technology: an insight into recent advancements and future trends in drug and vaccine delivery [J]. Assay Drug Dev Technol, 2021, 19: 97-114.
[35]
Hossian AKMN, Mackenzie GG, Mattheolabakis G. miRNAs in gastrointestinal diseases: can we effectively deliver RNA-based therapeutics orally? [J]. Nanomedicine(Lond), 2019, 14: 2873-2889.
[36]
Kumari N, Siddhanta K, Panja S, et al. Oral delivery of nucleic acid therapies for local and systemic action [J]. Pharm Res, 2023, 40: 107-122.
[37]
Durán‐Lobato M, Niu ZG, Alonso MJ. Oral delivery of biologics for precision medicine [J]. Adv Mater, 2020, 32: e1901935.
[38]
Hashim M, Korupolu R, Syed B, et al. Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine: a pharmacokinetic and pharmacodynamic study [J]. Pharmacol Res Perspect, 2019, 7: e00522.
[39]
Davies M, Pieber TR, Hartoft-Nielsen ML, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial [J]. JAMA, 2017, 318: 1460-1470.
[40]
Melmed S, Popovic V, Bidlingmaier M, et al. Safety and efficacy of oral octreotide in acromegaly: results of a multileft phase Ⅲ trial [J]. J Clin Endocrinol Metab, 2015, 100: 1699-1708.
[41]
Myers JT, Dasari A, Battiwala A, et al. SAT235 an orally administered robotic pill (RP) reliably and safely delivers the human parathyroid hormone analog hPTH (1-34)(teriparatide) with high bioavailability in healthy human volunteers: a phase 1 study [J]. J Endocr Soc, 2023, 7: bvad114.531.
[42]
Yamaguchi A, Van Dam J, Dhalla AK, et al. Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines [J]. Front Drug Deliv, 2022, 2: 955569.
[43]
Lee J, Sohn SW, Lee H, et al. Open-close mechanism of magnetically actuated capsule for multiple hemostatic microneedle patch delivery [J]. Int J Control Autom Syst, 2022, 20: 2285-2296.
[44]
Jiang XH, Wang N, Liu C, et al. Oral delivery of nucleic acid therapeutics: challenges, strategies, and opportunities [J]. Drug Discov Today, 2023, 28: 103507.
[45]
Abramson A, Kirtane AR, Shi Y, et al. Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections [J]. Matter, 2022, 5: 975-987.
[46]
Kaffash E, Shahbazi MA, Hatami H, et al. An insight into gastrointestinal macromolecule delivery using physical oral devices [J]. Drug Discov Today, 2022, 27: 2309-2321.
[47]
Brayden DJ. The centenary of the discovery of insulin: an update on the quest for oral delivery [J]. Front Drug Deliv, 2021, 1: 726675.
[48]
Zhu QG, Chen ZJ, Paul PK, et al. Oral delivery of proteins and peptides: challenges, status quo and future perspectives [J]. Acta Pharm Sin B, 2021, 11: 2416-2448.
[49]
Yang YX, Zhou RY, Wang YF, et al. Recent advances in oral and transdermal protein delivery systems [J]. Angew Chem Int Ed Engl, 2023, 62: e202214795.
[50]
Zhang ZH, Shang LR. Smart ingestible devices: orally delivering macromolecules and beyond [J]. Matter, 2021, 4: 3379-3381.
[51]
Schoellhammer CM, Langer R, Traverso G. Of microneedles and ultrasound: physical modes of gastrointestinal macromolecule delivery [J]. Tissue Barriers, 2016, 4: e1150235.
2024年第59卷第7期
PDF下载
239
105
引用本文
BibTeX
文章信息
doi: 10.16438/j.0513-4870.2024-0125
  • 接收时间：2024-02-07
  • 首发时间：2025-11-26
  • 出版时间：2024-07-12
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2024-02-07
  • 修回日期：2024-04-12
基金
国家自然科学基金资助项目(82374047)
作者信息
    浙江中医药大学药学院, 浙江 杭州 310000

通讯作者:

*魏颖慧, Tel: 13357178565, E-mail:
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2024-0125
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62199257
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持