Article(id=1222466390066455311, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466387184968430, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2018-1005, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1541433600000, receivedDateStr=2018-11-06, revisedDate=1543507200000, revisedDateStr=2018-11-30, acceptedDate=null, acceptedDateStr=null, onlineDate=1769388299719, onlineDateStr=2026-01-26, pubDate=1547222400000, pubDateStr=2019-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769388299719, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769388299719, creator=13701087609, updateTime=1769388299719, updator=13701087609, issue=Issue{id=1222466387184968430, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='1', pageStart='1', pageEnd='186', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769388299030, creator=13701087609, updateTime=1769389216051, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1222470233521115434, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466387184968430, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222470233521115435, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222466387184968430, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=61, endPage=65, ext={EN=ArticleExt(id=1222466391047922473, articleId=1222466390066455311, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=An
in vitro method for preliminarily screening competing agents to enhance drug permeation in cyclodextrin inclusion complexes, columnId=1222466389101761499, journalTitle=Acta Pharmaceutica Sinica, columnName=Special Reports: Promoting the Dissolution of Poorly Soluble Drugs, runingTitle=null, highlight=null, articleAbstract=
Cyclodextrin can increase the solubility of poorly soluble drugs, but also decrease the permeability of poorly soluble drugs in inclusion complexes simultaneously, which partially or completely counteracts the contribution of improvement in solubility to the oral absorption of poorly soluble drugs. If a competing agent is added to the system to compete binding sites of cyclodextrins with drugs, drug permeability can be improved by increasing the concentration of free drugs in the inclusion complex system. In this paper, a rapid in vitro screening method for competing agents of cyclodextrin inclusion complex is proposed based on the principle that good drug permeability is in accord with good cell uptake. The equilibrium constants between drugs and hydroxypropyl-beta-cyclodextrin (HPCD) were determined by phase equilibrium solubility method. Cinnarizine (CN) with a high equilibrium constant was selected as a competing agent, coumarin 6 (C6) and 9-octadecyl berberine (BD) with smaller equilibrium constants were selected as model drugs. Both changes of solubility and uptake by Caco-2 and A549 cells of C6 and BD were investigated different concentrations of CN to the HPCD solution of C6 and BD. The results showed that the uptake of C6 and BD increased in a CN concentration-dependent manner, and the solubility of C6 and BD in HPCD solution decreased with the prolongation of equilibrium time. It might be due to increased free drug concentrations that resulted from the competition of CN for drug binding sites with HPCD. In our study, in vitro cell uptake method was firstly used to validate the ability of CN as a competing agent to increase drug permeability (cell uptake). This method can be used for preliminarily screening of competing agents for drug-cyclodextrin inclusion complexes.
, correspAuthors=Hai-yan HU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2019 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=Yi-qin RAO, Shu-xuan LI, Peng-yu LI, Yi ZHANG, Hai-yan HU), CN=ArticleExt(id=1222466393962963937, articleId=1222466390066455311, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=提高环糊精包合物中药物渗透性的竞争剂体外筛选方法的建立, columnId=1222466389336642526, journalTitle=药学学报, columnName=专题报道：促进难溶性药物溶出, runingTitle=null, highlight=null, articleAbstract=
环糊精增加难溶性药物溶解度的同时可降低药物渗透性，从而部分甚至完全抵消溶解度增加对药物口服吸收的贡献。环糊精包合物体系中若加入能与药物争夺环糊精结合位点的竞争剂，则可通过增加体系中游离药物浓度而提高药物渗透性。本文基于药物渗透性强则细胞摄取增强的原理，拟建立环糊精包合物竞争剂的体外快速筛选方法。采用相平衡溶解度法测定药物与羟丙倍他环糊精（hydroxypropyl-beta-cyclodextrin，HPCD）的包合常数。选择包合常数大的桂利嗪（cinnarizine，CN）为竞争剂，包合常数小的香豆素6（coumarin 6，C6）和9-十八烷基小檗碱（9-octadecane berberine，BD）为模型药物。考察向C6和BD的HPCD溶液中加入不同浓度CN后，HPCD溶液中C6和BD溶解度的变化，以及Caco-2和A549细胞对HPCD包合物体系中C6和BD的摄取情况。结果显示，CN浓度依赖性地增加了细胞对C6和BD的摄取，延长平衡时间后，还降低了HPCD溶液中C6和BD的溶解度。这是因为CN竞争性地争夺药物与HPCD的结合位点，将药物置换出来增加了体系中游离药物的浓度。本文采用体外细胞摄取验证了竞争剂CN增加包合物药物渗透性（细胞摄取）的能力，该方法可用于药物-环糊精包合物竞争剂的初步筛选。
, correspAuthors=胡海燕, authorNote=null, correspAuthorsNote=
, copyrightStatement=版权所有©《药学学报》编辑部2019, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=Zbb4iICNGc/QX8kQh3qz1w==, magXml=kCY6ZnF81UPwuZJH3c+6gg==, pdfUrl=null, pdf=sfkHXwR7DY4dDIwnf0meyg==, pdfFileSize=620202, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=Lp70ZRWV7kT/wiEZVMdhPg==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=/SJIz25eECA59bKSE4z5tQ==, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=饶义琴, 李姝璇, 李彭宇, 章溢, 胡海燕)}, authors=[Author(id=1222466394470473742, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, 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=1222466394642440223, tenantId=1146029695717560320, 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The solubility of drugs in HPCD solution after adding different concentrations of CN. C6-HPCD solution containing 0.1 μg·mL<sup>-1</sup> C6 (A) and 0.3 μg·mL<sup>-1</sup> C6 (B); BD-HPCD solution containing 1 μg·mL<sup>-1</sup> BD (C) and 3 μg·mL<sup>-1</sup> BD (D) , figureFileSmall=AVnoBdPaDr+3g9Ux1nC4Sg==, figureFileBig=Lp70ZRWV7kT/wiEZVMdhPg==, tableContent=null), ArticleFig(id=1222466398002078020, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=EN, label=null, caption=null, figureFileSmall=46lWWamxmGrv8CcAXim3vQ==, figureFileBig=s3yKx5Vwj5bQD3F+gP6qvw==, tableContent=null), ArticleFig(id=1222466398085964110, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=CN, label=Figure 2, caption=
The effect of CN concentrations on uptake of C6 by Caco-2 cells in C6-HPCD solution. Imaging of C6 uptake by Caco-2 cells in C6-HPCD solution by laser confocal microscope (A); quantization analysis was performed on C6-HPCD solution containing 0.1 μg·mL<sup>-1</sup> C6 (B) and 0.3 μg·mL<sup>-1</sup> C6 (C). <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> control; <sup>#</sup><i>P</i> < 0.05, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> 0.1 μg·mL<sup>-1</sup> CN; <sup>&</sup> <i>P</i> < 0.05, <sup>& & &</sup> <i>P</i> < 0.001 <i>vs</i> 0.3 μg·mL<sup>-1</sup> CN; <sup>$</sup><i>P</i> < 0.05 <i>vs</i> 0.5 μg·mL<sup>-1</sup> CN. Scale bar = 50 μm , figureFileSmall=46lWWamxmGrv8CcAXim3vQ==, figureFileBig=s3yKx5Vwj5bQD3F+gP6qvw==, tableContent=null), ArticleFig(id=1222466398190821721, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=EN, label=null, caption=null, figureFileSmall=++NrKwve2rWTKmZajc8BFA==, figureFileBig=/K5SXLJks0CeeUbjSU4IVA==, tableContent=null), ArticleFig(id=1222466398308262241, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=CN, label=Figure 3, caption=
The effect of CN concentrations on uptake of C6 by A549 cells in C6-HPCD solution. Imaging of C6 uptake by A549 cells in C6-HPCD solution by laser confocal microscope (A); quantization analysis was performed on C6-HPCD solution containing 0.1 μg·mL<sup>-1</sup> C6 (B) and 0.3 μg·mL<sup>-1</sup> C6 (C). <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> control; <sup>###</sup><i>P</i> < 0.001 <i>vs</i> 0.1 μg·mL<sup>-1</sup> CN; <sup>& & &</sup> <i>P</i> < 0.001 <i>vs</i> 0.3 μg·mL<sup>-1</sup> CN; <sup>$$$</sup><i>P</i> < 0.001 <i>vs</i> 0.5 μg·mL<sup>-1</sup> CN. Scale bar = 50 μm , figureFileSmall=++NrKwve2rWTKmZajc8BFA==, figureFileBig=/K5SXLJks0CeeUbjSU4IVA==, tableContent=null), ArticleFig(id=1222466398438285676, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=EN, label=null, caption=null, figureFileSmall=Pp5ZAqawjgCo5n7AjPNOsA==, figureFileBig=b2Wr1zFmzDaRvjg2zmoWOw==, tableContent=null), ArticleFig(id=1222466398551531896, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=CN, label=Figure 4, caption=
Effect of CN with increasing concentrations on uptake of BD by Caco-2 cells in BD-HPCD solution. Imaging of BD uptake by Caco-2 cells in BD-HPCD solution by laser confocal microscope (A); quantization analysis was performed on BD-HPCD solution containing 0.1 μg·mL<sup>-1</sup> C6 (B) and 0.3 μg·mL<sup>-1</sup> C6 (C). <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> control; <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> 0.1 μg·mL<sup>-1</sup> CN; <sup>& &</sup> <i>P</i> < 0.01, <sup>& & &</sup> <i>P</i> < 0.001 <i>vs</i> 0.3 μg·mL<sup>-1</sup> CN; <sup>$$$</sup><i>P</i> < 0.001 <i>vs</i> 0.5 μg·mL<sup>-1</sup> CN. Scale bar = 50 μm , figureFileSmall=Pp5ZAqawjgCo5n7AjPNOsA==, figureFileBig=b2Wr1zFmzDaRvjg2zmoWOw==, tableContent=null), ArticleFig(id=1222466398639612288, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=EN, label=null, caption=null, figureFileSmall=YMa572V8sfFyOKzx2gHwww==, figureFileBig=6hKA4eXjTIvk3/Lem4yoIQ==, tableContent=null), ArticleFig(id=1222466398740275592, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=CN, label=Figure 5, caption=
Effect of CN with increasing concentrations on uptake of BD by A549 cells in BD-HPCD solution. Imaging of BD uptake by A549 cells in BD-HPCD solution by laser confocal microscope (A); quantization analysis was performed on BD-HPCD solution containing 0.1 μg·mL<sup>-1</sup> C6 (B) and 0.3 μg·mL<sup>-1</sup> C6 (C). <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>.<sup>***</sup><i>P</i> < 0.001 <i>vs</i> control; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> 0.1 μg·mL<sup>-1</sup> CN; <sup>& & &</sup> <i>P</i> < 0.001 <i>vs</i> 0.3 μg·mL<sup>-1</sup> CN; <sup>$$$</sup><i>P</i> < 0.001 <i>vs</i> 0.5 μg·mL<sup>-1</sup> CN. Scale bar = 50 μm , figureFileSmall=YMa572V8sfFyOKzx2gHwww==, figureFileBig=6hKA4eXjTIvk3/Lem4yoIQ==, tableContent=null), ArticleFig(id=1222466398874493333, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
| Drug | Linear equation | R2 | K |
| C6 | y =7.35×10-4x+8.2×10-6 | 0.999 4 | 89.7 |
| BD | y = 0.016 74 x+0.000 4 | 0.978 3 | 42.6 |
| CN | y = 0.001 46 x-8×10-5 | 0.999 3 | 826.7 |
), ArticleFig(id=1222466398979350941, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222466390066455311, language=CN, label=Table 1, caption=
Inclusion constants (K) of coumarin 6 (C6), 9-octadecane berberine (BD) and cinnarizine (CN) with hydroxypropyl-beta- cyclodextrin (HPCD)
, figureFileSmall=null, figureFileBig=null, tableContent=
| Drug | Linear equation | R2 | K |
| C6 | y =7.35×10-4x+8.2×10-6 | 0.999 4 | 89.7 |
| BD | y = 0.016 74 x+0.000 4 | 0.978 3 | 42.6 |
| CN | y = 0.001 46 x-8×10-5 | 0.999 3 | 826.7 |
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