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Article(id=1198622900719809328, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198622898320671473, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0495, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1650902400000, receivedDateStr=2022-04-26, revisedDate=1654704000000, revisedDateStr=2022-06-09, acceptedDate=null, acceptedDateStr=null, onlineDate=1763703568868, onlineDateStr=2025-11-21, pubDate=1673452800000, pubDateStr=2023-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763703568868, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763703568868, creator=13701087609, updateTime=1763703568868, updator=13701087609, issue=Issue{id=1198622898320671473, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='1', pageStart='1', pageEnd='234', issueExtLink='null', onlineDate='null', pubDate='1673452800000', pubDateStr='2023-01-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763703568296, creator='13701087609', updateTime=1763703697615, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1198623440782586642, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198622898320671473, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198623440782586643, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198622898320671473, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=208, endPage=216, ext={EN=ArticleExt(id=1198622902091346754, articleId=1198622900719809328, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Nanocrystals self-stabilized Pickering emulsion loaded with active components of Tongmai prescription: preparation, characterization and evaluation by Caco-2 cell model, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

It is of great significance to apply the nanocrystals self-stabilized Pickering emulsion (NSSPE) to traditional Chinese medicine (TCM) compounds, and to study the effect of NSSPE on the oral absorption of various components with different solubility and permeability. In the study, NSSPE of Tongmai prescription was prepared by the high pressure homogenization method with nanocrystals of main active components (puerarin, ferulic acid, salvianolic acid B and tanshinone IIA) of Tongmai prescription as solid particle stabilizers and a mixture of Ligusticum chuanxiong essential oil and Labrafil M 1944 CS as oil phase. The NSSPE had better physical stability than nanocrystals suspension and blank emulsion. The adsorption of nanocrystals on the surface of oil droplets was confirmed by scanning electron microscopy and fluorescence microscopy. The surface adsorption rates of puerarin, ferulic acid, salvianolic acid B and tanshinone ⅡA in NSSPE were 15.40% ±3.19%, 15.39% ±5.07%, 10.97% ±3.70% and 31.51% ±1.60%, respectively. When solid active components were prepared into nanocrystals suspension, the cellular uptake and transport across Caco-2 cells were increased significantly for puerarin and tanshinone IIA. The uptake rates of ferulic acid, ligustilide and tanshinone IIA in NSSPE were further increased compared with the physical mixture of nanocrystals suspension and oil, and the transports of ligustilide and tanshinone IIA were also significantly improved. The main absorption mechanisms of NSSPE were passive diffusion and caveolin-mediated endocytosis, which were determined mainly by the microstructure of NSSPE. In conclusion, NSSPE could be applied to complicated TCM. The "micro" and "nano" synergistic microstructure with drug nanocrystals adsorbed on the surface of micron-sized oil droplets could not only improve the physical stability of NSSPE, but also promote the absorption of various components in NSSPE, which made NSSPE a promising oral drug delivery system for TCM.

, authors=null, authorsList=Ji-fen ZHANG, Xin YE, Yan-hua WANG, Xiao-yu XU, Tao YI, authorCompany=null, correspAuthors=Tao YI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 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, fund=null), CN=ArticleExt(id=1198622903664210848, articleId=1198622900719809328, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=通脉方药效组分纳米晶自稳定Pickering乳剂的制备、表征及Caco-2细胞模型评价, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

将药物纳米晶自稳定Pickering乳液（NSSPE）应用于中药复方，研究NSSPE对复方中不同溶解性和渗透性成分口服吸收的影响，很有意义。本研究以通脉方主要药效成分葛根素、阿魏酸、丹酚酸B和丹参酮ⅡA组合物的纳米晶为固体微粒稳定剂，以川芎油∶Labrafil M 1944 CS为油相，采用高压均质法制备中药复方NSSPE。体外表征结果显示，NSSPE中药效组分纳米晶吸附于川芎油的油滴表面，较纳米晶混悬液和空白乳均具有更好的物理稳定性；NSSPE中葛根素、阿魏酸、丹酚酸B和丹参酮ⅡA在乳滴表面的吸附率分别15.40%±3.19%、15.39%±5.07%、10.97%±3.70%和31.51%±1.60%。Caco-2细胞模型研究显示，固体药效成分制备成纳米晶混悬液后，葛根素和丹参酮ⅡA的细胞摄取与转运都显著提高；纳米晶混悬液与川芎油制备成NSSPE后，阿魏酸、藁本内酯和丹参酮ⅡA的Caco-2细胞摄取量较纳米晶混悬液/油的物理混合物又进一步提高，藁本内酯和丹参酮ⅡA的跨膜转运也极显著提高。细胞转运机制主要是被动扩散和小窝蛋白介导的内吞，NSSPE的微观结构是影响其吸收机制的主要因素。本研究表明，NSSPE可应用于成分复杂、性质差异大的中药复方，药物纳米晶吸附于微米粒径的油滴表面形成“微”“纳”协同的微观结构，不仅能提高乳液的物理稳定性，还能促进各成分的细胞摄取和转运，有希望成为有潜力的中药复方口服新剂型。

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*易涛, Tel: 86-853-85993471, E-mail:
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China J Chin Mater Med (中国中药杂志), 2021, 46: 2051-2060., articleTitle=Study on oral absorption mechanisms of puerarin in nanocrystals self-stabilized Pickering emulsion, refAbstract=null)], funds=[Fund(id=1198702082619437361, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, awardId=2021-4322190044, language=CN, fundingSource=重庆市中医药重点建设学科西南大学中医康复学资助项目(2021-4322190044), fundOrder=null, country=null), Fund(id=1198702082753655093, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, awardId=RP/ESCSD-01/2020, language=CN, fundingSource=澳门理工大学资助研究项目(RP/ESCSD-01/2020), fundOrder=null, country=null), Fund(id=1198702082871095616, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, awardId=001/2016/A1, language=CN, fundingSource=澳门科学技术发展基金资助项目(001/2016/A1), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198702073379386128, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, xref=null, ext=[AuthorCompanyExt(id=1198702073383580435, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, companyId=1198702073379386128, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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Faculty of Health Sciences and Sports, Macao Polytechnic University, Macau 999078, China), AuthorCompanyExt(id=1198702073551352611, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, companyId=1198702073542964001, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.澳门理工大学健康科学及体育学院, 澳门 999078)])], figs=[ArticleFig(id=1198702079444349099, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=oUhbvx0bj9CL6z6VMCPwVg==, figureFileBig=Ut5me84sfHk1EzHYF599mg==, tableContent=null), ArticleFig(id=1198702079586955445, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Figure 1, caption= Appearances of nanocrystals suspension (NS, A-Ⅰ), blank emulsions (BE, A-Ⅱ) and nanocrystals self-stabilized Pickering emulsions (NSSPE, A-Ⅲ) during storage at room temperature and after centrifugation at 4 000 ×<i>g</i> for 15 min (B) , figureFileSmall=oUhbvx0bj9CL6z6VMCPwVg==, figureFileBig=Ut5me84sfHk1EzHYF599mg==, tableContent=null), ArticleFig(id=1198702079754727616, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=bntrmkelpRmARYCkqOm5mA==, figureFileBig=jLiTEmBBSkbnQpaqQLE+MA==, tableContent=null), ArticleFig(id=1198702079905722571, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Figure 2, caption= Morphology of NS (Ⅰ), BE (Ⅱ) and NSSPE (Ⅲ) observed by fluorescence microscopy (A) and scanning electron microscopy (B). Scale bar: 2 μm , figureFileSmall=bntrmkelpRmARYCkqOm5mA==, figureFileBig=jLiTEmBBSkbnQpaqQLE+MA==, tableContent=null), ArticleFig(id=1198702080052523216, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=bHZFIMbPW9+cp7bCE97lhg==, figureFileBig=GP8F3b8w7VgSivDxtCE6HQ==, tableContent=null), ArticleFig(id=1198702080199323865, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Figure 3, caption= Caco-2 cellular uptake rates of active components of Tongmai prescription in different preparations. <i>n</i> = 5, <span class="mag-xml-inline-formula">$\bar{x}$</span> ± <i>s.</i> <sup>Δ</sup><i>P</i> < 0.05, <sup>ΔΔ</sup><i>P</i> < 0.01 <i>vs</i> crude material suspension (CMS); <sup>##</sup><i>P</i> < 0.01 <i>vs</i> NS; <sup>**</sup><i>P</i> < 0.01 <i>vs</i> mixture of nanocrystals suspension and oil (NS-O) , figureFileSmall=bHZFIMbPW9+cp7bCE97lhg==, figureFileBig=GP8F3b8w7VgSivDxtCE6HQ==, tableContent=null), ArticleFig(id=1198702081373728995, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=Rk2aUS9TLgHCH0dWAaE9Xw==, figureFileBig=kQDXRw0CqabOyPETnXVNSg==, tableContent=null), ArticleFig(id=1198702081512141038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Figure 4, caption= The transports from apical (AP) to basolateral (BL) (A), from BL to AP (B), and efflux ratio (ER, C) across Caco-2 cells of active components of Tongmai prescription in different preparations. <i>n</i> = 4, <span class="mag-xml-inline-formula">$\bar{x}$</span> ± <i>s.</i> <sup>Δ</sup><i>P</i> < 0.05, <sup>ΔΔ</sup><i>P</i> < 0.01 <i>vs</i> CMS; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01 <i>vs</i> NS; <sup>**</sup><i>P</i> < 0.01 <i>vs</i> NS-O , figureFileSmall=Rk2aUS9TLgHCH0dWAaE9Xw==, figureFileBig=kQDXRw0CqabOyPETnXVNSg==, tableContent=null), ArticleFig(id=1198702081642164469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=rxA+pnnMvADKGHQUH4D5Eg==, figureFileBig=kYsu51nwjutA6hSgKt1kAw==, tableContent=null), ArticleFig(id=1198702081784770811, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Figure 5, caption= Caco-2 cellular uptake (A) and transport from AP to BL (B) of active components of Tongmai prescription in NSSPE with different endocytosis inhibitors. <i>n</i> = 5, <span class="mag-xml-inline-formula">$\bar{x}$</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01 <i>vs</i> control group , figureFileSmall=rxA+pnnMvADKGHQUH4D5Eg==, figureFileBig=kYsu51nwjutA6hSgKt1kAw==, tableContent=null), ArticleFig(id=1198702081872851200, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Active component NSSPE NS
0 d 1 d 14 d 0 d 1 d
Puerarin 6 018.3 ± 244.2 6 046.5 ± 178.7 5 783.4 ± 266.9 7 202.5 ± 168.0 7 050.9 ± 165.4
Ferulic acid 443.4 ± 19.7 439.4 ± 11.8 462.2 ± 12.1 253.4 ± 5.5 203.2 ± 28.6**
Salvianolic acid B 4 561.2 ± 263.5 4 602.2 ± 204.3 3 869.3 ± 326.1** 4 898.7 ± 162.6 4 428.6 ± 91.6**
Ligustilide 9 128.1 ± 555.8 9 088.6 ± 253.7 7 476.7 ± 255.5** N/A N/A
Tanshinone ⅡA 241.3 ± 37.4 231.4 ± 28.1 98.8 ± 12.3** 267.6 ± 6.3 134.2 ± 1.1**
), ArticleFig(id=1198702081965125896, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Table 1, caption=

Contents of active components of Tongmai prescription in NSSPE and NS during storage at room temperature. n = 3, $\bar{x}$ ± s. Unit: μg·mL-1. N/A: Ligusticum chuanxiong essential oil was not added. **P < 0.01 vs 0 d in each group

, figureFileSmall=null, figureFileBig=null, tableContent=
Active component NSSPE NS
0 d 1 d 14 d 0 d 1 d
Puerarin 6 018.3 ± 244.2 6 046.5 ± 178.7 5 783.4 ± 266.9 7 202.5 ± 168.0 7 050.9 ± 165.4
Ferulic acid 443.4 ± 19.7 439.4 ± 11.8 462.2 ± 12.1 253.4 ± 5.5 203.2 ± 28.6**
Salvianolic acid B 4 561.2 ± 263.5 4 602.2 ± 204.3 3 869.3 ± 326.1** 4 898.7 ± 162.6 4 428.6 ± 91.6**
Ligustilide 9 128.1 ± 555.8 9 088.6 ± 253.7 7 476.7 ± 255.5** N/A N/A
Tanshinone ⅡA 241.3 ± 37.4 231.4 ± 28.1 98.8 ± 12.3** 267.6 ± 6.3 134.2 ± 1.1**
), ArticleFig(id=1198702082107732235, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Active component Memulsion/mg Mwater/mg Moil/mg Madsorption/mg Adsorption ratio/%
Puerarin 154.75 ± 10.01 130.92 ± 4.94 < LOD 23.82 ± 33.54 15.40 ± 3.19
Ferulic acid 10.04 ± 1.35 8.19 ± 0.50 0.31 ± 0.03 1.54 ± 0.37 15.39 ± 5.07
Salvianolic acid B 117.21 ± 6.32 103.50 ± 4.38 0.85 ± 0.06 12.85 ± 3.11 10.97 ± 3.70
TanshinoneⅡ A 4.84 ± 0.43 0.08 ± 0.02 3.24 ± 0.09 1.53 ± 0.05 31.51 ± 1.60
), ArticleFig(id=1198702082262921491, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, language=CN, label=Table 2, caption=

The distribution of active components of Tongmai prescription in NSSPE. n = 4, $\bar{x}$ ± s. < LOD: Less than the limit of detection

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Active component Memulsion/mg Mwater/mg Moil/mg Madsorption/mg Adsorption ratio/%
Puerarin 154.75 ± 10.01 130.92 ± 4.94 < LOD 23.82 ± 33.54 15.40 ± 3.19
Ferulic acid 10.04 ± 1.35 8.19 ± 0.50 0.31 ± 0.03 1.54 ± 0.37 15.39 ± 5.07
Salvianolic acid B 117.21 ± 6.32 103.50 ± 4.38 0.85 ± 0.06 12.85 ± 3.11 10.97 ± 3.70
TanshinoneⅡ A 4.84 ± 0.43 0.08 ± 0.02 3.24 ± 0.09 1.53 ± 0.05 31.51 ± 1.60
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通脉方药效组分纳米晶自稳定Pickering乳剂的制备、表征及Caco-2细胞模型评价
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张继芬 1 , 叶鑫 1 , 王艳华 1 , 徐晓玉 1 , 易涛 2, *
药学学报 | 研究论文 2023,58(1): 208-216
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药学学报 |研究论文 2023 , 58 (1) : 208 -216
通脉方药效组分纳米晶自稳定Pickering乳剂的制备、表征及Caco-2细胞模型评价
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Faculty of Health Sciences and Sports, Macao Polytechnic University, Macau 999078, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198702077112316921, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, authorId=1198702075744973791, language=CN, stringName=易涛, firstName=涛, middleName=null, lastName=易, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, *, address=2.澳门理工大学健康科学及体育学院, 澳门 999078, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198702073542964001, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, xref=null, ext=[AuthorCompanyExt(id=1198702073547158307, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198622900719809328, companyId=1198702073542964001, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2. 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张继芬1, 叶鑫1, 王艳华1, 徐晓玉1, 易涛2, *
作者信息
  • 1.西南大学药学院, 重庆 400716
  • 2.澳门理工大学健康科学及体育学院, 澳门 999078
通讯作者:
*易涛, Tel: 86-853-85993471, E-mail:
Nanocrystals self-stabilized Pickering emulsion loaded with active components of Tongmai prescription: preparation, characterization and evaluation by Caco-2 cell model
Ji-fen ZHANG1, Xin YE1, Yan-hua WANG1, Xiao-yu XU1, Tao YI2, *
Affiliations
  • 1. College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
  • 2. Faculty of Health Sciences and Sports, Macao Polytechnic University, Macau 999078, China
出版时间: 2023-01-12 doi: 10.16438/j.0513-4870.2022-0495
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摘要
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将药物纳米晶自稳定Pickering乳液（NSSPE）应用于中药复方，研究NSSPE对复方中不同溶解性和渗透性成分口服吸收的影响，很有意义。本研究以通脉方主要药效成分葛根素、阿魏酸、丹酚酸B和丹参酮ⅡA组合物的纳米晶为固体微粒稳定剂，以川芎油∶Labrafil M 1944 CS为油相，采用高压均质法制备中药复方NSSPE。体外表征结果显示，NSSPE中药效组分纳米晶吸附于川芎油的油滴表面，较纳米晶混悬液和空白乳均具有更好的物理稳定性；NSSPE中葛根素、阿魏酸、丹酚酸B和丹参酮ⅡA在乳滴表面的吸附率分别15.40%±3.19%、15.39%±5.07%、10.97%±3.70%和31.51%±1.60%。Caco-2细胞模型研究显示，固体药效成分制备成纳米晶混悬液后，葛根素和丹参酮ⅡA的细胞摄取与转运都显著提高；纳米晶混悬液与川芎油制备成NSSPE后，阿魏酸、藁本内酯和丹参酮ⅡA的Caco-2细胞摄取量较纳米晶混悬液/油的物理混合物又进一步提高，藁本内酯和丹参酮ⅡA的跨膜转运也极显著提高。细胞转运机制主要是被动扩散和小窝蛋白介导的内吞，NSSPE的微观结构是影响其吸收机制的主要因素。本研究表明，NSSPE可应用于成分复杂、性质差异大的中药复方，药物纳米晶吸附于微米粒径的油滴表面形成“微”“纳”协同的微观结构，不仅能提高乳液的物理稳定性，还能促进各成分的细胞摄取和转运，有希望成为有潜力的中药复方口服新剂型。

Pickering乳液  /  纳米晶  /  葛根  /  丹参  /  川芎  /  口服

It is of great significance to apply the nanocrystals self-stabilized Pickering emulsion (NSSPE) to traditional Chinese medicine (TCM) compounds, and to study the effect of NSSPE on the oral absorption of various components with different solubility and permeability. In the study, NSSPE of Tongmai prescription was prepared by the high pressure homogenization method with nanocrystals of main active components (puerarin, ferulic acid, salvianolic acid B and tanshinone IIA) of Tongmai prescription as solid particle stabilizers and a mixture of Ligusticum chuanxiong essential oil and Labrafil M 1944 CS as oil phase. The NSSPE had better physical stability than nanocrystals suspension and blank emulsion. The adsorption of nanocrystals on the surface of oil droplets was confirmed by scanning electron microscopy and fluorescence microscopy. The surface adsorption rates of puerarin, ferulic acid, salvianolic acid B and tanshinone ⅡA in NSSPE were 15.40% ±3.19%, 15.39% ±5.07%, 10.97% ±3.70% and 31.51% ±1.60%, respectively. When solid active components were prepared into nanocrystals suspension, the cellular uptake and transport across Caco-2 cells were increased significantly for puerarin and tanshinone IIA. The uptake rates of ferulic acid, ligustilide and tanshinone IIA in NSSPE were further increased compared with the physical mixture of nanocrystals suspension and oil, and the transports of ligustilide and tanshinone IIA were also significantly improved. The main absorption mechanisms of NSSPE were passive diffusion and caveolin-mediated endocytosis, which were determined mainly by the microstructure of NSSPE. In conclusion, NSSPE could be applied to complicated TCM. The "micro" and "nano" synergistic microstructure with drug nanocrystals adsorbed on the surface of micron-sized oil droplets could not only improve the physical stability of NSSPE, but also promote the absorption of various components in NSSPE, which made NSSPE a promising oral drug delivery system for TCM.

Pickering emulsion  /  nanocrystal  /  Pueraria lobata  /  Salvia miltiorrhiza  /  Ligusticum chuanxiong  /  oral administration
张继芬, 叶鑫, 王艳华, 徐晓玉, 易涛. 通脉方药效组分纳米晶自稳定Pickering乳剂的制备、表征及Caco-2细胞模型评价. 药学学报, 2023 , 58 (1) : 208 -216 . DOI: 10.16438/j.0513-4870.2022-0495
Ji-fen ZHANG, Xin YE, Yan-hua WANG, Xiao-yu XU, Tao YI. Nanocrystals self-stabilized Pickering emulsion loaded with active components of Tongmai prescription: preparation, characterization and evaluation by Caco-2 cell model[J]. Acta Pharmaceutica Sinica, 2023 , 58 (1) : 208 -216 . DOI: 10.16438/j.0513-4870.2022-0495
正文
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口服给药是中药最传统、最常用的给药途径。然而, 许多中药的有效成分都存在水溶性差、口服生物利用度低的问题, 影响了临床应用与开发。为提高这些成分的口服吸收, 本课题组基于“药辅合一”的传统中医用药理念[1], 设计了一种以中药难溶性成分自身纳米晶为固体微粒稳定剂的新型乳液, 即药物纳米晶自稳定Pickering乳液(nanocrystals self-stabilized Pickering emulsions, NSSPE)[2]。NSSPE的最大特点是无外加稳定剂, 仅由水、油和活性成分3类物质构成, 难溶性成分部分溶解于油/水相, 部分以纳米晶形式吸附于乳滴界面形成固体微粒稳定膜而阻止乳滴合并聚集。与传统的表面活性剂乳液和Pickering乳液相比, NSSPE无表面活性剂和异相固体微粒, 消除了其带来的安全隐患; 与药物纳米晶混悬液相比, NSSPE无需稳定剂即可具有较好的稳定性。难溶性药物除了溶解于油相, 还可吸附于乳滴表面, 有利于提高载药量。本课题组前期分别以水飞蓟宾纳米晶[3]、葛根素纳米晶[4]为固体微粒, 成功构建了中药单体成分的NSSPE。大鼠药动学研究显示, NSSPE能显著提高水飞蓟宾、葛根素的口服生物利用度[3, 4]。
中医的用药特色是复方配伍, 多成分共同作用, 发挥多途径、多靶点的综合疗效。中药复方中的各种有效成分按溶解性可分为水溶性成分、水难溶性成分和(挥发) 油三类, 正好可对应于NSSPE的水相、纳米晶稳定剂和油相, 因此, NSSPE的结构特点很适用于中药复方。研究将NSSPE用于多组分的中药复方, 开发中药复方的新型口服制剂, 具有重要的临床意义。但是, 不同于单体结构性质明确、纯度高的特点, 中药复方药效成分众多, 各成分的理化性质存在很大差异, 这给NSSPE的应用带来巨大挑战。
以通脉方为例。通脉方由葛根、丹参和川芎按1∶1∶1的比例配伍组成, 具有活血化瘀、通脉养心的功效, 用于缺血性心脑血管疾病、动脉硬化、脑血栓、心绞痛等疾病的治疗。现代研究证实, 葛根素、阿魏酸、丹酚酸B、川芎挥发油和丹参酮ⅡA是其主要的药效物质[5]。这几种药效成分性质差异很大。在溶解度方面, 本课题组前期测得, 丹酚酸B在水中溶解度超过5 mg·mL-1, 葛根素和阿魏酸微溶于水(溶解度分别为3.01 ± 0.66和0.82 ± 0.04 mg·mL-1), 丹参酮ⅡA难溶于水(溶解度低于2×10-5 mg·mL-1)[6], 川芎油则不溶于水。在酸碱性方面, 丹参酮ⅡA为中性, 葛根素、阿魏酸具有一定的酸性, 丹酚酸B酸性较强。丹酚酸B和藁本内酯的化学稳定性较差, 易氧化、水解, 尤其是在碱性条件下[7, 8]。这几个成分的口服生物利用度都很低, 但原因各不相同: 丹酚酸B属于生物药剂学Ⅲ类药物, 渗透性很差[9]; 藁本内酯(川芎油最主要的成分) 溶解性极差; 葛根素、丹参酮ⅡA则是受溶解度和渗透性双重限制[10]。能否通过较为简单的工艺条件将这些性质差异巨大的药效成分同时载入, 成功构建中药复方药效组分NSSPE？NSSPE对不同溶解性、渗透性成分的口服吸收有何影响？这些都是非常值得研究的问题。
本研究以通脉方为例, 首次进行中药复方药效组分NSSPE的制备、结构表征和口服吸收机制研究。根据前期测定的通脉口服液和通脉颗粒等上市制剂中阿魏酸、丹酚酸B和葛根素的含量比例, 以及丹参药材中丹酚酸B和丹参酮ⅡA的含量比例, 将葛根素、阿魏酸、丹酚酸B、丹参酮ⅡA以1∶0.035∶0.7∶0.03配伍, 制备混合纳米晶作固体微粒稳定剂, 以川芎油为主要油相, 构建同时含有通脉方5种主要药效成分的NSSPE, 对其体外性质和微观结构进行表征, 并用Caco-2细胞模型研究这5种药效成分的口服吸收机制, 揭示NSSPE对不同性质成分口服吸收的影响, 为将NSSPE的应用从难溶性单体拓展至成分复杂的中药复方提供参考。
材料与方法
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仪器  FA2004A型电子天平(万分之一, 上海精天电子仪器有限公司); SB-5200D超声波清洗仪、JY98-3D超声波细胞粉碎机(宁波新芝生物科技股份有限公司); AH100D高压均质机(ATS工业系统有限公司); BT-90激光粒度分布仪(丹东百特仪器有限公司); Zetasizer Nano ZS粒度及zeta电位分析仪(ZEV3600, 英国马尔文仪器公司); PHS-3C酸度计(成都世纪方舟科技有限公司); LC-20AD高效液相色谱仪(岛津公司); G16-WS高速离心机(长沙湘仪离心机仪器有限公司); SIGMA300热场发射扫描电子显微镜(德国Zeiss公司); DFC310FX荧光倒置显微镜(德国Leica公司); Sorvall WX 100超速离心机(赛默飞世尔科技公司); CB53三气培养箱(德国Binder公司); Elx800型酶标仪(美国BioTek有限公司); MERS00002型跨膜电阻仪(美国Millipore公司); F-7000荧光分光光度计(日本日立公司); U3010紫外-可见分光光度计(日本株式会社日立高新技术那珂事业所)。
试剂  葛根素、阿魏酸、丹酚酸B、藁本内酯、丹参酮ⅡA对照品(纯度均大于98%, 成都瑞芬思生物科技有限公司); 阿魏酸原料药(纯度 > 98%, 南京泽郎生物技术有限公司); 丹酚酸B提取物(纯度 > 70%)、丹参酮ⅡA原料药(纯度 > 95%) (西安鸿生生物技术有限公司); 葛根素原料药(纯度 > 98%, 四川玉鑫药业有限公司); 油酸聚乙二醇甘油酯(Labrafil M 1944 CS, 法国佳法赛试剂有限公司); 川芎油(江西雪松天然药用油有限公司); 甲醇(色谱纯)、荧光素(Adamas公司); MEM培养基、HBSS (美国Gibco公司); 丙酮酸钠、高效RIPA裂解液、D-Hanks (Solarbio公司); 优质胎牛血清、胰蛋白酶、青链霉素(HyClone公司); Transwell小室(Corning公司); 氯丙嗪、阿米洛利、染料木素(纯度均 > 98%)、二甲基亚砜(Sigma公司); 其余试剂均为分析纯。
细胞  Caco-2细胞株(中国科学院典型培养物保藏委员会细胞库), 传代至15~20代。
通脉方药效组分NSSPE的制备  在前期工艺研究基础上[11], 确定通脉方药效组分NSSPE的制备过程如下: 分别称取葛根素、丹酚酸B、阿魏酸和丹参酮ⅡA原料药各0.2、0.14、0.007和0.006 g, 加入40 mL纯化水, 水浴超声30 min后再探头超声(超声强度为1 200 W, 工作时间3 s, 间歇时间3 s, 共3 min), 得粗混悬液。粗混悬液用0.5 mol·L-1的NaOH溶液调节pH为6.5后, 于80 MPa下高压匀质5 min, 得纳米晶混悬液。随后加入4.4 mL油相(川芎油∶Labrafil M 1944 CS = 9∶1), 80 MPa继续匀质4 min, 即得NSSPE。于40 mL纯水(预先用0.5 mol·L-1的NaOH溶液调节pH为6.5) 中加入4.4 mL油相, 同法制得不加固体药效组分的空白乳液。
通脉方药效组分NSSPE的性质与结构表征  以通脉方药效组分的纳米晶混悬液和空白乳液为对照, 对NSSPE的性质和结构进行以下表征。
粒径及分布、zeta电位  将各样品直接用粒度分析仪测定粒径和zeta电位。
体外稳定性  将各样品室温(30 ℃) 静置, 分别于0时刻、1和14天观察是否有分层、絮凝、沉淀等不稳定现象。
离心稳定性  取新制备的空白乳液和NSSPE 1.5 mL, 4 000 ×g离心15 min, 观察是否有分层、沉淀等现象。同时取乳液层, 纯水稀释200倍后于600 nm波长测定吸光度, 评价乳液层的浊度。
药效组分在乳液层的含量  分别在0时刻、放置14天和4 000 ×g离心15 min后的乳液层的上、中、下部各取100 μL乳液, 加500 μL甲醇∶氯仿= 1∶2溶解, 再用甲醇定容到5 mL, 0.22 μm微孔滤膜过滤后用HPLC测定药物含量。取纳米晶混悬液100 μL, 甲醇定容到1 mL, 0.22 μm微孔滤膜过滤后用HPLC测定各成分的含量。HPLC的色谱条件如下: Waters Symmetry® C18色谱柱(250 mm × 4.6 mm, 5 μm), 流动相为0.1%甲酸-甲醇。梯度洗脱程序如下: 0~22 min, 甲醇30%~36%; 22~30 min, 甲醇36%~60%; 30~40 min, 甲醇60%~70%; 40~50 min, 甲醇70%~85%; 50~60 min, 甲醇85%; 流速为1 mL·min-1。检测波长为280 nm, 柱温为30 ℃。该分析方法已按2020版药典的分析方法验证指导原则进行了相应的方法学验证。
微观结构  分别取纳米晶混悬液、空白乳液和NSSPE, 点样在载玻片上, 荧光显微镜观察样品的微观形态。分别取少量各样品点样于100 nm径迹蚀刻膜上, 自然晾干, 喷金60 s后扫描电镜观察微观形态和表面结构。
药物纳米晶在NSSPE乳滴表面的吸附  取30 mL新制备的NSSPE, 1 800 ×g离心15 min后测定乳液层的药物含量。取离心后的乳液层25 mL, 4 ℃、50 000 r·min-1离心1 h, 分离油相和水相, 分别测定油相、水相的体积和药物含量。按公式(1) 计算各成分的吸附率:
$ 吸附率 (\%)=\left(M_{\text {emulsion }}-M_{\text {oil }}-M_{\text {water }}\right) / M_{\text {emulsion }} \times 100 \% $
其中, Memulsion表示1 800 ×g离心后乳液层的药物含量; Moil表示50 000 r·min-1离心后上层油相的药物含量; Mwater表示50 000 r·min-1离心后下层水相的药物含量。
细胞毒性实验  将生长状态良好的Caco-2细胞用0.25%胰蛋白酶/0.02% EDTA消化, 调整细胞密度为每毫升1×105个。取细胞悬液100 µL接种于96孔板上, 放入含5% CO2、37 ℃的恒温细胞培养箱中培养。48 h后阴性对照组(即接种细胞后加等体积空白培养液) 和调零组(即不接种细胞只加入空白培养液) 更换新鲜培养液。给药组加入浓度分别为12.5、25、50、100、150、200和400 µg·mL-1 (以葛根素计) 的含药培养液, 将96孔板放入培养箱中。4 h后, 小心吸弃孔内溶液, PBS清洗2~3次, 各孔再加入100 µL完全培养基和10 µL四甲基偶氮唑蓝(MTT, 5 mg·mL-1), 继续孵育4 h, 小心吸弃孔内溶液, 每孔加入150 µL二甲基亚砜, 待结晶全部溶解后用酶标仪在490 nm测定吸光度, 按公式(2) 计算细胞存活率。
$ 细胞存活率 (\%) = [(实验组吸光度 - 调零组吸光 \\度)/(阴性组吸光度 - 调零组吸光度)] × 100% $
Caco-2细胞摄取实验  Caco-2细胞用0.25%胰蛋白酶/0.02% EDTA消化, 1 000 r·min-1离心3 min, 弃上清液。加入2 mL培养液, 将细胞分散均匀。将细胞混悬液以1×104个/cm2的密度接种于24孔板, 每孔1 mL。第1周隔天换液, 之后每天换液, 培养14天。吸去培养液, 每孔用37 ℃的HBSS洗涤3次, 第3次洗涤时于培养箱中孵育30 min后再弃去HBSS。
将固体药效组分(葛根素、阿魏酸、丹酚酸B和丹参酮ⅡA, 配比与NSSPE一致)、纳米晶混悬液、纳米晶混悬液和油相(川芎油∶Labrafil M 1944 CS = 9∶1) 的物理混合液、NSSPE分别用HBSS稀释至浓度为100 µg·mL-1 (以葛根素计), 得各样品的供试液。分别取各供试液1 mL, 加入到培养14天的Caco-2细胞中, 孵育2 h, 吸弃上清液, 用HBSS小心清洗细胞表面。加入100 μL裂解液冰上裂解30 min, 其中50 μL裂解液中加入150 μL甲醇, 涡旋5 min后15 000 r·min-1离心10 min, HPLC测定上清液中各成分的含量; 剩余50 μL裂解液用BCA试剂盒测定蛋白含量。按公式(3) 计算细胞摄取量[12]。
$ 细胞摄取量\left( {{\rm{ \mathsf{ μ} g}} \cdot {{\rm{g}}^{ - 1}}} \right) = 细胞摄取的药物量\left( {{\rm{ \mathsf{ μ} g}}} \right)/细 \\胞的蛋白量 {\rm{(g)}}$
Caco-2细胞单层模型双向转运实验  将生长状态良好的细胞以2×104个/cm2的密度接种于Transwell小室, 24 h后换液, 第1周内隔天换液, 之后每天换液, 直至21天。取跨膜电阻(TEER) > 350 Ω·cm-2、荧光黄的表观渗透系数(Papp) 在5×10-7 cm·s-1数量级或以下的Caco-2单层细胞模型用于细胞转运实验。
Caco-2细胞单层先用HBSS清洗3次, 第3次清洗时需在培养箱中孵育30 min后再弃去HBSS, 然后方可进行肠腔侧(apical, AP) →基底侧(basolateral, BL) 和BL → AP的转运实验。AP → BL的转运: AP侧加入0.5 mL 100 µg·mL-1 (以葛根素计) 的不同样品供试液, BL侧加入1.5 mL空白HBSS, 放入培养箱孵育, 分别在15、30、60、90和120 min从BL侧取样0.2 mL, 测定各成分浓度, 同时补充0.2 mL空白HBSS。BL → AP的转运: BL侧加入1.5 mL 100 µg·mL-1 (以葛根素计) 的不同样品供试液, AP侧加入0.5 mL空白HBSS, 在15、30、60、90、120 min分别从AP侧取样0.2 mL, 测定各成分浓度, 同时补充0.2 mL空白HBSS。
按公式(4)、(5) 计算各成分的Papp和外排率(ER):
$ P_{\mathrm{app}}=(\mathrm{d} Q / \mathrm{d} t) /\left(A \times C_0\right) $
$ \mathrm{ER}=P_{\mathrm{app}(\mathrm{BL} \rightarrow \mathrm{AP})} / P_{\mathrm{app}(\mathrm{AP} \rightarrow \mathrm{BL})} $
其中, Q为累积转运量, 代表各成分在接收室的总量(μg); dQ/dt为转运速率(μg·s-1); C0为供试液中各成分的初始浓度(μg·mL-1); A为Transwell小室的面积(cm2)。
吞噬抑制剂对NSSPE中各成分摄取的影响  Caco-2细胞摄取模型中分别加入含抑制剂(31 µmol·L-1氯丙嗪、50 µmol·L-1阿米洛利、100 µmol·L-1染料木素) 的HBSS 1 mL, 孵育1 h后吸弃HBSS。再分别加入含有等浓度抑制剂的NSSPE (以葛根素计, 浓度为100 µg·mL-1), 如上述操作进行细胞摄取实验。
吞噬抑制剂对NSSPE中各成分转运的影响  在Caco-2细胞单层模型的AP侧分别加入0.5 mL含有抑制剂(31 µmol·L-1氯丙嗪、50 µmol·L-1阿米洛利、100 µmol·L-1染料木素) 的HBSS, BL侧加入1.5 mL空白HBSS, 孵育1 h, 吸弃AP、BL侧的液体, 清洗2次。再在AP侧加入0.5 mL含有等浓度抑制剂的NSSPE (以葛根素计, 浓度为100 µg·mL-1), BL侧加入1.5 mL空白HBSS, 进行AP → BL的转运实验。
统计学分析  数据以平均值±标准差表示, 以SPSS 12.0软件进行统计学分析, P < 0.05被认为具有统计学意义。
结果与讨论
收起
1 通脉方药效组分NSSPE的性质与结构表征
纳米混悬液的粒径为0.39 ± 0.01 μm。由于在乳滴表面吸附有药物纳米晶, NSSPE的乳滴粒径(1.43 ± 0.09 μm) 显著高于空白乳液的1.26 ± 0.03 μm (P < 0.05); NSSPE的zeta电位为-54.17 ± 0.85 mV, 显著低于空白乳的-31.10 ± 0.36 mV (P < 0.01), 与纳米晶混悬液(-59.70 ± 0.50 mV) 相近。
通脉方药效组分纳米晶混悬液、NSSPE和空白乳液放置后的外观变化见图 1A, 4 000 ×g离心15 min后的外观见图 1B。结果显示, 纳米晶混悬液、空白乳液和NSSPE的外观完全不同。纳米晶混悬液为红褐色, 放置1天后底部就已有大量红色沉淀, 提示物理稳定性差; 14天后颜色变为深褐色, 提示可能有化学变化。空白乳液为白色乳状, 刚制备完(0时刻) 就已有油相析出, 放置14天后不仅顶部油相析出增加, 底部也变清亮; 离心后油相析出更明显, 乳层变清亮, 吸光度仅为0.04, 提示物理稳定性很差。NSSPE为均匀的象牙黄色乳液, 在14天内颜色无变化; 0时刻既无油相析出也无药物沉淀; 1天后有零星的油点析出, 但底部无药物沉淀; 14天后底部仅有微量沉淀, 顶部油相析出略有增加, 但明显少于空白乳; 离心后无油相或沉淀析出, 乳层吸光度为0.56。以上结果提示, 在不外加表面活性剂等稳定剂的条件下, NSSPE比纳米晶混悬液和空白乳液具有更好的物理稳定性, 原因主要是NSSPE的结构不同于空白乳液和纳米晶混悬液, 药物纳米晶在油滴表面的吸附不仅减少了油滴的聚集和析出, 也减少了纳米晶的相互聚集和沉降, 增强了整个体系的物理稳定性。
通脉方药效组分NSSPE和纳米晶混悬液室温放置后各成分的含量变化见表 1。表 1进一步证实, NSSPE较纳米晶混悬液具有更好的物理和化学稳定性。纳米晶混悬液放置1天后, 丹酚酸B和丹参酮ⅡA的含量分别减少了9.60%和49.85%。NSSPE室温(30 ℃) 放置1天后, 各成分在乳液层中的含量均无显著变化; 放置14天后, 仅丹酚酸B和丹参酮ⅡA的含量分别降低了15.17%和59.05%。这种下降速率显著低于纳米晶混悬液。丹酚酸B含量下降与其本身化学稳定性差有关, 易降解为丹参素、原儿茶醛、迷迭香酸等[7]。丹参酮ⅡA含量下降则主要是因为药物沉降。纳米混悬液中丹参酮ⅡA主要以纳米晶形式存在, 热力学不稳定, 易聚集使粒径增大, 最终聚集沉降。NSSPE中丹参酮ⅡA的沉降则可能是由于丹参酮ⅡA纳米晶的量超过了乳滴的最大界面吸附量, 多余的纳米晶从乳液表面解吸附而沉降下来。但在同样未加任何稳定剂的条件下, NSSPE中丹参酮ⅡA的沉降显著少于纳米晶混悬液, 进一步证实NSSPE的独特结构使其物理稳定性显著优于纳米晶混悬液。
荧光显微镜和扫描电镜观察到的通脉方药效组分纳米晶混悬液、NSSPE和空白乳液的形态见图 2。图 2A显示, NSSPE的乳滴表面有明亮的绿色荧光光圈(葛根素、阿魏酸、丹参酮ⅡA有绿色荧光), 在乳滴内部观察到较暗的绿色荧光, 并且整个背景也呈现出较暗的绿色荧光。这提示葛根素、阿魏酸、丹参酮ⅡA可能大部分以纳米晶的形式吸附在乳滴的油水界面, 少部分溶解在油相中, 另有少部分溶解在水相中。纳米晶混悬液背景呈现出绿色荧光, 同时观察到颗粒状的绿色荧光, 提示葛根素、阿魏酸、丹参酮ⅡA一部分溶于水相中, 另一部分以纳米晶的形式存在。空白乳液因不含葛根素、阿魏酸、丹参酮ⅡA, 故在荧光显微镜下呈现一片黑色。图 2B可见, 纳米晶混悬液中有大量颗粒状的药物, 大部分粒径小于0.5 μm; 空白乳液的乳滴粒径为1~2 μm, 表面光滑; NSSPE的乳滴粒径在1~3 μm左右, 表面有明显的吸附突出物, 显著区别于空白乳液。
如上所述, 表 1提示通脉方药效组分NSSPE中丹参酮ⅡA纳米晶的量可能超过了界面最大吸附量, 导致部分丹参酮ⅡA纳米晶从乳液表面解吸附而分布于水相中。因此, 在检测药效组分在NSSPE中的分布时, 先将NSSPE于1 800 ×g离心15 min。该条件既可将400 nm左右的纳米晶沉淀, 又不会导致乳液分层。离心后测得的NSSPE中各成分的分布见表 2。NSSPE中葛根素、阿魏酸、丹酚酸B因在水中具有一定的溶解度, 80%以上分布于水相; 丹参酮ⅡA因脂溶性较强而几乎不溶于水, 主要分布于油相。葛根素、阿魏酸、丹参酮ⅡA纳米晶的界面吸附率分别为15.40%、15.39%和31.51%。在吸附于乳滴界面的3种难溶性组分中, 葛根素的绝对量较多, 而阿魏酸和丹参酮ⅡA较少。原因可能是NSSPE中葛根素的含量最高, 以及葛根素在油水中的三相接触角更接近90° (葛根素、阿魏酸、丹参酮ⅡA的三相接触角分别为72.4° ± 4.6°、139.3° ± 2.1°和132.2° ± 1.2° [12])。
2 细胞毒性实验
通脉方固体药效组分的粗分散液(原料药直接分散于水中)、纳米晶混悬液和NSSPE在12.5~150 μg·mL-1的浓度范围内(以葛根素计), 细胞存活率均大于90%。在200和400 μg·mL-1时(以葛根素计), 粗分散液和纳米晶混悬液的细胞存活率都在80%左右, 而NSSPE的细胞存活率急剧下降, 仅为31.33% ± 1.04%, 其原因可能是NSSPE中的油相药效组分川芎油在高浓度时具有一定的细胞毒性。根据以上结果, 确定后续研究的给药浓度为100 μg·mL-1 (以葛根素计)。
3 Caco-2细胞摄取实验
Caco-2细胞对通脉方固体药效组分的粗分散液、纳米晶混悬液、纳米晶/油的物理混合物和NSSPE的摄取量见图 3。
图 3显示, 将通脉方固体药效组分制备成纳米晶混悬液后, 葛根素和丹参酮ⅡA的摄取量分别从15.50 ± 0.80和12.32 ± 0.42 μg·mg-1增加至20.76 ± 0.64和17.84 ± 0.25 μg·mg-1, 各提高了33.93%和44.80%。原因可能是纳米晶可增加难溶性成分的溶解度, 还可增大药物与细胞的接触面积, 从而增强难溶性药物的口服吸收[13, 14]。此外, 纳米晶还可能直接被细胞摄取[15, 16]。有研究显示, 在较低浓度时, 难溶性药物以纳米晶体形式被细胞直接摄取的速率常数可能高于以分子形式被动扩散的速率常数[17]。纳米晶混悬液中阿魏酸的细胞摄取无显著变化, 这可能与阿魏酸的给药量极低(仅每孔约3.5 μg) 有关。丹酚酸B因水溶性较强, 在纳米晶混悬液中以溶解的分子形式存在, 故细胞摄取量变化不大。
在纳米晶混悬液中加入油相制成物理混合物后, 阿魏酸的摄取量从纳米晶混悬液的2.52 ± 0.36 μg·mg-1显著增至67.30 ± 8.38 μg·mg-1。这是因为川芎油中本身就含有一定的阿魏酸, 加入川芎油后阿魏酸的给药量从每孔3.5 μg增至7.4 μg。葛根素和丹酚酸B因在川芎油中的溶解度很低, 所以细胞摄取量无显著变化。丹参酮ⅡA虽在川芎油中有一定的溶解度, 但其摄取量与纳米晶混悬液组相比也无显著差异, 提示单纯的加入油制成物理混合物并不能促进丹参酮ⅡA的细胞摄取。
与纳米晶混悬液/油的物理混合物不同, 将纳米晶混悬液和油通过高压均质制备成NSSPE后, 葛根素、阿魏酸、藁本内酯(川芎油最主要的成分) 和丹参酮ⅡA的摄取量较纳米晶混悬液/油的物理混合物分别增加了27.21%、220.13%、165.51%和54.43%, 而丹酚酸B无显著变化。比较NSSPE与纳米晶混悬液/油的物理混合物, 二者化学成分的性质和含量是相同的, 差异仅在于微观结构方面。NSSPE中油相以乳滴形式分散于水中, 油相表面可能吸附了葛根素、阿魏酸和丹参酮ⅡA的纳米晶, 同时一部分阿魏酸和丹参酮ⅡA还溶解在油相中。NSSPE虽然仍是一种非均相体系, 但比物理混合物具有更好的均匀性, 油滴具有更小的粒径和更好的亲水性, 使其更易与Caco-2细胞接触而被摄取。可见, 各成分细胞摄取量显著提高的原因主要在于NSSPE的独特微观结构。本课题组前期有关几种单体NSSPE的大鼠灌胃药动学实验也证实, NSSPE比纳米晶混悬液能更显著增加难溶性成分的口服吸收: 葛根素、水飞蓟宾NSSPE的曲线下面积分别为纳米晶混悬液的1.6和2.4倍[3, 4]。
4 Caco-2细胞转运实验
通脉方药效组分的不同制剂在Caco-2单层细胞模型上双向转运的Papp和ER的结果见图 4。将通脉方固体药效组分制备成纳米晶混悬液后, 葛根素、丹酚酸B和丹参酮ⅡA的双向转运都显著增强, 葛根素和丹酚酸B的Papp增加了约1倍, 丹参酮ⅡA的AP → BL方向Papp从固体药效组分粗分散液的未测得提高至(1.25 ± 0.18)×10-6 cm·s-1。不同于亲水性较强的难溶性组分葛根素, 丹参酮ⅡA的疏水性极强, 几乎不溶于水, 丹参酮ⅡA的原料药因粒径高达数微米, 几乎不可能跨膜转运; 而丹参酮ⅡA纳米晶的粒径仅约400 nm, 这种纳米级的尺寸促进了丹参酮ⅡA的细胞摄取和跨膜转运。
在纳米晶混悬液中加入油制成物理混合物后, 各成分在AP → BL和BL → AP两个转运方向的Papp与纳米晶混悬液相比均无显著性变化。这说明把油与纳米晶混悬液进行物理混合不能提高各成分的跨膜转运, 这一结果与细胞摄取实验的结果一致。
将纳米晶混悬液和油通过高压均质制备成NSSPE后, 葛根素、阿魏酸、丹酚酸B在两个转运方向的Papp均无显著变化; 但是藁苯内酯和丹参酮ⅡA的转运都显著增加。对于纳米晶和油相的物理混合物, 未测得川芎油的跨膜转运; 而高压均质制成NSSPE后, NSSPE的独特结构(即固体药物纳米晶吸附在油滴表面) 使川芎油能以更小更稳定的乳滴形式存在, 显著促进了川芎油的细胞转运。NSSPE中丹参酮ⅡA在AP → BL和BL → AP方向的Papp较纳米晶混悬液/川芎油的物理混合物分别增加了3.70和3.08倍。丹参酮ⅡA转运的显著增加可能是由于高压均质过程使丹参酮ⅡA比简单的物理混合更好地溶解在油相中, 而且NSSPE中的油滴(藁本内酯) 跨膜转运显著增加, 也可能使得溶解在其中的丹参酮ⅡA转运一并增多。
值得注意的是, 尽管纳米晶混悬液相对于固体药效组分粗分散液、NSSPE相对于纳米晶混悬液, 各成分转运的Papp或有显著改变, 但ER均无显著改变, 均小于1.5, 说明转运形式仍以被动转运为主, 各成分细胞转运的增加与转运形式改变无关。
与固体原料药粗分散液相比, NSSPE中各组分的细胞摄取与转运发生了非常大的改变: 葛根素的摄取量和AP → BL的Papp分别提高了65.87%和1.21倍, 丹酚酸B分别提高了20.10%和93.10%, 丹参酮ⅡA的摄取量提高了1.26倍, AP → BL的Papp从原料药的无法转运提高至(5.78 ± 0.68) ×10-6 cm·s-1。本研究的细胞摄取与转运实验结果提示, NSSPE促进难溶性成分Caco-2细胞转运的主要原因在于其独特结构, 即固体药物纳米晶吸附在油滴表面而形成稳定的微米级油滴, 具体可能与以下机制有关: ①难溶性药物制备成纳米晶后, 溶解度增加, 促进了药物分子的被动扩散转运; ②药物纳米晶使油以稳定的微米级油滴形式存在, 而且油滴界面吸附的亲水性药物纳米晶还可能增加了油滴的亲水性, 使之能更好地与细胞接触, 显著增加油的转运; ③油滴的转运增加又使得吸附在其表面的纳米晶和溶解于其中的药物分子一起转运增加。这可称为“微”“纳”协同转运效应。这种协同转运效应对中药新制剂研发具有重要意义。NSSPE不仅可在无(或少) 外加稳定剂的情况下同时载药中药的挥发(或脂肪) 油、脂溶性和水溶性药效成分, 还能提高各成分, 尤其是油和脂溶性成分的细胞摄取与转运, 有望提高各成分的口服生物利用度, 进而减小给药剂量, 提高药效成分的利用率和制剂的安全性。
5 吞噬抑制剂对NSSPE摄取与转运的影响
不同抑制剂对NSSPE在Caco-2细胞的摄取量和AP → BL转运的Papp分别见图 5。与对照组相比, 加入氯丙嗪(网格蛋白介导的内吞途径抑制剂[18]) 或阿米洛利(巨胞饮途径抑制剂[19]) 后, 5个成分的摄取量和AP → BL的Papp均无显著差异。这说明在NSSPE的Caco-2细胞摄取和转运中网格蛋白介导的内吞和巨胞饮途径的内吞作用很弱。加入染料木素(与小窝蛋白介导的内吞有关的抑制剂[18]) 后, Caco-2细胞对5种成分的摄取量都极显著降低(P < 0.01)。这提示Caco-2细胞对NSSPE各成分的摄取存在内吞作用, 且与小窝蛋白介导途径有关。各成分在油滴表面均有一定吸附, 故当内吞作用被染料木素抑制后, 各成分的细胞摄取都降低。但染料木素仅对丹参酮ⅡA在AP → BL转运有显著影响, Papp降低了38.91%。这可能与丹参酮ⅡA的理化性质有关, 它水溶性极差而脂溶性较好, 而且NSSPE中高达67%的丹参酮ⅡA以分子形式溶解于油相(表 2), 更具体的原因有待后续进一步探究。这也与葛根素单体NSSPE的研究结果一致[20]: 葛根素单体NSSPE跨Caco-2细胞的摄取转运中同时存在被动转运和小窝蛋白介导的内吞两种途径。NSSPE改变了部分药物成分的吸收机制, 这种改变可能与NSSPE的结构有关。
结论
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本研究将通脉方主要固体药效组分葛根素、阿魏酸、丹酚酸B和丹参酮ⅡA配伍, 以其纳米晶作为固体微粒稳定剂, 以川芎油∶Labrafil M 1944 CS (9∶1, v/v) 为油相, 采用高压均质法首次制备了中药复方药效组分的NSSPE。扫描电镜、荧光显微镜和药物分布实验证实了通脉方药效组分纳米晶在川芎油的油滴表面的吸附。这种微观结构使得该复方NSSPE较纳米晶混悬液和空白乳液具有更好的物理稳定性。Caco-2细胞模型研究结果显示, NSSPE中各成分的口服吸收机制存在被动扩散和小窝蛋白介导的内吞两种途径, 药物纳米晶吸附于微米粒径的油滴表面的微观结构可产生“微”“纳”协同转运效应。这种各成分相互促进、协同转运的机制可提高通脉复方药效组分NSSPE中各成分的吸收。
本研究首次证实NSSPE可应用于成分复杂、性质差异巨大的中药复方; 与纳米晶混悬液相比, NSSPE不仅在无外加稳定剂的情况下提高了制剂的物理稳定性, 还能促进所载药物的细胞摄取和转运。这些优点使NSSPE有希望成为有潜力的中药复方口服新剂型。
作者贡献: 王艳华制备通脉方组分中药NSSPE; 叶鑫进行结构表征; 叶鑫、王艳华共同完成细胞实验; 徐晓玉指导细胞实验; 易涛、张继芬共同设计实验方案; 张继芬全程指导实验并撰写论文; 易涛修改论文。
利益冲突: 所有作者声明不存在利益冲突。
基金
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  • 重庆市中医药重点建设学科西南大学中医康复学资助项目(2021-4322190044)
  • 澳门理工大学资助研究项目(RP/ESCSD-01/2020)
  • 澳门科学技术发展基金资助项目(001/2016/A1)
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2023年第58卷第1期
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doi: 10.16438/j.0513-4870.2022-0495
  • 接收时间：2022-04-26
  • 首发时间：2025-11-21
  • 出版时间：2023-01-12
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  • 收稿日期：2022-04-26
  • 修回日期：2022-06-09
基金
重庆市中医药重点建设学科西南大学中医康复学资助项目(2021-4322190044)
澳门理工大学资助研究项目(RP/ESCSD-01/2020)
澳门科学技术发展基金资助项目(001/2016/A1)
作者信息
    1.西南大学药学院, 重庆 400716
    2.澳门理工大学健康科学及体育学院, 澳门 999078

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