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Article(id=1308841529096110706, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841198224240856, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0407, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1741190400000, receivedDateStr=2025-03-06, revisedDate=1755532800000, revisedDateStr=2025-08-19, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981737635, onlineDateStr=2026-09-21, pubDate=1781193600000, pubDateStr=2026-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981737635, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981737635, creator=13701087609, updateTime=1789981737635, updator=13701087609, issue=Issue{id=1308841198224240856, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='6', pageStart='1881', pageEnd='2376', issueExtLink='null', onlineDate='null', pubDate='1781193600000', pubDateStr='2026-06-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981658750, creator='13701087609', updateTime=1789984187230, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851803500933401, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841198224240856, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851803500933402, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841198224240856, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2257, endPage=2265, ext={EN=ArticleExt(id=1308841529452626547, articleId=1308841529096110706, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Preparation of apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhalers and the effect on acute severe pneumonia, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

To identify a new treatment strategy for acute severe pneumonia and solve the bioavailability of apigenin in formulation, the research utilized dipalmitoylphosphatidylcholine (DPPC), as well as 2-hydroxypropyl-β-cyclodextrin as respiratory carriers, to develop the apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhalers (ACDLDPIs). The ACDLDPIs were prepared by grinding, film-dispersion and freeze drying. The formulation was optimized by orthogonal design, and its particle size, entrapment efficiency, electric potential, in vitro release and lung deposition were studied. Lipopolysaccharide (LPS)-induced rat acute lung injury model was used to evaluate acute severe pneumonia in vivo. The optimal formulation for apigenin cyclodextrin inclusion was obtained with the mole ratio of apigenin/cyclodextrin as (2∶1), concentration of cyclodextrin as 20% and grinding time as 90 min. The optimized prescription of the ACDLDPIs was apigenin inclusion complex/DPPC (1∶2), 15 min hydration time and the mass ratio of mannitol/DPPC (1∶1). Its encapsulation efficiency was (71.46 ± 3.18)%, and the drug loading was (8.36 ± 0.42)%. The particle size was 198.6 ± 4.4 nm (before rehydration) and 221.6 ± 5.5 nm (after rehydration). The zeta potential was 15.3 ± 2.1 mV. The aerodynamic particle size was 4.28 ± 0.77 μm. The pulmonary deposition rate (FPF) was 43.02%. The experiment was approved by the Experimental Animal Ethics Committee of Tongji University Affiliated Yangpu Hospital (No: LL-2023-ZRKX-002). The pharmacodynamic evaluation of acute severe pneumonia was evaluated in vivo. ACDLDPIs group had better therapeutic effect than apigenin group. The ACDLDPIs had suitable particle size, uniform distribution, good stability, high lung deposition rate and good therapeutic effect on acute severe pneumonia in vivo. The ACDLDPIs are promising medicines for the treatment of acute severe pneumonia.

, authors=Li-fei ZHU, Si-qi ZHANG, Ting-ting WU, Hong-jun CHEN, Yan HUO*, authorsList=Li-fei ZHU, Si-qi ZHANG, Ting-ting WU, Hong-jun CHEN, Yan HUO, authorCompany=null, correspAuthors=Yan HUO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 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=1308841530635420286, articleId=1308841529096110706, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=芹菜素包合物二棕榈酰卵磷脂脂质干粉吸入剂的制备及其治疗急性重症肺炎作用研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

为寻找急性重症肺炎新的治疗策略和解决芹菜素口服生物利用度的问题, 拟采用肺泡表面活性物质二棕榈酰卵磷脂(dipalmitoylphosphatidylcholine, DPPC) 和2-羟丙基-β-环糊精(2-hydroxypropyl-β-cyclodextrin, HP-β-CD) 作为肺吸入载体, 研制芹菜素包合物DPPC脂质干粉吸入剂。用研磨法、薄膜分散和冷冻干燥技术制备芹菜素包合物DPPC脂质干粉吸入剂。正交实验设计优化处方, 并对其粒径、包封率、电位、体外释放及肺部沉积进行研究。脂多糖(lipopolysaccharides, LPS) 诱导的大鼠肺炎模型可以表征急性重症肺炎并进行体内药效作用评价。筛选最优处方芹菜素与HP-β-CD的摩尔比2∶1、HP-β-CD浓度20%、研磨时间90 min, 制备得到芹菜素包合物。将芹菜素包合物与DPPC质量比1∶2、水化时间15 min、甘露醇与DPPC质量比1∶1, 最终制备得到芹菜素包合物DPPC脂质干粉吸入剂, 其包封率为(71.46 ± 3.18)%, 载药量为(8.36 ± 0.42)%, 复溶前后的粒径为198.6 ± 4.4和221.6 ± 5.5 nm, zeta电位为15.3 ± 2.1 mV。干粉吸入剂的空气动力学粒径为4.28 ± 0.77 μm, 体外肺部沉积率(FPF) 为43.02%。动物实验经同济大学附属杨浦医院动物伦理委员会批准(No: LL-2023-ZRKX-002)。对急性重症肺炎大鼠进行体内药效学评价, 测得芹菜素包合物DPPC脂质干粉吸入剂组治疗效果优于芹菜素原料药组。制备的芹菜素包合物DPPC脂质干粉吸入剂符合肺吸入颗粒标准、分布均匀、稳定性良好, 肺部沉积率高, 体内对急性重症肺炎有很好的治疗效果, 有望成为目前急性重症肺炎治疗的有效制剂。

, authors=朱李飞, 张思棋, 吴婷婷, 陈红君, 霍炎*, authorsList=朱李飞, 张思棋, 吴婷婷, 陈红君, 霍炎, authorCompany=null, correspAuthors=霍炎, authorNote=

作者贡献:

朱李飞负责研究设计、数据采集、处理和分析、撰写论文初稿; 张思棋和吴婷婷负责部分实验辅助; 陈红君负责提供相关实验材料; 霍炎负责研究规划、设计、实施、资金支持、论文修改。

, correspAuthorsNote=
霍炎, Tel: 86-21-65690520, E-mail:
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articleId=1308841529096110706, language=CN, orderNo=4, keyword=干粉吸入剂), Keyword(id=1308841532539634340, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=CN, orderNo=5, keyword=急性重症肺炎)], refs=[Reference(id=1308841533961503413, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, 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=Miyashita N. 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Respir Med, 2021, 176: 106239., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308841530878689919, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, xref=null, ext=[AuthorCompanyExt(id=1308841530887078528, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, companyId=1308841530878689919, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Pharmacy, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China), AuthorCompanyExt(id=1308841530891272833, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, companyId=1308841530878689919, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=同济大学附属杨浦医院药学部, 上海 200090)])], figs=[ArticleFig(id=1308841532652880549, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=EN, label=null, caption=null, figureFileSmall=qL2hcfVgrA330Xn4eqnxWA==, figureFileBig=+umkQuzFUgPNH4S3ygXDsA==, tableContent=null), ArticleFig(id=1308841532715795110, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=CN, label=Fig.1, caption=The X-ray diffraction of apigenin β-cyclodextrin inclusion complexe. A: Apigenin; B: 2-Hydroxypropyl-β-cyclodextrin; C: Mixture of apigenin and 2-hydroxypropyl-β-cyclodextrin; D: Apigenin 2-hydroxypropyl-β-cyclodextrin inclusion complex, figureFileSmall=qL2hcfVgrA330Xn4eqnxWA==, figureFileBig=+umkQuzFUgPNH4S3ygXDsA==, tableContent=null), ArticleFig(id=1308841532883567271, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=EN, label=null, caption=null, figureFileSmall=HgcjOZa0YU8AIfVaWdeUeQ==, figureFileBig=OGgCMXuUYW1T7pd7osfPeA==, tableContent=null), ArticleFig(id=1308841532946481832, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=CN, label=Fig.2, caption=Characterization of apigenin β-cyclodextrin inclusion complexe DPPC liposomes. A: Appearance of apigenin β-cyclodextrin inclusion complex DPPC liposomes; B: Morphology of apigenin β-cyclodextrin inclusion complex DPPC liposomes; C: Constructed dry powder inhaler suspension; D: Particle size of apigenin β-cyclodextrin inclusion complexe DPPC liposomes; E: Particle size of apigenin β-cyclodextrin inclusion complexe DPPC liposomes after hydration; F: Zeta potential of apigenin β-cyclodextrin inclusion complexe DPPC liposomes, figureFileSmall=HgcjOZa0YU8AIfVaWdeUeQ==, figureFileBig=OGgCMXuUYW1T7pd7osfPeA==, tableContent=null), ArticleFig(id=1308841533026173609, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=EN, label=null, caption=null, figureFileSmall=TnGXkP4/YsXJXQpUFmelSA==, figureFileBig=L9/zbLJ44boZYL47GRQZqA==, tableContent=null), ArticleFig(id=1308841533093282474, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=CN, label=Fig.3, caption=The morphology of apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhaler. 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A: Appearance of rat lung tissue; B: Histopathological sections (×200, squares indicate diffuse exudation; triangles represent bleeding; arrows indicate the infiltration of mononuclear macrophages and lymphocytes); C: Lung W/D ratios. n = 6, $ \overline{x} $ ± s. *P < 0.05, figureFileSmall=oPL/Zx5T6GUFQQeDq1wKuA==, figureFileBig=Mtzy5BL9eykR3YF/BRLKuA==, tableContent=null), ArticleFig(id=1308841533441409711, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841529096110706, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
NumberMolar ratio
(A)		Cyclodextrin concentration
(B)		Grinding time
(C)		Entrapment efficiency/%
12∶15%30 min65.75
22∶110%60 min74.49
32∶120%90 min89.56
41∶15%90 min35.12
51∶110%30 min58.64
61∶120%60 min74.14
71∶25%60 min49.85
81∶210%90 min57.24
91∶220%30 min46.04
K178.04750.24065.710
K255.96763.45751.883
K351.04371.36067.463
R27.00421.12015.580
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The design of orthogonall experiment and entrapment efficiency

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NumberMolar ratio
(A)		Cyclodextrin concentration
(B)		Grinding time
(C)		Entrapment efficiency/%
12∶15%30 min65.75
22∶110%60 min74.49
32∶120%90 min89.56
41∶15%90 min35.12
51∶110%30 min58.64
61∶120%60 min74.14
71∶25%60 min49.85
81∶210%90 min57.24
91∶220%30 min46.04
K178.04750.24065.710
K255.96763.45751.883
K351.04371.36067.463
R27.00421.12015.580
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FactorSum of squares of deviationsDegrees of freedomF-ratioF-critical valueSignificance
A1 240.94629.41119-
B683.19725.18119-
C436.98723.31419-
Error131.862
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Analysis results of variance

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FactorSum of squares of deviationsDegrees of freedomF-ratioF-critical valueSignificance
A1 240.94629.41119-
B683.19725.18119-
C436.98723.31419-
Error131.862
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Ratio of mass (apigenin inclusion complex/DPPC)Appearance of sampleFlowability (angle of repose)/°Drug loading/%
1∶1White, sparse atrophy> 37.013.71 ± 0.63
1∶2White, full< 37.08.36 ± 0.42
1∶3White, full< 37.06.12 ± 0.31
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Prescription screening of ACDLDPIs. DPPC: Dipalmitoylphosphatidylcholine; ACDLDPIs: Apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhalers

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Ratio of mass (apigenin inclusion complex/DPPC)Appearance of sampleFlowability (angle of repose)/°Drug loading/%
1∶1White, sparse atrophy> 37.013.71 ± 0.63
1∶2White, full< 37.08.36 ± 0.42
1∶3White, full< 37.06.12 ± 0.31
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芹菜素包合物二棕榈酰卵磷脂脂质干粉吸入剂的制备及其治疗急性重症肺炎作用研究
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朱李飞 , 张思棋 , 吴婷婷 , 陈红君 , 霍炎 *
药学学报 | 研究论文 2026,61(6): 2257-2265
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药学学报 |研究论文 2026 , 61 (6) : 2257 -2265
芹菜素包合物二棕榈酰卵磷脂脂质干粉吸入剂的制备及其治疗急性重症肺炎作用研究
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朱李飞, 张思棋, 吴婷婷, 陈红君, 霍炎*
作者信息
  • 同济大学附属杨浦医院药学部, 上海 200090
通讯作者:
霍炎, Tel: 86-21-65690520, E-mail:
作者简介:

作者贡献:

朱李飞负责研究设计、数据采集、处理和分析、撰写论文初稿; 张思棋和吴婷婷负责部分实验辅助; 陈红君负责提供相关实验材料; 霍炎负责研究规划、设计、实施、资金支持、论文修改。

Preparation of apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhalers and the effect on acute severe pneumonia
Li-fei ZHU, Si-qi ZHANG, Ting-ting WU, Hong-jun CHEN, Yan HUO*
Affiliations
  • Department of Pharmacy, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
出版时间: 2026-06-12 doi: 10.16438/j.0513-4870.2025-0407
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为寻找急性重症肺炎新的治疗策略和解决芹菜素口服生物利用度的问题, 拟采用肺泡表面活性物质二棕榈酰卵磷脂(dipalmitoylphosphatidylcholine, DPPC) 和2-羟丙基-β-环糊精(2-hydroxypropyl-β-cyclodextrin, HP-β-CD) 作为肺吸入载体, 研制芹菜素包合物DPPC脂质干粉吸入剂。用研磨法、薄膜分散和冷冻干燥技术制备芹菜素包合物DPPC脂质干粉吸入剂。正交实验设计优化处方, 并对其粒径、包封率、电位、体外释放及肺部沉积进行研究。脂多糖(lipopolysaccharides, LPS) 诱导的大鼠肺炎模型可以表征急性重症肺炎并进行体内药效作用评价。筛选最优处方芹菜素与HP-β-CD的摩尔比2∶1、HP-β-CD浓度20%、研磨时间90 min, 制备得到芹菜素包合物。将芹菜素包合物与DPPC质量比1∶2、水化时间15 min、甘露醇与DPPC质量比1∶1, 最终制备得到芹菜素包合物DPPC脂质干粉吸入剂, 其包封率为(71.46 ± 3.18)%, 载药量为(8.36 ± 0.42)%, 复溶前后的粒径为198.6 ± 4.4和221.6 ± 5.5 nm, zeta电位为15.3 ± 2.1 mV。干粉吸入剂的空气动力学粒径为4.28 ± 0.77 μm, 体外肺部沉积率(FPF) 为43.02%。动物实验经同济大学附属杨浦医院动物伦理委员会批准(No: LL-2023-ZRKX-002)。对急性重症肺炎大鼠进行体内药效学评价, 测得芹菜素包合物DPPC脂质干粉吸入剂组治疗效果优于芹菜素原料药组。制备的芹菜素包合物DPPC脂质干粉吸入剂符合肺吸入颗粒标准、分布均匀、稳定性良好, 肺部沉积率高, 体内对急性重症肺炎有很好的治疗效果, 有望成为目前急性重症肺炎治疗的有效制剂。

芹菜素  /  二棕榈酰卵磷脂  /  环糊精  /  干粉吸入剂  /  急性重症肺炎

To identify a new treatment strategy for acute severe pneumonia and solve the bioavailability of apigenin in formulation, the research utilized dipalmitoylphosphatidylcholine (DPPC), as well as 2-hydroxypropyl-β-cyclodextrin as respiratory carriers, to develop the apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhalers (ACDLDPIs). The ACDLDPIs were prepared by grinding, film-dispersion and freeze drying. The formulation was optimized by orthogonal design, and its particle size, entrapment efficiency, electric potential, in vitro release and lung deposition were studied. Lipopolysaccharide (LPS)-induced rat acute lung injury model was used to evaluate acute severe pneumonia in vivo. The optimal formulation for apigenin cyclodextrin inclusion was obtained with the mole ratio of apigenin/cyclodextrin as (2∶1), concentration of cyclodextrin as 20% and grinding time as 90 min. The optimized prescription of the ACDLDPIs was apigenin inclusion complex/DPPC (1∶2), 15 min hydration time and the mass ratio of mannitol/DPPC (1∶1). Its encapsulation efficiency was (71.46 ± 3.18)%, and the drug loading was (8.36 ± 0.42)%. The particle size was 198.6 ± 4.4 nm (before rehydration) and 221.6 ± 5.5 nm (after rehydration). The zeta potential was 15.3 ± 2.1 mV. The aerodynamic particle size was 4.28 ± 0.77 μm. The pulmonary deposition rate (FPF) was 43.02%. The experiment was approved by the Experimental Animal Ethics Committee of Tongji University Affiliated Yangpu Hospital (No: LL-2023-ZRKX-002). The pharmacodynamic evaluation of acute severe pneumonia was evaluated in vivo. ACDLDPIs group had better therapeutic effect than apigenin group. The ACDLDPIs had suitable particle size, uniform distribution, good stability, high lung deposition rate and good therapeutic effect on acute severe pneumonia in vivo. The ACDLDPIs are promising medicines for the treatment of acute severe pneumonia.

apigenin  /  dipalmitoylphosphatidylcholine  /  cyclodextrin  /  dry powder inhalation  /  acute severe pneumonia
朱李飞, 张思棋, 吴婷婷, 陈红君, 霍炎. 芹菜素包合物二棕榈酰卵磷脂脂质干粉吸入剂的制备及其治疗急性重症肺炎作用研究. 药学学报, 2026 , 61 (6) : 2257 -2265 . DOI: 10.16438/j.0513-4870.2025-0407
Li-fei ZHU, Si-qi ZHANG, Ting-ting WU, Hong-jun CHEN, Yan HUO. Preparation of apigenin β-cyclodextrin inclusion complexe DPPC liposomal dry powder inhalers and the effect on acute severe pneumonia[J]. Acta Pharmaceutica Sinica, 2026 , 61 (6) : 2257 -2265 . DOI: 10.16438/j.0513-4870.2025-0407
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肺炎是临床上常见的呼吸系统疾病, 引发它的因素有很多, 比如年龄、环境和感染等[1-3], 其中最常见的病因就是感染。新型冠状病毒(coronavirus disease 2019, COVID-19) 和流感已在全球范围流行, 严重危害人类健康, 干扰全球人民的正常生活[4]。目前临床上COVID-19和流感的重症患者多是以急性重症肺炎的临床表现为主。临床治疗目前仍无特效药物, 主要以抗生素加激素联合治疗, 对患者的不良反应大。因此, 研究人员迫切寻找新的治疗物质, 开发新型给药系统提高急性重症肺炎治疗效果。
芹菜素(apigenin, Api), 又称芹黄素, 是一种天然存在的黄酮类化合物, 在多种蔬菜、水果、豆类和茶叶中广泛存在。芹菜素具有广泛的药理作用, 如抗炎、抗菌、抗病毒、抗肿瘤以及抗氧化等作用[5-7]。与其他黄酮类物质(槲皮素、山柰黄酮) 相比具有低毒、无诱变性等特点。在抗菌方面, 有研究报道芹菜素对球菌和杆菌属均有较强的抑制作用[8]。在抗病毒方面, 芹菜素对流感病毒、蚊传基孔肯雅病毒和非洲猪瘟病毒有体外抵抗作用[9-11], 可减少病毒基因组RNA复制和蛋白质合成。芹菜素用于肺部吸入给药方面面临诸多挑战, 主要是由于其颗粒大小和吸收特性限制了其在肺部的高效释放。本研究采用环糊精包合物控制它的肺吸入微粒大小, 增强芹菜素在肺部吸入中的稳定性。此外, 环糊精包合物还能帮助降低药物在肺泡表面的吸收系数, 从而提高释放效率。脂质体作为肺部生物相容性的理想载体, 具有良好的生物相容性和可降解性, 延长药物肺部滞留时间, 提高生物利用度。因此, 作者设计制备芹菜素包合物二棕榈酰磷脂酰胆碱(dipalmitoylphosphatidylcholine, DPPC) 脂质干粉吸入剂对芹菜素用于肺部给药的效果将会显著提升。
肺泡表面活性物质是由肺泡Ⅱ型细胞分泌, 以单分子层形式覆盖于肺泡液体表面的一种脂蛋白, 主要成分为DPPC。它的主要功能是减弱表面张力对肺毛细血管中液体吸引作用, 避免液体外渗进入肺泡发生肺泡积液, 保持肺中的液体平衡, 建立局部屏障防止外源性感染和吸入颗粒的进入[12]。这也成为肺吸入药物进入肺泡内的主要难点。而且, 肺泡表面活性物质是维持呼吸的重要组成部分, 多种肺部疾病如COVID-19、急性呼吸窘迫症等的病理变化会导致其功能丧失或破坏, 引起肺水肿, 严重者造成呼吸困难, 甚至死亡。目前, 临床采用灌注外源性的肺泡表面活性物质, 重新构建肺泡空气-液体交换界面, 恢复肺泡呼吸功能, 减轻水肿的发展。有研究显示柚皮素DPPC脂质复合物能增加药物在肺泡表面的释放浓度, 并且提高药物吸收效率[13]。Yu等[14]证明了肺吸入白藜芦醇DPPC脂质体有利于药物肺部吸收, 提高抗炎作用。因此, 拟将DPPC作为脂质生物载体补充肺泡表面活性物质, 同时包裹并携带药物跨膜转运进入肺泡, 提高药物吸收效率, 协同治疗, 增强疗效。
肺吸入药物能够解决药物在肺内浓度过低这一主要难题, 同时能克服药物多次给药的时间依赖性或浓度依赖性的用药依从性问题, 提高患者顺应性。目前临床上抗菌和抗病毒药物多不能直接吸入, 需要借助于纳米粒、脂质体、微球等新型肺吸入给药系统才能有较好的肺内吸收[15, 16]。环糊精是一类环状低聚糖, 具有亲水的外表面和亲脂的中心腔。它在体内会被降解并已被证明是药用辅料, 其中2-羟丙基-β-环糊精被广泛使用, 它的空腔适合于捕获各种有机分子, 增加药物稳定性[17]、溶解度[18]和生物利用度[19], 并减轻局部刺激。有报道环糊精已经成为一种潜在肺部输送的赋形剂[20, 21], 可以改善肺部给药后的药物吸收[22]。DPPC脂质体与环糊精复合的协同机制国外尚有文献报道。DPPC是一种磷脂类脂质, 它与环糊精在水中可以形成稳定的脂质体复合物, 通过与疏水性的磷脂尾部相互作用, 可以包裹磷脂并形成纳米级颗粒[23], 从而增强药物释放的效率, 减少药物直接接触肺表面活性层。Chen等[24]已经制备出共载葛根素/黄连素包合物脂质体。Yu[25]制备黄芩苷β-环糊精包合物脂质体, 并研究其药动学。这些研究表明环糊精与脂质体存在结合的应用情况。干粉吸入剂作为一种肺部给药制剂, 具有吸入效率高、药物稳定性好、起效快等特点, 已经在多种肺部疾病的治疗中得到应用, 如哮喘、慢性阻塞性肺病等[26, 27]。干粉吸入剂能够递送大剂量药物, 并且药物为固态粉末, 可以应用于递送蛋白质、肽类药物, 这扩展了肺部给药制剂的应用范围。例如, 妥布霉素干粉吸入剂被用于铜绿假单胞菌感染的囊性纤维化患者的抗生素治疗[28]。磷酸奥司他韦干粉吸入剂被用于预防和治疗甲、乙型流感的抗病毒治疗[29]。以上研究表明其在肺部疾病治疗中的广泛应用和独特优势。如果本研究构建的芹菜素干粉吸入剂递送系统能成功治疗急性重症肺炎, 那么它可能会在未来成为急性重症肺炎治疗的一种新途径。
材料与方法
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试剂及药物  芹菜素(JL1806010006, 98%, 上海江莱生物科技有限公司); 2-羟丙基-β-环糊精(L1713050, 上海阿拉丁生化科技股份有限公司); 甘露醇(CM28132630)、胆固醇(CC28143003) (北京酷来搏科技有限公司); DPPC (850355P-A-321, 美国Avanti公司); 脂多糖(L2880, 美国Sigma公司); 其余试剂均为分析纯。
仪器  旋转蒸发仪(RE-52-2, 上海青浦西仪器有限公司); 冻干机(Scientz-10N, 宁波新芝冻干设备股份有限公司); 纳米激光粒度仪(Zetasizer Nano ZS, 英国Malvern公司); 吸入药物粒度碰撞器(Next Generation Impactor, NGI, 英国Copley公司); 高效液相色谱系统(包括1525二元泵、2489紫外检测器、2707自动进样器、智能柱温箱、色谱工作站, Waters公司); 电子分析天平(MS204S, 瑞士Mettler-Toledo公司); 透射电镜(JEM-2100, 日本电子株式会社); 扫描电镜(Inspect F50, 美国FEI公司); 超纯水仪(Synergy UV, 美国Millipore公司); 超速冷冻离心机(Allegra X-30R, 美国Beckman公司); 超净台(SG603A, 美国Baker公司); 恒温震荡器(THZ-82, 天津赛得利斯仪器公司); 倒置显微镜(CKX41, 日本Olympus公司)。
动物  雄性Sprague Dawley大鼠(180~200 g), 来自同济大学附属杨浦医院转化医学中心, 实验动物使用许可编号: SCXK (浙) 2024-0004; 所有动物处理和手术程序均严格按照实验动物使用指导原则进行。本研究经同济大学附属杨浦医院动物伦理委员会批准(No. LL-2023-ZRKX-002)。
芹菜素含量测定
对照溶液的制备  精密称取芹菜素对照品于量瓶中, 用甲醇溶解并定容, 制得含芹菜素0.5 mg·mL-1储备液。
色谱条件  色谱柱采用Kromasil C18 (200 mm × 4.6 mm, 5 μm), 流动相为乙腈-水(30∶70), 等度洗脱, 流速1 mL·min-1, 检测波长为270 nm, 柱温35 ℃, 进样量20 μL。
线性关系考察  精密吸取不同体积的芹菜素储备液于量瓶中, 用甲醇定容, 配制成2.5、5、10、20、40、80、160 μg·mL-1的系列芹菜素对照品溶液。按色谱条件进样, 以芹菜素峰面积(Y) 对质量浓度(X) 进行线性回归。
芹菜素包合物的制备  精密称量一定量β-环糊精于研钵, 加入适量水溶解。精密称量一定量芹菜素, 溶于一定量无水乙醇, 将所得芹菜素乙醇溶液加入含β-环糊精水溶液的研钵中, 充分研磨一定时间后, 放入烘箱45 ℃烘干, 用钢勺将干燥粉末刮下, 用10 mL乙酸乙酯洗涤两遍, 于通风橱中干燥后即得。
设计正交试验  选择影响芹菜素包合物包封率的3个主要因素, 即药物与环糊精摩尔比为2∶1、1∶1、1∶2, 环糊精浓度为5%、10%、20%, 研磨时间时间30、60、90 min。以包合物包封率为考察指标, 根据正交试验筛选最优处方。
芹菜素包合物包封率测定  将乙酸乙酯洗涤2次得到的芹菜素包合物, 用甲醇定容, 参考色谱方法测得浓度。根据公式(1) 计算包封率:
$\text { 包封率 (%) }=\text { 包封的药物量/投药量 } \times 100 \%$
芹菜素包合物性质评价
薄层色谱分析  分别精密称量一定量的芹菜素包合物、芹菜素、芹菜素和β-环糊精的物理混合物, 分别溶于无水乙醇制得3种溶液。分别吸取上述3种溶液各2 μL点于同一硅胶板上, 以二氯甲烷-甲醇(20∶1, v/v) 为展开剂展开后取出, 将硅胶板完全浸没于10%硫酸溶液3 s, 取出, 于烘箱中烘干。
X射线衍射分析  分别称取少量的芹菜素、β-环糊精、芹菜素和β-环糊精的物理混合物以及芹菜素包合物粉末进行X射线衍射分析。
芹菜素包合物DPPC脂质体干粉吸入剂制备  采用薄膜分散和冷冻干燥技术制备芹菜素包合物DPPC脂质体干粉吸入剂。称取适量DPPC、胆固醇, 加入乙醚与乙醇(1∶15) 混合溶液使溶解, 于60 ℃旋转蒸发器上蒸发1 h, 加入含有芹菜素包合物和甘露醇的磷酸盐缓冲溶液(PBS, pH 7.4) 水化30 min, 超声15 min, 即得芹菜素包合物DPPC脂质体。冷冻干燥48 h, 过200目不锈钢标准筛制备得芹菜素包合物DPPC脂质体干粉吸入剂。
芹菜素包合物DPPC脂质体干粉吸入剂性质评价
粒径及zeta电位  用纳米激光粒度仪对芹菜素包合物DPPC脂质体的粒度和zeta电位进行测定, 温度为25 ℃, 体积为1 mL, 每份样品平行测定3次。
形态  取1 mL芹菜素包合物DPPC脂质体用纯化水稀释1 000倍, 吸取5 μL滴至铜网上, 用滤纸吸去多余液体, 滴加体积分数5%磷钨酸溶液(pH 7.0) 负染, 吸去多余负染液, 室温下自然风干, 使脂质体粒子在铜网上浓缩沉积, 在透射电镜下进行观测并拍照。
粉体学性质  粉末粒径和形态观察: 取3份芹菜素包合物DPPC脂质干粉吸入剂, 用激光粒度仪测定粒子几何粒径(De)。用牙签将干粉吸入剂涂布在双面导电胶并固定的金属板上。以电子束40 mA, 20 min喷金制备可用于扫描电镜观察的样品, 在5.0 kV电压条件下观察待测样品的形态、大小等指标。
流动性  将粉末通过下孔径为5 mm的玻璃漏斗, 从10 cm的高度缓慢、均匀地落入平板上, 形成圆锥体。测量圆锥体的高度(h) 和基底的半径(r), 根据公式(2) 计算休止角(θ):
$\tan \theta=h / r$
振实密度称  取3份干粉吸入剂, 记录质量(W), 置于5 mL量筒中, 将量筒从5 cm高度落下, 反复振实7次, 读取粉末体积(V), 根据公式(3) 计算振实密度(ρtap):
$\rho_{\text {tap }}=W / V$
理论的空气动力学粒径  根据测得粒子几何粒径, 振实密度, 根据公式(4) 计算理论空气动力学粒径:
$D_{\mathrm{a}}=D_{\mathrm{e}}\left(\rho_{\operatorname{tap}} / \rho_0 X\right)^{1 / 2}$
其中, Da和De分别为空气动力学粒径和几何学粒径; ρtap为颗粒密度, 可以用最紧松密度代替即为振实密度, ρ0为参照密度, 等于1 g·cm-1, X为动态形态因子(球形时X = 1)。
包封率和载药量  精密量取芹菜素包合物DPPC脂质干粉吸入剂10 mg, 纯化水复溶, 加入预先溶胀的葡聚糖凝胶G-25色谱柱中分离, 顶部加纯化水洗脱, 收集洗脱液, 每管2 mL, 分别加入无水乙醇定容至10 mL, 参考色谱方法测得浓度。根据公式(1) 计算包封率, 根据公式(5) 计算载药量:
$\;\;\;\;\;\;\;\;载药量 = 包封的药物量/载药包合物 \mathsf{DPPC} 脂质\\干粉吸入剂总质量 × 100 \%$
肺部沉积率的测定  仪器气流速度设定为60 L·min-1, 分别称取20 mg芹菜素包合物DPPC脂质干粉吸入剂装入3号羟丙甲纤维素胶囊中, 然后取上述胶囊10粒, 逐粒置于药粉吸入器内, 连续吸入10粒, 每次10 s, 停泵后打开测定仪, 用20 mL纯化水清洗每个接收盘[装置、喉部、1~7级和微孔收集器(micro orifice collector, MOC) 共10个接收盘], 连续2次, 合并后转入50 mL量瓶, 将量瓶中的液体用无水乙醇定容。参考色谱方法测定每个接收盘中芹菜素含量, 根据公式(6) 计算药物肺部沉积率(fine particle fraction, FPF):
$\;\;\;\;\;\;\;\;\mathrm{FPF}=2 \sim 7 级和 \mathsf{MOC} 粉末中芹菜素的质量/射出\\芹菜素的质量 \times 100 \%$
芹菜素包合物DPPC脂质干粉吸入剂体外释放  称取3份芹菜素包合物DPPC脂质干粉吸入剂, 装入透析袋(截留相对分子质量1 000) 中, 并加入人工肺液[30] 3 mL, 置于50 mL含0.2%聚山梨酯-80的人工肺液中, 37 ℃恒温振荡, 于0.5、1、2、4、7、24、48 h取透析袋外溶液1 mL, 13 000 r·min-1离心5 min, 并补充相同温度和体积的人工肺液。同法取3份芹菜素原料药, 释药方法同上。参考色谱方法, 直接测定介质中药物的量, 并根据释药量拟合释药方程0级、1级、Higuchi和Ritger-Peppas, 确定释药机制[31]。
Higuchi方程: Ft = kHt1/2。其中, Ft为释放率, kH为Higuchi释放速率常数, t为时间。
Ritger-Peppas方程: lnFt = nlnt + lnk。其中, k为常数, t为时间, n为扩散指数。
芹菜素包合物DPPC脂质干粉吸入剂体内药效试验  将大鼠分为5组, 每组6只, 构建大鼠急性重症肺炎模型[32]。因为大鼠的肺部承受能力有限, 通过预实验选择了10 mg制剂粉末作为大鼠可承受的最优实验剂量。利用喉镜暴露声门, 正常组通过注射软管往大鼠气管内注射0.9% NaCl溶液。模型组大鼠先气管内滴注LPS (1 mL·kg-1, 5 mg·mL-1) 制模。辅料组、原料药组和制剂组大鼠给药方法与模型组相同, 然后辅料组气管内喷入10 mg包合物DPPC脂质干粉, 原料药组喷入1 mg芹菜素原料药, 制剂组喷入10 mg芹菜素包合物DPPC脂质干粉吸入剂(含1 mg芹菜素)。24 h后处死大鼠, 切除左肺, 记录肺组织湿/干重比(W/D)。取右肺进行苏木精-伊红(hematoxylin-eosin, H & E) 染色, 并用光镜观察肺组织病理改变。
统计学方法  采用GraphPad Prism 8软件进行统计学分析。实验数据以均数±标准差表示。采用单因素方差分析(ANOVA), 以确定组间差异显著性, P < 0.05认为差异有统计学意义。
结果
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1　芹菜素含量测定
以芹菜素峰面积(Y) 对质量浓度(X) 进行线性回归, 得回归方程为Y = 103.33X - 90.636, r2 = 0.999 9, 结果表明芹菜素在2.5~160 μg·mL-1与峰面积的线性关系良好。
2　芹菜素包合物的处方筛选
以包合物包封率为考察指标, 选择药物与包合物的摩尔比(A)、环糊精浓度(B)、研磨时间(C) 为影响因素, 每个因素3个水平, 选用L9 (34) 正交表进行试验, 优化芹菜素包合物的处方工艺(表1) 和方差分析(表2)。各因素对包封率的影响次序为A > B > C, 各因素的最佳水平为A1B3C3, 即药物与环糊精的摩尔比2∶1、环糊精浓度20%、研磨时间90 min。按最优处方测得芹菜素包合物包封率为(89.56 ± 4.51)%, 载药量为(25.09 ± 1.26)%, 表明优选处方得到芹菜素包合物包封率高、工艺稳定。
3　芹菜素包合物性质评价
通过薄层色谱分析, 于日光下检视, 3种样品点样后, 芹菜素、物理混合物在相应位置上显相同黄色斑点, 而芹菜素包合物在对照品相应位置上无斑点, 表明芹菜素已被环糊精包合形成了芹菜素β-环糊精包合物。
从X射线衍射图(图1) 中可以发现物理混合物衍射峰呈现芹菜素和β-环糊精衍射峰叠加特征, 而芹菜素包合物的衍射峰不是二者的单纯叠加, 比较物理混合物和包合物图谱, 可以看到在包合物图谱中28~30°、38~40°、42~44°及48~50°的特征峰峰消失, 16~22°的衍射峰强度减弱, 表明形成了新的物相, 证实芹菜素包合物形成。
4　芹菜素包合物DPPC脂质体干粉吸入剂处方筛选
筛选不同质量比芹菜素包合物∶DPPC (1∶1、1∶2、1∶3) 的芹菜素包合物DPPC脂质干粉吸入剂处方, 通过外观、流动性和载药量综合比较(表3), 选择芹菜素包合物与DPPC质量比1∶2, 作为干粉吸入剂最优处方。
5　芹菜素包合物DPPC脂质体干粉吸入剂性质评价
芹菜素包合物DPPC脂质体和干粉吸入剂(图2A) 重构后外观均呈类球形(图2B、C), 为多囊结构, 粒度圆整, 分散较好。芹菜素包合物DPPC脂质体的平均粒径为198.6 ± 4.4 nm, 多分散指数(polydispersity index, PDI) 为0.3 ± 0.1, 载药脂质体的zeta电位为15.3 ± 2.1 mV (图2D、F)。芹菜素包合物DPPC脂质体干粉吸入剂重构后的粒径为221.6 ± 5.5 nm (图2E), 表明冻干工艺不破坏芹菜素包合物DPPC脂质体的结构, 不影响稳定性。DPPC脂质体与肺内表面活性物质同源, 更易携带药物通过肺表面活性物质层, 到达病灶。同时纳米级的粒径和高分散性有助于提高细胞或细菌对药物吸收, 提高药效。
芹菜素包合物DPPC脂质干粉吸入剂为白色疏松粉末(图3A)。扫描电镜下, 包合物作为载体, 干粉吸入剂形态为不规则的颗粒, 颗粒表面凹凸不平, 有空隙, 颗粒大小不一, 聚团在一起, 粒径大小约10 μm (图3B)。休止角是22.15 ± 2.33° (< 37.0°), 流动性好, 振实密度为0.32 ± 0.06 g·mL-1, 排空率为(98.7 ± 1.4)%, 雾化性质为B级, 这些性质都说明了芹菜素脂质粉末适合用于制备干粉吸入剂, 通过人主动吸进肺部, 到达细支气管, 不易被排出。在肺部深处肺泡腔中, 补充因病毒或细菌破坏的肺表面活性物质, 恢复其功能, 提高与外界气体交换。同时释放药物, 治疗肺部炎症。
粒子的几何粒径、密度和形状都会影响空气动力学粒径[33]。空气动力学粒径是影响药物沉积部位的最主要因素, 一般认为空气动力学粒径在1~5 μm的粒子可以到达肺深部[34]。激光粒度仪测得芹菜素包合物DPPC脂质体干粉吸入剂几何粒径为7.57 ± 1.36 μm, 量筒法测得振实密度为0.32 ± 0.06 g·mL-1, 从而计算出空气动力学粒径是4.28 ± 0.77 μm, 在1~5 μm内, 适合肺部吸入的标准。
按最优处方测得芹菜素包合物DPPC脂质干粉吸入剂载药量为(8.36 ± 0.42)%, 芹菜素包合物DPPC脂质干粉吸入剂再分散后的包封率(71.46 ± 3.18)%。
6　肺部沉积率的测定
采用NGI体外模拟药物吸入肺中分布, 芹菜素包合物DPPC脂质干粉吸入剂在2~7级以及MOC接收盘中FPF为43.02%, 明显高于芹菜素原料药9.67% (图4A), 空气动力学质量中直径(mass median aerodynamic diameter, MMAD) 为4.88 μm, 几何标准偏差(geometric standard deviation, GSD) 为2.2。普通的原料药无法满足肺吸入要求, 需要制备优化的芹菜素包合物DPPC脂质干粉吸入剂, 提高肺部沉积率, 满足干粉吸入剂给药要求。
7　芹菜素包合物DPPC脂质干粉吸入剂体外释放
在人工肺液中, 芹菜素包合物DPPC脂质干粉吸入剂同原料药相比, 溶解释放明显优于芹菜素原料药(图4B)。芹菜素包合物DPPC脂质干粉吸入剂的累积溶出度达到79%, 而芹菜素为9%。芹菜素包合物DPPC脂质干粉吸入剂释放24 h后, 累积释放达到74%。通过释放方程拟合, 芹菜素包合物DPPC脂质干粉吸入剂释放机制符合Ritger-Peppas释放模型(lnFt = 0.17lnt + 3.852 5, r2 = 0.868 6), 其中n是扩散指数, 反映了释放机制的类型, 即当n = 0.17 < 0.45, 表明药物释放以Fickian扩散为主。芹菜素包合物DPPC脂质干粉吸入剂释药特点证明能够有效提高原料药肺内的释药量和释放速度。
8　芹菜素包合物DPPC脂质干粉吸入剂体内药效试验
如图5A所示, 空白对照组大鼠肺呈鲜红色, 无水肿。双肺气管无挤压泡。模型组大鼠肺呈深红色, 挤出双肺气管流出泡沫状液体。肺体积明显增大。芹菜素组和芹菜素包合物DPPC脂质干粉吸入剂组大鼠肺颜色与模型量组相同, 但液体渗出量少于模型组。
模型组肺组织切片显示大范围水肿积液, 肺泡结构破坏, 肺泡或细支气管内有大量炎性细胞浸润。相比之下, 芹菜素包合物DPPC脂质干粉吸入剂组肺组织水肿明显减轻, 水肿液渗出量少于原料药组和模型组(图5B)。说明芹菜素包合物DPPC脂质干粉吸入剂改善芹菜素的溶解性, 提高药物扩散效果。
如图5C所示, 与模型组相比, 药物治疗组肺W/D比显著降低(P < 0.05)。芹菜素包合物DPPC脂质干粉吸入剂组降低肺W/D比的效果(3.27 ± 0.65) 优于原料药组(3.63 ± 0.92), 无显著性差异。芹菜素包合物DPPC脂质干粉吸入剂促进芹菜素肺内吸收, 提高药物局部治疗效果。原料药组降低肺W/D比的效果明显优于辅料组(P < 0.05)。说明辅料和制剂技术对提高药效都有作用, 虽然辅料对治疗效果有一定的帮助, 但还是不及来自于脂质的技术的增效大。芹菜素包合物DPPC脂质干粉吸入剂改善芹菜素的溶解性, 提高药物扩散效果, 促进芹菜素肺内吸收, 提高药物局部治疗效果。
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芹菜素是天然存在的一种黄酮类化合物, 其分子结构中具有3个酚羟基、α, β不饱和酮、环醚和芳环。抗病毒方面, 芹菜素具有作用温和、毒副作用小、多靶点、多功能等优势[11]。但芹菜素水溶性低、稳定性差、生物利用度低, 限制了其临床应用[35]。随着纳米技术、材料科学及中药新剂型等研究领域的学科交叉, 为芹菜素治疗急性重症肺炎带来了新的希望。
本研究利用低毒性的乙醇、乙醚作为溶剂, 高相容性肺表面活性物质DPPC作为载体, 通过薄膜分散法和冷冻干燥技术制备得到芹菜素包合物DPPC脂质干粉吸入剂。它的平均粒径为198.6 ± 4.4 nm, zeta电位为15.3 ± 2.1 mV。透射电镜下芹菜素包合物DPPC脂质体和干粉吸入剂复溶后外观均呈类球形, 粒度圆整, 分散较好, 表明冻干工艺不破坏芹菜素DPPC脂质体的结构, 不影响稳定性。按最优处方制备的芹菜素包合物DPPC脂质干粉吸入剂包封率为(71.46 ± 3.18)%, 载药量为(8.36 ± 0.42)%, 表明优选处方得到的芹菜素包合物DPPC脂质干粉吸入剂包封率高、工艺稳定。扫描电镜下, 芹菜素包合物DPPC脂质干粉吸入剂形态为疏松、不规则的颗粒。干粉吸入剂休止角(26.6 ± 6.7)° < 37.0°, 空气动力学粒径4.28 ± 0.77 μm, 排空率(98.7 ± 1.4)%, 雾化性质B级, 适合肺部吸入的标准。将DPPC与体内肺表面活性物质相结合是一种有效的递送药物的方式, 可以避免药物在肺表面活性物质层的隔离和降解, 提高药物递送的有效性, 到达病灶。同时纳米级的粒径和高度分散性有助于提高肺对药物的吸收, 更好地发挥治疗作用。
体外释放实验验证在人工肺液中芹菜素包合物DPPC脂质干粉吸入剂释放性能良好。与原料药相比, 芹菜素包合物DPPC脂质干粉吸入剂具有更好的释放行为, 24 h后, 累积释药达74%。释放方程拟合符合Ritger-Peppas模型, 表明药物释放以Fickian扩散为主, 有效提高原料药肺内的释药量和释放速度。
对芹菜素包合物DPPC脂质干粉吸入剂进行的体外肺部沉积研究结果表明, 芹菜素包合物与DPPC质量比为1∶2时, 制备得到的干粉吸入剂具有优良的粉末性质, 有助于药物在肺内不同部位的沉积。在60 L·min-1气流速度条件下, 药物肺部沉积率为43.02%, 明显优于原料药9.67%。分析原因, 可能由于原料药多为晶体结构相互吸附, 流动性欠佳, 易于聚集。最优处方制备的芹菜素包合物DPPC脂质干粉吸入剂更能满足吸入颗粒的要求, 易沉积在肺深部。
急性重症肺炎主要发病机制是病毒或细菌的感染, 引起过度失控的炎性反应和促炎抗炎反应失衡, 病变巨噬细胞释放促炎性因子IL-6和TNF-α等, 导致肺组织损伤、水肿、表面活性物质失活和透明膜形成[36]。体内研究发现, 与原料药相比, 芹菜素包合物DPPC脂质干粉吸入剂可有效对急性重症肺炎有较好的治疗效果。证明制备成包合物DPPC脂质干粉吸入剂能有效克服芹菜素生物利用度低、水溶性差的限制, 从而提高肺内药物利用, 发挥药效。本实验仅对芹菜素包合物DPPC脂质干粉吸入剂的制备和体内药效进行了相关研究, 而芹菜素体内抑制过度炎症导致的肺实质性损伤及其机制, 有待进一步研究。因此, 芹菜素包合物DPPC脂质干粉吸入剂有望成为治疗急性重症肺炎的有效制剂, 克服临床上无有效治疗的不利窘境。

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doi: 10.16438/j.0513-4870.2025-0407
  • 接收时间：2025-03-06
  • 首发时间：2026-09-21
  • 出版时间：2026-06-12
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  • 收稿日期：2025-03-06
  • 修回日期：2025-08-19
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    同济大学附属杨浦医院药学部, 上海 200090

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2种不同金属材料的力学参数
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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
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