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Article(id=1308840423439819524, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840287129141340, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0727, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1750953600000, receivedDateStr=2025-06-27, revisedDate=1765814400000, revisedDateStr=2025-12-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981474026, onlineDateStr=2026-09-21, pubDate=1775923200000, pubDateStr=2026-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981474026, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981474026, creator=13701087609, updateTime=1789981474026, updator=13701087609, issue=Issue{id=1308840287129141340, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='4', pageStart='1001', pageEnd='1434', issueExtLink='null', onlineDate='null', pubDate='1775923200000', pubDateStr='2026-04-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981441528, creator='13701087609', updateTime=1789984228828, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851977992368434, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840287129141340, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851977992368435, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840287129141340, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1380, endPage=1388, ext={EN=ArticleExt(id=1308840423662117637, articleId=1308840423439819524, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Study on leuprolide acetate sustained-release lipid-liquid crystalline gel modulated by lipase inhibitor-regulated lipid degradation, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

This study developed a sustained-release lipid liquid crystalline (LLC) system for leuprolide acetate (LA) and investigated the feasibility of using the lipase inhibitor orlistat (Orl) to modulate the matrix degradation and prolong the drug release period. The LA-LLC formulation was characterized by using polarized light microscopy (PLM), rheological analysis, and in vitro release studies to guide optimization. The impact of Orl on the sustained-release performance of LA-LLC was evaluated through in vitro degradation, in vitro release, and pharmacokinetic studies in rats. All animal protocols were approved by the Laboratory Animals Care and Use Committee of Yantai University (registration number is YTU20210319) (Yantai, China). Results showed that the LLC system utilizing glycerol dioleate (GDO) as the oil phase exhibited optimal sustained-release characteristics. The optimized LA-LLC formulation comprised soybean phosphatidylcholine, GDO, ethanol, and LA at a mass ratio of 44.5∶44.5∶10∶1. This gel exhibited a hexagonal phase structure by PLM. It demonstrated shear-thinning capacity characteristic of a pseudoplastic fluid. In vitro degradation and release results indicated that Orl significantly inhibited lipid degradation and prolonged drug release. Pharmacokinetic results in rats indicated that the addition of inhibitor Orl prolonged the release period from 42 days to 56 days compared to the LA-LLC group. This study demonstrates that the LA-LLC system, with its structural stability and controllable release, can effectively prolong drug release by employing a lipase inhibitor to regulate matrix degradation. The results of the study provide a novel strategy for the sustained delivery of peptide drugs.

, authors=Li JIANG1, Yue-li LIU1, Xiao-hu TANG2, Guang-yi LENG2, Ai-ping WANG1, *, authorsList=Li JIANG, Yue-li LIU, Xiao-hu TANG, Guang-yi LENG, Ai-ping WANG, authorCompany=null, correspAuthors=Ai-ping WANG, 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=1308840425306284820, articleId=1308840423439819524, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=脂肪酶抑制剂调控脂质降解驱动的醋酸亮丙瑞林缓释脂质液晶凝胶研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究构建了醋酸亮丙瑞林(leuprolide acetate, LA)脂质液晶(lipid liquid crystalline, LLC)长效递送系统, 并探讨通过脂肪酶抑制剂奥利司他(orlistat, Orl)调控基质降解延长释药周期的可行性。研究采用偏振光显微镜、流变学、体外释放等对LA-LLC进行表征以优化制剂处方, 通过体外降解和体外释放及大鼠体内药代动力学实验评价Orl对LA-LLC长效性的影响, 动物福利和实验过程均遵循烟台大学实验动物伦理委员会规定(批准号: YTU20210319)。结果显示以二油酸甘油酯(glycerol dioleate, GDO)为油相的LLC体系表现出最优缓释特性, LA-LLC的最优处方为大豆磷脂-GDO-乙醇-LA质量比44.5∶44.5∶10∶1, 偏振光显微镜显示该凝胶呈现六角相结构, 流变学行为表现为剪切稀化的假塑性流体; 体外降解与释药结果表明, Orl能够显著抑制脂质的降解并延缓药物释放; 大鼠体内药代动力学结果显示, 与LA-LLC组相比, 加入Orl后释药周期从42天延长至56天。研究表明, 所构建的LA-LLC系统结构稳定且释放可控, 通过脂肪酶抑制剂调控基质降解可有效延长药物释放周期, 为多肽类药物长效化研究提供了新策略。

, authors=姜莉1, 刘悦利1, 唐小虎2, 冷广意2, 王爱萍1, *, authorsList=姜莉, 刘悦利, 唐小虎, 冷广意, 王爱萍, authorCompany=null, correspAuthors=王爱萍, authorNote=

作者贡献:

姜莉和刘悦利负责实验操作、数据分析和论文撰写; 唐小虎负责指导实验设计、指导完善实验的进行和论文的修改; 冷广意负责药代动力学实验、数据分析; 王爱萍负责方案设计、论文结构及修改定稿、学术把关。

, correspAuthorsNote=
王爱萍, Tel: 18553503188, E-mail:
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A: Effect of different GMO ratios; B: Effect of different GDO ratios; C: Effect of different MCT ratios; D: Comparison of release profiles from LLC prepared with GMO, GDO, and MCT; E: Effect of different solvents; F: Effect of different drug loading. n = 3, x ± s, figureFileSmall=MLsWuga87deo5a2tmPKUWQ==, figureFileBig=3gq5Ycin/jJFcW3yDawjIA==, tableContent=null), ArticleFig(id=1308840429827744580, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840423439819524, language=EN, label=null, caption=null, figureFileSmall=lvK1TnuGjR4Enu55Tp9R2w==, figureFileBig=T93/dMG7KsuTiDKdgzqNWQ==, tableContent=null), ArticleFig(id=1308840431505466181, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840423439819524, language=CN, label=Fig.4, caption=Polarized light microscopy images of LLC formulations, figureFileSmall=lvK1TnuGjR4Enu55Tp9R2w==, figureFileBig=T93/dMG7KsuTiDKdgzqNWQ==, tableContent=null), ArticleFig(id=1308840431580963654, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840423439819524, language=EN, label=null, caption=null, figureFileSmall=HlkaWA8AAUN9bouTwtZpBQ==, figureFileBig=X3GgKan40x8+1paM9k9/kQ==, tableContent=null), ArticleFig(id=1308840431656461127, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840423439819524, language=CN, label=Fig.5, caption=Rheological behavior of LLC. 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A: Volume changes of LLC bulk depots in lipase buffer; B: Degradation behavior of LLC bulk depots in lipase buffer; C: The in vitro LA release in lipase buffer; D: Plasma concentration of LA after a single subcutaneous injection in rats. n = 3, x ± s, figureFileSmall=u5xONcN7IhAdcyTZ4SijUw==, figureFileBig=A39GsgCrPG6CB7JzHZrvgw==, tableContent=null), ArticleFig(id=1308840432054920012, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840423439819524, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Oil phasePC/OilEtOH/%H2O/%LA/%Orl/%
F1GMO4∶610/1/
F2GMO5∶510/1/
F3GMO6∶410/1/
F4GDO4∶610/1/
F5GDO5∶510/1/
F6GDO6∶410/1/
F7MCT4∶610/1/
F8MCT5∶510/1/
F9MCT6∶410/1/
F10GDO5∶515/1/
F11GDO5∶57.57.51/
F12GDO5∶510/0.5/
F13GDO5∶510/2/
F14GDO5∶510/11
), ArticleFig(id=1308840432122028877, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308840423439819524, language=CN, label=Tab.1, caption=

The proportion of each component in lipid liquid crystalline (LLC). PC: Phosphatidylcholine; LA: Leuprolide acetate; GMO: Glyceryl monooleate; GDO: Glycerol dioleate; MCT: Medium chain triglycerides

, figureFileSmall=null, figureFileBig=null, tableContent=
Oil phasePC/OilEtOH/%H2O/%LA/%Orl/%
F1GMO4∶610/1/
F2GMO5∶510/1/
F3GMO6∶410/1/
F4GDO4∶610/1/
F5GDO5∶510/1/
F6GDO6∶410/1/
F7MCT4∶610/1/
F8MCT5∶510/1/
F9MCT6∶410/1/
F10GDO5∶515/1/
F11GDO5∶57.57.51/
F12GDO5∶510/0.5/
F13GDO5∶510/2/
F14GDO5∶510/11
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脂肪酶抑制剂调控脂质降解驱动的醋酸亮丙瑞林缓释脂质液晶凝胶研究
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姜莉 1 , 刘悦利 1 , 唐小虎 2 , 冷广意 2 , 王爱萍 1, *
药学学报 | 研究论文 2026,61(4): 1380-1388
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药学学报 |研究论文 2026 , 61 (4) : 1380 -1388
脂肪酶抑制剂调控脂质降解驱动的醋酸亮丙瑞林缓释脂质液晶凝胶研究
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姜莉1, 刘悦利1, 唐小虎2, 冷广意2, 王爱萍1, *
作者信息
  • 1烟台大学药学院, 新型制剂与生物技术药物研究山东省高校协同创新中心, 分子药理和药物评价教育部重点实验室, 山东 烟台 264005
  • 2绿叶制药集团有限公司, 先进药物递释系统全国重点实验室, 山东 烟台 264003
通讯作者:
王爱萍, Tel: 18553503188, E-mail:
作者简介:

作者贡献:

姜莉和刘悦利负责实验操作、数据分析和论文撰写; 唐小虎负责指导实验设计、指导完善实验的进行和论文的修改; 冷广意负责药代动力学实验、数据分析; 王爱萍负责方案设计、论文结构及修改定稿、学术把关。

Study on leuprolide acetate sustained-release lipid-liquid crystalline gel modulated by lipase inhibitor-regulated lipid degradation
Li JIANG1, Yue-li LIU1, Xiao-hu TANG2, Guang-yi LENG2, Ai-ping WANG1, *
Affiliations
  • 1Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai 264005, China
  • 2State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co. Ltd., Yantai 264003, China
出版时间: 2026-04-12 doi: 10.16438/j.0513-4870.2025-0727
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摘要
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本研究构建了醋酸亮丙瑞林(leuprolide acetate, LA)脂质液晶(lipid liquid crystalline, LLC)长效递送系统, 并探讨通过脂肪酶抑制剂奥利司他(orlistat, Orl)调控基质降解延长释药周期的可行性。研究采用偏振光显微镜、流变学、体外释放等对LA-LLC进行表征以优化制剂处方, 通过体外降解和体外释放及大鼠体内药代动力学实验评价Orl对LA-LLC长效性的影响, 动物福利和实验过程均遵循烟台大学实验动物伦理委员会规定(批准号: YTU20210319)。结果显示以二油酸甘油酯(glycerol dioleate, GDO)为油相的LLC体系表现出最优缓释特性, LA-LLC的最优处方为大豆磷脂-GDO-乙醇-LA质量比44.5∶44.5∶10∶1, 偏振光显微镜显示该凝胶呈现六角相结构, 流变学行为表现为剪切稀化的假塑性流体; 体外降解与释药结果表明, Orl能够显著抑制脂质的降解并延缓药物释放; 大鼠体内药代动力学结果显示, 与LA-LLC组相比, 加入Orl后释药周期从42天延长至56天。研究表明, 所构建的LA-LLC系统结构稳定且释放可控, 通过脂肪酶抑制剂调控基质降解可有效延长药物释放周期, 为多肽类药物长效化研究提供了新策略。

醋酸亮丙瑞林  /  脂质液晶凝胶  /  脂肪酶抑制剂  /  处方优化  /  缓释

This study developed a sustained-release lipid liquid crystalline (LLC) system for leuprolide acetate (LA) and investigated the feasibility of using the lipase inhibitor orlistat (Orl) to modulate the matrix degradation and prolong the drug release period. The LA-LLC formulation was characterized by using polarized light microscopy (PLM), rheological analysis, and in vitro release studies to guide optimization. The impact of Orl on the sustained-release performance of LA-LLC was evaluated through in vitro degradation, in vitro release, and pharmacokinetic studies in rats. All animal protocols were approved by the Laboratory Animals Care and Use Committee of Yantai University (registration number is YTU20210319) (Yantai, China). Results showed that the LLC system utilizing glycerol dioleate (GDO) as the oil phase exhibited optimal sustained-release characteristics. The optimized LA-LLC formulation comprised soybean phosphatidylcholine, GDO, ethanol, and LA at a mass ratio of 44.5∶44.5∶10∶1. This gel exhibited a hexagonal phase structure by PLM. It demonstrated shear-thinning capacity characteristic of a pseudoplastic fluid. In vitro degradation and release results indicated that Orl significantly inhibited lipid degradation and prolonged drug release. Pharmacokinetic results in rats indicated that the addition of inhibitor Orl prolonged the release period from 42 days to 56 days compared to the LA-LLC group. This study demonstrates that the LA-LLC system, with its structural stability and controllable release, can effectively prolong drug release by employing a lipase inhibitor to regulate matrix degradation. The results of the study provide a novel strategy for the sustained delivery of peptide drugs.

leuprolide acetate  /  lipid liquid crystalline gel  /  lipase inhibitor  /  formulation optimization  /  sustained-release
姜莉, 刘悦利, 唐小虎, 冷广意, 王爱萍. 脂肪酶抑制剂调控脂质降解驱动的醋酸亮丙瑞林缓释脂质液晶凝胶研究. 药学学报, 2026 , 61 (4) : 1380 -1388 . DOI: 10.16438/j.0513-4870.2025-0727
Li JIANG, Yue-li LIU, Xiao-hu TANG, Guang-yi LENG, Ai-ping WANG. Study on leuprolide acetate sustained-release lipid-liquid crystalline gel modulated by lipase inhibitor-regulated lipid degradation[J]. Acta Pharmaceutica Sinica, 2026 , 61 (4) : 1380 -1388 . DOI: 10.16438/j.0513-4870.2025-0727
正文
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醋酸亮丙瑞林(leuprolide acetate, LA)作为促性腺素释放素类似物, 用于治疗前列腺癌及子宫内膜异位症等[1], 其在体内易降解并被快速清除, 半衰期较短, 限制了其临床应用。因此, 开发其长效递送系统是药剂学领域的热点。目前, LA长效递药系统的研究已取得显著进展。其中, 基于聚乳酸-羟基乙酸共聚物[poly (lactic-co-glycolic acid), PLGA] 微球贮库技术的注射剂(如Lupron Depot®)已成功应用于临床, 能够实现单次注射长达1个月的药物持续释放[2]。LA原位凝胶制剂也展现出至少1个月的长效递送[3]。然而, 当前LA长效制剂的开发仍面临一些挑战: 如由于微球的物理刺激及有机溶剂可能会引发注射部位疼痛[4]; 单次给药体积过大, 3个月微球剂型单次注射体积可达2.0~2.5 mL[5]; 以及PLGA降解产生的局部酸性微环境影响多肽的稳定性, 显著降低生物利用度[6]; 凝胶制剂仅可实现1个月的释药周期等。基于此, 需要进一步开发LA新型递送系统, 以优化释放动力学与生物相容性。
脂质液晶(lipid liquid crystalline, LLC)是由两亲性脂质分子(如甘油酯、磷脂)在水相中自发形成的有序结构, 常见的晶型包括层状液晶、立方状液晶、六角状液晶等[7], 具有普适性药物适配能力、可控缓释、生物相容性和可降解性等优势。由于其独特的自组装结构与功能特性, 已经成为药物缓释递送领域备受关注的研究方向[8]。LLC适用于各种疏水和亲水小分子、多肽、蛋白质等多类药物的长效递送[9]。目前, 关于LLC递送系统的研究已取得一定进展, 多种两亲性脂质分子包括二油酸甘油酯(glycerol dioleate, GDO)、植烷甘油酸酯(phytanyl glycerate, PG)、单油酸甘油酯(glyceryl monooleate, GMO)等, 可在水性介质中自组装形成有序微观相结构[10]。LLC临床应用代表产品如丁丙诺啡长效皮下注射剂(Buvidal®)[11]能够实现每周或每月一次的给药频率; Long等[12]开发了一种由大豆磷脂酰胆碱(phosphatidylcholine, PC)、中链甘油三酯(medium chain triglycerides, MCT)和乙醇组成的可注射凝胶体系, 该体系在体外呈溶液状态, 皮下注射后原位凝胶化, 能够实现LA长达28天的持续释放。
尽管LLC凭借其分子结构中酯键的酶促水解敏感性, 在生物医学应用中展现出独特优势: 其可被体内脂肪酶(如胰脂肪酶、酯酶)特异性识别并催化降解, 形成生物触发式药物释放机制, 赋予载体良好的生物相容性与释放启动可控性; 然而, 这种水解敏感性也成为制约其长效缓释性能的关键因素[13]。生理环境下, 酯键的快速酶解会破坏LLC结构的完整性, 继而引起基质降解, 从而使药物释放。这通常使缓释周期局限在一个月以内, 难以满足对药物释放超过一个月的临床需求。奥利司他(orlistat, Orl)是一种有效的脂肪酶抑制剂, 能够通过β-内酯环与脂肪酶活性中心的丝氨酸残基发生不可逆的共价结合抑制酯键的水解作用[14]。Dully等[15]研究表明, Orl通过共价结合胰脂肪酶的活性位点, 有效抑制其对GMO脂质立方相的酶促降解作用, 使脂质基质的稳定性提升4倍以上。这种抑制作用显著延缓了疏水性药物(氯法齐明盐)从立方相中的释放, 将药物释放周期从数天延长至数周, 实现了通过调控基质降解速率来控制药物释放的目的。
本研究旨在构建基于脂肪酶抑制剂修饰的LA-LLC长效递送系统, 通过抑制基质中酯键的酶促水解速率, 突破传统LLC缓释周期的限制, 实现药物长达1个月以上的可控释放。本研究采用了3种基于甘油的LLC系统: GMO、GDO和MCT, 以及不同比例的大豆磷脂和溶剂, 制备了LA的LLC缓释制剂, 并通过引入脂肪酶抑制剂Orl调节LLC基质的降解动力学, 最终实现对药物释放的长效调控。
材料与方法
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试剂   醋酸亮丙瑞林(24071502, 威海润辉生物技术有限公司); 大豆磷脂(579010-1240148-05/713, 山东冠特生物工程有限公司); GMO、GDO (230614-P、241008-10, 璟熙医药科技深圳有限公司); MCT (0001926038, 禾大集团有限公司); 乙醇(20240806, 国药集团化学试剂有限公司); 乙腈(色谱级, 阿达玛斯试剂有限公司); 奥利司他、胰脂肪酶(B2521048、J2430527, 上海阿拉丁生化科技有限公司)。
仪器   流变仪(HAAKE MARS40, 赛默飞世尔科技公司); 电子天平(XPE204, 上海梅特勒-托利多仪器有限公司); 偏振光显微镜(XPL-3230, 上海梓梦科技有限公司); 超纯水机(MIQ 7000, 上海默克化工技术有限公司); 多点磁力搅拌器(RO 10, 德国IKA公司); pH计(S210, 梅特勒托利多集团); 水浴振荡器(SW22, 优莱博技术有限公司); 高效液相色谱仪(1260, 安捷伦科技有限公司)。
动物   SPF级雄性Wistar大鼠(8~10周龄, 260 ± 20 g), 购自山东朋悦实验动物繁育有限公司, 提供自由摄食和饮水条件, 饲养环境保持12 h光暗循环, 温度控制在22 ± 2 ℃, 相对湿度(50 ± 10)%。实验动物质量合格证编号: SCXK (京) 2021-0011; 并符合《中华人民共和国卫生部动物管理办法》 (2001年第55号文件)及《实验动物护理原则》 (NIH出版物第85-23号, 1985年修订)的相关规定。所有动物实验均严格经烟台大学动物实验伦理委员会批准(No.: YTU20210319)。
LLC前体溶液和储库的制备   将LA与不同比例的大豆磷脂溶解在乙醇中, 300 r·min-1搅拌1 h, 随后按表1加入处方量的GMO、GDO或MCT及其他处方组分, 继续搅拌以形成LLC前体溶液。同时, 分别配制仅含LA的LA-LLC、仅含Orl的Orl-LLC, 以及同时含有LA与Orl的LA-Orl-LLC前体溶液。所有样品均在测试前24 h制备。将LLC前体溶液缓慢注入水中, 原位形成LLC凝胶储库, 拍照并记录其形态特征。
LA-LLC体外释放行为   参考文献[16]中的方法, 称取Tween 80于PBS缓冲液(pH 7.4)中搅拌溶解, 配制成含0.1% Tween 80的释放介质溶液。精密称取LLC样品100 mg, 加入100 mL释放介质中, 置37 ℃、70 r·min-1恒温水浴振荡器中, 每个处方平行3份。分别于4 h和1、3、5、8、11、14、17、21、24、28天, 取4 mL作为供试液, 同时补充4 mL相同温度的新鲜释放介质。供试液经微孔滤膜过滤后HPLC测定浓度, 根据公式(1)和(2)计算累积释放度:
$ R_{n}\% = (C_{n} × 100 - C_{n-1} × 96) × 100\%/ (m × W)$
$ AR_{n}\% = AR_{n-1}\% + R_{n}\% $
其中, Cn、Cn-1第n、n-1时间点取样的供试品质量浓度(mg·mL-1); Rn为释放度; ARn为累积释放度; m为LLC质量(mg); W为载药量。
LA液相色谱条件   色谱柱: Agilent C18柱(250 mm × 4.6 mm, 5 μm); 流动相: 0.5%磷酸缓冲液-乙腈(75∶25); 柱温: 50 ℃; 检测波长: 220 nm; 流速: 1.5 mL·min-1; 进样量: 20 μL。
偏振光显微镜观察   采用偏振光显微镜表征制剂接触水性介质后的液晶相态。吸取约20 μL LLC前体溶液加到载玻片中央, 滴加1 mL纯化水, 覆盖盖玻片轻压使样品均匀铺展, 吸除多余水分。然后在交叉偏振光下进行观察, 分析液晶相态结构特征, 并进行图片采集。
流变学考察   采用流变仪分别研究LA-LLC、Orl-LLC与LA-Orl-LLC的流变性质。LLC前体溶液的流变学测量: 取适量样品于流变仪检测平台上, 以稳定剪切速率扫描(0.1~1 000 s-1)对F5处方的黏度进行测量。LLC储库的流变学测量: 在应变控制模式下, 样品间隙为1 mm, 频率范围为0.062 8至628 rad·s-1, 考察制剂的稳态黏度(η), 以及储能模量(G′)和损耗模量(G″)。所有测试均在25 ℃恒温条件下进行测量。
可注射性考察   为了评估制剂通过注射器成功给药的可行性, 通过使用21 G注射器抽吸/排出来评估可注射性。
含酶缓冲液的配制   缓冲液的配制: 配制含0.2 mol·L-1 Tris-HCl和2 mmol·L-1 CaCl2的溶液, 调节pH至7.4, 置于4 ℃冰箱备用。含酶缓冲液的配制: 将胰脂肪酶溶解于上述缓冲液中, 磁力搅拌20 min, 待酶充分溶解后, 以1 500 r·min-1, 4 ℃的条件离心5 min, 收集上清液以获得澄清的酶缓冲液。整个制备过程在冰浴条件下进行, 以避免酶的变性或过早活化。
LA-LLC和LA-Orl-LLC体外降解实验   将100 μL LA-LLC和LA-Orl-LLC的前体溶液注入15 mL含酶缓冲液中, 置于37 ℃、70 r·min-1恒温水浴振荡器中振荡孵育, 每组平行3份。注射后溶液原位形成凝胶储库。在预设时间点(1、3、6、10、14、18、21天)取出储库, 用纯化水冲洗以去除表面沉积的残留盐, 吸干样品表面多余水分后使用分析天平称重。根据公式(3)和(4)计算降解率和残留重量:
$\text {降解率}(\%)=\left(W_i-W_t\right) / W_i \times 100 $
$ \text {残留重量}(\%)=100 \%-\text {降解率} $
其中, Wi和Wt分别为样品的初始重量和最终重量。
LA-LLC和LA-Orl-LLC体外释放实验   精密称取LA-LLC和LA-Orl-LLC的前体溶液100 mg, 加入100 mL含酶缓冲液中, 每组平行3份, 置于37 ℃、70 r·min-1恒温水浴振荡器中。在预设时间点(2 h、1、3、6、10、14、18、21天)取出4 mL作为供试液, 同时补充相同温度的释放介质4 mL, 放回振荡器中继续振荡, 供试液经微孔滤膜过滤后HPLC测定浓度。
LA-LLC和LA-Orl-LLC药代动力学实验   选取体重260 ± 20 g的健康雄性Wistar大鼠, 随机分为两组, 每组3只, 含1%抑制剂Orl的LA-Orl-LLC组和未添加Orl的LA-LLC组, 以2 mg·kg-1剂量单次皮下注射给药。于给药后0.5、1、2、4、6 h和1、3、5、7、10、14、18、21、25、28、56天, 经大鼠眼眶后静脉丛采集0.5 mL血液, 收集至预先加入5 μL 50 TIU·mL-1抑肽酶和5 μL肝素的离心管中。样品于4 ℃条件下以4 000 r·min-1离心15 min, 分离血浆后将上清液保存于-80 ℃的冰箱, 采用超高效液相色谱-串联质谱测定血药浓度。使用Phoenix WinNonlin软件以非房室分析(noncompartmental analysis, NCA)方法计算药代动力学参数。
统计学分析   采用GraphPad Prism软件进行统计分析。体内药代动力学数据均以均值±标准差(x ± s)表示。两组间比较采用非配对t检验, P < 0.05表示差异具有统计学意义。
结果
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1　LLC储库的形成
LLC前体溶液与水相接触后的凝胶化结果如图1所示, GDO与磷脂可自发形成结构稳定的球状凝胶储库; GMO虽可与磷脂发生自组装行为, 但与GDO体系相比, 其在介质中形成的凝胶储库形状不规则; 而以MCT为油相的LLC体系注入介质后迅速分散。脂质的结构会影响脂质液晶的相态, 根据化合物结构(图2)分析, GMO分子因含有两个游离羟基而呈现强两亲性, 易与大豆磷脂形成高流动性层状相或水通道发达的立方相, 而其结构易受乙醇增溶破坏[17]。MCT虽具有强亲脂性, 但缺乏自组装能力, 难以构建稳定的凝胶结构, 同样不利于缓释效果的实现[18]。GDO的结构和磷脂的结构相似, 都含有两条疏水尾链, GDO凭借双疏水链和单极性头基的结构特性, 与磷脂排列更有序, 更易形成结构稳定的液晶结构, 该特性使其成为实现长效缓释的理想载体。
2　LA-LLC体外释放结果
LA-LLC体外释放曲线如图3所示。首先, 不同油相对LA-LLC的体外释放产生显著影响。图3A~D显示, GMO组在初始阶段即完全释放药物, 无缓释作用; GDO组呈现明显的缓释特性, 尤其是磷脂与GDO比例为5∶5时缓释效果最佳, 且4 h初始释放仅为(7.7 ± 1.3)%; MCT组则存在较高的初始释放, 磷脂: MCT为5∶5时的初始释放为(40.0 ± 3.5)%, 后呈现缓慢释放特征。因此, 本研究选择GDO作为LLC制剂的油相组分, 其双疏水链结构能与磷脂形成更紧密的分子排列, 有效延长药物释放周期[19]。
溶剂组成作为关键处方变量, 显著调控药物的释放行为(图3E)。溶剂为15%的乙醇时28天累积释放度达(88.3 ± 3.78)%, 而同时间10%乙醇的制剂累积释放度仅为(62.2 ± 2.2)%, 释放速率显著降低。其作用机制在于乙醇分子破坏脂质分子有序排列并降低体系黏度, 导致凝胶化时间延长及结构稳定性降低[20]。此外, 当固定溶剂总量为15%, 将其中7.5%乙醇替换为水时, LA释放减慢, 28天累积释放度为(73.8 ± 7.32)%, 这是由于水分子通过促进脂质分子有序组装, 形成更致密的分子网络结构, 同时使体系黏度增加, 形成更利于缓释的凝胶储库[21]。这减少了乙醇对脂质结构的破坏, 延长药物扩散路径, 从而降低释放速率并提升缓释性能。载药量筛选结果表明(图3F), 不同载药量会影响药物的释放动力学特征。其中, 1%载药量在有效控制突释效应的同时能够维持理想的缓释特性, 因此被选为本研究的最佳处方。
3　偏振光显微镜观察
偏振光显微镜是表征液晶相结构的常用方法, 通过特征纹理形态可区分不同相态。在偏振光照射下, 没有光学双折射的暗视野指示各向同性液体或反相立方相(reverse cubic phase, QⅡ), 而具有光学双折射纹理的一般为层状相(lamellar phase, Lα)或反相六角相(reverse hexagonal phase, HⅡ), 其中油状条纹及马耳他十字形为层状相的特征形貌, 扇形纹理则指示六角相的形成[22]。
偏振光显微镜表征结果如图4所示, 不同脂质体系呈现显著相态差异: GMO与MCT体系主要形成层状相或立方相, 而GDO体系则能形成反相六角相(F5)。这种相结构差异直接影响了药物释放行为, 如图3D所示, 从六角相LLC中释放的LA表现出更平缓的释放动力学, 其累积释放度显著低于立方相与层状相的GMO和MCT体系。在GDO体系中, 液晶相随组成变化而发生转变: 当磷脂与GDO比例为4∶6时, 暗场视野特征表明立方相的形成; 当比例升高至5∶5时, 体系转变为反相六角相; 而磷脂与GDO比例为6∶4时, 六角相特征不明显, LLC在偏光下呈现六角相和层状相结合的混合相。此结果表明LLC的相结构对药物的扩散速率有十分重要的影响, LA从LLC中扩散出来的速率具有以下规律: 六角相 > 立方相 > 层状相[23]。
溶剂的组成也显著影响相结构: 溶剂为10%乙醇时(F5), LLC呈六角相, 呈现高度有序的放射状扇形纹理, 是典型的六角状液晶相。这种紧密堆积结构通过延长药物扩散路径及降低水分渗透率, 显著延缓药物释放, 与体外释放结果相符。当乙醇比例升高至15%时, 体系从高度有序的六角相转变为层状相(F10), 从而导致LA释放速率明显加快(图3E)。这种相变源于乙醇可以通过氢键作用结合两亲性分子的头基, 扩大有效头基面积, 促进低曲率相态如层状相的形成, 其亲水结构可能会吸收更多的水分, 使含水量增加, 水通道扩大, 不利于药物的长效释放。而溶剂为7.5%乙醇和7.5%水的LLC (F11)呈现六角相与立方相共存的结构, 明显改善了乙醇含量过高对相结构的破坏的现象, 降低LA释放速率。此外, 载药量的不同也对LLC的相结构有一定的影响: 当载药量为1%~2%时, 体系形成高度有序的六角相, 而0.5%低载药量组(F12)则呈现六角相与立方相混合的松散分子排列, 证实载药量通过改变相有序性影响药物扩散动力学。
4　流变学测量
采用流变仪通过剪切应力-剪切速率关系评估了LLC前体溶液的黏度。如图5A所示, 应力在1~1 000 Pa, LA-LLC、Orl-LLC与LA-Orl-LLC前体溶液均表现出显著的剪切稀化行为, 符合假塑性流体特征, 表明其具备良好的可注射性, 能够顺利从注射器中推出[24]。当前体溶液与水性介质接触后, 脂质分子发生自组装并有序堆积, 迅速形成LLC凝胶储库。通过振荡频率扫描对该凝胶体系的黏弹性进行表征(图5B、C), 储能模量(G′)始终高于损耗模量(G″), 即损耗正切(tanδ = G″/G′)小于1, 证明体系已由液态转变为以弹性行为主导的凝胶状态[25], 表明凝胶储库具有良好的形状保持能力与稳定性, 是实现药物长效缓释的基础。
5　可注射性考察
LLC前体溶液展现出优异的可注射性能(图6), 该溶液可通过21 G规格的针头顺利挤出, 且在推注过程中无需施加过大压力, 体现出适宜的流变学特性与针头通过性。
6　LA-LLC和LA-Orl-LLC的体外降解
在模拟生理环境的酶缓冲液中, LLC前体溶液原位形成凝胶储库后, 未添加脂肪酶抑制剂Orl的LA-LLC组与含1% Orl的LA-Orl-LLC组的体积与质量变化呈现显著差异。如图7A所示, LA-LLC组凝胶储库在14天内发生明显结构崩解, 其直径由初始14.0 ± 0.3 mm缩减至9.2 ± 0.5 mm, 表明脂质基质受到脂肪酶的持续水解侵蚀。而LA-Orl-LLC组凝胶储库在整个观察期内保持结构完整性, 储库大小无明显变化。定量分析进一步证实了Orl对脂质降解的抑制作用, 如图7B降解动力学曲线所示, LA-LLC组6天时储库降解约50%, 而同一时间LA-Orl-LLC组的质量损失较小。至21天时, LA-LLC组完全降解, LA-Orl-LLC组仍保留(58.8 ± 2.1)%的残留重量(降解率41.2%)。研究结果表明Orl可有效阻断酶对脂质分子酯键的水解作用, 从而显著延缓LLC基质的降解速率, 为维持结构完整性和实现更长效缓释提供了保障。
7　LA-LLC和LA-Orl-LLC的体外释药结果
LA-LLC与LA-Orl-LLC在含脂肪酶缓冲液中的体外释放结果如图7C所示, 两组在释药初期均表现出约8%的初始释放, 这归因于凝胶表面药物的溶解。随后, 脂肪酶介导的基质降解逐渐成为影响释放行为的主要因素。LA-LLC组因介质中的脂肪酶持续水解凝胶基质中脂质分子的酯键, 导致基质结构崩解, LLC凝胶储库中的药物更快溶出。而LA-Orl-LLC组因Orl抑制了凝胶基质的降解, 从而呈现缓慢的体外释放。至21天时, LA-LLC组的累积释放度达(89.0 ± 4.2)%, 而LA-Orl-LLC组仅为(58.7 ± 2.6)%, 表明Orl通过抑制基质降解有效调控了药物的释放行为。由以上结果可知, 脂肪酶抑制剂Orl的加入可以有效抑制凝胶基质的降解, 从而更长周期维持LLC的六角相有序结构, 药物需通过更长的扩散路径释放, 同时致密的相结构降低了水分渗透进入内部, 共同促成缓释效应。
8　LA-LLC和LA-Orl-LLC药代动力学结果
LA-LLC和LA-Orl-LLC大鼠皮下注射后血药浓度-时间曲线如图7D所示, LA-LLC组在给药后1 h内突释达125.1 ng·mL-1, 随后血药浓度逐渐下降, 维持约42天的平稳释放。LA-Orl-LLC组给药后突释显著降低至57.4 ng·mL-1, 并维持释药周期长达56天(56天时血药浓度为0.09 ng·mL-1), 表明其提供了更持久的有效药物暴露。药代动力学参数结果显示, LA-Orl-LLC组在给药后的血药浓度突释(Cmax)显著低于LA-LLC组, 较低的Cmax可能有助于减轻LHRH激动剂常见的初始不良反应, 即睾酮激增[26], 从而有望提升患者的用药安全性和耐受性。LA-LLC的消除半衰期(t1/2)为122.15 ± 22.86 h, 而含抑制剂的LA-Orl-LLC组的t1/2显著延长至347.95 ± 26.7 h。此外, LA-Orl-LLC组和LA-LLC组AUC0-∞值分别为3 146.7 ± 203.25和3 401.1 ± 482.3 h·ng·mL-1 (P < 0.05)。研究结果表明, 在LLC体系中添加脂肪酶抑制剂Orl能有效降低突释, 显著延长LA的消除半衰期, 并将其体内有效释放周期从42天延长至56天。
讨论
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本研究成功构建了基于LLC的LA长效递送体系。在研究中发现, GDO与磷脂比例为5∶5时, 在水性介质中能自发形成稳定的六角相结构, 相较于GMO/MCT体系展现出更优的缓释性能。经多维度处方优化确立的最佳配比(磷脂/GDO/乙醇/LA = 44.5∶44.5∶10∶1)兼具假塑性流变特性与结构稳定性。值得注意的是, 由于LLC的酯键在生理条件下易被脂肪酶水解, 导致结构破坏与药物突释, 从而限制其长效缓释性能。通过引入脂肪酶抑制剂Orl, 不可逆抑制脂肪酶活性, 显著延缓了脂质基质的降解速率; 体外实验证明, Orl能有效维持LLC储库结构稳定, 并显著降低LLC的降解行为和LA累积释放度; 更将血药浓度维持周期从42天延长至56天。综上, 本研究通过酶抑制策略, 构建了兼具结构稳定性与药物释放可控性的LA长效递送系统, 也为其他多肽类药物长效化提供一种高效、安全的递送解决方案。

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doi: 10.16438/j.0513-4870.2025-0727
  • 接收时间：2025-06-27
  • 首发时间：2026-09-21
  • 出版时间：2026-04-12
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  • 收稿日期：2025-06-27
  • 修回日期：2025-12-16
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    1烟台大学药学院, 新型制剂与生物技术药物研究山东省高校协同创新中心, 分子药理和药物评价教育部重点实验室, 山东 烟台 264005
    2绿叶制药集团有限公司, 先进药物递释系统全国重点实验室, 山东 烟台 264003

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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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