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Article(id=1308842107117338919, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2026-0096, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1769443200000, receivedDateStr=2026-01-27, revisedDate=1773590400000, revisedDateStr=2026-03-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981875446, onlineDateStr=2026-09-21, pubDate=1783785600000, pubDateStr=2026-07-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981875446, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981875446, creator=13701087609, updateTime=1789981875446, updator=13701087609, issue=Issue{id=1308841897058198067, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='7', pageStart='2377', pageEnd='2820', issueExtLink='null', onlineDate='null', pubDate='1783785600000', pubDateStr='2026-07-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981825365, creator='13701087609', updateTime=1789984154811, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851667525792021, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851667525792022, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2737, endPage=2745, ext={EN=ArticleExt(id=1308842107331248424, articleId=1308842107117338919, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Preparation and preliminary evaluation of rifapentine composite thermosensitive gel, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

It is difficult for anti-tuberculosis drugs to reach the tuberculous cavity lesions, and the effects of conventional oral or intravenous administration are not satisfactory. In this study, a rifapentine composite thermosensitive gel with poly (lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) as the gel matrix was developed for bronchoscopic pulmonary interventional therapy of pulmonary tuberculosis to enhance the targeted drug delivery treatment effect for pulmonary tuberculosis. An optimal formulation for rifapentine lipid microspheres was screened via orthogonal design. The lipid microspheres were then mixed with PLGA-PEG-PLGA solution to prepare a composite thermosensitive gel. The formulation was then characterized. The erosion of the in-situ gel was evaluated using a membrane-free method, while the in-vitro release and release mechanism were assessed by dialysis bag method. Uptake of the drug in the gel by A549 cells was observed using confocal microscopy. Antibacterial assays were assessed using lung tissue homogenates collected at various time points following a single administration, in order to investigate the pulmonary retention of the thermosensitive gel after intratracheal instillation in rats. All animal experimental procedures were approved by the Experimental Animal Ethics Committee of Hebei Medical University (No: IACUC-Hebmu-P 2022084) and carried out in accordance with its guidelines. The particle size of the prepared lipid microspheres was 482.4 ± 0.22 nm, which increased slightly after incorporation into the composite gel. The gelation temperature of the composite gel was 34.47 ± 0.15 ℃, with a gelation time of 41.33 ± 1.70 s. The formulation exhibited good injectability before gelation while showed a suitable viscosity at gelation temperature. The drug release model fitted with the Ritger-Peppas equation. The results of laser confocal microscopy showed that the lipid microspheres effectively delivered lipophilic drugs into lung epithelial cells. Antibacterial testing of lung tissue extracts confirmed that a single dose of the composite gel could sustain antibacterial activity in rat lungs for at least 14 days. The rifapentine lipid microsphere-thermosensitive gel composite formulation significantly enhances the solubility of rifapentine. Its temperature-dependent phase transition from liquid to gel not only ensures feasibility for bronchoscopic administration but also enables prolonged and effective drug release at the lesion site, thereby achieving the design goal of efficient local therapy for tuberculosis.

, authors=Zhi-qiang SONG, Yu-lin SUN, Zhuo-huan LI, Lan YANG, Jie-ning DUN*, authorsList=Zhi-qiang SONG, Yu-lin SUN, Zhuo-huan LI, Lan YANG, Jie-ning DUN, authorCompany=null, correspAuthors=Jie-ning DUN, 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=1308842108757311797, articleId=1308842107117338919, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=利福喷丁复合温敏凝胶的制备与初步评价, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

抗结核药物很难达到结核空洞病灶内, 常规的口服或静脉给药效果并不理想。本研究构建了一种以聚(DL-乳酸羟基乙酸-聚乙二醇) 共聚物为基质的利福喷丁复合温敏凝胶, 用于肺结核的支气管镜肺部介入治疗以提高肺结核靶向给药治疗效果。通过正交设计筛选利福喷丁脂微球最优处方, 将其与基质溶液混合制备复合温敏凝胶, 并对其进行表征。无膜法考察凝胶的溶蚀情况, 透析袋法评价其体外释放行为。共聚焦显微镜观察A549细胞对药物的摄取情况, 使用给药后不同时间点的肺组织提取液进行抑菌实验, 考察大鼠经气管插管给以温敏凝胶后肺部的滞留情况。所有动物实验程序均经河北医科大学实验动物伦理委员会批准(No: IACUC-Hebmu-P 2022084), 并遵循其指导方针进行。得到的脂微球粒径482.4 ± 0.22 nm, 制成复合凝胶后粒径略有增大, 复合凝胶的胶凝温度为34.47 ± 0.15 ℃, 胶凝时间为41.33 ± 1.70 s, 胶凝后具有适宜的黏度, 体外释放符合Ritger-Peppas动力学模型。脂微球能顺利递送脂溶性药物进入肺上皮细胞。单次给药后大鼠肺内的抑菌效果可持续14天。以上结果说明该制剂可在适宜温度下呈现液态与凝胶态的转变, 既保证了药物经支气管镜给药的可行性, 又能确保病灶部位长时间有效释药, 可以实现肺结核高效局部治疗的设计构想。

, authors=宋志强, 孙玉林, 李卓欢, 杨澜, 敦洁宁*, authorsList=宋志强, 孙玉林, 李卓欢, 杨澜, 敦洁宁, authorCompany=null, correspAuthors=敦洁宁, authorNote=

#

共同第一作者.

作者贡献:

宋志强完成实验补充并撰写论文初稿; 孙玉林完成实验操作及部分数据整理; 李卓欢参与数据整理及图表绘制; 杨澜参与稿件审阅与修改; 敦洁宁为本研究通讯作者, 统筹课题执行, 并对论文进行全面修改与定稿。所有作者均阅读并同意最终稿内容。

, correspAuthorsNote=
敦洁宁, Tel: 18903213149, E-mail:
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LevelFctor
A/% (m/v)B/% (m/v)C/% (m/v)
11050.5
21370.7
31590.9
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The factors and levels of the orthogonal design

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LevelFctor
A/% (m/v)B/% (m/v)C/% (m/v)
11050.5
21370.7
31590.9
), ArticleFig(id=1308842113626898794, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842107117338919, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
SourceSum of squareDegree of freedomMean squareFP
A89 531.75244 765.8757.96< 0.01
B42 272.71221 136.3553.76< 0.05
C160 598.45280 299.22514.28< 0.01
Error112 503.78205 625.19
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Results of variance analysis

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SourceSum of squareDegree of freedomMean squareFP
A89 531.75244 765.8757.96< 0.01
B42 272.71221 136.3553.76< 0.05
C160 598.45280 299.22514.28< 0.01
Error112 503.78205 625.19
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ModelFormulaEquationr
Zero orderQ = KtQ = 3.228 9t + 12.2460.934 3
First orderln(1-Q) = -Ktln(1-Q) = -0.074 3t - 0.085 80.964 7
HiguchiQ = Kt1/2Q = 18.255t1/2 - 3.059 30.985 7
Ritger-PeppaslnQ = nlnt + ClnQ = 0.615lnt + 2.583 10.997 7
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In vitro release fitting results of RFP-LM-TSG

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ModelFormulaEquationr
Zero orderQ = KtQ = 3.228 9t + 12.2460.934 3
First orderln(1-Q) = -Ktln(1-Q) = -0.074 3t - 0.085 80.964 7
HiguchiQ = Kt1/2Q = 18.255t1/2 - 3.059 30.985 7
Ritger-PeppaslnQ = nlnt + ClnQ = 0.615lnt + 2.583 10.997 7
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利福喷丁复合温敏凝胶的制备与初步评价
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宋志强 , 孙玉林 , 李卓欢 , 杨澜 , 敦洁宁 *
药学学报 | 研究论文 2026,61(7): 2737-2745
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药学学报 |研究论文 2026 , 61 (7) : 2737 -2745
利福喷丁复合温敏凝胶的制备与初步评价
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宋志强, 孙玉林, 李卓欢, 杨澜, 敦洁宁*
作者信息
  • 河北医科大学药学院, 河北 石家庄 050017
通讯作者:
敦洁宁, Tel: 18903213149, E-mail:
作者简介:

#

共同第一作者.

作者贡献:

宋志强完成实验补充并撰写论文初稿; 孙玉林完成实验操作及部分数据整理; 李卓欢参与数据整理及图表绘制; 杨澜参与稿件审阅与修改; 敦洁宁为本研究通讯作者, 统筹课题执行, 并对论文进行全面修改与定稿。所有作者均阅读并同意最终稿内容。

Preparation and preliminary evaluation of rifapentine composite thermosensitive gel
Zhi-qiang SONG, Yu-lin SUN, Zhuo-huan LI, Lan YANG, Jie-ning DUN*
Affiliations
  • School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
出版时间: 2026-07-12 doi: 10.16438/j.0513-4870.2026-0096
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摘要
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抗结核药物很难达到结核空洞病灶内, 常规的口服或静脉给药效果并不理想。本研究构建了一种以聚(DL-乳酸羟基乙酸-聚乙二醇) 共聚物为基质的利福喷丁复合温敏凝胶, 用于肺结核的支气管镜肺部介入治疗以提高肺结核靶向给药治疗效果。通过正交设计筛选利福喷丁脂微球最优处方, 将其与基质溶液混合制备复合温敏凝胶, 并对其进行表征。无膜法考察凝胶的溶蚀情况, 透析袋法评价其体外释放行为。共聚焦显微镜观察A549细胞对药物的摄取情况, 使用给药后不同时间点的肺组织提取液进行抑菌实验, 考察大鼠经气管插管给以温敏凝胶后肺部的滞留情况。所有动物实验程序均经河北医科大学实验动物伦理委员会批准(No: IACUC-Hebmu-P 2022084), 并遵循其指导方针进行。得到的脂微球粒径482.4 ± 0.22 nm, 制成复合凝胶后粒径略有增大, 复合凝胶的胶凝温度为34.47 ± 0.15 ℃, 胶凝时间为41.33 ± 1.70 s, 胶凝后具有适宜的黏度, 体外释放符合Ritger-Peppas动力学模型。脂微球能顺利递送脂溶性药物进入肺上皮细胞。单次给药后大鼠肺内的抑菌效果可持续14天。以上结果说明该制剂可在适宜温度下呈现液态与凝胶态的转变, 既保证了药物经支气管镜给药的可行性, 又能确保病灶部位长时间有效释药, 可以实现肺结核高效局部治疗的设计构想。

利福喷丁  /  脂微球  /  PLGA-PEG-PLGA  /  温敏凝胶  /  支气管镜给药

It is difficult for anti-tuberculosis drugs to reach the tuberculous cavity lesions, and the effects of conventional oral or intravenous administration are not satisfactory. In this study, a rifapentine composite thermosensitive gel with poly (lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) as the gel matrix was developed for bronchoscopic pulmonary interventional therapy of pulmonary tuberculosis to enhance the targeted drug delivery treatment effect for pulmonary tuberculosis. An optimal formulation for rifapentine lipid microspheres was screened via orthogonal design. The lipid microspheres were then mixed with PLGA-PEG-PLGA solution to prepare a composite thermosensitive gel. The formulation was then characterized. The erosion of the in-situ gel was evaluated using a membrane-free method, while the in-vitro release and release mechanism were assessed by dialysis bag method. Uptake of the drug in the gel by A549 cells was observed using confocal microscopy. Antibacterial assays were assessed using lung tissue homogenates collected at various time points following a single administration, in order to investigate the pulmonary retention of the thermosensitive gel after intratracheal instillation in rats. All animal experimental procedures were approved by the Experimental Animal Ethics Committee of Hebei Medical University (No: IACUC-Hebmu-P 2022084) and carried out in accordance with its guidelines. The particle size of the prepared lipid microspheres was 482.4 ± 0.22 nm, which increased slightly after incorporation into the composite gel. The gelation temperature of the composite gel was 34.47 ± 0.15 ℃, with a gelation time of 41.33 ± 1.70 s. The formulation exhibited good injectability before gelation while showed a suitable viscosity at gelation temperature. The drug release model fitted with the Ritger-Peppas equation. The results of laser confocal microscopy showed that the lipid microspheres effectively delivered lipophilic drugs into lung epithelial cells. Antibacterial testing of lung tissue extracts confirmed that a single dose of the composite gel could sustain antibacterial activity in rat lungs for at least 14 days. The rifapentine lipid microsphere-thermosensitive gel composite formulation significantly enhances the solubility of rifapentine. Its temperature-dependent phase transition from liquid to gel not only ensures feasibility for bronchoscopic administration but also enables prolonged and effective drug release at the lesion site, thereby achieving the design goal of efficient local therapy for tuberculosis.

rifapentine  /  lipid microsphere  /  PLGA-PEG-PLGA  /  thermosensitive gel  /  bronchoscopy administration
宋志强, 孙玉林, 李卓欢, 杨澜, 敦洁宁. 利福喷丁复合温敏凝胶的制备与初步评价. 药学学报, 2026 , 61 (7) : 2737 -2745 . DOI: 10.16438/j.0513-4870.2026-0096
Zhi-qiang SONG, Yu-lin SUN, Zhuo-huan LI, Lan YANG, Jie-ning DUN. Preparation and preliminary evaluation of rifapentine composite thermosensitive gel[J]. Acta Pharmaceutica Sinica, 2026 , 61 (7) : 2737 -2745 . DOI: 10.16438/j.0513-4870.2026-0096
正文
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肺结核(tuberculosis, TB) 是人类史上的古老疾病之一, 人类至今仍然饱受结核病的困扰。我国作为全球22个结核高负担国家之一, 结核病防治工作任重道远[1]。虽然2012年到现在已有3个抗结核的新化药上市, 但抗结核药物研发仍然相对滞后[2]。此外, 药物使用疗程长、不良反应多等原因所导致的患者用药依从性差, 进一步加大了肺结核治疗的难度。因此, 着眼于现有抗结核药物剂型和给药途径的改良, 已成为当前肺结核治疗的研究热点之一。
肺结核靶向给药治疗包括吸入型肺部给药系统、注射型肺靶向给药系统和支气管镜局部注药。与吸入给药和注射给药相比, 支气管镜下局部给药注入药物剂量准确可控, 药物可以经导管直接注入病灶局部, 对于支气管结核、耐多药肺结核及空洞型肺结核靶向性更强, 局部抗结核药物浓度可以远高于血药浓度[3]。临床研究结果显示, 经支气管镜进行注药治疗的患者, 痰菌转阴率、病灶显效率、空洞愈合率等均较单纯全身用药者显著提高。但是临床常用的药物经生理盐水溶解或混悬后通过支气管镜灌洗注入局部病灶的方式, 存在局部留滞性差的问题, 注入后要求患侧卧位0.5 h以上才能确保不被排出。以凝胶特别是生物可降解凝胶代替以往治疗中所用的抗结核药物真溶液或混悬液, 达到病灶局部可以增加药物局部滞留能力, 延长药物作用时间, 缩短疗程, 提高患者依从性。
脂微球(lipid microsphere, LM) 是以植物油为基质, 外包以磷脂的纳米球, 本质为水包油(O/W) 分散体系, 可以改善难溶性药物的溶解度和稳定性, 提高药物的跨细胞膜吸收效率, 还可以降低药物刺激性和不良反应[4], 药物通常处于油相或油相界面中, 可以避免或减少局部刺激, 获得持续的药物释放[5]。将其与温敏凝胶相结合, 可具备制备简单, 延长药物的局部滞留时间, 提高生物利用度等优势。
本研究拟以利福喷丁(rifapentine, RFP) 为模型药物, 以可生物降解的聚(DL-乳酸羟基乙酸-聚乙二醇) 共聚物[poly (lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly (lactide-co-glycolide), PLGA-PEG-PLGA] 为基质, 结合脂微球制备温度敏感型复合原位凝胶, 旨在改善药物溶解度, 增强肺靶向性, 延长药物的肺部滞留时间, 提高局部药物浓度, 为RFP在肺结核靶向治疗领域提供新的实验依据。该凝胶基质的最终代谢产物为水和二氧化碳, 具有很好的生物安全性。
材料与方法
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仪器   高效液相色谱仪(LC-20AT, 日本岛津公司); 集热式恒温磁力搅拌(HWCL-5, 郑州长城科工贸有限公司); 型超声波清洗器(KQ-100A, 昆山市超声仪器有限公司); 高速匀浆机(FSH­2, 上海新诺仪器设备有限公司); 高速台式离心机(TCL-16B, 上海安亭科学仪器厂); 激光粒度分析仪(Nano ZS90, 英国马尔文公司); 脱色摇床(TY-80A, 金坛市精达仪器制造有限公司); 激光共聚焦显微镜(TCS SP5, 德国Leica公司)。
药品与试剂   利福喷丁(C10086496, 阿拉丁试剂公司); 大豆磷脂(2305018, 江苏曼氏生物科技有限公司); 甘油(20131023, 天津博迪化工股份有限公司); 油酸(20221020, 天津市化学试剂一厂); 维生素E (S12201001210, 浙江医药股份有限公司新昌制药厂); PLGA-PEG-PLGA (2025030417, 济南岱罡生物工程有限公司); 抗荧光衰减封片剂(含4′, 6-diamidino-2-phenylindole, DAPI, 20230419) 购自北京Solarbio公司; A549细胞(CCL-185, 美国生物标准品资源中心); RPMI 1640培养基、胰蛋白酶、胎牛血清(8123594, 3066349, 42F2391K美国Gibco公司); 耻垢分枝杆菌、金黄色葡萄球菌(北京生物保藏中心)。
实验动物   SD大鼠, 雌性, 30只, 购于河北医科大学实验动物中心, 实验动物许可证号: SCXK (冀) 2021-002, 所有实验均遵循河北医科大学实验动物伦理委员会的指导方针进行, 伦理审查编号: IACUC-Hebmu-P 2022084。
利福喷丁脂微球处方筛选   药物在不同油相中的溶解情况直接决定了脂微球对难溶性药物的载药能力。预实验中作者通过考察RFP在不同油相中的溶解性, 对油相进行了筛选, 并确定了玉米油为主要的油相成分。结合相关文献[6], 初步确定脂微球的基本组成为RFP、玉米油、豆磷脂、甘油、油酸、VE和蒸馏水。通过单因素考察确定各成分大致用量范围, 分别以油相用量(A)、乳化剂用量(B)、稳定剂用量(C) 为主要影响因素, 以脂微球稳定性为评价指标, 按L9 (33) 正交表进行试验安排, 因素水平表见表1。考虑到脂微球物理稳定性可以采用离心稳定常数(Ke) 进行快速比较, 而粒径也是评价脂微球质量的重要指标之一, 故以离心稳定常数(R1) 和粒径(R2) 为基础, 采用综合评分法(R = R1 + R2) 进行评价, 综合分值越低, 表明制剂稳定性越好。
在此空白处方基础上, 对投药量进行了筛选[7], 分别在空白处方中加入5、10、25、50 mg的药物, 制得利福喷丁脂微球(rifapentine lipid microsphere, RFP-LM), 使用超速离心法对其包封率进行测定。精密量取RFP-LM适量, 分别以15 000和12 000 r·min-1离心两次, 每次30 min, 高效液相色谱法(high efficiency liquid chromatography, HPLC) 测定下层水溶液中的药物含量, 根据公式(1) 计算包封率。
$ 包封率 (\%) = (m - m_{1})/m × 100\% $
其中: m为投入的药物总量, m1为水相中药物含量。
RFP-LM制备方法的筛选   采用高速剪切法制备脂微球, 制备过程中温度、剪切时间及剪切速度均会影响脂微球的稳定性。有文献指出, 在磷脂的相转变温度(70 ℃) 附近制备的脂微球具有较小的粒径和较好的稳定性[8], 剪切时间太长会增加乳滴间的碰撞, 导致乳滴聚集合并, 太短则乳化不完全, 可能会有油滴析出, 剪切速度则直接影响乳滴的大小。本试验考察了制备温度为60、70、80 ℃, 剪切时间为3、5、7、9、11 min, 以及剪切速度分别为10 000、11 000和12 000 r·min-1时对脂微球的外观及Ke值、粒径的影响。
RFP-LM的表征
RFP-LM外观性状及粒径   将制备的空白脂微球和载药脂微球置于透明的玻璃容器中观察其外观性状, 并采用马尔文粒度仪测定其平均粒径。
Ke的测定   取3批新制备的RFP-LM 2 mL置于离心试管中, 以4 000 r·min-1离心15 min, 精密量取下层液10 μL置于10 mL量瓶中, 用蒸馏水稀释至刻度。以蒸馏水为空白, 按照紫外分光光度法, 测定其吸光度(A), 取未离心脂微球同法稀释后测定吸光度值A0, 根据公式(2) 计算Ke。
$ K_{\rm{e}} = (A_{0} - A)/A × 100\%$
其中, A为脂微球离心稀释后测定的吸光度值; A0为脂微球未离心稀释相同倍数后测定的吸光度值。
利福喷丁脂微球温敏凝胶的制备    精密称取适量的PLGA-PEG-PLGA置于西林瓶中, 搅拌下加入定量的蒸馏水, 继续搅拌直至聚合物分散均匀, 于4 ℃冰箱保存至温敏凝胶充分地溶胀、溶解, 得到空白温敏凝胶基质水溶液。将处方量的RFP-LM在搅拌下缓慢地加入空白温敏凝胶基质水溶液中, 缓慢搅拌均匀即得利福喷丁脂微球温敏凝胶(rifapentine lipid microsphere thermosensitive gel, RFP-LM-TSG) 溶液。预试验发现, 浓度为20%的聚合物溶液具有适宜的粘度和相转变温度, 本试验选择浓度为20%的PLGA-PEG-PLGA溶液作为凝胶载体。RFP-LM的加入会改变PLGA-PEG-PLGA聚合物溶液的胶凝温度。分别考察脂微球与凝胶基质比例(v/v) 为3∶1、2∶1、1∶1、1∶2、1∶3时, RFP-LM-TSG的胶凝温度。
温敏凝胶的理化性质研究
粒径及粒径分布   室温下取RFP-LM-TSG, 用PBS溶解稀释后, 置于马尔文激光粒度仪下测定其粒径及分散指数(polymer dispersity index, PDI)。
胶凝温度与胶凝时间   RFP-LM-TSG的胶凝温度采用试管倒置法进行测定。取1 mL温敏凝胶溶液放入离心管置于水浴锅中, 将温度计水银球完全浸没于溶液中, 从室温开始缓慢升温, 每次升温1 ℃, 并保持1 min, 翻转离心管进行观察, 样品不发生流动的时间持续超过30 s时的温度即为胶凝温度[9]。将样品于室温放置1 h平衡温度, 取1 mL的RFP-LM-TSG置于西林瓶中, 将西林瓶置于35 ± 0.1 ℃的水浴中, 立即计时, 直至西林瓶中液体不再流动的时间, 即为胶凝时间[10]。
流变特性与通针性[11]   使用DV3T流变仪测定RFP-LM-TSG的流变特性, 以是否能通过注射器5号针头为标准, 考察RFP-LM-TSG的通针性。
RFP含量测定   采用HPLC测定原位凝胶中RFP的含量。色谱条件: Ultimate® XB-C18色谱柱(4.6 mm × 250 mm, 5 μm), 流动相为甲醇-0.037 5 mol·L-1磷酸二氢钾溶液(70∶30), 流速1.0 mL·min-1, 检测波长254 nm, 进样量20 μL, 柱温25 ℃。测得3批原位凝胶中RFP的平均含量为3.23 ± 0.08 mg·mL-1。
温敏凝胶体外特性研究
体外降解时间考察[12]   取0.5 mLRFP-LM-TSG置于具塞玻璃试管中, 置于37 ± 0.1 ℃恒温水浴振荡器中预热10 min, 待其完全转变为凝胶后, 称重并记录为W0, 沿管壁缓慢注入提前预热至37 ℃的pH 7.4的磷酸盐缓冲液3 mL持续振荡, 在设定的时间间隔内, 去除上层PBS降解介质, 并吸干瓶壁, 记录此时重量为Wt。然后重新放入恒温水浴中平衡10 min, 再补充等量新介质, 绘制温敏凝胶重量对时间的变化曲线。根据公式(3) 计算凝胶残留量。
$ 凝胶残留量 (\%) = (W_{t} - W)/ (W_{0} - W) × 100\% $
其中, W为具塞玻璃管的重量。
温敏凝胶的体外释放及释放机制   精密量取一定量的RFP游离药、RFP-LM, RFP-LM-TSG, 分别加入到已处理好的透析袋(8 000~14 000 D) 中, 将透析袋两端扎紧, 浸入装有释放介质的试管中, 使得透析袋内外总体积为20 mL。将试管置于37 ± 0.1 ℃恒温水浴中进行振荡(转速为100 r·min-1)。于不同时间点, 从释放介质中取0.5 mL溶液, 同时补给新鲜等体积的释放介质。HPLC测定药物含量, 按公式计算RFP的累积释放量Q, 并绘制药物的体外累积释放曲线[13]。
将体外释放实验数据进行零级动力学、一级动力学、Ritger-Peppas、Higuchi方程拟合, 根据拟合优度来判断曲线拟定情况, 进而判断RFP-LM-TSG体外释放类型。
$ Q = [C_{n}V_{n} + (C_{n-1}V_{n-1} + C_{n-2}V_{n-2} + C_{n-3}V_{n-3} + ......+ C_{1}V_{1})]/m × 100\% $
其中, Cn指第n次取样时通过外标法求得的RFP浓度, V指释放介质的总体积; Vn-1指第n-1次取样时取出的介质体积, Vn-2、Vn-3同理, m指透析袋内RFP的重量。
细胞摄取试验[14]   由于RFP不显示荧光, 为了观察细胞对LM制剂的摄取效果, 用脂溶性荧光染料香豆素6 (coumarin-6, Cou-6) 替代RFP制备Cou-6-LM, 进行细胞摄取的研究。取对数生长期的A549细胞, 制成浓度为每毫升5×104个的单细胞悬液, 吹打均匀后取0.1 mL滴于灭菌的圆形盖玻片上, 贴壁4 h后, 向每孔补加0.4 mL的培养基, 继续培养24 h。之后将每孔中替换为0.5 mL含Cou-6-LM的培养基(质量浓度分别为0.1、1.0、10 μg·mL-1), 37 ℃下继续孵育0.5、2、4 h后, 弃去含药培养基, 用PBS清洗3遍, 取出圆形盖玻片置于滴有DAPI封片剂的载玻片上, 激光共聚焦显微镜观察细胞对各制剂的摄取情况, 并使用Image Pro Plus 6.0软件对荧光强度进行分析。
RFP-LM-TSG的安全性研究   大鼠腹腔注射1%的戊巴比妥钠溶液(3.5 mL·kg-1) 麻醉, 待角膜反射消失后, 将其腹部朝上固定于热垫上, 脱去颈毛, 碘伏消毒后从锁骨上方纵行剪开5 mm颈部皮肤, 将肌肉钝性分离暴露气管, 于气管软骨间隙开一小孔, 使用自制插管装置将250 μL的RFP-LM-TSG注入肺底。
采用随机数字法将30只雌性SD大鼠分为10组, 每组3只, 分别在肺部给药2、4、8、24、48、72、96 h和11、13、14 d后, 将大鼠脱颈处死, 观察肺组织凝胶滞留情况并对重要脏器进行苏木精-伊红(hematoxylin-eosin, H & E) 染色对制剂安全性进行考察。
复合凝胶的初步药效学验证
考虑到结核杆菌的强传染性, 复合凝胶的药效学验证不进行肺结核建模实验, 采用体外抑菌圈实验替代检测不同时间点动物肺组织内RFP的生物效价, 考察其药物释放及治疗的持续性。
肺组织提取液滤纸片的制备   分别取大鼠气管插管给药后不同时间点的肺组织, 用生理盐水洗净, 滤纸擦干后称重, 置玻璃匀浆器中, 每克组织加入pH = 7.4的磷酸盐缓冲液1 mL, 制成匀浆, 分别用3 000和10 000 r·min-1离心两次, 每次10 min, 取上清液0.22 μm微孔滤膜过滤除菌, 制成肺组织匀浆液。将灭菌后的5 mm滤纸片分别浸入上述肺组织匀浆液中浸泡30 min后, 取出晾干, 制成肺组织提取液滤纸片。
含药滤纸片的制备   精密称取10 mg的RFP置于10 mL量瓶中, 加入3 mL甲醇溶解, 补加PBS溶液稀释至刻度, 得1.0 mg·mL-1的RFP母液。使用PBS溶液稀释得到质量浓度为2和4 μg·mL-1的标准RFP溶液。取同一批号的灭菌滤纸片浸入上述不同浓度的标准RFP溶液中放置30 min, 取出晾干, 制成含药滤纸片。
抑菌试验   分别将金黄色葡萄球菌和耻垢分枝杆菌菌液均匀涂布于营养琼脂培养基和脑心浸出液琼脂培养基上, 将含药滤纸片和肺组织提取液的滤纸片贴在培养基不同部位, 将培养皿倒置。于37 ℃恒温培养箱中培养24 h, 观察细菌生长情况, 并用游标卡尺测量抑菌圈直径, 考察RFP-LM-TSG在肺组织中的抑菌效果。
结果
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1　RFP-LM的制备与表征
1.1　RFP-LM的处方与制备
方差分析结果显示, 各因素对RFP-LM的稳定性和粒径均有较大影响, 差异具有统计学意义(P < 0.05, 见表2), 其中油酸用量是影响脂微球稳定性最主要的因素, 根据稳定性最优评分得到最佳处方为油相用量为10%, 大豆磷脂用量为9%, 油酸用量为0.5%。当投药量≤ 10 mg时包封率较高, 但载药量较低, 无法保证用药部位的持续抑菌浓度。投药量25和50 mg时包封率接近, 但50 mg时载药量更高, 因此确定50 mg为处方投药量。
综合考虑粒径与Ke值的变化结果, 发现制备温度为70 ℃、剪切时长为11 min时得到的脂微球各方面表现较优。3个剪切速度得到的脂微球粒径差异不大, Ke值逐渐减小, 但考虑到设备稳定性问题, 选择11 000 r·min-1作为制备时的剪切速度。
1.2　RFP-LM的表征
RFP-LM的外观如图1A所示, 空白脂微球呈乳白色不透明状, 载药脂微球为橙色不透明状, 均无分层、挂壁现象, 且表面无油滴。RFP-LM的平均粒径为482.4 ± 0.22 nm, PDI为0.264 ± 0.04, 粒径分布呈现单峰(图1B), 3批产品的离心稳定性常数(Ke) 测定结果为20.41 ± 1.39, 表明制备的RFP-LM粒径分布均匀, 较稳定。
2　RFP-LM-TSG复合物的制备与理化性质研究
2.1　RFP-LM-TSG的制备
脂微球与凝胶基质比例为1∶2 (v/v) 时, 胶凝温度为34.3 ℃, 符合实验要求, 图2A、B显示凝胶发生胶凝后黏度发生明显变化, 流动性变差。
结合1.1中RFP-LM的处方与制备的结果, 最终确定的RFP-LM-TSG制备方法为: 将0.05 g的RFP和大豆磷脂溶于无水乙醇, 加入1 g玉米油和0.5 g的维生素E, 加热至70 ℃充分溶解分散形成油相。将处方量的油酸、甘油与蒸馏水混合加热至70 ℃得到水相。冰浴条件下将水相缓慢加入油相中, 以11 000 r·min-1的速度剪切乳化11 min, 即得RFP含量0.5%的脂微球。将该脂微球缓慢地加入溶胀完全的20%温敏凝胶基质的水溶液中(v/v = 1∶2), 搅拌均匀即得RFP-LM-TSG溶液。
2.2　温敏凝胶的理化性质研究
RFP-LM-TSG的粒径为589.4 nm, PDI为0.142, 粒径分布集中, 表明脂微球与温敏凝胶的结合并未对制剂的稳定性造成影响(图2D)。凝胶的黏度随温度变化由1 090 mPa·s (室温) 增加到46 090 mPa·s (35 ± 0.1 ℃)。通针性结果显示, 该温敏凝胶未达到胶凝温度时呈现溶液状态(图2C), 可保证临床使用时顺利给药。胶凝温度为34.47 ± 0.15 ℃, 胶凝时间为41.33 ± 1.70 s, 说明凝胶达到肺部可快速胶凝从而避免患者移动引起的药物位移, 可以满足纤支镜肺部给药的要求。
3　温敏凝胶体外特性研究
3.1　凝胶的体外降解试验
RFP-LM-TSG的体外降解情况如图3A所示, 在最初几个小时内由于凝胶吸水溶胀, 凝胶的重量会逐渐增加, 之后随着时间的推移, 凝胶逐渐溶蚀降解, 因此凝胶重量逐渐降低。经过33天后, 大约90%的凝胶已被降解, 说明制备的RFP-LM-TSG具有适宜降解速率, 可长时间维持凝胶状态, 可作为良好的肺部给药剂型。不同制剂中RFP的体外释放结果如图3B所示, RFP游离药物的释放较快, 36 h后释放量已达到90%以上; 而RFP-LM和RFP-LM-TSG均有一定的缓释效果, 大约1个月后其累积释放量达到90%以上, 凝胶基质的存在并不会影响药物从脂微球中的释放。
3.2　温敏凝胶的体外释放及释放机制
RFP-LM-TSG的体外释放数据的动力学模型拟合结果如表3所示, 其中Q为t时间药物累积释放量。拟合系数r值越接近于1, 拟合效果越好。r值结果显示, RFP-LM-TSG的体外释放符合Ritger-Peppas动力学模型, n值为0.615, 介于0.45和1.0之间, 药物释放由溶蚀与扩散相结合共同决定。
4　细胞摄取实验
细胞摄取实验中, 绿色荧光为细胞摄取Cou-6后显示的荧光, 蓝色荧光为DAPI对细胞核染色后显示的荧光, merge代表两者合并图(图4), 图中可见Cou-6能够被摄取进入细胞。而且随着时间的进行和浓度的增加, 细胞对药物的摄取有明显的增长, 说明脂微球能顺利地将脂溶性药物递送进肺上皮细胞内。
5　RFP-LM-TSG的安全性研究
RFP为深橘红色, 大鼠气管插管给药2和4 h后肺组织给药部位能明显观察到RFP-LM-TSG的积聚, 随着时间的延长, 给药部位的颜色逐渐恢复正常。给药后, 大鼠无咳嗽、窒息现象, 毛发颜色、进食进水情况及日常活动均无任何异常表现, 解剖后胸腔无出血现象。表明该制剂在肺部滞留时期不会对大鼠的正常生活造成影响。给药14天后各脏器均呈现出正常的组织结构, 未见明显的急性损伤或病理改变(图5)。
6　复合凝胶的初步药效学验证
图6显示, RFP对照品溶液制备的对照滤纸片及不同时间点的肺组织匀浆制备的含药滤纸片周围都有抑菌圈, 表明RFP对照品及给药后不同时间点的肺组织匀浆对金黄色葡萄球菌及耻垢分枝杆菌均有一定的抑菌效果, 且抑菌效果至少可以持续两周。另外肺组织匀浆在制备过程中经PBS稀释, 提取液浓度低于肺部实际药物浓度, 故推测生物体中抑菌效果应优于抑菌实验结果。
讨论
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结核空洞病灶内结核菌代谢旺盛, 菌量大且生长繁殖活跃, 空洞周围有纤维增生, 血管分布稀少, 部分血管栓塞, 药物不能渗透空洞区, 结核空洞内的药物很难达到最低抑菌浓度, 所以常规的口服或静脉给药效果并不理想。另外, 结核分枝杆菌容易在胞内生长繁殖, 抗生素进入细胞的能力相对较弱, 而进入细胞的抗生素往往在胞内生理条件(pH值、蛋白结合和离子强度等) 下不稳定, 使得目前胞内感染的化疗效果很差, 多年来, 人们认识到改善胞内感染的化疗效果非常必要[15], 给药途径的改良并不能从根本上解决这个问题, 而制剂手段上提高肺结核靶向给药治疗效果相对来说可行性更高。
在现有抗结核药物中, RFP的体外抗结核杆菌作用强, 但口服吸收缓慢且不完全, 而且还有很强的胃肠道反应及肝毒性[16]。因此, 本课题考虑将RFP制成经支气管镜给药的肺靶向缓释制剂, 以达到降低药物的毒副作用及与其他药物之间的相互作用, 提高药物治疗指数的目的。处方前研究测定的RFP油水分配系数为1.98, 说明其脂溶性较高, 易透过生物膜, 低生物利用度应该与其溶解度过小有关, 如果想提高其肺部吸收, 应从增加药物的溶解度着手。本研究制备的原位凝胶制剂中RFP含量达到3.23 ± 0.08 mg·mL-1, 相较于RFP水中溶解度(3.046 mg·L-1) 提高了1 000倍, 能够很好地提升给药部位的浓度, 更好地发挥其局部抑菌作用。肺部属于直接与外界联通进行气体交换的场所, 吸入肺部的空气温度通常比体温低, 所以肺部的实际温度不能达到37 ℃, 但胶凝温度不能设置过低, 否则经纤支镜给药时容易过早胶凝导致不能正常使用。考虑到以上原因, 同时参考周中元等的相关文献[17], 最终确定胶凝温度为34~35 ℃, 以确保原位凝胶能以液体状态顺利通过给药细管, 并在到达肺底时能迅速胶凝。实际制备所得胶凝温度为34.47 ± 0.15 ℃, 经验证可以很好地满足以上各项要求。
药物体外释放试验得到的数据能在一定程度上反映药物的体内释药情况, 从而合理安排动物的采血和处死时间点, 减少试验动物的消耗和人员的浪费。目前国内外对于温敏凝胶体外释放的考察没有统一的方法和标准, 但主要基于两种模型, 有膜溶出模型和无膜溶出模型[18], 有膜溶出法又包括透析法[19]和Franz扩散池法。无膜溶出模型无法体现实际生物给药时特殊的膜结构及凝胶在膜表面的覆盖情况。而Franz扩散池法不能够很好地混合接收池与侧臂中的溶液。考虑到制备的脂微球温敏凝胶是用于肺部给药的剂型, 肺部体液较少, 因此最终选择透析袋法来模拟药物的释放过程。体外释放结果显示RFP-LM和RFP-LM-TSG均有一定的缓释效果, 但脂微球流动性较强, 可能会随着患者呼吸和体位变化等活动发生位移, 凝胶基质的存在对药物的释放没有影响, 但是可以保证制剂在肺底或结核空洞部位有足够长时间的滞留, 对于肺部疾病的局部治疗十分有利。
耻垢分枝杆菌属于低风险非致病菌, 而且与结核分枝杆菌有高度亲缘关系, 在细胞壁结构、部分代谢通路和基础生理机制上高度相似, 参考相关文献[20], 本研究中采用耻垢分枝杆菌替代结核分枝杆菌进行了抑菌实验的考察。RFP的最低抑菌浓度(minimal inhibitory concentration, MIC) 为0.12~0.25 mg·L-1 [21], 体外释放的结果显示各时间点药物释放浓度均远高于RFP的最低抑菌浓度, 该结果为后续抑菌试验的实施提供了一定研究基础。抑菌实验中作者发现各时间点肺组织中的药物在稀释一倍后仍然能够表现出足够的抑菌能力, 也进一步证实了14天内复合凝胶中药物在给药部位的释放能够达到RFP的MIC, 提示该复合凝胶可能会在临床上有很好的应用前景。
尽管本研究在体外实验中证实了利福喷丁复合温敏凝胶具有良好的释药特性和细胞摄取效率, 但仍存在一定的局限性。制剂的体外释放行为与体内复杂环境的相关性尚不明确, 另外当前的细胞实验结果无法完全模拟药物在体内的动态分布过程。针对以上问题, 后续课题组拟开展体内药代动力学研究, 验证其体内缓释特性。并寻求ABSL-3实验室的支持, 尝试建立肺结核动物模型, 考察复合凝胶对模型动物的治疗作用和使用安全性。同时进行一定规模的放大实验, 考察其规模化生产的可能性。期待通过上述补充性研究, 可以全面验证复合凝胶的应用潜力, 为实现其临床转化提供更坚实的实验依据。

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2026年第61卷第7期
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doi: 10.16438/j.0513-4870.2026-0096
  • 接收时间：2026-01-27
  • 首发时间：2026-09-21
  • 出版时间：2026-07-12
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  • 收稿日期：2026-01-27
  • 修回日期：2026-03-16
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    河北医科大学药学院, 河北 石家庄 050017

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敦洁宁, Tel: 18903213149, E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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