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Article(id=1200383186036445400, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200383177295515678, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0019, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1704729600000, receivedDateStr=2024-01-09, revisedDate=1713369600000, revisedDateStr=2024-04-18, acceptedDate=null, acceptedDateStr=null, onlineDate=1764123253592, onlineDateStr=2025-11-26, pubDate=1723392000000, pubDateStr=2024-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764123253592, onlineIssueDateStr=2025-11-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764123253592, creator=13701087609, updateTime=1764123253592, updator=13701087609, issue=Issue{id=1200383177295515678, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='8', pageStart='2183', pageEnd='2416', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764123251508, creator=13701087609, updateTime=1764225076631, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200810262870741499, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200383177295515678, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200810262870741500, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200383177295515678, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2396, endPage=2403, ext={EN=ArticleExt(id=1200383186506207473, articleId=1200383186036445400, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Rheology guided the preparation of suvorexant-copovidone solid dispersions via hot melt extrusion technology, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

The rheological properties of drug and carrier materials have a wide range of guiding significance for the formulation and process development of solid dispersions. In this study, the rheological properties of materials with different drug carrier ratios were systematically studied with suvorexant as the model drug and copovidone as the carrier material, which provided a sufficient basis for determining the formulation and process of solid dispersions. The optimal suvorexant-copovidone ratio obtained by oscillating temperature scanning was 1∶4. If the ratio is greater than 1∶ 4, the glass transformation temperature of the material will increase significantly, and the solubilization effect of the solid dispersion will show a downward trend. The results of oscillation temperature scanning and oscillation temperature sweep can show that when the extrusion temperature is greater than 150 ℃, the viscosity of the material is less than 10 000 Pa·s, and the melt can be extruded smoothly, and the best extrusion temperature of 160-180 ℃ can be obtained by combining the dissolution results. Finally, the dissolution of suvorexant tablets guided by rheological property studies in multiple media is similar to that of the commercially available tablets Belsomra. Therefore, rheological studies can screen and optimize the formulation and process of suvorexant solid dispersions at the mechanism level, which is of great significance to improve the success rate of R & D and shorten the R & D cycle of solid dispersions prepared by hot melt extrusion.

, correspAuthors=Yong-jun WANG, Ai-ping ZHENG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Peng ZHAO, Cong-hui LI, Si-yi SHUAI, Bing YANG, Hui ZHANG, Nan LIU, Zeng-ming WANG, Yong-jun WANG, Ai-ping ZHENG), CN=ArticleExt(id=1200383190616625607, articleId=1200383186036445400, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=流变学指导热熔挤出技术制备苏沃雷生-共聚维酮固体分散体, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

药物与载体材料的流变学性质对于固体分散体的处方和工艺开发具有广泛的指导意义。本研究以苏沃雷生为模型药, 共聚维酮为载体材料, 对不同药物载体比例的物料流变学特性进行了系统研究, 为确定固体分散体的处方和工艺提供了充分依据。振荡温度扫描结果可得最佳的苏沃雷生-共聚维酮比例为1∶4, 若比例大于1∶4, 物料玻璃态转化温度增加趋势显著, 同时固体分散体增溶效果会呈下降趋势。振荡温度扫描与振荡温度扫频结果可得, 当挤出温度大于150 ℃时, 物料黏度低于10 000 Pa·s, 熔体可顺利挤出; 同时结合溶出结果最终得到最佳的挤出温度为160~180 ℃。最后通过流变学特性研究指导开发的苏沃雷生片在多介质中溶出均与市售片剂Belsomra相似。因此, 流变学研究可以从机制层面筛选优化苏沃雷生固体分散体处方与工艺, 对提高热熔挤出制备固体分散体研发成功率及缩短研发周期具有重要意义。

, correspAuthors=王永军, 郑爱萍, authorNote=null, correspAuthorsNote=
*王永军, Tel: 86-24-23986325, E-mail: ;
郑爱萍, Tel: 86-10-66931694, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2024, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=jCaz42NkUKNgUe8BAw2ijQ==, magXml=pUE7eTAwkrZemE/qQKpWIg==, pdfUrl=null, pdf=OMMElUcckroWEUSaCBiO8g==, pdfFileSize=3718034, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=z3exP0c5BgQTrxWwPTVEOg==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=/k2OnZUSNWu+4tNWq7Wq/w==, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=赵朋, 李聪慧, 帅思祎, 杨兵, 张慧, 刘楠, 王增明, 王永军, 郑爱萍)}, authors=[Author(id=1201107064958448220, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383186036445400, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1201107065096860257, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383186036445400, authorId=1201107064958448220, language=EN, stringName=Peng ZHAO, firstName=Peng, middleName=null, lastName=ZHAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, address=1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
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A: VA64; B: PM (1∶5); C: PM (1∶4); D: PM (1∶3); E: PM (1∶2); F: PM (1∶1). 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A: 0.4%SDS solution; B: pH 1.2 buffer solution; C: pH 4.5 buffer solution; D: pH 6.8 buffer solution. <i>n</i> = 3, <span class="mag-xml-inline-formula"><tex-math id="M3">$ \stackrel{-}{x} $</tex-math></span> ± <i>s</i> , figureFileSmall=f+O0ienfaKNcYtnHnAiCdw==, figureFileBig=TzI5VgPumEzMhqavFDRl9Q==, tableContent=null), ArticleFig(id=1201107072239760067, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383186036445400, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
FormulationSuvorexant-VA64 mass ratioProcessing temperature/℃
F11∶1170
F21∶2170
F31∶3170
F41∶4170
F51∶5170
F61∶4140
F71∶4150
F81∶4160
F91∶4180
F101∶4190
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Solid dispersions formulations and process parameters

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FormulationSuvorexant-VA64 mass ratioProcessing temperature/℃
F11∶1170
F21∶2170
F31∶3170
F41∶4170
F51∶5170
F61∶4140
F71∶4150
F81∶4160
F91∶4180
F101∶4190
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MaterialVA641∶11∶21∶31∶41∶5
Torque/%72-7418-1919-2127-2932-3437-40
Melt pressure/bar10-1300-10-246-7
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Process parameters for VA64 and solid dispersions with different suvorexant content

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MaterialVA641∶11∶21∶31∶41∶5
Torque/%72-7418-1919-2127-2932-3437-40
Melt pressure/bar10-1300-10-246-7
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Reference temperature/℃Zero rate viscosity/Pa·sInfinite rate viscosity/Pa·sConsistency/sRate index
15034 7869070.462 60.555 5
1605 4661400.073 40.558 6
1701 436380.019 30.557 8
180431115.731 4e-30.557 3
19015842.108 4e-30.559 5
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Summary of cross parameters for PM (1∶4) at different temperatures

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Reference temperature/℃Zero rate viscosity/Pa·sInfinite rate viscosity/Pa·sConsistency/sRate index
15034 7869070.462 60.555 5
1605 4661400.073 40.558 6
1701 436380.019 30.557 8
180431115.731 4e-30.557 3
19015842.108 4e-30.559 5
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Temperatures /℃140150160170180190
Torque/%Excessive torque55-5943-4632-3423-2519-21
Melt pressure /bar17-224-73-40-10-1
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Process parameters for different processing temperatures of PM (1∶4)

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Temperatures /℃140150160170180190
Torque/%Excessive torque55-5943-4632-3423-2519-21
Melt pressure /bar17-224-73-40-10-1
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流变学指导热熔挤出技术制备苏沃雷生-共聚维酮固体分散体
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赵朋 1, 2 , 李聪慧 2 , 帅思祎 2 , 杨兵 2 , 张慧 2 , 刘楠 2 , 王增明 2 , 王永军 1, * , 郑爱萍 2, *
药学学报 | 研究论文 2024,59(8): 2396-2403
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药学学报 | 研究论文 2024, 59(8): 2396-2403
流变学指导热熔挤出技术制备苏沃雷生-共聚维酮固体分散体
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赵朋1, 2, 李聪慧2, 帅思祎2, 杨兵2, 张慧2, 刘楠2, 王增明2, 王永军1, * , 郑爱萍2, *
作者信息
  • 1.沈阳药科大学无涯创新学院, 辽宁 沈阳 110016
  • 2.军事医学研究院国家安全特需药品全国重点实验室, 北京 100850

通讯作者:

*王永军, Tel: 86-24-23986325, E-mail: ;
郑爱萍, Tel: 86-10-66931694, E-mail:
Rheology guided the preparation of suvorexant-copovidone solid dispersions via hot melt extrusion technology
Peng ZHAO1, 2, Cong-hui LI2, Si-yi SHUAI2, Bing YANG2, Hui ZHANG2, Nan LIU2, Zeng-ming WANG2, Yong-jun WANG1, * , Ai-ping ZHENG2, *
Affiliations
  • 1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
  • 2. State Key Laboratory of National Security Specially Needed Medicines, Academy of Military Medical Sciences, Beijing 100850, China
出版时间: 2024-08-12 doi: 10.16438/j.0513-4870.2024-0019
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摘要
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药物与载体材料的流变学性质对于固体分散体的处方和工艺开发具有广泛的指导意义。本研究以苏沃雷生为模型药, 共聚维酮为载体材料, 对不同药物载体比例的物料流变学特性进行了系统研究, 为确定固体分散体的处方和工艺提供了充分依据。振荡温度扫描结果可得最佳的苏沃雷生-共聚维酮比例为1∶4, 若比例大于1∶4, 物料玻璃态转化温度增加趋势显著, 同时固体分散体增溶效果会呈下降趋势。振荡温度扫描与振荡温度扫频结果可得, 当挤出温度大于150 ℃时, 物料黏度低于10 000 Pa·s, 熔体可顺利挤出; 同时结合溶出结果最终得到最佳的挤出温度为160~180 ℃。最后通过流变学特性研究指导开发的苏沃雷生片在多介质中溶出均与市售片剂Belsomra相似。因此, 流变学研究可以从机制层面筛选优化苏沃雷生固体分散体处方与工艺, 对提高热熔挤出制备固体分散体研发成功率及缩短研发周期具有重要意义。

流变学  /  热熔挤出  /  苏沃雷生  /  固体分散体  /  玻璃态转化温度  /  黏度

The rheological properties of drug and carrier materials have a wide range of guiding significance for the formulation and process development of solid dispersions. In this study, the rheological properties of materials with different drug carrier ratios were systematically studied with suvorexant as the model drug and copovidone as the carrier material, which provided a sufficient basis for determining the formulation and process of solid dispersions. The optimal suvorexant-copovidone ratio obtained by oscillating temperature scanning was 1∶4. If the ratio is greater than 1∶ 4, the glass transformation temperature of the material will increase significantly, and the solubilization effect of the solid dispersion will show a downward trend. The results of oscillation temperature scanning and oscillation temperature sweep can show that when the extrusion temperature is greater than 150 ℃, the viscosity of the material is less than 10 000 Pa·s, and the melt can be extruded smoothly, and the best extrusion temperature of 160-180 ℃ can be obtained by combining the dissolution results. Finally, the dissolution of suvorexant tablets guided by rheological property studies in multiple media is similar to that of the commercially available tablets Belsomra. Therefore, rheological studies can screen and optimize the formulation and process of suvorexant solid dispersions at the mechanism level, which is of great significance to improve the success rate of R & D and shorten the R & D cycle of solid dispersions prepared by hot melt extrusion.

rheology  /  hot melt extrusion  /  suvorexant  /  solid dispersion  /  glass transition temperature  /  viscosity
赵朋, 李聪慧, 帅思祎, 杨兵, 张慧, 刘楠, 王增明, 王永军, 郑爱萍. 流变学指导热熔挤出技术制备苏沃雷生-共聚维酮固体分散体. 药学学报, 2024 , 59 (8) : 2396 -2403 . DOI: 10.16438/j.0513-4870.2024-0019
Peng ZHAO, Cong-hui LI, Si-yi SHUAI, Bing YANG, Hui ZHANG, Nan LIU, Zeng-ming WANG, Yong-jun WANG, Ai-ping ZHENG. Rheology guided the preparation of suvorexant-copovidone solid dispersions via hot melt extrusion technology[J]. Acta Pharmaceutica Sinica, 2024 , 59 (8) : 2396 -2403 . DOI: 10.16438/j.0513-4870.2024-0019
正文
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热熔挤出(hot melt extrusion, HME) 技术因其制备过程无溶剂引入、可连续化加工、可在线监测且放大效应小[1,2], 目前已应用于制药加工领域, 特别是无定形固体分散体(solid dispersion, SD) 的开发[3-5]。热熔挤出技术主要通过热能和机械能使小分子难溶性药物熔融并分散在载体聚合物中来制备无定形固体分散体, 提高药物的溶解度进而提高其生物利用度[6]。最理想的固体分散体是药物与载体材料在分子层面上相互均匀混合形成的“固体溶液”, 其形成与性能和药物在载体材料中的“溶解度”有关。
在药品开发的早期阶段, 活性药物成分的可及性通常是受限的, 这对热熔挤出技术工艺的考察效率提出了较高的要求[7]。因此, 研究人员需要充分了解剪切力和高温对于所加工的材料的影响, 减少对处方工艺的盲目尝试, 进而提高处方工艺的研发效率。流变学研究可以通过测定物料在不同温度与不同角频率变化下物料的模量与黏度等变化情况, 模拟材料在热熔挤出加工条件下的受力和变化情况, 提供材料可加工性的全面信息, 为合理高效优化热熔挤出加工工艺参数提供参考和理论支持, 从而显著降低药物用量并节省大量时间成本[8-10]。
苏沃雷生(suvorexant) 是全球首个以食欲素受体为作用位点的失眠治疗药物, 主要用于难以入睡和/或维持睡眠为特征的失眠的治疗[11,12], 属于BCS Ⅱ类化合物, 溶解度低。但苏沃雷生热稳定性好, 可以采用热熔挤出制备无定形固体分散体来提高其溶解度[13]。在初步筛选的基础上, 选择了共聚维酮作为合适的聚合物结晶抑制剂制备固体分散体。目前, 流变学参数对于固体分散体中药物与载体材料比例的指导作用的相关研究较少, 本研究通过对物料的流变学参数进行考察, 指导固体分散体处方与工艺设计, 并以固体分散体溶出行为作为筛选指标, 最终得到合适的固体分散体药物载体比例与加工温度, 制备得到了质量良好的苏沃雷生无定形固体分散体, 并得到具备目标溶出行为的苏沃雷生片, 进而阐明了流变学在热熔挤出技术制备苏沃雷生固体分散体中的应用。
材料与方法
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试剂  苏沃雷生(批号: SV20090001, Hetero Drugs Limited); 共聚维酮(KollidonVA64, VA64) (批号: 19969836WO, 德国BASF公司); 微晶纤维素(批号: 2173952330, 型号: Avicel PH-101)、交联羧甲基纤维素钠(批号: TN19833106, 型号: Ac-Di-Sol SD711) (美国DuPont公司); 乳糖一水合物(批号: B590000980, 型号: Sheffield™316 Fast Flo, 美国KERRY公司); 硬脂酸镁(批号: MGS-U0210, 意大利FACI公司); 市售片剂Belsomra (20 mg) (批号: T038898, 日本MSD株式会社); 其余试剂均为分析, 实验用水为化水。
仪器  旋转流变仪(型号: HR10, 美国TA公司); 热熔挤出机(型号: Process 11)、高效液相色谱仪(型号: Vanquish) (美国Thermo Scientific公司); 电子天平(型号: BS323S)、电子天平(型号: BT25S) (德国Sartorius公司); 溶出仪(型号: RC806D, 天津天大天发科技有限公司); 差示扫描量热仪(型号: HS-DSC-101, 上海和晟仪器科技有限公司); X射线粉末衍射仪(型号: D/MAX-2600, 日本Rigaku公司); 单冲压片机(型号: DP/30, 北京国药龙立有限公司); 红外压片机(型号: HY-12, 天津天光光学仪器有限公司); 真空干燥箱(型号: DZF-6020, 上海一恒科学仪器有限公司); 片剂脆碎度硬度仪(型号: CJY-2C, 上海黄海药检仪器有限公司); 智能崩解仪(型号: ZB-ID, 天津鑫洲科技有限公司)。
流变学研究
样品制备  将苏沃雷生分别以1∶1、1∶2、1∶3、1∶4和1∶5的质量比与VA64进行混合, 称取适量物理混合物(physical mixture, PM), 使用红外压片机压成直径25 mm, 厚度1 mm的圆片, 在70 ℃下真空干燥1 h[14]。所有流变学实验均采用平行板夹具(直径25 mm), 间隙距离1 mm, 载样温度135 ℃[15]。
振荡温度扫描  以恒定频率10 rad·s-1和应变0.1%对共聚维酮和药辅混合物进行振荡温度扫描, 升温速率3 ℃·min-1, 温度扫描范围100~200 ℃。
振荡温度扫频  在0.1%应变下, 温度范围设定为150~190 ℃, 温度间隔10 ℃, 对1∶4比例的药辅混合物以角频率递减的方式从100 rad·s-1到1 rad·s-1进行频率扫描。
HME制备固体分散体  将苏沃雷生与VA64按一定比例混合均匀后, 缓慢加入热熔挤出机中, 设定螺杆转速为200 r·min-1以保证引入足够的机械能, 再经粉碎、过筛制得苏沃雷生固体分散体。考察苏沃雷生与VA64比例和加工温度对固体分散体的影响, 相应的变量如表 1所示。
苏沃雷生片的制备  取最优处方工艺制备的苏沃雷生固体分散体粉碎, 与微晶纤维素、乳糖、交联羧甲基纤维素钠、硬脂酸镁等辅料混合、然后用单冲压片机直接压片并包衣。
表征方法
含量测定  采用高效液相色谱法按下列色谱条件测定苏沃雷生固体分散体的含量。色谱条件: 流动相为乙腈-0.1 mol·L-1高氯酸钠溶液(48∶52), 流速1.0 mL·min-1, 检测波长254 nm, 进样量10 μL, 柱温40 ℃。
体外溶出实验  参照中国药典2020年版第四部溶出度与释放度测定法第二法(桨法) 进行测定, 水浴温度37 ± 0.5 ℃, 转速75 r·min-1, 测定苏沃雷生原料药、苏沃雷生-VA64 (1∶4) 混合物和苏沃雷生固体分散体在纯化水中的溶出曲线, 测定苏沃雷生片与市售片剂Belsomra在0.4% SDS溶液、pH 1.2盐酸溶液、pH 4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液中的溶出曲线, 分别于5、10、15、20、30、45、60、90 min取液5 mL并补充同体积和温度的溶出介质, 取出液体经0.22 μm滤膜过滤, 取续滤液, 作为供试品溶液。另精密称取苏沃雷生原料药适量, 用甲醇溶解并用溶出介质稀释定容为20 μg·mL-1的溶液作为对照品溶液。取两种溶液照含量测定的色谱条件进行测定, 按外标法以峰面积计算含量。
差示扫描量热法(differential scanning calorimetry, DSC)  使用差示扫描量热仪对苏沃雷生原料药、VA64、苏沃雷生-VA64 (1∶4) 混合物、固体分散体进行考察。称取适量样品于铝制坩锅中, 氮气流速50 mL·min-1, 升温速率10 ℃·min-1, 升温范围为30~200 ℃, 记录样品的热力学曲线。
粉末X射线衍射法(X-ray diffraction, XRD)  使用X射线衍射仪, 以Cu-Ka作为辐射源, 在5~90°的2θ范围内, 扫描速度2 °·min-1检测苏沃雷生原料药、VA64、苏沃雷生-VA64 (1∶ 4)物理混合物、固体分散体的晶型状态。
结果
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1 流变学玻璃态转化温度(thermo-rheological glass transition temperature, Tg,rheo) 对于固体分散体处方的指导作用
不同药物含量制备的固体分散体, 其稳定性、增溶效果、溶出速度可能有较大差异[16]。目前, 流变学参数对于固体分散体中药物与载体材料比例的指导作用的相关研究较少, 已有相关研究主要集中在通过流变学参数指导热熔挤出制备固体分散体工艺参数设计上或通过DSC热力学获取的玻璃态转化温度指导固体分散体处方方面, 本研究利用不同苏沃雷生与VA64比例的物理混合物的流变学测试得到相应的Tg,rheo值, 并以此为依据指导固体分散体中苏沃雷生与VA64比例的选择。采用流变仪振荡温度扫描模式模拟不同加工温度对载体材料及苏沃雷生-VA64混合物的影响, 载体材料与不同药物载体比例物料的振荡温度扫描结果见图 1。弹性模量与损耗模量交点被称为流变学玻璃态转化温度, 其是物料的固有特性, 可以反映材料的物态变化, 是材料内部分子运动形式转变的宏观表现。从结果上可知, 扫描初期, VA64的储能模量(storage modulus, G′) 大于损耗模量(loss modulus, Gʺ), 材料表现为高弹态, 聚合物链结合紧密, 黏度高, 不适于热熔挤出加工。随着加工温度上升, VA64的损耗模量在上升至峰值(约120 ℃时) 后持续下降; 其储能模量在前期几乎不变(平台期), 在接近损耗模量峰值时, 开始持续下降, 并且较损耗模量下降的更快, 当储能模量-温度曲线和损耗模量-温度曲线相交(即加工温度大于Tg,rheo) 后, 材料的储能模量小于损耗模量, 材料表现为玻璃态, 黏度低, 易形变, 更易于热熔挤出加工。材料黏度随温度的变化趋势与储能模量相似, 均为持续一段平台期, 然后随着温度上升而逐渐下降。
当苏沃雷生与VA64混合后, 与VA64相比混合物的储能模量、损耗模量与黏度下降更快(图 1), 苏沃雷生占比越高, 下降速度越快。这是由于药物为小分子化合物, 其熔融后药物分子插入聚合物链之间, 在其中发挥增塑剂的作用[17]。同时, 随着苏沃雷生加入量的增加, Tg,rheo也出现变化, 以苏沃雷生-VA64比例(以混合物中药物含量表示) 为横坐标, 以Tg,rheo为纵坐标, 绘制关系曲线图(图 2)。经对比研究发现混合物中药物比例在1∶4 (药物含量为20%)及以上时, 混合物Tg,rheo随着药物增加呈现出线性上升的趋势, 最终升高至153 ℃, 与苏沃雷生熔点温度162 ℃接近; 而药物比例在1∶ 4及以下时, 混合物Tg,rheo不受药物含量的影响, 数值几乎不变且与载体材料VA64 (药物含量为0%) 的Tg,rheo基本一致。上述现象表明苏沃雷生在VA64中比例较低时, 可以完全“溶解”于载体材料中, 此时混合物展现出VA64的热力学与动力学性质; 当苏沃雷生比例上升至1∶ 4以上时, 苏沃雷生超过其在VA64中的溶解度, 此时混合物逐渐呈现出苏沃雷生的热力学与动力学性质, 所得的固体分散体可能存在着转晶风险。由上述研究可知, 苏沃雷生-VA64比例不宜超过1∶4。
根据上述流变学研究结果, 采用热熔挤出技术制备不同苏沃雷生-VA64比例的固体分散体, 并记录加工过程参数(表 2)。实验结果显示, 随着苏沃雷生含量增加, 挤出机的扭矩、熔体压力下降, 表明苏沃雷生在其中充当增塑剂的作用, 降低了物料的黏度, 更易加工, 这与流变学中模量及黏度变化研究结果一致。DSC与XRD测定结果表明, 各比例下制备的固体分散体中药物均以无定形状态存在(图 3), 但其溶出行为却相差甚远(溶出结果如图 4所示)。药物载体比例在1∶4及以下时, 制备的固体分散体效果更好, 终溶更高。当药物比例逐渐升高超过1∶4后, 固体分散体中药物的量超出了其在VA64中的溶解度, 制备的固体分散体润湿效果差, 增溶能力低, 这与Tg,rheo和药物比例的关系契合。
上述研究表明, 流变学温度扫描研究可以表征材料在不同温度下的性能变化, 能有效模拟材料在热熔挤出过程中不同温度下物态的变化, 从而预测和指导处方的筛选, 特别是, 可以通过不同药物比例混合物的Tg,rheo来快速预测固体分散体的最佳药物载体比例。
2 流变学研究对于热熔挤出加工温度的指导作用
加工温度是热熔挤出技术中的关键工艺参数之一, 目前已有研究指出对于小型挤出机, 物料黏度在800~10 000 Pa·s对应的加工温度为合适的挤出加工温度[18]。本研究基于目前已有流变学指导热熔挤出工艺的研究现状, 对物料流变特性指导温度设定进行了更为细致的研究, 通过流变学指导与热熔挤出机反馈的参数相结合, 最终得到较好的加工温度范围。通过图 1A可知, 以恒定频率10 rad·s-1和应变0.1%的振荡温度扫描获取的苏沃雷生-VA64 (1∶4) 混合物的黏度-温度变化曲线显示苏沃雷生-VA64 (1∶4) 混合物的黏度在约150 ℃时等于10 000 Pa·s, 在约170 ℃时, 黏度等于800 Pa·s, 根据已有研究表明苏沃雷生-VA64 (1∶4) 混合物加工温度应在150~170 ℃之间。
对苏沃雷生-VA64 (1∶4) 混合物进行振荡温度阶梯扫频, 结果如图 5所示。在给定温度下, 也可采用Cross模型的零剪切速率黏度来估计各种药物聚合物组合的挤出机内材料的初始黏度[17]。对于热流变简单材料, 升高温度与延长作用时间可以产生等效的分子运动[19], 故在不同温度下测得的黏度随角频率变化曲线可以通过时温叠加获取特定加工温度下材料黏度随剪切速率的变化情况(图 5A)。Cox-Merz可以关联实验测得的复黏度与挤出机内稳态剪切黏度。经时温叠加获得的主曲线经Cox-Merz转换得到图 5B (以170 ℃为参考温度), 然后使用TRIOS软件中的Cross模型对主曲线进行拟合, 计算零剪切黏度。苏沃雷生- VA64 (1∶4) 混合物在不同温度下零剪切黏度随温度的升高而降低(表 3)。根据苏沃雷生-VA64 (1∶4) 混合物的零剪切黏度的结果可知, 苏沃雷生-VA64 (1∶4) 混合物在加工温度大于150 ℃小于180 ℃时, 其黏度在800~10 000 Pa·s之间, 可以顺利挤出。
结合以上流变学结果, 考察了140、150、160、170、180和190 ℃共6个加工温度。DSC与XRD测定结果表明不同加工温度下制备的固体分散体中药物均以无定形状态存在(图 6)。加工过程中过程参数见表 4, 温度越高, 扭矩与熔体压力越低, 相对更易加工, 这与流变学中模量及黏度变化研究结果一致。结果表明, 当加工温度在140 ℃时, 会使挤出机扭矩过大, 无法顺利加工, 加工温度在150~180 ℃时挤出、收集过程顺利, 但加工温度在190 ℃时, 挤出物温度过高, 无法很快冷却成型, 不便收集。结合流变学参数, 流变温度扫描物料黏度在10 000 Pa·s以下的温度为合适的加工温度下限, 加工温度的上限视物料的稳定性与挤出加工下游冷却的情况决定, 故根据加工情况而言150~180 ℃为合适的加工温度。根据Cross模型计算得到的零剪切黏度也可以为热熔挤出参数设定提供一定的参考, 其温度范围较流变温度扫描获取的更窄。结合制备的固体分散体溶出情况而言, 150 ℃下加工制备的固体分散体前期溶出相对较慢, 可能是150 ℃下苏沃雷生未能完全转化为无定形状态, 固体分散体内存在少量DSC与XRD检测限以下的微晶, 润湿效果差, 造成溶出前期速度的微小差异(图 7), 故最终拟定160~180 ℃为合适的加工温度。
3 苏沃雷生片性能评价
借助流变学研究指导处方工艺研究后, 确定最优处方为苏沃雷生-VA64比例为1∶4, 最适的加工温度为160~180 ℃。按上述处方工艺制备固体分散体, 并制备苏沃雷生片, 测定其溶出曲线。自制苏沃雷生片与市售片剂Belsomra在0.4% SDS溶液、pH 1.2盐酸溶液、pH 4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液中的溶出行为如图 8所示。根据CDE普通口服固体制剂溶出曲线测定与比较指导原则, 采用非模型依赖法中的相似因子(f2) 法来评价自制苏沃雷生片与市售片剂Belsomra的溶出曲线的相似性。相似因子作为供试制剂和参比制剂之间差异的平方和误差的对数变换, 通过公式(1) 计算相似因子:
$ {f}_{2}=50\mathrm{ }\times lg\left\{\right[1+{(1/n){\sum }_{t=1}^{n}({R}_{t}-{T}_{t}{)}^{2}]}^{-0.5}\times \mathrm{ }100\} $
其中, Rt为t时间参比样品平均溶出量; Tt为t时间受试样品平均溶出量; n为取样时间点的个数。
一般情况下, 当两条溶出曲线相似因子(f2) 数值不小于50时, 可认为溶出曲线相似。根据上述公式, 计算出不同介质中苏沃雷生片与市售片剂Belsomra的f2分别为69.1 (0.4% SDS溶液, n = 4), 66.4 (pH 1.2盐酸溶液, n = 6), 均大于50。同时, 在pH 4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液中苏沃雷生片与市售片剂溶出趋势相近, 但由于终溶均未达到85%以上, 未进行相似因子计算。这表明使用流变学结合筛选出的最优处方与工艺制备的固体分散体进而制备的片剂的体外溶出与市售片剂Belsomra相似, 自制固体分散体处方工艺良好, 流变学参数对于热熔挤出制备固体分散体有很大的指导作用。
讨论
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本研究通过测定VA64与苏沃雷生-VA64混合物的流变学参数指导热熔挤出加工固体分散体。振荡温度扫描获取的苏沃雷生-VA64混合物的Tg,rheo反映了苏沃雷生与共聚维酮的最佳比例。当苏沃雷生与共聚维酮的比例大于1∶4时, 其Tg,rheo会逐渐升高, 直至苏沃雷生熔点附近, 此时苏沃雷生超出了其在共聚维酮中的溶解度, 制备的固体分散体可能有较大的重结晶风险, 故最优的药物载体比例为Tg,rheo未发生变化时的比例, 即1∶4。同时, 通过振荡温度扫描与振荡温度扫频获取苏沃雷生-VA64混合物的黏度随温度变化情况。当加工温度140 ℃时, 物料黏度大于10 000 Pa·s, 挤出机扭矩过大, 无法顺利加工; 190 ℃时, 黏度过低, 物料难以冷却成型, 后续下游不便操作, 适宜的黏度下限由物料稳定性与下游冷却系统效率决定, 最终结合溶出结果, 确定最优的加工温度范围为160~180 ℃。使用最优处方工艺制备的固体分散体质量良好, 溶出明显改善, 同时以此制备的片剂与已上市制剂体外溶出相似。
热熔挤出制备固体分散体主要通过输入机械能与热能使物料在机体内部熔融、混合, 最终从模头以一定的形状挤出。在整个加工过程中, 材料的熔体流变学性质对于加工有着重要影响。通过测试载体辅料与药辅混合物的流变学特性, 可以预测固体分散体的处方与加工工艺, 很大程度上节约物料, 缩短处方与工艺筛选时间, 对于固体分散体制备过程中药物载体比例与工艺考察有着重要意义。
作者贡献: 赵朋、李聪慧具体完成撰写任务; 帅思祎完成文献检索和筛选; 杨兵完成了实验的设计与操作; 张慧、刘楠共同完成实验数据的分析; 王增明对文章撰写的内容进行了审校与把关; 王永军、郑爱萍确定文章方向及内容组成。
利益冲突: 本文所有作者声明不存在利益冲突关系。
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  • 国家重点研发计划资助项目(2023YFC2706100)
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2024年第59卷第8期
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doi: 10.16438/j.0513-4870.2024-0019
  • 接收时间：2024-01-09
  • 首发时间：2025-11-26
  • 出版时间：2024-08-12
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  • 收稿日期：2024-01-09
  • 修回日期：2024-04-18
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国家重点研发计划资助项目(2023YFC2706100)
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    1.沈阳药科大学无涯创新学院, 辽宁 沈阳 110016
    2.军事医学研究院国家安全特需药品全国重点实验室, 北京 100850

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*王永军, Tel: 86-24-23986325, E-mail: ;
郑爱萍, Tel: 86-10-66931694, E-mail:
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2种不同金属材料的力学参数
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species		 占总种数比例
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total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
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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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