Preparation of a Stable Indomethacin Supersaturated Solution Using Hydrophobically Modified Hydroxypropylmethylcellulose and α-Cyclodextrin.

IF 1.5 4区 医学 Q4 CHEMISTRY, MEDICINAL
Hiroki Akahoshi, Fumitoshi Hirayama, Kenjirou Higashi, Daisuke Iohara
{"title":"Preparation of a Stable Indomethacin Supersaturated Solution Using Hydrophobically Modified Hydroxypropylmethylcellulose and α-Cyclodextrin.","authors":"Hiroki Akahoshi, Fumitoshi Hirayama, Kenjirou Higashi, Daisuke Iohara","doi":"10.1248/cpb.c24-00748","DOIUrl":null,"url":null,"abstract":"<p><p>In the present study, the stability of a supersaturated solution of indomethacin (IM) was evaluated in hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) solutions, with and without parent cyclodextrins (CDs). A highly supersaturated state of IM was maintained in the HM-HPMC solution and was further stabilized by the addition of α-CD and β-CD. Notably, the highest level of supersaturation was achieved in HM-HPMC/α-CD solution, which maintained a high concentration of IM for up to 120 h. IM concentrations in these solutions exceeded the amorphous solubility, indicating that phase separation had occurred. To explore this phase separation, Nile Red, a fluorescent probe sensitive to hydrophobic environments, was added to the supersaturated solutions. A higher fluorescence intensity was observed in the HM-HPMC/α-CD solution compared with the HM-HPMC solution, indicating a significant formation of colloidal amorphous aggregates in the supersaturated solution. Cryogenic transmission electron microscopy (Cryo TEM) analysis confirmed the presence of these aggregates, which appeared irregularly shaped. These findings suggest that the combination of HM-HPMC and α-CD effectively stabilized the colloidal amorphous aggregates in the IM supersaturated solution. The addition of α-CD facilitated the dissociation of HM-HPMC into smaller particles, increasing the number of hydrophobic stearyl moieties available for interactions with amorphous IM aggregates, thereby enhancing the stability of the supersaturated state. The combination of HM-HPMC and α-CD offers a promising approach to improving the oral bioavailability of drugs with poor water solubility.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"39-45"},"PeriodicalIF":1.5000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical & pharmaceutical bulletin","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1248/cpb.c24-00748","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

In the present study, the stability of a supersaturated solution of indomethacin (IM) was evaluated in hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) solutions, with and without parent cyclodextrins (CDs). A highly supersaturated state of IM was maintained in the HM-HPMC solution and was further stabilized by the addition of α-CD and β-CD. Notably, the highest level of supersaturation was achieved in HM-HPMC/α-CD solution, which maintained a high concentration of IM for up to 120 h. IM concentrations in these solutions exceeded the amorphous solubility, indicating that phase separation had occurred. To explore this phase separation, Nile Red, a fluorescent probe sensitive to hydrophobic environments, was added to the supersaturated solutions. A higher fluorescence intensity was observed in the HM-HPMC/α-CD solution compared with the HM-HPMC solution, indicating a significant formation of colloidal amorphous aggregates in the supersaturated solution. Cryogenic transmission electron microscopy (Cryo TEM) analysis confirmed the presence of these aggregates, which appeared irregularly shaped. These findings suggest that the combination of HM-HPMC and α-CD effectively stabilized the colloidal amorphous aggregates in the IM supersaturated solution. The addition of α-CD facilitated the dissociation of HM-HPMC into smaller particles, increasing the number of hydrophobic stearyl moieties available for interactions with amorphous IM aggregates, thereby enhancing the stability of the supersaturated state. The combination of HM-HPMC and α-CD offers a promising approach to improving the oral bioavailability of drugs with poor water solubility.

疏水改性羟丙基甲基纤维素和α-环糊精制备稳定的吲哚美辛过饱和溶液。
在本研究中,研究了吲哚美辛(IM)过饱和溶液在疏水改性羟丙基甲基纤维素(HM-HPMC)溶液中,有和没有母体环糊精(CDs)的稳定性。IM在HM-HPMC溶液中保持高度过饱和状态,并通过α-CD和β-CD的加入进一步稳定。值得注意的是,在HM-HPMC/α-CD溶液中达到了最高的过饱和水平,该溶液中高浓度的IM保持了长达120 h,这些溶液中的IM浓度超过了非晶溶解度,表明发生了相分离。为了探索这种相分离,将对疏水环境敏感的荧光探针Nile Red添加到过饱和溶液中。与HM-HPMC/α-CD溶液相比,HM-HPMC/α-CD溶液的荧光强度更高,表明在过饱和溶液中形成了明显的胶体无定形聚集体。低温透射电镜(Cryo TEM)分析证实了这些聚集体的存在,其形状不规则。这些结果表明,HM-HPMC和α-CD的结合有效地稳定了IM过饱和溶液中的胶体非晶态聚集体。α-CD的加入促进了HM-HPMC解离成更小的颗粒,增加了可与无定形IM聚集体相互作用的疏水硬脂基基团的数量,从而增强了过饱和状态的稳定性。HM-HPMC与α-CD的联合为提高水溶性较差药物的口服生物利用度提供了一条很有前景的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
3.20
自引率
5.90%
发文量
132
审稿时长
1.7 months
期刊介绍: The CPB covers various chemical topics in the pharmaceutical and health sciences fields dealing with biologically active compounds, natural products, and medicines, while BPB deals with a wide range of biological topics in the pharmaceutical and health sciences fields including scientific research from basic to clinical studies. For details of their respective scopes, please refer to the submission topic categories below. Topics: Organic chemistry In silico science Inorganic chemistry Pharmacognosy Health statistics Forensic science Biochemistry Pharmacology Pharmaceutical care and science Medicinal chemistry Analytical chemistry Physical pharmacy Natural product chemistry Toxicology Environmental science Molecular and cellular biology Biopharmacy and pharmacokinetics Pharmaceutical education Chemical biology Physical chemistry Pharmaceutical engineering Epidemiology Hygiene Regulatory science Immunology and microbiology Clinical pharmacy Miscellaneous.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信