RRC ID |
69857
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著者 |
Togami K, Ogasawara A, Irie S, Iwata K, Yamaguchi K, Tada H, Chono S.
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タイトル |
Improvement of the pharmacokinetics and antifibrotic effects of nintedanib by intrapulmonary administration of a nintedanib-hydroxypropyl-γ-cyclodextrin inclusion complex in mice with bleomycin-induced pulmonary fibrosis.
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ジャーナル |
Eur J Pharm Biopharm
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Abstract |
Idiopathic pulmonary fibrosis is a chronic lung disease that is characterized by progressive abnormal reprogramming following injury of the pulmonary structure. In this study, we prepared a nintedanib (antifibrotic agent) and cyclodextrin (CyD) inclusion complex to improve the pharmacokinetics and antifibrotic effects of nintedanib following intrapulmonary administration. Hydroxypropyl-γ-CyD (HP-γ-CyD) enhanced the solubility of nintedanib without cytotoxic effects on WI-38 cells (lung fibroblasts) and NCI-H441 cells (alveolar epithelium model). Compared with nintedanib ethanesulfonate salt, the nintedanib-HP-γ-CyD inclusion complex exhibited prolonged distribution in the lungs following intrapulmonary administration in mice with bleomycin-induced pulmonary fibrosis. In addition, compared with nintedanib ethanesulfonate salt, the nintedanib-HP-γ-CyD inclusion complex exhibited higher stability in the bronchoalveolar lavage fluid and lower permeability in NCI-H441 cell monolayers. These results suggested that the inclusion complexation of nintedanib into HP-γ-CyD improved its pharmacokinetics following intrapulmonary administration by increasing its stability in the lungs and reducing its permeability through the alveolar cell membrane. Intrapulmonary administration of the nintedanib-HP-γ-CyD inclusion complex significantly reduced the intrapulmonary hydroxyproline content and limited pathological fibrotic changes. Overall, this study indicates that antifibrotic agent-CyD inclusion complexation intended for intrapulmonary administration can be used to prolong distribution in the lungs and lead to the expansion of idiopathic pulmonary fibrosis therapy.
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巻・号 |
172
|
ページ |
203-212
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公開日 |
2022-3-1
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DOI |
10.1016/j.ejpb.2022.02.009
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PII |
S0939-6411(22)00030-3
|
PMID |
35183716
|
MeSH |
Animals
Bleomycin*
Idiopathic Pulmonary Fibrosis* / chemically induced
Idiopathic Pulmonary Fibrosis* / drug therapy
Indoles / pharmacology
Mice
gamma-Cyclodextrins
|
IF |
4.604
|
リソース情報 |
ヒト・動物細胞 |
WI-38(RCB0702) |