Nintedanib esylate
(Synonyms: 乙磺酸尼达尼布; BIBF 1120 esylate) 目录号 : GC36745
Nintedanib esylate, as a kinase inhibitor, used for the treatment of non-small cell lung cancer suffered from first-pass metabolism which resulted in low oral bioavailability .
Cas No.:656247-18-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
HUVECs |
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Preparation Method |
The cell viability was detected after HUVECs were added with Nintedanib (1, 5, 10, 25, 50, and 100 µM) to determine the optimized incubation concentrations. |
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Reaction Conditions |
1, 5, 10, 25, 50, and 100 µM; for 24 hours |
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Applications |
When the concentration of Nintedanib was greater than 50 µM, a significantly declined viability of HUVECs was observed. |
| Animal experiment [2]: | |
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Animal models |
male TRAMP mice |
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Preparation Method |
In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6-10 weeks after stopping drug treatments. |
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Dosage form |
10 mg/Kg/day; p.o. |
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Applications |
In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. |
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References: Li L, et al. Nintedanib ameliorates oxidized low-density lipoprotein -induced inflammation and cellular senescence in vascular endothelial cells. Bioengineered. 2022 Mar;13(3):6196-6207. | |
Nintedanib esylate, as a kinase inhibitor, used for the treatment of non-small cell lung cancer suffered from first-pass metabolism which resulted in low oral bioavailability (~ 4.7%)[1]. Nintedanib is an effective inhibitor of multityrosine kinase receptors.
In vitro, treatment with 1-4 µM nintedanib in a dose-dependently manner in Keloid fibroblasts inhibited cell proliferation, induced G0/G1 cell cycle arrest, and suppressed migration and invasion of keloid fibroblasts[2]. In vitro test it shown that at 1 µM Nintedanib and 2.5 mM Pirfenidone decreased fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells[3]. In vitro, 0.01-1.0 µM nintedanib in IPF (Idiopathic pulmonary fibrosis) fibroblasts decreased the expression of collagen I and V, fibronectin, and FKBP10 and attenuated the secretion of collagen I and III[4].
In vivo efficacy test it exhibited that treatment with 5 mg/mL nintedanib in eye drops four times daily, the outgrowths of blood and lymphatic vessels were obviously inhibited compared with the controls[5]. In vivo, treatment with 3 µM and 5 µM nintedanib in mice up-regulated SP-D (Pulmonary surfactant protein D) messenger RNA expression[6]. In vivo experiment it demonstrated that treatment with nintedanib (50, 100 mg/kg) orally could obviously recover the experimental colitis-related symptoms of mice caused by DSS, such as weight loss, increased DAI, shortened colon length, and colonic tissue injury[7].
Kala SG, et al. Bioavailability enhancement of vitamin E TPGS liposomes of nintedanib esylate: formulation optimization, cytotoxicity and pharmacokinetic studies. Drug Deliv Transl Res. 2022 Nov;12(11):2856-2864.
Zhou BY, et al. Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization. Acta Pharmacol Sin. 2020 Sep;41(9):1234-1245.
Lehmann M, et al. Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis. Respir Res. 2018 Sep 15;19(1):175.
KnÜppel L, et al. A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly. Am J Respir Cell Mol Biol. 2017 Jul;57(1):77-90.
Lin T, et al. Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib. Drug Des Devel Ther. 2017 Apr 5;11:1147-1158.
Kamio K, et al. Nintedanib modulates surfactant protein-D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase-activator protein-1 pathway. Pulm Pharmacol Ther. 2015 Jun;32:29-36.
Li H, et al. Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways. Front Pharmacol. 2022 Jul 14;13:904420.
References:
Nintedanib esylate，作为一种激酶抑制剂，用于治疗非小细胞肺癌，首过代谢导致口服生物利用度低（~4.7%）[1]。 Nintedanib 是一种有效的多酪氨酸激酶受体抑制剂。
在体外，1-4 77777#8181;M nintedanib 以剂量依赖性方式治疗瘢痕疙瘩成纤维细胞，抑制细胞增殖，诱导 G0/G1 细胞周期停滞，并抑制瘢痕疙瘩成纤维细胞的迁移和侵袭[2]。体外试验表明，在 1 µM Nintedanib 和 2.5 mM Pirfenidone 下，小鼠和人类 3D-LTC 以及 pmATII 细胞[3] 中的纤维化基因表达（包括胶原蛋白 1a1 和纤连蛋白）降低。在体外，0.01-1.0 µM nintedanib 在 IPF（特发性肺纤维化）成纤维细胞中降低胶原蛋白 I 和 V、纤连蛋白和 FKBP10 的表达，并减弱胶原蛋白 I 和 III 的分泌[4] .
体内药效试验表明，5mg/mL尼达尼布滴眼液每天4次治疗，与对照组相比，血管和淋巴管的增生明显受到抑制[5]。在体内，用 3 µM 和 5 µM 尼达尼布治疗小鼠可上调 SP-D（肺表面活性蛋白 D）信使 RNA 表达[6]。体内实验表明，口服尼达尼布（50、100 mg/kg）可明显恢复DSS引起的小鼠实验性结肠炎相关症状，如体重减轻、DAI增加、结肠长度缩短、结肠组织损伤< sup>[7].
Kala SG, et al.尼达尼布乙磺酸盐维生素 E TPGS 脂质体的生物利用度增强:配方优化、细胞毒性和药代动力学研究。 Drug Deliv Transl Res. 2022 年 11 月；12(11):2856-2864。
Zhou BY, et al. Nintedanib 通过阻断多种激酶的磷酸化和增强受体内化来抑制瘢痕疙瘩成纤维细胞的功能。 Acta Pharmacol 罪。 2020 年 9 月；41(9):1234-1245。
Lehmann M 等人。尼达尼布和吡非尼酮对肺纤维化离体小鼠和人肺组织培养物中肺泡上皮细胞功能的不同影响。呼吸研究。 2018 年 9 月 15 日；19(1):175。
KnÜppel L, et al.尼达尼布和吡非尼酮的新型抗纤维化机制。抑制胶原原纤维组装。 Am J Respir Cell Mol Biol。 2017 年 7 月；57(1):77-90。
Lin T, et al.多激酶抑制剂尼达尼布在体外和体内抑制淋巴管生成。药物 Devel Ther。 2017 年 4 月 5 日；11:1147-1158。
Kamio K 等人。 Nintedanib 通过 c-Jun N-末端激酶-激活蛋白-1 通路调节 A549 人肺上皮细胞中表面活性蛋白-D 的表达。 Pulm Pharmacol Ther。 2015 年 6 月；32:29-36。
Li H, et al. Nintedanib 通过抑制 CEBPB/PCK1 和 CEBPB/EFNA1 通路减轻实验性结肠炎。前药理学。 2022 年 7 月 14 日；13:904420。
| Cas No. | 656247-18-6 | SDF | |
| 别名 | 乙磺酸尼达尼布; BIBF 1120 esylate | ||
| Canonical SMILES | O=C(C1=CC(NC/2=O)=C(C=C1)C2=C(NC3=CC=C(N(C)C(CN4CCN(C)CC4)=O)C=C3)/C5=CC=CC=C5)OC.CCS(=O)(O)=O | ||
| 分子式 | C33H39N5O7S | 分子量 | 649.76 |
| 溶解度 | DMSO: 92.85 mg/mL (142.90 mM and warming) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.539 mL | 7.6951 mL | 15.3903 mL |
| 5 mM | 0.3078 mL | 1.539 mL | 3.0781 mL |
| 10 mM | 0.1539 mL | 0.7695 mL | 1.539 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Enhanced oral bioavailability of Nintedanib esylate with nanostructured lipid carriers by lymphatic targeting: In vitro, cell line and in vivo evaluation
Eur J Pharm Sci 2021 Apr 1;159:105715.PMID:33453388DOI:10.1016/j.ejps.2021.105715.
The present research work was aimed to explore the ability of nanostructured lipid carriers (NLCs) to improve oral bioavailability of Nintedanib esylate (NE) via lymphatic uptake. The NE loaded NLCs (NE-NLCs) were fabricated using high speed homogenization followed by probe sonication method and physiochemically characterized. The NE-NLCs had particle size of 125.7 ± 5.5 nm, entrapment efficiency of 88.5 ± 2.5% and zeta potential of -17.3 ± 3.5 mV. DSC and XRD studies indicated that NE was converted to amorphous form. TEM images showed uniformly distributed spherical shaped particles. In vitro release study of NE-NLCs showed drug release of 6.87 ± 2.72% in pH 1.2 and 92.72 ± 3.40% in phosphate buffer pH 6.8 and obeyed higuchi model. Lipolysis study showed higher amount of drug in aqueous layer in NE-NLCs compared to NE-suspension. Tissue distribution study showed deeper penetration of FITC loaded NLCs compared to FITC solution. The cellular uptake across Caco-2 cells exhibited more uptake of FITC loaded NLCs. Cytotoxicity study using A549 cell line revealed higher potential of NE-NLCs in inhibiting tumor cell growth in comparison to that of suspension. The oral bioavailability of NE was ameliorated over 26.31 folds after inclusion into NLCs in contrast to NE-suspension. Intestinal lymphatic uptake of NE-NLCs in cycloheximide treated mice was lower as compared to control without cycloheximide treatment. Thus, the developed NE-NLCs can be an encouraging delivery strategy for increasing oral bioavailability of NE via lymphatic uptake.