结构对结肠稳定性和组织透性的影响
Farhan Taherali1,2, Nerisha Chouhan1, Fanjin Wang1
1Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK.
战略性体设计,包括循环化和D-氨基酸替代,增强了口服药物到结肠的输送. 这项研究改善了治疗结肠疾病的稳定性和透性.
科学领域:
- 制药科学 制药科学
- 药物运输 药物运输 药物运输
- 药用化学 医学化学
背景情况:
- 由于胃肠道稳定性和透性不佳,类药物通常需要通过肠道给药.
- 在将口服类药物输送策略转化为临床实践方面取得了有限的成功.
- 了解结肠分娩的设计对于治疗炎症性肠病和结肠直肠癌至关重要.
研究的目的:
- 调查循环化和D-氨基酸替代对结肠中的稳定性和透性的影响.
- 评估基于催产素的类药物,用于口服输送到结肠部位.
- 确定用于增强结肠药物递送的关键分子设计特征.
主要方法:
- 合成了11种基于催产素的类类似物,具有各种循环化修饰和D-氨基酸替代.
- 在人类结肠模型中评估了酶稳定性.
- 在老鼠结肠组织中测量了的透性.
主要成果:
- 与线性类似物相比,在原生催产素中的二硫化键循环化在人类结肠模型中提高了稳定性.
- 在1.5小时后,乙循环化增加了30.0%的稳定性;其他循环化没有显著的益处.
- 三种D-氨基酸替代 (Tyr,Ile,Leu) 显著改善了稳定性 (58.2%线性,79.1%周期性) 并增加了老鼠结肠组织的通透性.
结论:
- 战略性体设计,特别是循环和D-氨基酸替代,可以显著提高结肠输送的稳定性和透性.
- D-氨基酸替代可以通过有利地改变二次结构来改善的透性.
- 这项研究证明了口服类药物向结肠输送的可行策略.
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