College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China; Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, and Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Xi'an, 710032, China.
Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, and Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Xi'an, 710032, China.
Int J Pharm. 2024 Jul 20;660:124302. doi: 10.1016/j.ijpharm.2024.124302. Epub 2024 Jun 4.
Pulmonary fibrosis (PF) is a chronic, progressive, and fatal lung disease with a high mortality rate. Nintedanib, as a multi-tyrosine kinase inhibitor, is widely used as the first line drug for PF patients. However, only nintedanib oral formulations are used currently in clinic and show a low drug selectivity, significant first-pass effect and low bioavailability with 4.7%, thus limiting the clinical outcome of nintedanib. In this study, nintedanib was prepared in the form of nintedanib nanocrystalline (Nib-NC) and then encapsulated with hyaluronic acid (HA) to construct a nanocrystalline-in-adhesive delivery system Nib-NC@HA with high drug loading efficacy and pulmonary bio-adhesive properties, which could avoid the first-pass effects, increase the bioavailability and reduce the systemic side effects of nintedanib. After inhalation administration of Nib-NC@HA, due to the bio-adhesive properties of HA, Nib-NC@HA could prolong the retention time of drug in the lungs and inhibit the expression of inflammation associated factors such as IL-6, IL-1β and TNF-α in lung tissue, reduce the release of pro-fibrotic growth factor, and improve the lung function, thus showing enhanced anti-fibrotic effect than Nib-NC. The results suggested that Nib-NC@HA is an efficient and optimal targeted bio-adhesive delivery system for the lungs to treat pulmonary fibrosis.
肺纤维化（PF）是一种慢性、进行性和致命的肺部疾病，死亡率很高。尼达尼布作为一种多靶点酪氨酸激酶抑制剂，被广泛用作 PF 患者的一线药物。然而，目前临床上仅使用尼达尼布的口服制剂，其药物选择性低，首过效应显著，生物利用度仅为 4.7%，从而限制了尼达尼布的临床疗效。在本研究中，我们将尼达尼布制备成尼达尼布纳米晶（Nib-NC），然后用透明质酸（HA）包封，构建了具有高载药效率和肺部生物黏附特性的纳米晶黏附递药系统 Nib-NC@HA，可避免首过效应，提高生物利用度，降低尼达尼布的全身副作用。经吸入给予 Nib-NC@HA 后，由于 HA 的生物黏附特性，Nib-NC@HA 可延长药物在肺部的滞留时间，并抑制肺组织中与炎症相关的因子如 IL-6、IL-1β和 TNF-α的表达，减少促纤维化生长因子的释放，改善肺功能，从而显示出比 Nib-NC 更强的抗纤维化作用。结果表明，Nib-NC@HA 是一种高效、优化的肺部靶向生物黏附递药系统，可用于治疗肺纤维化。
