Gadhave Dnyandev, Quadros Mural, Goyal Mimansa, Ugale Akanksha R, Gupta Vivek
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, USA.
College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, USA.
AAPS J. 2025 Aug 11;27(5):129. doi: 10.1208/s12248-025-01119-5.
Nintedanib (Nint) is a potent tyrosine kinase inhibitor recently approved by the US FDA to treat idiopathic pulmonary fibrosis (IPF). Delivery of Nint through available approaches is highly challenging because of its poor solubility and rapid metabolic degradation via hydrolytic ester cleavage, thereby reflecting poor oral bioavailability (< 5%). Hence, the current study was focused on formulating a Nint-loaded microemulsion (Nint-ME) and investigating its therapeutic potential in experimental animals to overcome the constraints of available therapies. Nint-ME was prepared via low-energy O/W emulsification aqueous titration techniques and optimized using QbD approach. Optimized ME subjected to screen for globule size, polydispersity index, encapsulation efficiency, transmittance, surface charge, and viscosity and were found to be 23.8 ± 1.4 nm, 0.18 ± 0.03, 99.8 ± 2.4%, 99.4 ± 0.1%, -0.7 ± 0.01 mV, and 1.5 ± 0.3 cP, respectively. Additionally, 94.5 ± 3.1% Nint was released from Nint-ME through the dialysis cassette within 72 h, demonstrating first-order kinetics with R of 0.966. First-order and Higuchi release kinetic patterns support concentration-dependent release and Fickian diffusion from the matrix of Nint-ME. In-vitro permeation study of Nint across Caco2 colon epithelial cell monolayer depicted 48.1 ± 1.5 µg of cellular permeation out of 50 µg, ensuring the permeation potential of Nint-ME. Concurrently, an in-vivo pharmacokinetic study for optimized Nint-ME against Nint suspension reflected 41.0 ± 12.5% oral bioavailability, a 2-fold enhancement compared to plain Nint suspension. Existing work demonstrated the successful development of oral Nint-ME as a novel formulation for safe and effective delivery of Nint in IPF.
尼达尼布（Nint）是一种强效酪氨酸激酶抑制剂，最近被美国食品药品监督管理局（FDA）批准用于治疗特发性肺纤维化（IPF）。由于其溶解度差且通过水解酯裂解快速代谢降解，通过现有方法递送尼达尼布极具挑战性，因此口服生物利用度较低（<5%）。因此，本研究的重点是制备载有尼达尼布的微乳剂（Nint-ME），并在实验动物中研究其治疗潜力，以克服现有治疗方法的局限性。Nint-ME通过低能O/W乳化水溶液滴定技术制备，并采用质量源于设计（QbD）方法进行优化。对优化后的微乳剂进行了粒径、多分散指数、包封率、透光率、表面电荷和粘度的筛选，结果分别为23.8±1.4nm、0.18±0.03、99.8±2.4%、99.4±0.1%、-0.7±0.01mV和1.5±0.3cP。此外，72小时内通过透析盒从Nint-ME中释放出94.5±3.1%的尼达尼布，呈现一级动力学，R为0.966。一级和 Higuchi 释放动力学模式支持尼达尼布从 Nint-ME 基质中的浓度依赖性释放和菲克扩散。尼达尼布在Caco2结肠上皮细胞单层上的体外渗透研究表明，50μg中有48.1±1.5μg细胞渗透，确保了Nint-ME的渗透潜力。同时，针对优化后的Nint-ME与尼达尼布混悬液的体内药代动力学研究表明，口服生物利用度为41.0±12.5%，与普通尼达尼布混悬液相比提高了2倍。现有工作证明了口服Nint-ME作为一种新型制剂在IPF中安全有效地递送尼达尼布的成功开发。
