Insmed Incorporated, Bridgewater, NJ 08807, USA.
Int J Mol Sci. 2021 Jan 7;22(2):548. doi: 10.3390/ijms22020548.
Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.
屈昔多巴棕榈酸酯（TP）是屈昔多巴（TRE）的前体药物，TRE 先前已被制成可通过雾化器吸入的制剂。TP 在肺部有持续存在，全身暴露减少，体内缺氧性肺血管收缩的抑制作用延长。在此，我们报告了重新配方的努力，旨在开发一种更方便的基于溶液的计量吸入器（MDI）制剂的屈昔多巴棕榈酸酯，一种与雾化 TP 制剂（屈昔多巴棕榈酸酯吸入混悬剂，TPIS）的药代动力学（PK）和疗效特征相匹配的屈昔多巴棕榈酸酯吸入气雾剂（TPIA）。MDI 罐使用两阶段填充方法制造。利用气雾剂性能、配方溶解度和化学稳定性测定进行体外评估。对于体内研究，使用为 MDI 输送而修改的吸入塔向啮齿动物输送 TPIA 制剂。通过涉及体外评估制剂性能（TP 和赋形剂溶解度、化学稳定性、物理稳定性和气雾剂特性）和体内确证性测试（大鼠 PK 和功效、豚鼠咳嗽）的迭代过程，确定了一种有前途的配方。优化的配方 TPIA-W 表现出均匀的体外药物输送、适合每日一次给药的 PK 特征、在缺氧挑战模型中至少持续 12 小时的功效，以及比母体药物屈昔多巴高得多的咳嗽阈值。
