Aerosolised lung surfactant-based formulation stabilisation to optimise inhalable controlled drug delivery

外源性肺表面活性物质(LS)治疗早产儿和成人涉及动物来源的LS致密脂蛋白配方的气管内滴注(ITI)。大多数需要LS治疗的患者都是插管的，这导致了他们对雾化吸入制剂的偏好。目前的临床试验正在探索以ITI的形式和作为COVID19患者的雾化器的LS疗法，以治疗急性呼吸窘迫综合征、炎性风暴和促进呼吸。这些制剂深入到气体交换单元(肺泡)，尽管具有巨大的潜力，但仍处于起步阶段，不仅可用作肺表面活性物质的外源性治疗，还可用作可吸入药物的载体。一个主要的障碍是设计一种雾化制剂，它将保留LS的物理和化学特性，以达到和输送药物，并在到达肺泡时保持稳定。该项目旨在开发基于LS特性的新的稳定配方，以深入肺部，优化药物输送。该项目将需要以优化芯片平台上的器官的形式进行方法开发，以集成到光学荧光显微镜中。芯片平台上的器官将是我们目前在实验室工作的器官的实现。我们将实现该芯片，通过改变施加不同压力的不同正弦或二次流，在频率和持续时间上模拟不同的曝光制度。我们的预期结果是，在项目结束时，我们将确定如何更好地设计和稳定不同的LS雾化制剂，我们将了解这些配方如何在肺泡上皮细胞内化，并将表征肺泡上皮细胞的代谢和免疫反应，因此我们可以更好地设计未来的配方。EPSRC领域：粒子技术和生物物理学

Exogenous lung surfactant (LS) therapies in premature babies and adults involve intratracheal instillation (ITI) of animal-derived LS dense lipoprotein formulations. Most patients in need of LS therapy are intubated, which led to the preference for an aerosolised inhalable formulation. Current clinical trials are exploring LS therapy in form of ITI and also as nebulisers in COVID19 patients to treat the acute respiratory distress syndrome, inflammatory storm and facilitate breathing. These formulations, reaching deep into the gas-exchange units (alveoli), are in their infancy despite its enormous potential, not only to be used as lung surfactant exogenous therapy, but also as inhalable drug carriers. A major hindrance is to design a nebulised formulation that will retain the physical and chemical characteristics of LS to reach and deliver drugs and is stable when reaching the alveoli. This project aims at developing new stable formulations based in the LS properties to reach deep into the lungs to optimise drug delivery. This project will require method development in form of optimisation of an organ on a chip platform to be integrated into an optical fluorescence microscope. The organ on a chip platform will be an implementation to the current ones we have working in the lab. We will implement the chip to mimic different exposure regimes in frequency, and duration, by changing different sinusoidal or quadratic flows applying various pressures. Our expected outcome is that, by the end of the project, we will have determined how to better design and stabilise the different LS-based aerosolised formulations, we will have learnt how these formulations are internalised at the alveolar epithelium, and will have characterised the metabolic, and immune responses of the alveolar epithelial cells, so we can better design future formulations. EPSRC areas: particle technology and biophysics