Exploiting novel materials to overcome physiological barriers for oral inhalation of biologics

多肽、蛋白质和抗体等生物药物是功能强大的大分子药物，已被确定为治疗各种疾病的重要治疗药物。由于其高度的特异性和效力，预计生物制剂将主导大多数管道。由于它们对降解的高度敏感性和大分子尺寸限制了通过上皮的运输，生物制剂的给药在很大程度上局限于具有侵入性的非肠道途径，需要适当的训练。提供生物制剂的非侵入性方法非常受欢迎。口服吸入剂在输送生物制剂方面有很大的希望，因为肺的大表面积和高度的血管化使其能够快速全身吸收。这条路线还可以增加呼吸道中的药物浓度，使其适合于局部治疗肺部疾病，如严重的哮喘、呼吸道感染和肺癌，这些疾病是全球巨大的健康负担。吸入是非侵入性的，可以自我给药。通过将生物制品制成干粉形式，也提高了生物制剂的稳定性。这延长了产品的保质期，避免了冷链，减少了药品浪费和对环境的影响。生物制剂肺部输送的主要挑战是产生具有优异空气动力学特性的气雾剂，使颗粒能够有效地沉积在呼吸道中，克服沿呼吸道的粘液、表面活性物质和免疫屏障，同时保护脆弱的生物分子在生产和输送过程中免受各种压力和降解。为了进入血液，吸收促进剂还需要可控和可逆地增加上皮屏障的渗透性。该项目的目标是开发克服这些生理障碍的战略，方法是利用Croda开发的新材料(合成/天然衍生的脂类、聚合物、表面活性剂及其组合)，这些材料可以稳定生物制剂的降解，促进药物吸收并提高气雾剂性能。机器学习(ML)和药代动力学(PK)模型将被应用于辅助配方开发。该项目的目标是：(1)建立模拟人体呼吸道通透性分布的粘膜屏障模型；(2)研究一系列新材料的吸收促进和蛋白质稳定作用；(3)利用生成性ML模型识别新材料，以提高生物制剂的渗透性和稳定性；(4)设计吸入型生物制剂，使用辅料和颗粒工程技术的适当组合，并具有可扩展性；(5)使用基于生理的药代动力学(PBPK)模型预测制剂的PK分布。该项目与EPSRC REMITS保持一致，通过预测制药科学和制药过程工程加快向医疗保健应用的转变。它采用具有可扩展性的粒子工程技术，如喷雾干燥，以制备用于吸入的生物制剂的粉末气雾剂；利用新的材料组合来提高生物制剂的稳定性和输送效率；应用计算工具和建模来辅助配方开发。最终目标是建立生物制剂吸入给药平台，为未得到满足的医疗需求的疾病提供安全和有针对性的治疗。

Biological drugs such as peptides, proteins and antibodies are powerful macromolecules that have been established as important classes of therapeutics for the treatment of various diseases. With their high specificity and potency, it is anticipated that biologics will dominate most pipelines. Due to their high susceptibility to degradation and large molecular size that limits transport across the epithelium, administration of biologics is largely limited to parenteral routes which are invasive and require proper training. Non-invasive approach of delivering biologics is highly sought-after. Oral inhalation holds great promise for delivering biologics because of the large surface area and highly vascularisation of the lungs that enable rapid systemic absorption. This route can also increase drug concentration in the airways, making it suitable for the treatment of lung diseases for local action such as severe asthma, respiratory infections, and lung cancers, which are enormous global health burden. Inhalation is non-invasive with the possibility of self-administration. By formulating biologics in dry powder form the stability of biological formulation is also enhanced. This prolongs product shelf-life, avoids cold-chain, reduces drug wastage and environmental impact. The major challenges of pulmonary delivery of biologics are producing aerosols with excellent aerodynamic properties that allow effective deposition of particles in the airways, overcoming the mucus, surfactant, and immunological barriers along the respiratory tract, while protecting the fragile biomolecules from various kinds of stress and degradation during production and delivery. For delivery into the bloodstream, absorption enhancers are also required to increase the permeability of the epithelial barrier controllably and reversibly. The goal of this project is to develop strategies to overcome these physiological barriers, by utilising novel materials developed by Croda (synthetic/naturally derived lipids, polymers, surfactants, and their combinations) that can stabilise biologics from degradation, promote drug absorption and enhance aerosol performance. Machine learning (ML) and pharmacokinetic (PK) models will be applied to assist formulation development. The objectives of the project are: (1) establish models of mucosal barrier that simulate the human airway permeability profile; (2) investigate the absorption enhancing and protein stabilising effects of a series of novel materials; (3) utilise generative ML models to identify novel materials to improve permeability and stability of biologics; (4) engineering of inhaled biologics formulations using appropriate combination of excipients and particle engineering techniques with scalability; (5) predict the PK profile of the formulations using physiologically based pharmacokinetic (PBPK) model.This project aligns with EPSRC remits to accelerate translation to healthcare applications through predictive pharmaceutical sciences and pharmaceutical process engineering. It employs particle engineering techniques with scalability such as spray drying to prepare powder aerosol of biologics for inhalation; utilises novel material combinations to enhance stability and delivery efficiency of biologics; applies computational tools and modelling to assist formulation development. The ultimate goal is to establish inhaled delivery platform of biologics to produce safe and targeted treatments of diseases with unmet medical needs.