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

生物药物如肽、蛋白质和抗体是强大的大分子，其已被确立为用于治疗各种疾病的重要类别的治疗剂。由于其高特异性和效力，预计生物制剂将主导大多数管道。由于其对降解的高度敏感性和限制跨上皮转运的大分子尺寸，生物制剂的施用在很大程度上限于具有侵入性且需要适当训练的肠胃外途径。递送生物制剂的非侵入性方法非常受欢迎。口服吸入给药生物制剂带来了很大的希望，因为大的表面积和高度血管化的肺部，使快速全身吸收。该途径还可以增加气道中的药物浓度，使其适用于治疗肺部疾病，以局部行动，如严重哮喘，呼吸道感染和肺癌，这些疾病是巨大的全球健康负担。吸入是非侵入性的，可自行给药。通过配制干粉形式的生物制剂，生物制剂的稳定性也得到增强。这延长了产品的保质期，避免了冷链，减少了药物浪费和对环境的影响。生物制剂肺部递送的主要挑战是生产具有优异空气动力学特性的气雾剂，其允许颗粒在气道中有效沉积，克服沿着呼吸道的粘液、表面活性剂和免疫屏障，同时保护脆弱的生物分子在生产和递送期间免受各种压力和降解。为了递送到血流中，还需要吸收促进剂来可控地和可逆地增加上皮屏障的渗透性。该项目的目标是制定克服这些生理障碍的策略，利用禾大开发的新型材料（合成/天然衍生的脂质、聚合物、表面活性剂及其组合），这些材料可以稳定生物制剂，防止其降解，促进药物吸收并增强气雾剂性能。将应用机器学习（ML）和药代动力学（PK）模型来协助配方开发。该项目的目标是：（1）建立模拟人体气道渗透性的粘膜屏障模型;（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ML模型识别新材料，以改善生物制剂的渗透性和稳定性;（4）研究生物制剂的生物相容性和生物相容性。（4）使用赋形剂和具有可扩展性的颗粒工程技术的适当组合来工程化吸入生物制剂;（5）使用基于生理学的药代动力学（PBPK）预测制剂的PK特征该项目与EPSRC的使命一致，通过预测制药科学加速向医疗保健应用的转化，制药工艺工程它采用具有可扩展性的颗粒工程技术，如喷雾干燥，以制备用于吸入的生物制剂的粉末气雾剂;利用新型材料组合来提高生物制剂的稳定性和递送效率;应用计算工具和建模来辅助制剂开发。最终目标是建立生物制剂的吸入给药平台，为未满足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.