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

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.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.