Oral delivery of macromolecular drug - a mechanistic study of the mode of action of permeation enhancers for increasing drug bioavailability

This project aims to build a mechanistic understanding of the role of permeation enhancers in permeability of macromolecular drug molecules across epithelium following oral administration. The project approaches this via developing mechanistic understanding and in vitro - in silico - in vivo relationship as a prediction tool to optimise formulation design of permeability enhancement technology, with the view to improving the translation of in vitro data into in vivo (including human). Low oral bioavailability of macromolecular drugs, such as peptides, has directed their use as injections. New solutions are needed to increase transport of macromolecular drugs across intestinal epithelium and consequently improve their bioavailability following oral administration. AstraZeneca is developing a permeability enhancer technology to increase oral bioavailability of macromolecular drugs, and this project is a part of this research effort.
The project aligns with the EPSRC SFI CDT in Transformative Healthcare Technologies themes of Predictive Pharmaceutical Sciences and Advanced Product Design. Predictive Pharmaceutical Sciences - the project aims to establish a relationship between the descriptors of permeability enhancer and enhancement in macromolecular drug permeation across epithelium. We envisage that at the end of this project we will be able to correlate in vitro, in silico and in vivo data on permeability enhancement, as a predictive tool for permeability enhancer selection. Advanced Product Design - the project will lead to a design of advanced pharmaceutical products based on permeability enhancement technology.

Project aligned to Predictive Pharmaceutical Sciences and Advanced Product Design

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.