Long-acting formulations for subcutaneous delivery of therapeutic peptides

Reduced medicine dosing frequency is associated with increased patient compliance and improved therapeutic outcomes for patients. In recent years biologics, including peptide drugs, have been established as highly valuable and rapidly growing sector of pharmaceutical industry. Medicinal chemistry approaches are presenting an increasing number of novel peptide-based drugs against a range of diseases and targets. The development and clinical approval of peptidic drugs such as cyclosporine, desmopressin octreotide and semaglutide has advanced the field greatly over the past four decades. However, the emergence of larger, more complex (e.g., bicyclic) peptides/drug conjugates with challenging physicochemical properties demands the design and development of new delivery technologies for parenteral administration. The project will focus on advanced product design for long-acting formulations capable of high peptide loading and sustained drug release over the month-long timescale.

Background:
An established long-acting parenteral formulation is Haldol decanoate, which contains the fatty acid-linked drug, haloperidol, dissolved in sesame oil. Administered by deep-intramuscular injection, this formulation achieves steady-state drug levels over monthly dosing intervals. Polymer-based systems have emerged as an alternative technology for controlled parenteral release. Zoladex (registered trademark), is based on poly (D,L-lactide co-glycolide) [PLGA] polymer monolith technology and releases the peptide drug, goserelin, over a three month period. More recent developments include PLGA microsphere technology suspended in a lipid matrix for once weekly delivery of exenatide for type II diabetes (Bydureon, registered trademark). Vaccine countermeasures to the SARS-CoV2 pandemic have prompted the clinical approval of mRNA vaccines delivered as solid lipid nanoparticles (SLNs). With increasingly potent peptide drugs entering clinical testing it is essential that new delivery platforms are designed to deliver over protracted timescales in a safe and cost-effective manner. Here, we hypothesise that the addition of a lipid component to a polymeric carrier to create a hybrid delivery platform can enable extended drug release that is conducive to therapeutic peptide efficacy.

As is the case for low molecular weight drugs, the challenge associated with peptide formulation development is dictated by the physicochemical properties of the drug. Challenges pertinent to peptide delivery include the large diversity of peptide physicochemical properties taken together with the structural diversity and their metabolic lability. These features require the development of sophisticated, yet scalable and cost-effective formulations. This will be a challenging intellectual endeavour for an EPSRC CDT student.

After consultation with industrial partners, the following features have been highlighted as key features of any successful peptide formulations:
- Suitability for subcutaneous administration
- High drug loading
- Extended release over a month-long timescale retaining phys-chem stability
- Utilisation of common/safe pharmaceutical excipients
- Use of a scalable formulation method for future development

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.