Development of long-acting peptide formulations for subcutaneous delivery

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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