Development of long-acting peptide formulations for subcutaneous delivery

减少药物给药频率与增加患者依从性和改善患者治疗结果相关。近年来，生物制剂，包括肽类药物，已被确立为制药工业中极具价值和快速增长的部门。药物化学方法呈现出越来越多的针对一系列疾病和靶点的新型肽类药物。肽类药物如环孢菌素、去氨加压素奥曲肽和索马鲁肽的开发和临床批准在过去四十年中极大地推进了该领域。然而，更大、更复杂（例如，具有挑战性的物理化学性质的（双环）肽/药物缀合物需要设计和开发用于肠胃外给药的新递送技术。该项目将专注于先进的产品设计，用于能够在长达一个月的时间尺度内实现高肽负载和持续药物释放的长效制剂。背景：一种已确立的长效胃肠外制剂是癸酸氟哌啶醇，它含有溶于芝麻油的脂肪酸连接药物氟哌啶醇。通过深部肌内注射给药，该制剂在每月给药间隔内达到稳态药物水平。基于聚合物的系统已经成为控制胃肠外释放的替代技术。Zoladex（注册商标）是基于聚（D，L-丙交酯共-乙交酯）[PLGA]聚合物整体技术，并在三个月内释放肽药物戈舍瑞林。最近的发展包括悬浮在脂质基质中的PLGA微球技术，用于每周一次递送用于II型糖尿病的艾塞那肽（Bydureon，注册商标）。针对SARS-CoV 2大流行的疫苗对策促使以固体脂质纳米颗粒（SLN）递送的mRNA疫苗获得临床批准。随着越来越有效的肽类药物进入临床测试，新的递送平台必须设计成以安全和具有成本效益的方式在延长的时间尺度内递送。在这里，我们假设，添加脂质成分的聚合物载体，以创建一个混合传递平台，可以使延长药物释放，这是有益的治疗肽efficacy.As的情况下，低分子量药物，与肽制剂开发的挑战是由药物的物理化学性质决定的。与肽递送相关的挑战包括肽物理化学性质的巨大多样性以及结构多样性和它们的代谢不稳定性。这些特征要求开发复杂的、可扩展的和具有成本效益的配方。对于EPSRC CDT学生来说，这将是一项具有挑战性的智力努力。在与工业合作伙伴协商后，以下特征已被强调为任何成功的肽制剂的关键特征：-适合皮下给药-高载药量-在长达一个月的时间范围内延长释放，保持物理化学稳定性-使用常见/安全的药用辅料-使用可扩展的配制方法用于未来开发

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