Development of long-acting peptide formulations for subcutaneous delivery

减少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，包括多肽药物在内的生物制剂已成为制药工业中具有很高价值和快速增长的领域。药物化学方法提出了越来越多的新型肽类药物针对一系列疾病和靶点。环孢素、去氨加压素、奥曲肽、西马鲁肽等肽类药物的开发和临床批准，在过去四十年中极大地推动了该领域的发展。然而，更大、更复杂（如双环）肽/药物偶联物的出现具有挑战性的物理化学性质，要求设计和开发新的肠外给药给药技术。该项目将专注于能够在长达一个月的时间内实现高肽负载和持续药物释放的长效制剂的先进产品设计。背景：一种已建立的长效肠外制剂是癸酸氟哌啶醇，它含有脂肪酸连接的药物氟哌啶醇，溶解在香油中。通过深层肌肉注射，该配方在每月给药间隔内达到稳定的药物水平。聚合物为基础的系统已经成为控制肠外释放的替代技术。Zoladex（注册商标）是一种基于聚（D， l -丙交酯共乙醇酸酯）[PLGA]聚合物单体技术的多肽药物goserelin，在三个月的时间内释放。最近的发展包括悬浮在脂质基质中的PLGA微球技术，用于治疗II型糖尿病，每周给药一次艾塞那肽（Bydureon，注册商标）。针对SARS-CoV2大流行的疫苗对策促使作为固体脂质纳米颗粒（sln）递送的mRNA疫苗获得临床批准。随着越来越多的强效肽药物进入临床试验，设计新的给药平台以安全和具有成本效益的方式在较长时间内给药至关重要。在这里，我们假设将脂质成分添加到聚合物载体中以创建混合递送平台可以延长药物释放，从而有利于治疗肽的功效。与低分子量药物的情况一样，与肽制剂开发相关的挑战是由药物的物理化学性质决定的。肽传递的挑战包括肽的物理化学性质的巨大多样性，以及结构的多样性和代谢的不稳定性。这些特性需要开发复杂的、可扩展的、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，以下特征被强调为任何成功的肽制剂的关键特征：-适合皮下给药-高药物负荷-在长达一个月的时间尺度上延长释放，保持物理化学稳定性-利用常用/安全的药物辅料-使用可扩展的配方方法以供未来开发

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