Prediction of nanoparticle stability using advanced physico-chemical techniques.

各种形式的脂质纳米粒，包括固体脂质纳米粒、纳米结构脂质载体、脂质药物结合物和聚合物-脂质杂化纳米粒，作为一系列候选治疗药物的载体引起了人们的极大兴趣。然而，无论它们的精确结构如何，这些胶体颗粒都有共同的稳定性问题，如团聚/聚集和沉淀。虽然静电、立体或静电稳定纳米颗粒可以克服团聚/聚集以及控制沉淀的问题，但这些策略往往需要时间来开发，并在开发过程中导致候选材料的磨损。到目前为止，很少或没有工作系统地确定纳米颗粒的稳定性作为纳米颗粒组成、应力、生产后时间和纳米颗粒浓度的函数。当前项目的主要目标是通过使用独特的低容量采样技术组合来确定哪些物理决定因素(例如储存时间、纳米颗粒浓度以及外加应力(例如温度、pH、离子应力、赋形剂、血浆成分))破坏脂质纳米颗粒的稳定性，从而提出促进开发过程的规则。纳米颗粒正越来越多地被用于制备生物药物分子，如核酸。通过系统地了解纳米颗粒稳定性的物理决定因素，包括加速稳定性研究的压力，将有可能定义规则来生产包含所需稳定性配方的治疗剂。所需的理解将通过使用一系列先进的物理化学技术的新组合来获得，这些技术既可以‘在线’使用，也可以使用非常低的样本量。监管机构对这种详细的理解和产品特征的要求越来越高。这个项目的具体目标是：-利用一系列先进的物理化学技术，量化作为外部因素(pH、离子强度、温度、辅料)的函数的脂质纳米颗粒与纳米颗粒组合物之间的相互作用。-利用微流控流动下的RICS(和SANS)表征纳米颗粒的完整性(包括其有效载荷)以及没有聚集体。

Lipid nanoparticles, in their various forms - including solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugate and polymer-lipid hybrid nanoparticles - have attracted considerable interest as delivery vehicles for a range of therapeutic candidates. However, regardless of their precise structure, these colloidal particles share common stability issues such as agglomeration/aggregation and sedimentation. Whilst electrostatic, steric or electrosteric stabilization of the nanoparticles can overcome problems with agglomeration/aggregation as well as controlling sedimentation, such strategies frequently take time to develop and contribute to the attrition of the candidates during the development process. To date little or no work has systematically determined nanoparticle stability as a function of nanoparticle composition, stress, time after production, nanoparticle concentration.The main aim of the current project is to establish which physical determinants (e.g. storage time, nanoparticle concentration as well as the application of external stresses (e.g. temperature, pH, ionic stress, excipients, plasma components)) destabilise lipid nanoparticles by the use of an unique combination of low volume sampling techniques and thereby propose rules to facilitate the development process.Nanoparticles are increasingly being used to formulate biopharmaceutical molecules such as nucleic acids. By systematically understanding the physical determinants of nanoparticle stability, including stress to accelerate the stability studies, it will be possible to define rules to produce therapeutic-agent containing formulations of the required stability. The required understanding will be gained by the use of a novel combination of a range of advanced physico-chemical techniques that can either be used 'in-line' and/or use very low sample volumes. Such detailed understanding and product characterisation is increasingly required by the regulator. The specific aims of this project are:- Quantification of the interactions between lipid nanoparticles as a function of external factors (pH, ionic strength, temperature, excipients) with nanoparticle composition using a range of advanced physico-chemical techniques.- Characterisation of the integrity of the nanoparticles (including their payload) as well as the absence of aggregates using RICS (and SANS) under microfluidic flow.