INFORM 2020 - Molecules to Manufacture: Processing and Formulation Engineering of Inhalable Nanoaggregates and Microparticles

肺部疾病是全球主要的健康负担。全球有3亿哮喘患者，据预测，到2020年，慢性阻塞性肺病将成为第三大死因。吸入治疗性气雾剂是一种常见的治疗肺部疾病的医学策略。雾化疗法还可以在肺部达到较高的抗生素浓度来治疗感染。当气雾剂被靶向肺深部时，吸入疗法还提供了一种手段，以实现活性药物成分的全身浓缩，并避免注射在胃肠道中被破坏的药物，如胰岛素。尽管有潜力，但许多患者未能在治疗肺部疾病方面获得吸入疗法的全部好处，全身给药也未能实现其应得的市场突破。一些无效的原因是患者无法正确使用他们的治疗方法。然而，即使对那些拥有良好吸入器技术的患者来说，实现肺部的气雾剂沉积也是一个重大挑战。挑战是生产一种便携式剂型，其中包含可由患者重新分散的成分。再分散必须以具有肺透入所需特性的气雾剂的形式实现剂量的均匀。将潜在的可吸入颗粒物转化为可重复制造的配方产品，并在不同患者之间实现一致的雾化性能，带来了许多难以解决的挑战。吸入性药物领域的工业、学术和监管专家的协商一致会议确定了需要改进药物沉积性能的控制和一致性。此外，有必要提高我们对起始材料的特性如何以及为什么与制造条件相互作用从而导致气雾剂特性的批间和患者间差异的理解。挑战的核心是，使它们适合吸入的颗粒的特性(它们的小尺寸，不到5微米，小于人类头发的直径)也导致它们聚集在一起形成团聚。该项目的主题1将使用合成工程(一种基于药物成分分子结构的计算机模拟技术)来获得新的能力，以预测开发早期的团聚行为，以及团聚材料与配方中非活性成分的相互作用。主题2将使用新的测量技术，描绘粉末中的团聚如何相互作用，以了解和描述配方中的团聚阶段如何导致产品性能的患者间或批次间变化。主题3将巩固通过粉末成像获得的知识，以评估结块的根本原因。将开发更好的、综合的实验测量技术，以表征调节颗粒之间相互作用的程度和强度的材料特性。主题4侧重于开发新的计算模型，以表征在病人通过吸入器呼吸时发生的机械过程中以及在制造过程中加工粉末时团聚粉末的行为。该项目的最后一个组成部分是将在主题1-4中获得的知识整合到咨询小组选定的一系列测试产品中，以提高质量。这将通过使用预测和测量技术来实现，以告知配方科学家、设备设计师和工艺工程师适当的步骤，以减轻团聚对产品性能的影响。最终目标是使用开发的技术，将使用吸入性药物的患者的治疗益处从分子转化为制成品。

Lung diseases are a major global health burden. 300 million people live with asthma worldwide and it is predicted that chronic obstructive pulmonary disease will become the third-leading cause of death by 2020. The inhalation of therapeutic aerosols is a familiar medical strategy to treat lung diseases. Aerosol therapy can also achieve high antibiotic concentrations in the lung to treat infections. When aerosols are targeted into the deep lung, inhaled therapy also provides a means to achieve systemic concentrations of active pharmaceutical ingredients and avoid the need for injections of drugs that are destroyed in the gastrointestinal tract, such as insulin. Despite its potential, many patients fail to gain the full benefits of inhaled therapies in treating lung disease, and systemic drug delivery has failed to achieve the market break-through it deserves. Some of the ineffectiveness arises from the inability of patients to use their therapy correctly. However, achieving aerosol deposition in the lungs is a major challenge even for those patients with good inhaler technique.The challenge is to produce a portable dosage form containing components that can be redispersed by a patient. Redispersion must be achieved with uniformity of a dose in the form of an aerosol with the properties required for lung penetration. Turning potentially inhalable particles into formulated products that can be manufactured reproducibly, and that achieve consistent aerosolization performance between different patients poses many challenges that are poorly-solved. Consensus meetings of industrial, academic and regulatory experts in the field of inhaled medicine have identified the need to improve control and consistency of drug deposition performance. Additionally there is a need to improve our understanding of how and why the characteristics of starting materials interact with the manufacturing conditions to lead to inter-batch and inter-patient variability in aerosol characteristics. At the heart of the challenge is the fact that the very property of the particles that makes them suitable for inhalation (their small size which, at less than 5 microns, is less than the diameter of a human hair) also causes them to clump together as agglomerates.Theme 1 of the project will employ synthonic engineering (a computer modelling technique based on the molecular structures of pharmaceutical ingredients) to achieve new abilities to predict agglomeration behaviour early in development, and the interactions of agglomerate materials with inactive ingredients in the formulation. Theme 2 will use new measurement techniques that image how agglomerates interact with each other in powders to develop an understanding and characterize how the agglomerate phase in a formulation leads to inter-patient or inter-batch variability of product performance. Theme 3 will underpin the knowledge gained from powder imaging to assess the underlying causes of agglomeration. Better, integrated experimental measurement techniques will be developed to characterize the material properties that regulate the extent and strength of interactions between particles. Theme 4 focuses on developing new computational models to characterize the behaviour of agglomerated powders during the mechanical processes occurring when a patient breathes through an inhaler, and when powders are processed during manufacturing. The final component of the project is to integrate the knowledge gained in Themes 1-4 to engineer quality into a range of test products selected by an advisory panel. This will be achieved by using the prediction and measurement techniques to inform formulation scientists, device designers and process engineers of the steps that are appropriate to mitigate the effects of agglomeration on product performance. The ultimate goal is to use the techniques developed to translate the therapeutic benefits for patients using inhaled medicines from molecules to manufactured products.