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

肺部疾病是一个主要的全球健康负担。全世界有3亿人患有哮喘，据预测，到2020年，慢性阻塞性肺病将成为第三大死因。吸入治疗性气溶胶是一种常见的治疗肺部疾病的医疗策略。气雾剂疗法也可以在肺部达到高抗生素浓度来治疗感染。当气溶胶被靶向进入肺深部时，吸入疗法也提供了一种手段来达到有效药物成分的全身浓度，并避免需要注射在胃肠道中被破坏的药物，如胰岛素。尽管具有潜力，但许多患者未能获得吸入疗法治疗肺部疾病的全部益处，全身给药未能实现应有的市场突破。有些无效是由于病人不能正确使用他们的疗法。然而，即使对那些拥有良好吸入器技术的患者来说，实现肺部气溶胶沉积也是一项重大挑战。挑战在于生产一种便携式剂型，其中含有可由患者再分散的成分。再分散必须以具有肺部穿透所需特性的气溶胶形式的剂量均匀性来实现。将潜在的可吸入颗粒转化为可重复生产的配方产品，并在不同患者之间实现一致的雾化性能，这带来了许多难以解决的挑战。吸入医学领域的工业、学术和监管专家的共识会议已经确定需要改善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以导致批次间和患者间气溶胶特性变化的理解。这一挑战的核心在于，这些微粒适合吸入的特性（小于5微米，比人类头发的直径还小）也会使它们聚集成团块。该项目的主题1将采用合成工程（一种基于药物成分分子结构的计算机建模技术）来实现在开发早期预测团聚行为的新能力，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，对粉末中团块如何相互作用进行成像，以了解和表征配方中的团块相如何导致患者间或批次间产品性能的变化。主题3将巩固从粉末成像获得的知识，以评估结块的根本原因。更好的综合实验测量技术将被开发出来，以表征调节粒子间相互作用程度和强度的材料特性。主题4侧重于开发新的计算模型，以表征在患者通过吸入器呼吸和粉末在制造过程中加工时发生的机械过程中凝聚粉末的行为。该项目的最后一个组成部分是将主题1-4中获得的知识整合到由顾问小组选择的一系列测试产品中，以设计质量。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的步骤，以适当地减轻团聚对产品性能的影响。最终目标是利用所开发的技术将吸入药物患者的治疗益处从分子转化为制造产品。

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.