A Novel and Improved Commercially Viable, Cost -Effective Manufacturing Process for Fixed Dose Combination Dry Powder Inhaler Formulations

目前，很少(如果有的话)用于颗粒表面改性的制造工艺不会对核心颗粒的固有特性产生不利影响。用于DPI的最先进的混合技术，例如高剪切或湍流混合，通常不适合处理稳定性差的原料药，即使在合适的情况下，也会产生高度可变的产品产量。当要创建包含多个API的组合时，这会变得更加复杂。该项目的目标是为小分子原料药配方的生产提供改进的和商业上可行的成本效益工艺，这些配方已经作为固定剂量组合(FDC)DPI药物获得。到目前为止，这些产品已经被证明很难转化为仿制药。阿斯顿粒子技术(APT)有限公司创造了一种新的干式粒子包衣工艺，新注册为APT-HALE(Tm)，这可能会改变这方面的游戏规则。该方法具有许多独特的特点，已被单一原料药配方所证实。它在常温下运行，不需要使用挥发性有机化合物(VOC)或溶剂，不会产生热量，也不会造成颗粒磨损。它可以处理性能有问题的原料药，例如高电荷/高电荷保持力、高粘结性或严重的水分敏感性。它同样适用于稳定性较差的API，也适用于健壮的API。它已经成功地与现成的现成原料药和赋形剂一起使用，而不需要进行前处理。该工艺通过控制少量的关键工艺参数来运行，这些参数在干氮气中产生流态化状态，在这种状态下，每个细小颗粒首先被分散气体完全润湿，然后被较粗的载体颗粒吸附。该项目的主要目标是通过创建FDC DPI配方来验证该过程的广泛适用性，这些配方可以作为市场领先的创新产品的可信替代仿制药。在这样做的过程中，将对一系列已建立的、非专利的原料药进行组合调查。这一简单且相对“易于实施”的开发和扩大平台的应用最终可能导致注册一套通用FDC吸入器，从而满足处方者、支付者和患者的要求。如果该项目成功，从长远来看，这一平台技术不仅将被用于开发非专利组合配方，还将被用于那些含有新化学实体的配方。

At the present time there are few, if any, manufacturing processes for particle surface modification that do not adversely affect the innate properties of the core particles. State-of-the-art blending technologies for DPIs, e.g. high shear or turbula mixing, often are unsuitable for processing poorly stable APIs and even when suitable, create highly variable product outputs. This becomes even more complex when combinations containing more than one API are to be created. This project is targeted to deliver improved and commercially viable cost-effective processes for manufacture of formulations of small molecule APIs that are already available as Fixed Dose Combination (FDC) DPI medicines. These products have proven to be very difficult to turn into generic medicines until now. Aston Particle Technologies (APT) Ltd. has created a novel dry particle coating process, newly trademarked as APT-Hale(tm), which could be a game-changer in this regard. The process has many unique characteristics which have been confirmed with single API formulations. It operates at ambient temperature, requires the use of no volatile organic compounds (VOCs) or solvents, generates no heat and causes no particle attrition. It can handle APIs with problematic properties, such as high charge / high charge retentiveness, high cohesivity or acute moisture sensitivity. It can be applied equally to poorly stable APIs as to those that are robust. It has already been successfully used with readily available 'off the shelf' APIs and excipients with no pre-treatment. The process operates through control of a small number of critical processing parameters which create a fluidised state in dry nitrogen, in which every fine particle is firstly fully wetted by the dispersion gas and then adsorbed onto the coarser carrier particles. It is a primary aim of this project to validate the broad applicability of the process by creating FDC DPI formulations that can be progressed as credible substitutable generics for the market-leading, innovator products. In doing so, a range of established, off patent APIs will be investigated in combination. Application of this simple and relatively 'easy to implement' platform for development and scale up could eventually lead to registration of a suite of generic FDC inhalers that will meet the requirements of prescriber, payer and patient alike. If this project is successful, this platform technology will be utilised in the longer term not only in the development of generic combination formulations but also of those containing new chemical entities.