With over half a billion people worldwide suffering from a chronic respiratory condition and cases of COVID-19 climbing above 25 million globally, pulmonary drug delivery via specialist inhalation devices is more relevant than ever. Pulmonary drugs offer the best potential for optimal delivery to the lungs while minimizing systemic side effects–properties that have made pulmonary drugs the main treatment for asthma and chronic obstructive pulmonary disease (COPD) for decades. Pulmonary drug delivery may also be the most appropriate treatment for other serious conditions, including COVID-19.
We’ll explore the current status of pulmonary drug delivery and possible future opportunities in pulmonary drug development in this article.
肺药有很长的轨道记录，有效治疗哮喘和COPD等常见呼吸系统疾病
历史上肺药已被用来靶向药物给肺部的肺部，例如哮喘和COPD。目前的估计表明，全世界的27200万人有哮喘，近300万人有COPD(Box 1).1
In many countries these rates are set to increase in the coming years owing to higher smoking prevalence and ageing populations.2Indeed, the World Health Organization predicts that COPD will become the world’s third largest health threat by 2030.
通过短作用β2激动剂（SABA），哮喘和COPD的一线治疗已经历史统治。然后通过单独制定皮质类固醇，但最近作为具有长效毒蕈碱拮抗剂（喇嘛）和长效β2激动剂（Laba）的组合。这被称为单个设备中的“三重疗法”。3,4
在美国和西欧，干粉吸入器（DPI）是常见的，而吸入的皮质类固醇和SABA的加压计量吸入器（PMDI）是由于价格问题的最常用于发展中国家。
Pulmonary drugs are also used to treat idiopathic pulmonary fibrosis (IPF) and cystic fibrosis; both are chronic lung conditions characterized by progressive lung damage, and for which improved treatments are greatly needed.5., 6
具体而言，尽管使用吸入器，但如果令人痛苦或呼吸困难持续存在，则雾化肺处理有时用于COPD的患者。4.
其他肺部药物发育的呼吸系统症靶标包括Covid-19，结核病和肺部感染
其他呼吸系统疾病如结核病，肺癌等更一般（通常是未指明）呼吸道感染也是全球健康负担的巨大卫生负担1并且没有快速或简单的解决方案来满足这种全球挑战。
此外，Covid-19，在各大洲席卷7.creating a deep need for efficacious medications with industry and academic research bodies around the world seeking to develop pulmonary drugs for COVID-19.10-12
盒子1：呼吸道疾病事实
In 2017, chronic respiratory diseases affected nearly 545 million people worldwide (an increase of 23% since 2007) and caused the deaths of nearly 4 million people.1,8
| 哮喘1,827.2。7.million people affected worldwide Causes nearly half a million deaths per year | COPD.1,8近300万人受到全球影响的1850万人每年诊断 | Cystic fibrosis (CF)5.在欧盟，大约2000 - 3000名儿童，每年有CF | Idiopathic pulmonary fibrosis (IPF)6.以每10万人在欧洲和北美的每10万人的速度下出现 |
2017年，全球探索了179亿急性呼吸道感染，导致死亡380万人。1,8
| Lower respiratory tract infections1,81060万个案件总计260万人死亡 | 肺炎球菌 肺炎1,8由于<5年龄<5年的儿童呼吸道感染较低，这是死亡的主要原因 |
Tuberculosis1,82017年诊断患有900万个新案件的全球有119亿件案件。负责120万人死亡 |
肺癌是癌症最具诊断的癌症，占总癌症的11.6％，以及癌症死亡的最常见原因（占总数的18.4％）。9.肺癌宣称2017年的生命为190万人。8.
为了加快发展，公司正在使用腹腔内或鼻内行政路线for early screening studies as an alternative to inhalation before commencing first-in-human studies.
Pulmonary delivery has multiple benefits for respiratory and systemic diseases
在呼吸系统中直接将呼吸栓直接递送到他们的行动部位是肺配方的明显优势，但还有其他益处。
肺部递送还避免了一键的代谢，可以限制某些药物的口服生物利用度，从而促进下剂量，这又会导致系统性副作用更少。例如，当通过吸入递送时，蛋白质和肽药物可以更稳定，因为这些药物通常在胃肠道之前通过Gi散流降解它们之前。13-16
Pulmonary drug delivery for systemic conditions
The above benefits are partly responsible for driving research into pulmonary treatments for systemic diseases. One of the first well publicized pulmonary products for treating a systemic disease was Pfizer’s Exubera®. An inhaled form of insulin for treating diabetes, Exubera® was withdrawn in 2007 due to poor sales, blamed in part on the bulky and inconvenient inhaler. This drug created an initial setback to pulmonary delivery innovation with other companies reconsidering similar product developments.
然而，2014年6月，美国食品和药物管理局（美国FDA）批准了一种吸入胰岛素产品的Mannkind的AFRezza®。AFRezza®的初始销售也很慢，17.但到2020年1月，收入增加了一倍多，18.providing a clearer picture to sponsors that inhaled delivery for systemic diseases could be a possibility.
从长远来看，Exubera's®撤回并未阻碍肺部递送的兴趣。在过去的2年中，超过2,000个活跃的吸入研究 - 用于新的，组合和现有产品以及肺部递送方法和技术 - 已在临床试验中注册.GOV。这些研究涵盖了近1,500个适应症，呼吸系统和系统性，200多项试验涉及Covid-19患者。19.
粒子工程技术已经转化了药物制剂
The success of inhaled medications depends on many factors but primary ones include how the drug is formulated and the inhaler used to deliver it. The latter consideration is unique to pulmonary delivery, compared to other delivery routes.20
The key facets of an inhaled medication are the active ingredient and its formulation. Traditionally, the fine drug particles required for delivery in DPI devices have been produced by mechanical micronization using air jet mills. These fine particles are then often combined with a lactose carrier to improve drug stability and dose control, depending on the drug type or compound class.
More recently, however, particle engineering techniques (Box 2) have transformed inhaled drug formulations so more effective formulations can be devised, allowing for lower doses, which often correlate to a lower potential for side effects.
盒子2：一些粒子工程技术的例子
'干燥'技术这是最常见的粒子工程技术。实例包括喷雾干燥，冷冻干燥和真空泡沫干燥 |
超临界流体技术将药物溶解在超临界流体中;由于流体快速膨胀或通过流体沉淀而形成的颗粒形式 |
Sonocrystallization采用超声控制的结晶技术。For example, the Prosonix platform from Circassia Pharmaceuticals Plc—its fluticasone propionate pressurized metered-dose inhaler (pMDI) has been approved as the generic equivalent of GlaxoSmithKline’s Flixotide® pMDI by European decentralized procedure, following a filing to the UK Medicines and Healthcare Products Regulatory Agency |
专有技巧Examples include: Pulmatrix’s iSPERSE® platform—their PUR1900 drug (for fungal infections in the lungs of patients with cystic fibrosis) is currently in clinical testingLiquidia’s PRINT® (Particle Replication In Non-Wetting Templates) platformMannkind’s Technosphere® Technology—used in their insulin product, Afrezza® |
设备对肺部递送的临床成功至关重要，也可以延长专利生命
输送装置的性质可以对药物的成功显着贡献，而不管药物本身可能对患者有多有效和有益。
当有效的药物制剂与高效的交付设备结合使用时出现的独特益处解释了为什么可观的开发时间，努力和金钱致力于生产任何吸入装置。20
To put this importance into context, GSK’s Adavair® (Seretide) came off patent in the U.S. in 2010, but when combined with the Diskus® delivery device, Adavair remained patented through 2016. As a result, Adavair still generated revenues of over USD 5.5 billion in 2015 and around USD 2.1 billion in 2019.21
虽然一些早期的送货设备可能会脱离专利，但呼吸吸入器设备市场的大小相当大，并继续扩展，估计建议将达到2029年底的480亿美元 - CAGR 4.2％。22
为了有效，吸入装置必须与患者匹配，易于使用，宽容的技术，能够向用户提供关于剂量发射和技术的反馈。
看Box 3for an overview of the desired physical characteristics of an inhalation device.
Box 3: Desired physical characteristics of devices
| PRIMARY | 中学 |
|---|---|
易于使用
|
Easy dose loading
|
已经持续增长了已经巨大的呼吸市场
The value of the global respiratory drug delivery market is projected to reach USD 52.37 billion by 2021, which was an increase from USD 36.10 billion in 2016, compounding at an annual growth rate (CAGR) of 6.5% during the forecast period.
该市场的增长主要是通过越来越多的肺途径偏好的偏爱，越来越多的智能/数字吸入器形式的技术发展，以及呼吸疾病的升高发病，如COPD，哮喘和囊性纤维化。23The asthma segment accounts for the major share in the market during the forecast period due to increasing prevalence of this disease across the globe.
On a side note, the Asian market is expected to register the highest CAGR during this forecast period due to its rapidly increasing geriatric population, adoption of unhealthy lifestyles, urbanization, exposure to air pollution and prevalence of COPD in the region.
结论
The fact that some 2,000 active inhalation studies – including over 220 for COVID-19 at last count – are ongoing, demonstrates the interest in and pace of research into pulmonary drug delivery.
Covance处于非临床，临床，监管和医疗设备评估的最前沿，与这些尖端技术评估。特别是，我们拥有丰富的经验测试药物，用于肺部递送，表现超过150非临床吸入研究each year.
We are consistently optimizing study techniques, pulmonary drug formulations and devices, and are at the forefront of testing the novel formulation techniques that are transforming the precision of aerosol delivery. This focus is leading to more reliable study results and reductions in the drug quantities needed for pulmonary testing. Most importantly, this advanced engineering and constant advancement in aerosol and inhalation technology translates to patient benefits also: more efficient dosing and easier to use devices, thus helping reach better compliance.
Contact usto learn more about inhalation & pulmonary testing
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