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药剂学翻译

药剂学翻译

工业药剂学

翻译

学院:动物医学院

班级:药物制剂12-2

姓名:王雪野

学号:20120268

指导教师:符华林(教授)

5.8

AEROSOL DRUG DELIVERY气雾给药

Michael Hindle迈克尔·辛德

Virginia Commonwealth University, Richmond, Virginia

Contents目录

5.8.1 Introduction 引言

5.8.2 Human Respiratory Tract and Aerosol Particle Deposition人类呼吸道和气溶胶粒子沉积5.8.2.1 Human Respiratory Tract人的呼吸道感染

5.8.2.2 Mechanisms of Particle Deposition粒子沉积机制

5.8.2.3 Pharmacokinetics药代动力学研究

5.8.3 Therapeutic Indications for Aerosol Delivery气雾剂治疗的临床适应证

5.8.3.1 Current Applications目前的应用

5.8.3.2 Future Applications未来的应用

5.8.4 Aerosol Drug Delivery Devices气雾剂给药装置

5.8.4.1 Introduction引言

5.8.4.2 Characteristics of Ideal Delivery Device理想给药装置的特点

5.8.5 Metered Dose Inhalers计量吸入器

5.8.5.1 Introduction引言

5.8.5.2 Metered Dose Inhaler and HFA Reformulation计量吸入器和HFA新配方

5.8.5.3 Propellants抛射剂

5.8.5.4 Excipients 辅料

5.8.5.5 Valves阀门系统

5.8.5.6 Actuators推动器

5.8.5.7 Canisters灌装设备

5.8.5.8 Breath Actuation呼吸驱动

5.8.5.9 Spacers垫片

5.8.5.10 Dose Counters定量杯(室)

5.8.6 Dry Powder Inhalers干粉吸入器

5.8.

6.1 Introduction引言

5.8.

6.2 Size Reduction and Particle Formation Technologies减小颗粒尺寸与粒子形成技术5.8.6.3 Drug – Lactose Formulations药物-乳剂

5.8.

6.4 Dry Powder Inhaler Design干粉吸入器的设计

5.8.

6.5 Exubera吸入用胰岛素-Exubera

5.8.7 Nebulizers雾化器

5.8.8 Emerging Technologies新兴技术

5.8.8.1 Soft Mist Aerosols软雾喷雾剂

5.8.8.2 Respimat肺部输药器

5.8.8.3 AERx肺部稀释药-AERx

5.8.8.4 Mystic肺部药物运输器

5.8.8.5 Capillary Aerosol Generator毛细管气雾剂生成器

5.8.8.6 Staccato断续式给药

5.8.9 Conclusions结论

References参考文献

5.8.1 INTRODUCTION 引言

Aerosol drug delivery to the lungs has long been the route of choice for the treatment of respiratory diseases, including asthma and chronic obstructive airway disease. Metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers have been employed to successfully deliver a wide range of pharmaceuticals principally to the lungs for local action. However, with their unique characteristics, the lungs have now begun to be targeted as a means of noninvasive delivery of systemically acting compounds, including genes, proteins, peptides, antibiotics, and other small molecules [1, 2] . The primary function of the respiratory tract is gaseous exchange, transferring oxygen from the inspired air to the blood and removing carbon dioxide from the circulation. This pulmonary circulation offers rapid absorption and systemic distribution of suitable drugs deposited in the airways. Due to its anatomical structure, however, an important secondary role is the protection of the body from inhalation of foreign particles (including aerosol drug particles). The challenge of aerosol drug delivery is to overcome this highly effective barrier and accurately and reproducibly deliver aerosol drug particles in sufficient doses to their targeted sites within the lungs for either local action or systemic absorption. Effective aerosol drug delivery is tied to the aerosol inhaler that generates and delivers the respirable aerosol. This chapter will primarily focus on aerosol drug delivery devices, their development, and future prospects for pulmonary administration.

长期以来,使用气雾剂将药物传递到肺部都是呼吸系统疾病的首选给药途径,其中包括哮喘和慢性阻塞性呼吸道疾病。计量吸入器(MDI),干粉吸入器(DPI)和喷雾器已经成功广泛的用于向肺部运输药物,使药物在局部发挥作用。所以,因为气雾剂独有的特点,现在已经有药物通过肺部,向全身靶向无创性的给药,其中包括基因片段、蛋白质、肽类、抗生素和其他小分子药物[1,2]。呼吸道的主要功能是气体交换,传送随呼吸进入到血液的氧气,除去循环中的二氧化碳。这种肺循环使沉积在呼吸道的药物能迅速的吸收和系统性的分布。肺部给药有这种作用一方面是由于它的生理结构,然而,另一个重要的原因是机体吸入的外来颗粒的保护作用(包括气雾剂的药物颗粒)。气雾剂药物的传递需要克服这个高效的保护屏障,然后准确的、循环的将气雾剂的药物颗粒以足够的剂量通过肺部靶向性的传递到全身,使药物发挥局部或者全身性作用。有效的气雾剂药物传递依赖于生成气雾的气雾剂吸入器。本章重点在于介绍气雾剂给药装置和它的发展,还有肺部给药系统的前景展望。

5.8.2 HUMAN RESPIRATORY TRACT AND AEROSOL PARTICLE DEPOSITION 人体呼吸道和气雾剂粒子沉积

5.8.2.1 Human Respiratory Tract 人体呼吸道

The human respiratory tract can be divided into three main regions: first, the upper airways, including the nose, mouth and throat (oropharnyx), and the larynx [3] . The conducting airways consist of the regions from the trachea to the respiratory bronchioles and have airway diameters between 0.6 and 20 mm. The alveolar region consists of respiratory bronchioles and alveolar sacs and has airway diameters

between 0.2 and 0.6 mm. The lungs are a branching system which commences asymmetrically, dividing first at the base of the trachea. The left and right bronchi branch dichotomously into the conducting airways. There are approximately 23 generations before the respiratory bronchioles give way to the alveoli, the site of gaseous exchange [4] . This branching produces a progressive reduction in airway diameter and also significantly increases the total surface area of the lower airways [3] .Another important characteristic with respect to drug delivery is the extensive vascular circulation. The blood vessels supplying the conducting airways are part of the systemic circulation. In contrast, the alveolar region is connected to the pulmonary circulatory pathway; drugs absorbed into this circulation will avoid first – pass hepatic metabolism effects.

人体呼吸道可分为三个主要区域:第一,上呼吸道,包括鼻子,嘴和喉咙(口咽),和喉部[3]。传导气道包括从气管到呼吸性细支气管的区域,和具有0.6到20mm直径的气道。肺泡区域包括呼吸性细支气管和肺泡囊以及具有0.2和0.6mm直径的气道。肺是一个开始不对称的分支系统,在气管的底部第一分裂。左支气管和右支气管分成两支进入传导气道中。在呼吸性细支气管避让肺泡之前大约有23级气体交换的部位[4]。这些分支生成的气道直径逐步减小,也显著增加了下气道的总表面积[3]。药物传递的另一个重要特点是丰富的血管循环。供血的血管导气管是全身循环的一部分。与此相反,肺泡区被连接到了肺部的动态循环通道;药物吸收进入这个循环后会先避开肝脏首过代谢。

5.8.2.2 Mechanisms of Particle Deposition 粒子沉积机制

Aerosol particles are deposited in the lungs by three main mechanisms, and the site of deposition is dependent upon the predominating mechanism. Inertial impaction occurs because a particle traveling in an air stream has its own momentum (the product of its mass and velocity). As the direction of the airflow changes due to a bend or obstacle, the particle will continue in its original direction for a certain distance because of its inertia. Particles with a high momentum, due to high velocity or large size, are often unable to change direction before they impact on the surface

in front of them [5] . Impaction of particles entering the mouth with a high velocity occurs either at the back of the mouth or at the bend where the pharynx leads to

the trachea. Only a small fraction of particles greater than 15 μ m will reach the trachea following mouth breathing. The majority, due to their size, will impact in the oropharyngeal region. Deposition by impaction will also occur as the trachea splits into the left and right bronchus. As the velocity of the particles decreases, inertial impaction becomes a less important mechanism of deposition in the smaller airways. Following the removal of larger particles in the upper airways by inertial impaction,

gravitational sedimentation is the mechanism by which smaller particles (2 –5 μ m)

are deposited in the respiratory bronchioles and alveoli. These particles settle under gravity and accelerate to a steady terminal velocity when the gravitational force is balanced by the resistance of the air through which it is traveling [6] . It is a time - dependent process which is aided by breath holding [7] . Brownian motion or diffusion is a mechanism which signifi cantly affects only particles less than 0.5 μ m in diameter. These particles are subjected to bombardment by surrounding gas molecules causing random movement of the particles. In this situation, the diffusivity

of a particle is inversely proportional to its diameter. For an extensive mechanistic review of the area of particle deposition readers should consult Finlay (2001) [8] .

气雾颗粒沉积于肺部的主要机制有三个,但沉积的部位取决于占据主导的机制。发生惯性碰撞是因为在空气流中运动的颗粒都有自身的动量(质量和速度的乘积)。由于弯折或障碍物,气流方向会发生变化,颗粒会因为其惯性而继续在原来的方向上运动一段距离。由于颗粒高速运动或者大尺寸而具有高动量,所以颗粒往往无法在他们受表面影响之前改变方向。嵌塞的颗粒以高流速进入口腔后部或者进入通向气管的弯道中。只有一小部分直径大于15

μm的颗粒能到达下呼吸道的气管。大部分颗粒会因为尺寸问题而受到影响口咽区域的影响。嵌塞沉积也会像气管一样分裂成左支气管和右支气管。作为减小粒子速度的因素,惯性碰撞在较小的气道中成为一个不太重要的机制。随着大颗粒在上气道中被惯性冲击去除,重力沉降是更小的粒子(2 - 5μM)在呼吸性细支气管和肺泡中的沉积机制。这些颗粒在重力作用下加速加速直到重力被空气阻力平衡的时候达到一个终端速度[6]。这是一个通过呼吸辅助

并依赖时间的过程[7]。布朗运动和扩散是一种只对直径小于0.5μm的粒子才有的显著现象。这些小颗粒被周围随机运动的气体分子轰击。在这种情况下,粒子的扩散率与其直径成反比。关于颗粒沉积方面的详尽回顾,读者可以咨询Finlay(2001)[8]。

Aerosol particle size and polydispersity are major determinants of the site and mechanism of pulmonary deposition. Fundamental deposition studies using monodisperse aerosols together with mathematical models have established the

optimum aerosol particle size for lung deposition [9 –12] . Aerosols larger than 10 μ

m will deposit in the oropharyngeal region and will not be inhaled. Particles less than

3 μ m will be capable of penetrating into the alveolar region. Aerosols in the size

range 3 –10 μ m will be distributed in the central and conducting airways [13] . A

polydisperse aerosol containing a range of these particle sizes will allow deposition throughout the lungs. In theory, lung site deposition targeting should be possible by controlling the particle size of the inhalation aerosol [14] . However, a number of other signifi cant variables can affect deposition within the respiratory tract and these

often confound any efforts at targeting [15] . The patient’s respiratory cycle, both the

rate and depth of breathing, will affect aerosol deposition, and this is also the source

of large intersubject variability in deposition [16] . Slow and deep inhalations

are required for deposition in the peripheral airways, and this is the technique

often recommended for inhalation with the MDI [17] . A different technique may be

required for DPIs, where the patient’s inspiratory effort is often the powder

dispersion and delivery force. Flow rates greater than 60 L/min are commonly employed for powder inhalers [18, 19] . A final respiratory maneuver can be employed to promote deposition; breath holding up to 10 s is generally recommended to enhance deposition by sedimentation [17] . Other parameters that will affect lung deposition are the disease state within the lungs and its effect on airway caliber

together with the patient’s age and airway morphology [20 –27] .

气雾剂粒子的大小和多分散性是肺部沉积部位和机制的主要决定因素。在根本性沉积的

研究中,已经用单分散气雾剂连同数学模型确立了最佳的肺沉积的气雾剂粒子大小[9 –

12]。大于10μm的气雾剂颗粒将会沉积在口咽区,不会被吸入肺部,小于3μm的颗粒能够渗透进入肺泡区域。直径在3-10μm之间的气雾剂颗粒将会分布在中心和传导气管中[13]。一种多分散性的气雾剂颗粒的尺寸可以在肺部沉积。理论上,肺部沉积的靶向性可以通过吸入的气雾剂的颗粒大小来控制[14]。然而,许多其他显著变量会影响颗粒在呼吸道内的沉积,也会对靶向有影响[15]。患者的呼吸循环,呼吸速度和呼吸的深度都会影响气雾剂的沉积,这些也是沉积主体差异的来源[16]。缓慢而深的吸入剂需要沉积在周边气道中,而这种技术常常用于吸入MID的过程中[17]。

5.8.2.3 Pharmacokinetics药代动力学

Once deposited on the surface of the airways, the particle is subject to absorption and clearance processes depending upon its physical properties and the site of deposition [28 –30] . For example, a lipophilic small molecule deposited in the central airways would have a different pharmacokinetic profile than a 50 - kDa macromolecule deposited in the alveolar region. The former may undergo mucociliary clearance following deposition on a ciliated epithelial cell. Following dissolution, lipophilic drugs may be transported across the epithelium by passive transcytosis, while hydrophilic compounds are taken up by other pathways such as via tight junctions and endocytosis. Having overcome the barrier of the epithelial layer, the drug is available for distribution into the systemic circulation or to its site of action. Finally, the drug may also be subject to metabolism within the airways. For the macromolecule deposited in the peripheral airways, the absorption rate has been shown to be dependent upon molecular size. Larger molecules are subject to active processes such as caveolae or vesicular transport across the cell. Diffusion remains the predominant mechanism for smaller lipophilic macromolecules. Insoluble molecules can be phagocytosed by alveolar macrophages and removed via the lymphatic system or the mucociliary escalator. The pharmacokinetics of inhaled drugs is complicated by the fact that a significant fraction of the delivered dose is deposited in the oropharynx or removed from the lungs via mucociliary clearance and in both cases subsequently swallowed [31] . An often desired goal for a pulmonary formulation is prolonged action within the lung. Rapid clearance or metabolism results in short duration of action for most inhaled drugs. A number of approaches using formulation excipient additives have been investigated to increase the residency or prolong release of drug at its site of action within the lungs [32, 33] . Microspheres containing nanoparticles have been formulated as dry powders for inhalation offering sustained - release properties [34] . In addition, prodrugs which are activated locally

within the lungs have been used in an alternative approach [35 –37] .

The pharmacokinetic process of absorption, distribution, metabolism, and excretion within the lungs is an enormous subject area and readers are referred to specific reviews for further details [38 –43] . Of particular interest may be the subject of absorption enhancer methodologies for lung delivery, which is beyond the scope of

this chapter [44] .

颗粒一旦沉积在气道表面,就会被吸收和清除处理,这取决于它的物理性质和沉积的部位[28 –30]。例如,一种沉积在中央气道中亲脂性小分子比起沉积在肺泡区域的50-KDa

高分子来说会有不同的药代动力学,前者在沉积到纤毛上皮细胞之后可能被粘膜纤毛清除。继续溶出,亲脂性药物将会通过被动运输的方式跨过上皮细胞。而亲水性化合物则由其他途径,比如通过紧密连接的内吞作用的方式运输。在克服了上皮细胞层的屏障之后,药物就可以分布进入到全身循环或者其作用位点了。最后,药物也可能在气道内被代谢。沉积在周边气道的高分子的吸收率已经被证明取决于其分子大小有关。高分子物质通过细胞质膜微囊或小泡运输跨越细胞膜。扩散仍然是较小的亲脂性高分子的主要运输机制。不溶性分子可以通过肺泡巨噬细胞吞噬和淋巴系统或粘膜纤毛除去。事实上吸入药物的药代动力学是一个复杂的过程,因为输送剂量的一小部分会沉积在口咽或被粘膜纤毛清除而移除肺部随后在这两种情况之后被吞噬[31]。对于肺部制剂通常期望的目标是能延长药物在肺部中的作用时间。对于大多数吸入药物来说快速清除或代谢导致的结果是药物作用时间短。一些制剂用赋形剂的添加方法已被研究,方便于增加药物停留时长或延长药物在肺部作用部位的释放时间[32, 33]。含有纳米颗粒的微球已经被制为有持续释放性能的干粉吸入产品[34]。此外,在肺内

局部活化的前药,已运用在另一种做法中[35 –37]。

药物在肺中的吸收,分布,代谢和排泄等药物动力学过程是一个很大的主题板块,如要了解更多详细信息,请读者参考文献[38 –43]。另外一个特别有意义的主题可能是关于肺部药物吸收促进剂的方法学研究,但这超出了本章的范围[44]。

5.8.3 THERAPEUTIC INDICATIONS FOR AEROSOL DELIVERY气雾剂给药的临床适应征

5.8.3.1 Current Applications目前的应用

Aerosolized drug delivery is currently used to deliver a limited range of therapeutic classes of compounds. These are mainly for asthma and chronic obstructive airway disease. These classes of compounds include short - and long - acting β - adrenoceptor agonist, corticosteroids, mast cell stabilizers, and muscarinic antagonists. Of recent note is the popularity of combination products. These have obvious advantages from a patient compliance perspective. In addition, certain combinations of drugs have shown synergistic therapeutics benefits when compared to the drugs given by separate inhalers [45] . Long - acting β - adrenoceptor agonists and corticosteroids formulated as combination products are available as both MDIs and DPIs [46] . Also recently introduced was a MDI formulation, the R enantiomer of albuterol, which is believed to be mainly responsible for bronchodilation in the racemic mixture [47] . Zanamivir is licensed in the United States as an inhaled antiviral agent for the treatment of influenza [48] . Recombinant human deoxyribonuclease (rhDNAase) is available as a nebulizer product for the treatment of cystic fibrosis, in which it acts to liquefy viscous lung secretions [49] . And recently, insulin was approved as an inhaled powder for glycemic control in type I and II diabetes (see Section 5.8.6.5 ) [50] .

雾化药物给药目前被用于递送范围有限的治疗类化合物。它们主要是用于治疗哮喘和慢性阻塞性气道疾病。这类化合物包括短效和长效的β- 肾上腺素受体激动剂,糖皮质激素,

肥大细胞稳定剂和毒蕈碱受体拮抗剂。近期值得注意的是组合产品的普及。从患者的顺应性角度来看这些组合有明显的优势。此外,与那些通过单独吸入器给药的药物相比,某些组合药物显示出更好的协同治疗的优势[45]。长效β-肾上腺素能受体激动剂和皮质类固醇配制

成组合产品既可以做成计量吸入器也可做成干粉吸入器[46]。最近还推出了一个计量吸入器配方,沙丁胺醇的R对映异构体,它被认为是主要负责支气管扩张的外消旋混合物[47]。在美国,扎那米韦作为一种吸入抗病毒药物用于流感的治疗[48]。重组的人类脱氧核糖核酸酶(rhDNAse)已作为一种治疗囊性纤维化的喷雾器产品,起到液化粘稠的肺分泌物的作用[49]。而最近,胰岛素被批准做成吸入粉末,在I型和II型糖尿病中控制血糖(参见5.8.6.5)[50]。5.8.3.2 Future Applications未来的应用

Research and development are presently underway covering a vast array of novel applications. Clark (2004) provides an extensive list of products and their current

state of development [51] . A significant future advance will be the development

of inexpensive, noninvasive, stable, single - dose vaccine delivery via the lungs [52] . Efforts in this area are being led by the World Health Organization in the Measles Aerosol Project, and in a separate project, the Grand Challenges in Global Health initiative has funded a program to further develop an inhalation aerosol measles vaccine. Delivery of the measles vaccine via the lungs has been demonstrated to

be both safe and effective [53 –58] . Now the challenge of each of these projects is

to produce stable inhalation vaccine formulations to be delivered via inexpensive inhalers while maintaining both safety and efficacy [59] . The use of inhaled vaccinations in the event of a bioterrorism attack is also a potential application

[60, 61] .

目前正在进行的研究和发展涉及多方面的新用途。克拉克(2004)提供了一个多样化的产品列表还介绍了它们目前的发展状态[51]。在未来,廉价,非侵入性,稳定,单剂量的肺部给药疫苗将成为一个有重大意义的发展方向[52]。世界卫生组织的麻疹气雾剂项目正在

向这方面努力,在一个单独的项目中,全球健康行动计划资助的进一步发展吸入性气雾剂麻疹疫苗的项目面临着极大挑战。经肺给药的麻疹疫苗已被证明既安全又有效[53 - 58]。现在每个项目面临的挑战是如何在利用廉价的吸入器稳定输送吸入疫苗制剂的同时又可以保证

制剂的安全性和疗效[59]。在生物恐怖袭击事件中使用吸入疫苗也是吸入剂的一个潜在应用[60,61]。

The use of the inhalation route for the delivery of gene therapy is also an area

of significant interest [60, 62] . Cationic liposomes and polymers together with adenoviral vectors containing the reporting genes have been aerosolized using nebulizers for the majority of clinical studies. However, there are a significant number of challenges that must be overcome before pulmonary gene delivery is deemed completely successful, the most important being low gene transfer efficiency at the cellular level. This problem is not unique to inhalation therapy. Inhalation of a recombinant adenovirus containing the cystic fibrosis transmembrane regulator

(Ad2/CFTR) demonstrated the feasibility of this approach for the treatment of

cystic fibrosis [63, 64] . However, the limited duration of transfection and low cellular uptake efficiency still remain a barrier to full utilization of this route [60, 65] . There are a number of reviews that provide updates as to recent developments in this area [60, 66 –70] .

将吸入途径给药应用于基因治疗,目前也是人们十分感兴趣的新领域[60,62]。阳离子脂质体和聚合物与含有信使基因的腺病毒载体一起被喷雾器雾化用于大量的临床研究。然而,在肺部基因转运被确定完全成功之前,还要面临许多严峻的挑战,其中最重要的就是细胞水平上的基因转移效率较低。这个问题并不是吸入疗法遇到的唯一问题。吸入含有囊性纤维化跨膜调节器(Ad2的/ CFTR)的重组腺病毒,证明了这种方法可以用于囊性纤维化的治疗[63,

64]。然而,有限的转染和低细胞摄取效率仍然是使这条路线得到充分利用的一个障碍[60,

65]。这里还有一些资料,提供该领域最新的发展状况[60,66 - 70]。

Proteins are being considered for pulmonary applications [71, 72] . Leuprolide is a nonapeptide which has been investigated as both an MDI and DPI formulation for the treatment of prostrate cancer [73 –76] . Other hormones being investigated include calcitonin for the treatment of Paget disease and osteoporosis, parathyroid hormone to treat osteoporosis, growth hormone releasing factor for the treatment of pituitary dwarfism, and vasoactive intestinal peptide (VIP) for the treatment of pulmonary diseases [60, 77 –81] .

目前,正在考虑将蛋白质应用于肺部[71,72]。醋酸亮丙瑞林是一种九肽,它已被研

究并用于MDI和DPI配方中,作用是治疗前列腺癌[73 - 76]。其他用于治疗骨质疏松症和佩吉特氏病的激素也正在研究中,比如甲状旁腺激素治疗骨质疏松症,生长激素释放因子对垂体性侏儒症的治疗,还有血管活性肠肽(VIP),用于肺疾病的治疗[60,77 - 81]。

Other potential inhalation applications include drugs for both local and systemic delivery. Inhaled tobramycin is being investigated for the treatment of Pseudomonas aeruginosa exacerbations in cystic fibrosis [82, 83] . Liposomal ciprofloxacin is

being developed as a first - line defense against biowarfare agents (e.g., anthrax) [61] . Inhaled cyclosporine has been shown to improve survival rates and extend periods of chronic rejection - free survival in lung transplant patients [84] . Apomorphine has been proposed as an inhalation formulation for the treatment of erectile dysfunction [85] . Aerosol delivery of chemotherapeutic drugs has been advocated for the treatment of lung cancer [86] . Morphine and fentanyl have been investigated for alternative routes of administering analgesics [87 –90] . Heparin

and low - molecular - weight heparins have been aerosolized and advocated for the treatment of emphysema and thrombosis [91 –93] . Iloprost, a stable prostacyclin analog, has been aerosolized by nebulization for use in the treatment of pulmonary hypertension [94] . This list of potential new treatments approached via the inhalation route is not exhaustive; among the other compounds under investigation are α1 - antitrypsin, sumatriptan, ergotamine, nicotine as replacement therapy, pentamidine, and ribavirin. Readers should be aware that a large number of these examples are proof - of - concept studies that may not get beyond in vitro experiments and

animal studies.

其他潜在的吸入应用包括药物的局部和全身性输送。目前正在研究吸入妥布霉素对铜绿假单胞菌加重囊性纤维化的治疗作用[82,83]。正在开发脂质体环丙沙星,将其作为细菌战

(如炭疽)的第一道防线[61]。已经证实吸入型环孢菌素可以明显提高肺移植患者的存活率、延长慢性排斥反应的周期[84]。已被有提议将阿朴吗啡做成一种吸入剂,用于治疗勃起功能障碍[85]。通过气雾剂给药的化疗药物已被提倡用于肺癌的治疗[86]。研究吗啡和芬太尼类镇痛药的其他给药途径[87 - 90]。肝素和低分子肝素量已经被雾化并提倡将其用于肺气肿和血栓形成的治疗[91 - 93]。伊洛前列素是一种稳定的前列腺环素类似物,已经雾化并用于肺动脉高压的治疗[94]。这些潜在的通过吸入途径给药的新治疗方法名单并不详尽;其它化合物被研究的化合物还有,α1 - 抗胰蛋白酶,舒马,麦角胺,尼古丁,喷他脒和利巴韦林。读者应该知道,这些大量的例子都证明概念研究,无法超越在体外实验和动物研究。

5.8.4 AEROSOL DRUG DELIVERY DEVICES气雾剂给药装置

5.8.4.1 Introduction引言

As can be seen from the previous section, aerosol drug delivery continues to be an area of intensive research and development for the pharmaceutical industry. Not only are new applications for the pulmonary route being investigated, but also new delivery technologies are under development. The reformulation of MDIs with hydrofluoroalkane (HFA) propellants together with the potential of using the inhalation route as a means of systemic administration has led to significant technological advances in delivery devices. In parallel to MDI research DPIs have been developed from breath - actuated single - dose devices to both multiple - dose inhalers and active - dispersion DPIs. There is an extensive literature detailing the fundamental mechanisms of powder dispersion aimed at improving pulmonary deposition from powder inhalers. In addition, novel particle production technologies have been developed that provide alternatives to the traditional micronized powder for formulation in both MDIs and DPIs. Nebulizer technology has evolved from previously nonportable devices into high - efficiency, hand - held nebulizers that offer alternatives to the MDI and DPI for certain treatment regimes. Finally, novel soft mist inhalers that generate aerosols by solution atomization have emerged on the inhaler landscape. All this research has focused on improving aerosol deposition efficiency and reproducibility within the lungs, together with targeting the peripheral lungs for systemic absorption. The efforts of the last decade culminated in two significant events. First, the regulatory approval of Proventil HFA and QVAR, the first suspension and solution HFA MDIs, respectively. Second, in 2006, the U.S. and European regulatory authorities approved Exubera, an insulin DPI for the systemic treatment of type I and II diabetes. Exubera offered a noninvasive alternative to subcutaneous injections of insulin.

从前面的章节中可以看出,气雾剂药物给药仍然是制药工业深入研究和开发领域。对于肺途径的开发不仅限于它的新应用,还有它新的传输技术。氢氟烷(HFA)抛射剂的计量吸入器这种潜在给药途径已经让递送装置技术进步了一大步。与计量吸入器干、粉吸入器相关的吸入器已研发,开发了自然呼吸定量吸入器,多种剂量吸入器和主动分散干粉吸入器等装置。有大量的文献详细说明了粉体分散的基本机制,目的是在于改善药物的肺部沉积。此外,新的粒子的生产技术已经被开发,这替代了传统的微粉化粉末制剂在计量吸入器和干粉吸入器上的应用。雾化器技术已经从以前的非便携式设备进化成现在的高效率的设备,手携式喷雾器为某些治疗方案提供了MDI和DPI的替代品。最后,通过溶液雾化而产生气溶胶的新型软雾吸入器已经出现。所有的研究都集中在提高气溶胶沉积的效率和肺部内再现性,再加上针对外围肺部的全身性吸收。过去十年的努力在两方面有了显著成果。第一,监管部门批准

了Proventil HFA和QV AR,还有第一款悬浮溶液的HFA计量吸入器。第二,在2006年,美国

和欧洲监管部门批准了Exubera,一种用于I型和II型糖尿病的全身治疗的胰岛素雾化吸入剂。Exubera替代胰岛素的皮下注射,为患者提供了一种无创性的给药途径。

5.8.4.2 Characteristics of Ideal Delivery Device 理想输送装置的特征

With these developments, innovation continues toward development of the ideal inhaler. A number of authors have compiled lists of desired characteristics for an aerosol inhaler [95 –97] . These can be grouped into patient - desired or industry -

driven properties. From the patient’s perspective the overriding requirement is a device that is simple to operate. This is becoming increasing difficult to achieve as evidenced by the intensive patient education initiative that is being planned for the launch of the Exubera insulin inhaler. Poor compliance and adherence to prescribed

therapy may be related to patients’failure to use the inhaler correctly [98] . Inhalers should be portable and contain a large number of doses. The device should also give some indication to the patient when it is empty. The inhaler should be suitable for

use by all of the population, especially children and the elderly. Ganderton (1999) cited that from a device perspective aerosol generation should be independent of the patient’s inhalation and should continue for a substantial portion of the inspiratory cycle. This would minimize the reliance on coordinating inhalation and actuation

of the device [99] . Breath - actuated devices have been developed to address this issue. In order to achieve lung deposition targeting, the particle size distribution of

the aerosol should be capable of being altered depending upon the specific target region. For example, the central airways may be targeted with a 3 –5 μ m aerosol for the treatment of acute bronchoconstriction, while a smaller aerosol (1 –3 μ m) might be used for deep lung deposition and subsequent systemic absorption [99] . In addition, the dose should be delivered reproducibly with minimal oropharyngeal deposition, perhaps as a low - velocity aerosol. There should be a minimal number of small parts in the inhaler, and it should be robust and reliable when placed “in use. ”The manufacturer has the option of producing a disposable or refillable unit; however, the inhaler should protect the formulation from environment and not affect its stability.

Dolovich et al. (2005) have provided an extensive evidence - based evaluation of aerosol drug devices. They concluded that when selecting an inhalation delivery system the following should be considered: device and drug combination availability, clinical setting, patient age, the ability of the patient to use the device correctly,

device use with multiple medications, cost and reimbursement, drug administration time, convenience in outpatient and inpatient settings, and patient and physician preference [100] . Other reviews have compared the benefits and disadvantages of

inhalers from clinical and patients’perspectives [101, 102] .

随着技术的进步,吸入器的创新会继续朝着理想的吸入器发展。一些作者已经列出了理想型气雾剂吸入器所需的特性清单[95 - 97]。这些特性都可以归纳为病人的期望或产业驱动性能。从患者的角度来看,他们需要的是一种操作简单的装置。现在重症病人的教育倡议已变得越来越难以实现,所以正在计划推出的Exubera胰岛素吸入器前景不太乐观。依从性差和遵守规定的治疗可能导致患者未能正确的使用吸入器[98]。吸入器应便于携带,并含有大量的药物剂量。当它是空的时候,该装置也应给予患者一定的指示。该吸入器应适合所有的人口使用,尤其是老人和儿童。Ganderton(1999)举例说,从设备的角度来看气雾的产生应独立于患者的吸入,并应继续进行基本的吸气循环,这将对协调吸入和制动装置的依赖降到最小[99]。呼吸–驱动装置已被开发来解决这个问题。为了达到靶向肺沉积,气雾剂的粒度分布应能根据特定的目标区域而被改变。例如,可以通过中央气道用一个3-5μ米的气雾剂靶向性治疗急性支气管收缩,而较小的气雾剂(1 - 3μM)可能被用于深肺沉积和随后的全身性吸收[99]。此外,该剂量应以最小的口咽沉积可重复的递送,也许作为一种低速气雾剂。作为理想的吸入器,小部件应尽量的达到最少,并且在使用它的时候它的放置应该是稳健可靠的。制造商可选择生产一次性装置或有可再填充单元的装置,然而,厂家必须要保生证,他们生产的吸入器的稳定性不会受环境的影响。

Dolovich等(2005),对气雾剂药物设备的基础评估进行了广泛的调查研究。他们得出的结论是,在选择吸入给药系统时应考虑以下因素:设备和药物相结合的可用性,临床上患者年龄,患者正确使用设备的能力,多种药物设备的使用,费用报销,药物给药时间,方便的门诊和住院设置,以及患者和医生个人偏爱[100]。患者和临床使用对吸入器优缺点的反馈有益于吸入器的开发改进[101,102]。

5.8.5 METERED DOSE INHALERS定量吸入器

5.8.5.1 Introduction引言

Since their development, MDIs have been widely used for pulmonary aerosol drug delivery [103] . Despite their recognized limitations, they remain the device of choice

for many physicians around the globe. From a patient’s perspective, they are light,

portable, and robust and contain multiple doses of medication. They are also relatively simple to operate (press and fire); however, significant numbers of patients experience difficulties correctly using the MDI due to coordination problems [104] .To maximize lung drug deposition, actuation (pressing the MDI canister) by the patient must be coordinated with a slow, deep inhalation. Studies have reported that 51% of patients fail to operate the MDI correctly [104] . This leads to low lung deposition, high oropharyngeal deposition, and ultimately perhaps therapeutic failure. From the pharmaceutical industry perspective, the components are relatively inexpensive; however, the formulation and manufacturing have become increasingly complex. There are numerous studies describing the multifaceted and interactive effects of

propellant [105 –110] , excipient [111 –115] , metering valve [110, 116] , and actuator [116 –119] on the aerosol particle size characteristics of the MDI [120, 121] .To date, the success of the MDI has relied in part on the potency and relative safety of the bronchodilators and corticosteroids commonly used for the treatment of

respiratory disorders rather than its delivery efficiency. The relatively low and often variable aerosol deposition efficiency, only around 10 –20% of the nominal dose being delivered to the lungs, is the challenge that is beginning to be addressed as the

MDI looks to enter the next 50 years of aerosol drug delivery.

随着他们的发展,计量吸入器已被广泛地用于肺部气雾剂递药[103]。虽说他们的认识有局限性,但他们的设备仍然被全球各地许多医师使用。从患者的角度来看,它们是质轻,便携,坚固并且还包含多个剂量用药,他们操作起来也比较简单(按压控制)。然而,大部分的患者都因为协调方面的问题,在如何正确使用计量吸入器上有过困难经历[104]。为了最大限度地提高肺癌药物沉积,在致动(按压MDI罐)时,病人必须用一个比较缓慢的速度进行协调使其吸入。有研究报道称51%的患者无法使计量吸入器正常工作[104]。这会导致低肺沉积,高口咽沉积等问题,最终也许治疗只能以失败而告终。从制药业的角度看,组分相对便宜,然而,配方和生产正在变得越来越复杂。有许多研究描述了抛射剂的多面性和互动效果[105 - 110],赋形剂[111-115],计量阀[110,116],致动器[116 - 119],计量吸入器的气雾剂粒径特性[120,121]。迄今为止,MDI的成功是因为它的效力和支气管扩张剂的相对安全性以及皮质类固醇通常用于治疗呼吸系统疾病而不是它的递送效率。气溶胶的沉积效率相对低而且经常可变,通常只有约10 - 20%的标称剂量会被递送至肺部,所以着手解决未来50年气雾剂给药问题,计量吸入器是一个挑战也是一个开始。

5.8.5.2 Metered Dose Inhaler and HFA Reformulation定量吸入器和HFA新配方

The basic design and operation of the MDI has changed little over its lifetime. Aerosols are generated from a formulation of drug (0.1 –1% w/w) either suspended or in solution in the liquefied propellant. The formulation is held under pressure in a canister. Figure 1 shows the basic components of the MDI, consisting of a canister sealed with a metering valve which is inserted into a plastic actuator containing the mouthpiece. Aerosol generation takes place when the canister is pressed against the actuation sump by the patient. Actuation causes the outlet valve to open and the liquefied propellant formulation is released through the actuator nozzle and subsequently through the mouthpiece to the patient. Metered volumes between 20 and 100 μ L are dispensed, and as the pressurized propellant is released, it forms small liquid droplets traveling at high velocity. These droplets evaporate to leave drug particles for inhalation [117] . Purewal and Grant (1998) have assembled a definitive reference source for issues relating to the design, manufacturing, and performance of MDIs [122] .

计量吸入器的基本设计和操作几乎没有改变它的使用期限。气雾剂从药物制剂中产生(0.1 – 1% w/w)在悬浮或液化抛射剂溶液中任选其一。该制剂被压力压制在一个罐中。图1显示了MDI的基本组件,包括用计量阀密封的罐和被插入到塑料致动器中的嘴件。当患者按动阀门,所述罐被压靠在致动贮槽上,然后产生气雾。致动会导致出口阀打开、液化抛射剂制剂通过致动器喷嘴,随后通过吹口向患者释放。计量卷被分配在20和100μL之间,当加压抛射剂被释放时,它形成小液滴会高速运动。这些吸入的液滴会因为蒸发而离开药物颗粒[117]。Purewal和Grant(1998年)对有关设计、制造和计量吸入器的性能问题汇集了权威的参考源[122]。

药剂学翻译

The currently marketed MDIs may look similar to the devices that were first developed by Riker in 1950. However, due to the replacement of the ozone - depleting chlorofluorocarbon (CFC) propellants with HFA propellants, virtually all of the components of the MDI have been altered. In 1987, the Montreal Protocol was drawn up, leading to the eventual phase - out of CFC propellants. MDIs containing CFC propellants were granted essential - use exemptions until viable alternatives became available. Therefore, with this impending withdrawal, a consortium of pharmaceutical companies (IPACT - I and IPACT - II) worked to identify and toxicologically test At first look alternative propellants for MDIs. HFA 134a and HFA 227 were identified as viable alternatives and the task of reformulation began, it appeared that the most expeditious route to replacing a CFC product would be to produce a suspension HFA MDI with exactly the same in vitro characteristics as the CFC MDI. This would prove to be a time - consuming route [123, 124] . While some manufacturers focused on producing HFA products with identical characteristics to the current CFC versions to accelerate the pathway through clinical testing to market. Others undertook extensive research and development in the area of HFA formulation options, and this has led to the possibility of utilizing the MDI for both local and systemic administration. During this reformulation effort, the industry has taken the opportunity to address some of the other shortcomings of the MDI [125] . Among these issues were poor peripheral lung delivery, variable dose delivery, and limitations as to the dose capable of being delivered to the lung (typically about

1 mg) [126].

目前市场上销售的计量吸入器外形看起来可能类似于赖克在1950年首次开发的那款。然而,由于用HFA抛射剂替换了破坏臭氧层的氯氟烃(CFC)抛射剂,所以几乎所有计量吸入器的组件已经被改进。1987年,蒙特利尔议定书的制定,导致了氟氯化碳抛射剂的终结。含CFC的抛射剂计量吸入器规定了豁免使用量,直到有可行的替代品面世。因此,这个紧急撤离,使制药公司组成的财团(IPACT - I和IPACT - II)致力于识别替代抛射剂计量吸入器的

毒理学测试。HFA134a和HFA227被确定为可行的替代品,初步看来,这种更替CFC的HFA 计量吸入器将具有与CFC计量吸入器完全相同的体外特性。这将是一个十分耗时的路线[123,124]。然而一些厂商专注于生产和当前版本的CFC具有相同的特点HFA产品,并想以此来达到加速通过临床测试获得以市场的目的。其他人对HFA配方的选择方面进行了广泛的研究和开发,这使得MDI具有了用于局部和全身给药的可能性。因为在新配方方面取得了进展,该行业已借此机会解决了一些MDI的其他缺点[125]。这些问题是,外周肺递送较差,剂量输送可变以及限制了能够被递送到肺的剂量(通常约1毫克)[126]。

The replacement of CFC MDIs with inhalers formulated with the HFA propellants is now well underway in Europe. Although progress in the United States has been slower, with the introduction of suitable alternatives for albuterol inhalers, the FDA has ordered that CFC albuterol MDIs be withdrawn from the market by the end of 2008 [127] . Examples of reformulated products available in the United States include Ventolin HFA, which is a suspension albuterol sulfate formulation using HFA 134a alone. ProAir is an alternative albuterol sulfate product manufactured by Ivax which contains ethanol and HFA 134a. Xopenex HFA has recently been approved for marketing in the United States [128] . This product contains levalbuterol tartrate (R –albuterol enantiomer) together with HFA 134a, dehydrated alcohol, and oleic acid as a suspension formulation. Table 1 summarizes the HFA products currently available in the United States and their excipients. The following section will focus on the current options for formulation of drugs in HFA propellant systems and the challenges that are encountered as products are reformulated as HFA formulations.

现在氟氯化碳计量吸入器的更换与吸入配方与HFA推进剂在欧洲进展顺利。尽管在美国的进展一直比较缓慢,但随着沙丁胺醇合适的吸入替代品的引进,FDA已经下令,沙丁胺醇氟氯化碳计量吸入器将在2008年底撤出市场[127]。在美国可以重新使用的产品实例包括喘乐灵沙丁胺醇气雾剂,它是一种单独使用HFA134a的硫酸沙丁胺醇悬浮液制剂。PROAIR是由IV AX制造一种含有乙醇和HFA134a的硫酸沙丁胺醇替代品。最近Xopenex HFA(酒石酸左旋沙丁胺醇吸入气雾剂)已经在美国批准上市[128]。该产品含有左旋沙丁胺醇酒石酸(R - 沙丁胺醇对映体)和HFA134a,还有无水乙醇和混悬剂的油酸。表1总结了目前在美国可用的氢氟烷烃产品和其赋形剂。以下部分将侧重于当前HFA抛射剂的配方药物的选择以及重新为HFA配方所遇到的挑战。

药剂学翻译