The role of disposable inhalers in pulmonary drug delivery

Introduction: There is increasing interest in the pulmonary route for both local and systemically acting drugs, vaccines and diagnostics and new applications may require new inhaler technology to obtain the most therapeutically and/or cost-effective administration. Some of these new applications can benefit from the use of disposable inhalers.

Areas covered: Current trends in pulmonary drug delivery are presented in this review as well as the possible contribution of disposable inhalers to the improvement of pulmonary administration therein. Arguments in favour of disposable inhalers and the starting points for development of devices and their formulations are discussed. Also, a brief review of the state of the art regarding current disposable inhaler development is given.

Expert opinion: Prerequisites for the use of disposable inhalers, particularly dry powder inhalers, in applications such as childhood vaccination and for preventing or stopping pandemic outbreaks of highly infectious diseases (like influenza, bird flu, SARS) are that they are simple, cheap and effective. Not only do the devices have to be simple in design, but the drug formulations should also be cheap. This may require a different approach as the formulation may not need to be adapted to improve the inhaler must be designed to enhance formulation dispersion.     

Single-use disposable dry powder inhalers for pulmonary drug delivery

IMPORTANCE OF THE FIELD: The understanding of pulmonary drug delivery and thus its utilization for medical purposes has remarkably advanced over the last decades. It has been recognized that this route of administration offers many advantages and several drug delivery systems have been developed accordingly. Thereby, single-use disposable dry powder inhalers may be considered an economically and therapeutically valuable option for both local and systemic administration of drugs to treat a variety of different disease states. AREAS COVERED IN THIS REVIEW/WHAT THE READER WILL GAIN: This review highlights the required characteristics and potential applications of single-use disposable dry powder inhalers considering advantages as well as limitations of these drug delivery devices. Until now, such drug delivery systems have not become widely accepted. Several devices are available or under development and a few products have reached or completed the clinical phase, but none of them have received market authorization as yet. TAKE HOME MESSAGE: Recent advances in formulation and device design, however, can be considered encouraging and should eventually lead to a wider establishment of single-use disposable dry powder inhalers in pulmonary drug delivery.     

新型肺部给药系统-吸入粉雾剂

吸入粉雾剂 (又名粉雾吸入剂、干粉吸入剂、粉雾剂) 是一种新型的肺部给药系统, 具有稳定性好, 不含抛射剂氟里昂等优点, 近年来受到人们的广泛关注。粉雾剂由粉末吸入装置和供吸入用的干粉组成。本文就近年来粉雾剂的研究进展, 包括吸收机制, 粉雾剂品种, 吸入装置, 制备技术和评价特征参数等进行了综述。     

Dry powder inhalers for pulmonary drug delivery

The pulmonary route is an interesting route for drug administration, both for effective local therapy (asthma, chronic obstructive pulmonary disease or cystic fibrosis) and for the systemic administration of drugs (e.g., peptides and proteins). Well-designed dry powder inhalers are highly efficient systems for pulmonary drug delivery. However, they are also complicated systems, the the performance of which relies on many aspects, including the design of the inhaler (e.g., resistance to air flow and the used de-agglomeration principle to generate the inhalation aerosol), the powder formulation and the air flow generated by the patient. The technical background of these aspects, and how they may be tuned in order to obtain desired performance profiles, is reviewed. In light of the technical background, new developments and possibilities for further improvements are discussed.     

干粉吸入剂的研究进展

干粉吸入剂（DPI）具有独特的吸收方式和药动学特点,与定量气雾剂相比优点突出。粉体工学性质和给药装置设计一直是制约该剂型发展的重要因素。近十几年来随着药物微粉化技术和新型给药装置研究的不断进步,其应用范围越来越广,在国际药物制剂研发方面呈快速发展趋势。现参考国内外研究文献,对DPI给药方式的药物作用特点、DPI药物及载体粉末性质以及目前吸入装置的种类及主要特点等进行综述。     

Spray-freeze-dried dry powder inhalation of insulin-loaded liposomes for enhanced pulmonary delivery

Nowadays, growing attention has been paid to the pulmonary region as a target for the delivery of peptide and protein drugs, especially macromolecules with systemic effect like insulin, since the pulmonary route exhibits numerous benefits to be an alternative for repeated injection. Furthermore, encapsulation of insulin into liposomal carriers is an attractive way to increase drug retention time and control the drug release in the lung; however, its long-term stability during storage in the reservoir and the process of aerosolization might be suspected when practically applied. Thus, the aim of this study was to design and characterize dry powder inhalation of insulin-loaded liposomes prepared by novel spray-freeze-drying method for enhanced pulmonary delivery. Process variables such as compressed air pressure, pump speed, and concentration were optimized for parameters such as mean particle diameter, moisture content, and fine particle fraction of the produced powders. Influence of different kinds and amounts of lyoprotectants was also evaluated for the best preservation of the drug entrapped in the liposome bilayers after the dehydration–rehydration cycle. The in vivo study of intratracheal instillation of insulin-loaded liposomes to diabetic rats showed successful hypoglycemic effect with low blood glucose level and long-lasting period and a relative pharmacological bioavailability as high as 38.38% in the group of 8 IU/kg dosage.     

Dry powder inhalers for pulmonary drug delivery

The pulmonary route is an interesting route for drug administration, both for effective local therapy (asthma, chronic obstructive pulmonary disease or cystic fibrosis) and for the systemic administration of drugs (e.g., peptides and proteins). Well-designed dry powder inhalers are highly efficient systems for pulmonary drug delivery. However, they are also complicated systems, the the performance of which relies on many aspects, including the design of the inhaler (e.g., resistance to air flow and the used de-agglomeration principle to generate the inhalation aerosol), the powder formulation and the air flow generated by the patient. The technical background of these aspects, and how they may be tuned in order to obtain desired performance profiles, is reviewed. In light of the technical background, new developments and possibilities for further improvements are discussed.     

吸入粉雾剂的处方研究和制备工艺

吸入粉雾剂在治疗肺部疾病,如哮喘、慢性阻塞性肺病中应用广泛.文中广泛查阅欧盟、美国等国的吸入粉雾剂研发的要求,结合国内该剂型的研发和审批情况,对吸入粉雾剂的组成、处方筛选以及制备工艺进行详细的阐述.对吸入粉雾剂在处方筛选与制备过程中的影响因素加以详细讨论,为研发粉雾剂药学工作者提供有益的参考.     

气流速度对粉雾剂在呼吸道沉降的影响

目的 :研究吸入速度对不同粒径粉雾剂在呼吸道沉降的影响。方法 :以硫酸沙丁胺醇为模型药物 ,用双冲程试验仪评价不同的气流速度对吸入型粉雾剂在模拟肺部的沉降量。结果 :粒径为 5 4～ 10 0μm的重结晶乳糖为载体的硫酸沙丁胺醇混合型粉雾剂 ,增加吸入速度 ,提高药物在肺部的沉积量 ;而乳糖、甘露醇为载体 ,喷雾干燥法制备的粒径为 0 .5～ 6.5 μm粉雾剂 ,增加吸入速度 ,药物在肺部沉积量基本不变直至下降。结论 :物理混合型吸入剂随气流速度的增加 ,药物在肺部的沉降量增加。含载体喷干型吸入剂 (0 .5～ 6.5 μm)中的药物在肺部的沉降量取决于载体 (如甘露醇 )和吸入速度 (如 3 0 L· min-1 )。     

Dry powder inhalers in COPD,lung inflammation and pulmonary infections

Introduction: The number of pulmonary diseases that are effectively treated by aerosolized medicine continues to grow.

Areas covered: These diseases include chronic obstructive pulmonary disease (COPD), lung inflammatory diseases (e.g., asthma) and pulmonary infections. Dry powder inhalers (DPIs) exhibit many unique advantages that have contributed to the incredible growth in the number of DPI pharmaceutical products. To improve the performance, there are a relatively large number of DPI devices available for different inhalable powder formulations. The relationship between formulation and inhaler device features on performance of the drug–device combination product is critical. Aerosol medicine products are drug–device combination products. Device design and compatibility with the formulation are key drug–device combination product aspects in delivering drugs to the lungs as inhaled powders. In addition to discussing pulmonary diseases, this review discusses DPI devices, respirable powder formulation and their interactions in the context of currently marketed DPI products used in the treatment of COPD, asthma and pulmonary infections.

Expert opinion: There is a growing line of product options available for patients in choosing inhalers for treatment of respiratory diseases. Looking ahead, combining nanotechnology with optimized DPI formulation and enhancing device design presents a promising future for DPI development.     

干粉吸入剂的粉末定量分装设备浅析

干粉吸入剂是一种新兴呼吸道给药剂型,其吸入粉末的分装装置不同于常见的口服固体粉末分装装置。本文综述国际上常用的干粉吸入剂的粉末定量分装装置,包括标准定量器装置装置、真空滚筒分装装置、Xcelodose精确粉末微定量装置等,同时介绍几种较新的、处于研发阶段的粉末分装装置。     

Computer-aided design of dry powder inhalers using computational fluid dynamics to assess performance

Dry powder inhalers (DPIs) are gaining popularity for the delivery of drugs. A cost effective and efficient delivery device is necessary. Developing new DPIs by modifying an existing device may be the simplest way to improve the performance of the devices. The aim of this research was to produce a new DPIs using computational fluid dynamics (CFD). The new DPIs took advantages of the Cyclohaler® and the Rotahaler®. We chose a combination of the capsule chamber of the Cyclohaler® and the mouthpiece and grid of the Rotahaler®. Computer-aided design models of the devices were created and evaluated using CFD. Prototype models were created and tested with the DPI dispersion experiments. The proposed model 3 device had a high turbulence with a good degree of deagglomeration in the CFD and the experiment data. The %fine particle fraction (FPF) was around 50% at 60?L/min. The mass median aerodynamic diameter was around 2.8–4?μm. The FPF were strongly correlated to the CFD-predicted turbulence and the mechanical impaction parameters. The drug retention in the capsule was only 5–7%. In summary, a simple modification of the Cyclohaler® and Rotahaler® could produce a better performing inhaler using the CFD-assisted design.     

盐酸氨溴索干粉吸入剂的制备工艺

目的优化盐酸氨溴索干粉吸入剂的制备工艺。方法采用喷雾干燥法制备盐酸氨溴索干粉吸入剂,采用双层液体碰撞器测定盐酸氨溴索干粉吸入剂体外沉积率,扫描电镜观察粉粒的形态,激光粒度测定仪测定粒径大小,以产品收率、粉末的空气动力学径、休止角及体外沉积率为考察指标,通过正交设计结合多指标综合评价法优化最佳制备工艺。结果通过正交试验-多指标综合评价,最佳制备工艺为:进口温度110℃、喷液速度1.8 mL.min-1、泵压170 kPa、气流量0.7 m3.min-1。结论按最佳制备工艺制得的干粉收率的质量分数为62.10%,空气动力学径Da 3.05μm,休止角36.16°,沉积率32.05%。正交实验结合多指标综合评价法用于盐酸氨溴索干粉吸入剂制备工艺的优化实用有效。     

吸入粉雾剂产业化过程中的质量控制

吸入制剂尤其是吸入粉雾剂结构和功能的特殊性,决定其在产业化过程中质量控制的特异性。讨论吸入粉雾剂产业化过程中原辅料、包材、中间体、终产品及稳定性考察过程中的质量控制特异性考察项目及标准设定。     

硫酸特布他林干粉吸入剂制备工艺的优化研究

目的:优化硫酸特布他林干粉吸入剂的制备工艺。方法:采用喷雾干燥技术制备硫酸特布他林干粉吸入剂,采用双层液体碰撞器测定其体外肺沉积率,扫描电镜观察干粉的表观形貌,热重分析仪测定干粉的水分含量,激光粒度测定仪测定粒径大小,以产品收率、水分含量、粉末的空气动力学粒径及体外肺沉积率为考察指标,通过正交设计结合多指标综合评价法优化最佳制备工艺。结果:通过正交试验-多指标综合评价,最佳制备工艺为:喷雾压力190 kPa,干燥风速0.7 m3.min-1,供液速度7.0 mL.min-1,入口温度120℃。结论:按最佳制备工艺制得的干粉收率为50.54%,水分含量为0.467%,空气动力学粒径为1.80μm,体外肺沉积率为55.19%。正交试验结合多指标综合评价法用于硫酸特布他林干粉吸入剂制备工艺的优化有效可用。     

Disposition kinetics of ketotifen from liposomal dry powder for inhalation in rat lung

1. The aim of the present study was to understand the benefit of liposomal dry powder for inhalation (LDPI) of ketotifen fumarate (KF) over plain drug dry powder for inhalation as a pulmonary targetted drug-delivery system. 2. The KF liposomes, composed of egg phosphatidyl choline and cholesterol, were prepared by the lipid film hydration technique. The liposomal dispersion was freeze dried and formulated to a dry powder for inhalation. Values of 89.0-65.3% drug entrapment of freeze-dried liposomes were estimated in prepared batches. 3. Rehydrated KF liposomes formed by the hydration of LDPI or the plain KF solution was delivered to rat lungs by intratracheal instillation. Simultaneous monitoring of drug levels in the bronchoalveolar lavage and lung tissue enabled assessment of pulmonary drug disposition. 4. Cumulative drug levels in lung tissue after intratracheal administration revealed that with liposomes targetting factors were between 1.36 and 1.54. The maximal drug concentration in lung homogenate for LDPI was 42.0 micro g compared with 73.6 micro g for plain drug solution. 5. Similarly, the time to reach maximum drug concentration in the lung homogenate for liposomal dry powder was 9-12 h compared with 3 h for plain drug. 6. Hence, the use of LDPI of KF was found to provide desired drug levels in the lung for a long time and thereby increased pulmonary targetting 7. This is expected to enhance the therapeutic index of the drug and probably reduce the dose administered and the cost of therapy.     

Propellant-driven metered-dose inhalers for pulmonary drug delivery

The current market for pulmonary drug delivery is at a bottleneck. The therapeutic advantages of inhalation aerosols, and the potential for the lungs as a route for systemically acting drugs, vaccines and gene therapeutic agents, have resulted in a rapid growth of the industry. Alongside this, the environment of inhaler design and formulation has changed markedly in recent years. Environmental concerns over propellants, the commercial success of dry powder inhalers, and the apparent lack of advancement of propellant-driven metered-dose inhalers (pMDIs) has led to a less clear future for these devices. This review critically assesses these pressures and also potential opportunities for the pMDI. It is proposed that the future role of pMDIs will be determined by several important forces that can be classified under 'technology development' or 'market climate' categories. Technology development forces will be strengthened by the ability of the industry to have a systematic understanding of mechanisms of spray formation, perform subsequent and continued device and formulation advances, and a focus on all patient groups: particularly paediatric and geriatric populations. The ability to succeed in these areas will be largely determined by the willingness to invest in fundamental research of pMDI technologies.     

Paediatric pulmonary drug delivery: considerations in asthma treatment

Aerosol therapy, the preferred route of administration for glucocorticosteroids and short-acting β₂-adrenergic agonists in the treatment of paediatric asthma, may be given via nebulisers, metered-dose inhalers and dry powder inhalers. For glucocorticosteroids, therapy with aerosolised medication results in higher concentrations of drug at the target organ with minimal systemic side effects compared with oral treatments. The dose of drug that reaches the airways in children with asthma is dependent on both the delivery device and patient-related factors. Factors that affect aerosol drug delivery are reviewed briefly. Advantages and disadvantages of each device and device-specific factors that influence patient preferences are examined. Although age-based device recommendations have been made, the optimal choice for drug delivery is the one that the patient or caregiver prefers to use, can use correctly and is most likely to use consistently.     

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Salmeterol (SAL) is a long‐acting β2‐adrenergic agonist, which is widely used in the therapy of asthma. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled salmeterol in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two‐sequence, four‐period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co‐administered. Plasma concentration–time (C–t) data were initially analysed using classic non‐compartmental PK approaches, while the main objective of the study was to apply population PK modeling. The relative fraction of the dose absorbed via the lungs (R_L) was set as a parameter in the structural model. The plasma C–t profiles of salmeterol showed a biphasic time course indicating a parallel pulmonary and gastrointestinal (GI) absorption. A two‐compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like an i.v. bolus) was found to describe successfully the C–t profiles of salmeterol. The estimated R_L value was 13% suggesting a high gut deposition of inhaled salmeterol. Women were found to exert less capability to eliminate salmeterol than men, while body weight (in allometric form) was found to be an important covariate on the peripheral volume of distribution.