Aerosol Electrostatics I: Properties of Fine Powders Before and After Aerosolization by Dry Powder Inhalers

Purpose. To evaluate the dependence of fine particle dose charge (FPD charge) generated from powder inhalers on physico-chemical properties of the inhalation powder, inhaler type, deaggregation mechanism, dose number and/or retained powder. Methods. Electrostatic charges were determined on micronized powders and aerosolized fine particle doses withdrawn from two, high efficiency, multidose powder inhalers, Turbohalerand prototype Dryhaler. The behavior of terbutaline sulfate, budesonide, albuterol (sulfate and base), beclomethasone dipropionate and lactose was assessed before and after aerosolization. Results. Both inhalers conferred triboelectric FPD charges during aerosolization in the range –400 pC through +200 pC. Specific charges (charge/unit mass) on the fine particle doses of budesonide from Dryhaler were significantly less than those from Turbohaler (p < 0.01). Electrostatic charges on the potentially respirable cloud of terbutaline sulfate generated by Bricanyl Turbohaler were positive and/or negative and unpredictable. With Pulmicort Turbohaler, FPD charges on budesonide were always positive. Dryhaler was used to determine the chemical dependence of fine particle triboelectrification during the aerosolization of pure materials. A triboelectric series was constructed from the Dryhaler results ranking the powders from positive to negative as budesonide > lactose > albuterol sulfate > terbutaline sulfate albuterol beclomethasone dipropionate. Conclusions. While there was no evidence of FPD charge dependence upon dose number with either inhaler, FPD charges were dependent upon the powder under investigation, as well as the construction and deaggregation mechanism of the inhaler. The specific charge on the fine particle dose of budesonide from Turbohaler corresponded to approximately 200 electronic charges per particle, a value which is known to affect both total and regional aerosol deposition in the human lung. Electrostatic charge effects may be important determinants of aerosol behavior and should not be neglected.     

Investigation of Electrostatic Behavior of Dry Powder-Inhaled Model Formulations

The accumulation of electrostatic charge on drug particles and excipient powders arising from interparticulate collisions or contacts with other surfaces can lead to agglomeration and adhesion problems during the manufacturing process, filling, and delivery of dry powder inhaler (DPI) formulations. The objective of the study was to investigate the role of triboelectrification to better understand the influence of electrostatic charge on the performance of DPIs with 2 capsule-based dimensionally similar devices constructed with different materials. In addition, strategies to reduce electrostatic charge build up during the manufacturing process, and the processes involved in this phenomenon were investigated. Electrostatic charge measurements showed that there was a significant difference in electrostatic charge generated between tested formulations and devices. This affects particle detachment from carrier and thus significantly impacts aerosol performance. Conditioning fluticasone DPI capsules at defined temperature and humidity conditions reduced electrostatic charges acquired during manufacturing. Conditioning salmeterol DPI capsules at same conditions seemed disadvantageous for their aerosol performance because of increasing capillary forces and solid bridge formation caused by water absorption. Knowledge and understanding of the role of electrostatic forces in influencing DPI formulation performance was increased by these studies.     

Investigation of Electrostatic Behavior of a Lactose Carrier for Dry Powder Inhalers

Purpose  This study aims to elucidate the electrostatic behavior of a model lactose carrier used in dry powder inhaler formulations by examining the effects of ambient relative humidity (RH), aerosolization air flow rate, repeated inhaler use, gelatin capsule and tapping on the specific charge (nC/g) of bulk and aerosolized lactose. Materials and Methods  Static and dynamic electrostatic charge measurements were performed using a Faraday cage connected to an electrometer. Experiments were conducted inside a walk-in environmental chamber at 25°C and RHs of 20% to 80%. Aerosolization was achieved using air flow rates of 30, 45, 60 and 75 L/min. Results  The initial charges of the bulk and capsulated lactose were a magnitude lower than the charges of tapped or aerosolized lactose. Dynamic charge increased linearly with aerosolization air flow rate and RH. Greater frictional forces at higher air flow rate induced higher electrostatic charges. Increased RH enhanced charge generation. Repeated inhaler use significantly influenced electrostatic charge due to repeated usage. Conclusions  This study demonstrated the significance of interacting influences by variables commonly encountered in the use DPI such as variation in patient’s inspiratory flow rate, ambient RH and repeated inhaler use on the electrostatic behavior of a lactose DPI carrier.     

Effect of Relative Humidity on the Electrostatic Charge Properties of Dry Powder Inhaler Aerosols

Purpose

At present, there is no published data examining the effect of relative humidity on the electrostatic charges of dry powder inhaler aerosols. The charging behaviour of two commercial products, Pulmicort® and Bricanyl® Turbuhalers®, were investigated using an electrical low pressure impactor (ELPI).

Methods

ELPI was successfully modified to disperse the aerosols at 60 l/min. Four doses from each new inhaler were sampled at 15, 40, 65, and 90% RH. Particles deposited on the impactor stages according to their aerodynamic diameters and their charges were measured simultaneously by the electrometers. The drug in each size fraction was quantified using HPLC.

Results

Both products generated bipolar charges. The charging behaviour of the two types of inhaler showed different humidity dependence although the mass output was not significantly affected. The absolute specific charge of budesonide fine particles from Pulmicort® was the lowest at 40% RH but increased at lower and higher RHs. In contrast, the terbutaline sulfate fine particles from Bricanyl® followed the expected trend of charge reduction with increasing RH.

Conclusions

The distinct trends of charging of aerosols from Pulmicort® and Bricanyl® Turbuhalers® was explained by differences in hygroscopicity and other physicochemical factors between the two drugs.     

Improving inhaler technique,adherence to therapy and the precision of dosing: major challenges for pulmonary drug delivery

Introduction: The inhaled route has many advantages, but requires the patient to use, and to master the use of, an inhaler device. Poor inhaler technique and non-adherence to therapy lead to a highly variable lung dose in clinical practice, with subsequent loss of clinical efficacy and wastage of economic resources.

Areas covered: This paper discusses problems of poor inhaler technique, non-adherence to inhaler therapy, other issues relating to the precision of dose delivery, the consequences of these problems and how they can be addressed.

Expert opinion: The precision of dosing by the pulmonary route can be improved by appropriate choice of inhaler device and by education. It is vital to educate patients about their disease, about the importance of taking prescribed medications and about correct inhaler use. One-on-one sessions with healthcare professionals probably represent the most effective educational method. For some drugs and patient groups, inhalers containing small microprocessors may also be used to control inhalation technique, and hence, to obtain a more reproducible lung dose. As the range of drugs delivered by inhalation increases, the need for correct inhaler technique, adherence to therapy and precise dosing becomes more and more important.     

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.
Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30  min following inhalation of 2×100  μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin^® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24  h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.
Results The mean (s.d.) 30  min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9)  μg, respectively ( P <0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24  h period after inhalation was 187.9 (77.6) and 137.6 (40.0)  μg ( P <0.05).
Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.     

肺部给药系统的研究进展

介绍了呼吸道的特殊生理特征和功能以及药物的吸收过程,综述了近年来国内外肺部给药系统的进展,包括定量吸入剂、喷雾剂、干粉吸入剂、微球和脂质体的肺部给药。     

The rejuvenated pressurised metered dose inhaler

The pressurised metered-dose inhaler (pMDI) has now been available for 50 years. Once regarded as an inefficient and difficult-to-use device, the technology has evolved significantly over the last few years, particularly since the introduction of novel formulations containing hydrofluoroalkane (HFA) propellants. Many modern HFA pMDIs deposit drug more efficiently in the lungs, impact less forcefully on the back of the throat and feel less cold than their chlorofluorocarbon pMDI counterparts. An improved understanding of technical factors makes it possible to design HFA pMDIs to have specific spray properties, particularly in terms of fine particle dose and spray velocity. Device technology has also progressed with the introduction of compact and convenient breath-actuated, breath-coordinated and velocity-modifying devices, which help patients to achieve a reliable lung dose. Although it faces competition from dry powder inhalers and possibly from novel soft-mist inhalers containing liquid formulations, the rejuvenated HFA pMDI is a device with a significant future for asthma, chronic obstructive pulmonary disease and wider treatment indications.     

吸入粉雾剂中静电作用的影响因素概述

应用于吸入粉雾剂（DPI）的药物活性成分通常是小粒径绝缘体,容易在制备与运输过程中携带电荷,增加药物之间以及药物-载体之间的黏附性,影响药物在肺部的沉积。了解DPI中粘性粉末静电作用的影响因素是至关重要的,影响因素包括粉末的电阻率、粒度分布、晶习、晶型、引湿性、环境因素、制备条件以及储存条件等。还探讨了静电力对DPI药物含量均一性、递送剂量、原料药与载体的黏附/解吸附能力以及药物在呼吸道的沉积行为的影响。对静电力的认知与理解有助于DPI产品的安全性、质量以及临床有效性的提高。     

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.     

吸入给药的剂型选择和等效性验证

目前临床常用吸入给药的剂型包括定量吸入气雾剂（metered dose inhaler，MDI）、吸入粉雾剂／干粉吸入剂（Dry powder inhaler，DPI）和吸入喷雾剂（Nebulizer），这3种吸入给药剂型各有特点。如何正确选择所研发的药物的剂型，如何正确验证相同制剂间是否等效有其特殊性。本文结合吸入给药的药物吸收特点、各剂型特点及国外有关考虑，重点探讨了如何正确选择所研发的药物的剂型及如何正确验证相同制剂间是否等效。     

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.     

Delivery of antibiotics to the respiratory tract: an update

The use of inhaled medications for the treatment of pulmonary diseases has become an increasingly popular drug delivery route over the past few decades. This delivery route allows for a drug to be delivered directly to the site of the disease, with a lower dose than more conventional oral or intravenous delivery methods, with reduced systemic absorption and consequently reduced risk of adverse effects. For asthma this delivery route has become the ‘golden standard’ of therapy. It is not unexpected therefore, that there has been great interest in the prospect of using inhaled antibiotics for the treatment of both chronic and recurrent respiratory infections. Since the early 1980s, several investigations have demonstrated that antibiotics could be delivered safely by means of inhalation, using nebulisers as their delivery systems. Lately, antibiotics delivery via inhalation have seen a ‘revival’ in interest and most of these studies have focused on delivering antibiotics to the lungs by means of a dry powder format. This review focuses on recent advances in antibiotic inhalation therapy.     

可溶性载体对左旋硫酸沙丁胺醇胶囊型粉雾剂的体外影响

目的：通过对左旋硫酸沙丁胺醇胶囊型粉雾剂可溶性载体的考察,筛选出最佳的载体材料及制备工艺。方法：对于可溶性载体辅料,采用纳米磨与喷雾干燥仪分别制备药物、辅料的颗粒物,测定颗粒的理化性质及肺部有效沉积率。结果：喷雾干燥仪制备后,载体粒径在25.35~52.94 μm之间,其中乳糖外观圆整,粒径为25.35 μm,乳糖的休止角为33.20°,乳糖的含水量最低为0.99%,压缩度为17.68%,有效沉积率为14.21%,符合药典对粉雾剂的要求。结论：喷雾制备的乳糖,其粉体性能良好,是适合左旋沙丁胺醇粉雾剂的载体材料。     

鲑降钙素吸入粉雾剂的制备及其药剂学性质研究鲑降钙素吸入粉雾剂的制备及其药剂学性质研究

目的喷雾干燥法制备鲑降钙素吸入粉雾剂,考察其主要药剂学特性。方法按中国药典2000年版方法测定鲑降钙素吸入粉雾剂排空率及有效部位沉积量,扫描电镜观察粉粒的形态,激光粒度测定仪测定粉粒的粒径大小及分布,差热分析及X射线粉末衍射考察吸入粉雾剂载体的晶型。结果有效部位鲑降钙素沉积量均在10%以上,排空率均在90%以上;相对湿度在52%以下,粉粒呈圆整的分散状态;当RH=75%时粉粒发生较多的粘连和聚集;粉体平均粒径为1.67 μm;差热分析结果显示:吸入粉雾剂中L-亮氨酸的熔融热较单一组分在喷雾干燥后显著下降;X射线粉末衍射图谱中,吸入粉雾剂载体的衍射峰强度较喷雾干燥前显著下降。结论在鲑降钙素吸入粉雾剂载体系统中加入甘露醇,粉粒圆整,加入L-亮氨酸可形成超低密度载体;扫描电镜的结果提示,应严格控制吸入粉雾剂贮存时环境的湿度;喷雾干燥复合载体更有助于无定形的形成。     

New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy

Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity and mortality, pathological features of which are pulmonary inflammation and irreversible airflow obstruction. Current therapies for COPD are aimed at improvement of clinical symptoms and reduction of inflammation in the respiratory systems. There is a pressing need for the development of new COPD medication, particularly as no existing treatment has been shown to reduce disease progression. In spite of a better understanding of the underlying disease process, there have been limited advances in the drug therapy of COPD, in contrast to the enormous advances in asthma management. Several new therapeutic targets and strategies have been proposed, and new drug candidates, including bronchodilators, protease inhibitors anti-inflammatory drugs and mediator antagonists, are now in clinical development for COPD treatment. New dry powder inhaler (DPI) systems for inhaled COPD therapy have also been developed to maximize drug concentrations in the airway systems, while minimizing systemic exposure and associated toxicity. This article aims to review recent developments in COPD drugs and the delivery systems for inhalation therapy, with particular emphasis on device options and formulations of DPI systems.     

Particle Size and Charge Distribution Analysis of Pharmaceutical Aerosols Generated by Inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 μC/g, the individual particles were charged with a relatively high charge: ?2 to + 2 μC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3–5 μm.     

Challenges and opportunities in respiratory drug delivery devices

Recent reviews conclude that there is a need to improve the management of respiratory diseases treated with inhaled drugs, mainly asthma and chronic obstructive pulmonary disease (COPD). Healthcare professionals – mainly in primary care – seem to lack to some degree the evidence-based information required for the selection of the most appropriate respiratory drug delivery devices (inhalers) for the patients, whereas some of the patients often tend to have poor inhaler technique. This could have an impact on the ability to control the respiratory diseases in question. There are probably several reasons for these apparent challenges in the primary care arena. Owing to the abundance of inhalers available at present, especially for the treatment of asthma and COPD, it is quite a challenge to pick the ‘right’ inhaler for each patient. For an inhaler to be optimal, the patient has to be able to master the inhaler technique required for the specific inhaler. The patient–inhaler interfaces – mouthpieces or facemasks – can add important challenges that further diminish the efficacy of the treatment.     

Influence of Particle Size,Air Flow,and Inhaler Device on the Dispersion of Mannitol Powders as Aerosols

Purpose. To study the effect of particle size, air flow and inhaler type on the dispersion of spray dried mannitol powders into aerosols. Methods. Mannitol powders were prepared by spray drying. The solid state properties of the powders were determined by laser diffraction, X-ray powder diffraction, scanning electron microscopy, freeze fracture, Karl Fischer titration and gas pycnometry. The powders were dispersed using Rotahaler^® and Dinkihaler^®, connected to a multistage liquid impinger at different air flows. Results. Three crystalline mannitol powders with primary particle size (MMD) 2.7, 5.0, 7.3 m and a similar polydispersity were obtained. The particles were spherical with a density of 1.5 g/cm³ and a moisture content of 0.4 wt.%. At an air flow of 30 L/min all the powders were poorly dispersed by both inhalers. With the Rotahaler^® increasing the flow (60–120 L/min) increased the fine particle fraction (FPF) in the aerosols for the 2.7 m powder, and decreased the FPF for the 7.3 m powder; whereas the FPF for 5.0 m powder was unaffected. With the Dinkihaler^®, all the powders were near complete dispersion at 60 L/min. Conclusions. The FPF in the mannitol powder aerosols was determined by an interplay of the particle size, air flow and inhaler design.