Review of dry powder inhalers

The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find effective products that do not use chlorofluorocarbon (CFC) propellants. This paper reviews the factors to be considered in developing dry powder inhalers (DPIs), particularly the formulation, metering design and flow path in the device. The advantages and disadvantages of current DPIs are discussed and possible future approaches outlined.     

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。     

Pulmonary delivery of inhalable nanoparticles: dry powder inhalers

Pulmonary administration of inhalable nanoparticles (NPs) is an emerging area of interest. Dry powder inhalers may offer particular advantages for pulmonary administration of NPs. This article reviews research performed on the formulation of inhalable NPs as dry powder to achieve deep-lung deposition and enhance NP redispersibility. Moreover, the article summarizes up-to-date in vivo applications of inhalable NPs as dry powder inhalers.     

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.     

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.     

Latest advances in the development of dry powder inhalers

The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least another 30 under development. Clinicians recognize that DPIs are a suitable alternative to pressurized metered dose inhalers (pMDIs) for some patients but the relative performance of devices is often unclear. The problem is compounded by the need to reformulate pMDIs with new propellants, introducing further products to the market with associated variations in performance. This article reviews the DPIs currently available, the driving forces governing new designs, and the claimed advantages of DPIs in the development pipeline.     

Drug delivery characteristics of Bricanyl TurbohalerTM dry powder inhalers

The Turbohaler^TM is the one multidose reservoir type dry powder inhaler (DPI) with significant clinical usage but there is little information on the precision of its single dose delivery characteristics. The single dose delivery efficiency of terbutaline sulphate (nominally 500 μg) from two batches of Bricanyl Turbohalers^TM (11 and 59 devices) has therefore been studied at air flow rates of 28–30 and 60 1 min ⁻¹ which are clinically relevant test conditions for this DPI. At 60 1 min⁻¹ statistically significant differences both within and between batches were obtained for emitted dose (± SD, n = 110, 130), 421 ± 73, 387 ± 58μg and fine particle dose (0.5–6.4 μm MMAD), 249 ± 41, 214 ± 44μg. These data imply an emitted dose range of ± 50% and a fine particle dose range of ± 70% from this DPI system. Through-life total dose emission in terms of the average values remain consistent. Reducing air flow rates to approx. 30 1 min⁻¹ lowered the mean emitted dose by about one third with the clinically important fine particle dose being reduced 3-fold to 59 ± 25 μg; this underlines the likely sensitivity of effective delivery, to patients' lung function. These results reinforce the need to provide single dose data at clinically relevant flow rates in the assessment of DPI performance. Expressing data as mean performance for a cumulative series of dose units smooths down this single dose variability by a factor of two.     

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.     

A method for the aerodynamic design of dry powder inhalers

An inhaler design methodology was developed and then used to design a new dry powder inhaler (DPI) which aimed to fulfill two main performance requirements. The first requirement was that the patient should be able to completely empty the dry powder from the blister in which it is stored by inspiratory effort alone. The second requirement was that the flow resistance of the inhaler should be geared to optimum patient comfort. The emptying of a blister is a two-phase flow problem, whilst the adjustment of the flow resistance is an aerodynamic design problem. The core of the method comprised visualization of fluid and particle flow in upscaled prototypes operated in water. The prototypes and particles were upscaled so that dynamic similarity conditions were approximated as closely as possible. The initial step in the design method was to characterize different blister prototypes by measurements of their flow resistance and particle emptying performance. The blisters were then compared with regard to their aerodynamic performance and their ease of production. Following selection of candidate blisters, the other components such as needle, bypass and mouthpiece were dimensioned on the basis of node-loop operations and validation experiments. The final shape of the inhaler was achieved by experimental iteration.     

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。     

Influence of carrier on the performance of dry powder inhalers

The aim of this work is to study carriers which can become alternatives to monohydrate lactose in dry powder inhalers and to consider particle parameters that influence adhesion between drug and carrier in dry powder inhalers. Different forms of mannitol, lactose and maltitol were mixed with either terbutaline sulphate or formoterol fumarate. The blends were submitted to different adhesion tests where drug detachment from the carrier was obtained either through mechanical vibration or by aspiration. Parameters like particle shape, roughness, amorphous content and cristalline form may affect interactions between drug and carrier. In our case, crystallized forms of the carrier offered lower adhesion but better release of the active ingredient than spray-dried forms. The crystallized mannitol produced maximal fine particle dose. The blends of the mannitols and the two active ingredients gave different results. The two techniques used to assess the adhesion of drugs to carrier particles provide complementary information about drug/carrier interactions and detachment. The mechanical sieving allows to assess blend stability and the air-jet sieving makes it possible to determine how easily the drug separates from carrier. For the drugs tested, the results of fine particle doses are in agreement with the Alpine air-jet sieve results. The tests used are helpful for the choice of a new carrier in the field of the development of new carriers for dry powder inhalers.     

State of the art and new perspectives on dry powder inhalers

Modern local therapy for lung diseases is now largely based on pressurized metered-dose inhalers (MDIs). The research of alternatives to MDIs has recently accelerated, primarily due to environmental concerns related to the use of chlorofluorocarbon (CFC) propellants. The most recent and attractive solution to this problem is represented by the development of dry powder inhalers (DPIs), particularly designed to avoid the use of propellants. DPIs have been developed for specific products, therefore they possess a reduced versatility in term of application of the same device to different drugs. However, they did introduce new concepts in pulmonary drug delivery, solving some disadvantages of the pressurized devices. They are in their infancy and the efforts of researchers are now impressive. The future will certainly see many other devices containing additional innovative features for the effective respiratory delivery of drug. The goals still remain the delivery of precise and uniform drug doses and increasing the respirable fraction in relation to the dose emitted from the device.     

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 )。     

Applications of capsule dosing techniques for use in dry powder inhalers

Dry powder inhaler (DPI) devices that utilize two-piece capsules as the dose-holding system can require specialized dosing equipment to fill the capsules. Such products are known as 'premetered' because they contain previously measured doses in a dose carrier (the capsule). The capsule is either inserted into the device during manufacture or by the patient prior to use. The dose is inhaled directly from the device/premetered unit by the patient. Regardless of DPI design, the most crucial attributes are the reproducibility of the discharged dose and the particle size distribution of the drug within that dose. Filling inhalation powders into capsules often requires specialized equipment in order to handle the very low weights that are often contained in each dose. The equipment typically needs to incorporate in-process checks to confirm the filling process has been correctly performed, with the ability to reject any under- or over-filled capsules, in line with established quality criteria. In the majority of cases, such processing equipment is maintained in a temperature and humidity controlled environment to avoid moisture uptake and potential powder aggregation and, in particular, to ensure the powder is free flowing on introduction into the capsule. This ensures that the emitted dose is maximized and controlled according to industry guidelines and that the fine particle fraction provides an optimum clinical benefit. Several methods of dosing precise doses of powder into capsules are available and include dosator technology and tamp processes, as well as equipment that utilize the 'pepper-shaker' or 'pepper-pot' principle for the accurate dispensing of powders. This article reviews the suitability of each method with respect to dosing inhalation powder into capsules for use in DPI devices, and discusses why the pepper-pot principle could offer a number of clear benefits.     

Evaluation of SCF-engineered particle-based lactose blends in passive dry powder inhalers

The objective of this study was to assess the performance of SCF-engineered budesonide and albuterol sulfate powder blends in passive dry powder inhalers (DPI) relative to micronized drug blends. A number of lactose grades for inhalation were screened and the appropriate carrier and drug-to-lactose blending ratio were selected based on drug content and emitted dose uniformity. Aerosol performance was characterized by Andersen cascade impaction. Blend formulations of SEDS (solution enhanced dispersion by supercritical fluids) budesonide and albuterol exhibited a significant drug content uniformity (7-9% RSD) improvement over micronized drug blends (16-20% RSD). Further, the SEDS formulations demonstrated higher emitted dose and reduced emitted dose variability (10-12% RSD) compared to micronized powders (21-25% RSD) in the Turbospin, albeit without significant enhancement of the fine particle fraction. In contrast, SEDS powders exhibited increased fine particle fractions over micronized blends in the Clickhaler; improvements were more pronounced with albuterol sulfate. The performance enhancements observed with the SEDS powders are attributed to their increased surface smoothness and reduced surface energy that are presumed to minimize irreversible drug-carrier particle interactions, thus resulting in more efficient drug detachment from the carrier particle surface during aerosolization. As demonstrated for budesonide and albuterol, SEDS may enhance performance of lactose blends and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.     

Once-daily inhaled corticosteroids in children with asthma: dry powder inhalers

The cornerstone of pharmacological management of asthma in childhood is inhaled corticosteroids. These drugs are intended for long term treatment and, consequently, compliance is a major issue. Once-daily administration of maintenance medication would simplify treatment and it is likely that it would lead to better compliance. Moreover, the excellent safety profile of inhaled corticosteroid treatment tailored to disease severity may, theoretically, be further improved with once-daily administration. Studies comparing inhaled corticosteroids given once or twice daily to patients with asthma indicate that unstable asthma is best treated with at least 2 daily doses. On the other hand, it has been demonstrated that, if the asthma is stabilised, most children can be treated with inhaled corticosteroids once daily without loss of efficacy. Thus, the data suggest that newly diagnosed asthma, or asthma after deterioration, should first be reliably controlled with inhaled corticosteroids divided into at least 2 daily doses. Once-daily maintenance treatment should then be tried with the aim of improving compliance and quality of life. A dry powder inhalation device is probably the best choice for children from the age of 5 years.     

Application of spectrofluorometry for evaluation of dry powder inhalers in vitro

Andersen cascade impactor (ACI) is commonly used for the testing of pharmaceutical aerosols, which has to be coupled with an instrument for quantitative analysis of drug depositing on each stage of the ACI. This procedure consumes much time in operation. Therefore, this study was aimed at speeding up the process of drug analysis in aerosol formulations after obtaining samples from the ACI. From the results obtained, it was proved that the validated spectrofluorometric method was accurate and sensitive. It was capable of giving similar results to those we obtained from HPLC-UV analysis. There was no interference from the amount of lactose carrier incorporated in the formulation in the step of salbutamol analysis indicating specificity of the method. As a result, samples were analyzed without further separation. The detection limit was 0.1 microg/ml. Hence, spectrofluorometry can be used as a substitute method to HPLC-UV in determining the small quantity of salbutamol after aerosolization from dry powder aerosols. The present study suggests that spectrofluometry can be a rapid and efficient method in the pharmaceutical analysis of aerosols.     

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.     

Effect of rise in simulated inspiratory flow rate and carrier particle size on powder emptying from dry powder inhalers

The purpose of this study was to evaluate the effect of carrier particle size and simulated inspiratory flow increase rate on emptying from dry powder inhalers (DPIs). Several flow rate ramps were created using a computer-generated voltage signal linked to an electronic proportioning valve with a fast response time. Different linear ramps were programmed to reach 30, 60, 90, and 120 L/minute over 1, 2, or 3 seconds. At the lower flow rates, 100-ms and 500-ms ramps were also investigated. Three DPIs, Spinhaler, Rotahaler, and Turbuhaler, were used to test the effect of flow rate ramp on powder emptying. To test the effect of carrier particle size, anhydrous lactose was sieved into 3 particle sizes, and 20 mg of each was introduced into #2 and #3 hard gelatin capsules for Spinhaler and Rotahaler, respectively. Emptying tests were also carried out using the on/off solenoid valve described in the United States. Pharmacopeia (USP) (resulting in no ramp generation). Powder emptying increased from 9% to 46% for Rotahaler and 69% to 86% for Spinhaler from the shallowest (3 seconds to reach peak flow) to the 100-ms ramp for the 53-to 75-μm lactose size range at 30 L/minute. Similar trends were observed for larger particle size fractions at the same flow rate. However, at higher airflow rates (60, 90, and 120 L/minute), there was no significant increase in percentage of emptying within the ramps for a particular particle size range. Trends observed were similar for placebo-filled Turbuhaler and commercially available Rotacaps used with Rotahaler, with the steepest ramp demonstrating more complete emptying. Percentage of powder emptying determined by the USP solenoid valve overestimated the emitted dose compared with the ramp method at 30 L/minute for all 3 devices. Results indicate that there is a significant difference in powder emptying at 30 L minute from the shallowest to the steepest ramp within a particular size range. Within a particular particle size range, the USP method produced more complete emptying than even the steepest ramp, especially at the lower flow rates. Thus, when the USP device is used to estimate DPI emptying at lower flow rates, the results are likely to overestimate DPI performance significantly.