Novel alternative methods for the delivery of drugs for the treatment of asthma

Successful delivery of dry powder aerosols to the lung requires careful consideration of the powder production process, formulation and inhaler device. Newer production methods are emerging to prepare powders with desirable characteristics for inhalational administration. The conventional formulation approach of adding coarse lactose carriers to the drug to form binary powder systems to enhance powder flow and dispersion properties has been expanded to using finer carrier particles and hydrophobic materials, as well as ternary systems. Particle morphology and surface properties have also been explored to enhance powder performance. For the inhaler device, the new generation inhalers are designed to reduce or completely decouple the influence of air flow on the aerosol generation. Each of these determinants for powder aerosol delivery is reviewed with a strong focus on the patent literature that contains enormous information about the latest development in this field.     

Dry powder inhaler device influence on carrier particle performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer? and Handihaler? through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer?, reflecting the improved performance observed in vitro. Collisions within the Handihaler?, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.     

Influence of flow rate on aerosol particle size distributions from pressurized and breath-actuated inhalers.

Particle size distribution of delivered aerosols and the total mass of drug delivered from the inhaler are important determinants of pulmonary deposition and response to inhalation therapy. Inhalation flow rate may vary between patients and from dose to dose. The Andersen Sampler (AS) cascade impactor operated at flow rates of 30 and 55 L/min and the Marple-Miller Impactor (MMI) operated at flow rates of 30, 55, and 80 L/min were used in this study to investigate the influence of airflow rate on the particle size distributions of inhalation products. Total mass of drug delivered from the inhaler, fine particle mass, fine particle fraction, percentage of nonrespirable particles, and amount of formulation retained within the inhaler were determined by ultraviolet spectrophotometry for several commercial bronchodilator products purchased in the marketplace, including a pressurized metered-dose inhaler (pMDI), breath-actuated pressurized inhaler (BAMDI), and three dry powder inhalers (DPIs), two containing salbutamol sulphate and the other containing terbutaline sulphate. Varying the flow rate through the cascade impactor produced no significant change in performance of the pressurized inhalers. Increasing the flow rate produced a greater mass of drug delivered and an increase in respirable particle mass and fraction from all DPIs tested.     

Practical,regulatory and clinical considerations for development of inhalation drug products

The formulation and device collectively constitute an inhalation drug product. Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction. From the points of formulation, device and patient use, this article summarizes the inhalation drugs, including pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), and nebulizer that are currently available in the US and UK markets. It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency).     

Electrostatics of pharmaceutical inhalation aerosols

Objectives This review focuses on the key findings and developments in the rapidly expanding research area of pharmaceutical aerosol electrostatics. Key findings Data from limited in‐vivo and computational studies suggest that charges may potentially affect particle deposition in the airways. Charging occurs naturally in the absence of electric fields through triboelectrification, that is contact or friction for solids and flowing or spraying for liquids. Thus, particles and droplets emitted from pulmonary drug delivery devices (dry powder inhalers, metered dose inhalers with or without spacers, and nebulisers) are inherently charged. Apparatus with various operation principles have been employed in the measurement of pharmaceutical charges. Aerosol charges are dependent on many physicochemical parameters, such as formulation composition, device construction, relative humidity and solid‐state properties. In some devices, electrification has been purposefully applied to facilitate powder dispersion and liquid atomisation. Summary Currently, there are no regulatory requirements on characterising electrostatic properties of inhalation aerosols. As research in this area progresses, the new knowledge gained may become valuable for the development and regulation of inhalation aerosol products.     

What is the role of particle morphology in pharmaceutical powder aerosols?

Background: The aerosol performance of a powder for inhalation drug delivery is controlled by a number of physicochemical properties of the formulation, including particle size, density and morphology. Objective: The role of particle morphology in powder inhalers will be reviewed. Methods: Original research publications in the literature about the contribution of particle morphology to the aerosol performance of pharmaceutical powders have been selected, including both the lactose carriers and the drugs. Results/conclusion: Existing data showed that morphology of both the lactose carrier and drug particle can affect the aerosol performance of powders significantly, a factor which should be taken into consideration during the development of dry powder inhalation products.     

Importance of powder residence time for the aerosol delivery performance of a commercial dry powder inhaler aerolizer(®)

Abstract Background: The performance of dry powder aerosol delivery systems depends not only on the powder formulation but also on the dry powder inhalers (DPIs). Effects of turbulence, grid, mouthpiece, inlet size, air flow, and capsule on the DPIs performance have been investigated previously. Considering powder dispersion in DPIs is a time-dependent process, the powder residence time in DPIs is supposed to have a great impact on DPIs efficiency. This study sought to investigate the effect of powder residence time on the performance of a commercial DPI Aerolizer(?). Methods: A standard Aerolizer(?) (SD) and five modified devices (MD1, MD2, MD3, MD4, and MD5) were employed for this research. Computational fluid dynamics analysis was used to calculate the flow field and the powder residence time in these devices. Recombinant human interleukin-2 inhalation powders and a twin impinger were used for the deposition experiment. Results: The powder mean residence time in the secondary atomization zone of the devices was increased from 0?ms for SD to 0.33, 0.96, 1.42, 1.76, and 2.14?ms for MD1, MD2, MD3, MD4, and MD5, respectively. At a flow rate of 60?L/min, with an increase in the powder residence time in these devices, a significant gradual and increasing trend in the powder respirable fraction was observed from 29.1%±1.1% (MD1) to 32.6%±2.2% (MD2), 37.1%±1.1% (MD3), and 43.7%±2.1% (MD4). There was no significant difference in the powder respirable fraction between SD and MD1 or between MD4 and MD5. Conclusions: Within a certain range, increasing the powder residence time could improve the performance of Aerolizer(?) by increasing the powder-air interaction time (the main reason) and increasing the powder-device compaction (the secondary reason). Combination of high turbulence level and sufficient powder residence time could further improve the device performance.     

Development of a High Efficiency Dry Powder Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications

Purpose

The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device.

Methods

DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices.

Results

The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI.

Conclusions

High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD?<?1.5 μm, FPF_<5μm/ED?>?90%, and ED?>?80%.     

Physical characterization of component particles included in dry powder inhalers. II. Dynamic characteristics

Characteristics of particles included in dry powder inhalers is extended from our previous report (in this journal) to include properties related to their dynamic performance. The performance of dry powder aerosols for pulmonary delivery is known to depend on fluidization and dispersion which reflects particle interactions in static powder beds. Since the solid state, surface/interfacial chemistry and static bulk properties were assessed previously, it remains to describe dynamic performance with a view to interpreting the integrated database. These studies result in complex data matrices from which correlations between specific properties and performance may be deduced. Lactose particles were characterized in terms of their dynamic flow, powder and aerosol electrostatics, and aerodynamic performance with respect to albuterol aerosol dispersion. There were clear correlations between flow properties and aerosol dispersion that would allow selection of lactose particles for formulation. Moreover, these properties can be related to data reported earlier on the morphological and surface properties of the carrier lactose particles. The proposed series of analytical approaches to the evaluation of powders for inclusion in aerosol products has merit and may be the basis for screening and ultimately predicting particle performance with a view to formulation optimization.     

The effect of budesonide particle mass on drug particle detachment from carrier crystals in adhesive mixtures during inhalation.

The different fine particle fractions (FPFs) that are obtained, when different dry powder inhalers (DPIs) are used for the same powder formulation at the same flow rate, is the result of different powder de-agglomeration efficiencies for these DPIs. For adhesive mixtures, this is the efficiency with which the kinetic energy of the air flow through the DPI is converted into separation forces that detach drug particles from carrier crystals. We investigated the effect of drug particle diameter (mass) on drug-carrier separation during inhalation with three different inhalers (Sofotec Novolizer, Inhalator Ingelheim and a special test inhaler), at two different flow rates (30 and 60l/min). Two different size fractions were used as carrier material (45-63 and 100-150 microm). We measured decreasing amounts of residual drug on the carrier crystals after inhalation with increasing drug particle mass for all inhalers at both flow rates. The observed trends were the same for both carrier fractions. The decrease in residual drug on carrier is in agreement with increasing FPFs in an Erweka impactor. However, it has been calculated that the magnitude of the effect decreases with increasing de-agglomeration efficiency.     

Adhesion forces in interactive mixtures for dry powder inhalers--evaluation of a new measuring method.

Dry powder inhalers mostly contain carrier based formulations where micronized drug particles are adhered to coarse carrier particles. The performance of the dry powder inhaler depends on the inhaler device, the inhalation manoeuvre and the formulation. The most important factor influencing the behaviour of the formulation is the adhesion force acting between the active ingredient and the carrier particles, which can be measured using different methods, for example the centrifuge technique or atomic force microscopy. In this study the tensile strength method, usually applied to determine cohesion forces between powder particles of one material, is optimized for adhesion force measurements between powder particles of unlike materials. Adhesion force measurements between the carrier materials lactose or mannitol and the drug substance salbutamol sulphate using the tensile strength method and the atomic force microscopy show higher values with increasing relative humidity. Consequently, the fine particle fraction determined using the Next Generation Impactor decreases with increasing relative humidity as a result of the enhanced interparticle interactions.     

Inhalation drug delivery devices and emerging technologies

Driven by the pharmaceutical industry to realise the full potential of the lungs for local and systemic treatment of diseases, pulmonary drug delivery by inhalation aerosols has been undergoing rapid development in the past decade. This has led to novel invention of aerosol delivery devices including the propellant-driven metered-dose inhalers, dry powder inhalers and atomisers. Closely coupled to these inhaler devices are the formulations and new technologies that are required to produce particles of defined characteristics for improved delivery. This review highlights some of the recent advances in this expanding field.     

In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices.

Experiments were performed to determine the effect of different pharmaceutical aerosol inhalation devices on the deposition of monodisperse aerosols in an idealized mouth and throat geometry. The devices included two dry powder inhalers (Diskus and Turbuhaler), two nebulizers (Pari LC STAR and Hudson T-Updraft), and a metered dose inhaler with attached holding chamber (Aerochamber), in addition to a straight tube (1.7 cm inner diameter). Aerosol particles (DL-alpha tocopheryl acetate) of diameters of 2.5, 5, and 7 microm generated by a vibrating orifice generator were inhaled at steady air flow rates of Q = 5-90 L/min through the devices and into the mouth-throat. Deposition in the mouth-throat and after-filter were determined by ultraviolet (UV) spectrophotometric assay. The amount of deposition in the mouth and throat region was found to depend on the type of device that the aerosol entered through. Deposition in the extrathoracic region with the two types of jet nebulizers did not differ significantly (p > 0.1) from that of a straight tube or each other over their entire tested range of 590 > or = pd2Q > or = 11,375, where p is particle density (in g/cm3), d is particle diameter (in microm), and Q is flow rate (in cm3/s). The metered dose inhaler with attached holding chamber was found to differ from the straight tube only at two intermediate values of pd2Q = 5,145 and 16,033. The deposition occurring for the dry powder inhalers was found to be significantly greater than for the straight tube for all values of pd2Q > or = 10,954 for the Diskus and pd2Q > or = 9,435 for the Turbuhaler. Deposition with the dry powder inhalers was found to be up to 14 times greater than that with the straight tube. Thus, the inhaler geometry that the aerosol passes through prior to entering the mouth and throat region can greatly affect the deposition in the mouth-throat.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

Development and Comparison of New High-Efficiency Dry Powder Inhalers for Carrier-Free Formulations

High-efficiency dry powder inhalers (DPIs) were developed and tested for use with carrier-free formulations across a range of different inhalation flow rates. Performance of a previously reported DPI was compared with two new designs in terms of emitted dose (ED) and aerosolization characteristics using in vitro experiments. The two new designs oriented the capsule chamber (CC) at different angles to the main flow passage, which contained a three-dimensional (3D) rod array for aerosol deaggregation. Computational fluid dynamics simulations of a previously developed deaggregation parameter, the nondimensional specific dissipation (NDSD), were used to explain device performance. Orienting the CC at 90° to the mouthpiece, the CC₉₀-3D inhaler provided the best performance with an ED = 73.4%, fine particle fractions (FPFs) less than 5 and 1 μm of 95.1% and 31.4%, respectively, and a mass median aerodynamic diameter (MMAD) = 1.5 μm. For the carrier-free formulation, deaggregation was primarily influenced by capsule aperture position and the NDSD parameter. The new CC-3D inhalers reduced the percent difference in FPF and MMAD between low and high flows by 1–2 orders of magnitude compared with current commercial devices. In conclusion, the new CC-3D inhalers produced extremely high-quality aerosols with little sensitivity to flow rate and are expected to deliver approximately 95% of the ED to the lungs.     

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。     

Effect of device inhalational resistance on the three-dimensional configuration of the upper airway

Entrainment and de-aggregation of aerosol particles from dry powder inhalers (DPIs) is achieved by a forceful inhalation from the device by the patient and by the airflow resistance built into the device. The aerodynamic shear stress imposed by the upper airway also plays an important role in the de-aggregation process. In this study the effect of device airflow resistance on the upper airway shape is determined. Seven healthy subjects inhaled via a test inhaler of different resistances (0.2 x 10(5) to 2.2 x 10(5) N(0.5).s.m(-4)) while the upper airway was imaged using magnetic resonance imaging. Decreasing the test inhaler resistance led to an increase in the cross-sectional areas of the upper airway at the oral cavity, oropharynx and larynx, while the cross-sectional areas of the upper trachea remained rather constant. The mean volume of the upper airway also increased from 72 (22) cm3 (mean (SD)) to 101 (25) cm3 by decreasing device airflow resistance from 2.2 x 10(5) to 0.2 x 10(5) N(0.5).s.m(-4). In conclusion, this study shows a significant variation in the shape of the upper airway during inhalation via devices with different resistances. This may aid understanding of drug deposition in the lungs from DPIs.     

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.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.