Anne H. de Boer

The clinical relevance of dry powder inhaler performance for drug delivery

BACKGROUND Although understanding of the scientific basis of aerosol therapy with dry powder inhalers (DPIs) has increased, some misconceptions still persist. These include the beliefs that high resistance inhalers are unsuitable for some patients, that extra fine (<1.0 μm) particles improve peripheral lung deposition and that inhalers with flow rate-independent fine particle fractions (FPFs) produce a more consistent delivered dose to the lungs. OBJECTIVES This article aims to clarify the complex inter-relationships between inhaler design and resistance, inspiratory flow rate (IFR), FPF, lung deposition and clinical outcomes, as a better understanding may result in a better choice of DPI for individual patients. METHODS The various factors that determine the delivery of drug particles into the lungs are reviewed. These include aerodynamic particle size distribution, the inspiratory manoeuvre, airway geometry and the three basic principles that determine the site and extent of deposition: inertial impaction, sedimentation and diffusion. DPIs are classed as either dependent or independent of inspiratory flow rate and vary in their internal resistance to inspiration. The effects of these characteristics on drug deposition in the airways are described using data from studies directly comparing currently available inhaler devices. RESULTS Clinical experience shows that most patients can use a high resistance DPI effectively, even during exacerbations. Particles in the aerodynamic size range from 1.5-5 μm are shown to be optimal, as particles <1.0 μm are very likely to be exhaled again while those >5 μm may impact on the oropharynx. For DPIs with a constant FPF at all flow rates, less of the delivered dose reaches the central and peripheral lung when the flow rate increases, risking under-dosing of the required medication. In contrast, flow rate-dependent inhalers increase their FPF output at higher flow rates, which compensates for the greater impaction on the upper airways as flow rate increases. CONCLUSIONS The technical characteristics of different inhalers and the delivery and deposition of the fine particle dose to the lungs may be important additional considerations to help the physician to select the most appropriate device for the individual patient to optimise their treatment.

Changes in performance of the Pari eFlow rapid and Pari LC Plus during 6 months use by CF patients.

BACKGROUND Nebulized antibiotics are important in the treatment of cystic fibrosis. The Pari eFlow rapid with vibrating mesh is often used off-label for the administration of tobramycin (TOBI) because of a reduced nebulization time and easier handling compared to a classic nebulizer-compressor combination. Mesh technology may be vulnerable, however. Therefore, we investigated particle size distribution and output as well as changes in the performance of the eFlow before and after 6 months of use, in comparison with the Pari LC Plus nebulizer plus Turboboy compressor. METHODS Size distributions in the aerosols and nebulization times for TOBI were measured with laser diffraction technique; delivered doses by weighing. RESULTS New eFlows produce considerably larger droplets (X(50) = 3.5 mum) from TOBI than new LC Plus nebulizers (X(50) = 2.8 mum). After use, the X(50) increases for both systems (to 3.7 and 3.3 mum, respectively). The relative span of the size distribution {(X(90)-X(10))/X(50)} changes from 1.26 to 1.28 mum for eFlow and from 2.19 to 2.45 mum for LC Plus. The total nebulization time doubles for LC Plus, whereas in 51% of all experiments the eFlow switched off after 10 min, resulting in incomplete dose delivery. For the eFlow, changes during use are related to clogging of orifices. Once being clogged, only replacement of the mesh restores the original performance. CONCLUSIONS New eFlows produce larger droplets and in a narrower size range compared to new LC Plus nebulizers for TOBI, and therefore both devices are not equivalent. Theoretically a larger portion of the aerosol from eFlow is likely to be deposited in the upper airways. The performance of both tested nebulizers decreases after 6 months of use. For the eFlow, timely replacement of the mesh is necessary. These in vitro results underscore the importance of registration studies of new drug-device combinations.

The mode of drug particle detachment from carrier crystals in an air classifier based inhaler

No HeadingPurpose.To investigate the mode of drug particle detachment from carrier crystals in an air classifier as a function of the carrier size fraction, payload, and the circulation time in the classifier.Methods.Laser diffraction analysis of the aerosol cloud from the classifier has been performed at 10, 20, 30, and 60 l/min, using a special adapter, for different adhesive mixture compositions.Results.A significant part of the drug particles is detached from carrier crystals during inhalation as small agglomerates. Such agglomerates originate from the starting material or are newly formed on the carrier surface during mixing. The degree of agglomeration during mixing depends on the carrier size, payload, and surface rugosity. The size of the agglomerates that are formed during mixing, increases with the size of the carrier particles. Predominantly the largest drug particles and agglomerates are detached within the first 0.5 s of inhalation. After 0.5 s, smaller primary particles are dislodged.Conclusions.A high ratio of removal forces to adhesive forces causes a high drug detachment rate from carrier crystals in a classifier within the first 0.5 s of inhalation. The high ratio can be explained by dislodgment of agglomerates and the largest primary particles in the early phases of inhalation. At higher flow rates, detached agglomerates may be further disintegrated into primary particles before they are discharged from the classifier. Agglomeration of drug particles on the carrier surface is the result of the same forces that are responsible for pressing these particles firmly to the carrier crystals during mixing.

Devices and formulations for pulmonary vaccination

Introduction: Pulmonary vaccination could be a promising alternative to vaccination by injection. Administration of a vaccine to the lungs does not require the use of needles, which reduces the number of trained healthcare workers needed, the risk of needle-stick injuries and needle waste. Besides a systemic immune response, pulmonary vaccination may also induce a mucosal immune response. Such a local response may increase the effectiveness of vaccination against airborne pathogens. Although this route of administration has been studied for decades, no pulmonary vaccine is commercially available yet, due to various challenges mostly intrinsic to pulmonary drug delivery and vaccine formulation. Areas covered: This review discusses the inhalation devices and formulation strategies that may be suitable for the pulmonary administration of vaccines. In addition, critical parameters are addressed, such as the target population, to help assessing whether pulmonary administration of a specific vaccine may be feasible and beneficial or not. Expert opinion: A combined approach of inhalation device and vaccine formulation development is essential. This should result in a system that can effectively be used by the target population and can be produced at low costs. Only then, this challenging administration route can be successfully applied to large-scale vaccination programs.

Computational fluid dynamics (CFD) assisted performance evaluation of the Twincer™ disposable high-dose dry powder inhaler.

Objectives  To use computational fluid dynamics (CFD) for evaluating and understanding the performance of the high‐dose disposable Twincer™ dry powder inhaler, as well as to learn the effect of design modifications on dose entrainment, powder dispersion and retention behaviour.

New Mechanisms to Explain the Effects of Added Lactose Fines on the Dispersion Performance of Adhesive Mixtures for Inhalation

Fine excipient particles or ‘fines’ have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of ‘fine lactose fines’ (FLF, X50 = 1.95 µm) with a similar size and shape as micronised budesonide were studied and compared to those of ‘coarse lactose fines’ (CLF, X50 = 3.94 µm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions.

Pulmonary Vaccine Delivery: A Realistic Approach?

Pulmonary vaccine delivery has gained increasing attention during the last decade because this vaccination method combines potential advantages such as the fact that it omits the use of needles and may elicit immunity at the port of entry for many pathogens. In this review the current status of pulmonary vaccination, the potential advantages of pulmonary vaccine delivery, the hurdles to overcome in the future, and the overall perspectives of this vaccination strategy are described.

Effect of the spraying conditions and nozzle design on the shape and size distribution of particles obtained with supercritical fluid drying

In the perspective of production of dry therapeutic protein formulations, spray drying of lysozyme (as a model protein) into supercritical carbon dioxide was studied. The effects of the nozzle (i.e., co-current coaxial converging and converging-diverging, and T-mixer impinging) and process conditions (i.e., flow rates, pressure) on the drying of the lysozyme prepared in aqueous solution dried with supercritical carbon dioxide enriched with ethanol were investigated. The particle size distribution, width of particle size distribution and morphology were used to determine the effect of the various parameters assessed. Particles with a median size of approximately 1.5, approximately 5 or approximately 25 microns were produced depending of the nozzle selected. A basic comparative study of the nozzle was done by computational fluid dynamics, but the differences in particle size could not be depicted by these computations. The proportional increase of the flow rates (up to fivefold) caused a decrease in particle size (7- to 12-fold), and doubling the pressure caused a moderate decrease of the size (5-20%). The individual effect of the supercritical carbon dioxide, ethanol and solution streams was explained with a mass transfer model. Changing the ratio between flow rates slightly affected the particle size in various ways because of the swelling and shrinking stages of the drying droplet in supercritical carbon dioxide enriched with ethanol.

Comparative in vitro evaluation of four corticosteroid metered dose inhalers: Consistency of delivered dose and particle size distribution

INTRODUCTION Recent developments concerning pressurized metered dose inhalers (pMDIs) with inhaled corticosteroids (ICS) are the introduction of ciclesonide and the replacement of propellants. As the results of in vivo studies depend on pMDIperformance, it is necessary to evaluate pMDIs in vitro for delivered dose and particle size distributions under different conditions. METHODS Fluticasone 125microg, budesonide 200microg, beclomethasone HFA100microg, and ciclesonide 160microg were compared for delivered dose and particle size using laser diffraction analysis with inspiratory flow rates of 10, 20 and 30l/s. RESULTS The volume median diameter of budesonide was 3.5microm, fluticasone 2.8microm, beclomethasone and ciclesonide both 1.9microm. The mouthpiece retention was up to 30% of the nominal dose for beclomethasone and ciclesonide, 11-19% for the other pMDIs. Lifespan, flow rate, and air humidity had no significant influence on particle size distribution. The delivered dose of beclomethasone, budesonide, and ciclesonide remained constant over the lifespan. The delivered dose of fluticasone 125 decreased from 106% to 63%; fluticasone 250 also decreased whereas fluticasone 50 remained constant. CONCLUSIONS There is a significant difference in median particle size distribution between the different ICS pMDIs. Air humidity and inspiratory flow rate have no significant influence on particle size distribution. Ciclesonide 160 and beclomethasone 100 deliver the largest fine particle fractions of 1.1-3.1microm. The changes in delivered dose during the lifespan for the fluticasone 125 and 250 may have implications for patient care.

Drug content effects on the dispersion performance of adhesive mixtures for inhalation

The drug content in adhesive mixtures for inhalation is known to influence their dispersion performance, but the direction and magnitude of this influence depends on other variables. In the past decades several mechanisms have been postulated to explain this finding and a number of possible interacting variables have been identified. Still, the role of drug content in the formulation of adhesive mixtures for inhalation, which includes its significance as an interacting variable to other parameters, is poorly understood. Therefore, the results from a series of drug detachment experiments are presented in which the effect of drug content and its dependence on flow rate, the mixing time and the type of drug is studied. Furthermore, it is investigated whether the effect depends on the range within which the drug content is changed. Quantitative and qualitative multiple order interactions are observed between these variables, which may be explained by a shifting balance between three different mechanisms. The results therefore demonstrate that accounting for (multiple order) interactions between variables has to be part of quality by design activities and the rational design of future experiments.