Performance Of Dry Powder Inhalers Research Articles

Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014

Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014

Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers

Using salmeterol xinafoate (SX) as an active pharmaceutical ingredient, the effects of carrier lactose particle type, total lactose fines content and device resistance on dry powder inhaler performance were investigated in vitro. To mimic drug levels in commercial preparations, interactive mixtures containing 0.58% w/w SX were prepared by low shear tumble mixing. Three types of milled inhalation grade lactose were used (Lactohale® LH 200, Respitose® ML006 and ML001) and the concentration of fine lactose (Lactohale® 300) added was varied. The in vitro deposition of each mixture was studied using a next generation impactor and inhaler devices exhibiting different resistances, Rotahaler®<Aerolizer®<Handihaler®. Aerosol performance was evaluated based on the emitted dose (ED), mass median aerodynamic diameter (MMAD)±geometric standard deviation (GSD) and fine particle fraction (FPF). Increases of up to eight-fold in FPF were observed with increasing intrinsic fine lactose content. The addition of extra fine lactose increased the FPF further, although the effect diminished as more fines were added. The Aerolizer produced the best aerosol performance with any given powder blend, although suitable formulations were identified for each device as defined by the a priori success criteria: >80% ED and MMAD±GSD between 1–5μm. The results confirmed the factors under investigation to be important determinants of product performance, but demonstrated using realistic conditions how individual factor impact may be enhanced or mitigated by inter-dependency.

DEM analysis of the effect of electrostatic interaction on particle mixing for carrier-based dry powder inhaler formulations

Particle interactions play a significant role in controlling the performance of dry powder inhalers (DPIs), which mainly arise through van der Waals potentials, electrostatic interactions, and capillary forces. Our aim is to investigate the influence of electrostatic charge on the performance of DPIs as a basis for improving the formulation of the particle ingredients. The mixing process of carrier and active pharmaceutical ingredient (API) particles in a vibrating container is investigated using a discrete element method (DEM). The number of API particles attaching to the carrier particle (i.e., contact number) increases with increasing charge and decreases with increasing container size. The contact number decreases with increasing vibrational velocity amplitude and frequency. Moreover, a mechanism governed by the electrostatic force is proposed for the mixing process. This mechanism is different from that previously proposed for the mixing process governed by van der Waals forces, indicating that long-range and short-range adhesive forces can result in different mixing behaviours.

Influence of surface characteristics of modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization performance

The aim of this work is to investigate the effect of surface characteristics (surface roughness and specific surface area) of surface-modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization, and thus, the in vitro respirable fraction often referred to as fine particle fraction (FPF). By processing glass beads in a ball mill with different grinding materials (quartz and tungsten carbide) and varying grinding time (4 h and 8 h), and by plasma etching for 1 min, glass beads with different shades of surface roughness and increased surface area were prepared. Compared with untreated glass beads, the surface-modified rough glass beads show increased FPFs. The drug detachment from the modified glass beads is also more reproducible than from untreated glass beads indicated by lower standard deviations for the FPFs of the modified glass beads. Moreover, the FPF of the modified glass beads correlates with their surface characteristics. The higher the surface roughness and the higher the specific surface area of the glass beads the higher is the FPF. Thus, surface-modified glass beads make an ideal carrier for tailoring the performance of DPIs in the therapy of asthma and chronically obstructive pulmonary diseases.

Effect of turbulent kinetic energy on dry powder inhaler performance

Dry powder inhalers (DPIs) have been extensively used for delivering medication to the lungs. Different designs of DPI devices affect the aerosolization processes of the drug particles. The processes cannot be easily visualized in experiments, thus computational fluid dynamics were used to investigate the turbulence kinetic energy and particle impaction. In this research, 3 size ranges of lactose carrier and the Cyclohaler® and Inhalator® devices were used as models for the computational simulations. The velocity vector, the turbulence kinetic energy (TKE) and particle trajectory were obtained. An aerosol dispersion experiment was performed using the Andersen Cascade Impactor. The TKE was directly related to the flow-rate. The TKE in the Cyclohaler® was lower than that in the Inhalator® due to its narrow geometry and this resulted in a high velocity air-flow. In the Cyclohaler® the probability of deagglomeration by impaction was high because of the cyclone-like design while the cross grid of the Inhalator® was an important factor for deagglomeration of the particles. The FPF varied from 7 to 30% and the FPF increased as the flow-rate increased. The MMAD was in the range of 4–6μm. The carrier size also affected the probability of deagglomeration at 60 and 90L/min, but not at 30L/min. In summary, maximizing the TKE and the particle impaction rate by adding a grid and providing a cyclone-like design was key factor to achieve a high deagglomeration of the particles.

The clinical relevance of dry powder inhaler performance for drug delivery

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. 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. 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. 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. 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.

Surface roughness effects on the tribo-charging and mixing homogeneity of adhesive mixtures used in dry powder inhalers

For active pharmaceutical ingredients (APIs) delivered to the lung it is of main importance that they reach the deeper lung, in order to cause the intended therapeutic effect. To obtain inhalable powders that on the one hand are small enough to travel along the tiny airways finally reaching their target site and on the other hand show sufficient flowability, so-called adhesive mixtures are used. They consist of API particles in the size range of 0.5μm–5μm and carrier particles in the size range of 50μm–200μm, that, due to the size of the carrier, exhibit adequate flowability. However, when administered to the patient, the API has to separate from the carrier surface in order to be able to penetrate the deep lung. The performance of dry powder inhalers (DPIs) and adhesive mixtures is mainly governed by interparticle forces like Van der Waals and triboelectric forces. Carrier surface roughness modification is a new method to alter the contact area and thus the Van der Waals forces between API and carrier. Unfortunately the tribo-charging during handling, especially during the generation of the adhesive mixtures in a tumble blender, is strongly influenced by particle characteristics like particle surface roughness. Thus the mixing quality and stability and thereby the usability of the powder mixture might be additionally influenced by tribo-charging. Therefore the aim of the present work is to investigate whether tribo-charging during the mixing process is influenced by the carrier particle surface roughness. Further the influence of tribo-charging on mixing homogeneity is assessed. Net charge measurements are performed using a Faraday cup. As model API and carrier salbutamol sulfate and spray dried mannitol are used respectively. It is shown that the carrier particle characteristics impact tribo-charging of the pure carriers in a tumble blender. This influence is not observed for the adhesive mixtures of carrier and API. Nevertheless the homogeneity of the adhesive mixtures is still influenced by the charging of the carriers.

Triboelectrics: The influence of particle surface roughness and shape on charge acquisition during aerosolization and the DPI performance

For active pharmaceutical ingredients (API) delivered to the lung it is of main importance that they reach the deeper lung, in order to cause the intended therapeutic effect. To ensure lung deposition and uniform dosage, adhesive mixtures of API particles in the size range of 0.5μm–5μm and inert carrier particles in the size range of 50μm–200μm are used in dry powder inhalers (DPI). The performance of DPIs and adhesive mixtures are mainly governed by interparticle forces like Van der Waals and tribo-electric forces between the active and the carrier as well as between the particles of the adhesive mixture and between adhesive mixture particles and inhaler wall. The arising tribo-charge on the mixtures during handling is influenced by various particle and material characteristics. For adequate inhaler performance especially the charge arising on the powder during the release from the inhaler is of interest. Therefore the aim of this work is to investigate how tribo-charging during aerosolization and release of the powder from a common DPI (Novolizer®) is affected by the carrier particle characteristics of surface roughness and shape and how the accumulated charge further influences the inhaler performance. Tribo-charge measurement of the pure carriers and the adhesive mixtures was performed using an open-end faraday cup. As model API and carrier salbutamol sulphate and spray dried mannitol were used. It was possible to show that tribo-charging during aerosolization is significantly influenced by the above mentioned particle characteristics. Further it was shown that this charge has also significant effects on the important performance properties of the DPI like fine particle dose and fine particle fraction.

Performance of Dry Powder Inhalers with Single Dosed Capsules in Preschool Children and Adults Using Improved Upper Airway Models

The pulmonary administration of pharmaceutical aerosols to patients is affected by age-dependent variations in the anatomy of the upper airways and the inhalation pattern. Considering this aspect, different upper airway models, representing the geometries of adults and preschool children, and a conventional induction port according to the European Pharmacopeia were used for in vitro testing of dry powder inhalers with single dosed capsules (Cyclohaler®, Handihaler® and Spinhaler®). Deposition measurements were performed using steady flow rates of 30 and 60 L/min for the Handihaler®/Spinhaler® and 30, 60 and 75 L/min for the Cyclohaler®. The inhalation volume was set at 1 L. For the Cyclohaler®, the in vitro testing was supplemented by a pediatric inhalation profile. Slight differences of pulmonary deposition between the idealized adult (11%–15%) and pediatric (9%–11%) upper airway model were observed for the Cyclohaler®. The applied pediatric inhalation profile resulted in a reduction of pulmonary deposition by 5% compared to steady conditions and indicated the influence of the inhalation pattern on the amount of pulmonary deposited particles. The comparison of two pediatric upper airway models showed no differences. The performance of the Handihaler® was similar to the Cyclohaler®. The Spinhaler® showed an insufficient performance and limited reproducibility in our investigations.

Three-dimensional DEM–CFD analysis of air-flow-induced detachment of API particles from carrier particles in dry powder inhalers

Air flow and particle–particle/wall impacts are considered as two primary dispersion mechanisms for dry powder inhalers (DPIs). Hence, an understanding of these mechanisms is critical for the development of DPIs. In this study, a coupled DEM–CFD (discrete element method–computational fluid dynamics) is employed to investigate the influence of air flow on the dispersion performance of the carrier-based DPI formulations. A carrier-based agglomerate is initially formed and then dispersed in a uniformed air flow. It is found that air flow can drag API particles away from the carrier and those in the downstream air flow regions are prone to be dispersed. Furthermore, the influence of the air velocity and work of adhesion are also examined. It is shown that the dispersion number (i.e., the number of API particles detached from the carrier) increases with increasing air velocity, and decreases with increasing the work of adhesion, indicating that the DPI performance is controlled by the balance of the removal and adhesive forces. It is also shown that the cumulative Weibull distribution function can be used to describe the DPI performance, which is governed by the ratio of the fluid drag force to the pull-off force.

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

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. 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. 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. 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<5 μm/ED > 90%, and ED > 80%.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 22Edinburgh International Conference CentreEdinburgh, Scotland, UKDecember 7–9, 2011

Summary Background: In bronchial challenge testing lung deposition of the stimulus may be poorly controlled due to incorrect use of nebulisers. Furthermore, the need for freshly prepared solutions burdens personnel and budget. In this study we aim to develop a dry powder alternative with higher reproducibility, better stability and lower costs than the current nebulisation test. Methods: Different pharmacological stimuli in the solid state were characterised on physico-chemical properties to determine the optimal conditions for processing and storage and were tested on their potential for dry powder inhalation. Adenosine and methacholine were micronised and dispersed with the Twincer ™ dry powder inhaler (DPI). Laser diffraction technique was applied to measure particle size distributions in the aerosol clouds. Results: Adenosine allows processing under ambient conditions. It was mixed with a lactose carrier in various mass ratios to produce adhesive mixtures and nucleus agglomerates. With three formulations, almost the entire dose range could be delivered with the Twincer ™ DPI. However, the process of preparing nucleus agglomerates might not be suitable for upscaling. Currently, spherical pellets are investigated as a more robust alternative. Methacholine is very hygroscopic and should therefore not be exposed to a high relative humidity. The methacholine particles leaving the Twincer ™ had an appropriate particle size distribution for inhalation. However, inhaler retention was high and should be reduced by controlling processing and storage conditions. Conclusions: Dry powder adenosine and methacholine seem promising alternatives for nebulisation. Methacholine must be handled under dry conditions. The highest doses of adenosine require further fine tuning.

Formulation and evaluation of CFC free inhalers for beclomethasone dipropionate

Beclomethasone dipropionate CFC free inhalation formulations were developed with a view to treat asthma prophylactically. Dry powder inhalers (DPI) for beclomethasone dipropionate were prepared with different grades of lactose monohydrate. The influence of carrier and overages on performance of DPI was studied. Metered dose inhalers (MDI) with HFA based propellants were formulated with various doses, overages and different concentrations of alcohol. Formulated DPI and MDI were evaluated for various official and unofficial quality control tests. The influence of over doses on valve delivery, effect of overages on emitted dose and influence of alcohol on spray pattern from MDI were studied. The better fine particle fraction and emitted dose were obtained from the DPI formulated with 10:90 ratio of fine lactose: coarse lactose and with 20% w/w overages. The studies on MDI revealed that the 15% of overdoses are required for effective valve delivery and 20% overages are required for 100% drug delivery. 5-10%v/v alcohol was found to be preferable to get optimum emitted dose and fine particle fraction.

Fluidization and break-up of powder particle aggregates during constant and pulsating flow in converging nozzles

Deagglomeration of lactose particles during fluidization by air and the subsequent flow through converging nozzles was evaluated experimentally for constant (Q=5–30dm3/min) and pulsating airflows (Q=10/20dm3/min, f=1.6/4.3Hz). Discussion of observed effects was supported by results of CFD simulations of airflow pattern in the tested systems and calculations of the strain rate distribution. It was demonstrated that the increase of flow acceleration due to nozzle constriction leads to powder disaggregation (particle median size reduction from 5.6 to 3.2μm in the best case) on the cost of higher energy dissipation. The median size of aerosol particles obtained in the analyzed systems was correlated with the logarithm of the pressure drop. It was demonstrated that observed effect of particles deagglomeration relies on the focusing of aerodynamic stresses in the region of aerosol ejection to a stagnant fluid. Airflow pulsations were shown to enhance the break-up of powder aggregates but only in the systems of a low pressure drop. This effect is explained by amplification of particle–fluid interactions by flow unsteadiness. The results of the study were discussed in the perspective of possible application of proposed concepts to improve the performance of passive and active dry powder inhalers (DPIs).

Engineered Mannitol Ternary Additives Improve Dispersion of Lactose–Salbutamol Sulphate Dry Powder Inhalations

The aim of this study was to evaluate the influence of novel engineered fine mannitol particles (4.7%, w/w) on the performance of lactose-salbutamol sulphate dry powder inhaler (DPI) formulations to obtain promising aerosolisation properties. The results showed that the more elongated the fine mannitol particles, the weaker the drug-carrier adhesion, the better the drug content homogeneity, the higher the amount of drug expected to be delivered to the lower airways and the higher the total DPI formulation desirability. Linear relationships were established showing that mannitol particles with a more elongated shape generated powders with broader size distributions and that were less uniform in shape. The weaker the drug-carrier adhesion, the higher the fine particle fraction of the drug is upon aerosolisation. It is believed that more elongated fine mannitol particles reduce the number of drug-carrier and drug-drug physical contact points and increase the ability of the drug particles to travel into the lower airways. Additionally, a lower drug-carrier contact area, lower drug-carrier press-on forces and easier drug-carrier detachment are suggested in the case of formulations containing more elongated fine mannitol particles. Ternary 'drug-coarse carrier-elongated fine ternary component' DPI formulations were more favourable than both 'drug-coarse carrier' and 'drug-elongated coarse carrier' binary formulations. This study provides a comprehensive approach for formulators to overcome the undesirable properties of dry powder inhalers, as both improved aerosolisation performance and reasonable flow characteristics were obtained using only a small amount of elongated engineered fine mannitol particles.

Preparation and characterization of physically modified glass beads used as model carriers in dry powder inhalers

The aim of this work is the physical modification and characterization of the surface topography of glass beads used as model carriers in dry powder inhalers (DPIs). By surface modification the contact area between drug and carrier and thereby interparticle forces may be modified. Thus the performance of DPIs that relies on interparticle interactions may be improved. Glass beads were chosen as model carriers because various prospects of physical surface modification may be applied without affecting other factors also impacting interparticle interactions like particle size and shape. To generate rough surfaces glass beads were processed mechanically by friction and impaction in a ball mill with different grinding materials that were smaller and harder with respect to the glass beads. By varying the grinding time (4 h, 8 h) and by using different grinding media (tungsten carbide, quartz) surfaces with different shades of roughness were generated. Depending on the hardness of the grinding material and the grinding time the surface roughness was more or less pronounced. Surface roughness parameters and specific surface area were determined via several complementary techniques in order to get an enhanced understanding of the impact of the modifying procedure on the surface properties of the glass beads.

Freeze-Dried Mannitol for Superior Pulmonary Drug Delivery via Dry Powder Inhaler

To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol. Different mannitol powders were sieved to collect 63-90μm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance. Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF = 46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, α-+β-+δ- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, α-+β- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, β- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase. Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance.

Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance

Dry Powder Inhalers play a major role in today’s treatment of various respiratory diseases. A lot of effort has been put into the optimization of a device and the appropriate formulation regarding its local lung deposition. However, the complexity and interactions of different factors governing powder dispersion and, therefore, its inhalable fraction challenge research groups around the world.In the current work, binary lactose blends and adhesive ternary powder mixtures containing additional budesonide fines were produced and analyzed with dispersion measurements on the one hand and permeability and aeration measurements conducted with a powder rheometer on the other hand. By comparing the results of the bulk property and dispersion tests, it was expected to gain a better understanding about the effect of excipient fines addition to an adhesive powder mixture.It could be observed that with permeability testing it was possible to clearly differentiate between different amounts of fines within mixtures. However, no correlation between permeability or aeration test values and drug fine particle fraction could be determined for the observed range.Nevertheless, the use of different characterization techniques led to a clearer understanding about the influence of fines addition to an adhesive mixture. It could be demonstrated that after the surface of carrier crystals had been fully saturated, drug particles got incorporated in more stable fines’ agglomerates, which resulted in a decrease in fine particle fraction upon dispersion.

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

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. Comparison of predicted flow and particle behaviour from CFD computations with experimental data obtained with cascade impactor and laser diffraction analysis. Inhaler resistance, flow split, particle trajectories and particle residence times can well be predicted with CFD for a multiple classifier based inhaler like the Twincer™. CFD computations showed that the flow split of the Twincer™ is independent of the pressure drop across the inhaler and that the total flow rate can be decreased without affecting the dispersion efficacy or retention behaviour. They also showed that classifier symmetry can be improved by reducing the resistance of one of the classifier bypass channels, which for the current concept does not contribute to the swirl in the classifier chamber. CFD is a highly valuable tool for development and optimisation of dry powder inhalers. CFD can assist adapting the inhaler design to specific physico-chemical properties of the drug formulation with respect to dispersion and retention behaviour.

Effects of Device and Formulation on In Vitro Performance of Dry Powder Inhalers

The study examined the sensitivity of DPI in vitro performance to formulation and device changes. Rotahaler/Rotacaps was selected as the reference DPI drug product, and Aerolizer was selected as the test device. Since the test device was recognized to have much greater efficiency of dispersion, simple modifications to both formulation and device were made in an effort to provide a closer match to the in vitro performance of the reference product. The modifications included varying the drug and lactose particle sizes and/or lactose fine particle content in the test formulations, as well as lowering the specific resistance of the test device. These modifications were intended to address variables important for drug product performance for a defined experimental design and were not intended to mimic the extensive formulation and device design strategies that are employed in an industrial setting. Formulation and device modifications resulted in a modified test product that approached the reference product in the in vitro performance.