In vitro/in vivo correlation and modeling of emitted dose and lung deposition of inhaled salbutamol from metered dose inhalers with different types of spacers in noninvasively ventilated patients.

Substituting spacer by another in noninvasive ventilation (NIV) involves many variables, e.g. total emitted dose (TED), mass median aerodynamic diameter (MMAD), type of spacer, total lung deposition and total systemic absorption, which must be adjusted to ensure patient optimum therapy. Data mining based on artificial neural networks and genetic algorithms were used to model in vitro inhalation process, predict and optimize bioavailability from inhaled doses delivered by metered dose inhaler (MDI) using different spacers in NIV. Modeling of data indicated that in vitro performance of MDI-spacer systems was dependent mainly on fine particle dose (FPD), fine particle fraction (FPF), MMAD and to lesser extent on spacer type. Ex vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by FPF. In vivo model (24hQ) depended directly on spacer type, FPF and TED. Female patients showed higher 0.5hQ and 24hQ values than males. AeroChamber VC spacer demonstrated higher TED and 24hQ in vivo values. Results indicated suitability of MDI-spacer systems in achieving appropriate in vitro inhalation performance. The possibility of modeling and predicting both ex vivo and in vivo capabilities of MDI-spacer systems from knowledge of in vitro attributes enabled detailed focus on important variables required to deliver safe and accurate doses of salbutamol to ventilated patients.

A Comparison of the Performance of Efficient Data Analysis Versus Fine Particle Dose as Metrics for the Quality Control of Aerodynamic Particle Size Distributions of Orally Inhaled Pharmaceuticals.

The performance of two quality control (QC) tests for aerodynamic particle size distributions (APSD) of orally inhaled drug products (OIPs) is compared. One of the tests is based on the fine particle dose (FPD) metric currently expected by the European regulators. The other test, called efficient data analysis (EDA), uses the ratio of large particle mass to small particle mass (LPM/SPM), along with impactor sized mass (ISM), to detect changes in APSD for QC purposes. The comparison is based on analysis of APSD data from four products (two different pressurized metered dose inhalers (MDIs) and two dry powder inhalers (DPIs)). It is demonstrated that in each case, EDA is able to detect shifts and abnormalities that FPD misses. The lack of sensitivity on the part of FPD is due to its "aggregate" nature, since FPD is a univariate measure of all particles less than about 5 µm aerodynamic diameter, and shifts or changes within the range encompassed by this metric may go undetected. EDA is thus shown to be superior to FPD for routine control of OIP quality. This finding augments previously reported superiority of EDA compared with impactor stage groupings (favored by US regulators) for incorrect rejections (type I errors) when incorrect acceptances (type II errors) were adjusted to the same probability for both approaches. EDA is therefore proposed as a method of choice for routine quality control of OIPs in both European and US regulatory environments.

Evaluation of Abbreviated Impactor Measurements (AIM) and Efficient Data Analysis (EDA) for Dry Powder Inhalers (DPIs) Against the Full-Resolution Next Generation Impactor (NGI).

The full-resolution next generation impactor (NGI) and three abbreviated impactor systems were used to obtain the apparent aerodynamic particle size distribution (APSD) and other quality measures for marketed dry powder inhalers (DPIs) using the compendial method and efficient data analysis (EDA). APSD for the active pharmaceutical ingredient (API) in Spiriva® Handihaler®, Foradil® Aerolizer®, and Relenza® Diskhaler® was obtained using a full-resolution NGI at 39, 60, and 90 L/min, respectively. Two reduced NGI (rNGI) configurations, the filter-only configuration (rNGI-f) and the modified-cup configuration (rNGI-mc), and the fast-screening impactor (FSI) with appropriate inserts to provide a 5-µm cut size were evaluated. The fine particle dose (FPD) obtained using the FSI for Spiriva was statistically similar to that obtained using the full NGI. However, the FPD for both Foradil and Relenza obtained using the FSI was significantly different from that obtained using the full NGI. Despite this, no significant differences were observed for the fine particle fraction (FPF) obtained using the FSI relative to that obtained from the full NGI for any of the DPIs. The use of abbreviated impactor systems appears promising with good agreement observed with the full-resolution NGI, except for small differences observed for the rNGI-mc configuration. These small differences may be product- and/or flow rate-specific, and further evaluation will be required to resolve these differences.

Accessorized DPI: a Shortcut towards Flexibility and Patient Adaptability in Dry Powder Inhalation.

PURPOSE: In this work, a novel powder dispersion add-on device, the AOS (Axial Oscillating Sphere), was studied in conjunction with commercially available DPI devices to improve the powder dispersion. METHODS: An ordered mixture of formoterol fumarate and lactose was selected. We studied in two laboratories located at different altitudes the dispensing and dispersion of the drug at different flow rates, paying particular attention to a number of metrics of Fine Particle Dose (FPD). RESULTS: Two novel findings emerged from the data collected. First, the aerosol quality, measured as fine particle dose, can be increased by adding the accessory promoting the dispersion and de-aggregation of the formulation. The second finding was that, albeit the emitted dose was independent of altitude, the drug/lactose carrier DPI aerosolizing performance changed with the altitude of testing. In particular, fine particle dose depended on both altitude and device configuration. The RS01 inhaler without the AOS accessory used at higher altitude gave the lowest FPD values. By combining the AOS accessory with the DPI, however, the performance dependence on altitude/atmospheric pressure was essentially removed. CONCLUSIONS: Increasing inhaler performance can be achieved using an add-on accessory that enhances aerosol dispersion and minimizes flow rate dependency.

A Multi-laboratory in Vitro Study to Compare Data from Abbreviated and Pharmacopeial Impactor Measurements for Orally Inhaled Products: a Report of the European Aerosol Group (EPAG).

Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPDPIM were made by each organization using either the full-resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPDAIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPDAIM varied from 4.4 to 5.0 µm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPDPIM was fixed at 5 µm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPDAIM/FPDPIM], expressed as a percentage, was contained in the predetermined 85-118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques.

Inhaled corticosteroid delivery is markedly affected by breathing pattern and valved holding chamber model.

BACKGROUND: There is a scarcity of high-quality research on the efficient delivery of inhaled corticosteroids using valved holding chambers (VHCs) in children. METHODS: The delivered dose (DD) of fluticasone from a metered dose inhaler (pMDI) was tested using four VHCs: AeroChamber plus Flow-Vu (AC), Babyhaler (BH), EasyChamber (EC), and Optichamber Diamond (OD). The in vitro setup included an anatomical child throat model, Next Generation Impactor, and a breathing simulator to generate tidal breathing of a four and a 6-year-old child, and adult type single inhalation. RESULTS: OD showed the lowest proportion of fluticasone trapped in the throat with all breathing patterns. AC showed similar fine particle dose (FPD) in the respirable range (1-5 µm) irrespective of the breathing pattern. For BH, the median FPD 1-5 µm was highest during adult breathing. OD and EC showed higher overall DD and higher doses in the 1-5 µm range with paediatric breathing profiles compared to adult inhalation. The median DD and FPD 1-5 µm were significantly lower with BH compared to any other VHCs during tidal breathing. Compared to EC, the FPD of the other VHCs were skewed towards <2 µm particles. CONCLUSION: Fluticasone delivery is markedly affected by breathing pattern and VHC model. The observed differences in throat deposition and FPD delivered may have significant clinical implications for side effects and controlling airway inflammation. All VHCs intended for paediatric use should undergo testing using internationally recognised standardised methods incorporating clinically relevant paediatric breathing patterns.

Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder.

Treprostinil palmitil (TP), a prodrug of treprostinil, is being developed as an inhalation powder (TPIP) for the treatment of patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD). In ongoing human clinical trials, TPIP is administered via a commercially available high resistance (HR) RS01 capsule-based dry powder inhaler (DPI) device manufactured by Berry Global (formerly Plastiape), which utilizes the patient's inspiratory flow to provide the required energy to deagglomerate and disperse the powder for delivery to their lungs. In this study, we characterized the aerosol performance of TPIP in response to changes in inhalation profiles to model more realistic use scenarios, i.e., for reduced inspiratory volumes and with inhalation acceleration rates that differ from those described in the compendia. The emitted dose of TP for all combinations of inhalation profiles and volumes ranged narrowly between 79 and 89% for the 16 and 32 mg TPIP capsules at the 60 LPM inspiratory flow rate but was reduced to 72-76% for the 16 mg TPIP capsule under the scenarios at the 30 LPM peak inspiratory flow rate. There were no meaningful differences in the fine particle dose (FPD) at all conditions at 60 LPM with the 4 L inhalation volume. The FPD values for the 16 mg TPIP capsule ranged narrowly between 60 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L, while the FPD values for the 32 mg TPIP capsule ranged between 53 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L for the 60 LPM flow rate. At the 30 LPM peak flow rate, the FPD values for the 16 mg TPIP capsule ranged narrowly between 54 and 58% of the loaded dose at both extremes of the ramp rates for inhalation volumes down to 1 L. Based on these in vitro findings, the TPIP delivery system appears not to be affected by the changes in inspiratory flow profiles or inspiratory volumes that might be expected to occur in patients with PAH or PH associated with underlying lung conditions such as ILD.

Dissolution and Absorption of Inhaled Drug Particles in the Lungs.

Dry powder inhalation therapy has been effective in treating localized lung diseases such asthma, chronic obstructive pulmonary diseases (COPD), cystic fibrosis and lung infections. In vitro characterization of dry powder formulations includes the determination of physicochemical nature and aerosol performance of powder particles. The relationship between particle properties (size, shape, surface morphology, porosity, solid state nature, and surface hydrophobicity) and aerosol performance of an inhalable dry powder formulation has been well established. However, unlike oral formulations, there is no standard dissolution method for evaluating the dissolution behavior of the inhalable dry powder particles in the lungs. This review focuses on various dissolution systems and absorption models, which have been developed to evaluate dry powder formulations. It covers a summary of airway epithelium, hurdles to developing an in vitro dissolution method for the inhaled dry powder particles, fine particle dose collection methods, various in vitro dissolution testing methods developed for dry powder particles, and models commonly used to study absorption of inhaled drug.

Investigation of potential substandard dry powder inhalers on EU and North African markets - evaluation of the delivered and fine particle doses.

Purpose: Discovery of falsified Symbicort 320/9 Turbohaler identified in the UK in 2013 demonstrated that falsified dry powder inhalers were also present in the European market. This work aimed to investigate the current situation of formoterol-containing dry powder inhalers in Europe and North Africa by assessing their aerodynamic performance profile. Methods: A total of eight registered formoterol-based dry powder inhalers over the European and North African markets were involved in this study, including the reference drug Foradil. Samples were prepared using a multistage liquid impinger (MsLI) and further analyzed by a validated HPLC-UV method to determine the delivered and the fine particle doses (FPDs). This study also examined the impact of freezing-thawing cycles on sample stability in terms of analytical purpose handling. Results: No substandard dry powder inhalers were identified among the medicinal products involved in this work. The delivered dose (DD) of assessed drugs varied from 8.33 to 9.69 µg, while the FPD was between 1.86 and 3.35 µg. As expected, this work confirmed that the capsule composition and the barrier properties of the primary packaging can affect the FPD of dry powder for inhalation use. Conclusions: The FPD of products C and B was, respectively, 17.4 and 14.2% superior to Foradil, products D and H had the closest values compared to the original drug, and product F was 34.5% inferior. Additionally, this work showed that a high FPD can be achieved using HPMC capsules and moisture-impermeable primary packaging.

Characterization of dry powder inhaler performance through experimental methods.

Experimental methods provide means for the quality control of existing DPIs and for exploring the influence of formulation and device parameters well in advance of clinical trials for novel devices and formulations. In this review, we examine the state of the art of in vitro testing of DPIs, with a focus primarily on the development of accurate in vitro-in vivo correlations. Aspects of compendial testing are discussed, followed by the influence of flow profiles on DPI performance, the characterization of extrathoracic deposition using mouth-throat geometries, and the characterization of regional thoracic deposition. Additional experimental methods that can inform the timing of bolus delivery, the influence of environmental conditions, and the development of electrostatic charge on aerosolized DPI powders are reviewed. We conclude with perspectives on current in vitro methods and identify potential areas for future investigation, including the estimation of variability in deposition, better characterization of existing compendial methods, optimization of formulation and device design to bypass extrathoracic deposition, and the use of novel tracheobronchial filters that aim to provide more clinically relevant measures of performance directly from in vitro testing.

A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes.

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

Consistent Dosing Through the Salmeterol-Fluticasone Propionate Easyhaler for the Management of Asthma and Chronic Obstructive Pulmonary Disease: Robustness Analysis Across the Easyhaler Lifetime.

Background: Easyhaler (registered trademark by Orion Corporation) is a multidose dry powder inhaler (DPI) for the treatment of asthma and chronic obstructive pulmonary disease (COPD), designed to be simple and easy to use. Salmeterol-fluticasone propionate (S-F) Easyhaler (50/250 and 50/500 µg per dose), available in several European countries, provides combined inhaled corticosteroid and long-acting beta agonist therapy for the management of asthma and COPD. A requirement of the European Committee for Medical Products for Human Use guidelines is to demonstrate product performance under conditions that mimic real-life patient use. Therefore, our aims were to assess the robustness of the S-F Easyhaler by assessing the delivered dose (DD) and fine particle dose (FPD) throughout the inhaler lifespan and under simulated environmental stress conditions. Methods: This was a noncomparative exploratory in vitro study. Two batches and six to nine inhalers per batch from both dose strengths were used to assess drug delivery performance over the inhaler lifespan (doses 1-60). For determining the impact of simulated environmental stress (tests for exposure of dropping, vibration, moisture, and freeze-thawing) on DD and FPD, one batch and three inhalers per batch from both dose strengths were used per test, respectively. Aerodynamic particle size distribution was evaluated during the simulated dropping and vibration tests. Results: DD and FPD from both dose strengths of S-F Easyhaler performance remained consistent through the inhaler lifespan and simulated environmental stress did not affect its performance. Similar DD and FPD values were observed with or without dropping, vibration, exposure to moisture, and freeze-thawing, and no inhaler breakages occurred during the simulated tests. Conclusions: The in vitro performance of S-F Easyhaler at both dose strengths suggests that reliable dosing and robustness can be achieved under real-life stress conditions; S-F Easyhaler is a durable DPI for the management of asthma and COPD.

Increasing the fine particle fraction of pressurised metered dose inhaler solutions with novel actuator shapes.

In this paper we demonstrate that the use of multiple orifices can improve the fine particle fraction (FPF) of pressurised metered-dose inhaler solution formulations by up to 75% when compared to a single orifice with an equivalent cross sectional area (p<0.05). While prior work has relied on metal actuator components, improvements in micro injection moulding and micro drilling now make it possible to mass produce novel orifice shapes to achieve similar FPF gains in plastic parts, with orifice diameters less than 0.2 mm. The ability to create internal features inside the actuator is also demonstrated. We show through in vitro high speed imaging that twin orifice sprays merge quickly and act as a single, modified plume. We also show for the first time that FPF and fine particle dose (FPD) are strongly correlated with the distance at which the plume velocity decays to half its initial value (R2=0.997 and 0.95 respectively). When plume velocity & FPF are increased, mouthpiece deposition decreases. This suggests that while smaller orifices produce more fine particles, higher sustained plume velocities also entrain more of the fine particles produced at the periphery of the spray due to increased shear. The effect occurs within the mouthpiece and is thus unlikely to alter the flow field in the upper airway.

Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X50) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied. Eight MF-MDI formulations (one per batch) were manufactured based on a reduced factorial design of experiment (DOE) approach, which included relevant formulation levels with varying X50 (1.1 and 2 µm), concentration of ethanol (0.45, 0.9, 1.8, and 3.6%w/w), and oleic acid (0.001 and 0.025%w/w). The in vitro evaluation of these MF-MDI formulations indicated the importance of drug particle's X50, oleic acid, and ethanol canister concentration as critical formulation variables governing the performance of MF suspension-based MDI products. The effect of these formulation variables on DD, FPD < 5, ex-throat dose, and MDT was subsequently utilized to develop empirical relationships linking formulation factors with effects on in vitro performance measures. The developed strategy could be useful for predicting MF-MDI product performance during MDI product development and manufacturing. The systematic DOE approach utilized in this study may provide insights into the understanding of the formulation variables governing the MF-MDI product performance.

In vitro-in vivo correlation of cascade impactor data for orally inhaled pharmaceutical aerosols.

In vitro-in vivo correlation is the establishment of a predictive relationship between in vitro and in vivo data. In the context of cascade impactor results of orally inhaled pharmaceutical aerosols, this involves the linking of parameters such as the emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter to in vivo lung deposition from scintigraphy data. If the dissolution and absorption processes after deposition are adequately understood, the correlation may be extended to the pharmacokinetics and pharmacodynamics of the delivered drugs. Correlation of impactor data to lung deposition is a relatively new research area that has been gaining recent interest. Although few in number, experiments and meta-analyses have been conducted to examine such correlations. An artificial neural network approach has also been employed to analyse the complex relationships between multiple factors and responses. However, much research is needed to generate more data to obtain robust correlations. These predictive models will be useful in improving the efficiency in product development by reducing the need of expensive and lengthy clinical trials.

Bioequivalence assessment of pharmaceutical aerosol products through IVIVC.

Many pharmaceutical developers of generic orally inhaled products (OIPs) are facing significant issues in passing the regulatory requirement to show pharmacokinetic (PK) bioequivalence (BE) to the originator product. The core of the issue is that no reliable in vitro-in vivo correlation (IVIVC) is available to guide their development. In this paper, several issues are identified and means to improve the data used for developing an IVIVC are discussed. The article also presents an "IVIVC-free" approach for developing a formulation matching the originator's PK performance.

[Evaluation of Valved Holding Chambers Simulating Repurposing Use of Ciclesonide Metered-dose Inhaler by Patients with Pneumonia].

Achieving appropriate inhalation in patients with coronavirus disease 2019 (COVID-19) is a common challenge in the use of repurposed metered-dose inhaler (MDI) formulations. The purpose of this study was to evaluate the effect of five valved holding chambers (VHCs) on the inhalation of ciclesonide from Alvesco MDI. The aerodynamic particle size distribution of ciclesonide discharged from Alvesco MDI was evaluated using a Next Generation Impactor in the presence and absence of VHCs. The use of VHCs retained or slightly increased the amount of ciclesonide in the fine particle diameter range (aerodynamic particle size below 3 µm) (FPD) and reduced the amount at the induction port after coordinated inhalation. However, the use of VHC reduced the FPD of the formulation by increasing the time between the MDI discharge and the pump suction by various degrees among the five VHCs. These results indicated that use of the VHCs and minimizing the inhalation delay time should ensure sufficient inhalation of ciclesonide particles.

Novel approach for real-time monitoring of carrier-based DPIs delivery process via pulmonary route based on modular modified Sympatec HELOS.

An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values (R 2 = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.

In Vitro Flow Rate Dependency of Delivered Dose and Fine Particle Dose of Salmeterol/Fluticasone Propionate Easyhaler and Seretide Diskus with Patient Flow Rates Collected in a Randomized Controlled Trial.

BACKGROUND: The Easyhaler® device-metered dry powder inhaler containing Salmeterol and Fluticasone propionate (S/F) has been developed for the treatment of patients with asthma and chronic obstructive pulmonary disease (COPD). We report two studies which evaluated the in vitro flow rate dependence of delivered dose (DD) and fine particle dose (FPD) of S/F Easyhaler versus Seretide Diskus®. METHODS: A randomized controlled trial (RCT) assessed inspiratory flow parameters of S/F Easyhaler and Seretide Diskus in subgroups of patients with asthma (children, adolescents and adults, and elderly) and in COPD patients. The 10th, 50th, and 90th percentile airflow rates were determined and utilized in vitro, to evaluate flow rate dependence of DD and FPD. Flow rate dependence was evaluated relative to the result obtained at the 50th percentile and any values deviating from 100% indicated flow rate dependence. The volumetric flow rate dependence (Q) index derived from FPD at 10th and 90th percentile airflows was also evaluated. RESULTS: Overall, 227 patients were enrolled and randomized; 216 completed the RCT. In total, 55.5% of patients were female, and the mean age was 46.3 years. Clinically relevant airflow rates (46, 68, and 85 L/min for S/F Easyhaler and 44, 71, and 96 L/min for Seretide Diskus) were carried forward into the in vitro study, which demonstrated similar flow rate dependence of DD and FPD for S/F Easyhaler compared with Seretide Diskus; all values were within ±15% limits across the 10th, 50th, and 90th percentile airflow rates. Q index results suggested that both S/F Easyhaler and Seretide Diskus are medium airflow-dependent products. CONCLUSIONS: Similar in vitro flow rate dependence of DD and FPD was demonstrated for S/F Easyhaler compared with Seretide Diskus, across a range of clinically relevant airflow rates, collected from patients with asthma and COPD.

Real-life budesonide and formoterol dose emission from the medium and high strength fixed dosed combinations in a Spiromax® dry powder inhaler using inhalation profiles from patients with chronic obstructive pulmonary disease.

Dry powder inhalers (DPIs) are passive devices used to administer inhaled medication for the management of asthma and chronic obstructive pulmonary disease (COPD). DPIs require patients to generate a sufficient internal turbulent airflow force during each inhalation to deaggregate the powdered drug formulation into an emitted dose containing particles with the greatest likelihood of lung deposition. This internal force is generated by the interaction between the user's inhalation flow and the resistance of the DPI. Traditional compendial in vitro methods of measuring dose emission use a vacuum pump to simulate inhalation. We have adapted this in vitro method by replacing the square wave inhalation profile generated by a vacuum pump with the inhalation profiles of patients using an empty DPI. This method enables accurate assessment of the actual dose they would have inhaled. In the present study, real-life inhalation profiles were selected from 15 patients with COPD who inhaled through an empty placebo Spiromax® DPI. Ex vivo dose emissions were measured for the medium (emitted dose of 160 µg/4.5 µg) and high-strength (320 µg/9 µg) budesonide/formoterol formulations from the Spiromax DPI. These profiles were used to investigate the effect of the primary inhalation parameter-peak inhalation flow (PIF). Some profiles were modified to isolate other inhalation parameters (namely, inhaled volume [Vin] and acceleration rate of the inhalation maneuver [ACIM]). Both the medium-strength and high-strength DuoResp Spiromax displayed flow-dependent dose emission. When the PIF of a patient's inhalation maneuver increased from 26.8 L/min to 69.7 L/min, there was a significant (p < 0.05) effect on the dose-emission characteristics of the medium-strength and high-strength DuoResp Spiromax. At each PIF, an increase in Vin from approximately 500 mL to 2000 mL had no effect on the dose-emission characteristics of either strength. However, at each Vin there was a significant (p < 0.05) effect on the dose-emission characteristics as PIF increased. The effect of ACIM on the dose-emission characteristics was small. The ex vivo methodology used in this study provides a practical approach to identify the actual dose a patient might inhale during routine real-life use of the DuoResp Spiromax.