Henry Chrystyn

What the pulmonary specialist should know about the new inhalation therapies

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patients inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Inhaler competence in asthma: Common errors, barriers to use and recommended solutions

Whilst the inhaled route is the first line administration method in the management of asthma, it is well documented that patients can have problems adopting the correct inhaler technique and thus receiving adequate medication. This applies equally to metered dose inhalers and dry powder inhalers and leads to poor disease control and increased healthcare costs. Reviews have highlighted these problems and the recent European Consensus Statement developed a call to action to seek solutions. This review takes forward the challenge of inhaler competence by highlighting the issues and suggesting potential solutions to these problems. The opportunity for technological innovation and educational interventions to reduce errors is highlighted, as well as the specific challenges faced by children. This review is intended as a policy document, as most issues faced by patients have not changed for half a century, and this situation should not be allowed to continue any longer. Future direction with respect to research, policy needs and practice, together with education requirements in inhaler technique are described.

Choosing inhaler devices for people with asthma: Current knowledge and outstanding research needs

Recommendations in asthma guidelines presuppose that practitioners have the evidence, information, knowledge, and tools to select inhaler devices appropriate for individual patients. Randomised controlled trials usually exclude patients with suboptimal inhaler technique. There is therefore little evidence on which to base inhaler selection in the real world, where patients often use their inhalers incorrectly. The lung deposition of inhaled drug varies according to inhaler device, drug particle size, inhalation technique, and pattern of inspiratory flow. Even with training, not all patients can use their inhalers correctly and maintain inhaler technique; patients may have inability to handle the inhaler, strong negative preferences, or natural breathing patterns that do not match their prescribed inhaler. Therefore, matching device to the patient may be a better course of action than increasing therapy or training and retraining a patient to use a specific inhaler device. Several research questions require answers to meet the goal of helping prescribers make a more informed choice of inhaler type. Is the level of drug deposition in the lungs a key determinant of clinical short- and long-term outcomes? What should be measured by a clinical tool designed to check inhaler technique and therefore help with device selection? If we have a tool to help in individualising inhaler choice, will we achieve better asthma outcomes? Do we have to refine inhaler device choice for each individual, or will we get better outcomes if we select our current best option in light of current knowledge and apply this on a population level?

Inhaled corticosteroids for asthma: impact of practice level device switching on asthma control

BackgroundAs more inhaled corticosteroid (ICS) devices become available, there may be pressure for health-care providers to switch patients with asthma to cheaper inhaler devices. Our objective was to evaluate impact on asthma control of inhaler device switching without an accompanying consultation in general practice.MethodsThis 2-year retrospective matched cohort study used the UK General Practice Research Database to identify practices where ICS devices were changed without a consultation for ≥5 patients within 3 months. Patients 6–65 years of age from these practices whose ICS device was switched were individually matched with patients using the same ICS device who were not switched. Asthma control over 12 months after the switch was assessed using a composite measure including short-acting β-agonist and oral corticosteroid use, hospitalizations, and subsequent changes to therapy.ResultsA total of 824 patients from 55 practices had a device switch and could be matched. Over half (53%) of device switches were from dry powder to metered-dose inhalers. Fewer patients in switched than matched cohort experienced successful treatment based on the composite measure (20% vs. 34%) and more experienced unsuccessful treatment (51% vs. 38%). After adjusting for possible baseline confounding factors, the odds ratio for treatment success in the switched cohort compared with controls was 0.29 (95% confidence interval [CI], 0.19 to 0.44; p < 0.001) and for unsuccessful treatment was 1.92 (95% CI, 1.47 to 2.56; p < 0.001).ConclusionSwitching ICS devices without a consultation was associated with worsened asthma control and is therefore inadvisable.

Investigations of an optimal inhaler technique with the use of urinary salbutamol excretion as a measure of relative bioavailability to the lung

BACKGROUND--A simple non-invasive method, in which a urine sample is taken 30 minutes after drug administration, has previously been shown to be a measure of the relative bioavailability of salbutamol to the lungs. This technique has been used to determine an optimal inhaler technique with commercially available metered dose inhalers (MDI). METHODS--Ten healthy subjects were trained in the use of MDIs. Each inhaled 4 x 100 micrograms salbutamol in a series of experiments to examine the relative bioavailability to the lung after different respiratory manoeuvres. Urine collection intervals were 0-0.5 hours and 0.5-24 hours after administration. RESULTS--There was significantly greater elimination of unchanged salbutamol 30 minutes after administration, indicating a greater relative bioavailability of salbutamol to the lungs after (1) exhaling gently to residual volume rather than to functional residual capacity before inhalation; (2) slow inhalation (10 l/min) compared with fast inhalation (50 l/min); (3) breath holding for 10 seconds after inhalation compared with no breath holding. CONCLUSIONS--All patient information leaflets and healthcare personnel should standardise the instructions given to patients and should adopt the inhalation method proposed.

The Diskus™: a review of its position among dry powder inhaler devices

The use of dry powder inhalers (DPIs) to administer treatments for respiratory diseases has increased significantly in recent years. There is now a wide range of DPIs available that vary considerably in design, required operational techniques, output characteristics and drug delivery across a range of inhalation patterns. Different patient populations may find individual types of DPI easier to use correctly than others and selecting the right DPI for particular patient requirements will improve compliance with therapy. For example, some DPIs offer a greater resistance against inspirational flow rate than others which affects the total emitted dose and also fine particle mass of the aerosol released. An individual patient may therefore receive different amounts of drug when inhaling from different DPIs. Therefore, it is important that the prescriber is fully aware of the characteristics of the different types of DPI, so that he or she can prescribe the device that is most appropriate to an individual patients needs. This review explores the characteristics of currently available DPIs and evaluates their efficacy and patient acceptability. The differences in output characteristics, ease of use and patient preferences between available devices is shown to affect treatment efficacy and patient compliance with therapy. Changing the DPI prescribed to a patient to a cheaper or generic device may therefore adversely affect disease control and thereby increase the cost of treatment.

In-vitro intra- and inter-inhaler flow rate-dependent dosage emission from a combination of budesonide and eformoterol in a dry powder inhaler.

Some dry powder inhalers have profound inhalation flow rate-dependent dosage emission, and it has been suggested that there are links between the in vitro emitted dose, total lung deposition, and subsequent clinical response. We have measured the in vitro dosage delivery for a combination of budesonide and eformoterol in a new version of the Turbuhaler. At inhalation flow rates of 30, 60, and 90 Lmin(-1), the total dose emission for 10 separate inhalations from each of six inhalers was determined. The aerodynamic characteristics of the emitted dose using inhalation flow rates of 28.3 and 60 Lmin(-1) were measured using the Andersen Cascade Impactor. The mean (SD) emitted dose for budesonide, at 30, 60, and 90 Lmin(-1), was 37.5%(18.2%), 64.4%(16.6%), and 107.4%(36.0%) (of the nominal emitted dose), respectively, and for eformoterol were 38.0%(20.3%), 65.0%(16.8%), and 104.9%(36.2%) (of the nominal emitted dose), respectively. Variability of dose emission characteristics from each inhaler and between inhalers at each flow rate was found. The aerodynamic particle size characterization of the emitted dose at flow rates of 28.3 and 60 Lmin(-1) revealed a mean fine particle dose for budesonide of 11.9% and 28.6% of the nominal emitted dose, respectively, and similarly 10.0% and 26.3% for eformoterol. At 28.3 Lmin(-1), the majority of the emitted dose (54.8% for budesonide and 64.5% for eformoterol) was deposited in the throat and preseparator of the Andersen Cascade Impactor. The mass median aerodynamic diameters for budesonide and eformoterol at 28.3 Lmin(-1) were 3.2 and 3.6 microm, respectively, and similarly at 60 Lmin(-1) were 2.4 and 2.5 microm. The modified Turbuhaler containing a budesonide and eformoterol combined formulation shows intra- and inter-inhaler flow-dependent dosage emission. The clinical significance of the in vitro dose-dependent properties should be investigated.

Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation.

BackgroundAlthough patients have more problems using metered dose inhalers, clinical comparisons suggest they provide similar control to dry powder inhalers. Using real-life situations this study was designed to evaluate asthma control in outpatients with moderate to severe persistent asthma and to compare efficacy of fixed combinations of inhaled corticosteroids (ICS) and long acting beta-agonists (LABA).MethodsThis real-life study had a cross-sectional design. Patients using fixed combinations of ICS and LABA had their asthma control and spirometry assessed during regular visits.Results111 patients were analyzed: 53 (47.7%) received maintenance therapy of extrafine beclomethasone-formoterol (BDP/F) pressurized metered dose inhaler (pMDI), 25 (22.5%) fluticasone-salmeterol (FP/S) dry powder inhaler (DPI), and 33 (29.7%) budesonide-formoterol (BUD/F) DPI. Severity of asthma at time of diagnosis, assessed by the treating physician, was comparable among groups. Asthma control was achieved by 45.9% of patients; 38.7% were partially controlled and 15.3% were uncontrolled. In the extrafine BDF/F group, asthma control total score, daytime symptom score and rescue medication use score were significantly better than those using fixed DPI combinations (5.8 ± 6.2 vs. 8.5 ± 6.8; 1.4 ± 1.8 vs. 2.3 ± 2.1; 1.8 ± 2.2 vs. 2.6 ± 2.2; p = 0.0160; p = 0.012 and p = 0.025, respectively) and the mean daily ICS dose were significantly lower.ConclusionspMDI extrafine BDP/F combination demonstrated better asthma control compared to DPIs formulated with larger particles. This could be due to the improved lung deposition of the dose or less reliance on the optimal inhalation technique or both.

Determination of factors controlling the particle size in nanoemulsions using Artificial Neural Networks

The purpose of this study was to use Artificial Neural Networks (ANNs) in identifying factors, in addition to surfactant and internal phase content, that influence the particle size of nanoemulsions. The phase diagram and rheometric characteristics of a nanoemulsion system containing polysorbate 80, ethanol, medium chain triglycerides and normal saline loaded with budesonide were investigated. The particle size of samples of various compositions prepared using different rates and amounts of applied energy was measured. Data, divided into training, test and validation sets, were modelled by ANNs. The developed model was assessed and found to be of high quality. The model was then used to explore the effect of composition and processing factors on particle size of the nanoemulsion preparation. The study demonstrates the potential of ANNs in identifying critical parameters controlling preparation for this system, with the total amount of applied energy during preparation found to be the dominant factor in controlling the final particle size.

The Genuair® inhaler: a novel, multidose dry powder inhaler.

This article reviews the Genuair® inhaler, a novel, multidose, breath‐actuated dry powder inhaler. The inhaler design includes visual and acoustic feedback to reassure patients that they have taken their medication correctly, a dose indicator and a lock‐out mechanism to prevent the use of an empty inhaler. The inhaler has medium airflow resistance and uses an optimised dispersion system to ensure effective deagglomeration of the inhalation powder. In vitro studies have demonstrated that the inhaler delivers a reproducible aerodynamic aerosol quality and is reliable under various thermal and mechanical stress conditions. Further studies in vitro have demonstrated that the total emitted dose and fine particle dose are both consistent over a range of inhalation flows from 45 to 95 l/min, as well as being independent of inhalation volume (2 l vs. 4 l) and storage conditions. In healthy subjects, delivery of aclidinium bromide 200 μg via the inhaler achieved high lung deposition (approximately 30% of the metered dose). A further study has shown that patients with moderate or severe chronic obstructive pulmonary disease can generate sufficient inspiratory airflow through the inhaler to reliably inhale the full dose and reset the inhaler. The inhaler has been used to deliver aclidinium in many clinical trials and the available data indicate that it has high acceptability amongst patients.