The value of demonstration and role of the pharmacist in teaching the correct use of pressurized bronchodilators.

The use of an improper technique with metered-dose inhalers decreases the efficacy of the bronchodilators being administered. There is evidently a need for patients to watch a demonstration. Twenty-nine adult asthmatic patients from an allergy clinic were divided into three groups, each receiving a different form of instruction: an information sheet, personal instruction or a videotape presentation. Subsequently each patient was tested for correct use of the inhaler. There was no difference in mean scores for inhalation technique between the groups instructed in person and by videotape, but both were significantly better than the mean score of the group given only an information sheet. There was also no significant change in the scores at a follow-up test in the groups who saw the technique demonstrated. These results indicate the need for and value of the demonstration of proper technique with pressurized inhalers. A pharmacy-generated education system using videotape equipment or personal instruction by a pharmacist could readily solve the problem.     

Asthma in primary schools.

Seven schools in the Lewes area were visited to identify which children were using inhalational treatment for asthma. The attitudes of the parents and schools were assessed, as was the children''s skill in using inhalers. Five per cent of all children were receiving inhalational treatment with bronchodilator drugs. On average they had missed seven school days in the past year. The opinions of the parents about treatment appeared to be determined by the severity of the child''s asthma. Most schools coped well with giving bronchodilators, though there was no real understanding of the nature of the disease or treatment. Most children who had received pressurised inhalers could not use them satisfactorily.     

Advances in Device and Formulation Technologies for Pulmonary Drug Delivery

Inhaled pharmaceuticals are formulated and delivered differently according to the therapeutic indication. However, specific device-formulation coupling is often fickle, and new medications or indications also demand new strategies. The discontinuation of chlorofluorocarbon propellants has seen replacement of older metered dose inhalers with dry powder inhaler formulations. High-dose dry powder inhalers are increasingly seen as an alternative dosage form for nebulised medications. In other cases, new medications have completely bypassed conventional inhalers and been formulated for use with unique inhalers such as the Staccato® device. Among these different devices, integration of software and electronic assistance has become a shared trend. This review covers recent device and formulation advances that are forming the current landscape of inhaled therapeutics.     

Devices for Dry Powder Drug Delivery to the Lung

Dry powder inhalers (DPIs) are an important and increasingly investigated method of modern therapy for a growing number of respiratory diseases. DPIs are a promising option for certain patient populations, and may help to overcome several limitations that are associated with other types of inhalation delivery systems (e.g., accuracy and reproducibility of the dose delivered, compliance and adherence issues, or environmental aspects). Today, more than 20 different dry powder inhalers are on the market to deliver active pharmaceutical ingredients (APIs) for local and/or systemic therapy. Depending on the mechanism of deagglomeration, aerosolization, dose metering accuracy, and the interpatient variability, dry powder inhalers demonstrate varying performance levels. During development, manufacturers focus on improving aspects characteristic of their specific DPI devices, depending on the intended type of application and any particular requirements associated with it. With the wide variety of applications related to specific APIs, there exists a range of different devices with distinct features. In addition to the routinely used multi-use DPIs, several single-use disposable devices are under development or already approved. The recent introduction of disposable devices will expand the range of possible applications for use by including agents such as vaccines, analgesics, or even rescue medications. This review article discusses the performance and advantages of recently approved dry powder inhalers as well as disposable single-use inhalers that are currently under development.KEY WORDS: disposable, dry powder inhaler, particle deagglomeration, vaccination     

The influence of formulation and spacer device on the in vitro performance of solution chlorofluorocarbon-free propellant-driven metered dose inhalers

The purpose of this study was to evaluate the hypothesis that spacer devices have limited effect on the in vitro fine particle dose emitted from solution metered dose inhalers containing different proportions of HFA134a [1,1,1,2-tetrafluoroethane] propellant. Two solution formulations (80% and 97.5% wt/wt HFA134a) were tested across the actuator alone, actuator plus Aerochamber, and Ace holding chamber. Particle size distributions were determined using laser diffraction (LD) and cascade impaction (CI). Multimodal particle size distributions were identified using LD. CI analyses were characterized by a major mode located at ≈0.5 μm. The fine particle dose emitted from the inhaler spacer combinations containing 97.5% HFA134a was independent of the device setup used. Fine particle doses were influenced by spacer setup in 80% HFA134a formulations, indicating different plume dynamics of low vapor pressure formulations. Sampling inlet deposition was approximately O when spacer devices were used with either formulation. When spacers were not used, sampling inlet deposition was increased significantly. However, inlet deposition with the 97.5% HFA134a formulation was significantly less than that of the 80% HFA134a formulation (≈25% of emitted dose compared with 69% respectively). Thus, high propellant concentration formulations appear to have more robust in vitro performance. This is particularly important given the preponderance of poor patient compliance that is associated with spacer use. High propellant concentrations had the advantage of fine particle doses that were independent of the device setup and significantly lowered sampling inlet deposition when no spacer was used.     

Study of the RESS Process for Producing Beclomethasone-17,21-Dipropionate Particles Suitable for Pulmonary Delivery

The purpose of this research was to micronize beclomethasone-17,21-dipropionate (BDP), an anti-inflammatory inhaled corticosteroid commonly used to treat asthma, using the rapid expansion of supercritical solution (RESS) technique. The RESS technique was chosen for its ability to produce both micron particles of high purity for inhalation, and submicron/nano particles as a powder handling aid for use in next generation dry powder inhalers (DPIs). Particle formation experiments were carried out with a capillary RESS system to determine the effect of experimental conditions on the particle size distribution (PSD). The results indicated that the RESS process conditions strongly influenced the particle size and morphology; with the BDP mean particle size decreasing to sub-micron and nanometer dimensions. An increase in the following parameters, i.e. nozzle diameter, BDP mol fraction, system pressure, and system temperature; led to larger particle sizes. Aerodynamic diameters were estimated from the SEM data using three separate relations, which showed that the RESS technique is promising to produce particles suitable for pulmonary delivery.     

Clinical and economic consequences of a reimbursement restriction of nebulised respiratory therapy in adults: direct comparison of randomised and observational evaluations

Objective To compare the results of a randomised and an observational evaluation of the same policy that restricted reimbursement for nebulised respiratory medications in adult patients in a community setting.Designs Cluster randomised controlled trial and observational time series with historical controls.Setting Pharmacare, the government funded drug benefits plan for elderly people and patients receiving social assistance in British Columbia, Canada.Participants In the randomised controlled trial 104 clusters of medical practices, pair matched by geography and approximately by practice size, were randomised to the intervention group (449 patients affected by the policy on 1 March 1999), and the control group (offered a six month exemption, affecting 386 patients). The observational analysis included all Pharmacare beneficiaries (excluding the 386 exempt patients) who had used any nebulised drugs six months before the policy (4624 patients).Intervention Pharmacare restricted reimbursement for nebulised bronchodilators, steroids, and cromoglycate to patients whose doctors applied for an individual patient''s exemption, giving an appropriate clinical reason.Main outcome measures Number of contacts with doctors and services, emergency admissions to hospital, and utilisation of and expenditure for respiratory drugs in databases of British Columbia''s Ministry of Health.Results Contacts with doctors or emergency admissions to hospital did not increase in association with the restriction, regardless of the analytical approach. In the observational analysis, we found a reduction of $C24 per patient month in all nebulised drug use (95% confidence interval 19 to 29) and an increase of $C3 per patient month in all expenditure for inhalers (1.4 to 4.5). The randomised evaluation found savings of $C8 per patient month for nebulisers (P = 0.24) and no increase in spending on inhalers (P = 0.79). Correcting for 60% non-compliance by exempt doctors in a sensitivity analysis yielded similar results as the observational evaluation.Conclusions Observational as well as randomised analyses found moderate net savings and no increase in unintended healthcare outcomes after restricting reimbursement for nebulised respiratory drugs. Randomised policy trials are feasible and, if carefully implemented, likely to be concordant with observational evaluations.     

Challenges and Opportunities in Implementing the FDA Default Parametric Tolerance Interval Two One-Sided Test for Delivered Dose Uniformity of Orally Inhaled Products

The goal of this article is to discuss considerations regarding implementation of the parametric tolerance interval two one-sided test (PTI-TOST) for delivered dose uniformity (DDU) of orally inhaled products (OIPs). That test was proposed by FDA in 2005 as an alternative to the counting test described in the 1998 draft FDA guidance for metered dose inhalers and dry powder inhalers. The 2005 PTI-TOST, however, still has not found much use in practice despite the general desirability of parametric approaches in modern pharmaceutical quality control. A key reason for its slow uptake is that it rejects, with high probability, batches whose quality is considered acceptable by all other published regulatory and pharmacopeial standards as well as by the DDU specifications for many approved OIPs. Manufacturers therefore continue using nonparametric counting tests for control of DDU. A simulated case study presented here compares the consequences of the PTI-TOST compared to the counting test. The article discusses three possibilities that would help increase the uptake of the PTI-TOST approach, namely: product-specific quality standards, a different default standard suitable for the majority of OIPs, and integration of the PTI-TOST with a continuous verification control strategy rather than using it as an isolated-batch (transactional) end-product testing. In any of these efforts, if a parametric test is used, it is critical not to set the target quality close to, or at the boundary of the process/product capabilities, because PTI tests are designed to reject with high probability the identified target quality.     

Aerosol generation by metered-dose inhalers containing dimethyl ether/propane inverse microemulsions

Water soluble compounds were incorporated into metered-dose inhalers (MDIs) by using water-in-propellant lecithin microemulsions, in which dimethyl ether (DME) and propane acted as both continuous phase and propellant. Lecithin, water, and water soluble compounds were added to glass MDI containers, valves were crimped on, and propellants were added using a pressure burette. Aerosols were produced using commercially available actuators, and inertial impaction was used to determine the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction (FPF) of the resulting aerosols. The DME/propane/lecithin, microemulsion MDIs generated aerosols with particle size distributions suitable for pulmonary delivery (eg, MMAD 3.1 μm, FPF 59% for DME with lecithin content 3%, water content 2.5% [wt/wt]). Increasing water concentration (up to 8% wt/wt) was correlated with a reduction in FPF. Freezing and rewarming had no adverse effect on MMAD, GSD, or FPF. Storage of microemulsion samples for up to 3 weeks did not adversely affect the MMAD, GSD, or FPF. This approach may enable the pulmonary delivery of water soluble therapeutic agents via MDIs.     

Asthma caused by occupational exposures is common – A systematic analysis of estimates of the population-attributable fraction

Background

As 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.

Methods

This 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.

Results

A 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).

Conclusion

Switching ICS devices without a consultation was associated with worsened asthma control and is therefore inadvisable.     

Association of medication with the human plasma N-glycome

Glycosylation is highly variable depending on many environmental factors. Using our fully quantitative high-throughput normal phase hydrophilic interaction liquid chromatography platform we have identified glycosylation changes associated with medication in the plasma N-glycome from three different population cohorts: ORCADES from the Orkney Islands in Scotland and CROATIA-Vis and CROATIA-Korcula from the Croatian islands of Vis and Korcula. Associations between glycosylation and the use of hormones (oral contraceptives, hormone replacement therapy), nonsteroidal anti-inflammatory drugs (aspirin and other NSAIDs), oral steroids (prednisolone) and steroid inhalers (beclomethasone) were investigated. Significant differences associated with usage of oral contraceptives were found with increased core-fucosylated biantennary glycans. Decreases in core-fucosylated biantennary glycans, core-fucosylated triantennary glycans with outer-arm fucose, and high mannosylated glycans were associated with the use of anti-inflammatory drugs. All of the changes in glycosylation were independent of blood group status. In conclusion, hormones and anti-inflammatory medication were associated with changes in glycosylation, possibly as a result of the modulatory effect of these drugs on the inflammatory response. In general, cancer is associated with inflammation, and many glycoproteins in the plasma are acute phase related to the host response. These preliminary data indicate the importance of correcting the levels of glycans used as biomarkers for the effects of medication.     

Effects of Salbutamol and Isoprenaline Phenylephrine in Reversible Airways Obstruction

Ventolin (salbutamol) and Medihaler-Duo (isoprenaline/phenylephrine combination) standard pressurized inhalers were used to administer doses of two or six “puffs” to 16 patients with known reversible airways obstruction. The doses were administered in random order over two days. Both the Ventolin and Medihaler-Duo inhalers substantially increased FEV₁, but in the doses used salbutamol was more effective than isoprenaline/phenylephrine (P < 0·01). There was no significant difference between two and six puffs of salbutamol, though there seemed to be an advantage of six puffs of isoprenaline/phenylephrine over two puffs (P < 0·05). Adrenaline (1/1,000) 0·5 ml and atropine 0·6 mg produced similar increases in FEV₁ to those produced by salbutamol.The Pao₂ fell more than 5 mm Hg in three patients after salbutamol and in three after isoprenaline/phenylephrine. There was no significant fall in mean Pao₂ in any of the treatment groups. It is concluded that the Ventolin inhalant, administered in the conventional dose of two puffs, is as effective a bronchodilator as subcutaneous adrenaline and atropine, is more effective than the Medihaler-Duo, and is without detectable side effects.     

A Two One-Sided Parametric Tolerance Interval Test for Control of Delivered Dose Uniformity. Part 1—Characterization of FDA Proposed Test

The FDA proposed a parametric tolerance interval (PTI) test at the October 2005 Advisory Committee meeting as a replacement of the attribute (counting) test for delivered dose uniformity (DDU), published in the 1998 draft guidance for metered dose inhalers (MDIs) and dry powder inhalers (DPIs) and the 2002 final guidance for inhalation sprays and intranasal products. This article (first in a series of three) focuses on the test named by the FDA “87.5% coverage.” Unlike a typical two-sided PTI test, which controls the proportion of the DDU distribution within a target interval (coverage), this test is comprised of two one-sided tests (TOST) designed to control the maximum amount of DDU values in either tail of the distribution above and below the target interval. Through simulations, this article characterizes the properties and performance of the proposed PTI-TOST under different scenarios. The results show that coverages of 99% or greater are needed for a batch to have acceptance probability 98% or greater with the test named by the FDA “87.5% coverage” (95% confidence level), while batches with 87.5% coverage have less than 1% probability of being accepted. The results also illustrate that with this PTI-TOST, the coverage requirement for a given acceptance probability increases as the batch mean deviates from target. The accompanying articles study the effects of changing test parameters and the test robustness to deviations from normality.     

How to achieve better outcome in treatment of asthma in general practice.

The symptoms of many asthmatic patients are poorly controlled, and there are several reasons why this may be so. Doctors fail to find out about symptoms that asthmatic patients are experiencing. Doctors wrongly assume that regular use of bronchodilators in small doses is satisfactory treatment for asthma and that taking high doses of bronchodilator in an asthma attack may be dangerous. Doctors think that inhaled steroids may be dangerous and are reluctant to use them in effective doses. Doctors do not check that patients can use their inhalers properly and do not make enough use of large volume spacers, the best available method for giving inhaled asthma treatment. Doctors undermine patients'' confidence in advice on treatment by failing to ensure that consistent advice is given and often make the management of asthma more troublesome for the patient than the symptoms of asthma.     

Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs)

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."     

The Abbreviated Impactor Measurement (AIM) Concept: Part 1—Influence of Particle Bounce and Re-Entrainment—Evaluation with a “Dry” Pressurized Metered Dose Inhaler (pMDI)-Based Formulation

The abbreviated impactor measurement concept is a potential improvement to the labor-intensive full-resolution cascade impactor methodology for inhaler aerosol aerodynamic particle size distribution (APSD) measurement by virtue of being simpler and therefore quicker to execute. At the same time, improved measurement precision should be possible by eliminating stages upon which little or no drug mass is collected. Although several designs of abbreviated impactor systems have been developed in recent years, experimental work is lacking to validate the technique with aerosols produced by currently available inhalers. In part 1 of this two-part article that focuses on aerosols produced by pressurized metered dose inhalers (pMDIs), the evaluation of two abbreviated impactor systems (Copley fast screening Andersen impactor and Trudell fast screening Andersen impactor), based on the full-resolution eight-stage Andersen nonviable cascade impactor (ACI) operating principle, is reported with a formulation producing dry particles. The purpose was to investigate the potential for non-ideal collection behavior associated with particle bounce in relation to internal losses to surfaces from which particles containing active pharmaceutical ingredient are not normally recovered. Both abbreviated impactors were found to be substantially equivalent to the full-resolution ACI in terms of extra-fine and fine particle and coarse mass fractions used as metrics to characterize the APSD of these pMDI-produced aerosols when sampled at 28.3 L/min, provided that precautions are taken to coat collection plates to minimize bounce and entrainment.     

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.     

Clinical trial design in chronic obstructive pulmonary disease: current perspectives and considerations with regard to blinding of tiotropium

Randomised, double-blind, controlled trials are considered the gold standard for evaluating a pharmacological agent, as they minimise any potential bias. However, it is not always possible to perform double-blind trials, particularly for medications delivered via specific devices, e.g. inhalers. In such cases, open-label studies can be employed instead. Methods used to minimise any potential bias introduced by open-label study design include randomisation, crossover study design, and objective measurements of primary efficacy and safety variables. Concise reviews analysing the effect of blinding procedures of comparator drugs on outcomes in respiratory trials are limited. Here, we compare data from different chronic obstructive pulmonary disease trials with once-daily indacaterol versus a blinded or non-blinded comparator. The clinical trial programme for indacaterol, a once-daily, long-acting β₂-agonist, used tiotropium as a comparator either in an open-label or blinded fashion. Data from these studies showed that the effects of tiotropium were consistent for forced expiratory volume in 1 second, an objective measure, across blinded and non-blinded studies. The data were consistent with previous studies of double-blind tiotropium, suggesting that the open-label use of tiotropium did not introduce treatment bias. The effect of tiotropium on subjective measures (St George’s Respiratory Questionnaire; transition dyspnoea index) varied slightly across blinded and non-blinded studies, indicating that minimal bias was introduced by using open-label tiotropium. Importantly, the studies used randomised, open-label tiotropium patients to treatment allocation, a method shown to minimise bias to a greater degree than blinding. In conclusion, it is important when reporting a clinical trial to be transparent about who was blinded and how the blinding was performed; if the design is open-label, additional efforts must be made to minimise risk of bias. If these recommendations are followed, and the data are considered in the full knowledge of any potential sources of bias, results with tiotropium suggest that data from open-label studies can provide valuable and credible evidence of the effects of therapy.     

Aids to compliance with medication.

Elderly people may need to take several forms of medication, including tablets and capsules, inhalers, insulin, and eye drops. This article describes various aids that are designed to facilitate compliance.