Hydrofluoroalkane 134a Research Articles

Investigations into the Formulation of Metered Dose Inhalers of Salmeterol Xinafoate and Fluticasone Propionate Microcrystals

To investigate the aerosolization and behaviour of microparticles of salmeterol xinafoate (SX) and fluticasone propionate (FP) suspended in hydrofluoroalkane (HFA) propellant. Microcrystals of SX and FP were produced from poly(ethylene glycol) by antisolvent crystallization. The suspension behaviour and aerosolization of the microcrystals when formulated as metered dose inhalers (MDIs) in HFA 134a propellant was compared with that of microparticles produced by micronization (mSX and mFP) using a glass twin stage impinger and by laser light diffraction using a pressurized cell. FP microparticles underwent non-reversible aggregation in suspension as seen by a doubling in the volume median diameter compared to the raw material. The degree of aggregation of SX particles in suspension was found to decrease as the particle size of the original particles increased. However, because the SX aggregate size was lowest for the particles with the smallest initial size (mSX), the highest fine particle fraction (FPF) of SX was obtained from a suspension of mSX. The FPFs following aerosolization of FP suspensions were similar although the FPF was lowest for particles with the largest original size. The size of the aggregates in the HFA suspensions was found to correlate directly with the FPFs determined by impaction.

Computational Analyses of a Pressurized Metered Dose Inhaler and a New Drug–Aerosol Targeting Methodology

The popular pressurized metered dose inhaler (pMDI), especially for asthma treatment, has undergone various changes in terms of propellant use and valve design. Most significant are the choice of hydrofluoroalkane-134a (HFA-134a) as a new propellant (rather than chlorofluorocarbon, CFC), a smaller exit nozzle diameter and attachment of a spacer in order to reduce ultimately droplet size and spray inhalation speed, both contributing to higher deposition efficiencies and hence better asthma therapy. Although asthma medicine is rather inexpensive, the specter of systemic side effects triggered by inefficient pMDI performance and the increasing use of such devices as well as new targeted drug-aerosol delivery for various lung and other diseases make detailed performance analyses imperative. For the first time, experimentally validated computational fluid-particle dynamics technique has been applied to simulate airflow, droplet spray transport and aerosol deposition in a pMDI attached to a human upper airway model, considering different device propellants, nozzle diameters, and spacer use. The results indicate that the use of HFA (replacing CFC), smaller valve orifices (0.25 mm instead of 0.5 mm) and spacers (ID = 4.2 cm) leads to best performance mainly because of smaller droplets generated, which penetrate more readily into the bronchial airways. Experimentally validated computer simulations predict that 46.6% of the inhaled droplets may reach the lung for an HFA-pMDI and 23.2% for a CFC-pMDI, both with a nozzle-exit diameter of 0.25 mm. Commonly used inhalers are nondirectional, and at best only regional drug-aerosol deposition can be achieved. However, when inhaling expensive and aggressive medicine, or critical lung areas have to be reached, locally targeted drug-aerosol delivery is imperative. For that reason the underlying principle of a future line of "smart inhalers" is introduced. Specifically, by generating a controlled air-particle stream, most of the inhaled drug aerosols reach predetermined lung sites, which are associated with specific diseases and/or treatments. Using the same human upper airway model, experimentally confirmed computer predictions of controlled particle transport from mouth to generation 3 are provided.

Efficacy of Beclomethasone Dipropionate HFA 200 μg Once Daily in Chronic Obstructive Pulmonary Disease and Bronchial Asthma

The efficacy and safety of once-daily beclomethasone dipropionate (BDP; 200 microg), in combination with the propellant hydrofluoroalkane-134a (HFA) was compared with that of budesonide turbuhaler (BUD-TH) 400 microg twice daily and fluticasone propionate inhaler (FP-IH) 250 microg twice daily in 40 patients with bronchial asthma or chronic obstructive pulmonary disease. All patients had used inhaled corticosteroids for at least 1 month. On randomization, 20 patients were switched to HFA-BDP and 20 patients remained on their existing BUD-TH or FP-IH treatment. After 8 weeks, HFA-BDP demonstrated a greater improvement in spirometric values, respiratory symptoms and beta2-agonist use. No significant local adverse effects were observed. Blood cortisol levels remained in the normal range in both groups. We conclude that HFA-BDP (200 microg once-daily) offered more benefit in terms of clinical and spirometry indices than BUD-TH (400 microg twice daily) or FP-IH (250 microg twice daily) in patients with moderate asthma and chronic obstructive pulmonary disease.

Short‐term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydroflouroalkane‐134a

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.

Safety and clinical relief over 1 year with triamcinolone acetonide hydrofluoroalkane-134a nasal aerosol in patients with perennial allergic rhinitis

The intranasal corticosteroid triamcinolone acetonide (TAA) is an effective treatment for allergic rhinitis (AR). A new hydrofluoroalkane-134a (HFA)-propelled formulation (TAA-HFA) has been approved recently. This study assessed the safety and efficacy of TAA-HFA in patients with perennial AR over 1 year. A total of 396 patients aged 12-69 years with perennial AR (PAR) enrolled in this 1-year, open-label study. Patients received TAA-HFA, 220 microg, once daily for 2 weeks before adjusting their dose to 440 or 110 microg once daily as needed to control symptoms. Doses were standardized to 440 microg across all patients at approximately 4 months. Physical examinations, vital signs, and laboratory measurements were conducted at baseline, 6 months, and study end. Patient and physician global symptom evaluations were performed at visits 3-10. Patients recorded any adverse events (AEs) on daily diary cards. Of the 396 patients enrolled, 349 (88.1%) reported AEs. The most frequently reported AEs were pharyngitis, rhinitis, local reactions, headache, epistaxis, and sinusitis. Most AEs were mild to moderate in intensity; 34 patients discontinued because of AEs. There were no clinically relevant changes in physical examinations, vital signs, or laboratory measurements. A total of four serious AEs were reported; all were recorded as not related to study drug. Mean patient and physician scores of symptom relief showed significant relief from week 2 (visit 3) through the final visit. Long-term administration of TAA-HFA, 440 microg, exhibited a good safety and tolerability profile, while providing moderate-to-complete symptom relief as rated by patients and physicians.

Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study

Objective: This study compared the efficacy andtolerability of the combination of fluticasone propionate (FP) and salmeterol (SAL) delivered via a single hydrofluoroalkane (HFA) 134a metered-dose inhaler (MDI) with those of its 2 components alone delivered via a chlorofluorocarbon (CFC) MDI and placebo (PLA) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses (equivalent to FP 440–660 μg/d) of inhaled corticosteroids (ICSs). Methods: This was a randomized, double-blind,placebo-controlled, parallel-group study consisting of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period. Participants had to be ≥12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study. Patients had to have used ICS therapy for ≥3 months before the study and at a consistent dose for the previous month. Lack of asthma control was defined as a forced expiratory volume in 1 second (FEV 1) that was 40% to 85% of the predicted value. Patients could not enter the double-blind treatment period if they had 3 days when they required >12 puffs of rescue albuterol per day or >3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the randomization visit. Patients were randomized to receive one of the following treatments delivered via MDI twice daily for 12 weeks: FSC 220/42 μg HFA (2 inhalations of FSC 110/21 μg; 125 μg/21 μg ex-valve); FP 220 μg CFC (2 inhalations of FP 110 μg); SAL 42 μg CFC (2 inhalations of 21 μg); or 2 inhalations of PLA HFA. The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV 1 curve relative to the prerandomization baseline (FEV 1 AUC bl). The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV 1 at end point and the probability of not being withdrawn from the study due to worsening asthma. Tolerability assessments included electrocardiograms, routine clinical laboratory tests, vital signs, oropharyngeal examinations, and physical examinations. Adverse events were assessed at each clinic visit. Results: Thirty-two adolescent and 333 adult patientswere randomly assigned to receive double-blind treatment. The treatment groups were comparable at baseline with respect to demographic characteristics (mean age, 38–41 years; white race, 78%–88%) and pulmonary function (mean percent predicted FEV 1, 68%–69%; mean asthma symptom score, 1.6 [scale 0–5]; and mean daily albuterol use, 3.1 puffs). After 12 weeks of treatment, the mean FEV 1 AUC bl was significantly greater in patients who received FSC compared with those who received FP, SAL, or PLA (7.0, 3.6, 5.3, and 1.4 L-h, respectively; all comparisons, P ≤ 0.020). At end point, the mean change from baseline in morning predose FEV 1 for FSC was significantly greater than that for FP, SAL, and PLA (0.41, 0.19, 0.15, and −0.12 L; all comparisons, P ≤ 0.001). During 12 weeks of treatment, 7% of patients receiving FSC were withdrawn due to worsening asthma, compared with 24% of patients receiving SAL and 54% of patients receiving PLA ( P < 0.001); 11% of patients receiving FP were withdrawn due to worsening asthma. Treatment with FSC resulted in significant improvements in morning and evening peak expiratory flow compared with FP, SAL, and PLA (both, P < 0.001); need for rescue albuterol compared with FP and PLA ( P ⩽ 0.005); and asthma symptom scores compared with PLA ( P ⩽ 0.001). The tolerability of FSC was similar to that of FP or SAL alone. The incidence of possibly drug-related adverse events was generally similar across treatment groups, and the most common (occurring in ⩾ 2% of patients) were headache (1%–4%), throat irritation (1%–2%), candidiasis of the mouth/throat (0%–2%), unspecified oropharyngeal plaques (0%–2%), and palpitations (0%–2%). Conclusions: In these adolescent and adult patientswhose asthma was not controlled by medium doses of an ICS, FSC delivered via HFA 134a MDI (2 inhalations of 110/21-μg strength administered BID) was more effective in improving lung function than FP or SAL monotherapy or PLA. All treatments were well tolerated.

Pharmacokinetics of Beclomethasone Dipropionate in an Hydrofluoroalkane-134a Propellant System in Japanese Children with Bronchial Asthma

Hydrofluoroalkane-134a (HFA) has been shown to be a safe replacement for chlorofluorocarbons (CFCs) as a pharmaceutical propellant, with the advantage that it has no ozone-depleting potential. This is the first report of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized solution formulation using an HFA propellant system (HFA-BDP) in Japanese children with bronchial asthma. Plasma concentrations of beclomethasone 17-monopropionate (17-BMP),a major metabolite of BDP, following an inhaled dose of HFA-BDP (200 microg as four inhalations from 50 microg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters. The area under the concentration-time curve from time zero to the last quantifiable time (AUC(0-t)) was 1659 +/- 850 pg x h/mL (arithmetic mean +/- standard deviation (SD)), the maximum concentration observed (C(max)) was 825 +/- 453 pg/mL and the apparent elimination half-life (t(1/2)) was 2.1 +/- 0.7 hours. The time to reach Cmax Tmax was 0.5 hours in all patients. No special relationship was observed between these parameters and age or body weight. These parameters were compared with the previously reported parameters of American children with bronchial asthma. The Japanese/American ratio of the geometric means of each parameter was 1.36 for AUC(0-t), 1.04 for Cmax and 1.4 for t(1/2). The median of Tmax was 0.5 hours in American patients as well as Japanese patients. The pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma are reported for the first time and a similarity to those in American children is suggested.

The effects of polyvinyl alcohol on the in vitro stability and delivery of spray-dried protein particles from surfactant-free HFA 134a-based pressurised metered dose inhalers

The objective of the present study was to investigate the physical stability of spray-dried proteins within surfactant-free hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs) during prolonged storage. Two model proteins (lysozyme and catalase) were spray-dried and stabilised in the presence of excipients, and subsequently suspended within HFA 134a. The pMDIs were stored valve-up for 6 months at room temperature (ca. 25 °C). Activities of the proteins were determined using biological assays and the fine particle fraction of the pMDIs was measured using a twin-stage impinger. The biological activities of catalase and lysozyme were found to be preserved in the presence of sugars and/or 80% hydrolysed polyvinyl alcohol (PVA) during spray drying. In addition, suspending the stabilised proteins within HFA for up to 6 months had little effect on their activity. The aerosolisation performance of lysozyme or catalase formulations containing either sucrose or trehalose as stabilisers appeared to deteriorate as a function of storage time. However, those formulations containing PVA were found to generate the greatest fine particle fraction, which in some cases was up to 50%, and to possess excellent physical stability during storage. The results indicated that the presence of PVA in the spray-dried stabilised protein particles could enhance the physical stability of particles, when suspended in the surfactant-free HFA MDI formulations, without affecting the protein stability upon prolonged storage.

High-pressure aerosol suspensions—A novel laser diffraction particle sizing system for hydrofluoroalkane pressurised metered dose inhalers

In this study, a novel laser diffraction particle size analysis dispersion system, capable of sizing particles in situ within suspension hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs), was developed and tested. The technique was compared to four indirect particle sizing methods commonly used to determine the size of particles suspended in HFA pMDIs. The median volume diameter obtained using laser diffraction of both the salbutamol sulphate and fluticasone propionate suspended either in 2H, 3H-decafluoropentane or perfluoropentane (employed as surrogate propellants) was over one-order of magnitude larger than the particle sizes of the drugs suspended in HFA 134a. In contrast, the “in-flight” particle size using the Sympatec inhaler 2000 ® laser diffraction equipment undersized the particles, predicting higher delivery efficacy compared to the other sizing methods. However, the size of particles suspended in HFAs derived using the novel pressurised dispersion system, showed a linear correlation with the impaction results, r 2 = 0.8894 ( n = 10). The novel pressure cell sizing technique proved to be simple to use, has the ability to be automated and was accurate, suggesting it could be an essential tool in the development of new suspension-based pMDI formulations.

Systemic exposure to triamcinolone acetonide (TAA): Assessment of a new Hydrofluoroalkane-134a (HFA) propelled nasal aerosol

Systemic exposure to triamcinolone acetonide (TAA): Assessment of a new Hydrofluoroalkane-134a (HFA) propelled nasal aerosol

Salmeterol HFA is as effective as salmeterol CFC in children and adults with persistent asthma

In accordance with the Montreal Protocol 1987, initiatives to phase out and replace ozone-depleting chlorofluorocarbon (CFC) propellants with non-ozone-depleting propellants in metered-dose inhalers (MDIs) in the treatment of asthma and chronic obstructive pulmonary disease are underway. In view of this, two multi-centre, randomised, parallel-group, double-blind studies were conducted to compare the safety and efficacy of salmeterol xinafoate delivered by an MDI using the hydrofluoroalkane (HFA) 134a propellant with the licensed CFC formulation (Serevent) in asthmatic populations of children (4-11 years) and adults (12 years). Patients on a stable dose of inhaled corticosteroids with a scope for improvement based on mean morning peak expiratory flow (PEF) and symptoms were randomised to receive salmeterol HFA MDI 50 microg twice daily or salmeterol CFC MDI 50 microg twice daily for 12 weeks. The primary efficacy variable was mean morning PEF and secondary variables included other lung function parameters, symptom scores, use of relief medication and safety assessments. The difference between the treatments in adjusted mean morning PEF (salmeterol HFA-salmeterol CFC) were 2.5 and -3.2 L/min for per-protocol populations of children and adults, respectively. The lower limit of 95% confidence intervals for both populations was within the pre-defined limit (-15 L/min) set for non-inferiority. Similar results were observed in intent-to-treat (ITT) populations. In children, the two formulations resulted in a lack of any statistically significant difference in secondary efficacy parameters. A significant difference at endpoint in clinic forced expiratory volume in 1s was reported in favour of the HFA formulation in the adult population, although the magnitude of this effect was not considered clinically significant. The incidences of adverse events (AEs) were similar for both formulations and populations, and no safety concerns were generated. Together these data demonstrate salmeterol HFA MDI to be as effective as salmeterol CFC MDI in adults and children.

Beclomethasone versus placebo for chronic asthma

Background Inhaled beclomethasone dipropionate (BDP) has been, together with inhaled budesonide, the mainstay of anti‐inflammatory therapy for asthma for many years. A range of new prophylactic therapies for asthma is becoming available and BDP has been reformulated using a hydrofluoroalkane‐134a (HFA) propellant which is free from chlorofluorocarbon (CFC). Objectives The objectives of this review were to: (1) Compare the efficacy of BDP with placebo with both CFC and HFA propellants in the treatment of chronic asthma. (2) Explore the possibility that a dose response relationship exists for BDP in the treatment of chronic asthma. (3) To provide the best estimate of the efficacy of BDP as a benchmark for evaluation of newer asthma therapies. Search methods Electronic searches were current as of January 2003. Selection criteria Randomised parallel group design trials for a minimum period of four weeks, in children and adults comparing CFC‐BDP or HFA‐BDP with placebo in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. Data collection and analysis One reviewer extracted data; authors were contacted to clarify missing information. We analysed data with RevMan Analyses 1.0.2. Main results 60 studies recruiting 6542 participants met the inclusion criteria. CFC‐BDP (57 studies): In non‐oral steroid treated patients, at doses of 400mcg/day or less CFC‐BDP produced significant improvements from baseline in a number of efficacy measures compared with placebo, including forced expiratory volume in one second (FEV1) 360 ml (95% CI 260 to 460); FEV1 (% predicted) WMD 12.41% (95% CI 8.18 to 16.64) and morning peak expiratory flow rate (am PEF) WMD 35.95 L/min (95% CI 27.85 to 44.04). BDP also led to reductions in rescue beta‐2 agonist use compared with placebo of ‐2.32 puffs/d (95% CI ‐2.55 to ‐2.09) and reduced the relative risk (RR) of trial withdrawal due to an asthma exacerbation 0.25 (95% CI 0.12 to 0.51). Subgroup analyses based on treatment duration provide support to the proposal that a treatment period of greater than four weeks is required to realise a fuller treatment effect. In oral steroid treated patients BDP led to significantly greater reductions in oral prednisolone use WMD ‐4.91 mg/d (95% CI ‐5.88 to ‐3.94 mg/d) and greater likelihood of withdrawing oral steroid treatment RR 8.02 (95% CI 3.23 to 19.92). HFA‐BDP (3 studies): In non‐oral steroid‐treated patients, HFA‐BDP was significantly more effective than placebo in improving FEV1, morning and evening PEF, FEF25 to 75%, reduced asthma symptoms and beta2‐agonists daily consumption. Significant effects for such outcomes were apparent after six weeks of treatment. In oral steroid treated patients, HFA‐BDP improved significantly FEV1 and am PEF. The summary estimates for these outcomes suggested a high level of heterogeneity, and divergent aims of the studies may contribute to the variation we observed. Limited data on adverse events were reported. Authors' conclusions This review has quantified the efficacy of CFC‐BDP and HFA‐BDP in the treatment of chronic asthma and strongly supports its use. Current asthma guidelines recommend titration of dose to individual patient response, but the published data provide little support for dose titration above 400 mcg/d in patients with mild to moderate asthma. There are insufficient data to draw any conclusions concerning dose‐response in people with severe asthma.

Development and performance of a new hydrofluoroalkane (HFA 134a)-based metered dose inhaler (MDI) of salmeterol

In response to the Montreal Protocol, a salmeterol (Serevent) metered dose inhaler (MDI) has been developed containing the non-chlorofluorocarbon propellant, hydrofluoroalkane 134a (HFA), to replace the marketed Serevent chlorofluorocarbon (CFC) propellant MDI. This paper details the pharmaceutical assessment of salmeterol HFA MDI and confirms that this product meets the current Committee for Proprietary Medicinal Products regulatory requirements, and is comparable to the CFC MDI in product performance. Criteria investigated included fine particle mass (FPM), dose delivery and uniformity, priming requirements and simulated-use-testing. Dose delivery was unaffected by changing product orientation during storage. The mean dose delivered per actuation ranged from 21.3 to 22.4 microg, and all individual doses were within the +/-25% defined limits of the target ex-actuator dose of 21 microg. The FPM results, defined as the mass of particles between 1.1 and 4.7 microm in diameter (the sum of the mass deposited on stages 3-5 of the Andersen Cascade Impactor), were similar for the HFA and CFC products. The mean FPM values of the two HFA clinical batches were 8.7 and 10.1 microg, covering the values obtained during the development, and the one of the CFC clinical batch was 10.0 microg. Comparability in aerosol characteristics was also demonstrated when the salmeterol HFA inhaler was tested using a large volume spacer (Volumatic).

Novel method for the determination of solubility in aerosol propellants

A new on-line reverse-phase high-performance liquid chromatography method to determine the solubility of compounds in propellant-based metered-dose inhaler (MDI) formulations was developed. The new method uses a direct injection from an MDI vial into the port of a manual injector. The MDI vials were coupled with a filtration and injection assembly to filter the excess compound, and deliver the filtrate of the MDI vials to the injector port of the manual injector. A backpressure regulator was connected to the manual injector, to maintain the propellant in the liquid state after injection from the MDI vial. Phase separation studies were conducted to investigate the miscibility of hydrofluoroalkane 134a with different mobile-phase solvent compositions. Characterization of the new direct injection method was done by evaluating sample presentation and chromatography variables to determine the robust nature of the method. Beclomethasone dipropionate in ethanol/hydrofluoroalkane 134a was used as a model system for development. A chemically diverse set of nine compounds was used to evaluate solubility measurement reproducibility. Solubilities were determined at two different temperatures (25 and 37°C) and the average relative standard deviation for all of the solubility measurements was <4%.

Budesonide Modulite ®: Improving the changeover to CFC-free treatments

Inhaled corticosteroids have been recommended by national and international guidelines as the mainstay for anti-inflammatory treatment in patients with bronchial asthma. Inhaled corticosteroids are delivered by a variety of devices such as pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers. The choice of the devices is dependent on a number of clinical factors such as severity of the disease, ability of the patient to proper usage of the device and the preference of the patient and the doctor. The latter is not always based on strong arguments. Inhalation therapy for treatment of bronchial asthma is performed since more than 200 years using ‘‘asthma cigarettes’’. The first Jet-Nebulizers were brought up in the 1930s, and in 1956, the first CFC-containing pMDI was marketed (Riker Medihaler). These devices were mainly used to deliver inhaled beta-agonists and anticholinergics to the patient, with the benefit of rapid onset of action as compared to the traditional oral route. It took nearly 20 years to develop an inhaled corticosteroid with limited side effects due to a significant first pass metabolism. Dry powder inhalers were developed later. The majority of asthmatic patients is using pMDIs worldwide. The popularity of these devices is based on their design as they are easy to use, small and portable. pMDIs designed by different companies look much more alike than DPIs. The effect of a certain drug delivered by the respiratory route is dependent on a variety of different factors which amongst others are the ability of the patient to inhale correctly and to produce a sufficient inspiratory flow. Drug deposition and the local and systemic metabolism of the compound are important factors determining the effect and the side-effects. Recently, the technology to design and produce devices for respiratory delivery has improved markedly. However in contrast to the progress in inhaler technology, adherence and compliance to the recommended therapy with inhaled corticosteroids remain a serious problem which has to be minimized in order to ensure the clinical benefit of inhaled corticosteroids in patients with bronchial asthma. Chlorofluorocarbons (CFCs) have been used in many products such as refrigeration, plastics, nonmedical aerosol, etc. pMDIs traditionally have been formulated using CFC propellants 11 and 12. The emission of CFCs into the atmosphere is harmful to the ozone layer. This resulted in an Environmental Program under the auspices of the United Nations, and over 40 nations agreed to the Montreal protocol in 1987 for the reduction and later for the cessation of the use of CFCs. The production of CFCs was stopped in 1996 except for ‘‘essential uses’’. Essential uses included the manufacturing of pMDIs containing drugs for patients with airway diseases (asthma and COPD) and on therapy with pMDIs. The European Commission (Strategy for the Phase-Out of CFCs in Metered Dose Inhalers) decided later the criteria according to which CFC containing inhalers should be withdrawn. After years of research in this area, hydrofluoroalkane (HFA) 134a (norflurane) was selected as a ARTICLE IN PRESS

Multimodal particle size distributions emitted from HFA-134a solution pressurized metered-dose inhalers

The purpose of this research was to investigate the measurement and in vitro delivery implications of multimodal distributions, occurring near or in the respirable range, emitted from pressurized metered-dose inhalers (pMDIs). Particle size distributions of solution pMDIs containing hydrofluoroalkane-134a (HFA-134a) and ethanol were evaluated using 2 complementary particle-sizing methods: laser diffraction (LD) and cascade impaction (CI). Solution pMDIs were formulated from mixtures of HFA-134a (50%-97.5% wt/wt) and ethanol. A range of propellant concentrations was selected for a range of vapor pressures. The fluorescent probe, Rhodamine B, was included for chemical analysis. The complementary nature of LD and CI allowed identification of 2 dominant particle size modes at 1 and 10 micro m or greater. Increasing propellant concentrations resulted in increases in the proportion of the size distributions at the 1- micro m mode and also reduced the particle size of the larger droplet population. Despite significant spatial differences and time scales of measurement between the particle-sizing techniques, the fine particle fractions obtained from LD and CI were practically identical. This was consistent with LD experiments, which showed that particle sizes did not decrease with increasing measurement distance, and may be explained by the absence of significant evaporation/disintegration of larger droplets. The fine particle fractions (FPFs) emitted from HFA-134a/ethanol solution pMDI can be predicted on the basis of formulation parameters and is independent of measurement technique. These results highlight the importance of presenting particle size distribution data from complementary particle size techniques.

Electrostatic charge on spacer devices and salbutamol response in young children

Electrostatic charge on plastic spacer devices may affect the efficacy of inhaled drugs, but its consequences have never been evaluated in asthmatic children with airflow limitation. At the end of a positive metacholine challenge, 64 children (51.3±12.9 months, 32 boys, specific airway resistance (SRaw) 257.1±56.7% and forced expiratory volume in 1 s (FEV 1) 64.2±17.9% of the predicted value) inhaled one puff of hydrofluoroalkane-134a (HFA-134a) salbutamol (Ventoline ®), and 15 min later two other puffs (total dose of 300 μg), delivered through either a new static Babyhaler ® ( n=21), a detergent-coated, reduced static, Babyhaler ® ( n=20), or a metal NES-Spacer ® ( n=23) equipped with facemask. SRaw and FEV 1 were measured after each treatment and compared between groups by a Kruskal–Wallis test. The first 100 μg salbutamol induced a 151.7±43.9% decrease in SRaw and a 19.9±10.6% increase in FEV 1. Additional 200 μg salbutamol allowed a supplementary decrease of 35.1±25.7% in SRaw and increase of 12.1±11.8% in FEV 1, without significant difference between the spacer devices. Electrostatic charge on spacer devices does not affect bronchodilation with HFA-134a salbutamol in metacholine-challenged pre-school children. This could be in part explained by the use of supramaximal doses of salbutamol.

Extra-Fine Particles Improve Lung Delivery of Inhaled Steroids in Infants : A Study in an Upper Airway Model

The particles of a new hydrofluoroalkane-134a (HFA)-beclomethasone dipropionate (BDP) metered-dose inhaler (Qvar; 3M Pharmaceuticals; St. Paul, MN) are considerably smaller than those of chlorofluorocarbon (CFC)-BDP. This may improve lung deposition in infants who inhale nasally and have irregular breathing patterns and small airways. To compare the dose delivered to the lungs of HFA-BDP and CFC-BDP at different breathing patterns using an upper airway model of an infant. An anatomically correct upper airway model of a 9-month-old child with an open nasal airway was connected to an impactor and breathing simulator. HFA-BDP, 100 microg, and CFC-BDP, 100 micro g, were delivered to the model through a detergent-coated, small-volume spacer. The total dose leaving the model (lung dose), its particle size distribution, and median mass aerodynamic diameter (MMAD) were assessed during simulated tidal breathing with tidal volumes (VTs) of 50 mL, 100 mL, and 200 mL, and 30 breaths/min. Dose was expressed as percentage of nominal dose. Lung doses for HFA-BDP were 25.4%, 26.5%, and 30.7% compared with 6.8%, 4.8%, and 2.1% for CFC-BDP at VTs of 50 mL, 100 mL, and 200 mL, respectively. The dose of particles < 2.1 microm to the lung for HFA-BDP was 23 to 28% compared with 0.6 to 0.8% for CFC-BDP. The lung dose of CFC-BDP mainly consisted of particles between 2.1 microm and 4.7 microm. MMAD for HFA-BDP was 1.2 microm, and 2.6 to 3.3 microm for CFC-BDP depending on VT. The lung dose for CFC-BDP decreased significantly with increasing VT. HFA-BDP lung dose did not alter significantly with VT. In this infant model study, the use of HFA-BDP with a high dose of particles < 2.1 microm improves the dose delivered to the lungs substantially. Furthermore, the large proportion of extra-fine particles in HFA-BDP results in lung doses less dependent on breathing pattern compared with CFC-BDP.

One-Year Evaluation of the Safety and Efficacy of Ipratropium Bromide HFA and CFC Inhalation Aerosols in Patients with Chronic Obstructive Pulmonary Disease.

Ipratropium bromide (IB) is an established and effective first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A new IB metered-dose inhaler (MDI) using hydrofluoroalkane 134a propellant (IB HFA) has been developed as an alternative to the MDI containing chlorofluorocarbon (IB CFC). To compare the long-term safety and efficacy of IB HFA and IB CFC in patients with COPD. This was a randomised, open-label, parallel-group, 1-year, multi-centre trial. Primary endpoints included adverse events (AEs) and vital signs. Secondary endpoints included therapeutic response (>15% increase in forced expiratory volume in 1 second [FEV(1)] peak change from baseline), FEV(1) area under the response-time curve (AUC). Patients (n = 456) with moderate-to-severe COPD, who received either IB HFA (n = 305) or IB CFC (n = 151 ), both 42µg four times daily. There were no significant differences in the incidences of individual AEs between groups over the short and long term; respiratory disorders were the most common. The incidence of anticholinergic AEs possibly related to treatment was low (1.3% IB HFA, 0.7% IB CFC). Serious AEs occurred in 19.0% and 20.5%, and discontinuations due to AEs in 7.2% and 7.3%, of patients receiving IB HFA and IB CFC, respectively. Therapeutic bronchodilatory responses were achieved in 76-81% and 72-84% of patients, and AUC ranged from 0.117-0.148L and 0.117-0.174L, in patients receiving IB HFA and IB CFC, respectively. IB HFA had similar efficacy and tolerability to IB CFC over 1 year, supporting a seamless transition from the CFC MDI to the HFA MDI in both short- and long-term treatment.

Clinical equivalence between salbutamol hydrofluoroalkane pMDI and salbutamol Turbuhaler TM at the same cumulative microgram doses in paediatric patients

This study aimed to demonstrate equivalent efficacy and safety between salbutamol delivered via the HFA134a pMDI (Hydrofluoroalkane 134a pressurised Metered Dose Inhaler) and the Turbuhaler™ dry powder inhaler in asthmatic children. This was a randomised, double-blind, double-dummy, placebo-controlled, crossover study in 10 asthmatic children aged 6–15 years who demonstrated at least 10% reversibility of FEV 1 after inhaling 400 μg of salbutamol. On 5 single study days subjects received either placebo or cumulative doses of 100, 200, 400 and 800 μg of salbutamol at 30 minute intervals. Both devices were placebo on one study day, while each device was active on two study days. FEV 1 was measured before and 20 minutes after each dose. Heart rate was measured before spirometry. Mean FEV 1 and heart rate at each time point and the area under the dose response time curve (AUC) were analysed using ANOVA. FEV 1 increased similarly after cumulative doses of salbutamol on each of the study days, irrespective of device. Mean treatment difference in AUC was 0.01L.min (95%CI –0.05 to 0.08L). Heart did not differ at any dose. It is concluded that salbutamol delivery from a HFA pMDI and Turbuhaler™ is equivalent on a microgram basis in asthmatic children for efficacy and safety.