Hydrofluoroalkane Pressurized Metered-dose Inhaler Research Articles

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide.

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

Industry Update: the Latest Developments in Therapeutic Delivery

This month’s article covers the time frame 16 February–15 March 2011, a period which saw the conclusion of the hard-fought-for takeover of Genzyme by Sanofi-aventis and the purchase of ProStrakan by Kyowa Hakko Kirin. There was good news for GlaxoSmithKline, Human Genome Sciences and sufferers of systemic lupus erythematosus with the US approval of Benlysta®, the first new treatment for this serious and difficult-to-treat condition for more than 50 years. There was bad news for SkyePharma when AstraZeneca decided to discontinue production of Pulmicort® (budesonide) hydrofluoroalkane pressurized metered dose inhaler, developed by SkyePharma, due to unsolved, complex manufacturing issues. Finally, progress towards an EU-wide single patent took a massive leap forward when proposals were approved by the European Parliament and the Council of the EU, only to be knocked back when the European Court of Justice ruled that plans to create an EU-wide patent court structure were not compatible with EU law. As ever, the material for this article has been sourced mainly from company websites and press releases.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide.

A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

Treatment of Persistent Asthma With Symbicort® (Budesonide/Formoterol Inhalation Aerosol): An Inhaled Corticosteroid and Long-Acting β2-Adrenergic Agonist in One Pressurized Metered-Dose Inhaler

Objective. Budesonide/formoterol inhalation aerosol (Symbicort® AstraZeneca, Wilmington, Delaware) is an inhaled corticosteroid (ICS) and long-acting β2-adrenergic agonist (LABA) combination administered twice daily via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) approved in the United States for the long-term maintenance treatment of persistent asthma in patients ≥12 years of age whose asthma cannot be controlled by an ICS alone. The objective was to review efficacy, safety, and pharmacogenetic data on budesonide/formoterol pMDI in the treatment of persistent asthma. Methods. The authors searched PubMed and respiratory meeting databases to identify asthma studies of budesonide/formoterol pMDI. Studies involving traditional and patient-reported outcomes, safety, tolerability, or pharmacogenetics were included. Results. In two 12-week pivotal trials in adolescents and adults, treatment with budesonide/formoterol pMDI 160/4.5 μg × 2 inhalations (320/9 μg) twice daily for moderate to severe persistent asthma or 80/4.5 μg × 2 inhalations (160/9 μg) twice daily for mild to moderate persistent asthma, demonstrated greater efficacy and similar tolerability compared with placebo and the same nominal dose of its monocomponents. Comparisons with formoterol dry powder inhaler (DPI) for predose forced expiratory volume in one second (FEV1) and with budesonide pMDI for 12-hour mean postdose FEV1 demonstrated the anti-inflammatory and bronchodilatory contributions of budesonide and formoterol, respectively. Evaluations of patient-reported outcomes, including asthma-specific quality of life and treatment satisfaction, further supported the clinical benefits of budesonide/formoterol pMDI. In a 52-week tolerability study of patients aged ≥12 years, budesonide/formoterol pMDI was delivered at up to double the maximum dose (640/18 μg twice daily) and demonstrated a safety profile similar to that of budesonide (640 μg twice daily), with no unexpected pattern of abnormalities. Additional studies reported that budesonide/formoterol pMDI 320/9 μg twice daily and fluticasone propionate/salmeterol DPI 250/50 μg twice daily have similar efficacy and tolerability, with significantly more patients achieving ≥15% improvement in FEV1 within 15 minutes with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI. Moreover, inheritance of the Gly16Arg polymorphism of the β2-adrenergic receptor does not appear to affect clinical outcomes with budesonide/formoterol pMDI. Conclusion. Budesonide/formoterol pMDI administered twice daily is effective and generally well tolerated in patients whose asthma is not well controlled on ICS alone.

Budesonide/formoterol pressurized metered-dose inhaler for patients with persistent asthma

The combination of budesonide and formoterol administered in one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) is approved in the United States in two dosage strengths (budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations [160/9 microg] or 160/4.5 microg x 2 inhalations [320/9 microg]) in a fixed-dose, twice-daily regimen for the treatment of patients > or =12 years old with persistent asthma not adequately controlled with an inhaled corticosteroid (ICS) alone. This article reviews the clinical profile of budesonide/formoterol pMDI in patients with persistent asthma, including information on pharmacogenetics, efficacy, and tolerability. Studies of budesonide/formoterol pMDI in patients with asthma were identified through PubMed and respiratory meeting abstract databases. Budesonide/formoterol pMDI 160/9 microg has shown a rapid onset (within 15 minutes) of clinically significant bronchodilation that is faster than fluticasone propionate/salmeterol dry powder inhaler (DPI) 250/50 microg (within 30 minutes). The efficacy and tolerability profile of budesonide/formoterol pMDI 320/9 microg was similar to fluticasone propionate/salmeterol DPI 250/50 microg and budesonide/formoterol DPI 320/9 microg in adults and adolescents with persistent asthma. Short-term (12-week) and long-term (6- to 12-month) studies have established greater efficacy and similar tolerability of budesonide/formoterol pMDI compared with its monocomponents and placebo in patients with mild/moderate or moderate/severe persistent asthma. Studies evaluating patient-reported outcomes, including health-related quality of life and patient satisfaction with treatment, further support the benefits of budesonide/formoterol pMDI in patients with persistent asthma. In summary, budesonide/formoterol pMDI is an effective, well-tolerated treatment option for patients with persistent asthma for whom ICS/long-acting beta2-adrenergic agonist combination therapy is appropriate.

In Vitro Drug Delivery Performance of a New Budesonide/Formoterol Pressurized Metered-Dose Inhaler

A combination of the corticosteroid budesonide and the long-acting beta2-adrenergic agonist formoterol is available in the United States in a single hydrofluoroalkane pressurized metered-dose inhaler (pMDI) for treatment of persistent asthma. The in vitro performance of the product, including delivered dose uniformity, aerodynamic particle size distribution, and dose proportionality, was evaluated. Both marketed formulations of the product were assessed (budesonide/formoterol 80/4.5 microg and 160/4.5 microg). Delivered dose was determined throughout the canister life using an automated dose delivery test method, and aerodynamic particle size distribution was evaluated using an Andersen Cascade Impactor-both in six batches of the product. Proportionality was assessed in 16 batches across three formulation strengths of budesonide, including a development formulation of 40/4.5 microg. Budesonide/formoterol pMDI provided a consistent delivered dose, with a mean value within +/-15% of the label claim for both actives. All individual results were within +/-20% of label claim. Mean fine particle dose (dose fraction <4.7 microm) was 59 and 68% for budesonide and formoterol, respectively. Delivered dose of budesonide was proportional to labeled dose, and fine particle dose was slightly less than proportional. Changes in budesonide content did not affect formoterol dose. Budesonide/formoterol pMDI provides a consistent delivered dose with an appropriate respirable fraction for therapeutic effectiveness. The product satisfies the performance requirements of current U.S. pharmacopeial and regulatory standards for pharmaceutical pMDI products.

Efficacy and Tolerability of Budesonide/Formoterol in One Hydrofluoroalkane Pressurized Metered-Dose Inhaler in Patients with Chronic Obstructive Pulmonary Disease

Background: Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study.Objective: This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD.Methods: This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 μg × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); formoterol DPI 4.5 μg × two inhalations (9 μg); or placebo.Main outcome measures: The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1.Results: Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001). The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p ≤ 0.004). Both budesonide/formoterol doses were more effective than placebo (p ≤ 0.006) for controlling dyspnoea and improving health status (St George’s Respiratory Questionnaire). All treatments were generally well tolerated. The incidence of pneumonia was not different for active (3.4–4.0%) and placebo (5.0%) groups.Conclusions: Budesonide/formoterol pMDI (320/9 μg and 160/9 μg) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD. Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co-primary variables compared with formoterol DPI 9 μg. Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo.Electronic Supplementary MaterialSupplementary material is available for this article at 10.2165/00003495-200969050-00004 and is accessible for authorized users.

Comparison of the Bronchodilating Effects of Formoterol and Albuterol Delivered by Hydrofluoroalkane Pressurized Metered-Dose Inhaler

To compare the onset of bronchodilation with a new formoterol hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) with albuterol (salbutamol) HFA pMDI. Thirty patients with stable mild or moderate asthma (23 using inhaled corticosteroids, mean FEV(1) 82% of predicted, >or=15% reversibility to terbutaline 1mg after 30 minutes) received formoterol HFA (Oxis) 2 x 4.5microg, albuterol HFA (Ventoline) Evohaler) 2 x 100microg, or placebo at three separate visits in this randomized, double-blind, double-dummy, three-way crossover study. FEV(1) was measured before and 3, 10, 20, 30 and 60 minutes after inhalation. Change in FEV(1) at 3 minutes after inhalation was the primary variable. Mean baseline FEV(1) was stable on all study days (range 2.92-2.94L). FEV(1) values at 3 minutes were: formoterol 3.22L (8% increase), albuterol 3.23L (9% increase) and placebo 2.99L (both p < 0.001 vs placebo). Maximum FEV(1) increased similarly with formoterol and albuterol, with no differences observed between the active treatments at any time point. Patients rated treatment effective at 3 minutes in 15 of 30, 19 of 30 and 7 of 30 cases with formoterol, albuterol and placebo, respectively. All treatments were well tolerated. In stable, mild, or moderate asthma, formoterol 9microg and albuterol 200microg, both by HFA pMDI, provided equally rapid and effective bronchodilation.