Equivalent asthma control and systemic safety of inhaled budesonide delivered via HFA-134a or CFC propellant in a broad range of doses

Grzelewska-Rzymowska, Iwona; Małolepszy, J; Molina, M.; Sładek, Krzysztof; Zarkovic, J; Siergiejko, Zenon

doi:10.1016/j.rmed.2003.10.004

Cited by 16 publications

(7 citation statements)

References 16 publications

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“…A cumulative dosage schedule was selected to represent the self-administration of large doses of ␤ 2 -adrenoceptor agonist that may occur when a patient has a severe asthma attack. The Modulite™ HFA-propelled delivery system developed by Chiesi Farmaceutici used in this study has been successfully used to formulate other bronchodilatory agents, including budesonide and beclomethasone, providing equivalent asthma control to these medications delivered via CFC-propelled devices [4,6,7,[15][16][17] .…”

Section: Discussionmentioning

confidence: 99%

A Randomized, Double-Blind, Double-Dummy, Safety Crossover Trial Comparing Cumulative Doses up to 96 μg of Formoterol Delivered via an HFA-134a-Propelled pMDI vs. Same Cumulative Doses of Formoterol DPI and Placebo in Asthmatic Patients

et al. 2005

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Background: Formoterol’s effects on the cardiovascular system are well known, but whether these effects are altered by the reformulation of inhalers to replace CFC propellants with HFA propellants is not. Objectives: To evaluate the effect of cumulative doses up to 96 µg of formoterol delivered via an HFA-134a-propelled pMDI, on cardiac safety and the QTc interval, compared the same cumulative doses delivered via a DPI, in adult patients with moderate-to-severe asthma. Methods: This study was a multicenter, double-blind, double-dummy, placebo-controlled, three-period, crossover trial in which 22 patients with moderate-to-severe asthma received cumulative doses up to 96 µg of formoterol (12 + 12 + 24 + 48 µg) delivered via a pMDI or a dry power inhaler (DPI). Vital signs and fourteen 12-lead ECG measurements were taken at each clinic visit and at 5–10 days after the final drug administration. Results: An increase from baseline in QTc interval was observed with all formoterol treatment arms in a dose-dependent manner. The maximum increases were 56.3, 62.6 and 25.0 ms for the formoterol pMDI, formoterol DPI and placebo treatments, respectively. Heart rate was increased by 10.7, 14.9 and 6.5 bpm in the pMDI, DPI and placebo groups, respectively. Both formoterol treatments were also associated with a decrease in diastolic blood pressure compared with placebo. Conclusions: With respect to cardiovascular safety parameters, the administration of formoterol via a pMDI device is comparable to its delivery via a DPI.

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Section: Discussionmentioning

confidence: 99%

A Randomized, Double-Blind, Double-Dummy, Safety Crossover Trial Comparing Cumulative Doses up to 96 μg of Formoterol Delivered via an HFA-134a-Propelled pMDI vs. Same Cumulative Doses of Formoterol DPI and Placebo in Asthmatic Patients

et al. 2005

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“…This new, fl exible technology allows the manipulation of various components of the pMDI system (in particular the aerodynamic particle size and actuator orifi ce diameter which play key roles in lung deposition) to improve the dosing effi ciency of the inhalers [7][8][9] . Modulite ® technology is being used to reformulate a number of products and has already proven successful in beclomethasone dipropionate-and budesonide-containing inhalers [10][11][12][13] .…”

Section: Discussionmentioning

confidence: 99%

A Randomized, Double-Blind, Double-Dummy, Single-Dose, Crossover Trial Evaluating the Efficacy and Safety Profiles of Two Dose Levels (12 and 24 μg) of Formoterol-HFA (pMDI) vs. Those of a Dose Level (24 μg) of Formoterol-DPI (Foradil<sup>®</sup>/Aerolizer<sup>™</sup>) and of Placebo (pMDI or Aerolizer) in Moderate to Severe Asthmatic Patients

Bousquet

Guenolé²,

Duvauchelle³

et al. 2005

Respiration

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Background: Chlorofluorocarbons (CFCs) have traditionally been used as propellants in pressurized metered-dose inhalers (pMDIs), which are often used to deliver drugs to the lungs for the treatment of reversible obstructive airways diseases. However, CFCs are harmful to the environment and need to be phased out. In response to that phase-out of environmentally harmful CFCs, the pharmaceutical industry is developing a new generation of pMDI formulations for the inhaled treatment of asthma. These formulations contain hydrofluoroalkanes (HFAs) in redesigned metered-dose inhalers. Objectives: This study primarily sought to establish clinical equivalence between a new HFA-formulated formoterol pMDI and the conventional formoterol DPI in the treatment of patients with moderate-to-severe asthma. Methods: We enrolled 51 patients aged 18–70 years old who had stable persistent asthma. All patients were randomized to receive a single dose of each of the following 4 treatments in a double-blind, crossover manner: formoterol HFA pMDI 24 µg, formoterol HFA pMDI 12 µg, formoterol DPI 24 µg or placebo. Results: Of the 51 patients randomised, 46 were evaluable for efficacy. The 12-hour average FEV₁ was 2.885, 2.746, 2.916 and 2.353 liters in the HFA 24-µg, HFA 12-µg, DPI 24-µg and placebo groups, respectively. Assessment of 95% CIs revealed that the HFA pMDI 24-µg and DPI formulations were equivalent and that both were significantly superior to placebo (p < 0.001). Improvements in lung function were also significantly superior to placebo in the HFA 12-µg group, but the effect was more moderate than that observed in the higher dose groups. Conclusions: This study indicates that the formoterol HFA-formulated pMDI provides equivalent bronchodilating effect to the formoterol DPI at the 24-µg dose.

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“…The pressurized-metered dose inhaler (pMDI) is the most widely used device for delivering a drug into the airway. It is well known as a safe, convenient, and reliable delivery system used by 80% of asthmatics worldwide 8,9 . The key components of the pMDI are the container, propellant, concentrated drug formulation, metering valve, and actuator.…”

Section: Introductionmentioning

confidence: 99%

“…However, their production has been phased out under the Montreal protocol due to CFCs causing a depletion of ozone in the stratosphere 9,12 . Thus two new hydrofluo-roalkanes (HFAs), tetrafluoroethane (HFA 134a) and heptafluoropropane (HFA 227), have become the alternative propellants for use with pharmaceutical aerosols delivered in pMDIs.…”

Section: Introductionmentioning

confidence: 99%

“…Thus two new hydrofluo-roalkanes (HFAs), tetrafluoroethane (HFA 134a) and heptafluoropropane (HFA 227), have become the alternative propellants for use with pharmaceutical aerosols delivered in pMDIs. They have also similar advantages to CFCs for use in pMDIs and they do not damage the ozone layer 9,11,13 . However, their physicochemical properties, such as vapour pressure, polarity, and density are significantly different from CFCs 11 .…”

Section: Introductionmentioning

confidence: 99%

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Sukasame¹,

Boonme²,

Srichana³

2011

ScienceAsia

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The aim of this study was to develop budesonide as a suspension-based pressurized-metered dose inhaler (pMDI) using hydrofluoroalkanes (HFAs) propellants (HFA 134a, HFA 227, and HFA mixture) and stabilizing agents (oleic acid and sorbitan trioleate). A factorial design method was applied to investigate the effects of two factors (vapour pressure of the propellant system and concentration of stabilizing agents) on formulation performances. Each factor was studied in three levels. Twenty four designed formulations of budesonide suspension-based pMDI were prepared. The results indicated that the vapour pressure of the propellant system was an important factor that affected the content of the active ingredient (p < 0.05). The formulations containing HFA 134a (high level vapour pressure) gave drug contents above the maximum limit (> 120%), whereas the formulations containing HFA 227 (low level vapour pressure) gave low budesonide contents of approximately 50%. However, when a propellant mixture with intermediate vapour pressure was used, the budesonide contents were close to the acceptable range (80-120%). Consequently, the eight formulations containing the HFA mixture together with different types and concentrations of stabilizing agent were tested for their aerosol properties. The fine particle fraction measured by a twin-stage liquid impinger ranged between 32-38%. The mass median aerodynamic diameters obtained from the Andersen cascade impactor were approximately 3 µm for all formulations. No significant difference was found among those formulations. After 3 months of storage, the aerosol properties did not change, and good physical stability was achieved. The particulate budesonide was able to readily re-disperse in the HFA mixture and a homogeneous suspension could be maintained for up to 20 min.

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Equivalent asthma control and systemic safety of inhaled budesonide delivered via HFA-134a or CFC propellant in a broad range of doses

Cited by 16 publications

References 16 publications

A Randomized, Double-Blind, Double-Dummy, Safety Crossover Trial Comparing Cumulative Doses up to 96 μg of Formoterol Delivered via an HFA-134a-Propelled pMDI vs. Same Cumulative Doses of Formoterol DPI and Placebo in Asthmatic Patients

A Randomized, Double-Blind, Double-Dummy, Safety Crossover Trial Comparing Cumulative Doses up to 96 μg of Formoterol Delivered via an HFA-134a-Propelled pMDI vs. Same Cumulative Doses of Formoterol DPI and Placebo in Asthmatic Patients

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