Pharmacokinetic comparison of beclomethasone dipropionate extrafine aerosol from two inhaler devices in children with asthma

OBJECTIVE: The primary objective was to test the comparability of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized extrafine solution formulation in two inhalation devices in children with asthma. One inhaler was actuated using the press and breathe (P&B) technique and the other was breath-actuated (AH); both inhalers used HFA-134a as propellant. METHODS: Eighteen children aged between 9 years and 12 years entered and completed the study; written informed consent was obtained from all patients and their legal guardians. Each patient received, according to a randomized three-period crossover design, 200 microg BDP as four inhalations from 50 microg/actuation P&B, 200 microg BDP as four inhalations from 50 microg/actuation AH, and 400 microg BDP as four inhalations from 100 microg/actuation AH. Each patient was instructed on the proper use of each device once, at the screening visit. Patients self-administered all inhalations at the same time of day during the study without further coaching. Blood samples were collected for 24 h during each period to assay for the presence of BDP and metabolites. The log-transformed pharmacokinetic data were compared using a confidence-interval approach. RESULTS: Almost all the BDP-derived material in the plasma was the active metabolite beclomethasone 17-monopropionate; pharmacokinetic analyses were only performed for this metabolite. The ratios each of the pharmacokinetic parameters maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), between the AH and P&B inhaler devices, were 0.94 and 1.1, respectively, and the corresponding 95% confidence intervals demonstrated comparability of the devices. Dose proportionality of C(max) and AUC between the 200-microg and 400-microg doses was similarly shown. About twice as many inhalation errors occurred during the P&B administration as during the AH periods, but the incidence was still low and did not result in any change in pharmacokinetics. CONCLUSION: The rate and extent of drug absorption was comparable from the P&B and AH inhaler devices in children with asthma. Dose proportionality was also observed.     

Metered-dose inhaler add-on devices: an in vitro evaluation of the BronchoAir inhaler and several spacer devices.

Spacer devices minimize the drug deposition in the oropharyngeal region as they retain between 30% and 50% of the nominal drug dose. Additionally, they should increase the fine particle fraction of the emitted aerosol. A new effort to increase the lung deposition was the design of a new actuator, the BronchoAir inhaler, (BronchoAir Medizintechnik GmbH, Munich, Germany). This study was carried out to evaluate the usefulness of this new actuator device by comparing its fine particle fraction with that emitted with the standard actuators and with spacer devices. The fine particle fraction's of commercially available metered dose inhalers (MDIs) marketed with specific spacers were determined using a multistage liquid impinger (MSLI). The effect of the BronchoAir inhaler on fine particle fractions was quite dependent on the formulation causing a decrease as great as 43% with Beclomet forte (beclomethasone-17, 21-dipropionate [BDP]) and an increase as great as 35% with Arubendol (salbutamol) but causing a difference of less than 20% with the other six tested formulations. Deposition in the upper stages of the impinger was sometimes higher than it was for the standard actuator. Spacer devices decreased the deposition in the upper stages of the impinger significantly, and in some cases, the fine particle fractions were also decreased. Varying the spacer design showed the superiority of large-volume open spacers compared with spacers with other designs.     

Use of mometasone furoate administered via a dry powder inhaler in the treatment of asthma

Abstract

Background:

Inhaled corticosteroids (ICSs) are effective controller medications that treat the chronic inflammation of asthma. The goal of asthma treatment is to improve lung function, symptoms, and the ability to perform daily activities, while decreasing the risk of exacerbations. Mometasone furoate delivered via a dry powder inhaler (MF-DPI) is indicated for once-daily maintenance treatment of asthma in patients as young as 4 years old.     

布地奈德/福莫特罗吸入剂治疗哮喘的疗效和安全性

目的：比较布地奈德/福莫特罗吸入剂复方制剂和布地奈德吸入剂＋福莫特罗吸入剂治疗哮喘的疗效和安全性.方法：采用多中心随机开放活性药物对照研究,320例患者随机分为A,B两组,A组（布地奈德/福莫特罗吸入剂组,B/F组）158例,B组（布地奈德吸入剂＋福莫特罗吸入剂组,B＋F组）162例.主要疗效指标为晨间呼气蜂流速（mPEF）,次要疗效指标为夜间呼气峰流速（ePEF）、日间哮喘症状、短效β2受体激动剂吸入次数、夜间憋醒次数和随访时肺功能指标,并记录不良事件.结果：两组开始治疗后mPEF和ePEF明显升高,日间哮喘症状、短效β2受体激动剂吸入次数和夜间憋醒次数明显下降,变化值两组之间无显著性差异.肺功能变化两组之间差异也无显著性.两组中不良事件的发生率低,且在两组间相似.结论：布地奈德/福莫特罗吸入剂复方制剂与布地奈德吸入剂＋福莫特罗吸入剂两药联用疗效相似,耐受性良好.     

Inspiratory flow rates through a novel dry powder inhaler (Clickhaler) in pediatric patients with asthma.

Inspiratory flow profiles through a novel dry powder inhaler (DPI) (Clickhaler; Innovata Biomed Ltd, St. Albans, UK) were recorded in 17 pediatric patients (aged 7-16 years) with stable mild to moderate asthma. Most patients (n = 14) could generate high peak inspiratory flows (PIFs) (> 60 L/min) and high flows early in the flow profile. These flows have been shown to be adequate to deaggregate and deliver micronized drug with this delivery system.     

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind,randomized, placebo- and active-controlled trial

ABSTRACT

Objective: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173).

Research design and methods: Multicenter, randomized, double-blind 28‐day study of QID levalbuterol 90?µg, racemic albuterol 180?µg, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV₁ from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV₁ percent change from pre-dose curve and peak % predicted FEV₁. Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms.

Results: Levalbuterol significantly improved the least square mean peak percent change in FEV₁ compared with placebo (levalbuterol 25.6% ± 1.3% [p < 0.001]; racemic albuterol 21.8% ± 1.8% [p = ns]; placebo 16.8% ± 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (?p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV₁ < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (?p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT_c‐F that were similar to placebo.

Conclusions: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4–11 years with a safety profile that was similar to placebo.     

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173). RESEARCH DESIGN AND METHODS: Multicenter, randomized, double-blind 28-day study of QID levalbuterol 90 microg, racemic albuterol 180 mug, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV(1) from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV(1) percent change from pre-dose curve and peak % predicted FEV(1). Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms. RESULTS: Levalbuterol significantly improved the least square mean peak percent change in FEV(1) compared with placebo (levalbuterol 25.6% +/- 1.3% [p < 0.001]; racemic albuterol 21.8% +/- 1.8% [p = ns]; placebo 16.8% +/- 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV(1) < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT(c-F) that were similar to placebo. CONCLUSIONS: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4-11 years with a safety profile that was similar to placebo.     

The kinetics of cohesive powder de-agglomeration from three inhaler devices

Purpose

The purpose of the current investigation is to understand the kinetics of de-agglomeration (k_d) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180 l min⁻¹) from three dry powder inhaler devices (DPIs), Rotahaler^® (RH), Monodose Inhaler^® (MI) and Handihaler^® (HH).

Results

Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 μm, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k_d), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k_dvs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k_d was highest from RH and lowest from MI. Differences in k_d between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure.

Conclusion

This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants.     

The influence of inhaler selection on efficacy of asthma therapies

Many different devices are available to aid inhalational drug delivery. Although each device is claimed to have advantages over its rivals, the evidence to support greater efficacy of a particular device is scanty. Most comparative studies are underpowered or flawed in their design. They may use inappropriate end-points, or involve healthy subjects, whose response may be very different from the patient with acute severe asthma. The dosage of drug used in a trial may be at the shallow part of the dose-response curve, masking differences in devices. Only in a few cases have clinical trials detected a significant difference between devices, and trials have rarely taken patient preference into account. The most efficacious device in practice is likely to be the one that the patient will use regularly and in accordance with a health care workers' recommendations.     

Inhaler devices for asthma

Inhalation therapy is now the mainstay of treatment for asthma but for many patients such treatment is still not optimal. The delivered dose can vary widely between different delivery systems, and between patients, depending on how well they use a particular device. Many new inhaler devices are now available, and their competing promotional claims can confuse both prescribers and patients. In this article we review the devices marketed and discuss how to select the best one for a particular patient.     

Mometasone furoate dry powder inhaler for the treatment of asthma

Introduction: Asthma is a chronic inflammatory disease that causes significant morbidity and mortality. Inhaled corticosteroids are the preferred initial treatment for this disorder. Mometasone furoate dry powder is an inhaled corticosteroid that is approved for once-daily treatment of asthma in both adults and children as young as 4 years.

Areas covered: The goal of this paper is to review the clinical efficacy and safety of mometasone furoate dry powder inhaler for the treatment of asthma. A literature search using PubMed was done using the terms ‘mometasone furoate’, ‘inhaled corticosteroid’ and ‘asthma’, focusing on articles that highlighted clinical trials and addressed efficacy of the medication.

Expert opinion: Mometasone furoate dry powder inhaler has an excellent safety and efficacy profile. For patients with persistent asthma who require treatment with an inhaled corticosteroid, mometasone furoate is an excellent therapeutic choice.     

Mometasone furoate dry-powder inhaler for the control of persistent asthma

Mometasone furoate dry-powder inhaler (MF-DPI) is an inhaled corticosteroid (ICS) used for the treatment of persistent asthma in patients aged >or= 12 years. MF-DPI has low systemic bioavailability and high glucocorticoid receptor affinity compared with most other ICSs and modifies inflammatory mediators involved in the pathogenesis of asthma. MF-DPI, unlike other available ICSs, is approved for initiation as a once-daily in the afternoon (q.d. PM) regimen. Studies show that MF-DPI 200 or 400 microg q.d. PM treatment significantly improves lung function and symptom control in patients with mild, moderate or severe asthma. MF-DPI 400 microg q.d. PM is reported to be equivalent to fluticasone propionate 250 microg b.i.d. and beclometasone dipropionate 168 microg b.i.d. and more efficacious than budesonide 400 microg, b.i.d. or q.d. MF-DPI is generally well tolerated, with minimal effects on the hypothalamic-pituitary-adrenal axis.     

The analysis and prediction of functional robustness of inhaler devices.

The studies described in this paper were undertaken to develop a method for the quick analysis and prediction of robustness of inhaler devices, and to define a standard among inhaler devices against which the structural integrity of new innovations could be judged. In addition, an effort was made to correlate mechanical properties with product performance metrics. The effect of mechanical stresses, alone and in combination with elevated temperatures, on the in vitro performance of pressurized metered dose inhalers (pMDIs) was investigated. The innovator pMDI devices (Ventolin HFA, GlaxoSmithKline) tested proved to be functionally robust in response to extreme mechanical stresses, suggesting that they are appropriate standards on which acceptance criteria for new devices should be defined. The actuator seat where the valve stem is inserted was identified as the critical area of the pMDI. A comparison of innovator vs. generic albuterol MDIs revealed that generic products approved as "equivalent " to the innovator products by current standards are not necessarily equivalent in ruggedness. Finite-element models of the actuator seat of Ventolin HFA (polypropylene) and QVAR 40 (high-density polyethylene) (3M Healthcare Ltd.) capable of predicting mechanical failure of MDIs were established. The material properties as well as the actuator design influenced the operational limit of MDIs. Stress analysis using finite-element modeling could be effectively used for the selection of the optimal design and appropriate materials of construction, which could lead to the development of robust inhalers while shortening the product development cycle.     

Mometasone furoate dry-powder inhaler for the control of persistent asthma

Mometasone furoate dry-powder inhaler (MF-DPI) is an inhaled corticosteroid (ICS) used for the treatment of persistent asthma in patients aged ≥ 12 years. MF-DPI has low systemic bioavailability and high glucocorticoid receptor affinity compared with most other ICSs and modifies inflammatory mediators involved in the pathogenesis of asthma. MF-DPI, unlike other available ICSs, is approved for initiation as a once-daily in the afternoon (q.d. PM) regimen. Studies show that MF-DPI 200 or 400 μg q.d. PM treatment significantly improves lung function and symptom control in patients with mild, moderate or severe asthma. MF-DPI 400 μg q.d. PM is reported to be equivalent to fluticasone propionate 250 μg b.i.d. and beclometasone dipropionate 168 μg b.i.d. and more efficacious than budesonide 400 μg, b.i.d. or q.d. MF-DPI is generally well tolerated, with minimal effects on the hypothalamic-pituitary-adrenal axis.     

布地奈德气雾剂治疗儿童哮喘临床观察

目的：观察布地奈德（普米克）气雾剂治疗儿童哮喘的临床疗效。方法：首次吸入最小剂量为200μg/d，最大剂量μg/d，喘息控制后，在短期内减至200－400μg/d，以后根据临床症状，最高呼气峰流速值（PEF），布地奈德逐渐减至最小维持剂量。结果：治疗后与治疗前相比，经成组t检验，P均＜0．01，PEF％均有明显上升，结论：布地奈德气雾剂治疗儿童哮喘安全有效，方法简便。