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The Montreal Protocol on Substances That Deplete the Ozone Layer was an example of an amazing international collaboration that has already led to improvements in the ozone layer, although the full effects will not be seen for decades. As part of the process, large numbers of medical aerosols were reformulated such that chlorofluorocarbons were replaced as propellants in pressurised metered dose inhalers (pMDIs) by new hydrofluoroalkane (HFA) propellants. This involved a massive commitment by the pharmaceutical industry to ensure that those with respiratory ill health continued to receive their medication in familiar but improved inhalers. However, these HFA propellants have a global warming effect, and this has led specialist societies and health service leaders to more recently call for prescribers and patients to consider switching from pMDIs to inhaler devices without propellants, although many patients will still need a pMDI for use in an emergency.1 Others have recently additionally drawn attention to the benefits of using small-volume HFA 134a pMDIs or those containing …

The aerosol particle size distributions of solution-based pressurized metered dose inhalers containing 15%w/w ethanol and different quantities of nonvolatile component (NVC) (drug and glycerol) were evaluated at 25°C and 55°C, using a custom-built heating rig that preheated air prior to aerosolization. Particle size distributions were assessed using an Andersen cascade impactor and mass‐weighted cumulative aerodynamic diameter distributions were compared to a theoretical model that predicts the final size distribution, based on initial droplet size, vapor pressure of the formulation containing HFA 134a and percent NVC. In general, the mass median aerodynamic diameter was proportional to NVC1/3, with experimental particle size distributions following theoretical values. However, when comparing theoretical vs. experimental data over the range of mass-weighted cumulative aerodynamic diameter distributions between 10 and 90%, the 55°C experimental measurements more closely fitted the theoretical equation when...

Life cycle assessment (LCA) evaluates the environmental impact of a product based on the materials and processes used to manufacture the item as well as the item’s use and disposal. The objective of this LCA was to evaluate and compare the environmental impact of a metered dose inhaler, specifically the Proventil® HFA inhaler (Merk & Co., Inc., Kenilworth, NJ, USA), and an electric nebulizer, specifically the DeVilbiss Pulmo-Aide® nebulizer (DeVilbiss, Port Washington, NY, USA). GaBi LCA software was used to model the global warming potential (GWP) of each product by using substantiated data and well-justified assumptions for the components, manufacturing, assembly, and use of both devices. The functional unit used to model each device was one dose of the active drug, albuterol sulfate. The inhaler’s GWP, 0.0972 kg CO2-eq, was greater than the nebulizer’s even when uncertain parameters were varied ±100×. During the use phase ofa the inhaler, which accounted for approximately 96% of the inhaler’s total GWP, HFA 134a is used as a propellant to deliver the drug. The total GWP for the electric nebulizer was 0.0294 kg CO2-eq assuming that the mouthpiece was cleaned in a dishwasher, while it was 0.0477 kg CO2-eq when the nebulizer mouthpiece was hand washed between uses. The GWP breakeven scenario between dishwashing and hand washing occurred when the mouthpiece accounted for 10% of the dishwasher load.

OBJECTIVE To assess the literature that evaluates how variations in metereddose inhaler (MDI) technique affect lung distribution for inhaled corticosteroids (ICSs) formulated as MDI suspensions and solutions. DATA SOURCES PubMed (up to November 2012) and Cochrane Library (up to November 2012) were searched using the terms metered-dose inhalers, HFA 134a, Asthma/*drug therapy, and inhaled corticosteroids. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION All articles in English from the data sources that assessed MDI technique comparing total lung distribution (TLD) of MDI solutions or suspensions formulated with ICSs were included in the review. Five relevant studies were identified. DATA SYNTHESIS Five controlled studies compared how variations in MDI technique affect TLD for ICS MDI solutions with suspensions. MDI solutions resulted in greater TLD compared with larger particle MDI suspensions. Delayed or early inspiration upon device actuation of MDI solutions resulted in less TLD than coordinated actuation, but with a 3- to 4-times greater TLD than MDI suspensions inhaled using a standard technique. A sixth study evaluated inspiratory flow rates (IFR) for small, medium, and large particles. Rapid and slow IFRs resulted in similar TLD for small particles, while far fewer particles reached the airways with medium and large particles at rapid, rather than slow, IFRs. CONCLUSIONS Based on the literature evaluated, standard MDI technique should be used for ICS suspensions. ICS MDI solutions can provide a higher average TLD than larger-particle ICS suspensions using standard technique, discoordinated inspiration and medication actuation timing, or rapid and slow IFRs. ICS MDI solutions allow for a more forgiving technique, which makes them uniquely suitable options for patients with asthma who have difficultly with MDI technique.

The goals of this study were to determine the solubility values of solid organic solutes in pure HFA-134a and in HFA-134a/ethanol cosolvent systems (0–20%, w/w), and to investigate the relationship between these solubilities and a solute's physico-chemical properties. A direct inject on-line HPLC method was used to determine the solubility of 21 solutes in HFA-134a/ethanol. The samples were allowed to equilibrate for at least 48 h. The filtered sample was injected directly on an analytical HPLC column through a manual injector interface, and analyzed at an appropriate solute wavelength via HPLC. The solutes display diverse physico-chemical properties and yielded solubility values that ranged over four orders of magnitude. In general, a linear–linear solubility relationship was observed as the fraction of ethanol increased. The effects on solubilization ranged from 1.3 to 99.4 times when 20% (w/w) ethanol was introduced, relative to pure HFA-134a. A regression equation utilizing a solute's hydrogen bonding potential resulted in a significant correlation to the slope obtained from a linear model for solubility in HFA-134a with 0–20% (w/w) ethanol, and may be useful for pre-formulation studies.

Our purpose was to evaluate metered dose inhaler (MDI) formulations of ciclosporin (cyclosporine) for aerodynamic properties, chemical stability and bioactivity. Ciclosporin formulations (0.1, 0.5 and 1.0% w/w) were prepared in hydrofluoroalkane (HFA) propellants (134a and 227) containing 3 and 6% ethanol. Aerodynamic properties of the MDI formulations were analysed using an eight-stage Andersen cascade impactor and respirable mass and non-respirable mass, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined from the impaction profiles. The chemical stability of 0.1% ciclosporin in HFA 227 containing 3% ethanol formulation stored at room temperature and 40°C was evaluated by HPLC at 0, 14, 30 and 90 days. The bioactivity of ciclosporin MDI formulations was evaluated by determining the ciclosporin-mediated inhibition of interleukin-2 (IL-2) release from human Jurkat cells stimulated with phorbol 12-myristate 13-acetate (PMA). As ethanol concentration increased from 3 to 6%, respirable mass decreased from 2.3 mg per five actuations to 0.04 mg per five actuations for HFA 227 formulations, and from 1.5 mg to 0.09 mg per five actuations for HFA 134a formulations. The MMAD for both HFA 134a and 227 formulations increased with an increase in ciclosporin concentration. HPLC analysis showed ciclosporin to be extremely stable in HFA 227 at room temperature and 40°C. Stimulation of Jurkat cells with PMA released significant amounts of IL-2, which was inhibited by ciclosporin in a dose-dependent manner. This study shows the feasibility of developing chemically stable and bioactive HFA-based MDI formulations of ciclosporin.

This randomized, double-blind, parallel-group study compared the efficacy and tolerability of as-required salbutamol 100μg administered from either a chlorofluorocarbon (CFC) pressurized metered dose inhaler (pMDI; Ventolin TM ) or from a non-CFC hydrofluoroalkane (HFA) 134a pMDI (Ventolin TM CFC-free) in patients with mild to moderate asthma. All patients ( n = 423) continued with their standard asthma therapy, and recorded their daily use of study medication, morning and evening peak expiratory flow (PEF) and symptom scores, throughout the 4-week treatment period. Clinic lung function was measured at 2-week intervals. The median daily use of inhaled study medication remained constant at four actuations per day throughout the study in both treatment groups and statistical analysis indicated that the two formulations were equivalent. Small improvements in both treatment groups were reported in mean morning and evening PEF, clinic forced expiratory volume in 1 sec and clinic PEF and there were no significant differences between the two groups. Both formulations were well tolerated. This study indicates that as-required salbutamol 100μg administered via a HFA 134a pMDI is as effective and safe as the currently available CFC-propelled formulation.

The phasing out of chlorofluorocarbons (CFCs) requires the development of an alternative non-ozone depleting propellant for use in pressurized metered dose inhalers (pMDIs). The present study assessed the effects on tolerability and efficacy of a switch from the currently available formulation containing the CFC propellants 11 and 12 to an alternative non-CFC formulation using the propellant hydrofluoroalkane (HFA) 134a in patients with mild to moderate asthma. After a 4-week run-in period during which patients received salbutamol 200 microg four times daily from a CFC pMDI, 547 patients were randomized to 12 weeks of treatment with salbutamol 200 microg four times daily administered from either an HFA 134a pMDI (Ventolin CFC-free; 277 patients) or CFC pMDI (Ventolin, 270 patients). At the end of this period, all patients then received a further 4 weeks of treatment with the same dose of salbutamol via a CFC pMDI (run-out period). On the basis that high doses of beta2-agonists are known to increase heart rate, change in heart rate was selected as the primary outcome variable. Small increases in heart rate were observed during the treatment period and these changes were comparable in both groups; the 90% confidence interval for the treatment differences was within the predefined limits for clinical equivalence (+/- 10 beats min(-1)). The incidence of adverse events was similar in both groups and there were no reports of paradoxical bronchospasm. Furthermore, daily PEF measurements showed comparability in terms of lung function. Symptom scores and use of additional bronchodilator were also similar in both groups. These results demonstrate that salbutamol (800 microg day(-1)), formulated with HFA 134a is equivalent to the current CFC formulation in terms of tolerability and efficacy.

This multi-national, double-blind, randomized, parallel-group study compared the efficacy and tolerability of fluticasone propionate 500 μg twice daily propelled either by the non-chlorofluorocarbon (CFC) propellant, hydrofluoroalkane (HFA) 134a, or the CFC propellants 11 and 12 used in the established pressurized metered dose inhaler (pMDI). The study period was 12 months and involved 412 subjects with moderate to severe asthma (HFA 134a pMDI: n = 203; CFC pMDI: n = 209). For the first 3 months, subjects kept a daily record card and attended the clinic every 4 weeks. Thereafter, they kept daily diaries for 2 weeks before each clinic assessment, which were performed at the end of 6, 9 and 12 months. Mean morning peak expiratory flow (PEF) increased during the first week in both treatment groups. By the end of week 12 the adjusted mean increase from baseline in morning PEF was 21 and 23 l min −1 in the HFA 134a and CFC pMDI groups, respectively, and this increase was maintained throughout the 12-month study period. Similar improvements were detected in other diary card parameters and in clinic lung function measurements. The two groups were shown to be clinically equivalent in terms of all efficacy variables and there were no differences in tolerability. There were few reports of low serum cortisol levels during the 12-month study period, and serum cortisol levels were similar at baseline and after 12 weeks and 12 months of treatment in the two groups. In conclusion, the new HFA 134a fluticasone propionate pMDI is as effective and safe as the established CFC fluticasone propionate pMDI when used at a dosage of 1 mg day −1 .

The phasing out of chlorofluorocarbons (CFCs) requires the development of an alternative non-ozone depleting propellant for use in pressurized metered dose inhalers (pMDIs). The present study assessed the effects on tolerability and efficacy of a switch from the currently available formulation containing the CFC propellants 11 and 12 to an alternative non-CFC formulation using the propellant hydrofluoroalkane (HFA) 134a in patients with mild to moderate asthma. After a 4-week run-in period during which patients received salbutamol 200μg four times daily from a CFC pMDI, 547 patients were randomized to 12 weeks of treatment with salbutamol 200μg four times daily administered from either an HFA 134a pMDI (Ventolin TM CFC-free; 277 patients) or CFC pMDI (Ventolin TM , 270 patients). At the end of this period, all patients then received a further 4 weeks of treatment with the same dose of salbutamol via a CFC pMDI (run-out period). On the basis that high doses of β 2 -agonists are known to increase heart rate, change in heart rate was selected as the primary outcome variable. Small increases in heart rate were observed during the treatment period and these changes were comparable in both groups; the 90% confidence interval for the treatment differences was within the predefined limits for clinical equivalence (± 10 beats min −1 ). The incidence of adverse events was similar in both groups and there were no reports of paradoxical bronchospasm. Furthermore, daily PEF measurements showed comparability in terms of lung function. Symptom scores and use of additional bronchodilator were also similar in both groups. These results demonstrate that salbutamol (800μg day −1 ), formulated with HFA 134a is equivalent to the current CFC formulation in terms of tolerability and efficacy.

1 This paper reviews the results of preclinical toxicology studies on HFA-134a carried out by Glaxo Research and Development Ltd. 2 A comprehensive range of studies was conducted in ani mal models suitable for the type of investigation. 3 The inhalation route of administration was used in all in vivo studies (with the exception of local tolerance and sensitisation studies) as patients will be exposed only to vapour during actuation of metered-dose inhalers. Cell cultures used for in vitro studies were also exposed to the vapour. 4 There was no mortality of rodents or dogs at extremely high vapour concentrations (81%v/v). 5 HFA-134a was considered not to be toxic or oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.

Six male and six female Sprague-Dawley rats were ventilated head-only for 1 h on a 15% atmosphere of 1,1,1,2-tetrafluoroethane (HFA-134a) in air in a magnetic resonance imaging spectrometer. Results from these dynamic 19F NMR studies suggest that a steady-state in vivo concentration of HFA-134a was approached at approximately 25 min into the exposure. Quantitative integration analysis using an external standard estimated this plateau to be 58.3 +/- 11.9 mg of absorbed HFA-134a per rat. The HFA-134a 19F NMR signal disappeared rapidly following removal of the test atmosphere, with an elimination half-life of 4.6 +/- 0.6 min in the male rats and 4.9 +/- 1.5 min in the female rats. The data suggest that there was no statistical difference between the sexes in amount absorbed or in elimination half-lives.

HFA-134a, a chlorine-free hydrofluoroalkane, was administered for 1 h daily to beagle dogs by means of a system for inhalation by face mask. In this 1-yr study, animals received atmospheric air, air containing an additional 12% nitrogen, or air containing a nominal 12% HFA-134a for 376 or 377 days. HFA-134a was rapidly absorbed into and cleared from the blood. There were no treatment-related clinical signs or effects on body weight, food consumption, ophthalmoscopy, heart function, respiratory rate, pulse rate, haematology, blood biochemistry, urine analysis, or postmortem findings. HFA-134a was considered to be nontoxic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhaler formulations.

Beclomethasone dipropionate (BDP) is a long-acting inhaled corticosteroid, used for the treatment of asthma, and as an inhalation therapy with HFA-134a. The sample studied by X-ray crystallography was grown in a mixture of the aerosol propellant HFA-134a, C2H2F4, and 200-proof ethanol. The formula of the crystalline material is C28H37ClO7·2C2H6O·C2H2F4. In the crystal structure, disordered solvent occupies a channel which is perpendicular to the BDP mol­ecules. The latter are are stacked together by hydrogen bonding.

The objective of this study was to investigate the stability and aerosolization of pressurized metered dose inhalers (pMDIs) containing thymopentin nanoparticles. Thymopentin nanoparticles, fabricated by a bottom-up process, were suspended in hydrofluoroalkane (HFA) 134a together with cineole and/or n-heptane to produce pMDI formulations. The stability study of the pMDIs obtained was carried out at ambient temperature for 6 months. The amount of thymopentin and the aerosolization properties of pMDIs were determined using high-performance liquid chromatography (HPLC) and a twin-stage impinger (TSI), respectively. Based on the results, thymopentin nanoparticles were readily suspended in HFA 134a with the aid of cineole and/or n-heptane to form physically stable pMDI formulations, and more than 98% of the labeled amount of thymopentin and over 50% of the fine particle fraction (FPF) of the pMDIs were achieved. During storage, it was found that for all pMDIs more than 97% of the labeled amount of thymopentin and FPF greater than 47% were achieved. Moreover, the size of thymopentin nanoparticles in propellant containing cineole and n-heptane showed little change. It is, therefore, concluded that the pMDIs comprising thymopentin nanoparticles developed in this study were stable and suitable for inhalation therapy for systemic action.

In this paper, we demonstrate that co-spray-drying a model protein with sodium carboxymethylcellulose (NaCMC) protects protein integrity during spray-drying, and that the resultant spray-dried powders can be successfully dispersed in hydrofluoroalkane (HFA) propellant to prepare pressurised metered dose (pMDI) formulations that exhibit high respirable fractions. The spray-dried powders were formulated as HFA-134a pMDI suspensions in the absence of any other excipients (e.g. surfactants) or co-solvents (e.g. ethanol). The in vitro aerosolisation profile of these systems was assessed using the twin stage impinger; fine particle fractions (FPF)or = 50% of the recovered dose were obtained. Following storage for five months, the aerosolisation performance was reassessed; the NaCMC-free formulation demonstrated a significant decrease in FPF, whereas the performance of the NaCMC-modified formulations was statistically equivalent to their initial performance. Thus, formulation of pMDI suspensions using NaCMC-based spray-dried powders is a promising approach for the pulmonary delivery of proteins and peptides.

HFA-134a blood levels from four clinical studies were combined to give a preliminary description of its population pharmacokinetics. HFA-134a was absorbed promptly and was eliminated with a half-life of 5.1 min.

To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a.Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity.Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 microm). The formulation was observed to maintain its performance over 6 months at 40 degrees C/75% RH and 16 months at 25 degrees C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD(4.7 microm) values approaching 400 microg can be delivered in a single inhalation.Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.

The purpose of this study was to evaluate the Malvern Spraytec® with inhalation cell attachment as a means of analyzing the particle size distribution of aerosols from pressurized metered dose inhalers (pMDIs). The aerosol particle size distribution of various commercially available, placebo, and experimental pMDI formulations was determined using Spraytec® under various experimental conditions and the relevant data were compared with the Andersen cascade impactor data. The Spraytec® volume median diameter (Dv 50) values for commercial chlorofluorocarbon‐ and hydrofluoroalkane (HFA)‐based pMDIs were respectively smaller and higher compared with their reported mass median aerodynamic diameter values. It was possible to obtain a close agreement between Spraytec® Dv 50 and the reported mass median aerodynamic diameter values for a solution‐type pMDI formulation, Qvar 50, by equilibrating the pMDI to 55°C before the measurement and using a 20‐cm throat extension. Incorporation of a nonvolatile solvent propylene glycol (PG) in placebo pMDIs (15% w/w ethanol, 0.5–20.0% w/w PG in HFA 134a) showed an increase in Dv 50 with increasing concentration of PG. Furthermore, it was possible to obtain a correlation ( R 2 = 0.8037) between Spraytec® and Andersen cascade impactor data for the experimental nimesulide‐pMDI formulations containing 0.1% w/w drug, 0.25–10% w/w PG, and 15% ethanol in HFA 134a. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:349–363, 2004

We report for the first time the deposition pattern in the respiratory tract of a metered dose inhaler formulated with hydrofluoroalkane (HFA) 134a, in comparison with an inhaler containing chlorofluorocarbon (CFC) 12. The inhalers delivered 125 μg fusafungine per metered dose, and deposition was assessed using the non-invasive technique of gamma scintigraphy. Preliminary in vitro validation studies showed that the 99m Tc tracer acted as a good marker for the distribution of fusafungine. The in vivo study was carried out in 10 healthy volunteers who each inhaled a single dose of radiolabelled fusafungine on two occasions. The majority of the dose from the HFA 134a and CFC 12 fusafungine formulations was deposited in the oropharynx (mean 65.7 and 64.3%, respectively), with an average of only 2.4 and 3.2% deposited in the lungs. It was concluded that the deposition pattern for the new fusafungine formulation with HFA 134a propellant is similar to that of the existing formulation containing CFC 12.

BACKGROUND: Secondary to phasing out chlorofluorocarbons (CFCs), the fluticasone propionate (FP) pressurized metered-dose inhaler has been formulated in a nonozone-depleting propellant, hydrofluoralkane (HFA) 134a.OBJECTIVES: To demonstrate equivalent efficacy and safety of FP 200 µg daily propelled by HFA 134a to FP 200 µg daily propelled by CFCs 11 and 12 over a four-week treatment period in pediatric asthmatic patients.METHODS: The study was multinational, randomized, double blind and of parallel group design. Eligible patients aged 16 years and younger were steroid naive or receiving 500 µg/day or less of beclomethasone dipropionate, budesonide or flunisolide, or 250 µg/day or less of inhaled FP. The primary efficacy variable was mean morning peak expiratory flow with equivalence determined if the 90% CIs for the treatment differences between groups were within ±15 L/min.RESULTS: Three hundred fifteen patients (mean age 9.3±2.8 years) were randomly assigned; 158 patients received FP HFA 134a and 157 patients received FP CFC. Over the four-week treatment period, mean morning peak expiratory flow increased from baseline in both groups (14 L/min and 17 L/min, respectively), with a mean treatment difference of -2 L/min. Equivalence was demonstrated between the groups (90% CI -6 to +3 L/min; P=0.589). Both formulations were well tolerated with no serious drug-related events.CCONCLUSIONS: FP propelled by HFA 134a has equivalent efficacy and comparable safety to FP propelled by CFC propellants at a microgram equivalent dose in pediatric asthmatic patients.

Five commercially available spacers were investigated to determine their influence on the percentage of drug retained in the spacer device, percentage fine particle fraction (FPF), percentage deposited in the induction port, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). Betamethasone valerate (BMV) and triamcinolone acetonide (TAA) were used as model drugs in the pressurized metered dose inhaler (pMDI) formulations containing the propellant HFA 134a. The BMV was dissolved in an ethanol/HFA 134a system, and the TAA was suspended in HFA 134a using ethanol as a dispersing agent. The metering chamber volume of the valve was either 50 microl or 150 microl. The spacer devices investigated included the ACE, Aerochamber, Azmacort, Easivent, and Ellipse spacers. Each spacer device was attached to an Andersen Cascade Impactor powered by a vacuum pump. Cascade impaction data were used to derive the percentage drug deposited in the induction port, MMAD, GSD, and FPF. The BMV particles emitted from the spacers were finer than the TAA particles because the dissolved drug precipitated as the cosolvent evaporated. The TAA particles had significantly larger MMADs because many undissolved drug particles were contained within each droplet following actuation. After evaporation of the liquid continuous phase, the suspended drug aggregated to form larger agglomerates than those particles precipitated from the BMV pMDI solution droplets. The addition of a spacer device lowered the MMAD to less than 4.7 microm for particles from both the BMV pMDI solution and the TAA pMDI suspension. The addition of a spacer device also lowered the percentage drug deposited in the induction port. The FPF was significantly increased when a spacer device was used. The MMAD significantly decreased when a spacer device was added for the two model drugs when using the 150-microl metering valves, but the difference was not statistically significant when the 50-microl valves were used (P < .05). The GSD was not influenced by the use of a spacer device. The use of a spacer device will enhance pMDI therapy by reducing the amount of drug deposited in the oropharyngeal region, which will lead to fewer instances of local and systemic side effects. In addition, the spacer devices investigated will allow a higher dose of drug to reach the deep lung, which may permit the use of lower dosage regimens with increased therapeutic efficacy.

This multi-centre, randomized, double-blind, double-dummy, parallel-group study was designed to investigate the hypothesis of equivalent efficacy and comparable safety of two inhaled presentations of salmeterol/fluticasone propionate combination product (SALM/FP) 50/100 microg administered twice daily to patients with mild-to-moderate asthma for 12 weeks. The delivery systems were a 25/50 microg strength hydrofluoroalkane (HFA) metered-dose inhaler (MDI) and a Diskus inhaler (50/100 microg strength). A third group received FP 100 microg twice daily via a chlorofluorocarbon MDI (50 microg strength). A total of 497 patients aged 11-79 years with reversible airways obstruction who were symptomatic on inhaled corticosteroid (ICS) therapy and had room for improvement in lung function were randomized to treatment in a double-blind, parallel-group design (SALM/FP MDI: n=165; SALM/FP Diskus: n=167; FP MDI: n=165) for 12 weeks. A total of 383 patients completed the study according to the protocol. According to the primary efficacy variable, increase in mean morning PEF over weeks 1-12, the two inhaled presentations of SALM/FP were clinically equivalent (adjusted mean increases 43 and 46 l min(-1); treatment difference 3 l min(-1); 95% confidence interval: -6 to 11 l min(-1)). Equivalence was also demonstrated by all secondary efficacy measures. The SALM/FP MDI was significantly superior to the FP MDI for increase in mean morning PEF (treatment difference 19 l min(-1); P

The objective of this study was to investigate moisture ingress into pressurized metered dose inhalers (pMDIs) containing hydrofluoroalkane (HFA) propellants and the consequences of this ingress. Moisture ingress into the pMDIs containing tetrafluoroethane (HFA 134a) or heptafluoropropane (HFA 227) was evaluated and modeled. The influence of water level in pMDIs on the stability of pMDIs containing triamicinolone acetonide (TAA) and beclomethasone dipropionate (BDP) in terms of particle growth, fine particle fraction, and drug solubility in the propellant system was evaluated using scanning electron microscopy, particle size analysis, single-stage impaction, and HPLC. The water level in HFA-containing pMDIs increased during storage and the process obeyed a diffusion model. HFA 134a had a greater tendency to take up moisture from the environment than did HFA 227. Unlike TAA, the propensity for particle growth of the suspended BDP in HFA propellants was significantly depressed by the increase in water level in the pMDIs. As a result, the fine particle fraction of the emitted BDP aerosols significantly increased as the water level in the HFA propellant was increased. Moisture ingress into pMDIs containing HFAs occurred during storage. The influence of the increased water level in pMDIs on the physical stability of the pMDI formulation and the dose delivery performance was a function of the composition of the internal lining of the container, the type of drug and propellant, and storage temperature.

A rapid synthesis of the chlorofluorocarbon replacement compound 1,1,1,2-tetrafluoroethane (HFA-134a) was identified and utilized to prepare 99 + % radiochemically pure [18F]HFA-134a in 20–35% radiochemical yield. Four rats were then exposed to no-carrier-added (NCA) [18F]HFA-134a and monitored via coincidence detection. Following withdrawal of the test atmosphere of [18F]HFA-134a, the me an half-life of [18F]HFA-134a in four rats was determined to be 7.8 ± 1.5 min following a 10 s exposure and 8.1 ± 1.7 minutes following a 10 min exposure.

HFA 134a (1,1,1,2-tetrafluoroethane) is a ‘non-ozone depleting’ candidate for use as a drug propellant in multi-dose inhalers (MDIs). A means for assuring the safety of such a compound for human use is to check mat there is no excessive or unexpected accumulation in the body and selected regions. HFA 134a has been labelled with fluorine-18 and used with a highly sensitive whole-body γ-counting technique to measure the whole-body and regional absorption, distribution and retention of HFA 134a after administration in humans by single breath inhalation. In 7 healthy subjects, radiolabeled HFA 134a was mainly eliminated by ventilation during the first few minutes, with on average 7.2% of the radioactivity retained in the body at 10 min. This radioactivity cleared with an apparent terminal half-life of 1.5-4.2 h. At 5.5 h an average of < 1% of the administered dose (< 750 μg, ca 0.2 μCi) was retained in the body. The disposition of radioactivity was independent of the position of radiolabel. Hence, there was no evidence of degradative metabolism. Inhaled HFA 134a first distributed to all regions of the body and then cleared without evident accumulation in any specific region. The study supports the proposal that HFA 134a is a safe substitute for current propellants in MDIs.

Rationale Airway mucosal vasculature participates in absorption of inhaled drugs and inflammatory processes. We tested two soluble gases, HFA 134a and acetylene to determine non-invasively airway mucosal vascularity as a marker of airway inflammation. Methods Six steroid naive asthmatics and six healthy subjects were tested. Deadspace volume was assessed using Fowler's method. Subjects inhaled to TLC one soluble gas mixture containing 0.3% acetylene and another containing HFA 134a which were exhaled into a spirometer through a critical flow orifice to standardize flow. Instantaneous concentrations of these gases in the anatomical dead-space fraction were measured at the airway opening using a mass spectrometer. Time dependent uptake was assessed by increasing breathold times between 2.5 and 20 secs. Results Mean percentage uptake of acetylene and HFA 134a was for asthmatic subjects, median 25.1% (15.76%-31.79%) and 3.87% (2.0%7.48%) compared to normal subjects, median 14.4% (6.10%-20.83%) ( p p Conclusions Lack of time dependent uptake of HFA 134a renders it unsuitable to determine airway mucosal blood flow (AMBF). Our results demonstrated acetylene is the better gas to determine AMBF as a marker of airway inflammation. It has the potential to evaluate new and existing treatments with utility across the range of asthma severity and other inflammatory airway diseases.

A randomized, double-blind, cross-over study was conducted to assess the efficacy and safety of fluticasone propionate 1 mg twice daily administered via a pressurized metered dose inhaler (pMDI) containing the new non-chlorofluorocarbon (CFC) propellant (HFA 134a), or the established CFC propellants 11 and 12 in patients with severe asthma. The study comprised a 2-week run-in period followed by two 6-week treatment periods, with no washout period in between. One hundred and nineteen symptomatic adult patients with severe asthma, who were receiving inhaled beclomethasone 2–4 mg day −1 or equivalent, were randomized to treatment. Patients were randomized to one of two sequence groups (sequence 1: HFA 134a pMDI then CFC pMDI or sequence 2: CFC pMDI then HFA 134a pMDI). The sequence groups differed with respect to mean peak expiratory flow (PEF) at baseline; however, the magnitude of the increase in PEF from baseline during treatment was similar in the two sequence groups. Mean PEF at baseline was 334 l min −1 in sequence group 1 (HFA 134a→CFC pMDI) and this increased to 357 l min −1 and 366 l min −1 during treatment with the HFA 134a and CFC pMDI, respectively. In sequence group 2 (CFC→HFA 134a pMDI) mean PEF at baseline was 297 l min −1 and this increased to 336 l min −1 and 328 l min −1 during treatment with the HFA 134a and CFC pMDI, respectively. Based on an overall analysis of the two treatment groups at week 6, equivalence was demonstrated; the mean treatment difference (HFA 134a-CFC pMDI) in morning PEF was 0 l min −1 (90% confidence interval (CI), for difference between groups: −7, 6 l min −1 ). There was a comparable improvement in secondary efficacy variables, including clinic lung function measurements, in the two treatment groups. The incidence and type of most adverse events were similar in the two treatment groups. There was no difference in the adjusted geometric mean morning serum cortisol levels after treatment with the HFA 134a and CFC pMDI. Therefore, the fluticasone propionate HFA 134a pMDI constitutes a suitable replacement for the established CFC pMDI at a microgram equivalent dose.

This study compared the efficacy and safety of the fluticasone propionate 125 μg pressurized metered dose inhaler (pMDI) propelled by either hydrofluoroalkane (HFA) 134a or chlorofluorocarbon (CFC) propellants, in adult patients with asthma. HFA 134a is a non-ozone depleting propellant used as a replacement for the CFC propellants 11 and 12 which are being phased out in accordance with the Montreal Protocol. Three hundred and eighty patients with mild to moderate asthma and ‘room for improvement' in their treatment were randomized to receive fluticasone propionate 250 μg twice daily via pMDIs propelled by either CFC propellants 11 and 12 ( n = 195) or HFA 134a ( n = 185). Fluticasone propionate significantly improved lung function over the 4-week treatment period in both treatment groups. The improvement in mean morning peak expiratory flow (PEF) after 7 days of treatment was approximately 12 l min −1 in both groups, rising to approximately 22 l min −1 at the end of the 4-week treatment period. The adjusted mean difference between the two formulations over weeks 1–4 was −1 l min −1 (90% confidence interval: −7, 5 l min −1 ), confirming their equivalence. Clinical comparability was also demonstrated with respect to secondary efficacy variables, including daily symptom scores, evening PEF and clinic visit expiratory measurements. There were no clinically relevant differences in adverse events or serum cortisol levels between the two groups. The fluticasone propionate 125 μg HFA 134a pMDI is an effective and well tolerated product and is a suitable replacement for the fluticasone propionate 125 μg CFC pMDI at a microgram equivalent dose.

Beclometasone dipropionate (BDP) extrafine is a hydrofluoroalkane-based, chlorofluorocarbon (CFC)-free inhalation aerosol. This study was conducted to determine whether BDP extrafine and CFC-fluticasone proprionate (FP) aerosols were equivalent in terms of efficacy and tolerability in children with symptomatic mild-to-moderate asthma. Male and female patients (aged 5-12 yr) with an asthma diagnosis for > or =3 months, peak expiratory flow (PEF) > or =60% of predicted normal and suboptimal asthma control were randomised to double-blind treatment with BDP extrafine 200 microg day(-1) (n=139) or CFC-FP 200 microg day(-1) (n=141) for up to 18 weeks. After 6 and 12 weeks, study medication was 'stepped down' to 100 and 50 microg day(-1), respectively, if patients had achieved good asthma control. Patients with poor asthma control discontinued from the study and those with intermediate control continued in the study but did not undergo a dose reduction. The estimated treatment difference in morning PEF% predicted at 6 weeks was -1.9% (90% CI -4.9, 1.0). There was a trend towards a greater increase in forced vital capacity (% predicted) in the BDP extrafine group (5.3 versus 0.4%; p=0.084). A 'step-down' in therapy to 100 microg day(-1) was possible in 36% and 42% of patients in the BDP extrafine and CFC-FP groups, respectively, at 6 weeks. Both drugs were well tolerated. BDP extrafine and CFC-FP aerosols were equally effective at improving asthma control in children with mild-to-moderate asthma at the same daily dose.

The production of ozone-depleting chlorofluorocarbons (CFCs) was discontinued on 1 January 1996 for all uses deemed non-essential under the Montreal Protocol. However, the use of CFCs as propellants in pressurized metered dose inhalers (pMDIs) was classed as essential, providing an exemption from the agreement. Following extensive research, the hydrofluoroalkanes (HFA) 134a and 227 were identified as the only suitable replacements for CFC propellants in pMDIs. The drug delivery of pMDIs formulated with HFA 134a as a propellant and containing either salbutamol (100 μg per actuation) or fluticasone propionate (125 and 250 μg per actuation) have been assessed for dose uniformity and particle size distribution. All of the HFA 134a pMDIs delivered doses throughout the life of the canisters that were reproducible and within specified regulatory requirements. Each of the products provided an emitted dose which was within ±25% of the mean value indicating accurate and consistent dosing (93, 112 and 221 μg per metered dose for the salbutamol 100 μg and fluticasone propionate 125 and 250 μg HFA 134a pMDIs, respectively). These findings were unaffected by changing the storage orientation of the pMDI or by using the device in a manner designed to simulate typical patient use. The particle size distributions of HFA 134a pMDI doses did not differ significantly from those of the corresponding CFC pMDIs. As a result of the similar pharmaceutical performance, it is unnecessary to change the label claim dose of active drug when making the transition from a CFC to an HFA 134a pMDI for salbutamol (Ventolin TM ) and fluticasone propionate (Flixtide TM ). A seamless transition to non-CFC pMDIs will help to maintain the confidence of patients and healthcare professionals in asthma therapy.