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Background: The deposition of nasal aerosols from both aqueous formulations and propellant-based formulations has only minimally been described in rhinitis patients. This study quantified the regional nasal deposition of QNASL(™) (HFA-beclomethasone, nasal aerosol), Flonase(™) (fluticasone propionate, nasal spray) and Nasonex(™) (mometasone furoate monohydrate, nasal spray)., Methods: This study was an open label, crossover study in nine patients with allergic rhinitis. The regional nasal deposition of the three nasal products was compared and contrasted following delivery of the (99m)Tc-radiolabeled drug product in each product. The gamma images were merged with magnetic resonance images to quantify regional deposition within the patients., Results: The HFA propellant-based formulation (QNASL) resulted in an increased retention of drug product in the nasal cavity compared with the two aqueous formulations (Flonase and Nasonex). The aqueous based formulations resulted in increased amount of the delivered dose that dripped from the nostril (6/8 patients for each of the aqueous formulations and 0/8 patients for the HFA propellant formulation) following administration. The percentage of delivered dose that deposited in the back of the throats of the patients was increased and variable (0.1% to 17.6% with Flonase and 0.0 to 4.7% for Nasonex) for the aqueous formulations when compared to dose delivered for the HFA propellant formulation (0.0% to 1.7% for QNASL)., Conclusions: The regional deposition of the HFA propellant based formulation resulted in increased retention of drug product in the nasal cavity and decreased deposition in the back of the throat compared to the two aqueous formulations.

Inhaled corticosteroids (ICS) and β2-agonists are the primary pharmacotherapies of asthma management. However, suboptimal medication compliance is common in asthmatics and is associated with increased morbidity. We hypothesized that exhaled breath measurements of the aerosol used in the inhaled medications might prove useful as surrogate marker for asthma medication compliance. To explore this, 10 healthy controls were recruited and randomly assigned to ICS (Flovent HFA) or short acting bronchodilators (Proventil HFA). Both inhalers contain HFA-134a as aerosol propellant. Exhaled breath sampling and pulmonary function tests were performed prior to the inhaler medication dispersion, immediately after inhalation, then at 2, 4, 6, 8, 24, and 48 hours postadministration. At baseline, mean (SD) levels of HFA-134a in the breath were 252 (156) pptv. Immediately after inhalation, HFA-134a breath levels increased to 300 × 10(6) pptv and were still well above ambient levels 24 hours postadministration. The calculated ratio of forced expiratory volume in 1 second over forced vital capacity did not change over time following inhaler administration. This study demonstrates, for the first time, that breath HFA-134a levels can be used to assess inhaler medication compliance. It may also be used to evaluate how effectively the medicine is delivered., (© 2015 Wiley Periodicals, Inc.)

Topical nanoparticles are usually applied using semi-solid formulations, but the delivery process is often inefficient due to the poor drug release from the particles. The aim of this study was to investigate the capability of a dynamic foam to break open nanoparticles upon application to the skin and enhance drug delivery efficiency. Vitamin E acetate (VEAc) was selected as a model drug and loaded into lipid nanoparticles (50-60 nm) prepared by phase inversion. The highest drug loading was 18.9+/-1.2 mg/ml and the corresponding encapsulation efficiency was 81.5+/-4.1%. Dynamic foams were generated by emulsifying VEAc-loaded nanoparticle suspensions with hydrofluoroalkane using pluronic L62D. An in vitro permeation study demonstrated that VEAc did not release from the nanoparticles when administered as an aqueous suspension, but attained a flux of 18.0+/-2.1 (microg cm(-2) h(-1)) when applied using the foam. Drug release from the foam was shown to be a consequence of nanoparticle modification after dose administration and this led to the foam delivering 0.7+/-0.3% VEAc into the stratum corneum (SC) when applied to human skin.

Objective: Heptafluoropropane is an inert gas commercially used as propellant for inhalers. Since heptafluoropropane can be detected in low concentrations, it could also be used as a tracer gas to measure functional residual capacity and ventilation homogeneity. The aim of the present study was to validate functional residual capacity measurements by heptafluoropropane wash-in/wash-out (0.8%) during mechanical ventilation in small, surfactant-depleted lungs using a newborn piglet model., Design: Prospective laboratory and animal trial., Setting: Animal laboratory in a university setting., Subjects: Sixteen newborn piglets (age<12 hrs, median weight 1390 g [705-4200 g]) before and after surfactant depletion (Pao2<100 torr in Fio2=1.0) by lung lavage., Interventions: Heptafluoropropane was measured with a new infrared mainstream sensor connected with the flow sensor of the Dräger Babylog 8000. Accuracy and precision of the measurement technique were tested in a mechanical lung model with a volume range from 11 to 35 mL. Reproducibility of the method and its sensitivity to detect changes of functional residual capacity were assessed in vivo by variation of ventilatory variables., Measurements and Main Results: In vitro the absolute error of functional residual capacity was <1 mL (relative errors<3%) with a coefficient of variation<4%. The coefficient of variation of consecutive in vivo measurements was only slightly higher (<5.1%). Measurement of heptafluoropropane concentrations in blood showed no significant accumulation for repeated functional residual capacity measurements within short time periods. After lung lavage, the functional residual capacity decreased from 20.9 mL/kg to 14.5 mL/kg (p<.05) despite increased ventilatory pressures, and lung clearance index (p<.001) and moment ratios (p<.01) increased significantly due to uneven alveolar ventilation. In healthy lungs, the increase in peak inflation pressure and positive end-expiratory pressure by 3-4 cm H2O had only a moderate effect on functional residual capacity (20.9+/-8.6 vs. 26.0+/-11.9 mL/kg, p=.17) and no effect on ventilatory homogeneity, whereas in surfactant-depleted lungs the functional residual capacity increased from 14.5+/-6.7 mL/kg to 29.9+/-12.6 mL/kg (p<.001) and lung clearance index and moment ratios decreased significantly (p < .01)., Conclusions: Heptafluoropropane is a suitable tracer gas for precise functional residual capacity measurements tested in vitro and allows for reproducible measurements in ventilated small lungs without any adverse effects on mechanical ventilation. The sensitivity of the method is sufficiently high to demonstrate the effect of changes in ventilatory settings on the functional residual capacity and ventilation homogeneity.

Objective: To review the literature about hydrofluoroalkane as a propellent of pressurized metered-dose inhalers containing anti-asthma drugs., Sources of Data: Bibliographic search in electronic databases (MEDLINE, MDConsult, HighWire, Medscape and LILACS) and direct search referring to the past 15 years, using the key words hydrofluoroalkane, asthma and childhood were carried out., Summary of the Findings: 43 original articles on the replacement of chlorofluorcarbon by hydrofluoralkane were selected. Hydrofluoralkane showed to be a safe propellent, with pulmonary deposition ranging from 50 to 60%, and to have significant efficacy, when compared with placebo (p < or = 0.003) in controlled clinical trials. Most works using hydrofluoralkane included beclomethasone diproprionate. Approximate annual cost of a treatment with beclomethasone diproprionate/hydrofluoralkane was lower than with beclomethasone diproprionate/clorofluorcarbon. Some studies assessed salbutamol, fluticasone, flunisolide and the association fluticasone-salmeterol, with hydrofluoralkane as propellent in pressurized metered-dose inhalers., Conclusions: Efficacy and safety of hydrofluoralkane as propellent of bronchodilators and inhaled corticosteroids in adults was evidenced. In general, there was a better pulmonary deposition of particles. However, literature data on the use of hydrofluoralkane in the pediatric age group are still scarce and further studies with children and adolescents would be of great importance.

The clinical significance of small airway pathology makes these passages an important therapeutic target in asthma. Conventional chlorofluorocarbon-based formulations of inhaled corticosteroids for asthmatic inflammation produce aerosols with a relatively large particle size, and as such, offer poor access to the small airways. New corticosteroid formulations use hydrofluoroalkane propellants with a smaller average particle size, allowing better access to the distal lung. By extending the delivery of this medication to the peripheral lung and by increasing the efficiency of lung targeting, these new corticosteroid formulations provide more effective treatment at reduced drug doses.

Study Objectives: To compare the lung deposition of radiolabeled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) with chlorofluorocarbon fluticasone propionate (CFC-FP) and chlorofluorocarbon beclomethasone (CFC-BDP)., Design: Six-day, open-label, nonrandomized, crossover study., Setting: Clinical research laboratory., Participants: Nine healthy, nonsmoking, adult volunteers., Interventions: On each study day, participants inhaled one or two puffs of 99mTc-labeled HFA-BDP, CFC-FP, or CFC-BDP. All products delivered 50 micro g per puff ex-valve. Subjects used a respiratory training and monitoring device to meet predefined, standardized inhalation patterns. Immediately after inhalation of radiolabeled study drug, planar gamma camera images were obtained., Measurements and Results: Radiolabeled HFA-BDP had a higher deposition in the lungs (53% ex-actuator) compared with CFC-FP (12 to 13%) and CFC-BDP (4%). Conversely, CFC-FP and CFC-BDP had a much higher distribution to the oropharynx (72 to 78%, and 82%, respectively) than HFA-BDP (29%). HFA-BDP was deposited evenly throughout the lungs, while CFC-FP and CFC-BDP deposition was primarily in the large central and intermediate airways. Andersen particle size sampling gave mass median aerodynamic diameters for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 micro m, 2.0 micro m, and 3.5 micro m, respectively., Conclusions: Lung deposition was greater with HFA-BDP compared with CFC-FP and CFC-BDP. Deposition values appeared to be related to the particle size distribution of each inhaler, with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition.

In the drive to replace chlorofluorinated hydrocarbons (CFCs) by alternative more environmentally friendly propellants in pressurized metered dose inhalers (pMDIs), Chiesi has developed new inhalers using Modulite technology. The aim was to obtain CFC-free pMDIs which are equivalent, in terms of safety and efficacy, to the previous CFC devices at the same dose. When beclometasone dipropionate (BDP) and budesonide Modulite formulations were compared to the equivalent CFC products there was no significant difference in morning serum cortisol or urinary cortisol excretion, at the maximum recommended daily dose (2000 micrograms or 1600 micrograms respectively). Single dose pharmacokinetic studies in both healthy volunteers and asthmatic patients compared systemic exposure (B17MP levels) for BDP-CFC with BDP Modulite and extrafine BDP-HFA (QVAR). B17MP levels for BDP-CFC and BDP Modulite were comparable, but substantially less than that seen with extrafine BDP-HFA. After 6 weeks of treatment in asthmatic patients, B17MP AUC after inhalation of BDP (1000 micrograms twice-daily) from BDP Modulite was comparable with that obtained after BDP-CFC (Becloforte). Plasma profile of BDP and B17MP were similar after inhalation from BDP Modulite with standard actuator or delivered via a spacer, suggesting that pulmonary delivery of BDP to the lung is similar with both actuators.

The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide is a modification of the original chlorofluorocarbon (CFC) formulation. HFA flunisolide replaces CFC with an HFA propellant and uses a built-in spacer in its pressurized metered-dose inhaler. The average HFA flunisolide particle size is 1.2 microm compared with 3.8 microm for the CFC formulation. The smaller particle size improves lung targeting, allowing a reduction in the HFA flunisolide dose relative to CFC flunisolide while maintaining comparable efficacy. In a study of 12 healthy men, pharmacokinetic parameters were determined after single doses of 1000 microg CFC flunisolide delivered without a spacer, 340 microg HFA flunisolide delivered through a spacer, and 516 microg HFA flunisolide delivered without a spacer. A standard noncompartmental analysis of the concentration data was performed and mean (+/- S.D.) pharmacokinetic values were reported. Peak plasma concentrations (observed C(max)) were similar for the three treatments. Area under the curve up to the time corresponding to the last measurable concentration (AUC(0)(-)(tlast)) was similar for the CFC and HFA flunisolide, plus spacer groups (4.4 +/- 1.6 ng x h/mL and 5.0+/- 4.2 ng x h/mL, respectively); however, AUC(0)(-)(tlast) for the HFA flunisolide without spacer group was comparatively lower than for the CFC group (3.5 +/- 1.6 ng x h/mL). Observed C(max) and AUC(0)(-)(tlast) for 6 beta-OH flunisolide, the first-pass metabolite of flunisolide and an indicator of oropharyngeal deposition, were significantly higher in the CFC flunisolide group than in either HFA flunisolide group., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:424-432, 2002)

Our objective was to assess the deposition and pharmacokinetics of a novel formulation of flunisolide (Aerobid, Forest Laboratories) in hydrofluoroalkane (HFA) 134a delivered by pressurized metered dose inhaler (pMDI). The design was a two-way crossover investigation in 12 healthy male subjects comparing HFA-134a flunisolide by pMDI versus pMDI plus 50 mL spacer device. Four of these subjects also took part in a two-way crossover investigation comparing chlorofluorocarbon (CFC) flunisolide pMDI versus pMDI plus Aerochamber holding chamber. The imaging technique of gamma scintigraphy was used to quantify total and regional lung deposition of flunisolide. Plasma levels of flunisolide and its major metabolite (6beta-OH flunisolide) were also determined. The spacer and Aerochamber reduced oropharyngeal deposition dramatically for both the HFA and CFC products (mean 59.8 to 14.9% (p < 0.01) of ex-valve (metered) dose for HFA product; 66.3 to 12.3% (p < 0.01) of ex-valve dose for CFC product) owing to deposition of part of the dose on the walls of the add-on devices themselves. Lung deposition averaged 22.6 and 40.4% (p < 0.01) of the ex-valve dose for the HFA formulation used with pMDI alone and with pMDI plus spacer. Mean lung deposition of the CFC formulation delivered via the Aerochamber (mean 23.4%) was higher than that for the CFC pMDI alone (mean 17.0%), but this difference was not statistically significant. Lung deposition expressed as percentage ex-device (delivered) dose averaged 68.3% for HFA pMDI plus spacer and 19.7% for CFC pMDI. Plasma levels of flunisolide were higher for the pMDI plus spacer than for pMDI alone, reflecting higher lung deposition via the spacer, but plasma levels of the 6beta-OH flunisolide metabolite were higher for the pMDI alone as a consequence of higher oropharyngeal deposition. When delivered via the spacer, pulmonary targeting of the flunisolide HFA formulation was improved compared with the CFC formulation, which should benefit patients by providing satisfactory asthma therapy from a much-reduced delivered dose of flunisolide.

HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Production and consumption of CFCs are being phased out under the Montreal Protocol on Substances that Deplete the Ozone Layer. The safety and pharmacokinetics of HFC 134a and HFC 227 were assessed in two separate double-blind studies. Each HFC (hydrofluorocarbon) was administered via whole-body exposure as a vapor to eight (four male and four female) healthy volunteers. Volunteers were exposed, once weekly for 1 h, first to air and then to ascending concentrations of HFC (1000, 2000, 4000, and 8000 parts per million (ppm)), interspersed with a second air exposure and two CFC 12 (dichlorodifluoromethane) exposures (1000 and 4000 ppm). Comparison of either HFC 134a or HFC 227 to CFC 12 or air gave no clinically significant results for any of the measured laboratory parameters. There were no notable adverse events, there was no evidence of effects on the central nervous system, and there were no symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CFC 12 blood concentrations increased rapidly and in an exposure-concentration-dependent manner, although not strictly proportionally, and approached steady state. Maximum blood concentrations (C(max)) tended to be higher in males than females; in the HFC 227 study, these were statistically significantly (P < 0. 05) higher in males for each HFC 227 and CFC 12 exposure level. In the HFC 134a study, the gender difference in C(max) was only statistically significant (P < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Following the end of exposure, blood concentrations declined rapidly, predominantly biphasically and independent of exposure concentration. For the HFC 134a study, the t(1/2)alpha (alpha elimination half-life) was short for both CFC 12 and HFC 134a (<11 min). The t(1/2)beta (beta elimination half-life) across all exposure concentrations was a mean of 36 and 42 min for CFC 12 and HFC 134a, respectively. Mean residence time (MRT) was an overall mean of 42 and 44 min for CFC 12 and HFC 134a, respectively. In the HFC 227 study, t(1/2)alpha for both CFC 12 and HFC 227, at each exposure level, was short (<9 min) and tended to be lower in males than females. For CFC 12 mean t(1/2)beta ranged from 23 to 43 min and for HFC 227 the mean range was 19-92 min. The values tended to be lower for females than males for HFC 227. For both CFC 12 and HFC 227, MRT was statistically significantly lower (P < 0.05) in males than females and independent of exposure concentration. For CFC 12, MRT was a mean of 37 and 45 min for males and females, respectively, and for HFC 227 MRT was a mean of 36 and 42 min, respectively. Exposure of healthy volunteers to exposure levels up to 8000 ppm HFC 134a, 8000 ppm HFC 227, and 4000 ppm CFC 12 did not result in any adverse effects on pulse, blood pressure, electrocardiogram, or lung function., (Copyright 2000 Academic Press.)

This study compared the efficacy and safety of the fluticasone propionate 125 microg 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 microg 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 microg HFA 134a pMDI is an effective and well tolerated product and is a suitable replacement for the fluticasone propionate 125 microg CFC pMDI at a microgram equivalent dose.

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 randomized, double-blind, parallel-group study compared the efficacy and tolerability of as-required salbutamol 100 microg administered from either a chlorofluorocarbon (CFC) pressurized metered dose inhaler (pMDI; Ventolin) or from a non-CFC hydrofluoroalkane (HFA) 134a pMDI (Ventolin 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 100 microg administered via a HFA 134a pMDI is as effective and safe as the currently available CFC-propelled formulation.

This multi-national, double-blind, randomized, parallel-group study compared the efficacy and tolerability of fluticasone propionate 500 microg 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 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 microg per actuation) or fluticasone propionate (125 and 250 microg 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 microg per metered dose for the salbutamol 100 microg and fluticasone propionate 125 and 250 microg 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) and fluticasone propionate (Flixotide). A seamless transition to non-CFC pMDIs will help to maintain the confidence of patients and healthcare professionals in asthma therapy.

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.

Chlorofluorocarbon (CFC)-containing inhalers for use in the treatment of asthma are to be phased out under the terms of the Montreal Protocol (1). In this multi-centre, randomized, double-blind study, the therapeutic equivalence of two formulations of beclomethasone dipropionate (BDP) containing CFC or non-CFC (HFA134a) propellant, both delivered via the Easibreathe (Norton Healthcare Ltd, London, U.K.) inhaler, was determined in 229 asthmatic children. Each child received 100 microg doses of BDP (containing either CFC or HFA propellant) twice daily for 12 weeks. Both CFC and HFA formulations produced statistically and clinically significant improvements in patient's lung function and symptom scores when administered via the Easibreathe inhaler. The improvements in mean morning peak expiratory flow (PEF) were 41 l min(-1) and 34 l min(-1) for the BDP-HFA and BDP-CFC products respectively (P<0.001) and for mean evening PEF the improvements were 38 l min(-1) and 38 l min(-1), respectively (P<0.001). Similar findings were demonstrated for the other efficacy parameters. The two formulations were statistically equivalent with respect to efficacy. For mean morning PEF the estimated treatment difference (BDP-CFC/BDP-HFA ratio) was 102.6% (95% CI 99.1, 106.2). Similar equivalence was shown for the other efficacy parameters. Both products were well tolerated, with no difference in the adverse event profiles, effects on 24 h urinary cortisol or Candida colonisation. This study demonstrates that the new formulation of BDP with HFA-134a propellant is equivalent to and directly substitutable for BDP with the older CFC propellant in a dose for dose manner. This should enable a seamless transition from one product to the other when CFC containing products are eventually phased out. In addition this study has also shown that the Easibreathe inhaler is an effective delivery system for use with inhaled products for the treatment of asthma in children.

There are no established guidelines for judging equivalence between inhaled medications. The principles of establishing bioequivalence on the basis of bioavailability and pharmacokinetics may not be applicable to inhaled medications with predominantly topical and minimal systemic effects. For inhaled beta(2)-agonists, the most practical method of showing in vivo therapeutic equivalence is by comparing relative potencies (RPs) of pharmacodynamic effects (bronchodilation and bronchoprotection). A range of doses that includes placebo should be studied in an appropriate design with adequate sample size, and relative potency should be estimated. Hydrofluoroalkane and chlorofluorocarbon salbutamol are bioequivalent for both their bronchodilator (RP, 1.08; 90% confidence interval, 0.95%, 1.23%) and bronchoprotective effects (RP, 1.08; 90% confidence interval, 0.81%, 1.46%) with similar safety profile. Eighteen subjects are required in a cross-over design to demonstrate bronchoprotective bioequivalence with a confidence interval of 67% to 150% for the relative potency (80% power). For salbutamol, this can be achieved with a comparison of 100 and 200 microgram doses. Twelve subjects would suffice for a cumulative dose-response study for bronchodilator bioequivalence. For both outcomes, repeatability and quality control of measurements have to be ensured for an accurate interpretation of the results.

The initial water content of a group of 15 pharmaceutically and toxicologically acceptable surfactants showed a tendency to increase with the surfactant hydrophilic-lipophilic balance (HLB) value. Surfactant solubility was determined in chlorine-free "alternative propellants" (n-butane, propane, dimethyl ether [DME], 1,1,1,2-tetrafluoroethane (HFA-134a), and 1,1,1,2,3,3,3-heptafluoropropane [HFA-227ea], and trichloromonofluoromethane [CFC-11] in the absence of cosolvents such as ethanol. Water-soluble surfactants such as Carbowax, Sentry, PEG 300, Tween 20, and Brij 30, with high HLB values showed appreciable solubility in HFA-134a and HFA-227ea. In systems containing > or = 80% propellant by weight, each single-phase propellant-surfactant blend was screened for its ability to solubilize iodine and dissolve or solubilize water with increasing surfactant concentration. This screening was performed to investigate the possibility of formulating high-volatility, single-phase systems with increased polarity and solvency from these conventional excipients and vehicles. Ternary-phase diagrams show the regions of apparent single and multiple phase behavior in each system. Despite the increased polarity of the hydrofluoroalkanes (HFAs), appreciable water solubility was seen only with these surfactants in DME and in the hydrocarbons (HCs) n-butane and propane.

A 28-day double-blind parallel group study has been conducted to compare the safety and tolerability of HFA-134a, a chlorofluorocarbon-free propellant in a pressurized metered-dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C). Sixteen subjects were randomly assigned to receive one of the two MDIs, either four inhalations four times per day for 14 days or eight inhalations four times a day for 14 days, and were then crossed over to the alternative exposure regime with the same propellant for the next 14-day period. No clinically significant changes occurred in blood pressure, heart rate, electrocardiograms, pulmonary function (FEV1, FVC, FEF25-75%), haematology or serum chemistry. One subject in the MDI A group had elevated eosinophil counts throughout the study; there were no other remarkable clinical laboratory data. Fifty six adverse events were related to the study propellants; 34 of these occurred in the MDI C group and 22 in the MDI A group. For each adverse event no statistically significant differences were detected between propellant systems or between exposure levels. The most frequent adverse event was headache, which was reported by four subjects with each propellant system. Blood samples for HFA-134a in the MDI A group were collected on day 28 to measure systemic absorption. Blood levels of HFA-134a were detected in all subjects given this propellant within 1 min post-exposure, and these levels decreased to one-tenth of the original value by 18 min after the start of exposure. The safety and tolerability of an HFA-134a chlorofluorocarbon-free system was demonstrated over 28 days of exposure in healthy subjects. These negative results are clinically important because they indicate it will be safe to proceed with the study of this chlorofluorocarbon-free system in asthmatic patients.

1. Groups of 60 male and 60 female B6C3F1 mice or HanIbm Wistar rats were exposed to HFA-134a using snout-only inhalation exposure techniques for periods of one hour daily for at least 104 weeks. HFA-134a was delivered directly from cylinders at vapour concentrations of 2500, 15,000 and 75,000ppm for mice and from metered-dose inhalers at vapour concentrations of 2500, 10,000 and 50,000ppm for rats. 2. Intended dosages were achieved. 3. Evidence of absorption was found at each dose level and was dose related. 4. Neither species suffered treatment related effects on survival, clinical signs, body weights, haematology nor on the type, incidence, site or severity of gross lesions. 5. There was no effect of treatment on the type, incidence, site or severity of neoplasms in mice or rats. 6. There were no non-neoplastic findings related to treatment in mice. 7. HFA-134a was considered not to be oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.

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 animal 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.

HFA134a (1,1,1,2-tetrafluoroethane) is a nonozone-depleting candidate to replace the chlorofluorocarbons used as propellants in metered-dose inhalers (MDIs) for pharmaceuticals that are widely used in the treatment of respiratory tract disease. As a means for ensuring the safety of such a compound for human use, it is necessary to establish that there is no excessive or unexpected accumulation in the body and in selected regions. A sensitive whole-body gamma-counting technique has been used with 18F-labeled HFA134a to measure the whole-body and regional absorption, distribution, and retention of HFA134a after administration in humans by single-breath inhalation. In seven healthy subjects, labeled HFA134a was rapidly eliminated by ventilation during the first few minutes, with an average of 9.6% of the radioactivity retained in the body at 5 min. This radioactivity cleared with an apparent terminal half-life of 1.5-4.2 hr to leave, on average, < 1% of the administered dose (< 750 micrograms, approximately 0.2 microCi) retained in the body at 5.8 hr. Disposition of radioactivity was independent of the position of label. Thus, there was no evidence of any significant degradative metabolism. On average, only 0.0056% of the administered dose appeared in the urine within the first 2 hr. Later samples contained no significant radioactivity. Inhaled HFA134a first distributed to all regions of the body and then cleared without evident accumulation in any specific region.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Metered dose inhalers for the treatment of asthma use chlorofluorocarbons as propellants. These face an international ban due to their effect on the ozone layer. Salmeterol has been reformulated using the non-chlorinated propellant Glaxo inhalation grade HFA134a., Methods: The safety, tolerability and systemic pharmacodynamic activity of the salmeterol/HFA134a inhaler, the current salmeterol inhaler, and placebo (HFA134a) were compared in 12 healthy volunteers in a double blind, randomised crossover study using a cumulative dosing design., Results: Safety and tolerability were similar and the response was related to the dose over the range used (50-400 micrograms) with both salmeterol inhalers. The salmeterol/HFA134a inhaler showed no differences from the current inhaler for pulse rate, blood pressure, tremor, QTc interval, and plasma glucose levels. The salmeterol/HFA134a inhaler had significantly less effect on plasma potassium levels., Conclusions: In healthy volunteers the salmeterol/HFA134a inhaler is at least as safe and well tolerated as the current salmeterol inhaler, and has similar systemic pharmacodynamic activity.

Metered-dose propellant-driven aerosols of an antigenically reactive protein were produced by combining bovine gammaglobulin (BGG) with one of several surfactants soluble in Freon or dimethylether propellants. Small-particle protein aerosols were most effectively produced by lyophilizing surfactants and proteins prior to the addition of propellants. Up to 26% of the total aerosolized protein was of respirable size. Aerosol metering valves delivering small volumes were most effective in producing respirable-sized (< or = 4 micron median mass aerodynamic diameter) protein aerosols. Proteins were suspended in liquified propellants as both propellant-soluble molecules and visible sedimenting clusters which both contributed to making respirable-sized protein aerosol particles. Electron microscopy showed that respirable-sized protein particles were composed of variable-sized chain aggregates of spherical subunits. Proteins were antigenic after suspension in liquified propellant and release as aerosols, but antigenicity diminished with extended propellant exposure. Local immunity in the respiratory tract is a key factor in resistance to respiratory infections. Metered-dose propellant-driven aerosols offer a potentially attractive method for delivering small-particle aerosols of immunizing antigens or other therapeutic proteins to the respiratory tract.

The acute safety of the alternative chlorofluorocarbon-free (CFC-free) propellant HFA-134a from a pressurized metered-dose inhaler (MDI) was assessed in 12 healthy male subjects according to a double-blind, randomized, crossover design. On each of three consecutive days, cumulative doses of 1,2,4,8 and 16 inhalations were administered 30 min apart from one of three MDIs. The three MDIs contained either the HFA-134a CFC-free system without drug (HFA-Placebo), the CFC-free system with salbutamol sulphate (HFA-Salbutamol), or a conventional CFC propellant mixture without drug (CFC-Placebo). Pulmonary function (FEV1, FEF25-75%), cardiovascular performance (heart rate and blood pressure), objective tremor measurements and serum potassium were measured after each incremental dose. Similar responses for pulmonary function, cardiovascular performance, tremor and serum potassium were observed between the HFA-Placebo and CFC-Placebo groups. No statistically significant difference was seen in change from baseline of any parameter between the two propellant systems. The administration of HFA-Salbutamol produced statistically significant dose-related increases in heart rate, systolic blood pressure and tremor and a significant dose-related decrease in serum potassium; these responses were expected based on cumulative doses of active drug. Blood samples for HFA-134a analysis were collected to measure systemic absorption of this propellant. Levels of HFA-134a between 200 and 700 ng.ml-1 were detected in all subjects given the CFC-free system. This study shows that acute inhalation of HFA-134a in a CFC-free system is as safe as a CFC propellant system. Salbutamol sulphate in the CFC-free system can be delivered in a dose-linear fashion, without any noticeable change in the safety profile of active drug.

HFA-134a and HFA-227 (chlorine free hydrofluoro-alkanes) are at present in extensive nonclinical safety testing sponsored by two joint research consortia (IPACT-I, IPACT-II) of companies interested in metered dose inhalers (MDI). The rationale for toxicity testing of these CFC replacements is to predict safety of their use as drug propellants in MDI. Frequency of use, intervals and systemic exposure levels are key parameters. Intact animals and in-vitro systems repeatedly exposed to multiples of patient doses, under conditions comparable to human administration should not show adverse reactions. With an emphasis different from non-U.S. Health Authorities, the U.S. FDA insists on proof of toxic effects which may require excessive doses. This principle is questioned for essentially inert gases such as CFCs and HFA-134a and HFA-227 which only through the effects of oxygen deprivation at unreasonably high concentrations of the inhaled propellant/air mixture indirectly cause mild toxic effects in animals. Provided that no intrinsic toxic effects will be detected, chances are good that these CFC replacements will eventually be approved. In view of the estimated 5-year testing time frame and the risks involved, CFCs should remain available for MDI for some time in the future.