Hydrofluoroalkane Formulation Research Articles

Airway and Systemic Effects of Hydrofluoroalkane Formulations of High-Dose Ciclesonide and Fluticasone in Moderate Persistent Asthma

Airway and Systemic Effects of Hydrofluoroalkane Formulations of High-Dose Ciclesonide and Fluticasone in Moderate Persistent Asthma

The Effect of Reducing the Fine-Particle Mass of Salmeterol from Metered-Dose Inhalers on Bronchodilatation and Bronchoprotection Against Methacholine Challenge: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study

This study examined the clinical relevance of fine-particle mass (FPM) delivered from metered dose inhalers (MDIs) to bronchodilatation and bronchoprotection against methacholine challenge by comparing a marketed chlorofluorocarbon (CFC) formulation of salmeterol with an investigational hydrofluoroalkane (HFA)formulation. This was a randomized, double-blind, placebo-controlled, 3-way crossover study in patients with mild to moderate asthma who had a forced expiratory volume in 1 second (FEV (1)) of > or =60% predicted and a base-line provocation dose of inhaled methacholine required to produce a 20% decrease in FEV(1) (PD (20) [methacholine]) of < or =3.2 mg. On separate occasions, patients received 2 inhalations of salmeterol 25 microg from either the CFC MDI (FPM 14 microg), the investigational HFA MDI (FPM 7 microg), or placebo via CFC MDI. Serial measurements of FEV(1) were made over 90 minutes after dosing, followed by methacholine challenge. Efficacy end points were PD(20) (methacholine) and FEV(1) AUC (inc) (incremental area under the FEV(1) curve) over 15 to 90 minutes. The study was designed to demonstrate non-inferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness; for PD(20) (methacholine), noninferiority was predefined as 1.0 doubling dose of methacholine. The study enrolled 40 patients (65% men; mean age, 36.9 years). Both active treatments were significantly better than placebo in terms of PD(20) (methacholine) (P < 0.001). In the per-protocol population, the mean (SE) difference in bronchoprotection between the CFC MDI and placebo was 2.7888 (0.3432) doubling doses of methacholine (n = 32), and the difference between the investigational HFA MDI and placebo was 1.8268 (0.3418) doubling doses(n = 33). The adjusted mean (SE) treatment difference between the CFC MDI and HFA MDI was 0.9621 (0.3454) doubling doses. The upperlimit of the 95% CI (0.2714-1.6527) was greater than the predefined limit for noninferiority. There was no significant difference in FEV(1) AUC(inc) between formulations (mean treatment difference, 1.895 L . min; 95% CI, -4.893 to 8.684); however, both active treatments were significantly different from placebo (P < 0.001). FPM from different MDI formulations may affect the bronchoprotective properties of salmeterol. In this study, the formulation with the smaller FPM was associated with less-effective bronchoprotection, although there was no difference in bronchodilatation. This study did not demonstrate noninferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness.

Airway and Systemic Effects of Hydrofluoroalkane Formulations of High-Dose Ciclesonide and Fluticasone in Moderate Persistent Asthma

There are no data comparing the relative effects of high-dose ciclesonide (CIC) and fluticasone propionate (FP) on airway and systemic outcomes in patients with moderate persistent asthma. We elected to evaluate the relative effects of CIC and FP on the plasma cortisol response to stimulation with human corticotropin-releasing factor (hCRF) and bronchial hyperresponsiveness to methacholine as the primary outcome variables, in addition to secondary outcomes of overnight 10-h urinary cortisol (OUC) levels, exhaled nitric oxide levels, lung function, symptoms, and quality of life. Fourteen patients with moderate persistent asthma (mean FEV(1), 67% predicted [prior to each randomized treatment]) completed the study, which had a randomized, double-blind, double-dummy, crossover design, per protocol. Patients stopped receiving their usual inhaled corticosteroids for the duration of the study and instead began receiving salmeterol, 50 mug twice daily, and montelukast, 10 mg once daily, for the 2-week washout periods prior to each randomized treatment, in order to prevent dropouts after withdrawal from inhaled corticosteroid therapy. Patients received 4 weeks of either CIC, 200 microg ex-valve (160 microg ex-actuator) four puffs twice daily, plus FP-placebo, four puffs twice daily, or FP, 250 microg ex-valve (220 microg ex-actuator) four puffs twice daily, plus CIC-placebo, four puffs twice daily. Salmeterol and montelukast were withheld for 72 h prior to each postwashout baseline visit, and CIC or FP was withheld for 12 h prior to each posttreatment visit. FP, but not CIC, when compared to respective baseline values, significantly suppressed (p < 0.05) plasma cortisol levels as follows: FP prior to receiving hCRF: geometric mean fold difference, 1.2; 95% confidence interval (CI), 1.1 to 1.3; CIC prior to receiving hCRF: geometric mean fold difference, 0.9; 95% CI, 0.8 to 1.0; FP 30 min after receiving hCRF: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; CIC 30 min after receiving hCRF: geometric mean fold difference, 1.0; 95% CI, 0.9 to 1.2; OUC after FP administration: geometric mean fold difference, 1.9; 95% CI, 1.4 to 2.6; OUC after CIC administration: geometric mean fold difference, 1.2; 95% CI, 0.9 to 1.5. There was also a significantly lower (p < 0.05) mean value for OUC levels after FP administration than after CIC administration (geometric mean fold difference, 1.5; 95% CI, 1.1 to 2.0). Therapy with CIC and FP, compared to respective baselines, significantly increased (p < 0.05) the provocative concentration of methacholine causing a 20% fall in FEV(1), as follows: CIC: doubling dilution difference, 0.8; 95% CI, 0.1 to 1.6; FP: doubling dilution difference, 1.0; 95% CI, 0.1 to 2.0. It also significantly reduced (p < 0.05) exhaled nitric oxide levels, as follows: CIC: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; FP: geometric mean fold difference, 1.9; 95% CI, 1.3 to 2.8. There was no effect on other secondary efficacy outcomes. FP, 2,000 microg daily, but not CIC, 1,600 microg daily, significantly suppressed hypothalamic-pituitary-adrenal axis outcomes, with OUC levels being lower after FP administration than after CIC administration. Both drugs significantly improved airway outcomes in terms of methacholine bronchial hyperresponsiveness and exhaled nitric oxide levels. The present results would therefore suggest that CIC might confer a better therapeutic ratio than FP when used at higher doses.

Salmeterol HFA is as effective as salmeterol CFC in children and adults with persistent asthma

In accordance with the Montreal Protocol 1987, initiatives to phase out and replace ozone-depleting chlorofluorocarbon (CFC) propellants with non-ozone-depleting propellants in metered-dose inhalers (MDIs) in the treatment of asthma and chronic obstructive pulmonary disease are underway. In view of this, two multi-centre, randomised, parallel-group, double-blind studies were conducted to compare the safety and efficacy of salmeterol xinafoate delivered by an MDI using the hydrofluoroalkane (HFA) 134a propellant with the licensed CFC formulation (Serevent) in asthmatic populations of children (4-11 years) and adults (12 years). Patients on a stable dose of inhaled corticosteroids with a scope for improvement based on mean morning peak expiratory flow (PEF) and symptoms were randomised to receive salmeterol HFA MDI 50 microg twice daily or salmeterol CFC MDI 50 microg twice daily for 12 weeks. The primary efficacy variable was mean morning PEF and secondary variables included other lung function parameters, symptom scores, use of relief medication and safety assessments. The difference between the treatments in adjusted mean morning PEF (salmeterol HFA-salmeterol CFC) were 2.5 and -3.2 L/min for per-protocol populations of children and adults, respectively. The lower limit of 95% confidence intervals for both populations was within the pre-defined limit (-15 L/min) set for non-inferiority. Similar results were observed in intent-to-treat (ITT) populations. In children, the two formulations resulted in a lack of any statistically significant difference in secondary efficacy parameters. A significant difference at endpoint in clinic forced expiratory volume in 1s was reported in favour of the HFA formulation in the adult population, although the magnitude of this effect was not considered clinically significant. The incidences of adverse events (AEs) were similar for both formulations and populations, and no safety concerns were generated. Together these data demonstrate salmeterol HFA MDI to be as effective as salmeterol CFC MDI in adults and children.

Effects of hydrofluoroalkane formulations of ciclesonide 320μg once daily versus fluticasone propionate 220μg twice daily on methacholine hyperresponsiveness in mild-to-moderate persistent asthma

Rationale We evaluated the comparative efficacy of HFA formulations of CIC and FP, assessing methacholine challenge, in addition to exhaled nitric oxide, lung function, diary cards and quality of life. Methods 19 mild-to-moderate asthmatics completed the study in randomized, double-blind, double-dummy, cross-over fashion. Patients stopped their inhaled corticosteroids during the study and were commenced instead on salmeterol (SM) 50μg 1puff bid + montelukast (ML) 10mg qd for 2-week washout periods prior to each randomized treatment. Patients received 4 weeks of either CIC 200μg ex-valve (160μg ex-actuator) 2puffs qd (8am) + CIC-placebo (PL) 2puffs qd (8pm) + FP-PL 2puffs bid (8am/8pm), or FP 125μg ex-valve (110μg ex-actuator) 2puffs bid (8am/8pm) + CIC-PL 2puffs bid (8am/8pm). SM+ML were withheld for 72hours prior to post-washout visits and CIC or FP was withheld for 24hours prior to study visits. Results There was no significant difference between CIC vs. FP for the primary outcome of methacholine PC 20 as doubling dilution (dd) shift from respective baseline; mean difference: 0.4dd (95%CI −0.4–1.2). Moreover, there was no difference between treatments for the sequence of CIC first vs. FP second; mean difference: 0.2dd (95%CI −1.3–1.7) or FP first vs. CIC second; mean difference: 0.9dd (95%CI −0.1–1.8). There were also no differences for other secondary outcomes between treatments, either respective or irrespective of sequence, as change from baseline. Conclusion There were no differences between 4 weeks of CIC 320μg qd and FP 220μg bid on methacholine hyperresponsiveness in mild-to-moderate persistent asthma. Longer-term studies are indicated to evaluate their relative efficacy on asthma exacerbations.

Hydrofluoroalkane formulations of inhaled corticosteroids for the treatment of asthma.

Current international guidelines for the treatment of asthma advocate inhaled corticosteroids as first-line therapy for persistent symptoms. As chlorofluorocarbon (CFC)-based products are being phased out because of environmental concerns, new inhaler propellants, such as hydrofluoroalkane (HFA)-134a, have been developed. The reformulation of existing corticosteroid compounds into HFA propellants has resulted in two distinct classes of corticosteroid aerosols consisting of HFA suspensions and HFA solutions. The new HFA formulations of flunisolide and beclomethasone dipropionate exist as solutions, whereas HFA preparations of fluticasone propionate, triamcinolone acetonide, and mometasone furoate are formulated as suspensions. HFA suspensions retain the same particle size, deposition, and efficacy profiles as their CFC counterparts. HFA solutions, however, exist as extra-fine aerosols which have been shown to penetrate more effectively into the peripheral regions of the lung. Comparisons of HFA solutions with their CFC counterparts have demonstrated equivalent efficacy when given in smaller doses. The safety profiles of both HFA suspensions and solutions, given at equivalent doses, are comparable to CFC formulations. Increasing evidence suggests that inflammation of the small airways plays an important role in the pathogenesis of asthma. Currently, the clinical implications of long-term treatment of the peripheral lung using an extra-fine inhaled corticosteroid aerosol remain uncertain. Future studies, involving histopathologic and clinical endpoints, will be necessary to determine whether treatment with HFA solutions offers significant advantages over currently available therapies.

Effect of HFA-flunisolide on peripheral lung inflammation in asthma

Background: New hydrofluoroalkane (HFA) formulations of glucocorticoids have been shown to effectively control asthma. HFA glucocorticoids are deposited across all sizes of airways, including the small ones. However, it is not clear whether they can suppress peripheral airway inflammation. Objective: We sought to determine whether HFA-flunisolide could suppress peripheral inflammation in asthma. Methods: Twelve patients with mild to moderate asthma received HFA-flunisolide for 6 weeks. Transbronchial and endobronchial biopsy specimens were obtained before and after treatment, and spirometry was performed. Changes in inflammatory cells (eosinophils, neutrophils, lymphocytes, macrophages, basophils) and IL-5 and eotaxin were measured by using immunocytochemistry and in situ hybridization. Results: Lung function significantly improved after treatment (P < .05). HFA-flunisolide significantly reduced eosinophils, IL-5, and eotaxin in both peripheral and central airways (P < .01). Neutrophils significantly increased after treatment in peripheral and central airways (P < .05). The numbers of lymphocytes remained unchanged. Conclusions: These results show that HFA-flunisolide effectively suppressed eosinophilic inflammation in peripheral and central airways. These changes were accompanied by improvement in lung function. (J Allergy Clin Immunol 2003;112:58-63.)

Evaluation of efficacy and safety of flunisolide hydrofluoroalkane for the treatment of asthma

Background: Inhaled corticosteroids are currently recommended as first-line therapy for the long-term control and management of persistent asthma. Flunisolide hydrofluoroalkane (HFA) is a new formulation of the corticosteroid flunisolide that is delivered by a metered-dose inhaler containing an HFA propellant. HFA replaces the chlorofluorocarbon (CFC) propellant of the previous formulation, producing aerosols of smaller average particle size. Objective: This article reviews the physical and pharmacologic properties, deposition profile, and potential clinical benefits of flunisolide HFA for the treatment of asthma. Methods: Data included in this review were found via MEDLINE (search term, flunisolide HFA). Results: Flunisolide HFA has a mass median aerodynamic diameter (MMAD) of 1.2 μm, smaller than the 3.8 μm MMAD of the CFC formulation. Compared with flunisolide CFC, more of each flunisolide HFA dose reaches the lungs and less is deposited in the oropharynx. In addition, scintigraphic studies have found that the extra-fine particle size of flunisolide HFA gives it better access to small airways. In short- and long-term clinical studies, flunisolide HFA has been found to significantly increase pulmonary function relative to placebo. Although not statistically superior to the previous CFC formulation, flunisolide HFA exhibited small improvements in secondary efficacy measures, such as as-needed albuterol use and asthma symptoms, relative to flunisolide CFC. Furthermore, research suggests that the new HFA formulation has a low risk of systemic corticosteroid effects (eg, hypothalamic-pituitary-adrenal axis suppression, growth inhibition in children). Also, lower levels of oropharyngeal deposition, such as those seen with flunisolide HFA, are associated with lower incidence of local effects (eg, candidiasis). Conclusion: Flunisolide HFA offers effective asthma control with a high level of tolerability in an extra-fine particle formulation that distributes corticosteroid to all areas of the lung, including small airways.

Clinical studies in asthmatics with a new non-extra fine HFA formulation of beclometasone dipropionate (BDP Modulite®)

The main objective of the clinical development programme for BDP Modulitee, a new non-extra fine formulation of beclometasone dipropionate (BDP) in hydrofluoroalkane (HFA), has been to demonstrate therapeutic equivalence compared with standard BDP chlorofluorocarbon (CFC) products at the recommended posology (delivered dose and patient population), A total of I 158 asthmatic patients were included in five clinical studies and 658 patients were treated with BDP Modulite®. Four studies were undertaken in mild or moderate-to-severe asthmatic adults, while one study was carried out in children.The duration of treatment was 12 weeks in three studies and 6 weeks in the other two studies. A range of doses of BDP Modulite® from 200 μg bid up to 15001μg bid was evaluated against CFC comparators. The primary efficacy variable in all studies was morning PEFR while secondary variables included other lung function parameters, symptom scores and salbutamol use. All studies demonstrated equivalence of efficacy for morning PEFR for BDP Modulite® versus BDP-CFC when compared on a microgram for microgram basis.The secondary outcome variables also consistently support similar efficacy of the two products. The safety and tolerability profile for BDP Modulite® was similar to BDP-CFC; the incidence of adverse events was comparable between treatments and plasma and urinary cortisol were generally unchanged in patients receiving 1000 μg day −1 for 6–12 weeks. In conclusion, the results of the clinical studies with BDP Modulite® show that this new HFA formulation allows a seamless transition to CFC-free BDP thus simplifying the changeover.

Single‐dose study to compare the pharmacokinetics of HFA flunisolide and CFC flunisolide

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 μm compared with 3.8 μm 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 μg CFC flunisolide delivered without a spacer, 340 μg HFA flunisolide delivered through a spacer, and 516 μg 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 Cmax) were similar for the three treatments. Area under the curve up to the time corresponding to the last measurable concentration (AUC0–tlast) was similar for the CFC and HFA flunisolide, plus spacer groups (4.4 ± 1.6 ng·h/mL and 5.0 ± 4.2 ng·h/mL, respectively); however, AUC0–tlast for the HFA flunisolide without spacer group was comparatively lower than for the CFC group (3.5 ± 1.6 ng·h/mL). Observed Cmax and AUC0–tlast for 6β‐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.

Therapeutic significance of distal airway inflammation in asthma

Inflammation in asthma is not merely confined to the large central airways but also extends to the small peripheral airways. Distal lung inflammation can be observed even in patients with asthma with mild disease and normal spirometric readings. Subjects with asymptomatic asthma can exhibit significant increases in peripheral airway resistance, likely the result of distal lung inflammation. As determined from measurements of eosinophilic and other cellular infiltrates, the inflammatory response in the distal lung can exceed that in the large airways. Nocturnal asthma, a natural model of cyclic asthma worsening, is associated with an increase in nighttime distal lung inflammation, as evidenced by the accumulation of alveolar tissue eosinophils. Distal lung disease appears to increase the risk of recurrent asthma exacerbation, whereas disease-related anatomic changes in the small airways of the distal lung are prominent in fatal asthma. The clinical significance of distal lung disease makes this region an important therapeutic target. Chlorofluorocarbon (CFC)-based preparations of inhaled corticosteroids used to treat airway inflammation produce aerosols of relatively large particle size (~4 μm); such aerosols have poor access to the distal lung. New formulations of inhaled corticosteroids that use hydrofluoroalkane (HFA) propellants can have smaller particle sizes (~1 μm). Extrafine HFA aerosols have better access to the distal lung, with less oropharyngeal deposition. Imaging studies suggest that anti-inflammatory medication delivered as an extrafine aerosol produces beneficial changes in distal lung function. In one study, an HFA formulation of an inhaled corticosteroid reduced air trapping to a greater degree than a CFC formulation of the same corticosteroid. By extending the delivery of anti-inflammatory medication to the distal lung, the new HFA-based corticosteroids have the potential to treat asthma more effectively and at reduced steroid doses. (J Allergy Clin Immunol 2002;109:S447-60.)

Deposition and Pharmacokinetics of Flunisolide Delivered from Pressurized Inhalers Containing Non-CFC and CFC Propellants

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.

Safety of inhaled and intranasal corticosteroids: lessons for the new millennium.

Although inhaled and intranasal corticosteroids are first-line therapy for asthma and allergic rhinitis, there has recently been an increasing awareness of their propensity to produce systemic adverse effects. The availability of more potent and lipophilic corticosteroids and new chlorofluorocarbon (CFC)-free formulations has focused attention on these safety issues. The main determinant of systemic bioavailability of these drugs is direct absorption from the lung or nose, where there is no first-pass inactivation. Consequently, the systemic bioavailability of inhaled corticosteroids is greatly influenced by the efficiency of the inhaler device. Thus, when comparing different inhaled corticosteroids it is imperative to consider the unique drug/device interaction. The pharmacokinetic profile is important in determining the systemic bioactivity of inhaled and intranasal corticosteroids. For highly lipophilic drugs, such as fluticasone propionate or mometasone furoate, there is preferential partitioning into the systemic tissue compartment, and consequently a large volume of distribution at steady state. In contrast, drugs with lower lipophilicity, such as triamcinolone acetonide or budesonide, have a smaller volume of distribution. The systemic tissue compartment may act as a slow release reservoir, resulting in a long elimination half-life for the lipophilic drugs. For intranasal corticosteroids, a high degree of lipophilicity diminishes water solubility in mucosa and therefore increases the amount of drug swept away by mucociliary clearance before it can gain access to tissue receptor sites. This may reduce the anti-inflammatory efficacy in the nose, but might also reduce the propensity for direct systemic absorption from the nasal cavity. The hydrofluoroalkane (HFA) formulations of beclomethasone dipropionate are solutions and exhibit a much higher respirable fine particle dose than do the CFC formulations. Dose-response studies with one of the HFA formulations have shown therapeutic equivalence at half the dosage, with little evidence of adrenal suppression at dosages up to 800 microg/day. A lack of similar studies for another of the available HFA formulations has led to a discrepancy in the recommendations for equivalence. Although in vitro studies have pointed to a similar fine particle distribution for the HFA and CFC formulations of fluticasone propionate, this is not supported by in vivo data for lung bioavailability, suggesting that care will be required when switching these formulations. Prescribers of inhaled and intranasal corticosteroids should be aware of the potential for long term systemic effects. The safest way to use these drugs is to 'step-down' to achieve the lowest possible effective maintenance dosage.

Double-blind, placebo-controlled study of single doses of chlorofluorocarbon (CFC) and CFC-Free cromolyn sodium for exercise-induced bronchoconstriction

The objective of this study was to compare the protective effects of a single dose of either cromolyn sodium containing chlorofluorocarbon (CFC) as a propellant or CFC-free cromolyn sodium containing hydrofluoroalkane (HFA) as a propellant with those of placebo. Seventeen patients with documented exercise-induced bronchoconstriction received a single dose of each of the 2 formulations and placebo with washout periods between phases in a randomized, double-blind, 3-way crossover study. Exercise challenge was performed using a cycloergometer to achieve ≥70% of the predicted maximum heart rate. The highest of 3 pre-exercise measurements of forced expiratory volume in 1 second (FEV 1) was recorded for analysis. Postexercise FEV 1 was measured at 5, 10, 15, 20, 25, and 30 minutes after completion of the challenge. The mean maximum percent decrease in FEV 1 after exercise and the percent protection index were calculated for each treatment. The mean maximum percent decrease in postexercise FEV 1 was significantly lower ( P < 0.001) in both the CFC and HFA cromolyn sodium groups than in the placebo group (9.9%, 11.7%, and 24.9%, respectively). No significant difference in the maximum percent decrease in postexercise FEV 1 was noted betwwen the active treatments. The mean percent protection index was 58.7% and 58.0% for the CFC and HFA formulations, respectively. Results of this study suggest that HFA- and CFC-containing cromolyn sodium inhalation aerosols are equivalent in the prevention of exercise-induced bronchoconstriction.

The pharmacokinetics of inhaled hydrofluoroalkane formulations

To obtain the full picture of a formulation, the in vitro and the in vivo information can be looked upon as components of a “prediction bridge” where the in vitro information can be used to predict lung deposition, which in turn can be used to predict clinical outcome. This bridging concept can be used as a template to evaluate new information on emerging inhaled formulations. The concept was used to evaluate literature data on new hydroflouroalkane formulations of salbutamol and beclomethasone dipropionate (BDP). The new salbutamol hydroflouroalkane formulations seem to have properties similar to those of the old chlorofluorocarbon formulations even if the presented information on effect comparisons is limited. The first BDP hydroflouroalkane formulation is a solution formulation with in vitro properties that are quite different from those of the old chlorofluorocarbon suspension formulation. The BDP hydroflouroalkane formulation has a much greater fine particle mass, which eventually results in greater lung deposition and better clinical effect. (J Allergy Clin Immunol 1999;104:S246-9.)

Moisture transport into chlorofluorocarbon-free metered dose inhalers

Moisture is known to affect the stability of some metered dose inhalers (MDIs). Hydrofluoroalkanes such as tetrafluoroethane (134a) and heptafluoropropane (227) are known to have higher affinity for moisture than the currently used chlorofluorocarbon propellents. An initial study was conducted to determine the water vapor transmission rates of various elastomers that may be used as gaskets in MDIs. A further study was conducted to measure the moisture ingress rates of various chlorofluorocarbon-free MDIs. The data indicate that moisture transport into chlorofluorocarbon-free MDIs is influenced by the elastomeric nature of the gaskets used and the type of hydrofluoroalkane formulation and storage conditions used. (J Allergy Clin Immunol 1999; 104:S227-9.)

Chlorofluorocarbon to hydrofluoroalkane formulations: An industry perspective

The medications prescribed to treat asthma are provided in a range of delivery systems, designed to give patients a choice in how they take their inhaled medication. These include the mainstay of asthma therapy, the metered dose inhaler (MDI), and the breath-operated inhalers. One of the major challenges that all the leading companies in the respiratory area have faced in recent years is the environmental effects of chlorofluorocarbons. The pharmaceutical industry recognized the need to reformulate MDI products containing chlorofluorocarbons, and a number of companies began to develop alternatives in the late 1980s. To help facilitate this change in products, an industry consortium was formed (International Pharmaceutical Aerosol Consortium), and this has managed many of the overarching issues. After an extensive search was conducted, the most suitable alternatives were the hydrofluoroalkanes, which do not contain chlorine, are ozone friendly, and have lower global-warming potentials than the chlorofluorocarbons that they are replacing. To date it is estimated that the industry has invested over $1.0 billion ($US) on global research and development efforts. The first countries to launch the nonchlorofluorocarbon MDIs have been in Europe, and now salbutamol and 2 inhaled steroids are widely available across Europe in their nonchlorofluorocarbon form. Clinical testing has been extensive, and patient acceptance of the new products has proved to be high. Maintaining the smooth progress of the global transition is important, and continued dialogue between all key stakeholders should ensure success in this area. (J Allergy Clin Immunol 1999;104:S268-70.)

A Controlled Trial of Chlorofluorocarbon-Free Triamcinolone Acetonide Inhalation Aerosol in the Treatment of Adult Patients With Persistent Asthma

To compare the dose response, efficacy, and safety of inhaled triamcinolone acetonide (TAA) with a hydrofluoroalkane (HFA) propellant (75 microg/puff), TAA with a chlorofluorocarbon propellant (dichlorodifluoromethane [P-12]; 75 microg/puff), and placebo in adult patients with persistent asthma. Multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 514 adult patients with persistent asthma. Patients received 8 weeks of treatment with 150, 300, or 600 microg/d of TAA HFA, the same doses of TAA P-12, or placebo following a 5- to 21-day baseline period. Efficacy was assessed by spirometry, and by daily recordings of albuterol use, peak expiratory flow (PEF), asthma symptom ratings, and nighttime awakenings throughout the study. Linear trend analysis showed that both formulations of TAA at all doses produced statistically significant improvements compared with placebo in spirometry, asthma symptom scores, albuterol use, and PEF. Significant improvement was seen as early as 24 h for morning PEF and as early as 1 week for FEV(1) (TAA HFA, 600 microg/d; TAA P-12, 300 and 600 microg/d) and albuterol use (all doses of both formulations). The P-12 and HFA formulations had comparable efficacy. A dose response showing greater improvement with higher doses was evident for the majority of parameters for both formulations. The incidences of adverse events were similar across all treatment groups with no dose-related trends. HFA and P-12 formulations of TAA inhalation aerosol were therapeutically equivalent and showed comparable safety and dose-related efficacy in the treatment of patients with persistent asthma.

Controlled Trial of Two Formulations of Cromolyn Sodium in the Treatment of Asthmatic Patients ≥ 12 Years of Age

This multicenter, randomized, double-blind, placebo-controlled, parallel study compared the efficacy and safety of the hydrofluoroalkane (HFA) formulation of cromolyn sodium metered-dose inhaler (MDI) with the chlorofluorocarbon (CFC) formulation in asthmatic patients > or = 12 years old over a 12-week period. Stable asthmatics using only currently marketed cromolyn sodium and as-needed inhaled beta2-agonists were randomly assigned to treatment with HFA cromolyn sodium, CFC cromolyn sodium, or placebo, administered as two inhalations (2 mg) qid for 12 weeks. Prior to randomization, all patients were required to meet minimum symptom and/or pulmonary function test criteria after discontinuation of cromolyn sodium. Efficacy was assessed by changes in daily symptom scores, albuterol use, peak expiratory flow, pulmonary function measurements, and overall opinions of effectiveness. A total of 280 patients in 29 centers were randomly assigned to treatment with HFA cromolyn sodium (n = 94), CFC cromolyn sodium (n = 91), or placebo (n = 95). Patients treated with the HFA formulation of cromolyn sodium demonstrated a 28 to 33% improvement over placebo for all symptom scores (p < 0.05) and a 35% improvement over placebo in the use of albuterol MDI (p < 0.05). The patients' opinions of overall effectiveness favored HFA cromolyn sodium (p = 0.011) and CFC cromolyn sodium (p = 0.006) over placebo. The investigators' opinions indicated a statistically significant difference favoring CFC cromolyn sodium compared with both placebo (p < 0.001) and HFA cromolyn sodium (p = 0.042). No statistically significant differences existed among groups in the incidence of treatment-related adverse events. The HFA formulation of cromolyn sodium MDI is a well-tolerated and effective treatment for asthma patients > or = 12 years old. The safety and efficacy profile of the HFA formulation is comparable to that of the CFC formulation.

Evaluation of a non-chlorofluorocarbon formulation of cromolyn sodium (Intal) metered-dose inhaler versus the chlorofluorocarbon formulation in the treatment of adult patients with asthma: A controlled trial

Background: Cromolyn sodium is a nonsteroidal inhaled antiinflammatory agent for the treatment of asthma. As with other pressurized aerosol medications, the metered-dose inhaler (MDI) formulation currently contains chlorofluorocarbon (CFC) propellants. Because of their harmful effects on the environment CFCs are now generally banned from production and use. Alternative propellants under production for MDIs include derivatives of hydrofluoroalkane (HFA). This study uses HFA-227 in an MDI formulation of cromolyn sodium. Objectives: The objectives of the study were (1) to examine the efficacy and safety of an HFA formulation of cromolyn sodium (Intal) MDI and (2) to compare the HFA formulation with the CFC formulation. Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel study with two active groups (HFA-cromolyn sodium [ n = 113] and CFC-cromolyn sodium [ n = 107] ) and a placebo-treated group ( n = 105). Results: Patients treated with either formulation of cromolyn sodium MDI showed a statistically significant ( p < 0.05) improvement of 12% to 18% compared with placebo in symptom summary score, daytime asthma symptoms, and albuterol use. No statistically significant differences were observed in pulmonary function. Patient and physician opinions of overall effectiveness favored HFA-cromolyn sodium over placebo ( p = 0.01), with no other significant between-treatment differences. No statistically significant differences existed among groups in the incidence of treatment-related adverse events. Conclusion: The HFA formulation of cromolyn sodium MDI is a well- tolerated and active alternative treatment for asthma patients aged 12 years and more.(J Allergy Clin Immunol 1998;101:7-13.)