pulmicort and apaflurane

The pathology of asthma has clarified that the inflammatory process in the pulmonary airways of the asthmatic patients determines asthma symptom activity primarily. Among the anti-inflammatory agents currently available to treat asthma, glucocorticoids are the most effective, and the topically active agents, inhaled corticosteroids (ICS) are the most efficient. In Japan, two ICS are commercially available: beclomethasone dipropionate (BDP) and fluticasone propionate(FP). Both agents have been widely used and their clinical efficacy (BDP vs FP at half the microgram dose of the BDP) are largely comparable. In order to bring asthmatic patients maximal benefits of the ICS, enhancing treatment compliance and giving educations (including how to use the ICS) are mandatory. New ICS, which have better drug delivery and be topically more potent, will be available.

Topics: Administration, Inhalation; Administration, Topical; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Clinical Trials as Topic; Fluticasone; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Patient Education as Topic; Pregnenediones

Topics: Administration, Topical; Adult; Aerosol Propellants; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Chemistry, Pharmaceutical; Clinical Trials as Topic; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Nebulizers and Vaporizers

Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study.. This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD.. This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1, 964 patients aged >or =40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo.. The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1. .. Budesonide/formoterol 320/9 microg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001). The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p

Topics: Adult; Aerosol Propellants; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Follow-Up Studies; Forced Expiratory Volume; Formoterol Fumarate; Humans; Hydrocarbons, Fluorinated; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

The recently released handheld In-Check device can be used to measure the peak inspiratory flow rate (PIF) of patients and is reportedly useful in determining whether the PIF is sufficient for using inhaler devices. In this study, we evaluated the effects of instructions for the use of the device and of the device type based on measurements of the PIF in asthma.. One hundred and thirty-five asthmatic patients who used a fluticasone propionate Diskus (FP-DK) or a budesonide Turbuhaler (BUD-TH) were studied.. The PIF was measured by the In-Check device. For patients without a sufficient PIF of 50 l/min, instructions for the use of the device were given, and the device was changed to hydrofluoroalkan-beclomethasone dipropionate (HFA-BDP).. A significant correlation between the PIF and peak expiratory flow rate (p < 0.0001) was found. In 10 patients in whom the PIF did not increase to >50 l/min after instructions, the device was changed to HFA-BDP, which resulted in significant improvements in lung function in terms of the forced expiratory volume in 1 s (p = 0.018), peak expiratory flow (p = 0.038) and the maximum expiratory flow rates at 50% (p = 0.018) and 25% (p = 0.011).. Measurement of the PIF by the In-Check device is useful in the clinical management of asthma, to provide an appropriate device so as to improve lung function.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Androstadienes; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; Female; Fluticasone; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Inhalation; Male; Middle Aged; Respiratory Function Tests

The traditional chlorofluorocarbon (CFC) propellants used in pressurized metered-dose inhalers (pMDIs) have unacceptable environmental effects and are being replaced by alternatives such as hydrofluoroalkanes (HFAs). However, there is a need to ensure that pMDIs with these novel propellants are as effective and safe as their older counterparts.. Single-dose pharmacokinetic and multiple high-dose Phase I studies in healthy volunteers and randomized, controlled 12-week Phase III clinical trials in children, adolescents and adults with mild-to-moderate asthma have been performed to compare the efficacy and safety of HFA-based budesonide inhaler therapy with the traditional CFC-based pMDI.. The pharmacokinetic study in 40 persons showed comparable characteristics of CFC and HFApMDIs, with good dose-proportionality, at doses of 400, 800 and 1,600 microg. The high-dosage (1,600 microg/day) study in 48 subjects showed both inhaler types to be similar in terms of effects on hypothalamic-pituitary-adrenal axis function over 4 weeks. The pediatric clinical study involved 159 children and showed noninferiority of the HFA pMDI in terms of 12-week change in forced expiratory volume in 1 sec, other spirometric parameters and symptomatic measures. The adolescent/adult study in 321 subjects also showed similarity between the two formulations, in terms of 12-week primary endpoint (changes in morning peak expiratory flow rates) and other lung function and symptom measures. Both formulations were well-tolerated, with no safety issues being identified for the novel HFA inhaler in any study.. Budesonide HFA pMDI is pharmacokinetically and clinically comparable to the traditional CFC-based inhaler, with similar safety profile.

Topics: Adolescent; Adult; Aerosol Propellants; Aged; Asthma; Bronchodilator Agents; Budesonide; Child; Chlorofluorocarbons; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Hydrocarbons, Fluorinated; Hypothalamo-Hypophyseal System; Male; Metered Dose Inhalers; Middle Aged; Peak Expiratory Flow Rate; Pituitary-Adrenal System; Therapeutic Equivalency

Inhaled corticosteroids are powerful drugs that can suppress airway inflammation in asthmatic patients. Deposition of most of the inhaled corticosteroid occurs mainly in the central airways. However, a new hydrofluoroalkane formulation of beclomethasone dipropionate (HFA-BDP) is preferentially deposited in the distal airways. Inflammatory characteristics of induced sputum have been shown to differ in samples collected early after sputum induction compared with later.. To compare the effects of HFA-BDP and budesonide in a dry powder inhaler (DPI-BUD) on inflammatory cells and inflammatory cytokine expression in early and late induced sputa compared with placebo.. Seventeen patients with mild, intermittent bronchial asthma were randomly assigned to two treatment groups: eight patients received HFA-BDP and nine patients received DPI-BUD. Each patient was treated with one of the active treatments and placebo (for four weeks), with a two-week washout interval in between. Inflammatory cells and expression of interleukin (IL)-4 and IL-5 were measured in early and late induced sputa before and after active treatment, as well as before and after placebo treatment using immunocytochemistry and in situ hybridization.. Compared with placebo, eosinophils were significantly reduced in both early and late induced sputa after HFA-BDP treatment (P<0.05), whereas DPI-BUD had a significant effect only on early induced sputum. Both HFA-BDP and DPI-BUD decreased IL-4 expression in early and late induced sputa, but the effect was more prominent with HFA-BDP. IL-5 expression was reduced in both early and late induced sputa after HFA-BDP treatment. DPI-BUD significantly decreased IL-5 expression in early but not in late induced sputum. The number of lymphocytes was not altered by either treatment.. HFA-BDP reduced eosinophilic inflammation and T helper 2-type cytokine expression in both early and late induced sputa, whereas the effect of DPI-BUD on inflammation was predominantly demonstrated in early induced sputum.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aerosol Propellants; Algorithms; Anti-Asthmatic Agents; Asthma; Beclomethasone; Biomarkers; Budesonide; Cytokines; Double-Blind Method; Eosinophils; Female; Humans; Hydrocarbons, Fluorinated; Lymphocytes; Male; Powders; Sputum

To evaluate the efficacy and tolerability of a novel hydrofluoroalkane (HFA) pressurised metered dose inhaler (pMDI) formulation of budesonide (Pulmicort) versus the conventional chlorofluorocarbon (CFC) pMDI formulation in paediatric patients with asthma.. This was a Phase III, multicentre, 12-week, double-blind, randomised, parallel-group study involving children (6-12 years of age) with mild to moderate asthma. Patients received either budesonide HFA pMDI or budesonide CFC pMDI 200 mug twice daily, with or without a spacer (NebuChamber/Nebunette). Primary efficacy endpoint: mean percentage change in forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Secondary efficacy endpoints included changes in FEV(1) per cent of predicted normal, forced vital capacity, morning and evening peak expiratory flow rate, asthma symptoms and use of rescue medication.. A total of 159 patients received treatment (HFA 77, CFC 82). For mean percentage change in FEV(1) from baseline to week 12, the difference between the treatments (CFC pMDI - HFA pMDI) was -3.1% (95% confidence interval [CI] -8.0% to 1.8%) for the full analysis set and was not affected by spacer use. The upper CI was < 10% (the predefined non-inferiority margin), so non-inferiority was demonstrated. Improvements in the secondary efficacy endpoints with both budesonide formulations were not significantly different. In both groups there were similar numbers of adverse events and no evidence of oral candidiasis at week 12.. Treatment with budesonide HFA pMDI is effective and well tolerated in children with asthma and is clinically comparable to budesonide CFC pMDI.

Topics: Aerosol Propellants; Asthma; Bronchodilator Agents; Budesonide; Child; Chlorofluorocarbons; Double-Blind Method; Female; Humans; Hydrocarbons, Fluorinated; Male; Metered Dose Inhalers; Peak Expiratory Flow Rate; Treatment Outcome

This study was undertaken to investigate whether budesonide 4001 microg twice daily (Chiesi Farmaceutici S.p.A.) given with the HFA-134a propellant is equivalent in efficacy and safety to the same dose regimen delivered with the marketed CFC product in adult asthmatics with mild to moderate persistent asthma; the effects of budesonide HFA 800 microg once daily were also studied. After a 2-week run-in, a total number of 98, 103 and 97 patients were assigned to the 12-week treatment with budesonide given with HFA or CFC twice daily (morning and evening), or HFA once daily (morning), respectively. The main outcome variable morning PEFR, as well as evening PEFR and clinical symptoms (day-time and night-time asthma attacks, number of asthma-induced night-time awakenings and overall symptoms' scores) were measured daily by patients. Other standard pulmonary function testing were measured at clinic visits. A blood sample for morning serum dosing (8.00-10.00 AM) was taken at baseline and at endpoint. Adverse events and vital signs were also recorded. Significant improvements at endpoint in morning and evening PEFR, as well as in clinic PEFR and MEF50, were observed in both the twice daily groups only. An exact proof of equivalence between HFA and CFC given twice daily was demonstrated for the primary parameters, morning PEFR (equivalence pre-defined limits were +/- 40.27 l/min, difference between means = 4.0 l/min and 95% CI -6.9-14.9) and secondary parameters as evening PEFR: (limits +/- 40.19 l/min, difference between means = 2.1 l/min and 95% Confidence interval (CI) -9.4-13.5) and FEV1 (limits +/- 0.27 l, difference between means = 0.0 l and 95% CI -0.11-0.10). Less evident (but within limits) proofs of equivalence were shown in the comparisons with the once daily group. No substantial differences between the three groups were observed for the other efficacy variables, including symptoms and use of rescue salbutamol, which significantly improved over the run-in values in all groups. Minimal and non-significant decreases over pre-treatment values were observed in the three groups for morning serum cortisol levels: the analysis of individual data has shown a better outcome in the HFA twice daily regimen, compared with the other two groups. Again, a similar amount of patients in both the twice daily groups reported drug-related adverse events, which were more frequent in the once daily HFA group. Therefore, the results of this study have shown that inhaled budes

Topics: Administration, Inhalation; Adult; Aged; Anti-Asthmatic Agents; Asthma; Budesonide; Drug Administration Schedule; Female; Humans; Hydrocarbons, Fluorinated; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Ventilation; Therapeutic Equivalency; Treatment Outcome

The aim of the present study was to demonstrate an equivalent asthma control and safety of inhaled budesonide 200 microg unit-dose via a spacer device (Jet Spacer, Chiesi Farmaceutici S.p.A.) given with an HFA-134a or CFC propellant in stable patients treated with inhaled corticosteroids. A total number of 270 patients, 134 in the HFA-134a group and 136 in the CFC group, completed a 2-week run-in period and were then randomised to receive a daily dose of inhaled budesonide (low dose: 400 microg, medium dose: 800 microg, high dose: 1200 or 1600 microg), defined on the basis of the dose of previous inhaled steroids given twice daily for 12 weeks. Morning and evening PEFR, intake of rescue salbutamol, number of day-time and night-time asthma attacks, number of night-time awakenings due to asthma and clinical symptoms were recorded daily by patients on diary cards. Pulmonary function tests (FEV1, FVC, PEFR and MEF50) and vital signs were measured at the clinics at study entry, at the start of treatment and after 2, 4, 8 and 12 weeks thereafter. Morning serum cortisol (8.00-10.00 AM) was measured at baseline and in the final visit. Adverse events and vital signs were recorded throughout the total study period. Small increases vs. baseline for lung function (more markedly in the high-dose subsets) and significant decreases of symptoms and use of rescue salbutamol were similarly observed in both groups. Equivalence was demonstrated for the primary endpoint morning PEFR (difference between means = -1.51 l/min; 95% CI: -9.40-6.37 l/min; pre-defined limits: +/- 42.16 l/min, i.e. +/- 10% of the reference LSM) as well as for evening PEFR and FEV1, both in the ITT population or on a per-protocol basis. No statistically significant differences between groups were observed in any of the other efficacy variables. A similar proportion of drug-related adverse events was observed in the two groups, without drug-related serious events in either group. No evidence of adrenal depletion was also noted with both propellants. In conclusion, the budesonide HFA-134a formulation given with a spacer device provided an equivalent asthma control with that of a corresponding CFC product, when administered in stable patients treated with inhaled corticosteroids in a broad range of daily doses. The use of the new propellant did not modify the safety profile of inhaled budesonide.

Topics: Administration, Inhalation; Adult; Aerosol Propellants; Aged; Anti-Asthmatic Agents; Asthma; Budesonide; Chlorofluorocarbons; Dose-Response Relationship, Drug; Female; Humans; Hydrocarbons, Fluorinated; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Ventilation; Treatment Outcome

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.

Topics: Administration, Inhalation; Adult; Aerosol Propellants; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Chemistry, Pharmaceutical; Cross-Over Studies; Double-Blind Method; Drug Delivery Systems; Female; Humans; Hydrocarbons, Fluorinated; Hydrocortisone; Male; Nebulizers and Vaporizers; Therapeutic Equivalency

The present study demonstrates the equivalent efficacy for BDP 500 microg bid given via MDI with the new HFA-134a propellant (Chiesi Farmaceutici S.p.A., Parma) compared to a conventional CFC propellant (Becotide, Allen & Hanburys, UK). One hundred and sixteen adult patients with stable mild to moderate asthma (FEV1 > or = 60% of predicted normal) entered a 2-week run-in period where they maintained their own inhaled corticosteroids and were then assigned to a 12-week treatment with the test drug in a randomized, multicentre, double-blind, double-dummy, parallel-group design. Ninety-one patients completed the study period. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of daytime and nighttime asthma attacks, number of nighttime awakenings, and clinical symptoms were recorded daily by patients on a diary card. Pulmonary function tests (FEV1, FVC, PEFR, MEF50 and FEF25) were completed at study entry, at the start of treatment and every 2 weeks thereafter. Morning (08.00-10.00 AM) serum cortisol was measured at the start and at the end of treatment. Adverse events were collected for the total study period. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1 (the 95% CI of the treatments' difference was within the 5% of the LSM of BDP CFC). The other secondary pulmonary function tests measured at the clinic visit showed a satisfactory asthma control, albeit without statistically significant differences between groups. Decreases in the use of rescue salbutamol and in clinical symptoms were also reported in both groups, with no differences between them. Adverse events were reported in 81.4% of patients in the BDP HFA group and in 82.5% in the CFC group. There were 73 and 59 adverse drug reactions in the two groups, respectively; the difference was mainly due to differences in taste. No drug-related serious adverse events were reported in either group. No difference was seen for morning serum cortisol between baseline and end of treatment, or between groups. In conclusion, the BDP-HFA 134a formulation proved to be statistically equivalent to the standard BDP CFC product over 12 weeks in adult patients with mild to moderate asthma.

Topics: Adult; Aged; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Chemistry, Pharmaceutical; Chlorofluorocarbons; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocarbons, Fluorinated; Least-Squares Analysis; Male; Middle Aged; Patient Compliance; Peak Expiratory Flow Rate; Severity of Illness Index; Treatment Outcome; United Kingdom; Vital Capacity

To assess the long-term safety of hydrofluoroalkane 134a (HFA)-beclomethasone dipropionate (BDP) extrafine aerosol administered by the Autohaler compared with chlorofluorocarbon (CFC)-BDP administered by a press-and-breathe metered-dose inhaler (pMDI) and spacer (+S) in the treatment of children with asthma.. This 12-month, open-label, randomized, multicenter study enrolled 300 children who were aged 5 to 11 years and had well-controlled asthma on inhaled CFC-BDP or budesonide; 256 patients were using doses within the recommended range (200-400 microg) and were analyzed separately. Patients were randomized in a 1:3 ratio to continue on CFC-BDP+S at approximately the same dose as they were using before study entry or switch to HFA-BDP at half the daily dose.. Asthma control was well maintained in the HFA-BDP group as evidenced by lung function tests and asthma symptoms compared with CFC-BDP+S at approximately twice the dose. There were no significant differences between the HFA-BDP 100 to 200 microg and CFC-BDP+S 200 to 400 microg treatment groups in mean change from baseline in height (5.23 cm vs 5.66 cm at month 12, respectively) or mean growth velocity from day 1 to month 12 (5.27 cm/y vs 5.71 cm/y, respectively). There were no significant differences between groups in adrenal function tests or markers of bone metabolism.. In this long-term study in children with asthma, extrafine HFA-BDP provided long-term maintenance of asthma control at approximately half the dose compared with CFC-BDP+S. There were no clinically meaningful differences between HFA-BDP extrafine aerosol and conventional CFC-BDP+S with regard to growth or other systemic effects.

Topics: Administration, Inhalation; Aerosol Propellants; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Chemistry, Pharmaceutical; Child; Child Development; Child, Preschool; Chlorofluorocarbons; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Growth; Humans; Hydrocarbons, Fluorinated; Male; Respiratory Function Tests; Treatment Outcome

Hydrofluoroalkane-beclomethasone dipropionate Autohaler (HFA-BDP AH) is a breath-actuated chlorofluorocarbon (CFC)-free metered dose inhaler in which BDP is in a solution of HFA propellant. Budesonide Turbuhaler (BUD TH) is a breath-dependent dry powder inhaler.. To test the hypothesis that half the daily dose of HFA-BDP AH would provide an equivalent control of asthma symptoms to the BUD TH.. This was an 8-week open study in patients with symptomatic moderate-to-severe asthma, previously on BUD 500-1,000 microg x day(-1), or an equivalent. After 5-14 days' run-in, patients were randomized to HFA-BDP AH 800 microg x day(-1) or BUD TH 1,600 microg x day(-1). The intent-to-treat population consisted of 111 patients on HFA-BDP AH and 98 patients on BUD TH.. Mean change from baseline in PEF in the morning (AM PEF) at week 8 was 23.95 liters x min(-1) for HFA-BDP AH and 24.46 liters x min(-1) for BUD TH. A two-sided equivalence test using the 0.51 liter x min(-1) difference gave 95% confidence intervals within a defined equivalence interval of (-infinity, 25 liters x min(-1)) indicating that the mean change in AM PEF was equivalent for the two groups. There were no significant differences in the mean change from baseline in FEV1 or beta-agonist use. Patients using HFA-BDP AH had a significantly greater mean change from baseline in the percentage of days free from shortness of breath (p = 0.05), chest tightness (p = 0.02) and nights without sleep disturbance (p = 0.04) at week 3, and wheeze (p = 0.01), shortness of breath (p = 0.02), chest tightness (p < 0.01) and daily asthma symptoms (p = 0.03) at week 8. The incidence, type and severity of adverse events were similar in each group. At week 8, the mean change from baseline in corrected urine cortisol/creatinine ratio in a subgroup of patients was -0.36 for HFA-BDP and -4.88 for BUD TH (p < 0.01).. HFA-BDP 800 microg x day(-1) provided control of moderate-to-severe asthma with efficacy and safety at least similar to BUD TH 1,600 microg x day(-1).

Topics: Administration, Inhalation; Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Asthma; Beclomethasone; Blood Proteins; Budesonide; Cohort Studies; Creatinine; Eosinophil Granule Proteins; Eosinophils; Female; Follow-Up Studies; Forced Expiratory Volume; France; Germany; Humans; Hydrocarbons, Fluorinated; Hydrocortisone; Leukocyte Count; Male; Middle Aged; Netherlands; Peak Expiratory Flow Rate; Respiratory Function Tests; Ribonucleases; Treatment Outcome

The impending phaseout of chlorofluorocarbons as propellants in pressurized metered-dose inhalers used in the treatment of asthma has resulted in the development of alternative devices to deliver drug to the pulmonary airways. These alternative devices include metered-dose inhalers using environmentally friendly hydroflurocarbon propellants and breath-actuated dry-powder inhalers. The purpose of this study was to compare the single- and multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of a newly developed hydroflurocarbon formulation of triamcinolone acetonide (Azmacort HFA 225 mcg Inhalation Aerosol) to that of the dry-powder formulation of budesonide (Pulmicort Turbuhaler 200 mcg). This three-way crossover study used 18 normal healthy subjects each receiving a 675 mcg dose of triamcinolone acetonide, 600 mcg dose of budesonide, or placebo twice a day for 5 days. Serial plasma samples were collected after the first and last dose of test medication for pharmacokinetic analysis. Pharmacodynamics were assessed by changes in hypothalamic-pituitary-adrenal axis function as measured by 8 a.m. serum cortisol, 24-hour overnight serum cortisol AUC(0-24), and 24-hour urinary-free cortisol after the last evening dose of test drug. Tolerability was assessed through physical examinations, vital signs, 12-lead ECG, routine clinical labs, and adverse events recording. Both compounds were systemically absorbed. However, no significant drug accumulation was noted with chronic dosing. Chronic dosing did result in a statistically significant 20% reduction in basal 24-hour serum cortisol AUC(0-24) for both compounds. There were no clinically significant abnormalities in physical examination, vital signs, 12-lead ECG, or routine clinical labs noted during the study. Overall, the study drugs were well tolerated, with adverse events characterized as mild to moderate in severity.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosol Propellants; Analysis of Variance; Anti-Inflammatory Agents; Area Under Curve; Blood Pressure; Budesonide; Cross-Over Studies; Diarrhea; Dizziness; Dose-Response Relationship, Drug; Electrocardiography; Headache; Humans; Hydrocarbons, Fluorinated; Hydrocortisone; Male; Nebulizers and Vaporizers; Pulse; Triamcinolone Acetonide

The aerosol performance of budesonide solution-based pressurized metered-dose inhalers (HFA 134a), with various amounts of ethanol (5-30%, w/w) as co-solvents, was evaluated using impaction and laser diffraction techniques. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter was increased and the fine particle fraction showed a significant decline. Although data obtained from laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology - the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from 52% to 2.5% approximately, when the ethanol concentration was increased from 5% to 30%, respectively. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period; while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.

Topics: Administration, Inhalation; Aerosol Propellants; Aerosols; Anti-Inflammatory Agents; Budesonide; Chemical Phenomena; Drug Compounding; Drug Delivery Systems; Ethanol; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Metered Dose Inhalers; Microscopy, Electron, Scanning; Particle Size; Porosity; Solubility; Solutions; Solvents; Surface Properties; Volatilization

Inhaled corticosteroid (ICS) has played an important role in the management of asthma. Although several kinds of ICSs are currently available, there is no established strategy for ICS selection.. Using the data from the 2004 questionnaire surveys by the Niigata Asthma Treatment Study Group, we analyzed relationships between each patient and the ICS employed on the basis of patient background, asthma control and treatment, and indicated characteristics of ICS selection by the physician.. Of 2852 cases, 2279 (79.9%) were ICS users, and 1513 (66.4% of ICS users) were classified as being in the fluticasone propionate (FP) group, 438 (19.2%) in the budesonide (BUD) group, and 240 (10.5%) in the hydrofluoroalkane-beclomethasone (HFA-BDP) group, indicating that FP was a standard ICS in this study. The mean age was significantly lower in the BUD group (52.3+/-18.2 years) and was significantly higher in the HFA-BDP group (59.9+/-17.0 years) than that in the FP group (55.8+/-16.6 years). The proportion of female patients was significantly higher not in the HFA-BDP (46.5%) but in the BUD group (59.0%) than in the FP group (51.1%). These results indicated that BUD was frequently prescribed to young female and HFA-BDP was employed in the elderly patients irrespective of gender compared with FP.. Our study indicates that ICS selection is reasonably adapted to each patient's background at least in the surveyed area. We need to elucidate the characteristics of ICS selection further in the future as new ICS and devices are developed.

Topics: Administration, Inhalation; Age Factors; Androstadienes; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; Drug Prescriptions; Female; Fluticasone; Humans; Hydrocarbons, Fluorinated; Japan; Male; Middle Aged; Retrospective Studies; Sex Factors; Surveys and Questionnaires; Treatment Outcome

Pressurized metered-dose inhalers (pMDIs) have been recognized as potential devices for the delivery of systemically acting drugs, including biomolecules, to and through the lungs. Therefore, the development of novel excipients capable of imparting stability to suspension formulations in hydrofluoroalkane (HFA) propellants is of great relevance because many of the drugs of interest are poorly soluble in HFAs. In this work, we use ab initio calculations and chemical force microscopy (CFM) to determine the HFA-philicity of the biodegradable and biocompatible ester moiety quantitatively. The complementary information obtained from the binding energy calculations and adhesion force measurements are used to gain microscopic insight into the relationship between the chemistry of the moiety of interest and its solvation in HFA. A lactide (LA)-based copolymer surfactant was synthesized and characterized, and its ability to stabilize a dispersion of micronized budesonide in HFA227 was demonstrated. These results corroborate the ab initio calculations and CFM and show that the LA-based moiety is a suitable candidate for enhancing the stability of dispersions in HFA-based pMDIs.

Topics: Aerosol Propellants; Bronchodilator Agents; Budesonide; Hydrocarbons, Fluorinated; Metered Dose Inhalers; Polyesters; Pulmonary Surfactants

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.

Topics: Aerosol Propellants; Aerosols; Bronchodilator Agents; Budesonide; Chemistry, Pharmaceutical; Crystallization; Drug Stability; Hydrocarbons, Fluorinated; Lipids; Metered Dose Inhalers; Particle Size; Powders; Suspensions