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PubMed2004

Flunisolide HFA for the treatment of asthma: an old friend reformulated.

The environmental mandate to eliminate the production of ozone-depleting products including chlorofluorocarbon (CFC) propellants has encouraged much needed research into improving modes of delivery of inhaled corticosteroids and enhancing drug deposition. Consequently, flunisolide CFC, an inhaled corticosteroid with a proven track record in the treatment of asthma, has been reformulated using a hydrofluoroalkane (HFA) as a propellant and is now awaiting FDA approval. Flunisolide HFA is a solution aerosol, unlike flunisolide CFC which is a suspension aerosol. As a solution aerosol, flunisolide HFA has a smaller mean particle size than flunisolide CFC. In addition, the built-in spacer included in the flunisolide HFA inhaler acts to reduce ex-actuator particle size; the smaller particle size of flunisolide HFA results in an improved deposition profile. Flunisolide HFA has substantially more lung deposition and much less oropharyngeal deposition than flunisolide CFC. Limited information is currently available on the clinical performance of flunisolide HFA. A single dose-response study has been performed in adults and in children comparing multiple doses of flunisolide HFA and flunisolide CFC. These studies indicate that flunisolide HFA is effective in controlling asthma. No unusual safety concerns have been noted, although further studies are needed to determine the long-term systemic effects of flunisolide HFA.

Administration, Inhalation↗

PubMedDate not supplied

Multiple-dose proportionality study of flunisolide hydrofluoroalkane.

The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide is a modification of the original chlorofluorocarbon formulation. HFA flunisolide substitutes an HFA for a chlorofluorocarbon propellant and uses a built-in spacer in its pressurized metered-dose inhaler. An open-label, randomized, three-way crossover, multiple-dose study evaluated the dose proportionality of three doses of flunisolide HFA. Twenty-one healthy volunteers received the following doses twice daily for 4.5 days: 85, 170, and 340 micrograms. Plasma levels of flunisolide and of the flunisolide metabolite 6 beta-OH flunisolide were measured after single- and multiple-dose administration. After a single dose, dose proportionality was observed across the three dose levels for peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) up to both the time corresponding to the last measurable concentration (AUC0-tau) and the time to infinity (AUC0-infinity). After multiple doses, dose proportionality was observed for both Cmax and AUC at the medium and high doses. Predose plasma levels of flunisolide measured on day 4 were below the limit of detection. The elimination half-life of flunisolide ranged from 0.95 to 1.34 hours. After both single and multiple doses, dose proportionality was observed in dose-adjusted Cmax and AUC0-infinity for the inactive 6 beta-OH metabolite. HFA flunisolide was well tolerated. The lack of accumulation after repeated administration of HFA flunisolide suggests that the systemic exposure of flunisolide is low, which is a safety goal for inhaled corticosteroids.

Administration, Inhalation↗

PubMed1985

Optimal use of tube spacer aerosols in asthmatic children.

In a double blind cross-over study the bronchodilator response after eight different modes of inhalation of terbutaline from a pressurized aerosol with a tube spacer was assessed in fifteen asthmatic children. Slow inspiratory flow rates (15-30 l/min) were found to be associated with a statistically significant increase in response when compared with flow rates higher than 70 l/min (P less than 0.01). Tilting the head back during the inhalations and a breath-holding pause of 10 sec after the inhalation had no significant effect upon bronchodilation. In addition, bronchodilation was the same whether the children inhaled from RV or FRC, and whether they inhaled as deeply possible or only to about half the maximum volume. The results suggest that efforts should be made to develop a new and more simple set of instructions for the use of tube spacer aerosols.

Adolescent↗

PubMed2003

Equivalent asthma control and systemic safety of inhaled budesonide delivered via HFA-134a or CFC propellant in a broad range of doses.

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.

Administration, Inhalation↗

PubMed1993

[Analysis of fenoterol efficacy given as an aerosol using various mouth pieces].

The effect of different mouth pieces on efficacy of fenoterol was studied in 40 patients with atopic and non-atopic bronchial asthma with reversible bronchial constriction. Four devices were studied: standard MDI unit, MDI unit with Boehringer and Astra mouth pieces, MDI unit with spacer. PEF values were registered 7 hours following inhalation. Statistical differences were not significant within the whole group. In selected older patients (above 60 years of age) spacer and Astra mouth pieces produced significant changes.

Adult↗

PubMed2005

An indigenous spacer device for drug delivery in severely dyspnoeic patients.

Bronchodilator aerosols are commonly delivered through nebulizers or metered dose inhalers (MDI) to treat bronchospasm. Although the clinical results obtained with both these devices are comparable, the use of MDI offers several advantages like lower drug dose, reduced risk of complications, reliability of dosing, ease of administration, less personnel time and reduced cost. However, in non-intubated, spontaneously breathing patients, the amount of drug inhaled depends on the coordination of the inspiratory phase and delivery of the drug. In severely dyspnoeic or disoriented patients in the casualty department or intensive care settings, this is often not possible. Valved spacers and breath-actuated inhalers may not be easily available in such situations. Also, the spacer devices cannot be connected to the anatomical facemask and the need to discontinue oxygenation for aerosol delivery further limits their use.

Bronchial Spasm↗

PubMed1992

How much nebulised budesonide reaches infants and toddlers?

The amount of budesonide suspension actually delivered to six subjects (aged 4-30 months) by a jet nebuliser and spacer system (System 22) was determined. Two nebulisations were performed in each subject using a filter at the exhalation outlet of the inhalation chamber. An inhalation filter was additionally attached between the facemask and the spacer in the first test. The drug was inhaled during the second test. The nebuliser equipment was washed with ethanol and the amount of drug deposited was determined. The amount of budesonide deposited in the exhalation filter increased when the inhalation filter was omitted. Only 14% of the nominal dose (500 micrograms) of budesonide was found in the inhalation filter, increasing from nine to 19% with increasing age. Approximately 75% of the nominal dose was found in the nebuliser equipment. These findings must be considered when deciding the nominal dose of budesonide suspension to be given to infants and toddlers.

Administration, Inhalation↗

PubMed2001

Flunisolide HFA vs flunisolide CFC: pharmacokinetic comparison in healthy volunteers.

Two preparations of flunisolide, an inhaled corticosteroid, were compared in a parallel, multiple-dose study of 31 healthy volunteers. The new flunisolide preparation substitutes hydrofluoroalkane (HFA) for chlorofluorocarbon (CFC) as a propellant and incorporates a spacer into its pressurized metered-dose inhaler (pMDI). In this study, subjects were randomly assigned to receive flunisolide CFC 1000 microg bid; flunisolide HFA 170 microg bid; or flunisolide HFA 340 microg bid. Dosing was continued for 13.5 days. Plasma samples were analyzed after the first dose on day 1 and again after 13.5 days of treatment. No significant differences in day 1 dose-adjusted peak plasma concentrations (C(max)) were observed. Dose proportionality in C(max) and area under the concentration--time curves (AUC) was observed for the flunisolide HFA 170 and 340 microg bid groups on days 1 and 14. Day 1 mean dose-adjusted AUC was significantly greater in the flunisolide CFC 1000 microg bid group than in either flunisolide HFA group, indicating greater systemic availability of flunisolide CFC. Oral clearance and volume of distribution were significantly higher for flunisolide CFC than for flunisolide HFA. This may be due to greater oropharyngeal deposition by the flunisolide CFC formulation. Another indicator of greater flunisolide CFC oropharyngeal deposition was observed in C(max) and AUC(0--tlast) values for 6beta-OH flunisolide, the first-pass metabolite of flunisolide. The values of these pharmacokinetic parameters were significantly higher in the flunisolide CFC group than in the 340 microg bid flunisolide HFA group on days 1 and 14. However, this was not the case for cortisol values where flunisolide HFA accounted for less oropharyngeal deposition and more targeted delivery without adverse events. The study demonstrated that flunisolide HFA administered through a pMDI with built-in spacer was safe and well tolerated in healthy volunteers.

Adolescent↗

PubMed1992

A comparison of different intervals of administration of inhaled terbutaline in children with acute asthma.

Thirty asthmatic children, 5 to 14 years of age, 20 boys and 10 girls, were studied while having acute asthmatic attacks. Each group of 10 children received either a single dose of 6 puffs (1500 micrograms) or 3 doses of 2 puffs (500 micrograms) at 5-minute or 15-minute intervals of terbutaline pressurized aerosol inhaler through a 750-ml volumetric spacer. The onset of bronchodilatation was observed within 2 minutes in all. The 3 doses at 15-minute intervals gave the greatest bronchodilatation throughout the 6-hour study period in comparing with the other two regimens. Slightly insignificant increases in systolic blood pressure and heart rate were observed in all groups and there were no statistically significant differences among them. No serious side effects were observed.

Acute Disease↗

PubMed2005

EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin.

Development of a product for pulmonary delivery of insulin presented significant technology challenges for this first-in-class pharmaceutical product. These included developing (a) a chemically stabilized protein, (b) a dry powder formulation exhibiting required aerosol physical characteristics, (c) low-dose powder filling and packaging technology, and (d) a mechanical device for powder dispersal and reliable dosing to the patient. The insulin drug is formulated using a novel excipient combination to create a powder with a high glass transition temperature (Tg). The high Tg minimizes insulin mobility (thus reactivity), enabling ambient storage conditions. The formulation composition results in minimal hygroscopicity, where customized packaging produced product ruggedness to humidity. The formulated insulin powder is manufactured by spray-drying. This technology was further engineered to produce the desired reproducible powder characteristics with tight control over particle size and moisture content. A solution step prior to drying assures homogeneity and minimizes dependence on the physical form of the components. Novel low-dose filling and packaging technology reproducibly meters milligram quantities of microfine powder to meet stringent quality requirements for dose control. The technology for accurate, uniform, high-throughput metering of drug powders allows for automation and is scaleable for commercial operations. Finally, the mechanical device design provides powder deagglomeration and dispersion processes in a reusable dry powder inhaler with unique characteristics. The device was designed to rely on patient-generated compressed air as the energy source. A sonic discharge of air through the novel TransJector reproducibly extracts, deagglomerates, and disperses the inhalation powder. A clear holding (spacer-type) chamber allows for patient feedback via dose visualization, and separates powder dispersal from the inspiratory effort. The EXUBERA [Pfizer (New York, NY) and sanofi-aventis (Paris, France)] product provides insulin into the bloodstream with similar reproducibly and effectiveness as subcutaneous injections.

Administration, Inhalation↗

PubMed1989

Standard and double dose ipratropium bromide and combined ipratropium bromide and inhaled metaproterenol in COPD.

Inhaled ipratropium bromide (IPR) is effective in the management of COPD. The purpose of this study was to determine if doubling the standard dose of IPR resulted in greater bronchodilation and if the addition of an inhaled beta-agonist was superior to standard dose IPR alone. Twelve male patients with stable COPD completed a double blind, randomized trial. On each of three consecutive days, following baseline spirometry, all patients inhaled two puffs of IPR. This was followed by either two additional puffs of IPR, two puffs of metaproterenol (META), or two puffs of placebo. All inhalants were delivered by an InspirEase spacer. Spirometry was repeated at 30, 60, 120, and 180 minutes. The group mean percentage increases in the FEV1 and FVC from baseline were similar at all times tested for the three protocols. In conclusion, for the group, there was no objective benefit to doubling the standard dose of IPR or combining IPR with META. Two of 12 patients benefited from combining the two bronchodilators. A potential sequence for bronchodilator testing is suggested.

Administration, Inhalation↗

PubMed1995

Growth and the growth hormone axis in prepubertal children with asthma.

To determine the influence of asthma and its treatment with inhaled corticosteroids on growth, linear growth velocity, and the growth hormone axis in prepubertal children, we performed a longitudinal study for 12 months in 56 children with asthma, aged between 4.4 and 11.7 years. Height, weight, skin-fold thickness, and lung function were measured every 3 months and bone age at entry to and exit from the study. A 24-hour serum growth hormone concentration profile and fasting insulin-like growth factor I levels were measured halfway through the year. Seventy-four percent of boys and 62% of girls had heights below the 50th percentile. Growth velocity in the nonsteroid-treated control group (n = 13) was normal; 10 of 20 children taking beclomethasone grew slowly (14/20 used a dry powder device), and 4 of 19 children taking budesonide grew slowly (15/19 used a spacer). Three of four children using inhaled steroids and prednisolone grew slowly. In none of the treatment groups were measures of growth hormone secretion or levels of radioimmunoassayable serum insulin-like growth factor I affected. We conclude that slow growth in steroid-treated children with asthma does not appear to be associated with major perturbations in the growth hormone axis.

Administration, Inhalation↗

PubMed1983

Nasal inhalation as a cause of inefficient pulmonal aerosol inhalation technique in children.

In order to evaluate whether children can be taught the efficient use of a pressurized terbutaline aerosol with a tube spacer 71 children were given careful instruction in aerosol inhalation technique according to the manufacturer's instructions. Inhalation technique was assessed as being efficient when a child achieved an increase of more than 19% in FEV1 10 min after taking two puffs of terbutaline (each puff = 0.25 mg). After instruction about 37% of children aged 5-7 years and about 80% of children over 7 years were efficient in inhalation technique. Inhalation through the nose after actuation into the mouth accounted for about 50% of treatment failures, with the problem being more frequent in the younger age group. When this error was corrected about 83% of the children were efficient in the technique. Coordination problems and too rapid inspiration after actuation were also common errors. The findings stress the importance of checking all children's inhalation technique before prescribing inhalation therapy. Careful instruction was not enough. The possibility of nasal inhaling should be borne in mind when looking for causes of treatment failure.

Administration, Intranasal↗

PubMed2001

Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age, and device.

BACKGROUND: The objective was to investigate the local side-effects of inhaled corticosteroids (ICS) in daily life in asthmatic children, particularly the younger ones, by an observational prospective cross-sectional cohort study. METHODS: Asthmatic children (n=639, 75.9+/-48.9 months, 61.3% boys), treated with beclomethasone dipropionate (BDP) (721.0+/-287.3 microg per day) or budesonide (BUD) (835.5+/-684.9 microg per day) for at least 1 month, were recruited at the time of a scheduled visit. Local side-effects were researched by questionnaire (cough during inhalation, hoarseness, dysphonia, and thirsty feeling) and clinical examination (perioral dermatitis, oral candidiasis, and tongue hypertrophy). RESULTS: Exactly 63.3% of the children aged under 6 years and 59.5% of the older ones reported one local side-effect. Cough (39.7%) was dependent on young age, use of BDP, and mainly use of spacer device, with an OR of 4.7 (95% CI: 2.7-8.2). Thirsty feeling (21.9%) and hoarseness (14.1%) occurred in children using ICS and long-acting beta2-agonists. Dysphonia (11.1%) was favored by high doses of BDP and BUD, and by inhalation from spacer devices or nebulizers. No factor favored oral candidiasis (10.7%). Perioral dermatitis (2.9%) and tongue hypertrophy (0.1%) were associated with nebulization. CONCLUSION: Local side-effects of ICS are common in asthmatic children of all ages, and the device used constitutes the most influential factor.

Administration, Inhalation↗

PubMed1983

Aerosol treatment of bronchoconstriction in children, with or without a tube spacer.

To assess whether an extension tube between the aerosol source and the patient improves drug-inhalation therapy in children with acute bronchoconstriction, we treated 20 children under double-blind conditions with placebo or terbutaline delivered by a conventional aerosol or an aerosol with a tube spacer. Both terbutaline treatments resulted in a significant increase in forced expiratory volume in one second, as compared with placebo (P less than 0.001), but treatment with the tube-spacer aerosol produced significantly more improvement than did treatment with the conventional aerosol (P less than 0.01). The number of errors in inhalation technique was reduced when the spacer aerosol was used, and this reduction may account for the greater improvement in the children treated with the spacer.

Aerosols↗

PubMed2001

Albuterol delivery in a neonatal ventilated lung model: Nebulization versus chlorofluorocarbon- and hydrofluoroalkane-pressurized metered dose inhalers.

The aim of this study was to compare albuterol delivery in a neonatal ventilated lung model, using three delivery methods: 1) jet nebulizer; 2) chlorofluorocarbon-pressurized metered dose inhaler (CFC-MDI) actuated into an ACE(R) spacer; and 3) hydrofluoroalkane-pressurized MDI (HFA-MDI) actuated into an ACE(R) spacer. The bench model consisted of a mechanically ventilated infant test lung with ventilator settings to simulate a very low birth weight neonate with moderate lung disease. Albuterol solution (0.5%) was nebulized at the humidifier and temperature port, 125 cm and 30 cm from the Y-piece, respectively. Albuterol metered dose inhalers (MDIs) were actuated into an ACE(R) spacer that was tested in two positions: 1) inline between the endotracheal (ET) tube and the Y-piece; and 2) attached to the ET tube and administered by manual ventilation. Albuterol was collected on a filter at the distal end of the ET tube and was quantitatively analyzed by high performance liquid chromatography. Albuterol delivery by CFC-MDI (position 1, 4.8 +/- 1.0%, vs. position 2, 3.8 +/- 1.6%, P > 0.05) and HFA-MDI (position 1, 5.7 +/- 1.6%, vs. position 2, 5.5 +/- 2.4%, P > 0.05) were significantly greater than delivery by nebulization at 30 cm (0.16 +/- 0.07%) and 125 cm (0.15 +/- 0.03%) from the Y-piece (P < 0.001). A single actuation of albuterol MDI delivered the equivalent of nebulizing 2.5-3.7 mg of albuterol solution. We conclude that albuterol administered by MDI and ACE(R) spacer resulted in more efficient delivery than by nebulization in this mechanically ventilated neonatal lung model. There was no significant difference in drug delivery between CFC-MDI and HFA-MDI; nor did the placement of the spacer significantly affect drug delivery.

Administration, Inhalation↗

PubMed2002

Relative lung and systemic bioavailability of sodium cromoglycate inhaled products using urinary drug excretion post inhalation.

The relative lung and systemic bioavailability of sodium cromoglycate following inhalation by different methods have been determined using a urinary excretion pharmacokinetic method. On three separate randomised study days, 7 days apart, subjects inhaled (i) 4x5 mg from an Intal metered dose inhaler (MDI), (ii) 4x5 mg from an MDI attached to a large volume spacer (MDI+SP) and (iii) 20 mg from an Intal Spinhaler (DPI). Urine samples were provided at 0, 0.5, 1, 2, 5 and 24 h post dose. The mean (S.D.) amount of sodium cromoglycate excreted in the urine during the first 30 min post inhalation was 38.1 (27.5), 222.3 (120.3) and 133.1 (92.2) microg following MDI, MDI+SP and DPI, respectively. The mean ratio (90% confidence interval) of these amounts excreted in the urine over the first 30 min for MDI+SP vs. MDI, DPI vs. MDI and MDI+SP vs. DPI was 801.0 (358.0, 1244; p<0.002)%, 457.0 (244.0, 670.0; p<0.02)% and 262.4 (110.2, 414.5)%, respectively. Similarly for the 24 h cumulative amount of sodium cromoglycate excreted over the 24 h post inhalation the ratios were 375.4 (232.9, 517.9; p<0.005)%, 287.5 (183.4, 391.6; p<0.02)% and 211.4 (88.3, 334.5)%, respectively. The results highlight better lung deposition of sodium cromoglycate from a metered dose inhaler attached to a large volume spacer.

Administration, Inhalation↗

PubMed1994

Influence of spacer device on drug delivery to young children with asthma.

The budesonide dose delivered to the patient from three different spacer devices (Nebuhaler = 750 ml, Aerochamber = 140 ml, and Babyspacer = 260 ml) was assessed by measuring the budesonide dose deposited on a filter inserted between the spacer outlet and the mouth of the patient. Twenty children aged 10-25 months were given a single dose of 200 micrograms budesonide from each spacer device in a randomised crossover study. All spacers had a facemask attached and a one way valve system. The children breathed through the inhalation system for 30 seconds. Furthermore, the minute ventilation of the children through a tightly fitting facemask was measured. The filter dose of budesonide was significantly lower after Aerochamber treatment (39.4 micrograms, range 19-67 micrograms) than after Nebuhaler (53.5 micrograms, range 34-88 micrograms) and Babyspacer (55.5 micrograms, range 39-76 micrograms) treatment. The minute ventilation of the children varied from 1.4 l/min to 7.0 l/min (mean 5.0 l/min). This was sufficient to empty all spacers within the 30 seconds of inhalation. It is concluded that spacer volume does not seem to be so important for children aged 10-25 months as long as spacers with a volume lower than 750 ml are used.

Administration, Topical↗