Influence of single versus multiple actuations on the particle size distribution of beclometasone dipropionate metered-dose inhalers

The particle size distributions of beclometasone dipropionate delivered from Becotide and Respocort inhalers after single and multiple actuations were investigated using the Andersen Mark II Cascade impactor and the drug was quantified using high performance liquid chromatography. The fine particle mass and the mass median aerodynamic diameter were calculated. An apparent increase in mass median aerodynamic diameter was observed when the number of actuations increased. In addition, the fine particle mass decreased as the number of actuations increased. When performing and analysing cascade impaction study data differences between single versus multiple actuations must be considered. Regulatory guidelines should be amended to stipulate the number of actuations to be loaded into devices used to evaluate the particle size distribution of inhaled aerosol products.     

Metered-dose inhalers I: drug content and particle size distribution of beclomethasone dipropionate

Four commercially available beclomethasone metered dose inhalers were analyzed for both spray content uniformity and particle size. The drug contents of primed and unprimed sprays collected at the beginning of the lifetime of the canister were not significantly different from those collected throughout the experiment. Particle size analysis of the four products using the Anderson Cascade Impactor Mark II showed that the distribution profiles were not identical.An existing HPLC method was modified to quantitate single sprays for content uniformity and to measure the amount on an impactor stage for particle sizing.     

Influence of flow rate on aerosol particle size distributions from pressurized and breath-actuated inhalers.

Particle size distribution of delivered aerosols and the total mass of drug delivered from the inhaler are important determinants of pulmonary deposition and response to inhalation therapy. Inhalation flow rate may vary between patients and from dose to dose. The Andersen Sampler (AS) cascade impactor operated at flow rates of 30 and 55 L/min and the Marple-Miller Impactor (MMI) operated at flow rates of 30, 55, and 80 L/min were used in this study to investigate the influence of airflow rate on the particle size distributions of inhalation products. Total mass of drug delivered from the inhaler, fine particle mass, fine particle fraction, percentage of nonrespirable particles, and amount of formulation retained within the inhaler were determined by ultraviolet spectrophotometry for several commercial bronchodilator products purchased in the marketplace, including a pressurized metered-dose inhaler (pMDI), breath-actuated pressurized inhaler (BAMDI), and three dry powder inhalers (DPIs), two containing salbutamol sulphate and the other containing terbutaline sulphate. Varying the flow rate through the cascade impactor produced no significant change in performance of the pressurized inhalers. Increasing the flow rate produced a greater mass of drug delivered and an increase in respirable particle mass and fraction from all DPIs tested.     

A comparative analysis of the particle size output of beclomethasone diproprionate, salmeterol xinafoate and fluticasone propionate metered dose inhalers used with the Babyhaler, Volumatic and Aerochamber spacer devices

AIMS: To determine in vitro the effect of delay, inspiratory flow, and spacer washing on the drug output of metered dose inhalers (MDIs) used with different spacer devices. METHODS: The amount of drug in particles <5 microm diameter from MDI+spacer, sampling after a delay of up to 20 s, was measured using a Multistage Liquid Impinger. Drug output was also measured at different flow rates, and after washing the Babyhaler in household detergent. RESULTS: More fluticasone in small particles was recovered from the Babyhaler than the Volumatic or the Aerochamber spacers, and more beclomethasone and salmeterol was recovered from the Babyhaler and Volumatic spacers than from the Aerochamber. Washing the Babyhaler reduced the recovery of salmeterol, and did not alter the recovery of the other drugs tested. CONCLUSIONS: Spacer devices need to be fully evaluated for each drug prescribed for them.     

Aerodynamic particle size of metered-dose inhalers determined by the quartz crystal microbalance and the Andersen cascade impactor.

Given the rapid sizing capability and high sensitivity, the quartz crystal microbalance (QCM) cascade impactor has been evaluated for the size determination of metered-dose inhaler (MDI) aerosols. The effects of surfactants present in MDI formulations, crystal coating, particle bounce and crystal overloading on the QCM cascade impactor are investigated. To reduce particle bounce, it is necessary to coat the crystals and use new coated surfaces for each measurement. Mass median aerodynamic diameters (MMADs) obtained from the QCM cascade impactor are compared to those from the commonly used Andersen cascade impactor. For MDI formulations containing little or no surfactants, MMADs obtained from the QCM and Andersen cascade impactors are comparable. For MDI formulations containing a significant amount of surfactant (or any non-volatile excipients), the QCM cascade impactor measures the combined size distribution of the drug and non-volatile excipients. A technique is devised in this study to deduce the drug-only size distribution from the QCM impactor for surfactant-containing MDI formulations and show comparable results to the Andersen cascade impactor except for high drug load Intal. The QCM impactor has proved to be a useful tool for rapid size measurement of MDI formulations.     

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.     

Pharmacokinetics and dose proportionality of beclomethasone from three strengths of a CFC-free beclomethasone dipropionate metered-dose inhaler

As part of a development program to offer alternatives to chlorofluorocarbon (CFC) containing metered-dose inhalers, beclomethasone dipropionate has been formulated in a CFC-free system at three strengths: 50, 100, and 200 μg/actuation ex valve. To measure serum levels and dose proportionality of the beclomethasone derived from beclomethasone dipropionate, 13 mild to moderate asthmatic patients received a single dose of eight inhalations from each strength according to a double-blind crossover design. Seven patients were studied over 4 h and six patients over 12 h. For the total doses of 400, 800, and 1600 μg studied over 12 h, C_max and AUC increased in a ratio of 1:1·8:3·1. A good correlation was seen between the fine-particle mass delivered and the in vivo performance of the three strengths. From a clinical point of view, the predictable increases in serum levels with an increase in dose will permit the clinician to effectively titrate a patient with this product. © 1997 John Wiley & Sons, Ltd.     

Mass output and particle size distribution of glucocorticosteroids emitted from different inhalation devices depending on various inspiratory parameters.

Efficient inhalation therapy depends on successful delivery of the drug to the lung. The efficacy of drug delivery is not only influenced by the characteristics of the inhalation device, but also by the patient's handling of the device and by the inspiratory maneuver achieved through the device. We analyzed the output characteristics of three different chlorofluorocarbon (CFC)-free breath-actuated inhalers for inhaled glucocorticosteroids (BUD Turbohaler, FP Diskus/Accuhaler and HFA-BDP Autohaler, respectively). Mass output and particle size distribution of drug aerosol delivered by the inhalers were determined depending on different inhalation parameters in vitro using an Andersen cascade impactor. We found that, beside the peak inspiratory flow (PIF), other factors such as flow acceleration and inhalation volume also have significant effects on aerosol generation with respect to mass output and particle size distribution. Thus, these parameters should be taken into account when a suitable device for an individual patient is to be selected. The dependency on inspiratory parameters was most pronounced for the dry powder inhalers. The Turbohaler showed by far the highest variance in particle output (fine particle fraction ranging from 3.4% to 22.1% of label claim), whereas the Diskus was less dependent on variations in inhalation (10.6% to 18.5% of label claim). The most constant aerosol output was found for the Autohaler, which also released the highest fine particle fraction (43.1% to 56.6% of label claim).     

撞击器法评估吸入制剂空气动力学粒径分布的研究进展

空气动力学粒径分布（APSD）是吸入制剂体外质量评价的重要检测项目,级联撞击器法是国际公认的气溶胶APSD测定方法,并且已被多国药典收载。其通过体外模拟气溶胶经过呼吸道到达肺部不同部位的沉积情况,对吸入制剂的研究开发具有重要的指导意义。综述了目前国内外药典收载的双级液体撞击器、多级液体撞击器、马普尔-米勒撞击器、安德森级联撞击器、新一代撞击器等撞击器的主要结构以及应用情况。     

Evaluation of the Malvern Spraytec with inhalation cell for the measurement of particle size distribution from metered dose inhalers

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

Equivalence testing and equivalence limits of metered-dose inhalers and dry powder inhalers measured by in vitro impaction.

In this study, criteria for the acceptability of comparative in vitro equivalence testing are proposed. Furthermore, the following equivalence limits for in vitro impaction methods are postulated: the 90% confidence interval (CI) of the in vitro deposition ratio of the test product and the reference product should lie within 0.80-1.20. The aim of this study was to challenge these limits by applying them to in vitro impaction results of several groups of pressurized metered-dose inhalers and dry powder inhalers containing salbutamol and beclomethasone dipropionate. The deposition results were obtained with the Twin Impinger. All products had a marketing authorization in The Netherlands and were considered therapeutically equivalent within each group. The postulated equivalence limits/group were challenged by fictitiously assigning a preparation as a test product or reference product and calculating the 90% CI of the deposition ratio of the test and reference products. All possible combinations of products within a group were tested. The products were considered equivalent if the 90% CI of the quotient lay within 0.80-1.20. In most cases, the quotient of the test product and reference product remains within 0.80-1.20, but due to a high variability in the deposition results of several products, the 90% CI of the quotient sometimes falls outside the proposed equivalence limits. It is concluded that the equivalence limits postulated are rather conservative, with respect to accepting equivalence. The limits can therefore serve as a prudent predictor of equivalence within the acceptability criteria proposed, but have to be further validated.     

The therapeutic index of locally acting inhaled drugs as a function of their fine particle mass and particle size distribution: a literature review

The therapeutic index (TI) of locally acting inhaled drug products depends on a number of parameters and processes: the particle size distribution of the inhaled aerosol, the dose-efficacy response curves at the deposition sites, the amount of drug absorbed into the systemic circulation from the lung as well as the gastrointestinal (GI) tract, and the dose-effect curves for the different adverse drug reactions. In this review, we present qualitative scenarios, combining these effects and showing the possible influence of an envisaged change in the particle size distribution in the inhaled dose of a locally acting drug product on the TI. These scenarios are a valuable tool in the development of inhalation drug products. As a surrogate for the inhaled dose in vivo, we use the fine particle mass (FPM), measured by in vitro measurements. Using these scenarios, we reviewed the literature on bronchodilators and corticosteroids for reported associations between a change in the FPM and/or particle size distribution within the FPM, and the TI. We conclude that decreasing the particle size of an inhalation product may alter the TI both in a positive as well as a negative sense. So, smaller particle are not always better.     

In vitro performance characteristics of valved holding chamber and spacer devices with a fluticasone metered-dose inhaler

STUDY OBJECTIVE: To compare the in vitro aerosol deposition characteristics of several commercially available valved holding chamber (VHC) and spacer devices used with a fluticasone metered-dose inhaler (MDI). DESIGN: In vitro aerosol deposition study SETTING: University-affiliated research center. DEVICES: Seven VHC devices: BreatheRite, E-Z Spacer, EasiVent, AeroChamber, InspirEase, OptiChamber, and Space Chamber. Six spacer devices: OptiHaler, Aerosol Cloud Enhancer (ACE), Gentle-Haler, MediSpacer, Ellipse, and a 6-inch tube (1-inch inside diameter). INTERVENTION: The respirable dose (aerosol particles 1-5 microm) of fluticasone was determined by sampling 10 220-microg actuations from five runs with each spacer or VHC plus MDI combination, by using a well-established in vitro cascade impactor method. MEASUREMENTS AND MAIN RESULTS: Fluticasone aerosol was washed from the impactor with methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined with analysis-of-variance testing. Among spacers, Ellipse had the highest respirable dose (104 microg, p < 0.01). Respirable doses for the 6-inch tube (74.3 microg), Gentle-Haler (81.7 microg), and MediSpacer (82.6 microg) were no different from that of the MDI (p > 0.05), whereas respirable doses of OptiHaler (44.6 microg) and ACE (47.2 microg) were less than those of all other spacers (p < 0.001). Among VHC devices, respirable doses from EasiVent (35.6 microg), AeroChamber (47.0 microg), InspirEase (52.7 microg), OptiChamber (53.1 microg), and Space Chamber (58.3 microg) were not different (p > 0.05), whereas BreatheRite (13.1 microg) and E-Z Spacer (27.3 microg) respirable doses were less than those of the other VHC devices (p < 0.05). CONCLUSION: Spacers and VHC devices available in the United States do not demonstrate equivalent in vitro performance with the fluticasone MDI. The difference between highest and lowest respirable doses in each device category would likely lead to clinically relevant differences in the quantity of fluticasone delivered to a patient.     

Pulmonary peptide delivery: effect of taste-masking excipients on leuprolide suspension metered-dose inhalers.

The purpose of this study was to evaluate the effect of taste-masking excipients on in vitro and in vivo performance of a leuprolide metered-dose inhaler (MDI) suspension formulation. Taste-masking excipients (aspartame and menthol) were added to a leuprolide suspension MDI formulation. The leuprolide MDI formulation with the taste-masking excipients was characterized in terms of milling time, particle size distribution, dose delivery and uniformity, and drug absorption in dogs. The data were compared with a formula that did not contain taste-masking excipients. It was found that the longer milling time for the leuprolide suspension with the taste-masking excipients was required to obtain a similar particle size distribution compared with the formula without taste-masking excipients using a fluid energy mill. Although measurable differences in mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were not observed between the two formulations, the percent of particles < or = 5 microns and the actuator retention for the formula with the taste-masking excipients were significantly different from the formula without taste-masking excipients using the Marple-Miller cascade impactor. Taste-masking excipients did not show a significant effect on valve delivery and through-can dose uniformity. However, the mean ex-actuator dose was 150.4 mg for the formula with the taste-masking excipients and 162.2 mg for the reference formula, respectively, indicating a significant difference. In tracheostomized dogs, both formulations showed comparable pharmacokinetic parameters including Cmax, Tmax, AUC0-12 and bioavailability (F%), indicating that the taste-masking excipients do not have an effect on lung absorption of leuprolide acetate. Therefore, inclusion of taste-masking excipients in the leuprolide MDI suspension formulation showed a significant impact on drug micronization, exactuator dose, and particle deposition pattern. Mechanistically, the unfavorable performance of leuprolide MDI in the presence of taste-masking excipients could be due to modification of the properties of the suspension itself and alteration of propellant evaporation following actuation.     

Influence of load on particle size distribution of lactose-crystalline cellulose mixed powder

Effects of loads applied to a powdery layer of a mixture of lactose and crystalline cellulose (granules) on the microparticle formation were evaluated. In a 1:1 mixture, the number of particles size, 20 microm or smaller in diameter, was reduced under loading compared with the standard value. It tended to increase with increasing ratio of lactose. In samples with a particle size of 350 microm or less, the shear friction coefficient increased with increase in the load, reached a peak at a mixing ratio of 50%, and decreased with increase in the mixing ratio. These changes were similar to those of the number of particles 20 microm or smaller. These results suggest that particle formation and aggregation under loads are dependent on the mixing rate and that there is a range of mixing rates in which no changes in the particle size distribution are observed.     

Effect of rise in simulated inspiratory flow rate and carrier particle size on powder emptying from dry powder inhalers

The purpose of this study was to evaluate the effect of carrier particle size and simulated inspiratory flow increase rate on emptying from dry powder inhalers (DPIs). Several flow rate ramps were created using a computer-generated voltage signal linked to an electronic proportioning valve with a fast response time. Different linear ramps were programmed to reach 30, 60, 90, and 120 L/minute over 1, 2, or 3 seconds. At the lower flow rates, 100-ms and 500-ms ramps were also investigated. Three DPIs, Spinhaler, Rotahaler, and Turbuhaler, were used to test the effect of flow rate ramp on powder emptying. To test the effect of carrier particle size, anhydrous lactose was sieved into 3 particle sizes, and 20 mg of each was introduced into #2 and #3 hard gelatin capsules for Spinhaler and Rotahaler, respectively. Emptying tests were also carried out using the on/off solenoid valve described in the United States. Pharmacopeia (USP) (resulting in no ramp generation). Powder emptying increased from 9% to 46% for Rotahaler and 69% to 86% for Spinhaler from the shallowest (3 seconds to reach peak flow) to the 100-ms ramp for the 53-to 75-μm lactose size range at 30 L/minute. Similar trends were observed for larger particle size fractions at the same flow rate. However, at higher airflow rates (60, 90, and 120 L/minute), there was no significant increase in percentage of emptying within the ramps for a particular particle size range. Trends observed were similar for placebo-filled Turbuhaler and commercially available Rotacaps used with Rotahaler, with the steepest ramp demonstrating more complete emptying. Percentage of powder emptying determined by the USP solenoid valve overestimated the emitted dose compared with the ramp method at 30 L/minute for all 3 devices. Results indicate that there is a significant difference in powder emptying at 30 L minute from the shallowest to the steepest ramp within a particular size range. Within a particular particle size range, the USP method produced more complete emptying than even the steepest ramp, especially at the lower flow rates. Thus, when the USP device is used to estimate DPI emptying at lower flow rates, the results are likely to overestimate DPI performance significantly.     

Influence of particle size on rectal absorption of aspirin.

The rectal absorption of aspirin from theobroma oil suppositories was studied in seven human subjects using urinary excretion measurements. The effect of particle size on the excretion rate and cumulative amount of total salicylate excreted was demonstrated by the administration of a 600-mg dose as powdered aspirin and as aspirin disks having 0.023 as much surface as powdered aspirin. In vitro dissolution profiles of aspirin from the suppositories were studied. By the NF XIII Method II, the time required for 50% of the aspirin to dissolve from the suppository was 50 and 100 min for the powdered aspirin and the aspirin disks, respectively. In the bioavailability study, the diffusion equilibrium was attained at approximately 4-5 and 9-10 hr after the rectal administration of powdered aspirin and aspirin disks, respectively. No correlation was found between bioavailability and the dissolution profiles as determined by the USP XVIII dissolution method.     

Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 microC/g, the individual particles were charged with a relatively high charge: -2 to + 2 microC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3-5 microm.     

Aerodynamic size distribution,hygroscopicity and deposition estimation of beclomethasone dipropionate aerosol

Aerodynamic size distribution and aerodynamic mass per dose of beclomethasone dipropionate aerosol were measured at 24 and 95% relative humidity. At high humidity, the count median aerodynamic diameter was unchanged, mass median aerodynamic diameter increased from 2·01 μm to 2·68 μm, particle number/dose from 41·3 times 10⁶ to 78·3 times 10⁶, and aerodynamic mass per dose from 23·7 to 60·0μ g. The quantity of active ingredient estimated to be in the 23·7μg aerodynamic mass at low humidity was 19·7 μg. From data previously available describing average deposition fraction as a function of aerodynamic diameter, 6·7 μg or 13% of the total dose of 50μg produced by the metered dose canister would be expected to deposit in the lower respiratory tract.