Inspiratory flow rates and volumes with the Aerolizer dry powder inhaler in asthmatic children and adults

OBJECTIVE: To assess the peak inspiratory flow rate (PIFR) and forced inspiratory vital capacity (FIVC) through the formoterol (Foradil*) Aerolizer* in patients with mild, moderate and severe asthma. RESEARCH DESIGN AND METHODS: PIFR and FIVC were assessed in 33 adults and 32 children using a spirometer alone (baseline), a spirometer with an adaptor, and a spirometer with an adaptor and the Aerolizer inhaler (placebo loaded). RESULTS: Of adult patients using the Aerolizer inhaler, 73% had PIFR values of >100 l/min and 91% had values of >60 l/min. PIFR in adults was reduced from a mean baseline of 283 l/min to 118 l/min through the loaded Aerolizer inhaler. Similarly, 75% of children using the Aerolizer inhaler had PIFR values >80 l/min and 91% had values of > 60 l/min. The mean PIFR in children was reduced from a baseline of 154 l/min to 100 l/min through the loaded Aerolizer inhaler. Only small mean decreases from baseline were observed in FIVC through the loaded Aerolizer inhaler: 8.4% in adults and 3.8% in children. FIVC values of > 2.0 litre were achieved in 82% of adults, and 81% of children achieved FIVC values of >1.5 litre. CONCLUSIONS: This study, albeit in a relatively small patient population, suggests that most children and adults with asthma can generate PIFRs of > 60 l/min and FIVCs of > 1.5 litre through the Aerolizer inhaler regardless of their disease severity. Such findings compare extremely favourably with other dry powder inhalers.     

Peak inspiratory flow rates generated through the Novolizer and the Turbuhaler dry powder inhaler devices by children with stable asthma.

We compared the peak inspiratory flows (PIF) generated through a novel dry powder inhaler device, the Novolizer (PIF-N), and the Turbuhaler (PIF-T). Forty-six pediatric patients with stable bronchial asthma were randomized in an open-label, multicenter, crossover trial. No drug was administered during the inhalation maneuvers that were spaced by 10 min. There was neither a carryover nor a sequence effect. The patients were characterized by mean age of 8.5 years, mean FEV(1) of 1.79 L, and mean PIF without any device (baseline, PIF-B) of 185 L/min. Through the devices mean PIF-N of 94 L/min and mean PIF-T of 69 L/min were achieved, calculated from the maxima of three inhalations. This resulted in p < 0.0001 for the difference. The median PIFN/PIF-T ratio was estimated as 1.39. Each child achieved a higher PIF-N than PIF-T and was able to release the feedback mechanisms of the Novolizer indicating sufficient inhalation performance. We conclude that the PIF through the Novolizer is higher than the PIF through the Turbuhaler in stable asthmatic children. The flow rates achieved through the Novolizer allow for sufficient lung deposition even in children as young as 6 years.     

Inspiratory flow rates through a novel dry powder inhaler (Clickhaler) in pediatric patients with asthma.

Inspiratory flow profiles through a novel dry powder inhaler (DPI) (Clickhaler; Innovata Biomed Ltd, St. Albans, UK) were recorded in 17 pediatric patients (aged 7-16 years) with stable mild to moderate asthma. Most patients (n = 14) could generate high peak inspiratory flows (PIFs) (> 60 L/min) and high flows early in the flow profile. These flows have been shown to be adequate to deaggregate and deliver micronized drug with this delivery system.     

Novel system to investigate the effects of inhaled volume and rates of rise in simulated inspiratory air flow on fine particle output from a dry powder inhaler

This study evaluated the effect of inhaled volume and simulated inspiratory flow rate ramps on fine particle output from dry powder inhalers (DPIs). A simple, robust system was developed to account for “rate of rise” (ramp) effects while maintaining a constant air flow through a multi-stage liquid impinger (MSLI), used for sizing the emitted particles. Ramps were programmed to reach 30 and 60 L/min over 100 milliseconds; 500 milliseconds; and 1, 2, and 3 seconds. Rotahaler was chosen as the test DPI. Testing was done with simulated inhalation volumes of 2 L and 4 L. Testing was also carried out using the USP apparatus 4. At 30 L/min, for a 2 L volume, the amount of drug exiting the device in fine particle fraction (FPF) increased from 2.33 μg to 6.04 μg from the 3-second ramp to the 100-millisecond ramp, with 11.64 μg in FPF for the USP (no ramp) method. At the same flow rate, for a 4 L volume, FPF increased from 2.23 μg to 8.45 μg, with 10.25 μg for the USP method. At 60 L/min, similar trends were observed. In general, at both flow rates, an increase in FPF was noted going from the shallowest to the steepest ramp. However, there were no significant differences in FPF when a 2 L inhaled volume was compared with a 4 L volume at each flow rate. Overall, these data suggest that the existing USP apparatus may overestimate FPF at flow rates lower than those recommended by the USP.     

Pulmonary drug delivery from the Taifun dry powder inhaler is relatively independent of the patient's inspiratory effort.

The Taifun dry powder inhaler (Leiras OY, Turku, Finland) is a breath-actuated, multidose device, each metered dose containing 200 micrograms of budesonide. A two-way randomized crossover gamma scintigraphic study was performed in 10 asthmatic patients to determine the in vivo deposition pattern of budesonide inhaled from the Taifun. In vitro radiolabelling validation studies demonstrated that the radiolabel could be used as an accurate marker to assess in vivo drug deposition. Patients used either maximal inspiratory effort (targeted peak inhalation flow 30 L/min) or submaximal inspiratory effort (targeted peak inhalation flow 15 L/min) on each study day. Mean (S.D.) whole lung deposition (% of metered dose) was 34.3 (5.8)% and 29.6 (5.9)% for the two inhalation flows. The intersubject coefficient of variation in lung deposition was less than 20% on both study days. Drug was deposited uniformly across the central, intermediate, and peripheral lung regions for maximal and submaximal inspiratory efforts. The study suggests that the Taifun is a superior drug delivery device compared with many other inhalers, in terms of the amount of drug deposited in the lungs, the reproducibility of the lung dose, and the relative flow--independence of lung deposition.     

Effect of carrier particle shape on dry powder inhaler performance

The aim of this study was to characterise the aerosolisation properties of salbutamol sulphate (SS) from dry powder inhaler (DPI) formulations containing different carrier products. The difference in the elongation ratio (ER) of the different carriers was highlighted. Different set of carriers, namely commercial mannitol (CM), commercial lactose (CL), cooling crystallised mannitol (CCM), acetone crystallised mannitol (ACM) and ethanol crystallised mannitol (ECM) were used and inspected in terms of size, shape, density, crystal form, flowability, and in vitro aerosolisation performance using Multi Stage Liquid Impinger (MSLI) and Aerolizer^® inhaler device. Solid-state and morphological characterization showed that CM product was in pure β-form having particles with smaller ER (CM: ER = 1.62 ± 0.04) whereas ACM and ECM mannitol particles were in pure α form with higher ER (ACM: ER = 4.83 ± 0.18, ECM: ER = 5.89 ± 0.19). CCM product crystallised as mixtures of β-form and δ-form and showed the largest variability in terms of particle shape, size, and DPI performance. Linear relationships were established showing that carrier products with higher ER have smaller bulk density (D_b), smaller tap density (D_t), higher porosity (P), and poorer flow properties. In vitro aerosolisation assessments showed that the higher the ER of the carrier particles the greater the amounts of SS delivered to lower airway regions indicating enhanced DPI performance. Yet, DPI performance enhancement by increasing carrier ER reached a “limit” as increasing carrier ER from 4.83 ± 0.18 (ACM) to 5.89 ± 0.19 (ECM) did not significantly alter fine particle fraction (FPF) of SS. Also, carrier particles with higher ER were disadvantageous in terms of higher amounts of SS remained in inhaler device (drug loss) and deposited on throat. Linear relationship was established (r² = 0.87) showing that the higher the carrier ER the lower the drug emission (EM) upon inhalation. Moreover, poorer flowability for carrier products with higher ER is disadvantageous in terms of DPI formulation dose metering and processing on handling scale. In conclusion, despite that using carrier particles with higher ER can considerably increase the amounts of drug delivered to lower airway regions; this enhancement is restricted to certain point. Also, other limitations should be taken into account including higher drug loss and poorer flowability.     

Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products.

Both the dose delivered from the device and the particle size of the medication are important parameters for inhalation products because they influence the amount of drug that is delivered to the patient's lung. The inspiratory flow rate may vary from dose to dose in a given patient and between patients. The Marple-Miller Cascade Impactor, a new multistage inertial impactor that operates at two flow rates (30 and 60 liters/min) with comparable particle size cut-offs, provides a means to study the effect of inhalation flow rate on the particle size distributions of inhalation products. The medication delivery, mass median aerodynamic diameter (MMAD), and fine particle mass were determined, in a randomized fashion, for albuterol, beclomethasone, budesonide, and terbutaline in both metered dose inhaler (MDI) and dry powder inhaler (DPI) products as a function of flow rate. In all cases, independent of drug or device used, the MDI products had a more reproducible respirable dose than the breath-actuated DPI products tested as a function of inhalation flow rate.     

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.     

Salvianolic acid B dry powder inhaler for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF) is a serious and fatal pulmonary inflammatory disease with an increasing incidence worldwide. The drugs nintedanib and pirfenidone, are listed as conditionally recommended drugs in the “Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis”. However, these two drugs have many adverse reactions in clinical application. Salvianolic acid B(Sal B), a water-soluble component of Salvia miltiorrhiza, could alleviate bleomycin-induc...     

Drug delivery performance of the mometasone furoate dry powder inhaler.

The mometasone furoate dry powder inhaler (MF-DPI) is a multiple-dose, breath-actuated inhaler that uses agglomerates of micronized MF and lactose. In vitro analyses evaluated dose uniformity, variability, and particle size distribution of the MF-DPI. Tests of first, middle, and end doses from 10 inhalers each of the 200-microg MF/inhalation and 400-microg MF/inhalation dose sizes found that delivered doses (doses emitted from the inhaler) ranged from 91% to 112% of claimed doses for all tested DPIs. The mean MF doses delivered at 28.3 L/min were 100% and 94% of the doses delivered at 60 L/min for the 200-microg and 400-microg dose sizes, respectively; the relative standard deviation of doses was < or = 6.1% within this range of inhalation rates. At a flow rate of 60 L/min, the mean delivered doses, compared to claimed doses for inspiration times of 1-3 sec, were 102-104% for the 200-microg dose size and 98.8-102% for the 400-microg dose size. The mean cumulative fraction of dose delivered at 60 L/min for 2 sec which consisted of particles of <6.5 microm in diameter was 39.9% (+/-2.5 SD; n = 9) for the 200-microg dose size and 35.6% (+/-3.4 SD; n = 9) for the 400-microg dose size. All MF-DPI inhalers tested were well within U.S. and European compendial standards and regulatory guidelines for dose uniformity. An appropriate and reproducible fraction of the delivered dose was within the optimal particle size range for therapeutic effectiveness.     

干粉吸入剂的粉末定量分装设备浅析

干粉吸入剂是一种新兴呼吸道给药剂型,其吸入粉末的分装装置不同于常见的口服固体粉末分装装置。本文综述国际上常用的干粉吸入剂的粉末定量分装装置,包括标准定量器装置装置、真空滚筒分装装置、Xcelodose精确粉末微定量装置等,同时介绍几种较新的、处于研发阶段的粉末分装装置。     

The effect of flow rate on drug delivery from the Pulvinal, a high-resistance dry powder inhaler.

Dry powder inhalers vary widely in their resistance to flow. When the resistance is high, airway resistance can be neglected and inspiration rates will be determined primarily by the device. Provided that the patient can generate adequate flow rates to aerosolize the dose, variability of emitted dose and fine particle dose should be reduced. For in vitro simulation, these concepts are explored using a Pulvinal device. In conditions likely to be encountered in patient use, the emitted dose showed little dependence (80-102 micrograms) as the flow rate increased from 28 to 63 L/min. The fine particle dose was more sensitive, increasing by a factor of 1.6 from 22 to 35 micrograms. These variations are less than those observed with the Turbohaler, a device of intermediate resistance and very much lower than those observed with the Rotahaler, a low-resistance device.     

Minimal inspiratory flow from dry powder inhalers according to a biphasic model of pressure vs. flow relationship

Inhalation therapy using the dry powder inhaler (DPI) is now the first choice for obstructive pulmonary diseases. We previously measured relationships between inspiratory pressure (PI) and flow rate of almost all of the DPIs available in Japan, and described an importance of inspiratory efforts. In the present study, we further analyzed the data obtained in the previous study. Although there were linear relationships between PI and flow2, the slope became steeper when PI was less than a certain value (critical PI, existed between 15-20 cmH2O). When PI was less than critical PI, linear rather than parabolic regression between PI and flow yielded better fits (r > 0.90, p < 0.001). Inspiratory flows at the critical PI were 53.9 (Diskus), 65.8 (Diskhaler), 45.9 (Turbuhaler for Pulmincort), 48.6 (Turbuhaler for Symbicort) and 38.0 l/min (Twisthaler). These findings suggested that flow through the DPI becomes laminar rather than turbulent flow in the range below critical PIs. We suggest that patients should inhale from the DPIs with inspiratory pressure higher than critical PI.     

Scintigraphic assessment of drug delivery from the Ultrahaler dry powder inhaler.

A new dry powder inhaler, the Ultrahaler, has been developed to deliver nedocromil sodium for the prophylaxis of asthma. This study was performed to compare the lung deposition of nedocromil sodium inhaled from the Ultrahaler at two different inhaled flow rates with that from a pressurised metered dose inhaler (MDI). A scintigraphic study was conducted in 12 healthy volunteers. On each study day, volunteers received a single 4.2 mg dose of nedocromil sodium from the Ultrahaler, using either an optimal (fast) inhaled flow rate or a suboptimal (slow) inhaled flow rate, or two doses of 2 mg nedocromil sodium from an MDI using an optimal (slow) inhaled flow rate. Used optimally, the Ultrahaler deposited significantly more (p < 0.05) of the metered dose in the lungs than either the Ultrahaler used suboptimally or the MDI used optimally [mean (SD) lung deposition values of 13.3 (4.8)%, 9.8 (3.5)%, and 7.5 (2.9)%, respectively]. Oropharyngeal deposition averaged over 80% of the dose for all three treatment regimens. This scintigraphic study demonstrated in vivo proof of concept for the Ultrahaler dry powder inhaler, and provided quantitative data on the relationship in lung deposition between the Ultrahaler and MDI which differed from that predicted by the in vitro fine particle fraction.     

Sustained mechanical and clinical functionality of the flexhaler dry powder inhaler

Flexhaler is a multiple-dose, inspiratory flow-driven dry powder inhaler that is a newer version of Turbuhaler, and is identical to the Symbicort Turbuhaler. Sustained performance is of the utmost importance to ensure consistent drug delivery throughout the lifespan of the inhaler. We report functionality testing results of Flexhaler inhalers used in two large-scale 12-week studies of budesonide (Pulmicort) and returned for testing. Functionality tests included measurement of airflow resistance and inspection of vital parts for the mechanical functionality of the inhaler, including visual inspection of the indicator wheel and function check of dose loading. In addition, delivered dose, particle size distribution, moisture content, and microbial counts were evaluated. Seven hundred sixteen out of 720 units were returned. Airflow resistance was not affected by the handling of the Flexhaler inhalers during use (prior to use, average airflow resistance: 67 Pa(0.5)*s*L(-1); returned inhalers: 66 and 67 Pa(0.5)*s*L(-1) in each study, respectively. The average dose delivered remained as intended after prolonged clinical use [95% (range 88 -103%) vs. reference of 99% (range 93-104%) before issue]. Relative fine particle dose ( <5 mum) after use was 107% (range 96-111%) of the reference value before issue. Moisture content in the inhaler desiccant was 3-25%, suggesting variability in storage conditions. Among the 28 inhalers randomly selected for microbiological testing there was no or very limited microbial growth. All 14 inhalers returned with functionality issues operated as intended and no reported functionality issues could be confirmed. Flexhaler inhalers operated as intended during these two clinical trials. These results should reassure both clinicians and patients with respect to the consistent quality of this unit for the delivery of dry powder formulations for inhalation.     

Effect of mouth wash on the removing fluticasone propionate delivered by dry powder inhaler in mouth

The effect of mouth wash on the removal of drug residues in both mouth and pharynx after the use of fluticasone propionate dry powder inhaler (FP-DPI) was studied. The concentration of FP in mouth wash after sprinkle and inhalation of Flutide 50, 100, 200 Rotadisk was determined by HPLC-UV. The total amount of the removed FP was measured by the sum of the concentration of FP in 5 times of mouth washes. The mouth wash procedures removed totally 79.3 +/- 4.4% (50 micrograms), 68.5 +/- 3.6% (100 micrograms), 69.3 +/- 3.4% (200 micrograms) of sprinkled amount of FP and 29.5 +/- 11.1% (50 micrograms), 35.6 +/- 6.6% (100 micrograms), 31.6 +/- 8.3% (200 micrograms) of inhaled, respectively. It was required for the removal of 90% of the totally recovered FP to do two times of mouth washes in each case. These data suggest that the mouth wash is an effective precaution for candidiasis induced by FP delivered by DPI.     

Influence of the moisture on the performance of a new dry powder inhaler

An accelerated stability test was carried out on two prototypes of a new dry powder inhaler (DPI) to verify the influence of moisture uptake on the performance of the device. The prototypes were stored at 40 degrees C and 75% relative humidity (RH) for different storage times and their performance was assessed in terms of emitted dose and respirable fraction (Twin Impinger). At the same time intervals, the water content of the powder contained in the drug reservoir was evaluated using Karl Fischer's method. The respirable fraction was strongly influenced by the moisture content of the powder, on the contrary, the dosing precision and reproducibility is independent of this variable. The results show that a suitable protection from the external environment is necessary to prevent moisture uptake in the powder and the consequent loss of efficiency of the delivery device.     

Effect of an external resistance to airflow on the inspiratory flow curve

Inhalation is a convenient way to deliver drugs to the respiratory tract in the treatment of respiratory diseases. For dry powder inhalers (DPI's), the principle of operation is to use the patient-generated inspiratory flow as energy source for emptying of the dose system and the delivery of fine drug particles into the respiratory tract. Resistance to airflow of the inhaler device is a major determinant for the inspiratory flow profile through the dry powder inhaler that can be generated by the patient. Therefore, resistance to airflow is one of the design parameters for DPI's, that could be used to control the inspiratory flow profile, and is one of the parameters to optimise particle deposition in the airways. In this study the effect of resistance to airflow on different parameters of the inspiratory flow curves as generated by healthy subjects, asthmatics and COPD patients was determined. As a result of increased resistance to airflow, the peak inspiratory flow (PIF), the flow increase rate (FIR) and the inhaled volume to reach PIF is decreased. On the other hand, the total inhalation time as well as the 80% dwell time is increased. In general, tuning of the resistance to airflow in the design of a dry powder inhaler may improve the drug deposition in the respiratory tract.     

In vitro testing of two formoterol dry powder inhalers at different flow rates.

The efficiency of two different dry powder inhaler systems for the application of the beta2-sympathomimetic drug Formoterol in the lungs has been tested in vitro. Particle size distributions for each device have been measured at four different flow rates (28.3, 40, 60, and 80 L/min) using an Andersen-Impactor. Mass median aerodynamic diameters (MMAD) of the dispersed powder and deposition of the drug in the respiratory tract was determined using a semiempirical lung deposition model. The optimum output for both devices determined by in vitro measurements is supposed to be achieved with flow rates of 40-60 L/min. The Oxis Turbuhaler delivers the smaller particles as the Foradil P Aerolizer and, thus, the Formoterol deeper into the lungs, but the high specific airflow resistance will influence the ability of patients with severe asthma and children to use the system.     

Pharmacodynamic study of procaterol hydrochloride dry powder inhaler: evaluation of pharmacodynamic equivalence between procaterol hydrochloride dry powder inhaler and procaterol hydrochloride metered-dose inhaler in asthma patients in a randomized, double-dummy, double-blind crossover manner

Therapeutic equivalence between procaterol hydrochloride dry powder inhaler (Meptin DPI) and procaterol hydrochloride metered-dose inhaler (Meptin MDI), the currently marketed formulation, was assessed in 16 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 mcg of either Meptin DPI or Meptin MDI, and then crossed over in Period II after a washout interval of 3--28 days. Pharmacodynamic equivalence was accessed using AUC (FEV1)/h and peak FEV1 as indices, and the data were analyzed by analysis of variance (ANOVA). Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were --0.0995 to --0.0204 (L) for mean AUC (FEV1)/h and --0.102 to --0.022 (L) for mean peak FEV1, both within the acceptance criteria of --0.15 to 0.15 (L). Meptin DPI was therefore assessed as being equivalent to the current Meptin MDI.