Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulization

AIMS: Clinical studies comparing nebulized drug delivery systems could be flawed because of the high doses used. We have compared lung and total systemic delivery of salbutamol from a nebuliser with that from a metered dose inhaler by measuring urinary recovery of drug and its sulphate metabolite. METHODS: Twelve healthy volunteers provided urine samples at 0, 0.5, 1, 2, 4, 8, 12 and 24 h after the start of dosing. Formulations and doses were 5 x 100 microg oral solution (ORAL), 5 x 100 microg from a metered dose inhaler (MDI), 2.5 mg using a nebuliser (NEB) and NEB with 25 g oral charcoal (NEBC). Each study phase was separated by 7 days and the order of dosing was randomized. RESULTS: Mean (s.d.) 30 min urinary salbutamol excretion after ORAL, MDI, NEB and NEBC was 0.4 (0.7), 12.1 (3.7), 15.0 (3.9) and 18.2 (5.7) microg, respectively (all P<0.001 compared with ORAL). When normalized for the dose available for inhalation from MDI, NEB and NEBC, the mean (s.d.) 30 min urinary excretion of salbutamol was 2.4 (0.7), 2.9 (0.6) and 2.7 (0.6)%, respectively, with a mean ratio (90% confidence interval) between NEB and NEBC, of 95.3 (91.1, 99.5)%. The mean (s.d.) excretion of salbutamol plus its metabolite over 24 h post ORAL, MDI, NEB and NEBC dosing was 297.9 (38.3), 290.3 (41.4), 266.5 (44.6) and 151.7 (40.9) microg, respectively. The mean ratio (90% confidence interval) between MDI and ORAL, and NEB and ORAL were 97.5 (94.1, 101.0) and 90.7 (81.2, 100.2)%, respectively. The NEBC data indicate that 6.07 (1.04)% of the nominal nebulized dose was delivered to the lungs. CONCLUSIONS: The 30 min urinary recovery of salbutamol, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the lung deposition of nebulized systems. Similarly, the urinary 24 h recovery of salbutamol plus its metabolite, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the delivery of nebulized drug to the systemic circulation.     

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.
Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30  min following inhalation of 2×100  μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin^® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24  h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.
Results The mean (s.d.) 30  min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9)  μg, respectively ( P <0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24  h period after inhalation was 187.9 (77.6) and 137.6 (40.0)  μg ( P <0.05).
Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.     

Assessment of different methods of inhalation from salbutamol metered dose inhalers by urinary drug excretion and methacholine challenge

AIMS: Methods to determine the lung delivery of inhaled bronchodilators from metered dose inhalers include urinary drug excretion 30 min post inhalation and methacholine challenge (PD20). We have compared these two methods to differentiate lung delivery of salbutamol from metered dose inhalers using different inhalation methods. METHODS: In phase 1 of the study, on randomized study days, 12 mild asthmatics inhaled placebo, one and two 100 microg salbutamol doses from a breath actuated metered dose inhaler, in randomized fashion on different days. In phase 2, they inhaled one 100 microg salbutamol dose from a metered dose inhaler using a SLOW (20 l min(-1)) and a FAST (60 l min(-1)) inhalation technique and a slow inhalation delayed until after they had inhaled for 5 s (LATE). Urinary excretion of salbutamol (0-30 min) and PD20 were measured after each dose. RESULTS: Following placebo, one and two 100 microg salbutamol doses, the geometric mean for PD20 was 0.10, 0.41 and 0.86 mg respectively and the mean (SD) urinary drug excretion after one and two doses was 2.25 (0.65) and 5.37 (1.36) microg, respectively. After SLOW, FAST and LATE inhalations the geometric mean for PD20 was 0.50, 0.40 and 0.42 mg, respectively, and mean (SD) salbutamol excretion was 2.67 (0.84), 1.90 (0.70) and 2.72 (0.67) microg, respectively. Only the amount of drug excreted during the FAST compared with the SLOW and LATE inhalations showed a statistical difference (95% confidence interval on the difference 0.12, 1.54 and 0.06, 1.59 microg, respectively). CONCLUSIONS: Urinary salbutamol excretion but not PD20 showed differences between the inhalation methods used. When using a metered dose inhaler slow inhalation is better and co-ordination is not essential if the patient is inhaling when they actuate a dose of the drug.     

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.     

经定量压力气雾器与喘必疗雾化器吸入特布他林对哮喘患者的作用比较

本文比较了10例哮喘患者直接从定量压力气雾器或经喘必疗雾化器单剂量(0.5mg)吸入特布他林的支气管舒张效果。测定吸药前和吸药后15,30,60和120min的肺功能结果:8例使用定量压力气雾器正确者加用喘必疗雾化器与否效果相同,其余2例不能正确使用定量压力气雾器者用喘必疗雾化器后支气管舒张效果提高。     

Relative lung deposition of salbutamol following inhalation from a spacer and a Sidestream jet nebulizer following an acute exacerbation

Background

Studies comparing inhalation methods in acute exacerbations have not assessed lung deposition.

Methods

Five 100-μg salbutamol doses were inhaled from a metered dose inhaler plus spacer (MDI + SP) and 5 mg was nebulized (NEB) following acute exacerbation hospitalization. Urinary salbutamol excretion was determined at 30 min (USAL0.5) and over 24 h (USAL24) postinhalation together with forced expiratory volume in 1 s (FEV₁).

Results

The USAL0.5 mean ratio (90% confidence interval) post MDI + SP and NEB [n = 19 asthma, 11 chronic obstructive pulmonary disease (COPD)] was 1.01 (0.81, 1.26). USAL24 was less (P < 0.001) following MDI + SP, whereas FEV₁ was similar. Only a small difference between asthmatics and COPD patients was observed for the MDI + SP in that the USAL0.5 was higher in the asthmatics for the spacer method.

Conclusion

The relative lung deposition after inhaling 500 μg salbutamol from MDI + SP is similar to 5 mg from a Sidestream nebulizer following an acute exacerbation.

What is already known about this subject

• Studies have shown that a large volume spacer attached to a metered dose inhaler provides similar bronchodilator effects to nebulized dosing during the management of patients following an acute exacerbation.
• Due to the high doses used, these effects could be measured at the top of the dose–response relationship and the response limited due to the patient''s exacerbation.
• Although clinical end-points are the gold standard to show comparability, some indication of similar lung deposition is useful to consolidate any claims.

What this study adds

• The urinary pharmacokinetic method we have used postinhalation provides an index of lung deposition for inhalation methods that can be incorporated into the routine management of patients with an acute exacerbation.
• This is the first study to identify and compare lung deposition and systemic delivery for inhalation methods within the setting of the routine management of asthma and chronic obstructive pulmonary disease patients following hospitalization due to an acute exacerbation.
• The study highlights the comparability of the doses for the two inhalation methods evaluated with respect to lung deposition, systemic delivery and bronchodilator response.

     

Effectiveness and acceptability of a domiciliary multidrug inhalation treatment in elderly patients with chronic airflow obstruction: metered dose inhaler versus jet nebulizer.

The aim of this study was to compare the immediate and long-term bronchodilator effect as well as the patient acceptability of a 2-week, multidrug, inhalation treatment delivered by a metered dose inhaler (MDI) versus a jet nebulizer in a group of elderly patients with chronic obstructive pulmonary disease (COPD) or asthma and an at least partially reversible airflow obstruction. Twenty elderly outpatients (17 men; mean +/- SD age, 67 +/- 2 years; mean +/- SD baseline forced expiratory volume in 1 second [FEV1], 46.5 +/- 14% of predicted value) with COPD or asthma participated in the study, which was of an open, randomized, crossover design. After a 1-day baseline evaluation, including patient history, clinical examination, and spirometry, participants were randomly assigned to receive a multidrug inhalation treatment (a combination of salbutamol, ipratropium, and flunisolide) with either an MDI or a jet nebulizer. Two weeks later, they were shifted to treatment with the alternative system for a further 2 weeks. FEV1 was measured on the first and fourteenth days of each treatment period, on each occasion both before and 30 minutes after the morning inhalation. At the end of the study, patients were asked to express a personal preference for one of the two inhalation treatments with regard to effectiveness and acceptability by filling out a simple questionnaire. Both the MDI and jet nebulizer had a significant immediate bronchodilator effect on the first and fourteenth days of treatment, with no differences between treatments. No long-term bronchodilator effect was seen with either aerosol delivery system. Patient preferences were clearly in favor of the jet nebulizer with regard to effectiveness and in favor of the MDI with regard to acceptability. In conclusion, in elderly patients with COPD or asthma and partially reversible airflow obstruction, a maintenance multidrug bronchodilator/anti-inflammatory inhalation treatment produced a statistically significant and clinically relevant bronchodilator effect without substantial differences between the two delivery systems. Most patients considered the MDI to be more acceptable and the jet nebulizer to be more effective. These preferences should be taken into consideration when prescribing a maintenance aerosol inhalation treatment.     

Comparison of conventional metered dose inhaler and breath actuated inhaler in elderly patients

Elderly patients frequently fail to achieve or to retain a competent inhaler technique using a conventional metered dose inhaler. In a prospective, randomised, crossover study of 44 subjects aged 64–94 (mean 78) years, we compared a metered dose inhaler (MDI) with a breath actuated inhaler (BAI) in terms of inhaler technique, ease of teaching and patient acceptability. Patients were stratified according to physical, functional or cognitive impairment before randomisation. Structured tuition was provided at the start of treatments, and technique was graded weekly and retaught if deficient. At the start of the treatment periods satisfactory technique was observed in 14 of 35 patients (six impaired, eight unimpaired) using the MDI and in 14 of 35 patients (three impaired, 11 unimpaired) using the BAI (P = 1.0). At the end of the four-week treatment periods satisfactory technique was observed in 19 of 30 patients (seven impaired, 12 unimpaired) using the MDI and in 27 patients (11 impaired, 16 unimpaired) using the BAI (P = 0.01). Mean weekly teaching times (minutes) were similar (MDI 7.0, BAI 6.5, P = 0.41) and there was no difference in terms of patient acceptability (P = 0.38). A breath actuated inhaler may be the preferred device for elderly patients as a greater proportion were able to retain satisfactory inhaler technique.     

影响慢性阻塞性肺疾病患者正确使用定量型气雾剂的因素分析及对策

目的 探讨慢性阻塞性肺疾病（COPD）患者正确使用定量型气雾剂的必要性和可行性. 方法 对120例COPD患者使用定量型气雾剂,按使用的7个步骤进行初试记录.出院前复试,出院后2周再次复试.比较患者在初、复试中的正确使用率. 结果 初始时,120例COPD患者中能正确使用定量型气雾剂者18例（15%）,常见的错误为：先按压后吸气（90例次）、连喷几次后再吸气（30例次）、吸气后无屏气（28例次）、吸人激素后无漱口（20例次）、使用前无摇匀（18例次）、先吸入糖皮质激素后再吸入β2受体激动剂（80例次）.出院前复试时总的正确使用率增至88例（73%）.出院2周第二次复试时总的正确使用率降至56%（68例）. 结论 定量型气雾剂在COPD患者中使用的正确率低影响疗效.建立规范化的指导和定期培训才能保证使用的正确性和有效性.     

Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged

AIMS: Urinary salbutamol post-inhalation has been shown to be an index of lung deposition. The possibility of using the urinary method for prolonged periods of inhalation (such as nebulized therapy) has been evaluated. METHODS: On separate study days volunteers received salbutamol 5 x 100 microg via either oral administration (ORAL), oral with 5 g oral charcoal (ORAL + C), inhaled from a metered dose inhaler (MDI) or MDI plus 5 g oral charcoal (MDI + C). Each dose was separated by 2 min, i.e. administration time of 8 min. Urine samples were provided at 0, 30, 40, 60 and 120 min postdose. Also seven subjects inhaled 5x100 microg doses from the MDI on five separate occasions and provided urine 0-30 min post dose. RESULTS: No salbutamol was detected in urine samples following ORAL + C. The mean (s.d.) amounts of salbutamol excreted in the urine in the first 30 min post ORAL, MDI and MDI + C were 0.42 (0.55), 11.01 (3.77) and 11.60 (3.68) microg, respectively. The ratio of urinary salbutamol following MDI and MDI + C to ORAL in the 0-30 min collection period was 26.2 and 27.8, and between 30 and 40 min postdose was 5.1 and 4.7, respectively. There was no difference between urinary salbutamol over the first 30 min following MDI and MDI + C with a mean ratio (90% confidence interval) of 95.6 (84.0, 107.2). The mean (s.d.) coefficient of variation for the 30 min urinary salbutamol elimination following inhalation of 5 x 100 microg doses from the MDI by seven subjects (on 5 separate study days) was 9.4 (2.3)%. CONCLUSIONS: The 30 min urinary salbutamol method can be used for an inhalation period of up to 8 min to identify the relative bioavailability to the lung. Samples taken after this time period are affected by excretion of the oral absorbed fraction. Most nebulisers deliver their dose within this administration time.     

Reservoir design and dose availability with long-term metered dose inhaler corticosteroid use.

The effect of reservoir design and long-term use with inhaled metered dose inhaler (MDI) corticosteroids on aerosol dose availability was examined. Beclomethasone dipropionate (Vanceril) was delivered by MDI with three brands of available reservoir devices: the AeroChamber, the OptiHaler, and the Aerosol Cloud Enhancer (ACE). An in vitro lung model simulated inspiration. Long-term use was simulated by exhausting five MDI canisters of beclomethasone through each sample of reservoir tested. Each canister exhausted through a reservoir represented approximately 1 month of use with one drug. Total inhaled dose was collected at the reservoir mouthpiece and measured using a spectrophotometric assay. Dose delivery was measured before simulated use and after each MDI canister was exhausted through the reservoir. Three samples of each brand were tested with cleaning and three samples were tested without cleaning. With cleaning, the AeroChamber, OptiHaler, and ACE delivered significantly different average doses of 16.6, 10.3, and 8.7 micrograms per MDI actuation, respectively, (P = 0.0017) over time of use. Changes in dose delivery over time of use were not significant (P = 0.2011). Without cleaning, the same three brands averaged 21.1, 9.7, and 7.8 micrograms per MDI actuation, respectively, (P = 0.0019), and changes in dose delivery over time were not significant (P = 0.3265). Reservoir design can affect the delivery of an inhaled corticosteroid, although the delivery over 4 to 5 months remained stable.     

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.     

Physiochemical and pharmacological characterization of a Delta(9)-THC aerosol generated by a metered dose inhaler

The goal of the present study was to formulate a Delta(9)-tetrahydrocannabinol (Delta(9)-THC) metered-dose inhaler (MDI) that can be used to provide a systemic dose of Delta(9)-THC via inhalation. Following physiochemical characterization and accelerated stability testing of the aerosol, mice were exposed to the aerosol and evaluated for pharmacological effects indicative of cannabinoid activity, including hypomotilìty, antinociception, catalepsy, and hypothermia. The fine particle dose of Delta(9)-THC was 0.22 +/- 0.03 mg (mean +/- S.D.) or 25% of the emitted dose and was not affected by accelerated stability testing. A 10-min exposure to aerosolized Delta(9)-THC elicited hypomotility, antinociception, catalepsy, and hypothermia. Additionally, Delta(9)-THC concentrations in blood and brain at the antinociceptive ED(50) dose were similar for both inhalation and intravenous routes of administration. Finally, pretreatment with the CB(1) receptor antagonist SR 141716A (10 mg/kg, i.p.) significantly antagonized all of the Delta(9)-THC-induced effects. These results indicate that an MDI is a viable method to deliver a systemic dose of Delta(9)-THC that elicits a full spectrum of cannabinoid pharmacological effects in mice that is mediated via a CB(1) receptor mechanism of action. Further development of a Delta(9)-THC MDI could provide an appropriate delivery device for the therapeutic use of cannabinoids, thereby reducing the need for medicinal marijuana.     

A critical comparison of the dose delivery characteristics of four alternative inhalation devices delivering salbutamol: pressurized metered dose inhaler, Diskus inhaler, Diskhaler inhaler, and Turbuhaler inhaler.

Salbutamol is a short-acting beta 2 agonist which is effective as a rescue therapy in the treatment of asthma. This study uses in vitro test methods to compare the capability of four alternative devices to deliver an accurate and precise dose of salbutamol. It is demonstrated that the conventional metered dose inhaler (MDI) achieves excellent accuracy and precision in dose delivery. Additionally, it is the most efficient inhaler in terms of generating in-vitro a fine particle fraction from the dose. A spacer device has been shown to further enhance the dosing characteristics. When tested over a wide range of inspiratory air flow rates, the Diskus (GlaxoWellcome, Hertfordshire, UK) has comparable accuracy and precision to the MDI tested at 60 L/min, and it offers an advantage over two alternative dry powder inhalers (DPIs), delivering a more consistent dose across the range of flow rates tested and being more efficient at generating a fine particle fraction than either Turbuhaler (Astra, Lund, Sweden) or Diskhaler (GlaxoWellcome) at both 28 and 60 L/min inspiratory flow rates. Diskus, Diskhaler, Ventolin, Volumatic, and Rotadisk are trademarks of the GlaxoWellcome Group of companies. The Accuhaler is the alternative to the Diskus in those countries where the Diskus trademark is not available. Inspiryl and Turbuhaler are trademarks of the Astra Group of companies.     

驱动器的规格与吸入辅助装置对气雾剂体外沉积性质的影响

目的 考察驱动器的规格——孔径、孔长以及吸入辅助装置的使用对气雾剂体外沉积性质的影响.方法 以自制丙酸氟替卡松混悬型气雾剂为模型药物,装配不同规格的驱动器,使用Andersen多级撞击器(Andersen cascade impactor,ACI)测定体外沉积率;将丙酸氟替卡松气雾剂装配筛选好的特定规格的驱动器,分别在不使用吸入辅助装置与使用吸入辅助装置的情况下,对体外沉积性质进行对比研究.结果 在孔径固定的情况下,随着孔长的延长,驱动器的残留量降低,Andersen多级撞击器装置的L型连接管沉积量增加,微细粒子剂量降低.在孔长固定的情况下,随着孔径的增加,驱动器的残留量降低,Andersen多级撞击器装置的L型连接管沉积量增加,微细粒子剂量降低.根据试验结果、混悬型气雾剂本身的剂型特点以及驱动器的实际使用情况,最终,将0.42 mm孔径、0.70 mm孔长的驱动器作为优选驱动器;在使用吸入辅助装置的情况下,Andersen多级撞击器装置L型连接管的沉积量极大地降低,微细粒子剂量增加,原来沉积在L型连接管的大粒子很大一部分被截留在吸入辅助装置当中.结论 驱动器的规格会对吸入气雾剂的体外沉积产生一定的影响,在药品研发的过程中,可根据气雾剂产品的具体特点(溶液型或混悬型,原料药的粒径大小等)进行驱动器的筛选;吸入辅助装置的使用可以提高气雾剂的药物利用率,推荐患者用药时使用.     

Comparison of in vitro and in vivo efficiencies of a novel unit-dose liquid aerosol generator and a pressurized metered dose inhaler

Gamma scintigraphic imaging was employed in 10 healthy volunteers to compare the total and regional lung deposition of aerosols generated by two delivery platforms that permitted microprocessor-controlled actuation at an optimal point during inhalation. An aqueous solution containing 99mTc-DTPA was used to assess the deposition of aerosols delivered by inhalation from two successive unit-dosage forms (44 microl volume) using a prototype of a novel liquid aerosol system (AERx Pulmonary Delivery System). This was compared with aerosol deposition after inhalation of two 50 microl puffs of a 99mTc-HMPAO-labeled solution formulation from a pressurized metered dose inhaler (MDI). The in vitro size characteristics of the radiolabeled aerosols were determined by cascade impaction. For the AERx system, the predicted lung delivery efficiency based on the product of emitted dose (60.8%, coefficient of variation (CV)=12%) and fine particle fraction (% by mass of aerosol particles <5.7 microm in diameter) was 53.3% (CV=13%). For the solution MDI, the emitted dose was 62.9% (CV=13%) and the predicted lung dose was 44. 9% (CV=15%). The AERx system demonstrated efficient and reproducible dosing characteristics in vivo. Of the dose loaded into the device, the mean percent reaching the lungs was 53.3% (CV=10%), with only 6. 9% located in the oropharynx/stomach. In contrast, the lung deposition from the solution MDI was significantly less (21.7%) and more variable (CV=31%), with 42.0% of the radiolabel detected in the oropharynx/stomach. Analysis of the regional deposition of the radioaerosol indicated a homogeneous pattern of deposition after delivery from the AERx system. A predominantly central pattern of distribution occurred after MDI delivery, where the pattern of deposition was biased towards a central zone depicting the conducting airways. The AERx system, in contrast to MDIs, seems highly suited to the delivery of systemically active agents via pulmonary administration.     

Deposition of corticosteroid aerosol in the human lung by Respimat Soft Mist inhaler compared to deposition by metered dose inhaler or by Turbuhaler dry powder inhaler.

Fourteen mild-to-moderate asthmatic patients completed a randomized four-way crossover scintigraphic study to determine the lung deposition of 200 microg budesonide inhaled from a Respimat Soft Mist Inhaler (Respimat SMI), 200 microg budesonide inhaled from a Turbuhaler dry powder inhaler (Turbuhaler DPI, used with fast and slow peak inhaled flow rates), and 250 microg beclomethasone dipropionate inhaled from a pressurized metered dose inhaler (Becloforte pMDI). Mean (range) whole lung deposition of drug from the Respimat SMI (51.6 [46-57]% of the metered dose) was significantly (p < 0.001) greater than that from the Turbuhaler DPI used with both fast and slow inhaled flow rates (28.5 [24-33]% and 17.8 [14-22]%, respectively) or from the Becloforte pMDI (8.9 [6-12]%). The deposition pattern within the lungs was more peripheral for Respimat SMI than for Turbuhaler DPI. The results of this study showed that Respimat SMI deposited corticosteroid more efficiently in the lungs than either of two widely used inhaler devices, Turbuhaler DPI or Becloforte pMDI.     

Performance of large- and small-volume valved holding chambers with a new combination long-term bronchodilator/anti-inflammatory formulation delivered by pressurized metered dose inhaler.

The treatment of both the bronchoconstriction and inflammatory aspects of asthma simultaneously by a single pressurized metered dose inhaler (pMDI) represents a significant advance in convenience to the patient. However, a valved holding chamber (VHC) may still be needed to reduce the coarse component of the dose that is likely to deposit in the oropharyngeal region, and a small sized device may offer significant advantages to the patient from the standpoint of compliance with therapy. VHCs representing small (adult AeroChamber Plus with mouthpiece, 149-mL) and large (Volumatic, 750-mL) devices have been compared in an in vitro evaluation with Seretide/Advair (hydro-fluoro alkane [HFA]-formulated fluticasone propionate [FP = 125 microg/dose] and salmeterol xinafoate [SX = 25 microg/dose]) by Andersen Mark-II eight-stage impactor operated at 28.3 L/min following compendial methodology. Fine particle fraction, based on the size range from 1.1 to 4.7 microm aerodynamic diameter, from either large or small VHCs with either component (69-79%) was similar [p > or = 0.08], and significantly greater than that from the pMDI alone (approximately 40%) [p < 0.001]. Fine particle dose emitted by the VHCs for SX (8.2 +/- 0.8 microg for the AeroChamber Plus and 7.7 +/- 0.5 microg for the Volumatic) were comparable, and also similar to the fine particle dose delivered by the pMDI when used without a VHC (7.6 +/- 0.6 microg). Fine particle doses for the FP component delivered by the two VHCs (46.4 +/- 3.4 microg for the AeroChamber Plus and 46.3 +/- 2.7 microg for the Volumatic) were equivalent, but were slightly greater than the corresponding fine particle dose from the pMDI alone (39.1 +/- 2.6 microg). However, this difference (approximately 20%) is close to the limit of resolution based on intermeasurement variability and is unlikely to have clinical significance, given the interpatient variability seen with inhaled drug therapy. It is therefore concluded that either of these VHCs has equivalent in vitro performance with this combination formulation in terms of the portion of the dose emitted from the pMDI that is likely to reach the receptors in the lungs.     

Comparison of the extrapulmonary beta2-adrenoceptor responses and pharmacokinetics of salbutamol given by standard metered dose-inhaler and modified actuator device

1. Ten healthy subjects were randomised to inhale salbutamol via a standard metered-dose inhaler (MDI), or via a modified metered-dose actuator device (MA). Previously published radiolabelled aerosol data had shown that the MA device produced a lower aerosol velocity, reduced oropharyngeal deposition, but with unchanged pulmonary deposition. 2. Dose-response curves (DRC) were constructed with the following cumulative doses of salbutamol: 200 microg, 600 microg (200 microg + 400 microg), 1400 microg (600microg + 800 microg) ad 2600 microg (1400 + 1200 microg). Dose increments were made every 30 min and measurements of extrapulmonary beta2-adrenoceptor responses were performed 20 min after each dose. In addition, plasma salbutamol concentrations were also measured immediately before and for up to 60 min after the last dose. 3. Baseline values were not significantly different between the two study days for any of the measured parameters. 4. Cmax (ng ml(-1)) for plasma salbutamol (as means and 95% CI for difference between MA and MDI) was: 2.0 (0.3-3.7), P = 0.03. Values for t(max) (min), median and range: MA 5 (5-10) vs MDI 5 (5-10); and AUC 0-60, (ng ml(-1) min, mean and 95% CI for difference between MA and MDI): 69 (-5-143), were not significantly different between the two devices. 5. There was a significant (P < 0.01) left shift in the DRC with the MA device compared with the MDI, for hypokalaemic, finger tremor, chronotropic and electrocardiographic (Twave, Q-Tc) responses to salbutamol. Values for the hypokalaemic response (mmol l(-1)) at 2600 microg were (as change from baseline, means and 95% CI for difference between MA and MDI): 0.23 (0.10-0.36). 6. Thus, the MA device produced greater systemic absorption of salbutamol, and associated extrapulmonary beta2-adrenoceptor responses compared with a standard MDI. These results, therefore, suggest that data from radiolabelled aerosol deposition studies may not predict the systemic absorption of inhaled beta2-adrenoceptor agonists.     

沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度

目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:T_(max)(0.22±0.07)和(1.8±0.6)h,C_(max)(3.4±1.1)和(3.9±1.4)μg·L~(-1),T_(1/2)(4.5±1.5)和(4.6±1.1)h,AUC_(0-20min)(0.9±0.3)和(0.16±0.10)μg·h·L~(-1).两种给药途径的T_(max)和AUC_(0-20 min)之间差异显著(P<0.01).AUC_(0-20min)(nihal)为 AUC_(0-20 min)(po)的 8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为 57％±24％.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.