In vivo-in vitro comparison of deposition in three mouth-throat models with Qvar and Turbuhaler inhalers.

In vitro polydisperse aerosol deposition in three mouth-throat models, namely, the USP (United States Pharmacopeia) mouth-throat (induction port), idealized mouth-throat, and highly idealized mouth-throat, was investigated experimentally. Aerosol particles emitted from two commercial inhalers, Qvar (pMDI) and Turbuhaler (DPI), were used. The in vitro deposition results in these three mouth-throat models were compared with in vivo data available from the literature. For the DPI, mouth-throat deposition was 57.3 +/- 4.5% for the USP mouth-throat, 67.8 +/- 2.2% for the idealized mouth-throat, and 69.3 +/- 1.1% for the highly idealized mouth-throat, which are all relatively close to the in vivo value of 65.8 +/- 10.1%. In contrast, for the pMDI, aerosol deposition in the idealized mouth-throat (25.8 +/- 4.2%) and the highly idealized mouth-throat (24.9 +/- 2.8%) agrees with the in vivo data (29.0 +/- 18.0%) reported in the literature better than that for the USP mouth-throat (12.2 +/- 2.7%). In both cases, the USP mouth-throat gives the lowest deposition among the three mouth-throat models studied. In summary, both the idealized mouth-throat and highly idealized mouth-throat improve the accuracy of predicted mean in vivo deposition in the mouth-throat region. This result hints at the potential applicability of either the idealized mouth-throat or highly idealized mouth-throat as a future USP mouth-throat standard to provide mean value prediction of in vivo mouth-throat deposition.     

Dynamic change of the upper airway during inhalation via aerosol delivery devices.

Although it is likely that the upper airway is a major factor in the large inter- and intra-subject variation in deposition of inhaled drug aerosols in the lung, data on the configuration of the upper airway during inhalation is sparse. We have developed a unique method, using magnetic resonance imaging, to reconstruct the upper airway in three dimensions during inhalation from aerosol devices used to deliver medication to patients with asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Ten healthy adults were imaged while inhaling from a pressurized metered dose inhaler (pMDI), a spacer used with pMDI (spacer), and a high-resistance dry powder inhaler, the Turbuhaler (DPI). The mean cross-sectional area of the oropharyngeal region was significantly larger (Wilcoxon's signed-rank test with Bonferroni correction, p < 0.0167) when the DPI (281 [143] mm2, mean [SD]) was used compared to the spacer (205 [32] mm2, p = 0.016) or pMDI (152 [48] mm2, p = 0.013). Considerable variations in the cross-sectional areas of the oral cavity, oropharynx, and larynx were seen when compared to the upper trachea. The main cause for this was the varying position of the tongue during inhalation via the devices. Although differences were observed when comparing the total volume of the upper airway during inhalation via the DPI (70 [17] cm3) to the pMDI (56 [20] cm3, p = 0.037) or spacer (59 [12] cm3, p = 0.022), these did not reach significance. This study shows that there are very significant variations in the configuration of the upper airway when different devices are used for inhalation. These changes are likely to be produced by a number of factors, including tongue position, device airflow resistance, and patient effort.     

A dry powder inhaler with reduced mouth-throat deposition.

A novel, compact, and highly efficient dry powder inhaler (DPI) with low mouth-throat deposition is described. The performance of this DPI was evaluated by measuring both (1) the total aerosol deposition in and distal to an idealized mouth-throat cast and (2) the fine particle fraction (FPF) using a standard Mark II Anderson impactor. Ultraviolet (UV) spectroscopy techniques were used in the aerosol deposition measurements. Two inhalation aerosol powders, namely budesonide (extracted from a Pulmicort/Turbuhaler multi-dose device, 200 microg/dose) and ciprofloxacin + lipid + lactose (in-house), were dispersed by the DPI at a steady inhalation flow rate of 60 L/min. The newly developed DPI had a total aerosol delivery distal to the mouth-throat cast of 50.5% +/- 3.04% and 69.7% +/- 1.5% for the budesonide and ciprofloxacin + lipid + lactose aerosols, respectively. This is a significant improvement over the Turbuhaler original device delivery of 34.5% +/- 5.2%, particularly considering that in vitro mouth-throat deposition dropped from 27.5% +/- 5.4% with the budesonide Turbuhaler to 11.0% +/- 3.5% with the present inhaler. The different lung deliveries from the same inhaler for the two formulations above also confirm that the overall performance of an inhaler is optimizable via powder formulations.     

Comparison of In Vitro Deposition of Pharmaceutical Aerosols in an Idealized Child Throat with In Vivo Deposition in the Upper Respiratory Tract of Children

Purpose

Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition.

Methods

In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered.

Results

In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2?±?2.3% of delivered dose) compared well (p?>?0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8?±?12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0?±?1.5%) matched in vivo extrathoracic deposition (p?>?0.05) in 6 to 16 year old children with cystic fibrosis (70.4?±?21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR.

Conclusions

The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.     

InVitro Evaluation of Optimal Inhalation Flow Patterns for Commercial Dry Powder Inhalers and Pressurized Metered Dose Inhalers With Human Inhalation Flow Pattern Simulator

This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort^® Turbuhaler^®, and Sultanol^® Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort^® Turbuhaler^® (DPI). Conversely, lower PFR is desirable for Sultanol^® Inhaler (pMDI).     

Comparison of the lung absorption of FK224 inhaled from a pressurized metered dose inhaler and a dry powder inhaler by healthy volunteers.

FK224 is a cyclopeptide drug with poor oral absorption due to proteolysis in the gastrointestinal tract. The objectives of this study were to investigate the absorption of FK224 from the lung in healthy volunteers, and compare the pharmacokinetic profiles of FK224 after inhalation from a pressurized metered dose inhaler (pMDI) and dry powder inhaler (DPI). The pMDI (Suspension type, 1 mg as FK224/puff) and DPI (4 mg and 10 mg as FK224/capsule, using Spinhaler as the device) were developed by formulating the same micronized particles of FK224 which were premixed with beta-cyclodextrin (beta-CyD) to improve the solubility of FK224. In the case of pMDI, 1, 4 or 8 mg was inhaled by the corresponding number of puffs with the pMDI. In addition, the in vitro drug delivery characteristics of the inhalers were evaluated using a multistage liquid impinger. In both inhalers, it was observed that FK224 could be absorbed into the systemic circulation from the lungs of the healthy volunteers, and the AUC and C(max) were proportionally increased depending on the emitted dose after inhalation. However, the pharmacokinetic (PK) parameters for DPI were significantly higher than that of pMDI, in spite of usage of the same fine particles for the formulations in both inhalers. Based on the distribution from the in vitro examination, the fine particle dose, which is defined as the dose region delivered as particles <3.8 microm, was calculated from the emitted dose inhaled by the healthy volunteers. It was found that the PK parameters for both inhalers were proportionally increased depending on the predicted fine particle dose regardless of the type of inhaler. This suggests that the absorption from the lung is influenced by the fine particle dose. We concluded that DPI is a suitable inhaler for FK224, and the alveolus, which is generally known as the site of action of the fine particles, is a possible absorptive site for FK224.     

Targeting drugs to the airways: the role of spacer devices

Aim: Spacer devices are inhalation aids of varying dimension and complexity, specifically designed to overcome problems with the use of pressurised metered dose inhalers (pMDIs). The aim of this review is to examine the current understanding about these inhalation devices and discuss their advantages and disadvantages. Methods: The pertinent literature concerning the characteristics and effects of spacers on delivery and lung deposition of inhaled medications, as well as their clinical efficacy in patients with reversible airway obstruction, is examined. Results: Spacers minimise problems of poor inhalation technique with pMDI, reduce oropharyngeal deposition and increase lung deposition. Spacers improve the clinical effect of inhaled medications, especially in patients unable to use a pMDI properly. Compared to both pMDIs and dry-powder inhalers, spacers may increase the response to β-adrenergic bronchodilators, even in patients with correct inhalation technique. A pMDI plus spacer has proven to be viable lower cost alternative to the use of a nebuliser for delivering large bronchodilator doses in patients with severe acute asthma or chronic obstructive pulmonary disease. The use of large-volume spacers is recommended for delivering high doses of inhaled corticosteroids, and may permit a lower maintenance dose to be used. Conclusion: pMDIs may be routinely fitted with a spacer, especially in situations where correct pMDI use is unlikely.     

Use of inhaler devices in pediatric asthma

Inhalation is the preferred route for asthma therapy, since it offers a rapid onset of drug action, requires smaller doses, and reduces systemic effects compared with other routes of administration. Unfortunately, inhalation devices are frequently used in an empirical manner rather than on evidence-based awareness.A wide variety of nebulizers are available. Conventional jet nebulizers are highly inefficient, as much of the aerosol is wasted during exhalation. However, incorporating an extra open vent into the system has considerably increased the amount of drug that patients receive. Breath-assisted open vent nebulizers limit the loss of aerosol during exhalation, but are dependent on the patient's inspiratory flow. Ultrasonic nebulizers produce a high mass output and have a short nebulization time, but are inefficient for delivering suspensions or viscous solutions. Adaptive aerosol delivery devices release a precise dose that is tailored to the individual patient's breathing pattern. Nebulizers have several drawbacks, and their use should be limited to patients who cannot correctly manage other devices.Pressurized metered-dose inhalers (pMDI) are practical, cheap and multidose. However, there are several problems with their use. Breath-actuated MDI are easy to use and can be activated by very low flow. However, young children may not be able to use them efficiently. Dry powder inhalers (DPI) are portable and easy to use. They are indicated either for rescue bronchodilator therapy or for regular treatment with inhaled corticosteroids and long-acting bronchodilators. The use of spacers reduces oropharyngeal deposition and improves drug delivery to the lung. Spacers do not require patient coordination, but some general rules must be followed for their optimal use.Thus, the choice of a delivery device mainly depends on the age of the patient, the drug to be administered and the condition to be treated. Proper education is also essential when prescribing an inhalation device.     

Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial

BACKGROUND: Inhaled corticosteroids (ICSs) are the preferred maintenance therapy for adults and children with mild, moderate and severe persistent asthma, with the addition of a long-acting beta(2)-adrenoceptor agonist to ICS therapy recommended for patients with moderate or severe persistent asthma. The efficacy and safety of the combination of budesonide and formoterol delivered via dry powder inhaler (DPI) is well documented. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol pressurised metered-dose inhaler (budesonide/formoterol pMDI; Symbicort pMDI, AstraZeneca LP, Wilmington, DE, USA) with budesonide pMDI (Pulmicort pMDI, Astra [corrected] Zeneca, Lund, Sweden), formoterol DPI (Oxis Turbuhaler, AstraZeneca, Lund, Sweden), budesonide plus formoterol in separate inhalers (budesonide pMDI + formoterol DPI) and placebo. STUDY DESIGN: This was a 12-week randomised, double-blind, double-dummy, placebo-controlled study. SETTING: This multicentre study was conducted in the respiratory specialty clinical practice setting. PATIENTS: The study included 596 patients > or =12 years of age with moderate to severe persistent asthma previously receiving ICSs. INTERVENTIONS: After 2 weeks on budesonide pMDI 80 microg x two inhalations (160 microg) twice daily, patients received budesonide/formoterol pMDI 160 microg/4.5 microg x two inhalations (320 microg/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) + formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo twice daily. MAIN OUTCOME MEASURES: There were two prespecified primary efficacy variables: mean change from baseline in morning predose forced expiratory volume in 1 second (FEV(1)), obtained approximately 12 hours after the most recent administration of study medication at home and immediately before the next administration of study medication at the clinic; and mean change from baseline in 12-hour FEV(1), assessed as the average change in FEV(1) from serial spirometry over the 12-hour period after administration of the morning dose of study medication at the clinic. RESULTS: Mean changes from baseline in morning predose FEV(1) at end of treatment were greater (p < or = 0.049) with budesonide/formoterol pMDI (0.19L) versus budesonide pMDI (0.10L), formoterol DPI (-0.12L) and placebo (-0.17L). Mean changes from baseline in 12-hour FEV(1) were greater (p < or = 0.001) with budesonide/formoterol pMDI after 1 day (0.37L), 2 weeks (0.34L) and at end of treatment (0.37L) versus budesonide pMDI (0.11, 0.15 and 0.15L) and placebo (0.09, -0.03 and -0.03L), and after 2 weeks and at end of treatment versus formoterol DPI (0.19 and 0.17L). Fewer (p < or = 0.025) patients receiving budesonide/formoterol pMDI versus monoproducts or placebo met worsening asthma criteria. Results were similar in the budesonide/formoterol pMDI group and the budesonide pMDI + formoterol DPI group on all measures. All treatments were well tolerated with similar safety profiles. CONCLUSIONS: In this population, twice-daily budesonide/formoterol pMDI provides asthma control significantly greater than the monocomponents or placebo and comparable with budesonide pMDI + formoterol DPI. Safety profiles were similar for all treatments.     

On the use of dry powder inhalers in situations perceived as constrained.

Dose delivery from dry powder inhalers (DPIs) are dependent on the inhalation effort of the patient. Some patient groups, including asthmatic children, patients with acute asthma, and patients with advanced chronic obstructive pulmonary disease (COPD) are perceived as having problems in readily inhaling from a DPI in an efficient way; this opinion is based on alleged low inhalation flows. A review of the literature however shows that these groups can use a DPI in an efficient way and gain good clinical effect from its use. Particularly, it has been shown that children can generate a good peak inhalation flow through a DPI, albeit a lower inhaled volume. Similarly, patients with acute asthma can use a DPI in an efficient way, even reaching a better clinical effect with the DPI than with a pressurized metered dose inhaler with a spacer. Finally, it was shown that patients with severe COPD can generate the inhalation flows needed to generate an efficient drug aerosol from a DPI. Collectively, the discussed patient groups seem to perform as well as other subjects when it comes to their ability to generate an adequate inhalation flow through a DPI.     

The inhalation manager: a new computer-based device to assess inhalation technique and drug delivery to the patient.

The rational choice of an inhalation device is a cornerstone in the effective management of asthma and COPD. In this publication, we describe the development of a new system, the Inhalation Manager, which, for the first time, offers the possibility to assess the entire inhalation maneuver of patients using original devices under everyday conditions. So far the Inhalation Manager allows the measurement of inspiratory maneuvers of patients through placebo inhalation devices of the most common breath-actuated CFC-free inhalers in the market for the three main glucocorticosteroids Budesonide [Turbohaler (TH), dry powder inhaler (DPI)], Beclomethasone dipropionate [Autohaler (AH), breath-actuated pressurized metered dose inhaler (pMDI)], and Fluticasone propionate [Diskus (DI), DPI] by means of a pneumotachometer. In addition, it allows allocation of the individual maneuver to the expected drug delivery values (mass output and particle size distribution) of these three devices. In a field trial, the inhalation technique of 628 (TH), 794 (AH), and 795 (DI) patients, respectively, was tested in 72 pulmonologist practices with the Inhalation Manager. For patients in the 18-59-year-old group, the Inhalation Manager detected the following percentages needing improvement: 1.5% for the Autohaler device, 16.7% for the Diskus, and 38.9% for the Turbohaler. In the 60-99-year-old group, percentages needing improvement were 1.5%, 31.5%, and 66.1% for the Autohaler, Diskus, and Turbohaler, respectively. Therefore, the Inhalation Manager could become an essential tool in asthma management by finding the most suitable inhaler for an individual patient and by training the optimal inhalation technique.     

Inhalation profiles in asthmatics and COPD patients: reproducibility and effect of instruction.

Turbuhaler and Salbutamol-Diskus produce therapeutic doses at peak inspiratory flow (PIF) of >30 L/min. However, the optimum flow for Fluticasone-Diskus and Turbuhaler, in terms of total emitted dose and fine particle mass, is >60 L/min. The Turbuhaler achieved a higher output at this flow, as compared to Diskus. For pMDI 25 < PIF < 90 L/min, an actuation time of 0.0-0.2 sec is optimal. The aim of this study was to examine the incidence of optimum inhalation profiles, the effect of instruction, reproducibility, and the relationship between inhalation profiles and patient characteristics in stable asthmatics and mild/moderate/severe COPD patients. For each device, triplicate inhalation profiles were recorded during 6 sessions in a 10-week period. All patients achieved PIF > 30 L/min using Diskus. After instruction, all Diskus inhalations were performed with >60 L/min, except 7% of the inhalations of the severe COPD patients. At least 95% of the Turbuhaler inhalations was also performed with the minimum flow; however, 19% of the inhalations of the severe COPD patients were not optimally performed. The hand-lung coordination was inadequate in 40% of pMDI inhalation profiles, and 80% was performed with a too high flow. The reproducibility of PIF of both dry powder inhalers (DPIs) was very high (coefficient of variation = 4-10%). The reproducibility of the pMDI variables was lower (coefficient of variation = 9-18%). The major lung function variables predictive for PIF(diskus) and PIF(turbuhaler) were maximal inspiratory mouth pressure (MIP), PIF, and inspiratory capacity. No significant predictive lung function variables for PIF(pMDI) were found. Most patients performed reproducible optimum inhalation profiles through Diskus and Turbuhaler. However, in the severe COPD group, 7-19% of the patients were not able to generate the optimum flows through the DPIs. For these patients, a flow-independent aerosol delivery system might be more suitable. The majority of patients were using the pMDI incorrectly. Instruction had no effect. So, we concluded that the pMDI should not be used in these patient groups because of the coordination problems.     

Pharmacokinetics of budesonide and formoterol administered via 1 pressurized metered-dose inhaler in patients with asthma and COPD

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C(max)) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C(max) were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C(max) were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C(max) were similar and formoterol AUC and C(max) 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.     

Formulation of a protein with propellant HFA 134a for aerosol delivery

The purpose of this study was to investigate the formulation and delivery of a protein in a pressurized metered-dose inhaler (pMDI) containing HFA 134a as the propellant for aerosol delivery. Ethanol and surfactants, including polyoxyethylene 10 oleyl ether (Brij 97), polyoxyethylene 20 oleyl ether (Brij 98), polyoxyethylene sorbitan monooleate (Tween 80) and Aerosol OT (AOT), were investigated as formulation adjuvants to improve the dose delivery characteristics of the model protein (bovine serum albumin) containing pMDI formulations. The aqueous solution of a surfactant and protein was lyophilized to obtain a solid carrier system of the protein. Readily dispersible suspensions were obtained by suspending this solid carrier system in HFA 134a with ethanol as a dispersing aid. The formulations containing Tween 80 resulted in the highest respirable fraction. This study suggested a potential formulation containing a lyophilized complex of surfactant and protein readily dispersible in HFA 134a for delivering a therapeutic protein to the respiratory tract by inhalation.     

In vitro effect of a holding chamber on the mouth-throat deposition of QVAR (hydrofluoroalkane-beclomethasone dipropionate).

Experimental work has been conducted on the effect of an add-on holding chamber (Aerochamber) on the characteristics of deposition in a mouth-throat model using 100-microg hydrofluoroalkane-beclomethazone dipropionate (QVAR) metered dose inhalers at inhalation flow rates of 28.3, 60, and 90 L/min. A filter or cascade impactor downstream of the mouth-throat collected aerosol not depositing. The results emphasize the important well documented effect of a valved holding chamber (VHC), in reducing drug deposition in the mouth-throat. This reduction is largest (24% of nominal dose) at the lowest flow rate tested, becoming insignificant at 60 L/min. Total amount of drug delivered distal to the mouth-throat increases with flow rate both with and without a holding chamber, increasing from 42% to 69% of the nominal dose without a VHC as the inspiratory flow rate increases from 28.3 to 90 L/min. The effect of the holding chamber on post mouth-throat delivery was small, reaching significance only at the highest flow rate (90 L/min), where an increase by 8% of the nominal dose was observed. No significant effect on MMAD of beclomethasone-dipropionate occurred when the holding chamber was used. An argument based on the interaction between induced turbulence and particle inertia is used to shed light on the above observations.     

吸入装置的演变过程及研究进展

吸入装置通过不同的气溶胶发生原理,结合相应的药物形态形成了现有的药械组合式吸入制剂,目前已广泛应用于吸入治疗领域。但在临床使用过程中也逐渐暴露出一些问题,如患者使用压力定量吸入气雾剂(pressurized metered-dose inhaler,pMDI)时协调性不够,使用干粉吸入剂(dry powder inhaler,DPI)时吸力不足,患者使用依从性差等。新型吸入装置致力于通过装置性能的改善弥补吸入装置目前存在的缺点,并结合智能化和云端管理扩展功能等,提高患者的使用依从性,从而进一步提高临床治疗效果。     

Evaluation of Enhanced Condensational Growth (ECG) for Controlled Respiratory Drug Delivery in a Mouth-Throat and Upper Tracheobronchial Model

Purpose  

The objective of this study is to evaluate the effects of enhanced condensational growth (ECG), as a novel inhalation drug delivery method, on nano-aerosol deposition in a mouth-throat (MT) and upper tracheobronchial (TB) model using in vitro experiments and computational fluid dynamics (CFD) simulations.     

Pharmacokinetics of budesonide and formoterol administered via a series of single-drug and combination inhalers: four open-label, randomized, crossover studies in healthy adults

Objective: To investigate the pharmacokinetics of budesonide and formoterol administered concomitantly in healthy adults. Methods: Three single-dose, open-label crossover studies (n=28 each) were conducted (Study I: budesonide pMDI, formoterol DPI, budesonide pMDI+formoterol DPI; Study II: budesonide/formoterol pMDI, budesonide pMDI+formoterol DPI; Study III: budesonide/formoterol pMDI [three budesonide formulation strengths; constant formoterol]). Study IV (n=28) assessed steady state pharmacokinetics (budesonide/formoterol pMDI [two/four inhalations twice daily, 5-day treatment; four inhalations, single-dose]). Results: Study I: no pharmacokinetic interactions were observed between budesonide and formoterol. Study II: AUC ratios were 97.9% (budesonide) and 82.2% (formoterol) (budesonide/formoterol pMDI versus budesonide pMDI+formoterol DPI). Study III: formoterol AUC was comparable across budesonide/formoterol pMDI formulation strengths; budesonide AUC increased with formulation strength in proportion to fine particle dose. Study IV: dose proportionality was demonstrated for budesonide (AUC ratio, 104.3%) and suggested for formoterol (AUC ratio, 117.6%) with budesonide/formoterol pMDI (steady state); budesonide and formoterol AUC was higher with repeated versus single-dose budesonide/formoterol pMDI (four inhalations). Conclusions: No pharmacokinetic interactions were observed between budesonide and formoterol. Budesonide dose variation in budesonide/formoterol pMDI did not affect formoterol exposure. Steady state budesonide/formoterol pMDI dose-doubling yielded proportional increases in budesonide and formoterol exposure. Copyright © 2008 John Wiley & Sons, Ltd.     

Design optimization of a novel pMDI actuator for systemic drug delivery.

Pressurized metered dose inhalers (pMDIs) are the most widely prescribed and economical respiratory drug delivery systems. Conventional pMDI actuators-those based on "two-orifice-and-sump" designs-produce an aerosol with a reasonable respirable fraction, but with high aerosol velocity. The latter is responsible for high oropharyngeal deposition, and consequently low drug delivery efficiency. Kos' pMDI technology is based on a proprietary vortex nozzle actuator (VNA), an innovative actuator configuration that seeks to reduce aerosol plume velocity, thereby promoting deep lung deposition. Using VNA development as a case study, this paper presents a systematic design optimization process to improve the actuator performance through use of advanced optical characterization tools. The optimization effort mainly relied on laser-based optical diagnostics to provide an improved understanding of the fundamentals of aerosol formation and interplay of various geometrical factors. The performance of the optimized VNA design thus evolved was characterized using phase Doppler anemometry and cascade impaction. The aerosol velocities for both standard and optimized VNA designs were found to be comparable, with both notably less than conventional actuators. The optimized VNA design also significantly reduces drug deposition in the actuator as well as USP throat adapter, which in turn, leads to a significantly higher fine particle fraction than the standard design (78 +/- 3% vs. 63 +/- 2% on an ex valve basis). This improved drug delivery efficiency makes VNA technology a practical proposition as a systemic drug delivery platform. Thus, this paper demonstrates how advanced optical diagnostic and characterization tools can be used in the development of high efficiency aerosol drug delivery devices.     

In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices.

Experiments were performed to determine the effect of different pharmaceutical aerosol inhalation devices on the deposition of monodisperse aerosols in an idealized mouth and throat geometry. The devices included two dry powder inhalers (Diskus and Turbuhaler), two nebulizers (Pari LC STAR and Hudson T-Updraft), and a metered dose inhaler with attached holding chamber (Aerochamber), in addition to a straight tube (1.7 cm inner diameter). Aerosol particles (DL-alpha tocopheryl acetate) of diameters of 2.5, 5, and 7 microm generated by a vibrating orifice generator were inhaled at steady air flow rates of Q = 5-90 L/min through the devices and into the mouth-throat. Deposition in the mouth-throat and after-filter were determined by ultraviolet (UV) spectrophotometric assay. The amount of deposition in the mouth and throat region was found to depend on the type of device that the aerosol entered through. Deposition in the extrathoracic region with the two types of jet nebulizers did not differ significantly (p > 0.1) from that of a straight tube or each other over their entire tested range of 590 > or = pd2Q > or = 11,375, where p is particle density (in g/cm3), d is particle diameter (in microm), and Q is flow rate (in cm3/s). The metered dose inhaler with attached holding chamber was found to differ from the straight tube only at two intermediate values of pd2Q = 5,145 and 16,033. The deposition occurring for the dry powder inhalers was found to be significantly greater than for the straight tube for all values of pd2Q > or = 10,954 for the Diskus and pd2Q > or = 9,435 for the Turbuhaler. Deposition with the dry powder inhalers was found to be up to 14 times greater than that with the straight tube. Thus, the inhaler geometry that the aerosol passes through prior to entering the mouth and throat region can greatly affect the deposition in the mouth-throat.