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.     

Influence of Impactor Operating Flow Rate on Particle Size Distribution of Four Jet Nebulizers

When a nebulizer is evaluated by the Andersen Cascade Impactor (ACI), the flow rate is generally maintained at 28.3 L/min, as recommended by the manufacturer. However, the nebulizer flow rate that a patient inhales is only around 18 L/min. Because the drive flow of a nebulizer is approximately 6–8 L/min, the nebulized drug is mixed with outside air when delivered. Evaluating impactor performance at the 28.3 L/min flow rate is less than ideal because an additional 10 L/min of outside air is mixed with the drug, thereby affecting the drug size distribution and dose before inhalation and deposition in the human lung. In this study we operated the ACI at an 18.0 L/min flow rate to test whether the effect of the changing ambient humidity was being exaggerated by the 28.3 L/min flow rate. The study was carried out at three different relative humidity levels and two different impactor flow rates with four commercially available nebulizers. The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) of the droplets were found to increase when the impactor was operated at a flow rate of 18 L/min compared to that of 28.3 L/min. The higher MMAD and GSD could cause the patient to inhale less of the drug than expected if the nebulizer was evaluated by the ACI at the operating flow rate of 28.3 L/min.     

Influence of impactor operating flow rate on particle size distribution of four jet nebulizers

When a nebulizer is evaluated by the Andersen Cascade Impactor (ACI), the flow rate is generally maintained at 28.3 L/min, as recommended by the manufacturer. However, the nebulizer flow rate that a patient inhales is only around 18 L/min. Because the drive flow of a nebulizer is approximately 6-8 L/min, the nebulized drug is mixed with outside air when delivered. Evaluating impactor performance at the 28.3 L/min flow rate is less than ideal because an additional 10 L/min of outside air is mixed with the drug, thereby affecting the drug size distribution and dose before inhalation and deposition in the human lung. In this study we operated the ACI at an 18.0 L/min flow rate to test whether the effect of the changing ambient humidity was being exaggerated by the 28.3 L/min flow rate. The study was carried out at three different relative humidity levels and two different impactor flow rates with four commercially available nebulizers. The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) of the droplets were found to increase when the impactor was operated at a flow rate of 18 L/min compared to that of 28.3 L/min. The higher MMAD and GSD could cause the patient to inhale less of the drug than expected if the nebulizer was evaluated by the ACI at the operating flow rate of 28.3 L/min.     

In-vitro intra- and inter-inhaler flow rate-dependent dosage emission from a combination of budesonide and eformoterol in a dry powder inhaler.

Some dry powder inhalers have profound inhalation flow rate-dependent dosage emission, and it has been suggested that there are links between the in vitro emitted dose, total lung deposition, and subsequent clinical response. We have measured the in vitro dosage delivery for a combination of budesonide and eformoterol in a new version of the Turbuhaler. At inhalation flow rates of 30, 60, and 90 Lmin(-1), the total dose emission for 10 separate inhalations from each of six inhalers was determined. The aerodynamic characteristics of the emitted dose using inhalation flow rates of 28.3 and 60 Lmin(-1) were measured using the Andersen Cascade Impactor. The mean (SD) emitted dose for budesonide, at 30, 60, and 90 Lmin(-1), was 37.5%(18.2%), 64.4%(16.6%), and 107.4%(36.0%) (of the nominal emitted dose), respectively, and for eformoterol were 38.0%(20.3%), 65.0%(16.8%), and 104.9%(36.2%) (of the nominal emitted dose), respectively. Variability of dose emission characteristics from each inhaler and between inhalers at each flow rate was found. The aerodynamic particle size characterization of the emitted dose at flow rates of 28.3 and 60 Lmin(-1) revealed a mean fine particle dose for budesonide of 11.9% and 28.6% of the nominal emitted dose, respectively, and similarly 10.0% and 26.3% for eformoterol. At 28.3 Lmin(-1), the majority of the emitted dose (54.8% for budesonide and 64.5% for eformoterol) was deposited in the throat and preseparator of the Andersen Cascade Impactor. The mass median aerodynamic diameters for budesonide and eformoterol at 28.3 Lmin(-1) were 3.2 and 3.6 microm, respectively, and similarly at 60 Lmin(-1) were 2.4 and 2.5 microm. The modified Turbuhaler containing a budesonide and eformoterol combined formulation shows intra- and inter-inhaler flow-dependent dosage emission. The clinical significance of the in vitro dose-dependent properties should be investigated.     

Variation in pediatric aerosol delivery: importance of facemask.

We have quantified in vitro the influence of the facemask on the amount of drug delivered (e.g., inhaled mass) by jet nebulizer and pressurized metered dose inhaler (pMDI) valved holding chamber (VHC) combinations (non-detergent-coated and detergent-coated). Pediatric breathing patterns were used with a breathing simulator, which was connected to a face onto which each device was positioned. An inhaled mass filter interposed between the simulator and the face captured the aerosolized drug. Budesonide inhalation suspension (0.25 mg) was used with the jet nebulizers and fluticasone propionate (220 microg) pMDI with the VHCs. Maximal drug delivery was measured using constant flow through each device. Breathing pattern effects were assessed for sealed devices (no leaks) and with facemasks (possible leaks at the facemask). Inhaled mass from both nebulizers and pMDI VHCs was affected by breathing pattern, but compared to nebulizers the pMDI VHCs were significantly more variable and sensitive to several factors. The influence of VHC conditioning combined with effects of breathing pattern resulted in the inhaled mass ranging from 0.7 +/- 0.5 to 53.3 +/- 6.2%. Nebulizers were less variable (9.6 +/- 0.7 to 24.3 +/- 3.1%). Detergent coating of VHC markedly increased the inhaled mass and reproducibility of drug delivery (27.2 +/- 1.4 to 53.3 +/- 6.2%) for pMDI VHC combinations, but these effects were lost in the presence of facemasks. Using pediatric patterns of breathing, nebulizer/facemask combinations delivered 4.1 +/- 0.8 to 19.3 +/- 2.3% of the label dose while pMDI and detergent-coated VHC delivered 4.0 +/- 1.6 to 28.6 +/- 2.5%. Facemask seal is a key factor in drug delivery. Leaks around the facemask reduce drug delivery and for pMDI VHCs can negate effects of detergent coating.     

Allergen challenge and deposition of nedocromil sodium in asthma.

We examined whether the acute protective effect of nedocromil sodium aerosol could be enhanced by increasing the deposition uniformity of the drug in the lungs of adult patients with allergic asthma. Ten patients with mild-to-moderate asthma were challenged with the same doses of allergen on two occasions in a randomized manner. Thirty minutes before these challenges, patients inhaled 4 mg nedocromil sodium, admixed with the radioisotope (99m)technetium. Radiolabeled drug was inhaled during slow (25.4 +/- 4.6 L/min) and faster (58.0 +/- 7.3 L/min) inhalations from a 700 ml holding chamber. Percent changes in FEV(1) at the same top dose of allergen on the two treatment visits were compared. Lung deposition fraction (LDF) and indices of distribution uniformity, quantified from gamma camera images, were also compared. Acute protection against allergen challenge was similar and complete after slow or faster inspiration of nedocromil sodium. Mean (+/- SD) allergen-induced changes in FEV(1) were -1.05 +/- 2.78% and -0.39 +/- 2.80%, respectively, compared to -26.30 +/- 8.49% on a screening challenge (no drug). Mean LDF was also similar on the two visits, averaging 16.4 +/- 4.6% and 16.1 +/- 7.2% of administered drug, respectively. Distribution of nedocromil sodium was most uniform after slow inspiration, but increased uniformity was not related to enhanced protection. Complete protection against acute bronchoconstriction induced by inhaled allergen can be obtained with 4 mg of nedocromil sodium aerosol, inhaled from a large volume holding chamber, 30 min before the exposure, and at inspiratory flow rates between approximately 20-60 L/min. Protection does not appear to be enhanced by increased uniformity of drug distribution within the lungs.     

Inhalation characteristics and their effects on in vitro drug delivery from dry powder inhalers Part 2: Effect of peak flow rate (PIFR) and inspiration time on the in vitro drug release from three different types of commercial dry powder inhalers

Three commercial dry powder inhalers with completely different dosing and powder disintegration principles were evaluated in an in vitro deposition study. A four-stage cascade impactor was used for the range of flow rates between 20 and 60 1/min. Turbuhaler, Diskhaler and Spinhaler showed increasing amounts of drug discharged from the dose system with increasing peak inspiratory flow rate (PIFR). Only for the Spinhaler, was discharge influenced by total inspiration time as well. All three inhalers also showed improved powder disintegration with increasing PIFR. Highest fine particle yield was obtained from the Turbuhaler, reaching a maximum of 35–40% of the nominal dose at flow rates of 50–60 l/min. In comparison, less than 10% of the nominal dose from the Spinhaler and on average 23% from the Diskhaler were released as fine drug particles at 60 l/min. From the work of inspiration involved, it has been concluded that a short and fast inspiration through the Turbuhaler gives an optimal result from fine particle output and from efficiency point of view.     

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.     

The effects of carrier size and morphology on the dispersion of salbutamol sulphate after aerosolization at different flow rates

We have investigated the interdependence of various factors (particle size, surface smoothness, carrier particle shape, inhalation flow rate) on the deposition of a model drug (salbutamol sulphate) after aerosolization from a model inhaler device (Rotahaler). Different batches of alpha-lactose monohydrate were prepared to have different particle size, particle shape and surface smoothness. Each batch of lactose was then mixed separately with salbutamol sulphate in a ratio of 67.5 : 1 (w/w), under similar conditions. Drug deposition from each formulation was investigated using a 4-stage liquid impinger after aerosolization at 28.3, 60.0 and 96.0 L min(-1) via a Rotahaler. At a flow rate of 28.3 L min(-1), a large portion of drug particles was not emitted from the inhaler, the % emission varying from 29.6% to 66.6% for all formulations investigated. Drug emission tended to increase with particle size of the carrier whilst fine particle fraction, fine particle dose and dispersibility appeared to increase with decreasing particle size but increasing elongation ratio of the carrier particles. Increasing the flow rate to 60.0 L min(-1) was shown to increase drug emission since > 75% total dose was found to be emitted from the inhaler. Again, smaller or more elongated lactose particles resulted in a higher fine particle dose or fine particle fraction of salbutamol sulphate than the coarser carrier, although they produced a similar (analysis of variance P > 0.05) drug emission. Increasing the flow rate to 96.0 L min(-1) did not increase drug emission. Increasing the flow rate resulted in an increase in the fine particle fraction and fine particle dose of salbutamol sulphate from all formulations. The flow rate of the airstream appeared to play the most important role, followed by particle size and elongation ratio of the carrier particles, with the surface smoothness relatively less significant in determining the deposition of salbutamol sulphate from the Rotahaler.     

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.     

Aerosol characterization of three corticosteroid metered dose inhalers with volumatic holding chambers and metered dose inhalers alone at two inspiratory flow rates.

Inhaled corticosteroids are first-choice drugs in the treatment of chronic asthma. A metered dose inhaler (MDI) equipped with a spacer device is easier to use for patients with a poor inhalatory technique; it favors a reduction in the size of the particles delivered to the patient and thus a reduction in the incidence of local and systemic side effects of these drugs. The aim of this study was to determine the particle characteristics of fluticasone propionate (FP), flunisolide (FLUN), and beclomethasone dipropionate (BDP), each administered at a rate of 250 micrograms per puff and at inspiratory flow rates of 30 and 60 L/min in vitro, to estimate the particle characteristics of these drugs aspirated via an MDI alone and via a large-volume holding chamber (Volumatic). Compared with the MDI alone, at 30 L/min, the Volumatic (Glaxo Wellcome, Ware, UK) significantly reduced the mass median aerodynamic diameter (MMAD) and increased the fine particles (< 5 microns and < 2 microns) generated by all three drugs. At 60 L/min, the MMAD increased and the generation of fine particles decreased with both devices. These data suggest that the inspiratory flow applied by means of the devices may be a determinant for the deposition of the drug in the lower airways in that by increasing the inspiratory flow, the MMAD increases and the percentage of fine particles decreases, probably because of the reaggregation favored by the higher flows.     

Particle characteristics and lung deposition patterns in a human airway replica of a dry powder formulation of polylactic acid produced using supercritical fluid technology.

Polylactic acid (PLA) powders have been used as vector particles to carry pharmaceutical material. Drugs incorporated in the PLA powder can be retained in the lung for a longer period and may be more effective than free-form drugs. A new formulation of L-PLA dry powder, which was easy to disperse in the air, was produced by using a supercritical technology. The L-PLA powder was characterized in terms of physical particle size and aerodynamic size as generated with a Turbuhaler dry powder inhaler (DPI). Electron microscopy analysis of the particles indicated that they were individual particles in bulk form and became aggregate particles after generation by the Turbuhaler. Aerodynamic particle size analysis using both an Aerodynamic Particle Sizer (APS) aerosol spectrometer and Andersen impactor showed that the aerodynamic size decreased as the flow rate in the Turbuhaler increased from 28.3 to 90 L min(-1). Deposition patterns in the human respiratory tract were estimated using a realistic physical replica of human airways. Deposition of the L-PLA was high (80.8%) in the oral airway at 28.3 L min(-1) and an average of 73.4% at flow rates of 60 and 90 L min(-1). In the lung region, the deposition totaled 7.2% at 28.3 L min(-1), 18.3% at 60 L min(-1), and 17.6% at 90 L min(-1). These deposition patterns were consistent with aerodynamic size measurement, which showed 76 to 86% deposition in the USP/EP (US Pharmacopoeia/European Pharmacopoeia) induction port. As the flow rate increased, fewer aggregates were formed resulting in the smaller aerodynamic particles. As a result, more particles penetrated the oral airways and were available for deposition in the lung. Our results showed that L-PLA particles as manufactured by the supercritical technology could be used in a DPI that does not require the use of carrier particles to facilitate aerosol delivery.     

Experimental measurements of particle deposition in three proximal lung bifurcation models with an idealized mouth-throat.

In this paper, particle deposition in three idealized proximal lung bifurcation models with an idealized mouth-throat were investigated experimentally. These bifurcation models included (1) a small symmetric bifurcation, (2) an intermediate asymmetric bifurcation, and (3) a large symmetric bifurcation. An idealized mouth-throat geometry (the "Alberta geometry") was used as the inlet to these bifurcation models. Monodisperse aerosol particles of DEHS (di-2-ethylhexyl-sebecate) oil with mass median diameters in the range of 2.5-7.5 microm were employed at steady flow rates of 30-90 L/min. Particle deposition measurements were conducted by gravimetry. The results show that particle deposition in the mouth-throat and trachea accounts for the major portion of total deposition in the entire models used, and particle deposition fraction in the proximal lung bifurcations is lower compared with that deposited in the regions upstream (the mouth-throat and the trachea). Total particle deposition efficiency increases with increasing either inertial parameter or Stokes number. Total particle deposition varies appreciably from model to model. The laryngeal jet is the key factor dominating particle deposition within the trachea. An effect of Reynolds number on particle deposition efficiency in the trachea is observed. In addition, particle deposition in the bifurcation region is influenced little by the upstream flow condition, and therefore the effect of the laryngeal jet on deposition seemingly does not propagate to the bifurcations downstream.     

Aerosol tribocharging and its relation to the deposition of Oxis™ Turbuhaler® in the electrical next generation impactor

Although there have been published electrostatic characterisation studies of drug‐only Turbuhaler® and lactose carrier–drug formulations, there has not been an investigation into spheronised agglomerates containing micronised lactose and eformoterol, such as in Oxis® Turbuhaler®. Ten doses of Oxis® (12 µ g eformoterol) were dispersed into an electrical next generation impactor (eNGI) in a single run, and runs were conducted in triplicate to determine the aerosol performance and aerosol charge distribution at flow rates of 30, 60 and 90 L/min. Eformoterol fine particle fraction (FPF) reached a maximum of 50%–60% at 60 and 90 L/min, whereas lactose FPF increased from 31% to 42% when flow rate was increased from 30 to 90 L/min. Specific net charge (C/µ g) within the eNGI stages increased from 30 to 60 L/min, but then decreased at 90 L/min. These results were attributed to the shift in balance between surface charging after interparticle and particle–surface collision (dominant at 30 and 60 L/min) and charge separation after impact fragmentation of agglomerates (dominant at 90 L/min). However, the aerosol charge profiles do not suggest that electrostatic forces play a major role in the deposition of Oxis® Turbuhaler® dry powder formulation.     

Accuracy of delivery of cefazolin, chloramphenicol, and vancomycin by a controlled-release membrane infusion device

The effects of flow rate and drug concentration on the accuracy of in vitro delivery of cefazolin, chloramphenicol, and vancomycin by a new controlled-release membrane infusion device, MICROS, were studied. Cefazolin, chloramphenicol, and vancomycin 1 g in sterile water for injection 10 mL were injected into the drug chamber of the device and delivered through an administration set with 0.9% sodium chloride injection from a primary line. Drug delivery was studied at four flow rates (0.5, 1.0, 1.5, and 2.0 mL/min). In addition, three concentrations of each drug (25, 50, and 100 mg/mL for cefazolin and vancomycin, and 50, 100, and 200 mg/mL for chloramphenicol) were studied at a fixed flow rate of 1 mL/min. Samples were collected in triplicate every 2.5-5.0 minutes using a fraction collector over a 90-minute period for cefazolin and a 120-minute period for chloramphenicol and vancomycin. The concentration of each drug was measured by high-performance liquid chromatography. At various flow rates, the time for delivery of greater than or equal to 95% of each dose ranged from 30 to 55 minutes for cefazolin, 45 to 70 minutes for chloramphenicol, and 50 to 65 minutes for vancomycin. At various concentrations, greater than or equal to 95% of each dose was delivered in 40 to 55 minutes for cefazolin, 40 to 70 minutes for chloramphenicol, and 50 to 60 minutes for vancomycin. The desired delivery times were 30-60 minutes for cefazolin and chloramphenicol and 50-70 minutes for vancomycin. Delivery of cefazolin and vancomycin by the MICROS membrane infusion system was accurate. Some delay was encountered in the delivery of chloramphenicol.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Comparison of delivery characteristics from a combination metered-dose inhaler using the Andersen cascade impactor and the next generation pharmaceutical impactor

The purpose of this research was to compare two cascade impaction devices for the aerodynamic particle size assessment of a combination metered-dose inhaler (MDI) product, Combivent. Particle size analysis was performed using an Anderson Mark II cascade impactor (ACI) and a Next Generation Pharmaceutical Impactor (NGI), both fitted with a preseparator and either a 1 L glass chamber or USP throat, and operated at various flow rates. Particle size distributions (PSDs) and dose delivery profiles were assessed by means of the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle fraction <5 micron aerodynamic diameter (FPF(<5 microm)), and induction port deposition fraction (IPF). Under their normal operating conditions, the ACI (28.3 L/min) and the NGI (30 L/min) yield similar PSDs and dose delivery profiles. However, this equivalent performance for the ACI and the NGI no longer exists at a higher flow rate of 60 L/min. Furthermore, changes in PSD results may also be obtained between different operators and/or when different induction port designs were employed. Thus, it is strongly recommended that special care be taken to eliminate variation in experimental parameters and/or selection of ancillary devices such as the preseparator, induction port or throat, to insure good repeatability and reproducibility when testing inhalation drugs.     

Variability of fine particle dose and lung deposition of budesonide delivered through two multidose dry powder inhalers

OBJECTIVE: To assess the reliability of dosing through two budesonide multidose dry powder inhalers (DPI) as derived from the in-vitro variability of the fine particle dose (FPD) and the in-vivo variability of the lung deposition at different flow rates. METHODS: The same two DPIs [device N (Novolizer) and device T (Turbuhaler)] were compared in both studies. In the in-vitro study, the variability of the FPD, measured at flow rates of 30-100 L/min, was determined for equal flow rates and at comparable maximal inspiratory pressures (MIP). In the in-vivo study in healthy subjects (scintigraphic, randomised, crossover design) the variability of the lung deposition was determined at targeted flow rates of 45, 60 and 90 L/min for device N, and at 60 L/min for device T. RESULTS: The variability of the FPD was lower with device N than with device T by 34%-86%. The differences were statistically significant for flow rates of 60, 70, 90 and 100 L/min (not significant for 40, 50 and 80 L/min) in the in-vitro study. Results for comparable MIPs showed analogous differences (79%, p = 0.004, at the clinically relevant MIP of 4.5 kPa). The variability of the lung deposition was clearly lower with the device N than with the device T. The difference was statistically significant (p = 0.029) at a comparable targeted flow rate of 60 L/min. CONCLUSIONS: Thus, this study showed that device N is likely to improve the reliability of inhalation therapy by reducing both the variability of the delivered drug and that of the lung deposition. The reliability of inhalation therapy and consequently the quality of long-term control of asthma and the patient's compliance might improve when choosing the DPI with the better characteristics.     

Formulation development of inhalation powders for FK888 using the E-haler to improve the inhalation performance at a high dose, and its absorption in healthy volunteers.

FK888 is a candidate selective NK1 receptor antagonist, and it exhibits poor absorption from the gastrointestinal tract in healthy volunteers. In a previous study, the optimized dry powder inhaler (DPI) formulation with carrier lactose using the Spinhaler was developed, although the maximum dose per capsule was only 5mg because the fine particle fraction (FPF) was reduced at doses over 5mg. The objective of this study was to develop an optimized DPI formulation for higher doses, such as 40 mg, with proportional systemic absorption. The Spinhaler and E-haler were used as the inhalation devices, and the in vitro deposition was evaluated using a multistage cascade impactor at different flow rates (28.3 and 60 l/min). When hydroxypropyl methylcellulose (HPMC) capsules were used as the container, and spherical soft agglomerates of fine FK888 particles (soft pellets) and the E-haler were used, the fraction of particles emitted from the inhalation system (Em) was significantly improved, to over 80% of the nominal dose, and no significant difference was found between the airflow rates (84.3+/-2.3% for 28.3 l/min, 88.1+/-3.6% for 60 l/min). It was also found that the E-haler was an extremely suitable device for obtaining the higher respirable particle percentage of emitted particles (RP) in the 40 mg formulation with the soft pellets contained in HPMC capsules (35.0+/-1.8% for 28.3 l/min and 42.5+/-3.5% for 60 l/min), compared with the Spinhaler (13.8+/-3.0% for 28.3 l/min and 28.9+/-1.0% for 60 l/min). Using the formulations with the E-haler, proportional systemic absorption was achieved up to 40 mg FK888 in healthy volunteers (62.91+/-27.58, 103.70+/-40.19 and 254.79+/-85.01 ngh/ml as AUCs for 10, 20 and 40 mg FK888, respectively; R(2)=0.9641). It is also expected that the E-haler will act as an efficient device when a higher dose, such as 40 mg, is required in clinical situations.     

Inhaled steroid delivery from small-volume holding chambers depends on age, holding chamber, and interface in children.

The relationship between the amount of inhaled steroids delivered from pressurized metered-dose inhalers used with their recommended holding chambers and age of the patients using these devices was studied in an open randomised cross-over filter study. We recruited 1-2-month-old healthy infants (n = 21), 2-3-year-old asthmatics (n = 13), 4-6-year-old asthmatics (n = 15), and 10-15-year-old asthmatics (n = 20). Each child inhaled two puffs, administered by a single investigator, of both budesonide through Nebuchamber and fluticasone propionate through Babyhaler, on two occasions. Moreover, the 4-6-year-old group inhaled via both facemask and mouthpiece. Drug, collected on a filter interposed between holding chamber and patient, was analysed by high performance liquid chromatography. Filter dose, expressed in percent of the nominal dose, was analysed in a mixed effect linear regression model with age group, holding chamber and inhalation interface (facemask or mouthpiece) as fixed effects and subject as random effect. Filter dose from both holding chambers increased significantly with age, from 3% with Babyhaler and 7% with Nebuchamber in the youngest children, to 40-41% with both holding chambers in adolescents. Nebuchamber delivered more drug than Babyhaler (p = 0.002), but variability in drug delivery (about 11%) was similar between holding chambers. Filter dose decreased from 35% to 22% with Babyhaler, and from 42% to 27% with Nebuchamber when using a mouthpiece rather than a facemask (p < 0.0001). Delivery of inhaled steroids used with their recommended holding chambers depends from age and holding chamber, but also from the inhalation interface. Lung deposition and clinical studies comparing inhalation from holding chambers with mouthpiece and facemask are urgently required.