Laboratory Study Comparing Pharmacopeial Testing of Nebulizers with Evaluation Based on Nephele Mixing Inlet Methodology.

Determination of fine droplet dose with preparations for nebulization, currently deemed to be the metric most indicative of lung deposition and thus in vivo responses, involves combining two procedures following practice as described in the United States Pharmacopeia and the European Pharmacopeia. Delivered dose (DD) is established by simulating tidal breathing at the nebulizer, collecting the medication on a filter downstream of the nebulizer mouthpiece/facemask. Fine droplet fraction (FDF

Modeling dispersion of dry powders for inhalation. The concepts of total fines, cohesive energy and interaction parameters.

A range of carrier based dry powder formulations consisting of micronized drug, carrier lactose and, in some formulations, lactose fines were produced and tested for dispersibility, i.e. fine particle fraction (FPF). Two different drugs were used, budesonide (BUD) and beclomethasone dipropionate (BDP). A model based on the total amount of fines (TF) and the cohesive energy (CE) of the formulation is proposed, where TF is the sum of added drug, lactose fines and the fines inherent to the carrier. The expression for CE is derived from regular solutions theory and allows calculation of interparticle interaction parameters. The model was able to describe experimental data well, such as the decrease in FPF when the proportion of drug is increased at a constant TF level and the non-linear effects seen when a cohesive drug is added to carrier. BDP and BUD were found to be 5.3 times and 1.8 times more cohesive than lactose fines respectively. The model hence provides a link between the macroscopic behavior of a dry powder formulation and the interaction between the different species at the particulate level.

In vitro delivery of budesonide from 30 jet nebulizer/compressor combinations using infant and child breathing patterns.

BACKGROUND: An aerosol of budesonide inhalation suspension is delivered when used with various jet-nebulizer/compressor combinations. The constant introduction of new nebulizer/compressor combinations raises the question of whether the performance of these match the performance of existing devices. The aim of this study was to determine in vitro the inhaled mass and aerosol characteristics of budesonide inhalation suspension from a selection of jet-nebulizer/compressor combinations presently marketed in the United States, Europe, and Japan. METHODS: The in vitro characterization was performed using standardized and published methods. Each nebulizer was charged with 1 vial (2 mL) of budesonide inhalation suspension 0.25 mg/mL (0.5 mg budesonide) and run until end of aerosol formation. Droplet size and distribution was determined using a cooled impactor at air flow of 15 L/min. The inhaled mass of budesonide (ie, mass on the inhalation filter) was collected using a breathing simulator that mimicked the breathing patterns of an infant and a child. The aerosol was collected on filters placed between the nebulizer mouthpiece and the breathing simulator. Budesonide was quantified via standard high-performance liquid chromatography. RESULTS: The mass median aerodynamic diameter of the aerosol measured with the cooled impactor ranged between 4.8 mum and 9.9 mum, and the geometric standard deviation ranged between 1.7 mum and 2.1 mum. The inhaled mass of budesonide expressed as a percentage of the nebulizer charge ranged from 1% to 9% (infant) and from 4% to 20% (child). CONCLUSIONS: The in vitro budesonide mass collected on the inhalation filter and delivery characteristics differed considerably between the 30 nebulizer/compressor combinations. The present in vitro characterization of jet nebulizers can be used as a guidance for selection of jet-nebulizer/compressor combinations for delivery of the budesonide nebulization suspension in the home-care setting. Further investigations of new nebulizer/compressor combinations are warranted.

Determination of nebulizer droplet size distribution: a method based on impactor refrigeration.

Size distributions of droplets generated by nebulizers are difficult to determine because of evaporation after aerosolization. We describe a method whereby a Next Generation Pharmaceutical Impactor (NGI; MSP Corporation, Shoreview, MN) is refrigerated at 5 degrees C before connecting it to the nebulizer in order to ensure an environment inside the NGI at close to 100% relative humidity (RH). This, in turn, reduces droplet evaporation between the nebulizer and impaction. The method development was performed with a Pari LC Plus jet nebulizer operated at 2.0 bar, with the NGI set at a flow rate of 15 L/min and with salbutamol 5.0 mg/mL as the test solution. The droplet size distributions were expressed in terms of mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). Variation in test conditions showed that the NGI should be cooled for at least 90 min, that nebulization should be started within 5 min after removal from the refrigerator, and that coating of collecting cups to prevent "bouncing" is not necessary. Variation of ambient temperature and humidity had no relevant effect on results. MMAD and GSD results showed that refrigeration of the NGI resulted in droplet size distributions that are likely to reflect those originally delivered at the mouthpiece by the nebulizer. The method was shown to be robust, accurate with recovery of test solutions exceeding 99%, reproducible, and to be suitable for use with a wide range of commercially available nebulizers.

Jet nebulizers versus pressurized metered dose inhalers with valved holding chambers: effects of the facemask on aerosol delivery.

The delivery of an aerosolized drug to a child is a complex process requiring an interaction between parent, child, and inhalation device. Recent studies have shown that the facemask can be a key factor affecting aerosol delivery, particularly the influence of leaks between the facemask and the face. To further quantify these effects and design around them, we have developed a bench model consisting of a breathing simulator, an inhaled mass filter, and a "pediatric face." This paper reviews the development of this model and details important decisions made in its configuration, particularly inhaled mass filter location (e.g., between device and facemask, or in mouth) and mouth diameter (4 or 18 mm). With the final design, we used the model to measure the impact of the "blow-by" technique on nebulizer inhaled mass. In a separate series of experiments, we studied the effects of a "crying" pediatric breathing pattern on inhaled mass for both nebulizers and pressurized metered dose inhalers with valved holding chambers (pMDI VHCs). Results indicated that the location of the inhaled mass filter was a critical factor in assessing aerosol delivery through facemasks and that the "mouth diameter" was not an important variable. Failure to locate the filter in the mouth behind the face, especially for jet nebulizers, failed to accurately measure effects of the facemask and significantly overestimated aerosol delivery. Blow-by results indicated that a 1-cm gap between the facemask and the face was not critical when using a front-loaded facemask. Finally, even with optimal design, the combination of an aerosol generator and facemask with a crying breathing pattern reduced the inhaled mass to 1% of the label dose.

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.