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Research and Studies - Recognition by the medical community

• Emerging Treatment
• Safety & Efficacy
• Budesonide Administration
• Pulmonary Administration
• Effectiveness of Topical Antibiotics
• Deposition of Aerosolized Particles

Budesonide Administration

Budesonide Administration with a Novel Aerosol Generator: An In Vitro Evaluation

Introduction

Budesonide (Pulmicort® Respules®, Astra USA) is approved for use with pneumatic jet nebulizers which deliver from 2 to 18% drug mass of the nominal charge. Ultrasonic nebulizers have been shown to be inefficient in nebulizing suspensions.

Aerogen's novel Aerosol generator (AG) technology is a domed aperture plate with numerous precision-formed, micron-sized holes coupled with a micro-pumping action that creates a fine-droplet, low-velocity aerosol without propellants or compressors. Droplet size and aerosolization (flow) rate are proportional to aperture hole diameter.

Using Pulmicort, we assessed the AG's in vitro delivery of inhalation suspensions with respect to flow rates, aerosol size distribution, and estimated respirable drug. The Pari LC Plus® was included as a comparison nebulizer.

Figure 1: Cross section of aerosol generator

Figure 2

Methods

PARTICLE SIZE

Up to 1 mL volumes of Pulmicort were aerosolized. Aerosol droplet size was evaluated by laser diffraction (Malvern/INSITEC, San Ramon CA), and drug distribution by the eight-stage cascade impactor (Graseby Andersen, Smyrna GA).

"INHALED" DRUG

Two mL doses of Pulmicort (0.5 mg) were aerosolized until end-of-dose. "Inhaled" drug was collected on Respirgard� bacterial/viral filters (Marquest Medical Products, Englewood CO) situated between the device and a Series 1101 Breathing Simulator (Hans-Rudolph, Inc., Kansas City MO). The breathing simulator modeled a pediatric breathing pattern of 200 mL tidal volume, 25 breaths/min, and 0.5 duty cycle. Budesonide was extracted from the filters and quantified by HPLC.4 All data are reported as mean � SD.

Results

AG FLOW RATE AND VOLUME MEDIAN DIAMETER

Aerosol generators were fitted with 2 mL reservoirs and sprayed downward (gravity-fed). The encouraging results with large VMD AGs warranted testing in alternative inhaler configurations with a "finer" aerosol size distribution using the Pari as a "baseline" for inhaled drug.

Figure 3 : Aerosol generator

Table 1: AG flow rate and VMD

INHALED DRUG MASS FOR AEROGEN NEBULIZER

A proprietary capillary-feed delivers the liquid to the AG. These units also have smaller VMDs (4.4-5.6 �m) than the gravity-fed AGs in the first table. Pulmicort aerosolization rates with capillary feed were 0.11 to 0.15 mL/min. In contrast, solution flow rates in the same units were 0.33 to 0.49 mL/min.

Figure 4: Aeroneb Portable Nebulizer System

Table 2: Inhaled drug mass for Aerogen nebulizer

Representative size distribution profile of Aerogen Nebulizer

One mL dose volume was aerosolized into an Andersen Mark II cascade impactor run at a constant inspiratory rate of 28.3 LPM.

Table 5: Representative size distribution profile of Aerogen nebulizer

INHALED DRUG MASS FOR PARI LC PLUS

Pari LC Plus units were used with a DeVilbiss PulmoAide® compressor. Aerosolization rates were 0.62 to 0.69 mL/min. These results were compared with AG configurations (below).

Figure 6: Pari LC Plus

Table 3 : Inhaled drug mass for Pari LC Plus

Representative size distribution profile of Pari LC Plus

One mL was aerosolized into an Andersen Mark II cascade impactor run at a constant inspiratory rate of 28.3 LPM.

Figure 7: Representative size distribution profile of Pari LC Plus

INHALED DRUG MASS FOR AERODOSE™ 5.5 INHALER

The 5.5 inhaler is a breath-actuated clinical prototype. Drug is gravity-fed from a reservoir to the AG. Inhalers were selected to span particle size specification. Aerosolization rates were 0.61 and 0.71 mL/min.

Figure 8: Aerodose 5.5 Inhaler

Table 4: Inhaled drug mass for Aerodose 5.5 Inhaler

Representative size distribution profile of Gravity-fed Aerodose Inhaler

0.3 mL was aerosolized into an Andersen Mark II cascade impactor run at a constant inspiratory rate of 28.3 LPM.

Figure 9: Representative size distribution profile of Aerodose 5.5 Inhaler

RETAINED DOSE & "VOLUME"

Dose "volume" remaining in the nebulizers was estimated by mass balance. Drug content was determined by HPLC.

Table 5: Retained dose & "volume"
*As compared with Pari LC Plus, P < 0.05 (Student's "t" test)

Discussion

AG technology delivers inhalation suspensions such as Pulmicort which have drug particle mass median sizes of 2.2 to 2.9 �m and irregular shape suspended in an aqueous medium.

AG technology aerosolizes solutions rapidly. AGs selected for a finer aerosol size than the Pari aerosolize budesonide suspensions more slowly (34%). However, flow rate recovers when the AG is fed by gravity. The design of the gravity-feed Aerodose 5.5 prototype inhaler facilitates very rapid flow rates (234% of Pari values).

Given a 500 �g nominal dose, the Pari's inhaled budesonide (60-85 �g) is not significantly different (P > 0.05) from the Aerogen nebulizer (63-84 �g).

However, due to the increased fine particle fraction, the Aerogen nebulizer (51-68 �g) has almost twice the "respirable" dose of the Pari (30-37 �g).

The respirable dose of the pocket-sized Aerodose 5.5 (148- 184 �g) is even greater, and likely due to finer aerosol size and reduced retained drug.

Conclusion

Our data indicates that Aerogen aerosol generator technology can nebulize suspensions as well as or better than reported for pneumatic jet nebulizers.

Acknowledgement

The authors thank Mila Heramia, Des Tesheshigo, and Rahat Katyal for their technical expertise.

References

Smaldone, et al., J Aerosol Med 11(2):113-125, 1998.
Nikander, et.al., J Aerosol Med 12(2):47-53, 1999.
The breath-actuated Aerodose 5.5 was operated continuously at 28.3 lpm.
British Pharmacopoeia 2000, pp 234-5.
Jackson WF, Nebulised Pulmicort Therapy, Clinical Vision Ltd, Oxford, p 25.
Aerogen AG technology is not indicated for use with Pulmicort Respules.

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