Summary Report: In vitro analysis of the Singing Arrow OxyphoneÔ Delivery System and VixOne Disposable Nebulizer with Unit Dose Albuterol (2.5mg/3ml)

(Poster Presentation at American Thoracic Society meeting in Toronto, May 2008)

The Aerosol Research Laboratory at The Nemours Children’s Clinic investigated the in vitro performance of the Oxyphone aerosol delivery system in comparison to the performance of a conventional jet nebulizer system using the VixOne nebulizer with an aerosol facemask held tightly to the face (AFM), and with the mask held at a distance of 2 cm from the face (AFM @2) to simulate blow-by conditions with a mask. We used a 3.0 ml fill volume (2.5 mg loading dose) of Albuterol for all studies.

We measured the drug output characteristics of 5 new nebulizers to determine the particle size distribution, inhaled dose, residual dose, nebulizer output and estimated lung dose. A PARI Proneb Ultra air compressor powered all nebulizers. Each nebulizer was studied once, for a total of 5 measures per delivery system.

PARTICLE SIZE DISTRIBUTION

Laser particle sizing was determined with an Insitec Spraytec laser system using a closed inhalation cell. Aerosol particles were drawn across the laser at a constant 15 LPM flow.  Measurements were made for 2 minutes at 1-second intervals from 1 minute after the beginning of nebulization. All data was averaged over the duration of the study. We measured the following parameters:

1. VMD:  Volume Mean Diameter
2. GSD:    Geometric Standard Deviation
3. %< 3m: The percent of particles < 3 microns
4. %< 5m: The percent of particles < 5 microns

NEBULIZED DRUG OUTPUT

Drug output was determined using a breath simulator (PARI Compas) and by assaying drug quantities contained on an inspiratory filter as well as the residual drug within the nebulizer at the conclusion of nebulization. Drug quantities were determined with a spectrophotometer at 276l. Duration of nebulization was held constant at 6 minutes for all studies. Residual volume and nebulizer output were also determined gravimetrically.

Materials:

1)      Drug:  Albuterol Sulfate Inhalation Solution (Warrick Pharmaceuticals) 2.5 mg / 3ml. Loading dose: 3 ml       

2)      "ADAM" toddler face model (Trudell Medical)

3)      Pediatric aerosol face mask (Salter Labs model 1120),

4)      PARI Proneb Ultra air compressor

5)      Devices (n=5):

a.       VixOneÔ small volume, disposable medication nebulizer (Westmed)

b.      OxyphoneÔ Nebulizer Phone (Singing Arrow)

Methods:

Particle Sizing

All nebulizers were charged with 3.0 ml Albuterol sulfate solution. Nebulizers were weighed dry, full, and at the end of each study to determine gravimetric output and residual volume. Nebulizers were connected to the Inhalation cell of the Spraytec Laser using a flexible airtight connector. The nebulizer and inhalation cell were oriented in a horizontal position. The output end of the inhalation cell was connected to an adjustable flow vacuum pump set to 15 Lpm flow. Each study was timed from the beginning of nebulization. Particle sizing was begun after 1 minute of nebulization and analyzed continuously for the following 2 minutes. All data points were then averaged for each measure.

Drug Output

Five devices were studied one time each. The devices were weighed dry, after the addition of 3.0 ml albuterol sulfate, and at the conclusion of nebulization. The nebulizer was connected to the delivery device to be studied (OxyphoneÔ, aerosol facemask, or facemask at 2 cm from the face). The ADAM toddler face model contained removable filter material (cotton balls) within its oral cavity to collect deposited drug during inhalation. The model was connected to the PARI COMPASS breath simulator programmed to produce the following breathing pattern:

1)      Breath rate:     25 bpm

2)      Tidal Volume: 150 ml

3)      I:E ratio:          1:2

At the end of nebulization, the nebulizers were weighed to determine gravimetric change, and washed with distilled water to collect residual drug. The filters were washed with a known quantity of water to elude deposited (inhaled) drug. Each sample was the evaluated for drug concentration with a spectrophotometer at 276l.

Output measurements made were:

1. Duration of nebulization
2. Residual dose (RD): Total drug remaining in the nebulizer.
3. Inhaled dose (ID):  Total drug captured on the inspiratory filter
4. Fine Particle Dose (FPD):  The proportion of inhaled dose with particles £ 5 microns. (Extra-fine particle dose would be the inhaled dose with particles £ 3 microns, and is felt to be closer to the actual potential lung dose in children by some investigators)
5. Output (FPD per minute):  The calculated FPD delivered per minute of nebulization
6. FPD %:  The FPD expressed as percent of nominal dose

RESULTS

n = 5

 mean ± sd

1. AFM: Aerosol Face Mask

2. AFM@2: Aerosol Face Mask 2 cm from face

COMMENTS:

The ADAM model was chosen to represent a 2-3 year old face and upper airway. The advantage of the model is that the size is appropriate, and the surface has pliancy just like skin and subcutaneous tissue. However, we encountered drawbacks with the ADAM model that had to be overcome to proceed. The model was constructed by Trudell Medical to test output from metered dose inhalers used with spacer devices. The output from those devices is small and easily captured on standard filter material. However, with a nebulizer there is far more drug solution output, which saturated normal filter material early in nebulization. Cotton balls were substituted for the filter material, and that procedure had to be validated by spiking filters with known quantities of albuterol and analyzing them for content.

To avoid saturating the cotton balls, the nebulization was run for 6 minutes (not until sputter), and filters were changed every 2 minutes. The filters for one nebulization were pooled and the effluent analyzed for albuterol content. Thus the inhaled doses reported above will slightly underestimate the dose if the nebulizer had been run to dryness.

The results show that if we use 5 microns as a cutoff for estimated lung dose, the fine particle dose inhaled as a percent of the starting nebulizer dose is 7.6% for Oxyphone, 4.6% for aerosol mask, and 2.2% for aerosol mask blow-by. If we use 3 microns as a cutoff for estimating lung dose, the percentages are 5.0%, 3.0%, and 1.4% respectively (not shown). The 3 micron cutoff is probably more appropriate for young children, and correlates well with some of the historical PK and scintigraphy literature.

It was somewhat of a surprise that Oxyphone, with the mouthpiece about 4 cm from the mouth of the model, exceeded the performance of a close-fitting mask. To check the data, the experiment was repeated with the VixOne and a corrugated tube held 4 cm from the model. The results were similar. The 50% reduction in FPD when the mask was taken away by 2 cm was an expected result.

What does this mean?

A model is just a model, but this information can have very positive impact on predicting the performance of the Oxyphone in the real world. The key to devices like Oxyphone are to distract the youngster during an aerosol treatment to 1) avoid crying, and 2) to allow the aerosol stream to target the nose/mouth for as long as possible during nebulization. In the real world, crying or fussing may reduce the actual dose to the lung by another 75%, and causes anguish for the caregivers. Facemasks are known to cause fussiness and crying in a significant proportion of infants and toddlers. Holding a facemask away from the face (to avoid crying) causes a reduction in available aerosol by 50%, as seen by these data and other data sets that we have generated. Using blow-by with a corrugated tube is far more successful in a model, but the child can still move around a lot, causing the caregiver to “chase” them with the nebulizer, and lose more drug to the atmosphere. The Oxyphone provides positive feedback to the child, and helps to keep the aerosol stream directed toward the child as long as they are listening to the tune from the earpiece, thus avoiding crying, fussiness, and chasing. 

David Geller MD, Bert Kesser RRT