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Evaluation of a new spacer device for delivery of drugs into the Equine respiratory tract.
 
Funch-Nielsen, H., Roberts, C.A.1, Weekes, J.S.1, Deaton, C.M.1 and Marlin, D.J.1
Equine HealthCare APS, Denmark and 1Centre for Equine Studies, Animal Health Trust, Newmarket, UK.

 

Introduction

Pulmonary inflammatory disorders occur commonly in the horse. Systemic administration of corticosteroids may be associated with adverse sequelae.

Delivery of drugs directly into the affected airways may improve local drug concentrations as well as reducing systemic uptake.

 

Inhaled corticosteroids are widely used in the treatment of human inflammatory lung conditions, including asthma and chronic obstructive pulmonary disease.

 

Equine recurrent airway obstruction (RAO) is characterised by a marked inflammatory response in the presence of aeroallergens, such as moulds.

 

Nebulisation of liquid corticosteroid preparations has been used, but a number of spacer devices have been developed to allow administration to horses of metered dose inhalers (MDI) designed for human use.

 

Aims
To determine the efficiency of the Equine Haler™ for delivering fluticasone propionate from a metered dose inhaler into the equine lung.

 

To determine the pulmonary distribution of inhaled fluticasone propionate administered with the Equine Haler™

  

Materials & Methods
General
6 healthy adult horses and 2 healthy adult ponies were studied. All horses were considered healthy based on TW & BAL cytology & bacteriology, clinical examination, thoracic radiographs and V/Q imaging.

 

Horses were administered ~3.5 µg/kg of fluticasone propionate labelled with 99mTechnetium from a new design of spacer (Equine Haler™).

 

Horses were sedated with romifidine 50 µg/kg bodyweight for imaging.

 

Sequential overlapping scintigraphic images were obtained of the right caudal lung, right cranial lung, cranial thorax, trachea, and head.

 

Estimates of the lung border were obtained with 99mTechnetium-MAA (1 MBq/kg).

 

Markers containing 99mTechnetium were placed within each image to allow referencing between images.

 

Labelling
A single batch of Flixotide Evohalers (250µg per actuation) were used.

 

Radiolabelling was performed as described by Newman et al (1999) using a seven stage Anderson Cascade Impactor Mk and a flow rate of 28 l/min.

 

PSD was determined with the MDI, actuator and spacer combined.

 

Particle size distribution (PSD) was determined on

 

  • Unlabelled FP
  • 99mTc Labelled FP - low activity
  • 99mTc Labelled FP - high activity

 

The activity and PSD of each MDI was determined prior to use.

 

Prior to each use, the count rate per second (cps) per actuation of the MDI was determined at a recorded time for subsequent decay correction to allow quantitative analysis of images.

  

Imaging
Images were obtained using a large field of view gamma camera fitted with a low energy general purpose collimator.

 

Acquisition parameters: dynamic acquisition; 128 x 128 matrix; 60 x 2 s frames.

 

Analysis
Images were analysed using HERMES software (Nuclear Diagnostics Ltd).

 

All images were motion corrected. Inhalation and MAA perfusion images were registered.

 

Results
In Vitro Studies
The mean PSD of FP and radiolabel for 99mTc Labelled FP were found to be similar (Figure 2) indicating that the deposition of the radiolabel within the lungs was likely to reflect that of FP.

 

 

Figure 2. Mean PSD for FP and 99mTechnetium as a % of total metered dose from 99mTc labelled FP

 

 

Figure 3. Particle size distribution (µg) of FP delivered from a Flixotide Evohaler with and without a Volumatic spacer (data from Cripps et al 2000) and PSD of FP from the Flixotide Evohaler used in conjunction with the Equine Haler™.¨

  

  

The mass of respirable particles (sum of deposition on stages 3 to 5 or 1.1 - 4.7 um) of FP delivered from the spacer was 96 ± 28 µg (mean ± sd; range 72-127 µg). It was noted that the variation appeared to be related to the angle of the MDI when actuated. It was observed that when the MDI actuator port was not facing directly at the second inspiratory valve that the delivery was low. When care was taken to ensure the MDI actuator port was facing directly at the second inspiratory valve the delivery was always higher.

In Vivo Studies
As expected, there was relatively high deposition of labelled FP around the nostril and upper airways as far as the larynx (Figure 4).

The labelled FP appeared to be distributed throughout the lung according to the distribution of Krypton gas used for ventilation studies. The labelled FP also appeared to reach the periphery of the lung as judged from comparison with images of perfusion obtained with Tc-MAA (Figure 5).

Mean lung deposition for all animals was 8.2 ± 5.2 % of the dose administered (range 2.3 -18.6%).

  

  

Figure 4. Distribution of 99mTc-labelled fluticasone propionate after administration of 3.5µg/kg bodyweight using the Equine Haler™.

  

  

Figure 5. a) Distribution of 99mTc-labelled fluticasone propionate after administration of 3.5ug/kg bodyweight using the Equine Haler™ within the lung of one horse and approximate lung border as determined by subsequent 99mTc-MAA.

 

b) Example of lung image obtained during inhalation of 81Mkrypton gas in a horse with no history of respiratory disease.

 

 

Discussion
The Equine Haler appears to achieve an acceptable and even deposition of labelled FP within the equine lung.

Low delivery may be related to the angle at which the MDI is actuated into the spacer.

The Equine Haler™ was tolerated by all animals after a short familiarisation prior to the study.

References
Cripps, A., Riebe, M., Schulze, M. and Woodhouse, R. (2000) Respiratory Medicine, 94 (Supplement B), S3-S9.