Aerosolized Drug Delivery Devices

Aerosolized drug therapy has been the standard treatment approach in human medicine for patients with noninfectious respiratory disease for 20 years. Administration via inhalation improves drug safety and efficacy by reducing the total therapeutic dose, minimizing drug exposure to other body systems, and allowing direct delivery of the drug to the lower respiratory tract. In most instances, the response to aerosolized drug administration is more rapid than to systemic drug administration. The equine patient is an ideal candidate for inhalation therapy for several reasons: a highly cooperative nature, obligate nasal breathing, rostrally placed and large nares, slow breathing rate and inspiratory flows, and a spectrum of diseases amenable to topical treatment.

However, initially devices such as nebulizers designed for delivery of aerosolized drugs to the lower respiratory tract of horses were cumbersome, expensive, and marginally efficacious. Today, efficient systems for drug delivery are being developed rapidly and inhalation therapy has become increasingly popular for treatment of lower respiratory tract disease. The most important aspects of aerosol administration for horses are efficient pulmonary drug delivery and ease of administration. The disadvantages of the aerosol route of administration include inability to access obstructed airways, high start-up costs, frequency of drug administration, potential for direct airway irritation by some aerosol preparations, respiratory contamination with environmental microorganisms, and contributions to air pollution from propellants. To date, inhalation therapy for horses has focused predominantly on administration of bronchodilating agents and corticosteroid preparations for treatment of recurrent airway obstruction (heaves). Aerosolized antimicrobial agents are under investigation for treatment of bacterial infection of the lower respiratory tract in horses. Bioactive proteins (insulin, antithrombin III, growth hormone) and hormones in aerosol currently being studied in humans may have future application in the horse.

Aerosols are denned as a gas containing finely dispersed solid or liquid suspended particles. The primary determinants of the efficiency of pulmonary deposition of an aerosol preparation include size, shape, viscosity, density, and hygroscopic growth of particles. Most therapeutic aerosols are heterogeneous (heterodispersed), and their aerodynamic behavior is described best by the mass median aerodynamic diameter (MMAD). Aerosol preparations with an MMAD of 1 to 5 microns produce the best therapeutic results in humans and are the target particle size for inhalation therapy in horses. These small particles penetrate deep within the respiratory tract, and particles less than 2 microns can penetrate alveoli. The cross-sectional area (cm2) of the lung increases dramatically at the level of the respiratory zone; therefore the velocity of gas flow during inspiration rapidly decreases at this level. Because the velocity of gas falls rapidly in the region of the terminal bronchioles, small particles sediment out in these airways. Moderate-size particles (5 to 10 microns) frequently settle out by sedimentation in larger more central airways (trachea, bronchi). Large aerosolized particles (>10 microns) affect the upper respiratory tract via inertial impaction. The majority (90%) of particles below the target size (<0.5 microns) are inhaled and exhaled freely and rarely affect the respiratory tract.

In addition to particle size, the patient’s tidal volume, inhalation and exhalation flow rates, and upper respiratory tract anatomy affect pulmonary drug deposition. Because these physiologic factors, in particular nasal breathing, affect pulmonary drug deposition, equine clinicians cannot extrapolate data generated from human subjects regarding specific drugs or devices to equine patients. Finally, all aerosolized solutions should be isotonic with neutral pH and should not contain chemical irritants such as benzalkonium, ethylenediaminetetraacetic acid (EDTA), chlorbutol, edetic acid, and metabisulfite.

Metered-Dose Inhalant Systems

Mechanical Nebulizers

Ultrasonic nebulizers and jet nebulizers are ozone-friendly delivery systems, used as alternatives to metered-dose inhaler. Ultrasonic nebulizers produce aerosol particles using vibrations of a quartz (piezoelectric) crystal, and particle size is inversely proportional to the operating frequency. High quality ultrasonic nebulizers are required to produce satisfactory particle size. Jet (pneumatic) nebulizers operate by the Venturi effect (dry air compressor) to fragment therapeutic solutions into aerosol particles.

The diameter of particles generated by a jet nebulizer is inversely proportional to the airflow, and minimum gas flow rates of 6 to 8 L/min are required to generate suitable particle diameter (<5 μm) for pulmonary delivery. Jet nebulizers are readily accessible, inexpensive, and easy to use. The primary disadvantage of jet nebulization is noise generated by the system. Ultrasonic nebulizers are silent; however, they are expensive and fragile. High pressure jet nebulization (Hudson RCI, Temecula, Calif.) using a delivery system developed for horses (Nebul, Agritronix Int, Meux, Belgium) delivers approximately 7% of the drug to the pulmonary system, and ultrasonic nebulization (Ultra-Neb, DeVilbiss, Somerset, N.J.) delivers approximately 5% of the drug to the pulmonary system. Deposition of radiolabeled drug into peripheral pulmonary fields using jet nebulization is superior to ultrasonic nebulization. Pulmonary contamination with environmental bacteria and fungi may occur using these aerosol delivery systems; therefore rigorous disinfection of the equipment is required to avoid this complication. Aerosol therapy via jet and ultrasonic nebulization requires an administration time of approximately 10 to 20 minutes, versus less than 2 minutes for many metered-dose inhaler drug dosages.

Dry Powder Inhalant (DPI) Devices