Metered-Dose Inhalant Systems

By | 2012-11-11

Several devices have been designed for convenient administration of aerosolized drugs formulated in a metered-dose inhaler () cannister to horses with recurrent airway obstruction (). The advantages of an metered-dose inhaler system include rapid administration, consistent ex-valve dose delivery, minimal risk of pulmonary contamination with environmental microorganisms, ease of cleaning/maintaining equipment, wide availability, and no requirement for electricity. Pulmonary drug delivery in human patients using metered-dose inhaler devices varies with the specific device, drug preparation, and patient technique. Ideally, the metered-dose inhaler is actuated in early inhalation, during a slow (5-second) breath, followed by a 10-second period of breath holding to allow particles to deposit in the lower airway. These conditions are met only in humans. The equine patient inhales over 2 to 3 seconds with no breath hold so that lung deposition is lower.

Chlorofluorocarbon () propellant has been an essential component of metered-dose inhaler drug delivery systems. However, chlorofluorocarbons were recognized to have a depleting effect on the ozone layer in 1985. One chlorofluorocarbon molecule is capable of destroying 100,000 molecules of stratospheric ozone and chlorofluorocarbon molecules persist in the atmosphere for centuries. Propellants containing chlorofluorocarbons are being phased out of most applications, and newly developed inhalant products are formulated with chlorofluorocarbon-free, ozone-friendly solution propellants. Hydrofluoroalkane-134a () is an inert, non-toxic replacement propellant for chlorofluorocarbons. It is eliminated from the body by ventilation, without evidence of accumulation or metabolism. Because hydrofluoroalkane-134a formulations are dissolved in solution, rather than held in suspension, shaking is not necessary between actuations allowing immediate administration of drug with each breath.

The efficacy of hydrofluoroalkane-134a formulation of some drugs (salbutamol, fenoterol, ipratropium) is equivalent or greater than the chlorofluorocarbon preparations. The hydrofluoroalkane-134a formulations of beclomethasone, for example, produce a greater total mass of fine drug particles, which improves pulmonary drug deposition and reduces the required daily dose substantially. A twofold to tenfold improvement occurs in pulmonary drug delivery of beclomethasone using an hydrofluoroalkane-134a formulation over a chlorofluorocarbon formulation depending on the delivery device. Less actuated drug is deposited in the pharynx using an hydrofluoroalkane-134a propellant, which reduces the incidence of local and systemic side effects. Because of the greater uniformity of fine particle size, the hydrofluoroalkane-134a formulations reduce the need for a spacer in the drug delivery device because spacers are used to enhance fine particles by exclusion of larger particles.

The Equine AeroMask (Trudell Medical International, London, Ontario) is the most versatile of the delivery systems because it can be used for administration of aerosolized drugs via metered-dose inhaler devices, nebulization solution, or dry powder inhaler. This system allows the clinician to administer any drug that is available for human asthma therapy to horses with heaves. Drug is actuated or nebulized into a spacer device designed with a one-way inspiratory valve. The mask must fit snugly around the muzzle to ensure adequate negative inspiratory pressure to facilitate drug delivery. Based on radiola  beling studies, drug delivery to the lower respiratory tract through the use of the Equine AeroMask with an metered-dose inhaler is approximately 6% of actuated drug when a chlorofluorocarbon propellant is used and approximately 14% of actuated drug when an hydrofluoroalkane-134a propellant is used. The large portion of the drug that does not reach the lung is either retained in the spacer or trapped on the surface of the external nares. Drug is distributed uniformly throughout all pulmonary fields.

The Equine Aerosol Drug Delivery System (EADDS, developed by 3M Animal Care Products is a novel, handheld device designed for administration of aerosolized drugs in horses. The EADDS fits snugly into the left nostril of the horse and therefore avoids a large wastage of drug on the external nares. The operator actuates a puff at the onset of inhalation, denoted by a flow indicator within the device. The operator must pay close attention to the timing of drug delivery, because drug delivered during mid- to late inhalation may reach the tracheal lumen only to be exhaled. The advantage of the EADDS is efficiency of drug delivery. The mean MMAD generated using this system with a chlorofluorocarbon propellant is 2.3 ± 2 microns, and approximately 23% of actuated drug is delivered to the lower respiratory tract. The mean MMAD using an hydrofluoroalkane-134a propellant is 1.1 microns, and approximately 43% of actuated drug is delivered to the lower respiratory tract in horses.

Ventilation imaging using radiolabeled aerosol confirms that drug is deposited in all pulmonary fields with minimal deposition in the nasal cavity, oral pharynx, or trachea. Currently, the EADDS is approved and commercially available only for administration of albuterol sulfate in an hydrofluoroalkane-134a propellant (Torpex, Boehringer-Ingleheim Vetmedica, Inc., St. Joseph, Mo.). The device was not designed for administration of interchangeable drugs using human MDIs. Rather, the device is distributed with a preloaded canister of albuterol sulfate and is designed for disposal after the drug has been dispensed.

The Equine Haler (Equine Healthcare APS, Hillerod, Denmark) is a spacer device that fits over the entire left nostril of the horse and is designed for administration of aerosolized drug using any human metered-dose inhaler device (). The mean particle size generated using the Equine Haler is 2.1 microns with a range of 1.1 to 4.7 μm (fluticasone/chlorofluorocarbon-free propellant). Drug deposition in the lower respiratory tract was reported to be 8.2 ± 5.2% of the actuated dose with diffuse pulmonary drug delivery that is adequately distributed to the periphery of the lung. As for the AeroMask, nasal trapping and retention in the spacer contributed to drug wastage. Unlike the AeroMask, the Equine Haler can accommodate any size horse without difficulty in creating an airtight seal over the muzzle. Poor pulmonary drug delivery can occur if the administrator does not pay particular attention to align the metered-dose inhaler with the spacer and the spacer apparatus with the nasal passages of the horse during actuation. In all cases, the reaction of the horse to the release of the aerosol, by jerking of the head, or alteration of breathing pattern can detract for lung delivery.

In summary, the EADDS system delivers a much greater proportion of drug to the lung but must be inserted into the nostril. The AeroMask and Equine Haler are less efficient because of drug trapping on the nares but have the advantage of being less invasive, and both incorporate spacer-valve combinations that reduce asynchrony of actuation with inspiration and do a better job of selecting fine particles, an important consideration when employing chlorofluorocarbon-based MDIs.