Targeting by Control of Hygroscopic Growth

Most inhaled medications are hygroscopic; that is, they accumulate water and grow in size. Some particles are deliquescent; that is, they become a droplet solution as water accumulates. Growth depends on relative humidity, and conversion to a droplet usually takes place rather abruptly at a specific humidity, termed the deliquescent point. Growth continues as humidity rises, with size increasing exponentially as humidity increases to greater than 95%. Respiratory tract temperature and humidity [18] and health implications of particle growth [19] have been reviewed. The size change caused by particle hygroscopic growth affects the total deposition and deposition site of inhaled hygroscopic particles.

Clinical studies indicate that smaller particles are more effective than larger particles when given for bronchodilation [20,21]. Optimal particle size has traditionally been chosen without regard for aerosol hygroscopic properties. Inhaled particles can grow considerably as they accumulate water in the humid respiratory tract. The size change would affect deposition pattern and quantity. Manipulation of hygroscopic growth to a slow growth rate that would allow better penetration to peripheral airways is the goal of most efforts to control growth.

Past efforts to target a specific deposition site were based on the control of particle size at inhalation. Also, efforts to control growth of particles by adding substances with surfactant properties have been reported. Addition of lauric and capric acids to disodium fluorescein markedly reduces particle growth [22], as does the addition of a cetyl alcohol monolayer to saline droplets [23]. Such a reduction of growth would be expected to facilitate particle penetration to more distal lung regions before deposition. The extent to which commonly used therapeutic aerosols grow at respiratory tract humidity needs further study.

Most MDIs contain surfactant materials that might be expected to affect growth. The shift in size distribution caused by exposure of MDI-produced aerosols to high (95-96%) humidity is modest. The MMAD of a metaproterenol sulfate aerosol from an MDI increased from 4.05 mm at 16% relative humidity to 5.22 mm at 98% relative humidity [23], and similar studies indicate growth also for sodium cromolyn [25]. The high humidity used in these studies was not as high as the 99.5% humidity present in distal lung [26].

Information from measurements at these high levels does indicate significant influence. Particles generated from a hypotonic solution penetrate further than do particles of similar initial size generated from a hypertonic solution [27]. Similar observations made using bronchodilators generated as supersaturated particles indicate a twofold to threefold growth from 0 to 99.5% RH, while disodium cromoglycate remains a crystalline structure up to 90% relative humidity and grows only 1.26-fold over this size range [28]. These data indicate, as one would predict, that hypotonic particles evaporate in vivo while the hypertonic particles presumably grow, so, in either case, particle concentration moves toward equilibrium at isotonicity. There are few studies documenting effects of hygroscopic size changes in vivo. There is probably potential for the application of growth control particle generation to medical aerosols, but we do not yet have sufficient understanding of the process to make clinical application practical.

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