Pulmonary deposition efficiency

Pulmonary deposition efficiency Location of pulmonary deposition Pulmonary residence time (dissolution rate and other factors) Oral bioavailability Degree of oral deposition Systemic clearance Volume of distribution Protein binding... 

Pulmonary deposition efficiency depends on physicochemical characteristics, such as density of the aerosol or dry powder particles [33-35], Generally, particle diameters less than than 5 pm are required for efficient pulmonary delivery [36, 37], Pulmonary deposition also depends on the nature of the delivery device and differs between metered dose inhalers (MDIs). For example, pulmonary deposition expressed as the ratio of pulmonary versus total (pulmonary + oral) absorbed drug, ranged from 15-55% for a number of salbutamol devices and from 66-85% for drugs with lower oral bioavailabilities such as budesonide. 

Traditionally, pulmonary deposition of MDIs has been in the range of 10-20% [38-40], An increase in pulmonary deposition efficiency of MDIs has been achieved with the use of spacer devices [41-46], Aerosol deposition in the human lung has also been optimized after administration from a microprocessor-controlled pressurized MDI [47, 48], Improvement of pulmonary deposition of up to 40%... 

It is clear that pharmacokinetic studies in humans provide significant information for inhalation drugs. Relevant key parameters obtained from PK studies include the pulmonary deposition efficiency, parameters assessing... 

For drugs with zero oral bioavailability this method also provides a direct estimate of the pulmonary deposition efficiency of the device. For drugs with distinct oral bioavailability, this method, combined with charcoal-block, enables calculation of both pulmonary and oral availabilities [86],... 

Mechanisms responsible for ultrafine particle-induced toxicity could include (1) increased surface area available for reaction with other atmospheric components to produce free radicals or to act as a carrier for acids or organic compounds (2) rapid penetration of epithelial layers into the interstitium (160) and (3) high pulmonary deposition efficiency and increased dose delivered to the alveolar regions of the lung. 

Pulmonary delivery of insulin for systemic absorption in the treatment of diabetes has been studied extensively since the early days of insulin discovery almost a century ago. Colthorpe et al. and Pillai et al. demonstrated in rabbit and monkey models, respectively, that the deeper into limg the dose of insulin was delivered, the higher was the bioavailability. The work of Laube, Benedict, and Dobs showed the need to achieve deep pulmonary deposition of this molecule for efficient absorption in humans. Handheld liquid and dry powder delivery systems have been developed to generate insulin-containing aerosols with the majority of the particles in the aerodynamic size range 1-3 pm. The relative bioavailability compared with subcutaneous injection based on the insulin contained in the dosage form was 110/ [52] powder system and for the aqueous-based... 

Regardless of the method used to generate the aerosol, efficient pulmonary deposition of the active agent is critically dependent on the aerodynamic diameter of the inhaled particle. Aerodynamic diameter is the physical property of a particle, which defines how it will behave in an airstream, and depends on the particle geometric size, density, and shape. An in-depth discnssion of how particle shape affects aerodynamic diameter is beyond the scope of this review therefore, the cited examples will assume a spherical particle. 

In the pulmonary region, air velocities are too low to impact particles small enough to reach that region, and the mechanisms of deposition are sedimentation and Brownian diffusion. The efficiency of both processes depends on the length of the respiratory cycle, which determines the stay time in the lung. If the cycle is 15 breaths/min, the stay time is of the order of a second. Table 7.1 shows the distance fallen in one second and the root mean square distance travelled by Brownian diffusion in one second by unit density particles (Fuchs, 1964). Sedimentation velocity is proportional to particle density, but Brownian motion is independent of density. Table 7.1 shows that sedimentation of unit density particles is more effective in causing deposition than Brownian diffusion when dp exceeds 1 pm, whereas the reverse is true if dp is less than 0.5 pm. For this reason, it is appropriate to use the aerodynamic diameter dA equal to pj dp when this exceeds 1 pm, but the actual diameter for submicrometre particles. 

Early work identified deep lung deposition as an imperative to absorption efficiency, and a number of studies have demonstrated higher bioavailabilites (absorption efficiencies) for peripherally deposited aerosols [51]. However, despite a decade of work, the absorption mechanisms that facilitate transfer from the pulmonary epithelium to the blood are still not well understood. Two mechanisms are believed to operate, transcellular and pericellular. There is some evidence that small invaginations called caveolae may be involved in transcellular transport, whereas pericellular transport is via leaky tight junctions. 

Various techniques of particle delivery are used to deduce pulmonary and systemic effects from the wide parameters of potential toxicological influences. The specific techniques that are currently employed in these studies include intratracheal instillation, intratracheal aspiration, and intratracheal inhalation. Of these different delivery techniques, intratracheal installation is a useful technique to assess the potential health effects of different particles efficiently and cost effectively. Intratracheal instillation is characterized by saline suspended particles administered directly into the trachea of the animal being tested. Intratracheal installation provides a relatively easy way to compare the toxicology between different materials. However intratracheal installation is not able to assess particle deposition. Intratracheal aspiration involves droplet administration of suspended particle matter in the form of a puff of air. Intratracheal inhalation is the most relevant for toxicity and risk assessment. Intratracheal inhalation involves nanoparticulate aerosol formation at constant concentrations during the exposure. 

E Ungaro, I. d Angelo, C. Coletta, R. d Emmanuele di Villa Bianca, R. Sorrentino, B. Perfetto, M.A. Tufano, A. Miro, M.I. La Rotonda, E Quaglia. Dry powders based on PLGA nanoparticles for pulmonary delivery of antibiotics Modulation of encapsulation efficiency, release rate and lung deposition pattern by hydrophilic polymers. J Control Release 157,149-159, 2012. 

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