Deposition mechanisms, pulmonary

An ideal in vitro model for the characterization of aerosol formulations would incorporate cell types from various regions of the lung (tracheal, bronchial, and alveolar) and would facilitate simulation of deposition mechanisms by impaction, sedimentation, and diffusion of a high-metered singlebolus inhalation. In the future, such systems may reduce the need for animal studies and may offer to correlate in a predictive way the results from such in vitro tests to clinical bioavailability data after pulmonary drug delivery in vivo. 

Aerosols for pulmonary drag delivery are delivered via the mouth. Three principal deposition mechanisms operate within the lower respiratory tract (Figure 10.4) ... 

Deposition mechanisms Inhalation manoeuvre Pulmonary administration Pulmonary drug delivery Therapeutic aerosol Biopharmaceutics Particle size Dry powder inhaler Metered-dose inhaler Nebuhser Novel liquid inhaler... 

Several groups investigated the use of liposomes for the intra-pulmonary delivery. Farr et al. (1985) showed that the deposition of aerosolized liposomes in the human lung depends on the aerosol particle size. Short-term retention profiles for MLVs and SUVs deposited in the lung were indicative of clearance via the mucociliary transport mechanism. 

Fig. 17. Biological model recommended for describing the uptake and retention of cerium by humans after inhalation or ingestion. Numbers in parentheses give the fractions of the material in the originating compartments which are cleared to the indicated sites of deposition. Clearance from the pulmonary region results from competition between mechanical clearances to the lymph nodes and gastrointestinal tract and absorption of soluble material into the systemic circulation. The fractions included in parentheses by the pulmonary compartment indicate the distribution of material subject to the two clearance rates however, these amounts will not be cleared in this manner if the material is previously absorbed into blood. Transfer rate constants or functions, S(t), are given in fractions per unit time. Dashed lines indicate clearance pathways which exist but occur at such slow rates as to be considered insignificant compared to radioactive decay of the cerium isotopes.

As shown in Table II , the ash contents increased by approximately 2-fold for bract and leaf and about 5-fold for stem and bur. The authors argued that if the mechanism by which cotton dust interacts with the pulmonary function is through an aqueous extraction of material deposited in the airways, the inorganic fraction should not be ignored since it is the most readily extractable. 

The size of the fibrous particles that appear to induce disease in the animal models is compatible with the measured respiratory range in humans (Lipp-man, 1977). Most particulate deposition takes place not in the upper or conducting portion of the airways but in the alveolar region of the pulmonary tree (the respiratory unit). Some surface deposition may occur at bifurcations in the bronchial tree, but the actual amount at each location is influenced by anatomy, specific to the species—probably to an individual—as well as the variety of fiber. A large proportion of airborne particulates are rejected as part of the normal clearance mechanisms in animals, but in humans clearance mechanisms may be compromised by smoking, for example. We are unaware of any experiments on fiber toxicity using smoking rats ... 

Even when the appropriate inhaler is chosen, the influence of the disease state cannot be ignored. Disease states can influence the dimension and properties of the airways and hence the disposition of any inhaled drug. Thus, great care must be taken when extrapolating the findings based on intratracheal administration to different animal species in order to predict deposition profiles after inhalation of aerosol formulations by patients suffering from airway disease. DPIs are not appropriate in many diseases when the ability to have sufficient airflow is hindered. Since many diseases that we would like to treat via pulmonary administration of biomolecules cause a decrease in airflow, we must be careful in the decision of which type of inhalation mechanism to choose. 

Matthys, H. and Kohler, D. (1985). Pulmonary deposition of aerosols by different mechanical devices. Respiration, 48, 269-276. 

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. 

Q6 A thrombus is a blood clot which is fixed to the blood vessel wall. When it detaches and is carried in the blood, it is known as an embolus. Both thrombi and emboli can block blood vessels and deprive tissues of oxygen. In arteries blood clots usually form because the inner surface has been altered by deposition of atheroma. In contrast venous thrombosis results from slow or stagnant blood flow in veins, or defects in mechanisms which normally oppose inappropriate coagulation. Three major risk factors for pulmonary embolism are (i) venous stasis, (ii) hypercoagulability ofblood and (iii) injury to vascular endothelium following trauma or plaque rupture. 

Fok TF, al Essa M, Monkman S, Dolovich M, Girard L, Coates G, et al. Pulmonary deposition of salbutamol aerosol delivered by metered-dose inhaler, jet nebulizer, and ultrasonic nebulizer in mechanically ventilated rabbits. Pediatr Res 1997 42(5) 721-727. 

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