The size and shape of particles are primordial factors that condition their deposition in the lungs. The size is defined by what is called the mass median aerodynamic diameter (MMAD) or diameter of a particle of mass equal to the average particle diameter of a population, meaning the diameter of a particle in which 50% of the aerosol mass is greater and the other 50% is smaller.1 Depending on their size and shape, the particles can be deposited by means of four mechanisms:

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  Impaction. This is the physical phenomenon by which the particles of an aerosol tend to continue on a trajectory when they travel through the airway, instead of conforming to the curves of the respiratory tract.2 Particles with enough momentum (product of the mass and velocity) are affected by centrifugal force at the points where the airflow suddenly changes direction, colliding with the airway wall. This mainly happens in the first 10 bronchial generations, where the air speed is high and the flow is turbulent.3 This phenomenon mainly affects particles larger than 10μm, which are mostly retained in the oropharyngeal region, especially if the drug is administered by dry powder inhalers (DPI) or metered-dose inhalers (MDI).4

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  Interception. This is mainly the case of fibers, which, due to their elongated shape, are deposited as soon as they contact the airway wall.

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  Sedimentation. This is the physical phenomenon by which particles with sufficient mass are deposited due to the force of gravity when they remain in the airway for a sufficient length of time. This predominates in the last 5 bronchial generations, where the air speed is slow and the residence time is therefore longer.3

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  Suspension. This is the phenomenon by which the particles of an aerosol move erratically from one place to another in the airways. This happens as a consequence of the Brownian diffusion of particles with an MMAD smaller than 0.5μm when they reach the alveolar spaces, where the air speed is practically zero. These particles are generally not deposited and they are expelled once again upon exhalation.

The particles of aerosolized drugs usually have a uniform shape and are symmetrical on several planes. They rarely are smaller than 1μm, and therefore the predominating mechanisms are impaction and sedimentation.5

It can generally be considered that particles with an MMAD higher than 10μm are deposited in the oropharynx, those measuring between 5 and 10μm in the central airways and those from 0.5 to 5μm in the small airways and alveoli. Therefore, for topical respiratory treatment it is best to use particles with an MMAD between 0.5 and 5μm. This is what is known as the breathable fraction of an aerosol.6

Because particles are transported through the airway by an air current, their trajectories are affected by its characteristics. The air flow in the lungs is determined by the tidal volume and respiratory rate. Sbirlea-Apiou et al.7 demonstrated that in the first four generations of the airway, the deposition increases for any size particle as the inspiratory flow increases. However, the opposite is true in the last generations of the airway, where the deposition of particles is inversely proportional to this flow. This is due to that fact that the increased inspiratory flow reduces the residence time of the particles in the airway, therefore the effects of the severity and of the Brownian movement will be quite lower. Obviously, a minimal inspiratory flow is necessary to drag the particles toward the interior of the bronchial tree.

The probabilities of particle deposition by impaction increase when the particles themselves are larger, the inspiratory airflow is greater, the angle separating the two branches is wider and the airway is narrower.8

In pathologies such as chronic bronchitis or asthma, which may alter the lung architecture with the appearance of bronchoconstriction, inflammation or secretion accumulation, the deposition of aerosolized drugs is modified. The smaller caliber of the airway increases air speed, producing turbulence in places where the flow is usually laminar. The airway obstruction also means that the air tends to be displaced toward unobstructed areas, and therefore the drug will also tend to be deposited mostly in healthy areas of the lung.9

The particles of aerosolized drugs can be hygroscopic to a greater or lesser extent. Hygroscopicity is the property of some substances to absorb and exhale humidity depending on the setting in which they are found. This means that they can get larger or smaller in size upon entering into the airway, with the consequent modification in the deposition pattern compared to what was initially expected. The diameter that a particle reaches after hygroscopic growth depends on its initial diameter, the intrinsic properties of the particle, and the environmental conditions in the airways. The mole fraction of water vapor contained in the airway has been demonstrated to be an important factor related with the increase in the MMAD of the aerosol particles.10 In general, it is considered that hygroscopic growth does not have much of an effect in particles with MMAD less than 0.1μm; meanwhile it is very intense in particles with MMAD larger than 0.5μm.11

The hygroscopicity of molecules can be used to try to favor the deposition of inhaled drugs. Studies have been developed in which an aerosol was administered with a submicrometric or nanometric MMAD in order to reduce extrathoracic loss, taking advantage of later growth due to hygroscopicity, which enabled the particles to be retained within the lungs.12,13

Once deposited in the airways, the particles can be carried by the mucociliary system, degraded or absorbed into the systemic circulation or the lymph ducts.9 The first of these mechanisms is found in the conducting airways (from the trachea to the terminal bronchioles), which have ciliated epithelium that are covered by two layers of mucus: a low-viscosity periciliary layer, or sol, and a thicker layer that covers the former, or gel. This biphasic layer of mucus protects the epithelium from dehydration, helping to humidify the air and providing a protective barrier by trapping inhaled particles.14 The insoluble particles are trapped by the gel and they are moved toward the pharyngolaryngeal region by the movements of the ciliated epithelium, where it is either coughed up or swallowed.15,16 The clearance speed depends on the number of ciliated cells and the cilia beat frequency, and it may be affected by factors that influence the function of the cilia or the quantity or quality of the mucus. In cystic fibrosis (CF), for example, very thick mucus is produced that does not correctly move along with the cilia. This is due to a mutation in the gene that codes the CFTR receptor, which regulates the passage of the chloride ion through the surface of the epithelial cells.17

The soluble particles are eliminated by absorptive mechanisms. The liposoluble molecules cross the respiratory epithelium by passive transport; the hydrosoluble molecules can cross the epithelial barrier either through the intercellular spaces or by active transport (by mechanisms of endocytosis and exocytosis).18 Once in the submucosal region, the particles can enter the systemic circulation, bronchial circulation or lymphatic system.9 The particles that are deposited in the alveoli can be devoured and eliminated by the alveolar macrophages if they are insoluble particles (non-absorptive mechanism)19; if they are soluble, they can be absorbed into the systemic circulation.20

There are basically two types of nebulizers: jet and ultrasonic. Jet nebulizers are based on the Bernouilli effect, according to which a compressed gas that passes through a narrow orifice creates a low-pressure area upon exiting. If at this low-pressure point we connect a tube that has a thin layer of liquid, the low pressure will cause this liquid to be aspirated in small droplets. Ultrasonic nebulizers use piezoelectric crystals that vibrate at a high frequency within the nebulizing chamber, transmitting the vibratory energy to the liquid that is in contact with it, converting said liquid into an aerosol.30 Jet nebulizers can generally aerosolize most drug solutions, and ultrasonic nebulizers may not be effective if viscous suspensions or solutions are used.31

Nebulizers can administer high doses of medication in patients who are not able to coordinate or cooperate and they are able to administer several substances mixed together in one same solution. The minimal inspiratory flow needed for the aerosol produced by a nebulizer to reach the lungs is 6–8l/min.2 However, there are high amounts of drug lost as much of the medication is retained in the nebulizer dead-space, or it is lost in the room air during expiration. It has been estimated that only 10% of the dose that is initially placed in the nebulizer will be effectively deposited in the lungs.32 The large droplets are deposited in the oropharynx, while the droplets are too small to penetrate in the lungs and are once again expelled during expiration.

Pulmonary deposition may be increased by modifying the patient's way of inhaling. Most patients inhale by using circulating volume. If the patient takes a deep breath and holds it in, the quantity of medication retained in the lungs may increase 14%–17%.8 Probably the most practical way to modify the deposition pattern is to reduce the size of the droplets that are generated. This can be done with ultrasonic nebulizers by making the piezoelectric crystal vibrate at a greater frequency; doing so with jet nebulizers can increase the compressed gas flow.33

Metered dose inhalers (MDI) are devices used to administer aerosolized drugs that emit a fixed dose of medication with each pulse. They have a metallic chamber containing a suspension or solution of the drug with a liquid propellant that, at room temperature and atmospheric pressure, turns to its gaseous phase. A key piece in this system is the dosage valve, which releases at each pulse a controlled, reproducible dose of medication. The drug is released at a high speed (at more than 30m/s through the mouthpiece) and in the form of particles with an MMAD of between 2 and 4μm.34 MDI have a series of advantages, such as their small size (making them easy to handle), the exactness of the dosage, the possibility to fit them to spacer chambers, the fact that they do not require high flows to be inhaled and their low cost in general. Their main drawbacks are the difficulty inherent in synchronizing activation–inhalation and the low dose that reaches the lungs, which has been estimated at approximately 10%–20% of the dose emitted.35,36 The high release speed and the large size of the particles generated mean that more than half of these impacts in the oropharyngeal region.36 Another drawback of MDI is the possible variation in the dose released at each pulse if the device is not correctly shaken.34

In the past, the propellant used was chlorofluorocarbons (CFC), but due to their harmful effects on the ozone layer, they have been banned by the United Nations. The substitute currently used in MDI are hydrofluoroalkanes (HFA).37 HFA transform into their gaseous state at a higher temperature than CFC,38 reducing the cold freon effect, which is the interruption of breathing when the particles impact against the back wall of the oropharynx. There are currently on the market MDI-HFA with salbutamol, fluticasone, beclomethasone, anticholinergics, and the combination of salmeterol–fluticasone.34 The development of MDI with HFA has also been able to reduce the size of the aerosol droplets and, therefore, improve the lung deposition of the drug. In the case of beclomethasone–HFA, with an MMAD of 1.1μm, it has been demonstrated that up to 56% of the initial dose is deposited.39–41

The optimal conditions for the inhalation of an aerosol using an MDI are to start breathing from functional residual capacity, activating at that moment the inhaler, inhale using an inspiratory flow less than 60l/min and follow the inspiration with 10s of apnea.42 This method increases deposition by sedimentation in the more peripheral areas of the airway. The minimal inspiratory flow necessary for its use is approximately 20l/min.2

One way to avoid the lack of coordination between the patient and the device are to use inhalation chambers that fit on the mouthpiece of the MDI. The aerosol goes into the chamber and the particles that are too big impact against its wall and are retained there, while the smaller particles remain in suspension within the chamber until they are inhaled by the patient. In addition, the space that the chamber provides between the MDI and the mouth of the patient allows the aerosol to lose speed, reducing impaction against the oropharynx. In this manner, local adverse effects are reduced and the lung deposition of the drug is increased.43 It has been demonstrated that MDI used with inhalation chambers are as effective as nebulizers in the treatment of acute asthma attacks.44

Furthermore, with the aim of avoiding a lack of coordinated activation and inhalation, new MDI have been developed that automatically release the medication when the patient inhales, such as Autohaler® and Easybreath®; these devices have been shown to improve the lung deposition of drugs in patients for whom coordination is difficult.45 In addition, they require less inspiratory flow than conventional MDI, at around 18–30l/min, which makes them more adequate for patients with physical limitations, children and the elderly.34,46

Dry powder inhalers (DPI) were designed with the aim to eliminate the inherent coordination difficulties of MDI. They administer individual doses of drugs in a powder form contained in capsules that should be broken open before their administration (unidose systems), or in blisters that move around in a device or have powder reservoirs (multidose systems).

Other advantages of DPI are that they do not require propellants for their administration, which makes them more respectful of the environment, and many of them have an indicator of the doses remaining. The main drawbacks are that patients perceive to a lesser degree the drug entering the airway, which may complicate treatment compliance, and its price is generally higher than that of MDI. DPI should be stored in a dry setting, as humidity favors the agglomeration of the powder that can obstruct the inhalation system.37

The dose that reaches the lungs is similar to MDI, and less than 20% of the initial dose actually reaches the lungs. It has been demonstrated that if the inhalation technique is correct, there is no difference between the administration of a drug by means of DPI or MDI.47 The use of low inspiratory flow, humidity, and changes in temperature are all factors that have been shown to worsen the lung deposition of medications with DPI.48

In the case of DPI, the “aerosol” is produced by the inspiratory effort of the patient.47 An inspiratory flow of at least 30l/min is necessary for the powder medication to become dispersed and reach the lungs, which may be difficult to be done in the elderly, children or patients with severe respiratory disorder.49 The air is directed toward the container with loose powder, which generally consists of particles that are too large to penetrate the airway due to the formation of powder agglomerations or to the presence of large-sized particles that transport the drug, such as lactose. The dispersion of the powder into particles that enter into the inhaled fraction is produced by the formation of turbulent airflows inside the powder container, which break the powder agglomerations up into smaller-sized particles and separate the transport particles from the drug.50 The particles that are generated have a final MMAD that ranges from 1 to 2μm.51,52 Every DPI has a different airflow resistance that determines the inspiratory effort necessary to disperse the powder. The greater the resistance of the device, the more difficult it is to generate the inspiratory effort, but at the same time the deposition of the drug in the lungs is greater.53,54