Inhaler devices have the advantage of delivering high drug concentrations directly to the disease site, achieving a similar or superior therapeutic effect at a lower dose than is required with systemic administration.
2.6.1 Particle size
The deposition and distribution of inhaled drugs within the lung depends on several factors, including particle size. Fine particles are distributed in peripheral airways at low levels of drug per unit surface area, while large particle aerosols are deposited at higher density on central airways [311]. Inhaled drugs usually consist of particles of varying size, with the size calculated using mass median diameter (When 50% of particle mass appears above and below this point) and aerodynamic diameter (The diameter of a sphere of unit density that has the same settling velocity as the particle
regardless of shape or density). The mean mass aerodynamic diameter (MMAD) is calculated from a cumulative distribution curve of the different particle sizes and volumes and geometric standard deviation (GSD) measures the variability of particle sizes within the aerosol [312].
Lung deposition occurs by inertial impaction (>5µm), gravitational
sedimentation (0.4-5µm) or diffusion (<0.4µm), with the majority of
particles with a diameter of 5-10 µm deposited in the large conducting
airways. In the alveoli there is negligible air velocity and deposition occurs by sedimentation and diffusion [313]. Particles > 10 µm are generally
deposited in the oropharyngeal region and subsequently swallowed, while particles <3 µm have an 80% chance of reaching the lower airways with 50-
60% being deposited in the alveoli [314].
2.6.2 Delivery device.
Various devices are available to deliver inhaled drugs including nebulisers, metered-dose inhalers (MDI) and dry-powder inhalers (DPI). Each has advantages and disadvantages.
There are two main types of nebuliser device. The jet nebuliser uses the Bernoulli principle, with compressed air passing through a narrow orifice to produce an area of low pressure, drawing drug solution from a fluid reservoir and producing shattered droplets. Ultrasonic nebulisers use a high frequency vibrating crystal to generate a fountain of small droplets.
Nebulisers do not require patient co-ordination or a specific inhalation technique, but the majority of nebulised drug deposits within the apparatus or is released into the environment. Small amounts are deposited in the oropharynx and often only around 10% of the drug reaches the lungs [315].
Nebuliser solutions with a low pH and/or hypo-/hyper-osmolality can cause bronchoconstriction and hence alter drug deposition [316,317].
Metered-dose inhalers are compact and portable, with the drug aerosol driven by chlorofluorocarbons (CFC) or hydrofluoroalkanes (HFAs) through a nozzle at a velocity of over 30 metres per second. Even with effective delivery (good hand-mouth coordination and an appropriate inspiratory flow rate), only around 10-20% of emitted drug reaches the lung with many inhalers, with approximately 50-80% delivered to the oropharynx due to the large particle size and velocity of delivery [318]. Although effective use of the MDI requires good hand-mouth co-ordination, over 50% of subjects were unable to manage this in one study [319]. The inspiratory flow rate is an important variable for drugs with a MMAD of 1-5 µm, since very high
flow rates reduce total lung deposition and peripheral penetration, since more drug is deposited by inertial impaction in the conducting airways and oropharynx [320]. With slow inhalation and an increase in tidal volume, deposition in the peripheral regions of the lung is enhanced [321-323], while a ten-second-breath hold reduces the immediate exhalation of drug deposited in the peripheries.
The addition of a holding chamber or spacer device to a MDI can decrease the proportion of drug deposited in the oropharynx (reducing the mean particle size and slowing aerosol velocity) and can increase peripheral drug deposition [324].
Dry powder inhalers were designed to eliminate the need for hand-mouth co-ordination and have the environmental advantage of not using chlorofluorocarbon propellants. Various devices are available, producing variable lung deposition (12-40%), with around a quarter of the drug being
retained in the device [325-327]. Lung delivery is enhanced by a rapid inspiratory rate, since airflow through the inhaler provides the required turbulence to separate drug from carrier particles and produce particles small enough to be carried into the lower airways [328]. Poor deposition can relate to slow inspiration rates or factors (high humidity, changes in temperature) that impair the deaggregation of drug particles from larger carrier particles. Modern dry powder inhlers are breath actuated and require an inspiratory flow rate of 30-130 L/min to achieve an aerosol in the appropriate range [329].
2.6.3 Pulmonary factors. 2.6.3a Drug deposition
Pulmonary factors including airway narrowing and inflammation can affect the deposition of an inhaled drug. Airway obstruction increases turbulence and disturbs the normal laminar flow, with inhaled aerosols directed towards unobstructed airways and less drug delivered to obstructed areas. Airway obstruction is associated with central deposition of the inhaled drug, with deposition depth correlating with FEV1 [322,330]. Severe obstruction causes
a heterogeneous central distribution, unlike the uniform and peripheral distribution seen in normal lungs.
2.6.3b Drug clearance
Various factors protect the lung against inhaled particles, including airway geometry, humidity and clearance mechanisms. The complex airway branching system with progressively smaller airways encourages particles to deposit by impaction [331]. The high relative humidity ensures that
hygroscopic particles increase in size (upto five fold) as they move from an area of low temperature and humidity into the airways, encouraging central distribution within the lung [332-334].
Following deposition, inhaled drugs are degraded, absorbed into the systemic circulation or cleared from the lungs. Within conducting airways, most drug is cleared by ciliated epithelia which stretch from the trachea to terminal bronchioles. Particulate matter is trapped in the mucus layer and beating of the cilia generates upward movement of the particles towards the pharynx and subsequently, the gastrointestinal tract. Mucociliary function is usually impaired with airflow obstruction, with secretions and particulate matter removed by coughing. Despite this, there is an inverse relationship between FEV1 and drug clearance [335].
Some soluble particles are absorbed, with lipophilic molecules passively transported through airway epithelium and hydrophilic molecules crossing extracellular pathways or being actively transported into the circulation or lymphatics [336]. Alveolar drug particles are either phagocytosed by macrophages and slowly cleared from the lungs or absorbed into the pulmonary circulation [337]. Drug metabolism within the lung plays a minor role in drug clearance; although metabolising agents are found throughout the airways and alveoli, more than 95% of inhaled proteins are absorbed intact [338].