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Methods to identify drug deposition in the lungs following inhalation.

Inhalation of bronchodilators and anti-inflammatory agents enables direct delivery to the therapeutic sites in the airways for the management of asthma and chronic obstructive pulmonary disease. Figure 1 shows that following inhalation up to 20% of the dose is delivered to the lungs whilst the majority is swallowed [1, 2]. The proportion of the dose delivered to the lungs, following inhalation, will be cleared either by the mucociliary convenor belt or by absorption through the airway wall into the systemic circulation. The latter is the fraction of the dose that will exert the clinical effect within the airway wall. The total amount of drug which enters the systemic circulation via the pulmonary and gastrointestinal routes, has the potential to cause extra-pulmonary side-effects. The high first pass effect of some corticosteroids (e.g. fluticasone) limits this potential. 
 
 
 
Figure 1 
 
Pharmacokinetic description of an inhaled dose. 
 
 
 
Drug particles less than 5 µm have the greatest probability of deposition in the lung [3], whereas those less than 2 µm tend to be concentrated in the alveoli [4, 5]. The dose emitted from an inhaled product contains a large proportion of particles within the 2–5 µm range ensuring a fairly even distribution throughout the lungs [2]. When comparing inhaled products, especially generic against innovator or different devices, emphasis is placed on the in-vitro aerodynamic particle size characteristics measured using cascade impactors. Regulatory authorities view these as important quality-control procedures but for equivalence they focus on the amount delivered to the airways and to the body. 
 
Table 1 lists the pharmacokinetic and scintigraphic methods that have been developed to identify the amount of drug delivered to the lungs following an inhalation. Pharmacokinetic methods are indirect measurements because they utilize measurements from serum [6–8] or urine [9, 10]. Figure 1 illustrates how these methods identify the amount of drug delivered to the systemic circulation via the lungs and gastrointestinal tract; thus procedures to differentiate between these two routes of absorption are required. These procedures are mentioned in Table 1. Although these methods do not differentiate between the distribution of drug into different zones of the lungs they do provide an index of the relative amount of the inhaled dose which has the potential to produce a clinical effect within the airways. The methods are therefore useful in crossover studies to investigate the equivalence between two inhaled products or differences between inhalation techniques. Following inhalation, drug is distributed to all parts of the airway and that the total dose, rather than pulmonary distribution, is related to the clinical effect [2]. This is consistent with reports that suggest that the receptors for the β-adrenoceptor agonists [4, 5, 11–13] and the inflammatory markers [14–18] are distributed throughout the airways. 
 
 
 
Table 1 
 
Summary of the methods used to identify the bioequivalence of inhaled products. 
 
 
 
Scintigraphic methods following inhalation using two [1, 19, 20] and three [21–23] dimensional imaging are direct methods for the determination of lung deposition. These techniques, which have been extensively described elsewhere [24], can highlight the zones of the lungs into which the drug is deposited. However, they do not differentiate between the removal of drug from the lungs by systemic absorption or by mucociliary clearance, and also require modification to the original drug formulation.