Drug Targeting Organ-Specific Strategies

74 3 Pulmonary Drug Delivery: Delivery To and Through the Lung
the correct size distribution during adequate inhalation. The inspiratory flow as the driving
force for discharge of the dose system, fine particle generation during powder disintegration
and particle deposition in the respiratory tract is one of the most important parameters. If the
patient is unable to achieve the threshold values (for the relevant flow parameters) for good
inhaler performance, the fine particle fraction will be too low for adequate efficacy. If the
flow rate is too high, a substantial loss of the fine particle dose by inertial deposition in the
oropharynx must be expected.
The nature of the flow curve achieved, depends on three different factors: the instructions
given to the patient, the patient’s effort following these instruction and the resistance to airflow
of the DPI (Figure 3.4). Most instructions for use of DPIs prescribe forceful and deep inhalation.
Patient interpretation of these instructions often vary considerably. Patient variables
also include age, gender, condition and clinical assessment. In Section 3.9 the attainable
pressure drops across external resistances as a function of clinical condition will be discussed
more in detail. The DPI’s resistance is a consequence of its design. Narrow channels in the
dose system and the disintegration principle in addition to turbulent air zones, increase the
resistance and reduce the attainable peak flow rate through the device. This is an advantage
from the deposition point of view. High resistance DPIs generally have a high disintegration
efficacy and do not require high flow rates to achieve an acceptable dose of fine particles. Recently,
a multi-dose dry powder inhaler has been introduced (Sofotec Novolizer) in which
the resistance can be controlled over a certain range by means of a sheath flow around the
aerosol cloud, without changing the fine particle output [55].
3.8 Airflow Resistance
The underpressure created in the respiratory tract is the driving force for the airflow through
an inhalation device. The attainable underpressure and the rate of the airflow both depend
on the total resistance in the airways and inhaler. The pressure drop achieved during inhalation
is furthermore a function of the anatomy of the lungs, the effort made by the patient,
pathological factors and the presence of exacerbations (e.g. in case of asthma).
A large proportion of the airflow resistance in the airways (internal resistance: R i) is offered
by the upper respiratory tract in which the airflow is already turbulent at relatively low
flow rates of 30 to 40 l min –1 (R E > 2000: see also Section 3.2.1). During quiet mouth breathing,
the mouth, pharynx, larynx and trachea account for 20–30% of total airway resistance.
The same region contributes as much as 50% to total resistance during heavy breathing however.
In the small peripheral airways (those less than 2 mm in diameter), resistance is quite
low and the contribution to R i is not more than 10–20% [21].
For nebulizers and MDIs, the external resistance (R E) is quite low. Different approaches
have been made to describe the external airflow resistance of DPIs. Olsson and Asking [99]
derived an empirical relationship between flow rate (Φ) and pressure drop (∆P), ∆P = C.Φ 1.9 ,
for a number of inhalers (such as Rotahaler, Spinhaler and Turbuhaler) in which they
define the proportionality coefficient (C) as the airflow resistance. This relationship differs
only slightly from the general (theoretical) equation for orifice types of flow constrictions:
Φ V = Fu(A) x (2∆P/ρ A) 0.5 (3.2)