Drug Targeting Organ-Specific Strategies

tion has been deteriorated. However, pulmonary obstructions usually restrict the expiratory
performance rather than the inhalation manoeuvre (e.g. [102,103]). Therefore, maximal inspiratory
pressure (MIP) values of asthmatic and COPD patients can be of the same order of
magnitude as that of healthy subjects [104]. Only severe COPD patients may not be able to
generate MIPs higher than 1.5–2.0 kPa.The effect of airflow resistance and clinical condition
on the generated pressure drop across an external airflow resistance is summarized in Figure
3.5 (data derived from reference [104]).The data show that in vitro testing of dry powder
inhalers at only 4 kPa, as prescribed by various guidelines, is inadequate for the prediction of
their performance in practice.
Attained flow parameters during inhalation can either be calculated (Eq. 3.1) from recorded
pressure drop curves or measured directly, using the equipment described in Section 3.9.1.
Various studies report peak inspiratory flow rate (PIFR) values for healthy and diseased
adult subjects calculated from data on inhalation without external resistance (so-called ‘control
values’)(e.g. [22,100,105,106]). As for the attainable pressure drop, asthma, COPD and
cystic fibrosis may decrease PIFR, depending on the severity of the disease. The addition of
an external airflow resistance, such as a DPI strongly affects the PIFR.Within the range of resistances
for marketed DPIs, the average PIFR at maximal inhalation by healthy adults may
decrease from 159 l min –1 (for R = 0.015 kPa 0.5 min l –1 , equals the Rhone Poulenc Spinhaler)
to only 62 l min –1 (for R = 0.040 kPa 0.5 min l –1 , equals the Astra Turbuhaler) [22].
A maximal average flow rate of approximately 60 l min –1 through the Turbuhaler has also
been reported for asthmatics (e.g. references [103,107,108]).
Various flow parameters may be relevant to good DPI performance.The effect of PIFR on
the in vitro dose of fine particles from DPIs has been the subject of many studies (e.g.
[109–112]. The actual dose of the fine particle fraction produced varies with the ranges of
flow rates applied. The flow rate being the measuring principle used for the study and definition
of the fine fraction. Most studies show a strong increase in fine particle output with increasing
PIFR for the ASTRA Turbuhaler [110–112]. For the Glaxo Diskus and
Diskhaler, the effect of PIFR is less extreme: in some cases an more or less constant, but
also a much lower output of approximately 15 to 25% of the label claim, has been obtained
[109,110]. Some recent studies refer to the fact that the Pulmicort Turbuhaler also has a
constant fine particle yield if the acceleration towards peak flow (flow increase rate: FIR) is
high enough [113,114]. For a FIR > 8 l s –2 , the fine particle output is already maximal at flow
rates above 40 l min –1 . For capsule inhalers, the inhalation time has to be long enough for all
the particles to pass rapidly through the narrow holes pierced in the capsule ends before inhalation
stops.
3.9.1 Measurement of the Inspiratory Flow Curve
3.9 Inspiratory Pressure and Relevant Flow Parameters 77
Many different techniques are available for flow measurement and for recording of respiratory
functions or flow parameters in particular (e.g. [115,116]). However, not all methods are
appropriate for measurement of inhalation flows, either because they have low frequency responses
or they influence the shape of the inspiratory flow curve by a large volume or by the
inertia of the measuring instrument (e.g. rotameters). They may also interfere with the
aerosol cloud from the inhalation device during drug deposition studies.