Pharmaceutical Manufacturing Handbook: Production and

DRY POWDER INHALERS 703
recognized as critical to ensuring reproducible in vitro emitted and fi ne particle
doses. Jones and Price (2006) have recently surveyed the literature in this area and
provided a comprehensive review [196] . Modifi cation of the surface characteristics
of the lactose particle has been used as an alternative approach to control the adherence
of drug particles to the lactose surface [197 – 200] . Alternative sugar carriers
have also been investigated; these appear to possess many of the same performance -
limiting characteristics as lactose [201] . Finally, tertiary additives have also been
used to improve the aerosolization properties of DPI formulations [202] . The majority
of the studies described above relate to in vitro testing of DPI formulation performance,
and little is known about the clinical signifi cance of these studies.
Moisture ingress into a powder formulation is a particular concern as it may signifi
cantly decrease the aerosolization performance of the formulation [203, 204] .
Increased adhesion of particles is often seen following exposure to high - RH environments
[205, 206] . Moisture ingress has also been shown to affect drug stability
[170] . The pharmaceutical industry has used a number of approaches to protect
powder formulations from the ingress of moisture during storage and for their “ in -
use ” life. The Turbuhaler incorporates a desiccant in the base of the inhaler to keep
the power reservoir free from moisture [207] . Unit - dose blisters used in the Diskus
are sealed in a foil strip pack to protect each individual dose prior to inhalation
[208] . It is also essential that the patient not exhale into the DPI immediately prior
to inhaling the dose.
Electrostatic charge can also infl uence the performance of DPI formulations. A
number of studies have investigated the interactions of drug and lactose particle
charge with respect to aerosolization properties and drug retention by the plastic
components within the inhaler [209 – 212] .
5.8.6.4 Dry Powder Inhaler Design
Inhalation Flow Rate The main function of a DPI is to facilitate dispersion and
delivery of inhalable drug particles. An extensive patent and scientifi c literature
exists describing the ever - increasing number of DPI device designs [33] . Powder
dispersion in the early passive DPIs was provided in part by the inspiratory effort
of the patient. This removed the necessity to coordinate patient inhalation with
actuation and delivery of the dose (in contrast to MDIs). These passive DPIs were
“ breath actuated, ” with the patients ’ inspiratory effort dispersing, aerosolizing, and
delivering the powder during the inhalation cycle. The airfl ow rate through the
inhaler was determined by the inherent device resistance and the inspiratory force
exerted by the patient [18] . Devices such as the Spinhaler, Rotahaler, and Diskhaler
are low - resistance devices requiring relatively high inspiratory fl ow rates to disperse
the powder formulations by turbulent deaggregation. These simple devices have low
aerosolization effi ciencies with only 5 – 20% of the dose being delivered to the lungs
[166] The inhalation fl ow rate dependence of passive DPIs has been cited as a
potential problem in their use, especially given the large intersubject fl ow rate variability
within the patient population (especially for the young and older patients).
In vitro testing revealed that for certain DPIs there was large variability in both the
delivered dose and the aerodynamic particle size distribution as a function of the
inhalation fl ow rate [203, 213 – 216] . Similar clinical studies also revealed a fl ow rate
dependence for certain DPIs while others were observed to perform with a degree