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ne of the longstanding challenges facing the People who suffer from these aforementioned illnesses David Harris
O United States Pharmacopeia (USP) is the necessity
to provide guidance for testing standards that are
will not necessarily have impaired lung function. The
current test point of a 4 kPa pressure drop across the
representative of typical use. The USP maintains DPI is unlikely to be representative of what will be
a formal revision process, which is reliant upon achieved in typical use.
‘substantial interaction’ between their stakeholders As engineers and scientists responsible for the
(the public, and scientific and technical groups) and development of DPIs to treat a range of conditions,
their Council of Experts. As engineers and scientists we should believe that an in-depth understanding of
working within the field of respiratory drug delivery, the nature of the lung power of the target therapeutic
it is up to us, therefore, to challenge existing testing group is prerequisite to achieving a successful inhaler
methodologies, and strive to constantly reduce the gap design. Only once armed with this information can we
between results produced within the laboratory to expect to achieve clinical results that marry well to
those acquired in clinical studies. those generated within the laboratory.
Passive dry powder inhalers (DPIs) rely solely upon
the inspiratory effort provided by the patient to Usefully measuring lung power
produce a respirable aerosol. Historically, DPIs have There is little published literature available on the
been used to administer medication for the direct measurement of lung power — most research has been
treatment or relief of chronic obstructive pulmonary conducted using inhaler devices with fixed resistances,
disease (COPD) and asthma. People who suffer from each inhaler representing just a single datum on a lung
either of these, characteristically, have impaired lung power profile. Also to be considered is the relatively short
function and are less able to inhale forcefully through duration of an inspiratory manoeuvre — usually less than
an aerodynamically resistive DPI. Studies researching 2 s; half that of the prescribed test duration by the USP
the lung power of these groups report that a flow for a medium resistance inhaler.3 Of course, this is
rate of 60 L/min can typically be achieved through a
medium resistance device (corresponding to a
pressure drop across the device of 4 kPa).1 I However,
a new generation of DPIs is under development to
cover a range of diseases and illnesses, including the
systemic delivery of a wide range of molecules to
treat conditions such as diabetes, pain management,
allergic reactions and sexual dysfunction. In addition,
numerous pharmaceutical companies are developing
inhalable vaccines to overcome problems associated
with parenteral administration, such as needle-stick
injury and the requirement for refrigeration of the
vaccines throughout the shipping cycle. There are
two distinct advantages of delivering drugs directly
into the lungs:2
● There is a high rate of absorption into the
I. A ‘medium’ resistance inhaler device requires a pressure drop of 4 kPa to draw an airflow rate of 60 L/min.
through it. As the resistance is given by the ratio of the square root of pressure drop to airflow rate, medium
resistance is 0.105 √cm H2O/(L/min) (conventional units).
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Harris
considerably shorter as far as the drug is milliseconds, all data above 80% of
concerned as it will have typically exited the peak datum value were averaged
the inhaler within 100–300 ms. In terms (i.e., the top 20%), and this mean value
of developing a testing methodology, taken to be the peak flow rate (or
this means that a fast response time of pressure) for that particular resistance.
Figure 1 Schematic illustration of equipment to the measurement instrumentation is An example is illustrated by the purple
measure lung power. required to capture the dynamic nature triangles overlaid on the profile of
of the inhalation event. Orifice 5 (Ø7.4 mm) (Figure 3). This
Q Orifice plate(s) A similar technique, albeit on a larger was believed to be a more
(various resistances) scale, is used to measure the power representative measure as it rules out
Mouthpiece
response of in-line centrifugal fan spikes in the profile and is effectively
motors.4 I adapted this technique to the average peak period of the
Airwatts work on a much smaller scale, to inhalation. The mean peak flow rate
box measure the pressure/flow temporal achieved by our example volunteer
profiles of 16 healthy, adult volunteers through Orifice 5 was 158.3 L/min,
(Figure 1). A low volume (200 cm3) which is 94% of the absolute peak
‘airwatts’box was designed to minimize value, 168.7 L/min. It is accepted that
P capacitance effects and, using nine this method will slightly under predict
orifice plates, a wide range of inhaler the power of our volunteers’ lungs.
(Courtesy of Virginia Commonwealth University)
resistances could be represented. Each Several parameters are captured
orifice was pressure-mapped to simultaneously, including; pressure III
determine its discharge coefficient, Cd, airflow rate, power and airflow
Figure 2 Example of flow rate profiles acquired for according to Equation 1, thus allowing velocity IV, which was used to
one volunteer. flow rate to be accurately deduced from measure the power response of
350 static pressure data. II human lungs.
Ø15.0 mm The first order derivative of these
Equation 1
300 Ø12.9 mm four parameters has been calculated
Ø11.0 mm using a straightforward linear
250 Ø9.0 mm regression of the data falling
Flow rate (L/min)
data, which may only last a few with no additional resistance to the
120
100
II. 200 cm3 is 5–10% of a normal adult’s lung capacity. There must be sufficient
80
volume to remove the dynamic head component of the airflow through the
60 box, to measure static pressure accurately — but this must be traded off
against having too high a volume, which reduces the responsiveness of the
40 Linear regression
system to measure high rates of change in pressure or airflow rate.
20 III. Specifically ‘mouth pressure’. The airwatts box method effectively measures
0 the pressure drop that would be achieved within the mouth at any point
0 200 400 600 800 1000 1200 1400 1600 during the inhalation event, and the subsequent airflow rate that will result
Elapsed time (ms) through the resistance that is providing that pressure drop.
Power (airwatts) Airflow rate (Ls-1) Pressure drop (kPa) Figure 4 Pressure profile of healthy human lungs.
Equation 2 14
800
Mean peak airflow acceleration (m/s2) Smallest hole not included
700
600
500
y = 128.57Ln(x) + 855.96
400 R2 = 0.9032
300
200
100
0
0.01 0.10 1.00
Airflow resistance (√cm H2O/(L/min))
25
Smallest hole not included
Mean peak power (airwatts)
20
15
10
0
0.10 0.10 1.00
Airflow resistance (√cm H2O/(L/min))
Harris
Key points
● For the new generation of DPIs customized solutions
the current test point of a 4 kPa
is unlikely to be representative
of what will be achieved in
typical use. The mean mouth
pressure achieved by our group
of healthy volunteers through a
medium resistance device is
tailor-made specialty chemicals
approximately 8 kPa —
equivalent to triple the nominal
power prescribed by the USP.
● Airflow acceleration in
particular is likely to influence proven track record in specific industries
the aerosolization of drug
formulation within the DPI:
The instantaneous rise in
airflow rate achieved in almost our focus, your success
all in vitro test apparatus is As a specialist in custom additives and auxiliaries, high-
clearly unrepresentative of the manufacturing, Saltigo provi- tech monomers, electronic
half a second our volunteers des tailormade solutions for chemicals, dyes, pigments,
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methodologies prescribed by
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