TAILORING DRY POWDER INHALER PERFORMANCE BY - RCPE

770 Maas et al.
Three batches (A, B, C) of each formulation (mannitol
60 ◦ C, 90 ◦ C, 120 ◦ C) were examined, and the coefficient
of variation of the dose of each batch was calculated in
order to get a measure of the uniformity of the delivered
dose. The mean and the standard deviation of the three
coefficients of variation of each formulation were calculated
(mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C). They are given in
Fig. 6. There is no significant difference between the formulations,
the mean of the coefficients of variation having
values of 33.6% for formulations containing mannitol
60 ◦ C, 37.8% for formulations containing mannitol 90 ◦ C,
and 18.0% for formulations containing mannitol 120 ◦ C.
Because the coefficients of variation of the delivered
dose are not substantially higher than the coefficients of
variation of the metered mass of the formulations metered
by the built-in metering device of the inhaler, the
poor uniformity of the delivered dose may be attributed
to the inadequate flowability and dosing of the formulations,
which, in turn, results from the small particle size
of the carrier obtained by the laboratory spray dryer. In order
to prepare particle sizes of the carrier between 50 and
200 µm, which are normally used in commercially available
products, larger spray dryers will be used. In contrast,
there is no hint that the poor uniformity of the delivered
dose may have been caused by an arbitrary amount of the
formulation being retained on the walls of the inhaler on
actuation.
3.5 Retained Dose
By relating the delivered dose of active to the metered
mass of the drug (which is calculated from the metered
variation
coefficient or the delivered dose / %
55,0
50,0
45,0
40,0
35,0
30,0
25,0
20,0
15,0
10,0
5,0
0,0
mass of the formulation by multiplying the respective
value with the amount of drug present in the formulation),
a measure of the fraction of drug, which is delivered to the
patient, vice versa retained in the inhaler and the mouthpiece
adapter, was obtained. The amount of drug delivered
is 77% for formulations containing mannitol 60 ◦ C
and mannitol 90 ◦ C, and 78 % for formulations containing
mannitol 120 ◦ C, indicating that the amount retained
also is independent on the surface topography of the carrier
(Fig. 7).
3.6 Fine Particle Fraction
The FPF is defined as the fraction of the active with an
aerodynamic particle diameter ≤5 µm devided by the total
amount of the active found in the impactor, and is an
indicator for the fraction of the active reaching the lower
part of the lungs in relation to the total amount of drug
delivered to the patient. The experiments were carried out
using the experimental setup described in the European
Pharmacopoeia (Ph. Eur. 2008c). Fifty puffs equivalent to
approximately 4 mg of drug were delivered from the Novolizer
device to the NGI. The amount of drug on each
stage was measured using HPLC.
Three batches (A, B, C) of each formulation (mannitol
60 ◦ C, 90 ◦ C, 120 ◦ C) were examined, and the mean and
standard deviation of the FPF of the three batches were
calculated. Figure 8 shows that the FPF decreases from
formulations containing mannitol spray dried at 60 ◦ C
(mannitol 60) to formulations containing mannitol spray
dried at 90 ◦ C (mannitol 90) and finally to formulations
containing mannitol spray dried at 120 ◦ C (mannitol 120)
Mannitol 60 °C Mannitol 90 °C Mannitol 120 °C
FIG. 6: Coefficient of variation of 10 doses of formulations containing mannitol carrier particles spray dried at 60 ◦ C,
90 ◦ C, and 120 ◦ C); n = 3, mean ± standard deviation.
Begell House Digital Library, http://dl.begellhouse.com Downloaded 2011-3-4 from IP 129.27.117.213 by Technische Universitaet Graz
Atomization and Sprays