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Pharmaceutical Surface Science Research Group, Department of Pharmacy and Pharmacology, University of Bath, BA2 7AY Bath, UK
DFE Pharma, Klever Strasse 187, 47574 Goch, Germany
c
Malvern Instruments Ltd., Enigma Business Park, Grovewood Road, WR14 1XZ Malvern, UK
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 21 July 2014
Received in revised form 8 November 2014
Accepted 8 November 2014
Available online 13 November 2014
The aim of the study was to investigate how the ne particle content of lactose carriers prepared with
different types of lactose nes regulates dry powder inhaler (DPI) formulation performance of a cohesive
batch of micronised budesonide. Budesonide formulations (0.8 wt%) were prepared with three different
lactose carriers (Lactohale (LH) LH100, 20 wt% LH210 in LH100 and 20 wt% LH300 in LH100). Fine particle
fraction of emitted dose (FPFED) and mean mass aerodynamic diameter (MMAD) of budesonide was
assessed with a Next Generation Impactor (NGI) using a Cyclohaler at 90 l/min. Morphological and
chemical characteristics of particles deposited on Stage 2 were determined using a Malvern Morphologi
G3-ID. The results indicate that increasing concentration of lactose nes (<4.5 mm) not only increased
the FPFED but also the MMAD of budesonide, suggesting drug deposition in agglomerates. Presence of
agglomerates on Stage 2 was conrmed by morphological analysis of particles. Raman analysis of
material collected on Stage 2 indicated that the more ne lactose particles were available the more
agglomerates of budesonide and lactose were delivered to Stage 2. These results suggest drug-nes
agglomerate formation is an important mechanism for how lactose nes improve and regulate DPI
formulation performance.
2014 Elsevier B.V. All rights reserved.
Keywords:
Lactose
Dry powder inhaler
Raman spectroscopy
1. Introduction
In dry powder inhaler (DPI) formulations, drug particles with
aerodynamic diameters of less than 5 mm are required to target the
conducting airways. The particle size is conventionally achieved by
secondary processing of crystalline drug using energy intensive
air-jet micronisation (Chan, 2006). However, due to the high
interparticle forces in micronised, cohesive Geldart type C (Geldart,
1973) powders, and low doses required for drug delivery to the
lungs, metering of and uidising a drug only dose is onerous. Thus,
to allow adequate metering and increased owability of the
powder, the micronised drug is commonly formulated with
coarser, uidisable Geldart type A (Geldart, 1973) carrier particles.
54
Size 3 hydroxypropylmethylcellulose (HPMC) capsules (Qualicaps, Spain) were manually lled with 12.5 mg of the formulations.
A Cyclohaler device (Teva Pharmaceuticals, The Netherlands) was
used for aerosolising the formulations into a Next Generation
Impactor (NGI, Copley Scientic, Nottingham, UK) equipped with a
pre-separator. Air was drawn through the impactor at 90 l/min for
2.7 s (Kubavat et al., 2012) as controlled by a TPK critical ow
55
LH100
+20% LH210
+20% LH300
%<4.5 mm
1.29
6.02
23.04
24.10 0.24
26.63 0.13
39.74 1.34
2.58 0.02
3.14 0.01
3.36 0.03
56
Fig. 2. (A) Number based and (B) volume converted circular equivalent (CE)
diameter distributions of particles collected on a microscope slide placed on Stage
2 of the Next Generation Impactor from formulations prepared with LH100 (solid
line), 20% LH210 in LH100 (short dash) and 20% LH300 in LH100 (long dash) as
carrier for micronised budesonide aerosolised at 90 l/min on a Cyclohaler.
Table 2
The 10th, 50th and 90th percentiles of number based and volume converted circular equivalent (CE) diameter distributions and mean values of high sensitivity (HS) circularity
and convexity of material collected on Stage 2 of the Next Generation Impactor.
Number based particle size (mm)
LH100
+20% LH210
+20% LH300
a
b
d10
d50
d90
d10
d50
d90
HS circularitya
Convexityb
1.56
1.72
1.86
3.84
3.62
3.94
5.77
6.14
6.72
3.68
3.60
3.95
5.35
5.98
6.53
8.06
9.48
10.4
0.859
0.846
0.824
0.986
0.983
0.980
Convexity is calculated as convex hull diameter of a particle divided by the actual perimeter of the particle.
High sensitivity (HS) circularity is calculated as 4p times the area of the particle over perimeter squared.
57
Table 3
Proportions of budesonide, lactose and agglomerates of the two species deposited
on Stage 2 of the Next Generation Impactor from the different formulations
aerosolised on Cyclohaler at 90 l/min. The data are based on Raman analysis of 1353
(LH100), 1095 (+20% LH210) and 1156 (+20% LH300) particles collected on a
microscope slide placed on Stage 2.
LH100
+20% LH210
+20% LH300
Lactose (%)
Budesonide (%)
Agglomerates (%)
37.4
79.0
77.3
48.8
9.5
5.7
13.8
11.5
17.0
Fig. 3. A 50 magnication eld of view photomicrograph of particles deposited on Stage 2 of the Next Generation Impactor (left), the Raman spectra of the highlighted
particle (top right) and the library spectra of a-lactose monohydrate (middle right) and budesonide (bottom right).
58
Table 4
The mean standard deviation (n = 3) amount of budesonide recovered from Stage 2 of the Next Generation Impactor, total proportion of species containing budesonide of the
particles analysed by Raman for each of the formulations and the amount of pure budesonide and budesonide in agglomerates on Stage 2 based on the Raman analysis.
LH100
+20% LH210
+20% LH300
3.37 0.10
4.78 0.10
9.82 0.14
62.6
21.0
22.7
2.6
2.2
2.4
0.7
2.6
7.4
59
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