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INTRODUCTION
Dry powder inhalers (DPI) are a novel route for
drug delivery, with the capability of targeting
disease states both locally (in the case of lung
diseases such as asthma), and systemically (e.g.
in the delivery of proteins and peptides). For
effective deposition in the lower airways and deep
lung, drug particles with aerodynamic particle
sizes of <5 mm are required. However, such
systems are highly cohesive due to the high
Correspondence to: Paul M. Young (Telephone: 61 2 9036
7035; Fax: 61 2 9351 4391; E-mail: py@pharm.usyd.edu.au)
Journal of Pharmaceutical Sciences, Vol. 96, 13311341 (2007)
2007 Wiley-Liss, Inc. and the American Pharmacists Association
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correlation with the particle size analysis, confirming that increasing the mill time resulted in
both a decrease in median particle diameter with
a concurrent increase in fines material. Representative high magnification images of the freshly
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amorphous content (Fig. 5) (R2 0.999), correlating with the concurrent decrease in median
diameter observed by size analysis. Again, such
observations may be expected, since amorphous
content was introduced into the sample by surface
molecular modification during the milling process.17 As the degree of comminution decreases, it
is logical to conclude that the introduction of
surface molecular damage would follow suit. In
comparison, organic-DVS analysis of the 60 min
mill time recrystallized sample suggested a
completely crystalline material (0.0% amorphous
content). Since the milling process, would most
likely induce amorphous domains on the surface
of the lactose, differences in interfacial forces
between NST and the freshly milled or recrystallized system should exist. The freshly milled
sample, under the experimental conditions used
here, would be thermodynamically unstable and
would have surface amorphous domains with a
degree of molecular mobility relative to the
environmental conditions (45% RH). Clearly,
under such conditions, the force of interaction
would be higher and result in a reduced FPF
when compared to the re-crystallized lactose
system.
In Vitro Aerosolization Performance
The aerosolization performance of NST from
blends of milled and recrystallized lactose monohydrate was studied using a MSLI. Analysis of the
deposition data suggested milling resulted in no
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being observed for freshly milled and recrystallized lactose monohydrate samples, respectively.
Again, as with the variation of FPF with mill time
data, linearity for the freshly milled samples only
existed up to a certain extent (equivalent to
40 min or 13.9% fines), after which, the FPF
decreased.
More importantly, when compared to the influence of mill time, the relationship between the
fines content of either freshly milled or recrystallized samples and FPF indicated no significant
difference with respect to fines content (ANOVA,
p < 0.05). In simple terms, samples with less than
15% fines resulted in no significant difference in
FPF between samples of milled or recrystallized
lactose monohydrate carriers containing similar
fines percentage. Such observations correlate with
previous investigations. Zeng et al.,6,9 and Islam
et al.,7,12 reported a significant reduction in FPF
with a reduction in fines content. The FPF was
returned to the original level when the fines
removed were restored, and further improved with
increasing fines content. Various studies reported
a trend of improved FPF when fine particles
(lactose monohydrate, glucose or PEG 6000) were
introduced to coarse carrier mixtures, irrespective
of coarse carrier particle size.8,10,11,32
In general, two mechanisms have been proposed to explain such observations: the active site
theory and multiplet/agglomeration theory.
In simple terms, the active site theory suggests
that the increasing carrier fine concentration
occupies high energy-active sites, thus promoting drug adhesion to occur at relatively lower
energy-passive sites.6,811,33 Clearly, the result of
such an effect would be the easier detachment
of drug particles and thus increased FPF.
However, although the existences of such sites
have been experimentally verified in recent
publications,1619,33 it is suggested that at such
high drug loadings (5% w/w) active site effects
would be minimal. Alternatively, adhesion and
redistribution of ingredients, when fines are
present, may produce a mixed agglomerate of
drug and fine material (forming multiplets or
agglomerates). Such agglomeration may result in
improved drug aerosolization, since, due to simple
physics, dispersion of larger agglomerates from
larger carrier particles will be achieved at lower
forces, when compared to typical individual drug
carrier systems.10 In the case of such high drug
loadings, the authors propose that this mechanism
would most likely dominate FPF.
Although such general theories are attractive, a
deviation from linearity at high fine concentrations (>15% fines) still exists. One of the most
likely explanations for the observed decrease in
FPF in samples with fines >15% is a mixed
agglomerate theory, where at high fines concentrations drug-lactose monohydrate agglomerates
fail to adhere to the larger lactose monohydrate
carrier particles and become segregated. Such
segregation results in a biphasic system in that the
typical ordered mix of micronized drug/lactose
monohydrate becomes a two-component blend:
the carrier/drug agglomerate particles and the
free agglomerates. Such a blend may result in
deviation from an expected agglomeratecarrier
relationship. To further investigate the potential
for such segregation, the particulate structure of
formulations containing different levels of fine
lactose monohydrate were investigated. Representative SEM images of formulations containing
18.0% (60 min freshly milled lactose monohydrate)
and 10.1% (60 min recrystallized lactose monohydrate) fines are shown in Figure 9A and B,
respectively.
When comparing samples containing >15%
fines (Fig. 9A), large drug-fine agglomerates, that
were clearly separated from the coarse carrier,
were present in the system. In contrast, with
moderate fines content (Fig. 9B), a homogenous
blend of mixed drug-fine agglomerates adhering to
the coarse carrier surface was depicted. From such
observations, it is reasonable to assume, that a
critical agglomerate size may exist in drug-fine-
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CONCLUSION
REFERENCES
1. Edge S, Kibbe A, Kussendrager K. 2006. Lactose,
Monohydrate. In: Rowe RC, Sheskey PJ, Owen
SC, editors. Handbook of pharmaceutical excipients, 5th Edition. London: Pharmaceutical Press.
pp 389395.
2. Steckel H, Markefka P, teWierik H, Kammelar R.
2004. Functionality testing of inhalation grade
lactose. Eur J Pharm Biopharm 57:495505.
3. Bell JH, Hartley PS, Cox JS. 1971. Dry powder
aerosols. I. A new powder inhalation device.
J Pharm Sci 60:15591564.
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