SELF-ASSEMBLED CORTICOSTEROID MICROPARTICLES

FOR INHALATION DELIVERY

Giovanni Caponetti, Loretta Maggi, Laura Zanellotti, Cristina Veneziani, Paolo Corvi Mora
Eratech S.r.l., Piacenza, ITALY
E-mail: g.caponetti@eratech.it

Keywords: INHALATION, MICROSUSPENSIONS, CORTICOSTEROIDS, SPRAY DRYING


INTRODUCTION

The administration of drugs via inhalation using
nebulizers represents a common practice in respiratory
therapy.
Despite their limited portability and noisiness,
nebulizers have always been the easiest inhalation
devices to use. As a matter of fact great development
efforts are still undergoing for new ones as companies
try to further improve disease management and
compliance.
Unfortunately, the potential innovations to be
introduced in therapy by new inhalation devices are not
supported by comparable formulation advancements as
the administration of water insoluble drugs is very poor
with conventional inhalatory suspensions.
The formulation issues arising from insoluble active
materials relate to the reproducible manufacturing of a
suspension containing micronized drug particles whose
tendency to aggregate over time dramatically limits
their physical stability and reproducible dosing.
In order to offer a formulative advancement to the
common practice, the aim of this work was to prepare
and characterize a dry powder formulation containing
water insoluble corticosteroids that could be prepared
using a relatively easy method and was capable to
generate, upon extemporaneous dispersion in a small
volume of water, a stable inhalable microsuspension in
which the dispersed drug particles have optimal
particle size and improved administrable dosage.
The microsuspension obtained had also to be
characterized by a particle size distribution lower than
the one achievable by conventional preparative
techniques with consistent preparation reproducibility
due to the storage as a dry powder until its use.
Respirability had also to be improved over current
inhalation products.
The technology that was developed under this concept
had been called E
disp
TM
.

EXPERIMENTAL METHODS

Dry powder microparticles containing budesonide
(presented in this paper as drug model) were prepared
by spray drying a 5% w/v solution of
Budesonide/Lactose/Tween80 (1/97/2) in a
water/ethanol mixture (70/30) using a LabPlant SD06
spray dryer.
Dry powder was collected and sized using a Sympatec
Helos particle size analyser utilizing a Rodos
dispersing unit.
Extemporaneous microsuspensions were prepared
dispersing a sufficient amount of dry powder in 2 ml of
distilled water in order to achieve a budesonide
concentration of 0.5 mg/ml as in similar commercial
inhalation drug products. The microsuspension was
tested for particle size using a Sympatec Helos particle
size analyser equipped with a Sucell dispersing unit for
liquid samples and a Small Volume Adaptor (SVA).
Sedimentation profiles were tested using a LUM
GmbH Lumifuge centrifuge working at 300 rpm
measuring the transmittance variations of opaque
suspensions under centrifugation against time.
In vitro respiratory properties were tested using a Multi
Stage Liquid Impinger (MSLI) working at 30 litres per
minute for 5 minutes and using a Medel Clenny
nebulizer loaded with 2ml of E
disp
TM
microsuspension
and comparing it with a commercial Pulmaxan 500
budesonide drug product.

RESULTS AND DISCUSSION

Scanning electron microscopy performed on dry
powder microparticles demonstrated a spherical
morphology with visible particle size of the sample
well below 20 m as indicated by the scale bar.


Figure 1: Budesonide E
disp
TM
dry powder

Upon dispersion in distilled water, the powder
underwent rapid dissolution of the formulation soluble
portion leading to a self-assemblying of budesonide
and the formation of very small micro- and
nanoparticles as demonstrated by Figure 2. In this
figure, a SEM picture of a filtered microsuspension
shows a large number of budesonide micro- and
nanoparticles with particle size below 2 m and no
spherical morphology.


Figure 2: Budesonide E
disp
TM
microsuspension
particles

Particle size distribution tests performed on the dry
powder and the liquid suspension presented in Figure 3
confirmed the size reduction effect observed by SEM
upon dispersion of the dry powder in the liquid
medium. The microsuspension obtained showed a
Volume Mean Diameter (VMD) of 1.83 m with 90%
of the whole distribution (X
90
) being below 3.57 m
and generated by an initial dry powder having a VMD
of 3.33 m and X
90
of 5.93 m .
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
f
r
e
q
u
e
n
c
y

q
3
*
(
x
)
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
d
e
n
s
i
t
y

d
i
s
tr
i
b
u
t
i
o
n
q
3
l
g
(x
)
0.10 0.10 0.5 1 5 10 50
parti cl e size / m
Dr y Powder Mi crosuspensi on
x(10 %)
m
x(50 %)
m
x(90 %)
m
VMD
m
0,88 2,89 5,93 3,33
0,59 1,42 3,57 1,83

Figure 3: Budesonide E
disp
TM
formulation size
distributions of initial dry powder and final
microsuspended drug particles.

The characterization of the sedimentation profiles
performed on micronized budesonide dispersed in a
small volume of water showed a marked sedimentation
effect represented in Figure 4 as a sequence of profiles
with steep transmittance changes over time
corresponding to a rapidly moving sedimentation front.


Figure 4: Micronized Budesonide suspension
sedimentation profile

Differently, the transmittance profiles collected during
vitro respirability tests performed on the Budesonide
the sedimentation test of the E
disp
TM
microsuspension
showed very limited sedimentation effect typical of an
extremely stable microsuspension.

Figure 5: E
disp
TM
microsuspension sedimentation
profile

In
E
disp
TM
microsuspension in comparison with Pulmaxan
500, a commercially avaliable budesonide product,
demonstrated an increased potential lung deposition
profile with Fine Particle Fractions that were
27.3%5.5 for Pulmaxan and 52.4%0.6 for E
disp
TM

microsuspension and Mass Median Aerodynamic
Diameters (MMAD) of 7.3m1.4 for Pulmaxan and
4.1 m0.1 for E
disp
TM
microsuspension.
0%
5%
10%
15%
20%
25%
30%
35%
40%
T+R+M Stage 1 Stage 2 Stage 3 Stage 4 Filter
Stage #
A
m
o
u
n
t

D
e
p
o
s
i
t
e
d

(
%
)
PULMAXAN
Budesonide Edisp

Figure 6: Budesonide E
disp
TM
formulation and
ONCLUSIONS
he present work indicated that it is possible to
EFERENCES
. VVAA, (2001), European Respiratory Society
Guidelines on the use of nebulizers, Eur.
Respir. J . 2001; 18:228-242

commercial Budesonide formulation MSLI deposition
profiles.

C

T
produce very stable microsuspensions generated by
self-assemblying effect of insoluble drug molecules
when dispersed in water with the aid of a formulation
that allows for the control of this assemblying effect.
The microsuspensions obtained are characterized by
improved particle size distribution and physical
stability over conventional inhalatory suspensions
consequently increasing also their aerosol performance.

R

1