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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 µm as indicated by the scale bar.

the sample well below 20 µm as indicated by the scale bar. Figure 1: Budesonide E

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 µm and no spherical morphology.

density distribution q3lg(x)

frequency q3*(x)

density distribution q3lg(x) frequency q3*(x) Figure 2: Budesonide particles E d i s p T M

Figure

2:

Budesonide

particles

E disp TM

microsuspension

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 µm with 90% of the whole distribution (X 90 ) being below 3.57 µm and generated by an initial dry powder having a VMD of 3.33 µm and X 90 of 5.93 µm .

Differently, the transmittance profiles collected during the sedimentation test of the E disp TM microsuspension showed very limited sedimentation effect typical of an extremely stable microsuspension.

effect typical of an extremely stable microsuspension. Figure profile 5: E d i s p T

Figure

profile

5:

E disp TM

microsuspension

sedimentation

In vitro respirability tests performed on the Budesonide 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 microsuspension and Mass Median Aerodynamic

TM

Diameters (MMAD) of 7.3µm±1.4 for Pulmaxan and
1.8

1.8 x(10 %) x(50 %) x(90 %) VM D 1.6 µm µm µm µm 0,88
1.8
x(10 %)
x(50 %)
x(90 %)
VM
D
1.6
µm
µm
µm
µm
0,88
2,89
5,93
3,33
0,59
1,42
3,57
1,83
1.4
1.4
1.2
1.2
1.0
1.0
Microsuspension
Dry P owde r
0.8
0.8
0.6
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0.4
0.4
0.2
0.2
0
0
0.0.1010
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5
10
50

1.6 4.1 µm±0.1 for E disp TM microsuspension.

40% PULMAXAN 35% Budesonide Edisp 30% 25% 20% 15% 10% 5% 0% T+R+M Stage 1
40%
PULMAXAN
35%
Budesonide Edisp
30%
25%
20%
15%
10%
5%
0%
T+R+M
Stage 1
Stage 2
Stage 3
Stage 4
Filter
Amount Deposited (%)

Stage #

Figure 6: Budesonide E disp TM formulation and commercial Budesonide formulation MSLI deposition profiles.

C ONCLUSIONS

T he present work indicated that it is possible to 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 EFERENCES

particle size / µm

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.

time corresponding to a rapidly moving sedimentation front. Figure sedimentation profile 4: Micronized Budesonide

Figure

sedimentation profile

4:

Micronized

Budesonide

suspension

1 . VVAA, (2001), “European Respiratory Society Guidelines on the use of nebulizers”, Eur. Respir. J. 2001; 18:228-242