Bioavailability Enhancement of Itraconazole with Solid Solutions

Based on Soluplus
F. Guth1, M. Becker2, R. Buesen2, K. Kolter1
R & D Pharma Ingredients
Toxicology, BASF SE, 67057 Ludwigshafen, Germany | E-mail: karl.kolter@basf.com

Polyethylene glycol-polyvinyl caprolactam-polyvinyl

acetate graft copolymer (Soluplus) based solid solutions increase the solubility and oral bioavailability of
poorly soluble active ingredients.
This study compares the physicochemical properties
and the in-vivo performance of a commercially available itraconazole drug product with a Soluplus
based formulation. The results from a kinetic test in
Beagle dogs showed a more than 20-fold increase in
bioavailability compared to the crystalline substance
and a more than 2-fold increase compared to the
commercial drug product.

Introduction
The bioavailability of BCS II substances which are
poorly soluble but are once dissolved readily absorbed in the human body, can significantly be improved by making a solid solution [1]. Polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate graft copolymer (Soluplus), a polymeric solubilizer with an
amphiphilic structure, has the capability to form solid
solutions with many active ingredients and is very suitable for the use in hot melt extrusion. Earlier studies
with itraconazole demonstrated a 20- to 30-fold increase in the area under the curve (AUC) compared to
crystalline active or physical mixture formulations [2].
It is the aim of this study to compare the performance
of a Soluplus based formulation with a commercially
available and therefore optimized drug product.

Experimental Methods

Dissolution tests were conducted with an USP apparatus #2 (paddle) operating at 50 rpm and using
700 mL hydrochloric acid (0.08 molar), pH 1.1 (simulated gastric fluid) as dissolution medium. Samples
were taken manually through a 0.2 m filter. Since
Soluplus forms large drug loaded micelles [3], a
10 m filter was used for the analysis of these samples. The amount of dissolved itraconazole was immediately measured by UV spectroscopy at 258 nm.
In-vivo characterization
Each of the 5 Beagle dogs received all test formulations in the same order with an interval of 7 days between administrations. The formulations were applied in gelatine capsules (Torpac Inc. US #11)
as mixtures consisting of 70% test formulation,
15% Avicel PH 102 (FMC BioPolymer) and 15 %
Kollidon CL (BASF). The capsules were filled individually for each dog with an itraconazole dose of
10 mg/kg body weight. The animals received the
capsules in a fasted state. Blood samples were taken
at 30, 60, and 90 minutes as well as 2, 4, 8, 24, 48
and 72 hours after administration. Water was offered
ad libitum and food at 2 hours after the administration.
Plasma samples were stored in a freezer and analyzed using (ESI(+)-LC-MS/MS) (column: Phenomenex
Luna C18 (2) 100 x 2 mm i.d., mobile phase: acetonitrile / water (60:40, v/v) containing 0.01 % formic
acid (v/v); limit of quantification (LoQ) was 25 ng/ml).

Results and Discussion

Itraconazole with a mean particle size of 2.5 m was

obtained from Selectchemie.
Itraconazole Soluplus extrudate (relation 20:80)
was prepared by melt extrusion in a 16 mm twin
screw extruder equipped with a 3 mm die (Polylab,
Thermo-Fisher, Germany) at 160 C, 200 rpm and a
feed rate of 1000 g/h. Extrudates were milled to a
size of max 250 m.
Sempera (Jannsen-Cilag): hard gelatine capsules
with 100 mg itraconazole in the form of drug layered
pellets (batch #AIL4A00).
In-vitro characterization
Dynamic scanning calorimetry (DSC): Samples were
dried over night at 100C under vacuum. The analy-

Kinetic screening in Beagle dogs

The test formulations were tolerated well and there
were no clinical findings. The results for the in-vivo
screening in Beagle dogs are summarized as plasma
concentration time profiles of itraconazole (Figure 4).
Some test animals absorbed itraconazole faster and
to a higher extent than others. This inter-individual
difference contributes to the high standard deviation
that was obtained for the mean concentration values
at the respective times. However, despite these dif-

sis was performed in a DSC Q2000 V24.4 Build 116

(TA Instruments) at a heat rate of 20 k/min.

Figure 1a: SEM itraconazole - Soluplus milled extrudate

ferences, the overall ranking of the tested formulations was the same for each dog.
Both formulations achieve a significant increase in
bioavailability compared to crystalline itraconazole.
Results from in-vitro dissolution tests and in-vivo
plasma concentrations after oral administration correlate only partially. The in-vivo performance of the
itraconazole Soluplus extrudate was much better
than expected.

Conclusion
100

Figure 1b: SEM Sempera

drug release [%]

Abstract Summary

6.0

Itraconazole crystalline

90

Itraconazole - Soluplus extrudate

80

Sempera

70
60
50
40
30
20

5.0

10
0

Sempera

4.0

Itraconazole - Soluplus extrudate

30

60

90

120

t [min]

Itraconazol crystalline

3.0

Figure 3: Dissolution from itraconazole formulations in

simulated gastric fluid

2.0
1.0

It is possible to achieve a tremendous increase in oral bioavailability in Beagle dogs

when itraconazole is formulated as solid solution with Soluplus.
The mean plasma concentrations achieved
with Soluplus were approximately twice as
high as those obtained with a commercially
available drug product.
The superior performance can be explained
by the capability of Soluplus to form stable
solid solutions and by the formation of itraconazole loaded micelles upon dissolution.

0.0
1.0
50

50
100
Temperature (C)

150

200

Figure 2: DSC analysis (2K/min)

DSC:
The itraconazole-Soluplus extrudate was amorphous and known to form solid solutions at the given
concentration. Itraconazole in Sempera seemed
mainly amorphous, but an interpretation of the DSC
curves was impossible due to overlaid peaks from
other excipients (Figure 2).
Dissolution
The samples (standardized to a content of 100 mg
itraconazole) were added to the dissolution medium
as powders and in the case of Sempera as pellets,
but all without capsules. Figure 3 shows the dissolution in simulated gastric fluid (SGF). The crystalline
itraconazole has a very poor solubility and dissolves
only slowly. Both formulations, itraconazole in the
form of a solid solution with Soluplus and the commercial Sempera bring significant improvement and
enable supersaturated solutions. The dissolution
profiles are similar.

Table 1: Pharmacokinetic data after oral administration of

itraconazole formulations; AUC = area under the curve

AUC 0-72h
[ng*h/ml]
823

Test substance
Itraconazole crystalline

Itraconazole-Soluplus
extrudate

AUC 0-h
[ng* h/ml]
840

8503

9374

18558

21828

Sempera

1000

ng/mL

Heat - Flow (W/g)

900

Itraconazole crystalline

800

Sempera

700

Itraconazole - Soluplus extrudate

600
500
400
300
200
100

References
[1] M. Repka et al, Applications of Hot-Melt Extrusion for Drug Delivery, Expert Opinion on Drug
Delivery 5, 12 (2008)
[2] D. Djuric et al., An Innovative Amphiphilic Graft
Copolymer for the Formation of Solid Solutions
by Hot Melt Extrusion, AAPS Annual Meeting and
Exposition, Los Angeles CA, USA 2009
[3] H. Hardung et al, Combining HME & Solubilization. Soluplus The Solid Solution, Drug Delivery
Technology 10, 3 (2010)
[4] D. Djuric et al, Characterization of Polymeric Micelles from Solid Solutions with a Polyvinyl Caprolactam - Polyvinyl Acetate - Polyethylene Glycol Graft Copolymer and Itraconazole, 38th
Annual Meeting and Exposition of the Controlled
Release Society (CRS), National Harbor MD, USA
2011

0
0

10

20

30

40
hours

50

60

70

80

Figure 4: Comparison of mean plasma concentration profile

(mean, n=5)

39th CRS Annual Meeting; July 1518, 2012; Qubec City, Canada
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