Drug Metabolism and Pharmacokinetics 32 (2017) 273e276

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Drug Metabolism and Pharmacokinetics

journal homepage: http://www.journals.elsevier.com/drug-metabolism-and-
pharmacokinetics

Note

Avoidance of food effect on oral absorption profile of itraconazole by

self-micellizing solid dispersion approach
Yoshiki Kojo, Kanako Kobayashi, Saori Matsunaga, Hiroki Suzuki, Yoshiki Seto,
Hideyuki Sato, Satomi Onoue*
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-
8526, Japan

a r t i c l e i n f o a b s t r a c t

Article history: The present study was aimed to avoid pharmacokinetic transitions of itraconazole (ITZ) evoked by high-
Received 3 February 2017 fat meal intake by employing a self-micellizing solid dispersion (SMSD) approach. The dissolution
Received in revised form behavior of SMSD/ITZ was assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). To
29 May 2017
evaluate the food effect on the oral absorption profile of ITZ, a pharmacokinetic study was conducted on
Accepted 6 June 2017
orally-dosed ITZ samples in fasted and high-fat meal-fed rats. Crystalline ITZ showed a 9.0-fold higher
Available online 15 June 2017
dissolution amount of ITZ in fed-state SGF (FeSSGF) than in fasted-state SGF (FaSSGF), whereas there was
no significant difference in the dissolution amount of ITZ in SMSD/ITZ between FeSSGF and FaSSGF. In
Keywords:
Biorelevant media
fed- and fasted-state SIF, SMSD/ITZ exhibited reduced variation of ITZ dissolution, possibly leading to
Dissolution suppression of the food effect on the dissolution behavior of ITZ. After the oral administration of crys-
Food effect talline ITZ to high-fat meal-fed rats, the oral bioavailability of ITZ was 14-fold higher than that in fasted
Itraconazole rats. In contrast, orally-dosed SMSD/ITZ in fed rats exhibited limited transition of pharmacokinetic
Oral bioavailability behavior regardless of food intake due to the improvement in the dissolution behavior of ITZ even under
Self-micellizing solid dispersion fasted conditions. SMSD technology could be an efficacious dosage option for the consistent oral ab-
sorption and clinical outcomes of ITZ.
© 2017, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.

1. Introduction
Hydrophobic drugs are basically lipophilic, so oils in the food
and secreted bile acids induced by food intake can contribute to the
solubilization of these drugs [1], leading to positive food effect on
oral absorption of the drugs. Oral administration of lipophilic drugs
with low water solubility and high membrane permeability,
namely drugs classified into biopharmaceutical classification sys-
tem (BCS) class II, can demonstrate inconsistent oral bioavailability
(BA) due to their variable dissolution behaviors and consequent
absorption profiles depending on the gastrointestinal (GI) condi-
tions [2]. Inconsistent oral BA that departs from the therapeutic
window of the drug may evoke undesirable side effects and
reduced efficacy, and limitations on co-administration of drugs
with food might lower patient compliance. Thus, solubility
enhancement without dependence on the conditions in the GI tract
is a promising strategy to achieve consistent pharmacokinetic
behavior after oral administration of lipophilic drugs.
Improvement of oral BA under fasted condition could be a key
factor to avoid the variation in oral BA of drugs between fasted and
fed conditions [3]. Recently, self-micellizing solid dispersion
(SMSD) technology was developed as a new solubilization tech-
nology [4]. It can be defined as a solid dispersion system with use of
amphiphilic polymer as a carrier. The SMSD system could achieve

Abbreviations: AUC0e2, area under the curve of dissolved itraconazole vs. time from 0 to 2 h; AUC0e∞, area under the curve of blood concentration vs. time from 0 h to
infinity; BA, bioavailability; BCS, biopharmaceutical classification system; DMSO, dimethyl sulfoxide; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state
simulated intestinal fluid; FeSSGF, fed-state simulated gastric fluid; FeSSIF, fed-state simulated intestinal fluid; GI, gastrointestinal; IS, internal standard; ITZ, itraconazole; PK,
pharmacokinetic; SD, solid dispersion; SGF, simulated gastric fluid; SIF, simulated intestinal fluid; SMSD, self-micellizing solid dispersion; SMSD/ITZ, self-micellizing solid
dispersion of itraconazole; TEM, transmission electron microscopy; Tmax, time to maximum concentration; UPLC/ESI-MS, ultra-performance liquid chromatography equipped
with electrospray ionization mass spectrometry.
* Corresponding author.
E-mail address: onoue@u-shizuoka-ken.ac.jp (S. Onoue).

http://dx.doi.org/10.1016/j.dmpk.2017.06.001
1347-4367/© 2017, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
274 Y. Kojo et al. / Drug Metabolism and Pharmacokinetics 32 (2017) 273e276
high solubilizing potential for poorly water-soluble compounds
because of its self-micellization property by amphiphilic polymer
with encapsulation of a lipophilic drug through hydrophobic
interaction when it is introduced into aqueous medium. It has been
reported that the application of SMSD system to BCS class II drugs
including cyclosporine A [5], itraconazole (ITZ) [6], and tranilast [4]
can significantly improve the oral BA of these drugs, possibly due to
the enhanced dissolution of the SMSD system. In a previous report
[6], ITZ-loaded SMSD (SMSD/ITZ) employing Soluplus® showed
improved dissolution behavior in acidic (pH1.2) and neutral con-
ditions (pH6.8) compared with crystalline ITZ, in spite of the low
solubility of ITZ especially in neutral conditions, resulting in stable
oral absorption of ITZ even under hypochlorhydric conditions.
Although Soluplus®-based SMSD/ITZ could have the potential to
provide stable dissolution and consistent oral absorption of ITZ
even under the variable conditions of GI tract owing to the non-
ionic property and high solubilization effect of Soluplus®, far less
is known about the feasibility and applicability of the SMSD system
to avoid the pharmacokinetic transitions of poorly water-soluble
drugs evoked by variable conditions in GI tract, especially food
intake. These findings prompted us to apply the Soluplus®-based
SMSD system to suppress severe pharmacokinetic transitions
caused by the food effect.
The aim of present study was to evaluate the possible reduction
of positive food effect on oral BA of lipophilic drugs by using SMSD
technology. ITZ was selected as a model drug of BCS class II com-
pound, and SMSD/ITZ with use of Soluplus® was prepared by the
solvent evaporation method as previously reported [6]. The disso-
lution behavior was evaluated using biorelevant medium, including
fasted-state simulated gastric fluid (FaSSGF), fasted-state simulated
intestinal fluid (FaSSIF), fed-state simulated gastric fluid (FeSSGF),
and fed-state simulated intestinal fluid (FeSSIF), prepared in
accordance with a previous report [7]. Pharmacokinetic behavior
after oral administration of ITZ samples in fasted and high-fat meal-
fed rats was evaluated to estimate the food effect on oral BA of ITZ.
2. Materials and methods
2.1. Materials
Crystalline ITZ was obtained from Kaken Pharmaceutical Co.,Ltd
(Tokyo, Japan). Soluplus® was supplied from BASF Japan Co.,Ltd
(Tokyo, Japan). 1,4-dioxan was purchased from Wako Pure Chemical
Industries (Osaka, Japan).
2.2. SMSD formulation of ITZ
2.2.1. Preparation
Solvent evaporation method was used for preparation of SMSD/
ITZ in accordance with previous report [6]. Briefly, crystalline ITZ
and Soluplus® were weighed to 45 mg and 255 mg, respectively,
and co-dissolved in 1,4-dioxane. The solution was mixed well and
frozen at 80  C using a Lyostar II®freeze-dryer (SP Industries Inc.,
Warminster, PA, USA).
2.2.2. UPLC/ESI-MS analysis of ITZ
The quantitative analysis of ITZ in the SMSD/ITZ and plasma
samples was operated in accordance previous reports [6] with use
of Waters Acquity UPLC/ESI-MS system (Waters, Milford, MA).
2.3. Transmittance electron microscopy (TEM)
Water suspended SMSD/ITZ was placed on 200 mesh nickel grid
with formvar/carbon-coating. The SMSD/ITZ were visualized by
negative staining with 1% (w/v) molybdenum solution and
observed under an H-7600 transmission electron microscope
(Hitachi, Tokyo, Japan).
2.4. Dissolution test of ITZ formulation
Dissolution testing on ITZ samples was carried out for 120 min
in 50 mL of each dissolution medium with constant stirring of
50 rpm by stirrer at 37  C. Each powder sample (1.0 mg-ITZ) was
weighed in the dissolution medium (theoretical concentration of
ITZ: 20 mg/mL). Samples (0.2 mL) were collected and super-
centrifuged with 10,000 rpm for 10 min. Supernatant of sample was
diluted with methanol. The concentrations of ITZ were determined
by Waters UPLC/ESI-MS system.
2.5. Pharmacokinetic studies
2.5.1. Animals
300 ± 50 g of male SpragueeDawley rats for 8e9 old (Japan SLC,
Shizuoka, Japan), were housed by two rats in cage in the laboratory
with temperature (24 ± 1  C) and humidity (55 ± 5%). All animal
experiment conducted for in the present study followed the
guidelines approved by the Institutional Animal Care and Ethical
Committee of the University of Shizuoka.
2.5.2. Food conditions
The rats under fasted- and high fat meal fed-condition were
used to evaluate the effect of food intake on pharmacokinetic
behavior of ITZ after oral administration. Under fasting condition,
rats were not given food from 12 h before administration of ITZ
formulation. Under fed condition, rats were not given food from
24 h before administration of ITZ formulations and then high fat
meal was administered to rats 12 h before administration of ITZ
formulations. High fat meal was composed of normal food for rats
and lard, in which total fat amount were 50% of total caloric con-
tents of meal.
2.5.3. Pharmacokinetic study
After oral administration of crystalline ITZ (30 mg/kg) or SMSD/
ITZ (10 mg-ITZ/kg) suspended in 1 mL of 0.5% methylcellulose so-
lution, plasma concentration of ITZ was assayed in accordance with
reported method [6]. The calculation of pharmacokinetic parame-
ters for ITZ samples were carried out by noncompartmental anal-
ysis with WinNonlin® program (Ver. 4.1, Pharsight Corporation,
Mountain View, CA).
3. Results and discussion
The dissolution test in each biorelevant medium was carried out
to estimate the food effect on the dissolution behavior of ITZ under
fasted and fed conditions. The dissolved concentration of ITZ
reached a plateau below 200 ng/mL in the dissolution test of
crystalline ITZ in FaSSGF (Fig. 1A-I) and FaSSIF (Fig. 1B-I). The dis-
solved amount of crystalline ITZ increased in FeSSGF (Fig. 1A-II) and
FeSSIF (Fig. 1B-II), compared to that in each fasted-state simulated
fluid, due to the encapsulation of ITZ into emulsions composed of
oil and taurocholic acid in the biorelevant mediums. The increase of
AUC0e2 in FeSSGF to that in FaSSGF was calculated to be 9.0-fold
(Supplementary Table 1). Between FeSSIF and FaSSIF, the increase
of AUC0e2 value was 3.3-fold. These results could partly explain the
mechanism of variable oral absorption of ITZ between fasted and
fed condition. In contrast, SMSD/ITZ showed improved dissolution
behavior compared with crystalline ITZ in all tested mediums,
especially under fasted conditions. In the results from dissolution
testing of SMSD/ITZ, the variations of AUC0e2 value in both SGF and
SIF were suppressed as evidenced by 1.1- and 1.6-fold increase,
 Y. Kojo et al. / Drug Metabolism and Pharmacokinetics 32 (2017) 273e276
Fig. 1. Dissolution behavior of ITZ samples in biorelevant medium. (A) Dissolution profiles of ITZ samples in (A-I) FaSSGF (pH1.6), (A-II) FeSSGF (pH5.0), (B-I) FaSSIF (pH6.5), and (B-
II) FeSSIF (pH6.5). ;, crystalline ITZ and △, SMSD/ITZ. Data represent mean ± SE of 3 experiments.
respectively, possibly leading to the consistent oral absorption of
ITZ with limited effects of food intake. Soluplus® is a graft copol-
ymer consisting of polyvinyl caprolactam, polyvinyl acetate, and
polyethylene glycol. The polymer can exhibit an amphipathic
property attributed to its hydrophilic and hydrophobic residues,
which could contribute to the formation of micelles in water [8],
possibly resulting in significantly improved dissolution properties
of poorly water-soluble compounds [9]. TEM imaging revealed that
SMSD/ITZ formed uniform micelles in touch with water (Fig. S1).
The diameter of each micelle formed by SMSD/ITZ seemed to be
below 150 nm, which was consistent with the reported particle size
of 127 nm measured by dynamic light scattering [6]. The enhanced
dissolution behavior of ITZ in SMSD/ITZ could be attributable to the
micellization potency of Soluplus®. Improving the dissolution
behavior of a hydrophilic drug in the stomach could increase the
absorbable fraction of the drug in the small intestine. SMSD/ITZ
with improved dissolution in acidic condition would lead to
improved oral BA even in the fasted condition, resulting in the
avoidance of pharmacokinetic transition caused by the food effects.
To confirm the hypothesis about the avoidance of the food effect
by the application of SMSD system to ITZ, a pharmacokinetic study
of ITZ samples in rats under fasted and high-fat meal-fed conditions
was conducted. Based on the results of the pharmacokinetic study,
oral absorption profiles of crystalline ITZ were significantly influ-
enced by food intake (Fig. 2). The Cmax values of crystalline ITZ in
fasted and fed conditions increased from 9.8 to 149.4 ng/mL,
respectively (Supplementary Table 2). The AUC0e∞ of crystalline ITZ
in the fasted condition was 88.8 ng h/mL, and increased 13.0-fold
under the fed condition. In the dissolution study of crystalline
ITZ, the AUC0e2 ratio of dissolution amount between fasted- and
fed-state simulated fluids was obviously larger in gastric simulated
275
fluid than that in small intestinal simulated fluid. These results
could suggest that the variable oral absorption of crystalline ITZ
was mainly caused by the variation of amount dissolved in the
stomach. In contrast, there was no significant difference in phar-
macokinetic profiles between fasted and fed conditions in the
SMSD/ITZ administrated group, due to the marked improvement of
oral absorption character in the fasted condition as evidenced by
the AUC0e∞ value of 837.0 ng h/mL. The increase of BA value be-
tween fasted and fed conditions was reduced from 13.0-fold for
crystalline ITZ to 1.1-fold with SMSD/ITZ, and the increase of Cmax
was also decreased from 15.2-fold to 1.1-fold, indicating a limited
food effect on the pharmacokinetic transition of ITZ. Food intake
and its components change various physiological conditions of the
GI tract, including the GI tract motility, secretion of digestive fluids,
and pH condition, which can affect the pharmacokinetic behavior
of lipophilic drugs. Previously, there was little variability in the oral
absorption profile of SMSD/ITZ between normal and hypochlo-
rhydric model rats, indicating that the SMSD system inhibited the
transition of dissolution behavior caused by pH changes [6]. In the
dissolution test, the AUC0e2 value of SMSD/ITZ in fasted-state
simulated gastric fluids was almost the same on that in fed-state
simulated gastric fluids, indicating that the dissolution behavior
of SMSD/ITZ is not strongly affected by the components of GI fluids.
For clinical use, the commercial oral solution of ITZ (Sporanox®,
Janssen Pharmaceutica) solubilized by 2-hudroxypropyl-b-cyclo-
dextrin shows higher oral bioavailability with reduced food effect
than crystalline ITZ. However, the excipients for solubilization of
ITZ such as cyclodextrins and surfactants could have the toxic po-
tential to induce tissue irritations and cytotoxicities in GI tract after
oral administration [10], and the photosatability of ITZ under liquid
state can be a problem as reported previously [6]. Considering these
276 Y. Kojo et al. / Drug Metabolism and Pharmacokinetics 32 (2017) 273e276
Fig. 2. Plasma concentration-time profile of ITZ after oral administration of ITZ sam-
ples in rats under (A) fasted condition and (B) fed condition with high-fat meal. ;,
crystalline ITZ (30 mg/kg, p.o.) and △, SMSD/ITZ (10 mg-ITZ/kg, p.o.). Data represent
mean ± SE of 6 experiments.
points, the application of Soluplus® to SMSD system can achieve the
stable solubilization and consistent absorption profile of ITZ with
low toxicity even under variable condition in GI tract.
In conclusion, SMSD/ITZ exhibited improved dissolution
behavior of ITZ, especially in FaSSGF. Although the oral BA of
crystalline ITZ was strongly influenced by food condition, SMSD/ITZ
showed reduced a food effect on oral BA, possibly due to the
improvement of dissolution behavior in the GI tract by the micel-
lization. From these results, SMSD technology could be a promising
strategy for better medication of ITZ with consistent oral BA,
regardless of food intake.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Young
Scientists (B) (No. 15K18928; Y. Seto and 16K18950; H. Sato) from
the Ministry of Education, Culture, Sports, Science and Technology
of Japan, and a grant from the Takeda Science Foundation.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.dmpk.2017.06.001.
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