asian journal of pharmaceutical sciences 11 (2016) 122123

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P-017

Development of nanocrystal formulation of

mebendazole with improved dissolution and
pharmacokinetic behaviors

Naofumi Hashimoto *, Kayo Yuminoki, Haruka Takeuchi, Chiaki Okada

Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan

A R T I C L E I N F O

Article history:
Available online 25 November 2015

Keywords:
Mebendazole
Nanocrystal
Wet beads milling
Oral absorption

Nanosizing by wet beads milling is a method to improve the
solubility of poorly water soluble compounds [1,2]. Mebendazole
(MBZ) is a well-known anthelmintic drug in wide clinical use.
There were some reports that MBZ had the anticancer effect
in preclinical study. However, the bioavailability of MEB is low
(<10%) due to the poor solubility in water (0.5 g/mL). The
present study aimed to develop the nanocrystal formula-
tions of MEB to improve dissolution behavior and enhance oral
absorption.
The MBZ nano-suspension was prepared by milling with zir-
conia beads (milling media) in polymer aqueous solution
(dispersion stabilizer) by the rotation/revolution pulverizer [3].
Then, milled MBZ powder was prepared by freeze-drying the
MEB nano-suspension. Four polymers (polyvinyl alcohol (PVA),
hydroxypropylcellulose-SSL (HPC), methylcellulose (MC), and
copolymer of PVA, acrylic acid and methyl methacrylate (POVA))
were used to evaluate the dispersion stabilities of the MBZ nano-
suspension and the re-dispersion stability of the milled MBZ
powder. Dispersion stability, re-dispersion stability, and crys-
tallinity of the MBZ nano-suspensions and the milled MBZ
powders were evaluated by particle size analyzer and powder
X-ray diffraction (PXRD), respectively. In addition, the disso-
lution behavior and the oral absorption of the milled MBZ
powder were evaluated. The MBZ nano-suspensions with PVA
and HPC had better dispersion stability [the diameters at 90%
of the population distribution (D90) = ca. 0.210 m] than the MBZ
nano-suspensions with MC and POVA (D90 > 1 m). The milled
powder with PVA showed the good re-dispersion stability when
the mass ratio of PVA to MEB was more than three (Fig. 1a).
On the other hand, five of the mass ratio of HPC to MEB was
necessary to re-disperse the milled MBZ powder in water. There-
fore, the milled MBZ powder with PVA (MBZ: PVA = 1:3) was used
to evaluate the crystallinity, the dissolution behavior and the
oral absorption. The PXRD patterns of the milled MBZ were
similar to that of the original MBZ, which showed that the
milled MBZ maintained its crystallinity. In comparison of the

* E-mail address: hashimoto@pharm.setsunan.ac.jp.

Peer review under responsibility of Shenyang Pharmaceutical University.
http://dx.doi.org/10.1016/j.ajps.2015.11.096
1818-0876/ 2016 Production and hosting by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 asian journal of pharmaceutical sciences 11 (2016) 122123 123

Fig. 1 Particles size distribution of the original MBZ (black line) and the milled MBZ with PVA (red line) (a) and plasma
concentrations of MBZ after oral administration of the original MBZ () and the milled MBZ () with PVA to rats (b).

original MBZ with the milled MBZ powder, the dissolution be-
havior of MBZ in aqueous solutions adjusted pH 1.2 and pH
6.8 were improved by milling to nanoparticles. After oral ad-
ministration of the milled MBZ powder (10 mg MBZ/kg) in rats,
the enhanced oral absorption of MBZ was observed with
increases of Cmax and AUC08 by 4- and 3-fold, respectively, com-
pared with those of the original MBZ (Fig. 1b). The nanosizing
approach was effective to enhance the bioavailability of MBZ.
From the improvement of oral absorption, the nano-sized MBZ
could increase the probability of application for the cancer
treatment.
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