Optimization of a novel wax matrix system using aminoalkyl methacrylate copolymer E and ethylcellulose to suppress the bitter taste of acetaminophen.

Abstract

The purpose of the present study was to design and evaluate a novel wax matrix system containing various ratios of aminoalkyl methacrylate copolymer E (AMCE) and ethylcellulose (EC) as functional polymers in order to achieve the optimal acetaminophen (APAP) release rate for taste masking. A two factor, three level (3(2)) full factorial study design was used to optimize the ratios of AMCE and EC, and the release of APAP from the wax matrix was evaluated using a stationary disk in accordance with the paddle method. The disk was prepared by congealing glyceryl monostearate (GM), a wax with a low melting point, with various ratios of polymers and APAP. The criteria for release rate of APAP from the disk at pH 4.0 and pH 6.5 were calculated to be more than 0.5017 microg/(mlxmin) and less than 0.1414 microg/(mlxmin), respectively, under the assumption that the particle size of spherical matrix should be 100 microm. In multiple regression analysis, the release of APAP at pH 4.0 was found to increase markedly as the concentration of AMCE increased, whereas the release of APAP at pH 6.5 decreased as the EC concentration increased, even when a high level of AMCE was incorporated. Using principle component analysis, it was found that the viscosity of the matrix affects the pH-dependent release of APAP at pH 4.0 and pH 6.5. Furthermore, using multiple regression analysis, the optimum ratio of APAP:AMCE:EC:GM was found to be 30:7:10:53, and the release pattern of APAP from the optimum wax formulation nearly complied with the desired criteria. Therefore, the present study demonstrated that the incorporation of AMCE and EC into a wax matrix system enabled the appropriate release of APAP as a means of taste masking.

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Optimization of a novel wax matrix system using aminoalkyl methacrylate
copolymer E and ethylcellulose to suppress the bitter taste of acetaminophen


Kai Shiino1, Yasunori Iwao1, Atsuo Miyagishima, Shigeru Itai*

Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences,
University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

1Both authors contributed equally to this work.


*Address correspondence to: Shigeru Itai, Ph.D.
Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences,
University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Tel.: +81 54 264 5610, Fax: +81 54 264 5615,
E-mail address: s-itai@u-shizuoka-ken.ac.jp

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Abstract
The purpose of the present study was to design and evaluate a novel wax matrix system
containing various ratios of aminoalkyl methacrylate copolymer E (AMCE) and ethylcellulose (EC)
as functional polymers in order to achieve the optimal acetaminophen (APAP) release rate for taste
masking. A two factor, three level (32) full factorial study design was used to optimize the ratios of
AMCE and EC, and the release of APAP from the wax matrix was evaluated using a stationary disk
in accordance with the paddle method. The disk was prepared by congealing glyceryl monostearate
(GM), a wax with a low melting point, with various ratios of polymers and APAP. The criteria for
release rate of APAP from the disk at pH4.0 and pH6.5 was calculated to be more than 0.5017 μg/
(ml∙min) and less than 0.1414 μg/ (ml∙min), respectively, under the assumption that the particle size
of spherical matrix should be 100 μm. In multiple regression analysis, the release of APAP at pH4.0
was found to increase markedly as the concentration of AMCE increased, whereas the release of
APAP at pH6.5 decreased as the EC concentration increased, even when a high level of AMCE was
incorporated. Using principle component analysis, it was found that the viscosity of the matrix
affects the pH-dependent release of APAP at pH4.0 and pH6.5. Furthermore, using multiple
regression analysis, the optimum ratio of APAP: AMCE: EC: GM was found to be 30: 7: 10: 53, and
the release pattern of APAP from the optimum wax formulation nearly complied with the desired
criteria. Therefore, the present study demonstrated that the incorporation of AMCE and EC into a
wax matrix system enabled the appropriate release of APAP as a means of taste masking.

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Keywords: Taste masking; Acetaminophen; Aminoalkyl methacrylate copolymer E; Ethylcellose;
Multiple regression analysis; Principle component analysis


1. Introduction
Drugs with an unacceptably bitter taste are generally difficult for patients to swallow,
resulting in poor compliance and a subsequent reduction in their efficacy. Therefore, taste masking is
used to mask the unpleasant taste of drugs and plays an important role in oral dosage forms,
especially for drugs used by infants or elderly patients (Albertini et al., 2004; Kayumba et al., 2007).
Acetaminophen (APAP), which is often used as an analgesic and antipyretic agent for
infants and children, has a bitter taste (Hansen et al., 1999; Suzuki et al., 2004; Zheng and Keeney,
2006). Numerous studies on masking the bitter taste of APAP have been conducted, and coating
techniques using polymers were found to be useful (Pearnchob et al., 2003; Yoshida et al., 2009).
However, a crucial disadvantage of these coating techniques is that organic solvents are often used to
dissolve the polymers. Consequently, the potential toxicity of residual solvents in the body, the
environmental pollution caused by liquid waste, and the high manufacturing costs are matters of
concern. Recently, aqueous-based coating systems, in which the polymers are dispersed in aqueous
rather than organic solvents, have been developed. However, removing the aqueous solvent during

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the drying process takes a long time due to the low volatility of the solvents used (Cerea et al., 2004).
In the present study, we examined a wax matrix system containing functional polymers as a
means of suppressing the bitter taste of APAP. One of the advantages of this system is that none of
the above mentioned solvents or drying processes are required because it uses a wax with a low
melting point that quickly congeals at ambient temperatures. In addition, as the solvent is not
removed, this method produces a dense film without the empty spaces caused by other systems.
Furthermore, since this system is cost-effective and easy to industrialize, we consider it to be more
effective than coating technologies. Previously, Yajima et al. reported a wax matrix formula in which
glyceryl monostearate (GM) was included as a wax with a low melting point and aminoalkyl
methacrylate copolymer E (AMCE) was included as a functional polymer, in order to mask the bitter
taste of clarithromycin (CAM) (Yajima et al., 1996). AMCE is a cationic copolymer based on
demethylaminoethyl methacrylate and neutral methacrylic esters and dissolves at < pH5 (Xu et al.,
2008). Due to the pH-dependent properties of AMCE, the wax matrix containing CAM remained
intact in the buccal cavity; i.e., at pH6.5 for taste masking, and then the CAM was dissolved quickly
from the wax matrix in the stomach; i.e., at pH4.0, without lowering its bioavailability.
However, it is well known that the solubility of CAM differs under different pH conditions;
namely, the solubility of CAM is quite high at pH 2.4 (10 mg/ ml) or at pH 5.4 (5.5 mg/ ml), whereas
it is about negligible at pH 7.4 (Nakagawa et al., 1992; Salem and Duzgunes, 2003; Sharma, 2003).
Therefore, the success described by Yajima et al. can probably be attributed to not only the effects of

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AMCE but also the pH-dependent solubility of CAM. In contrast, the solubility of APAP is about 20
mg/ ml, which is much larger than that of CAM, and its solubility is not affected uniformly by all pH,
suggesting that the incorporation of AMCE alone would not control the release of APAP as desired.
Therefore, we next focused on ethylcellulose (EC) as a means of controlling the release of APAP
from the wax matrix. EC polymers are widely known to be pH independent and water-insoluble
materials. Recent evidence has suggested that the combination of EC and methacrylic polymers at
different ratios is able to control drug release (Sanchez-Lafuente et al., 2002; Huang et al., 2006;
Feng et al., 2008). Based on these reports, the authors speculated that the incorporation of EC into a
wax matrix containing AMCE would control the release of APAP as desired, but little information is
available regarding wax matrices composed of a combination of EC and AMCE.
The purpose of the present study was to design and evaluate a novel wax matrix containing
APAP, AMCE, and EC at different ratios as a means of masking the bitter taste of APAP, and our goal
was to optimize the ratio of AMCE and EC to ensure the appropriate release of APAP.


2. Material and methods
2.1. Materials
Acetaminophen (APAP) was kindly provided by Iwaki Pharmaceutical Co. Ltd. (Shizuoka,
Japan), aminoalkyl methacrylate copolymer E (AMCE; Eudragit® EPO) was from Röhm Degussa