Journal of Controlled Release 110 (2006) 581 586

www.elsevier.com/locate/jconrel

Preparation of amoxicillin intragastric buoyant sustained-release

tablets and the dissolution characteristics
Tadakazu Tokumura *, Yoshiharu Machida
Department of Drug Delivery Research, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
Received 6 September 2004; accepted 24 October 2005
Available online 27 December 2005

Abstract
An intragastric buoyant sustained-release tablet (IGB-T) containing 100 mg of amoxicillin (AMX) was prepared to eradicate gastric
Helicobacter pylori. A tablet prepared by compressing the mixture of hydroxypropylcellulose-H (HPC-H), citric acid (17.2 mg), sodium hydrogen
carbonate (22.8 mg) and AMX was employed as the basic system for preparing IGB-T. The weight and diameter of the tablets were designed to be
about 300 mg and 10 mm, respectively. IGB-T containing 5 mg of AMX and HPC-H (255 mg) was buoyant and showed a sustained-release
pattern in water. However, when AMX was increased and HPC-H decreased to maintain the tablet weight (300 mg), there was no apparent
sustained-release pattern. To prepare IGB-T containing 50 mg of AMX, the surface of the tablet was coated with HPC-H after a tablet was
prepared from the mixture of AMX (50 mg), HPC-H (210 mg), citric acid (17.2 mg), and sodium hydrogen carbonate (22.8 mg). This tablet (IGBT50-Coating) was buoyant and showed a sustained-release pattern in water. However, to complete IGB-T with 100 mg of AMX, it was necessary
not only to coat the surface of the tablet but also to use granulated AMX with a particle size of 300 500 Am (IGB-T100-Coating-300-500G). IGBT100-Coating-300-500G was confirmed to be buoyant for 24 h while maintaining a tablet shape and showed a sustained-release pattern in water
and buffer solutions of pH 1.2 and 6.8.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Intragastric buoyant sustained-release tablets; Amoxicillin; Hydroxypropylcellulose-H; Coating; Granulation; Dissolution

1. Introduction
Gastric Helicobacter pylori infection is associated with
chronic (type B) gastritis and peptic ulcer [13]. H. pylori are
often observed to adhere to the anteral epithelium of the human
stomach and gastric metaplasi in the duodenum. Gastric and
duodenal ulcers are believed to develop as the result of damage to
the gastric mucosa by cytotoxic substances (ammonia, cytotoxin,
etc.) produced by H. pylori [4]. In developed countries, at least
20% of people younger than 20 years old and 50% of those older
than 60 years old are infected [5]. In developing countries, the
rate of infection is much higher, with a prevalence of 85% in
northern Nigeria and 7179% in other African countries [6].
H. pylori are highly sensitive in vitro to most antibiotics, of
which the minimal inhibitory concentrations for 90% of strains
(MIC90, Ag/ml) are as follows: penicillin 0.03, ampicillin 0.06,
tetracycline 0.12, erythromycin 0.06, cephalexin 2, metronida* Corresponding author. Tel./fax: +81 3 5498 5760.
E-mail address: tokumura@pep.ne.jp (T. Tokumura).
0168-3659/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2005.10.032

zole 2, bismuth subcitrate 16 [7] and amoxicillin 0.06 [8].

However, the eradication of H. pylori from patients is difficult
even with the best current therapies (multidrug strategies),
because many patients suffer from adverse side effects from the
medication [4]. In Japan, amoxicillin, clarithromycin, and
lansoprazole are used for the eradication of H. pylori (triple
therapy) as conventional tablets or capsules. These conventional
preparations do not remain in the stomach long, and therefore
high doses of antibiotics must be administered to patients. These
high doses are considered to bring about adverse effects. To
solve this problem, a novel drug delivery system that localizes
the antibiotics at the site of infection to achieve bactericidal
concentrations would be desirable. When a novel drug delivery
system is achieved, the doses of the antibiotics can be reduced.
As a result, the frequency of adverse effects will decrease.
We have been studying intragastric buoyant preparations to
develop a drug delivery system for the stomach, and/or to
prolong the retention time of various dosages through the
gastro-intestinal tract [9 11]. These preparations were considered useful for the development of a dosage to eradicate H.

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T. Tokumura, Y. Machida / Journal of Controlled Release 110 (2006) 581 586

2. Materials and methods

(HPC-H), citric acid (anhydride), and sodium bicarbonate were

mixed well and directly compressed under 120 kg/cm2 for 30 s
using a Shimadzu hydraulic press. The formula of IGB-Ts is
shown in Table 1. Each component without AMX was dried in a
desiccator with silica gel before use for IGB-T preparation. The
IGB-Ts prepared were stored in the desiccator. In the case of IGBT100-Coating-300-500G, AMX and HPC-L were mixed and the
mixture was granulated by adding ethanol. The granules were
dried for 30 min at 60 -C, and sieved. The diameter of the
granules used was in the range of 300500 Am. The granules,
HPC-H, citric acid, and sodium bicarbonate were mixed, and
then 305 mg of the mixture was compressed to prepare a tablet
(IGB-T100-300-500G). A 2% HPC-H solution in ethanol was
used for the coating for IGB-T50, IGB-T100, and IGB-T100300-500G. A needle was stuck into a tablet. The tablet with the
needle was put into the 2% HPC-H solution by holding the
needle, and then dried at room temperature. After 2 or 3 times
repetition of the procedure, the needle was put off from the tablet.
The hole of the surface of the tablet was covered with the 2%
HPC-H solution. The coated tablets were dried for 24 h or more at
room temperature before use. IGB-T50, IGB-T100, and IGBT100-300-500G coated by HPC-H showed as IGB-T50-Coating,
IGB-T100-Coating, and IGB-T100-Coating-300-500G, respectively. The weight, thickness, diameter, and the weight of coating
layer for the tablets prepared are shown in Table 2.

2.1. Materials

2.3. Dissolution test

Amoxycillin was purchased from Sigma Chemical Company (St. Louis, MO, USA). Hydroxypropylcellulose-H and -L
(HPC-H and HPC-L) were supplied by Nippon Soda Co., Ltd.
(Tokyo, Japan). Citric acid (anhydrous), sodium hydrogen
carbonate, and ethanol were of special reagent grade from
Wako Pure Chemical Industries, Ltd. (Osaka, Japan). HPLC
grade acetonitrile was purchased from Wako Pure Chemical
Industries, Ltd. (Osaka, Japan). Other reagents used were of
special reagent grade. HPC-H was selected as the hydrogel
base of IGB-Ts because HPC-H had no acidic and basic
functional group in the chemical structure and formation of
hydrogel is independent of the pH values in the solutions.

Release characteristics of the tablets were evaluated using

Japanese Pharmacopoeia (JP) XIV apparatus, and the paddle
method of JP XIV at 100 rpm of paddle speed. The media used
were 900 ml of water, and the first and the second fluids of JP
XIV (pH 1.2 and 6.8), which were maintained at 37.0 T 0.5 -C.
The first fluid (pH 1.2) has 2.0 g of NaCl and 7 ml of HCl in
1000 ml. The second fluid (pH6.8) has 250 ml of 0.2M KH2SO4
and 118 ml of 0.2M NaOH in 1000 ml. Six milliliters of sample
solution was taken at appropriate time intervals and assayed by
HPLC. Fresh medium was added to replace the sample taken.

2.2. Preparation of tablets

The HPLC system consisted of a Shimadzu model LC-9A

pump, SIL-6B auto-injector, SPD-6A UV photometrical
detector, and CTO-6B column oven equipped with a
Shimadzu model SCL-6B system controller and C-R4A

pylori. Therefore, we studied an intragastric buoyant sustainedrelease tablet containing AMX. AMX was selected because (1)
AMX is usually used for the eradication of H. pylori as a
component of triple therapy in Japan, (2) AMX has strong
activity for H. pylori, (3) the oral bioavailability of AMX is
poor, and unabsorbed AMX affects intestinal bacteria, which is
considered to be one reason for the side effects.
To achieve the eradication therapies, a desired AMX
preparation must have three characteristics; (1) the ability of
raising concentration of AMX in stomach filled with meal above
MIC as soon as possible, (2) showing the prolonged retention
time in the stomach, (3) a sustained-release property to maintain
the drug concentration in the stomach. The commercially
available preparations of AMX have only the first characteristics.
Therefore, we have tried to prepare an intragastric sustainedrelease tablet with (2) and (3) characteristics described above.
We have previously reported several different types of the
intragastric buoyant preparations [9 12]. After considering each
type, we started the investigation by reference to the paper
reported by Watanabe et al. [11], because the intragastric
buoyant system used in the report was independent of the pH
of the gastro-intestinal fluid, and this was very important for our
study.

The intragastric buoyant sustained-release tablets (IGB-T)

were prepared as follows: AMX, hydroxypropylcellulose-H

2.4. Determination of AMX by HPLC

Table 1
Formula of IGB-Ts
Components

AMX
AMX granulated
HPC H
Citric acid
Sodium hydrogen carbonate
HPC-H for coating
Total (mg)

IGBT0

T5

T10

T15

T25

T50

T100

260
17.2
22.8

300

255
17.2
22.8

300

10

250
17.2
22.8

300

15

245
17.2
22.8

300

25

235
17.2
22.8

300

50

210
17.2
22.8

300

100

160
17.2
22.8

300

IGB-T50Coating

IGB-T100Coating

IGB-T100Coating-300-500 G

50

210
17.2
22.8
8 10
308 310

100

160
17.2
22.8
8 10
308 310

105
160
17.2
22.8
10 15
315 325

T. Tokumura, Y. Machida / Journal of Controlled Release 110 (2006) 581 586

583

Table 2
Weight, thickness, diameter and the weight of the coating layer for each tablet prepared
Tablets

Weight (mg)

Thickness (mm)

Diameter (mm)

Weight of coating layer (mg)

IGB-T5
IGB-T10
IGB-T15
IGB-T25
IGB-T50
IGB-T50-Coating
IGB-T100-300-500G*
IGB-T100-Coating-300-500G*

6
6
6
11
13
10
13
13

293.7 T 3.1
295.5 T 3.7
295.5 T 2.1
298.4 T 3.1
297.7 T 2.5
307.6 T 1.9
305.2 T 1.0
319.1 T1.2

3.16 T 0.03
3.19 T 0.05
3.18 T 0.03
3.22 T 0.02
3.13 T 0.03
3.40 T 0.04
3.30 T 0.04
3.58 T 0.05

9.98 T 0.02
10.03 T 0.09
9.99 T 0.04
10.05 T 0.00
10.04 T 0.01
10.14 T 0.0
10.04 T 0.00
10.25 T 0.05

9.66 T 1.21

13.50 T 0.87

Each value represents the mean and SD.

*: data for the typical lot are shown.

chromatopac, all from Shimadzu (Kyoto, Japan). The chromatographic column was a YMC Pack AM312 ODS (150 
6 mm, i.d.) obtained from YMC Co., Ltd. (Kyoto, Japan). The
values for the flow rate, the wavelength for determination, and
the temperature of the column were 1 mL/min, 273 nm, and
40 -C, respectively. The mobile phase used for the determination of AMX was acetonitrile water HClO4 NaClO4
(128:872:1:5, V/V/V/W). The retention time of AMX was
about 8 min. The concentration of AMX was calculated using
a linear calibration curve. In the case of dissolution tests using
the first fluid, the injection sample for HPLC was prepared by
the following procedure: a 200 AL of sample solution was
added to 200 AL of the second fluid of JP XIV, and then
mixed well. For the dissolution test using the second fluid, a
200 AL of sample solution was added to 400 AL of pH4 buffer
solution. The pH 4 buffer solution was prepared by mixing the
first and the second fluids of JP XIV. In the case of the test
using water, a 20-AL of the sample solution was injected
directly onto the HPLC column.
2.5. Evaluation method of buoyancy for IGB-Ts
The buoyancy of IGB-T was evaluated in the dissolution
test. The time required for IGB-Ts to come to the surface of the
dissolution test medium (T buoy) was determined.

The buoyancy was affected by the amount of citric acid and

sodium bicarbonate in the tablets. The content of the
effervescing agent was decided from Watanabes data [11].
All IGB-Ts with different AMX contents were rapidly buoyant
(Fig. 1). This result shows that the amounts were suitable and
that the reproducibility of Watanabes data was confirmed.
Fig. 2 shows the AMX-release characteristic of IGB-T5,
-T10, -T15, -T25, and -T50. In the case of IGB-T5, the
transparent hydrogel of HPC-H was formed on the surface of
all tablets examined, and the shape of the tablet was maintained
to the endpoint of the dissolution test. The tablet remained on the
surface of the dissolution test medium after 6 h. Using the
surface gel layer, a sustained drug release pattern should be
obtained. However, in two of the three tablets examined for IGBT10, and in all tablets for IGB-T15-50, the transparent hydrogel
layer on the surface was not sufficient to maintain the tablet
shape and to sustain the drug release. In these cases, fragments of
cloudy hydrogel containing AMX were buoyant on the surface
of the dissolution test medium. Owing to the increased surface
area of the hydrogel layer and its loose structure, the dissolution
rate was considered to be increased. The fragments of the
hydrogel remained on the surface of the dissolution test medium
until the hydrogel dissolved completely.

25

3. Results and discussion

IGB-Ts containing 5 50 mg of AMX were prepared and the

dissolution test was performed using water. It was found that
all IGB-Ts were buoyant and that the T buoy decreased as the
AMX content increased. Fig. 1 shows the variation of T buoy
among IGB-Ts containing different amounts of AMX. The
T buoy value for IGB-T without AMX was 21 min. In this case,
the hydrogel of HPC-H, which was transparent, was made on
the surface of the tablet, and water slowly penetrated the tablet
through the gel layer. The addition of AMX into the tablet was
considered to cause an increased penetration rate of water. This
accelerated the reaction between citric acid (anhydride) and
sodium bicarbonate. As a result, the values of T buoy decreased
with the increase of AMX content in IGB-Ts.

Tbuoy (min)

20

3.1. Effect of AMX content on the buoyancy and the dissolution

characteristic of IGB-Ts in the dissolution test using water

15

10

10

15

20

25

30

35

40

45

50

AMX in IGB-T (mg)

Fig. 1. Effect of AMX content (mg) in IGB-T on the time required for IGB-T
to come to the surface of the dissolution test medium (Tbuoy). Tbuoy was determined
in the dissolution test using water at 37-C. AMX content shows the weight of AMX
in 300 mg, the weight of IGB-T. Each point represents the mean and SD (n =3).

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T. Tokumura, Y. Machida / Journal of Controlled Release 110 (2006) 581 586

100

80

Percent released (%)

Percent released (%)

100

60
40
20
0

80

60

40

20

0
0

Time (h)

12

16

20

24

Time (h)

In the case of fluorouracil (5-FU), reported by Watanabe

[11], the same system was used but the IGB-T with 25 mg 5FU had a sustained release property by maintaining the tablet
shape during drug release. This difference between 5-FU and
AMX was considered to be caused by the different drug
properties between AMX and 5-FU. In comparison with 5-FU,
AMX may inhibit the formation of the HPC hydrogel layer or
promote the absorption of water into the tablet. It was found
from the above results that additional pharmaceutical design
was required to obtaining the sustained release of AMX in a
tablet containing more than 5 mg of AMX. Therefore, we
initially attempted an additional pharmaceutical design for
IGB-T containing 50 mg of AMX.
3.2. Evaluation of IGB-T50-coating and its release
characteristics in the dissolution test using water
An improvement of the formation of HPC hydrogel layer
was considered most important for the preparation of IGB-T
containing 50 mg of AMX. Therefore, IGB-T50 was coated
with HPC-H, to obtain an HPC hydrogel layer on the surface of
the tablet. Fig. 3 shows the effect of the coating for IGB-T50
on the release pattern of AMX. The value of T buoy was
13.93 T 1.58 min. These results clearly indicate that the coating
improved the formation of the HPC hydrogel layer, and that
sustained AMX release was achieved. After 24 h, the IGB-T50coating remained on the surface of the dissolution test medium,
and the shape of tablet was maintained. The release rate within
8 h can be approximated by 0-order kinetics. The drug release
rate over time after 8 h is considered to be delayed by the
decrease of the release area on the surface of tablet due to the
slow dissolution of the gel layer.
3.3. Evaluation of IGB-T100-Coating-300-500G and its
release characteristics
IGB-T containing 100 mg of AMX (IGB-T100-coating) was
prepared similar to the preparation of IGB-T50 coating. As a

Fig. 3. Release profiles of AMX from IGB-T50 (>) and IGB-T50-Coating (?)
in water. Each point represents the mean and SD of 3 determinations.

result of the dissolution test, no sustained drug release pattern

was obtained, and the pattern was the same as that of IGB-T50
(Fig. 4). The value of T buoy was 4.25 T 0.60 min. The fragments
of cloudy hydrogel remained on the surface of the medium
until the hydrogel dissolved completely. This result indicates
that the action of the coating was not enough to give a
sustained dissolution pattern for tablets containing 100 mg of
AMX.
In order to form an HPC hydrogel layer on the surface of
coated tablets containing 100 mg AMX, we considered
decreasing the amount of AMX on the surface of the tablet
before coating. Forming the gel layer of HPC-H that was
suitable for IGB-T was inhibited by AMX content above 5 mg/
300 mg (1.7%) as shown in Fig. 2. The coating layer consists
of HPC-H. The coating layer formed the suitable gel layer
when IGB-T50-Coating and not formed when IGB-T100100

Percent released (%)

Fig. 2. AMX-release characteristics of IBG-T5 (?), IBG-T10 (>), IBG-T15

(r), IBG-T25 (g), and IBG-T50 (n). Each point represents the mean and SD of
3 determinations.

80

60

40

20

0
0

12

16

20

24

Time (h)
Fig. 4. Release profiles of AMX from IGB-T100-Coating and IGB-T100Coating-300-500 G in water, and the effect of pH on the profiles of AMX from
IGB-T100-Coating-300-500 G. (?): IGB-T100-Coating in water, (>): IGBT100-Coating-300-500 G in water, (q): IGB-T100-Coating-300-500 G at pH
6.8, (r): IGB-T100-Coating-300-500 G at pH 1.2. Each point represents the
mean and SD of 3 6 determinations.

T. Tokumura, Y. Machida / Journal of Controlled Release 110 (2006) 581 586

Table 3
Effect of the particle size of granulated AMX on the T buoy

585

4. Conclusion

Particle size (Am)

T buoy (min, mean T S.D.)

Intact
106
106 150
150 300
300 420
420 500
500 850

0.17
3.67 T 0.18
4.45 T 0.42
15.80 T 3.23
11.38 T 0.59
20.22 T 6.59
34.17 T 12.18

2
3
3
3
3
3
3

Coating. It was seemed from this result that the higher

concentration of AMX on the surface of the tablet inhibited
forming the gel layer. We considered that if there was the area
not containing AMX on the surface of the tablet the gel layer
might be formed. Therefore, it was tried to prepare IGB-T100
using granulated AMX.
The particle size of the granulated AMX was decided from
the result of a preliminary study. In the relationship between
the T buoy values as shown in Fig. 1 and the drug release
patterns in Fig. 2, when the T buoy was under 5 min the
sustained-release pattern was not obtained. In this preliminary
study the T buoy values over 5 min were seemed to be required.
IGB-T100 was prepared using granulated AMX with different
particle sizes, and T buoy was determined. Table 3 shows the
results of the preliminary study. The results indicate that
granules with a small particle size are not effective, but with a
particle size over 150 Am, T buoy was increased. The T buoy
values of the particle size 150 300 Am and over were over
5 min. T buoy values of the particle size 150 300 Am was
15.80 T 3.23, which was markedly increased, but had large
variation. The mean value of 300 420 Am was smaller than
that of 150 300 Am, which was considered to be due to the
large variation of the data. The increasing particle size from
150 to 850 Am was found to cause the increase of T buoy values
from 15.80 to 34.17 min. The large T buoy value is a demerit as
the intragastric buoyant tablets. In addition, there is a
possibility to indicate the problem of the uniformity of
AMX content in the tablets. From this result, we decided to
use particle sizes of granulated AMX ranging from 300 to
500 Am to prepare the tablet.
The release characteristics of IGB-T100 coating-300-500G
in water and in buffer solutions of pH 1.2 and 6.8 are shown
in Fig. 4. The values of T buoy in water, pH 1.2 and pH 6.8
buffer solutions were 12.30 T 1.89, 23.05 T 9.52, and 48.88 T
17.33 min, respectively. The release pattern of AMX from
IGB-T100-Coating-300-500G in water was similar to that with
IGB-T50-Coating. IGB-T100-Coating-300-500G was confirmed to be buoyant for 24 h in all dissolution test media
while maintaining tablet shape, and showed a sustained release
pattern similar to IGB-T50 coating. At pH 1.2, the percent
released decreased over time after 4 h, due to the degradation
of AMX in acidic conditions [13,14]. It was found from these
results that IGB-T100-Coating-300-500G had buoyancy and
sustained release properties in different pH solutions. This
novel pharmaceutical preparation indicates the usefulness of
eradication therapy.

IGB-T of AMX was prepared according to Watanabes

report. IGB-T containing 5 mg AMX could be prepared, but it
was impossible to increase AMX content. IGB-T with 50 mg
AMX was prepared by adding a coating layer of HPC-H to the
surface of IGB-T50 (IGB-T50-Coating). For IGB-T containing
100 mg AMX, granulated AMX of 300 500 Am of particle
size was used, and the surface of the tablet was coated with
HPC-H (IGB-T100-Coating-300-500G). IGB-T50-Coating and
IGB-T100-Coating-300-500G were confirmed to be buoyant
for 24 h while maintaining tablet shape and indicated a
sustained-release pattern in water. The same characteristics of
IGB-T100-Coating-300-500G were also confirmed in buffer
solutions of pH 1.2 and 6.8.
We have prepared AMX tablets with floating and
sustained-release functions as described above, and an
additional study will be performed to add the rapid-release
characteristic.
Acknowledgments
The authors are very grateful to Miss Mihoko Iwasawa,
Miss Shiori Yoshida, Miss Noriko Kitamura, Miss Sachiko
Tadokoro, Miss Michiko Nishiya, Miss Saki Morimitsu, and
Miss Jyunko Motoki for their assistance in the experimental
work.
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