ISSN: 2469-584X

Geng et al. J Clin Gastroenterol Treat 2019, 5:068

DOI: 10.23937/2469-584X/1510068
Volume 5 | Issue 2
Journal of Open Access

Clinical Gastroenterology and Treatment

Research Article

High Anti-Acid Omeprazole Lightweight Capsule for Gastro-Enter-

ic System Acid-Related Disorders Treatment
Longjian Geng1, Lidong Han1, Lulu Huang2, Ziheng Wu3, Zhenghong Wu1* and Xiaole Qi1* Check for
updates
1
Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing, PR China
2
National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; WHO Collaborating Centre
for Tropical Diseases; National Center for International Research on Tropical Diseases, Ministry of Science and Technology;
Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, PR China
3
Parkville campus, Monash University, Australia
*Corresponding author: Zhenghong Wu, Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University,
Nanjing 210009, PR China, Tel: +0086-150-6220-8341, Fax: +0086-025-8317-9703
Xiaole Qi, Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing 210009, PR China, Tel:
+0086-150-6220-8341, Fax: +0086-025-8317-9703

Abstract Keywords
Background and aims: Utilization of diverse anti-acid ma- Omeprazole, β-cyclodextrin encapsulation, Drug delivery
terials is necessary for the preparation of compound ome-
prazole capsules. However, to gain the satisfied anti-acid
effect, use of large amount of anti-acids is always difficult
to swallow. This study aimed to develop a lightweight com-
Introduction
pound omeprazole capsule which could achieve immedi- Acid-related disorders (ARDs) are defined as a cat-
ately drug releasing with high anti-acid ability in stomach.
egory of gastrointestinal disorders that are closely re-
Methods: Omeprazole was encapsulated in β-cyclodextrin lated to the effects of acid attacks [1]. ARDs mainly
to improve the drug solubility and stability. The influence of include peptic ulcer diseases (PUD), gastroesophageal
different factors on the efficiency of the drug encapsulation
was investigated. In addition, the omeprazole inclusions reflux disease (GORD) and functional dyspepsia (FD)
were assessed by Fourier transform-infrared spectroscopy, [2-3]. In recent years, the incidence rate has gradually
differential scanning calorimeter, and X-ray diffraction. Fi- increased about 5 times in western countries [4]. In
nally, anti-acids materials such as magnesium oxide (MgO) general, changes in lifestyle such as weight loss [5-
and sodium bicarbonate (NaHCO3) were used to reduce the
7], elevation of the head [8], abdominal breathing [9],
weight of the capsule contents.
and smoking cessation [10], can relieve acid-related
Results: Compared to the market omeprazole capsule symptoms. Medications including proton pump inhib-
(ENCHENG®), the omeprazole compound capsule demon-
strated significantly improved drug dissolution (the maxi- itors (PPIs) [11] and H2 receptor antagonists [12] can
mum release ratio was 95.42 ± 2.51%) in simulated gastric also help. Studies have shown that PPIs have better
environment. Moreover, rabbit pharmacokinetics showed effects than H2 receptor antagonists in the relief of
that the area under the plasma concentration-time curve Acid-related symptoms and are the first choice for the
(AUC0-t) was significantly increased to 54180.11 ± 6483.16
min·ng·mL-1 (p < 0.05), compared with that (39011.55 ±
treatment of most ARDs [13-15].
6637.08 min·ng·mL-1) of the currently used capsules (EN- Currently, omeprazole (OMZ) is a representative
CHENG®).
drug of the first generation of PPIs. It inhibits the pro-
Conclusions: The light compound omeprazole capsule ton pump in the gastric parietal membrane and pre-
could be an effective and swallowable oral delivering sys- vents H+ in the cell wall from being transported into the
tem for Acid-Related Disorders.

Citation: Geng L, Han L, Huang L, Wu Z, Wu Z, et al. (2019) High Anti-Acid Omeprazole Lightweight
Capsule for Gastro-Enteric System Acid-Related Disorders Treatment. J Clin Gastroenterol Treat 5:068.
doi.org/10.23937/2469-584X/1510068
Accepted: September 24, 2019: Published: September 26, 2019
Copyright: © 2019 Geng L, et al. This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction
in any medium, provided the original author and source are credited.

Geng et al. J Clin Gastroenterol Treat 2019, 5:068 • Page 1 of 11 •

DOI: 10.23937/2469-584X/1510068 ISSN: 2469-584X

gastric juice, thereby inhibiting the secretion of gastric (Anhui Sanhe Pharmaceutical Excipient Co., Ltd.,
juice. It is widely used for the treatment of gastric and China), Hydrocarbonate Sodium (NaHCO3, [Nanjing
duodenal diseases [16,17], and it also has a good ther- Chemical Reagent Co., Ltd., China]), Lightweight Mag-
apeutic effect on most ARDs [11]. OMZ is very poorly nesium Oxide (MgO, [Xisheng Scientific Co., China]),
soluble [18], but it has high permeability and is highly HPMC Capsule (0 #, [Suzhou Capsule Co., Ltd, China]).
absorbable (> 90%) in the intestinal tract. It belongs to All other reagents were of analytical grade.
the biopharmaceutics classification system (BCS) class
II [19] and the dissolution rate is a key factor for that
Preparation of OMZ-CD
ensures a better release. Therefore, increasing the sol- Briefly, the clathrate was prepared by the satu-
ubility can effectively improve the release behavior of rated aqueous solution method. The β-CD was com-
OMZ. Cyclodextrin (CD) is a water-soluble cyclic oligo- pletely dissolved in sodium hydroxide (NaOH) aque-
saccharide obtained by hydrolysis of starch [20]. It has ous solution (pH = 11). Different amounts of OMZ
a hydrophobic cavity and a hydrophilic outer surface. It powder were then added to the β-CD solution in a
can form inclusion complexes with hydrophobic drug molar ratio of 1:1, 1:2, or 1:3. The mixture was stirred
molecules to increase solubility and stability [21-23]. at different temperatures (30, 45, and 60 °C) for 1,
CD has been extensively studied due to its low toxicity 3, and 5 h respectively. After the solution was left to
and low immunogenicity [24]. β-cyclodextrin (β-CD) is cool to room temperature and stored at 4 °C for 12
the cheapest available CD [25] and its use to form OMZ hours, it was filtered by suction, washed with anhy-
inclusion complexes (OMZ-CD) could improve solubility drous ethanol three times, and vacuum dried at 25 °C
and stability. for 12 hours to obtain OMZ-CD.
OMZ is known for being easily decomposed into a The encapsulation efficiency (EE) of OMZ-CD pow-
structure that is not efficiently absorbable by humans der which we got was obtained by dissolving 10 mg of
in an acidic environment, as its oral formulation is usu- OMZ-CD in 50 mL of ethanol for 30 minutes under ul-
ally an enteric preparation [26]. The enteric coating trasound. After dissolution, the sample was diluted to
protects the drug against gastric acid damage, but its 100 mL with sterile ultra-pure water (ddH2O), and then
release delays drug release. In February and March of analyzed with UV-752 spectrophotometer (Qinghua,
2006, the Food and Drug Administration of the United Shanghai, China) at 302 nm (standard curve A = 0.0418C
State (US FDA) approved OMZ capsules (OMZ/Sodium + 0.0159, R2 = 0.9992). The EE was calculated using the
bicarbonate) and compound OMZ chewable tablets following equation:
(OMZ/Sodium bicarbonate/magnesium hydroxide) re- the molar amount of OMZ in OMZ − CD
=
spectively [27]. The specifications of the capsules were EE ( % ) the molar amount of â − CD in OMZ − CD ×100%
20 mg/1100 mg and 40 mg/1100 mg, and those of the
chewable tablets were 20 mg/0.6 g/0.7 g and 40 mg/0.6 Property of OMZ-CD
g/0.7 g [28]. Both of these drugs have been formulated X-Ray diffraction crystallography: The crystallinity
with the addition of micronized antacids [29], so that of freshly prepared sample was obtained at room tem-
they can rapidly increase the pH of gastric juice to re- perature by PXRD (MAX 2500 X-ray diffract meter, Riga-
lease OMZ, and rapidly reach the maximum concen- ku, Japan). The step size is 0.02°. The angle is from 3° to
tration in plasma. However, the weight of the capsule 40°, scan speed of 8°/min on 40 mA, 40 kV conditions
contents is as high as 1160 mg [30], which makes swal- [31]. Samples were made from OMZ powder, simple
lowing difficult. It is therefore vital to use other safe β-CD powder, physical mixture of OMZ and β-CD, and
antacids and reduce the weight of the preparations so milled OMZ-CD powder, then were analyzed after dry-
that smaller capsules can be used to reduce swallowing ing.
difficulty.
Differential scanning calorimeter (DSC): DSC-204
In this study, we successfully prepared OMZ-CD, (Netzsch, Germany) system was used to obtain the
which were characterized and compared with micron- thermo grams of the samples [32]. All experiments
ized OMZ. An improved OMZ immediate-release cap- were operated from 45 to 300 °C at a heating rate of
sule was prepared, and in vitro release behavior and 10 °C/min under constant purging of nitrogen at 20
pharmacokinetics studies in rabbits were investigated. mL/min. Samples were made from OMZ powder, sim-
ple β-CD powder, physical mixture of OMZ and β-CD,
Materials and Methods and milled OMZ-CD powder, then were analyzed af-
Materials ter drying.
The following materials were obtained from com- Fourier transform-infrared spectroscopy (FTIR):
mercial suppliers and used as received: OMZ (Shou- FTIR spectrometer (Paragon, 1000, PerkinElmer, USA)
guang Fukang Pharmaceutical Co., Ltd, China), OMZ was used to obtain FTIR spectra at room temperature.
Control (China National Institute for the Control of OMZ powder, β-CD powder, physical mixture of OMZ
Pharmaceutical and Biological Products, China), β-CD and β-CD, and milled OMZ-CD powder were triturated

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DOI: 10.23937/2469-584X/1510068 ISSN: 2469-584X

with KBr in a ratio of 1:100 before pressed to form pel- and immediately filtered through a 0.45 μm-micropo-
lets. The scanned range was from 400 to 4000 cm-1 with rous membrane. One milliliter of 0.1 mol/L NaOH solu-
the application of 16 scans at a nominal resolution of 4 tion was added to 5 mL of the filtrate (the test solution).
cm−1. Samples were analyzed after drying [33]. The corresponding drug concentration and cumulative
release percentage were calculated by HPLC peak area
Measurement of inclusion ratio: The inclusion ratio
[37].
was determined by the equimolar continuous change
method [34,35]. Different concentrations of OMZ and Choice of antacids
β-CD mixed solution (total concentration of 1.0 × 10-4
The pH-time curves of NaHCO3 and Na2CO3, MgO and
mol/L) was prepared with pH 11 NaOH solution. The
Mg(OH)2 were compared to determine the type of ant-
molar fraction of OMZ was from 0.1 to 0.9, the rest was
acid. The amount of one antacid was fixed while that of
β-CD. The solution was then incubated in a shaker at
another antacid varied. The final amount of antacid was
200 rpm at 5 °C for 6 h, and left for 12 h. The optical
determined by comparison of the pH-time curves. The
density (OD) was measured with UV-752 spectropho-
antacid was added to 50 mL of 0.1 mol/L HCl solution
tometer (Qinghua, Shanghai, China) at 302 nm with the
and stirred at a constant rate of 100 r/min. After 6 min-
NaOH solution at pH 11 used as blank. The inclusion ra-
utes, 1.0 mol/L HCl solution was added at a rate of 0.5
tio was determined based on the UV absorption data.
mL/min by a constant flow pump. The pH was measured
Measurement of saturated solubility: Equal doses with a pH meter (Inesa, Shanghai, China) [28].
(OMZ 20 mg) of OMZ, OMZ and β -CD, and OMZ-CD
ware prepared with 1 × phosphate-buffered saline Preparation of compound omeprazole capsules
(PBS) pH 6.86 into a 10 mL brown volumetric flask, The prescribed amount of OMZ-CD, NaHCO3, and
respectively. The solutions were placed in a 25 °C wa- MgO was sieved through 60 mesh 3 times, and the mix-
ter bath thermoshake for 24 h to reach the equilibri- ture was evenly filled into HPMC No. 0 capsules.
um. After the shaking was completed, the suspension
was centrifuged at 3500 rpm for 10 minutes and the In vitro release of OMZ compound capsule
precipitate was filtered through a 0.45 μm of microp- Marketed capsules and the capsules we developed
orous membrane. Then amount of OMZ in the filtrate were put into 50 mL of 0.1 mol/L HCl solution and
was measured accordingly [36]. stirred at a constant rate of 100 r/min. After 6 min,
The concentration of OMZ was measured by high-per- 1 mol/L HCl solution was added at a rate of 0.5 mL/
formance liquid chromatography (HPLC) using LC-10AT min by a constant flow pump. All the solutions were
(Shimadzu, Tokyo, Japan). All HPLC tests were carried incubated in a (37 ± 0.5)°C -water bath during the en-
out in a reversed-phase column (Inertsil® ODS-SP, 4.6 tire process. At 5, 10, 15, 20, 30, 45, and 60 minutes,
mm × 250 mm, i.d. 5 μm, GL Sciences, Tokyo, Japan) at 500 μL of the solution were immediately collected and
35 °C and under ultraviolet spectrophotometer at 302 filtered with a 0.45 μm-microporous membrane. One
nm. A mixture of methanol and water (75:25, v/v) was milliliter of 0.01 mol/L NaOH solution was added to 100
used as mobile phase at a flow rate of 1.0 mL/min. All μL of the filtrate (the test solution). The corresponding
measurements were performed in triplicate. drug concentration and cumulative release percentage
were calculated by HPLC peak area [28].
Measurement of acid resistance: OMZ-CD powder
and micronized OMZ were taken as the prescriptions In vivo pharmacokinetic study of OMZ compound
and mixed with 50 mL of 0.1 mol/L hydrochloric acid capsule
(HCl) solution. A volume of 500 μL of the solution was
Drug administration: The animals were obtained
sampled at 5, 10, 15, 20, 30, 45, and 60 minutes after
from the Laboratory Animal Center of China Phar-
stirring and filtered with a 0.45 μm-microporous mem-
maceutical University. Healthy New Zealand rabbits
brane. An amount of 200 μL of the filtrate was accu-
(weighing 1.6-2.0 kg) were fasted overnight and divid-
rately weighed, and 2 mL of 0.01 mol/L NaOH solution
ed into two groups. Meeh-Rubner’s formula was used
was added to be the test solution. The peak area was
to determine the dose and drugs were filled in small
determined by HPLC (Shimadzu, Kyoto, Japan) to esti-
capsules to give the rabbits.
mate the remaining drug content.
After a single oral administration of marketed com-
In vitro drug release: Pre-metered micronized OMZ,
pound capsules (ENCHENG®), about 2 mL blood sam-
OMZ-CD powder, and OMZ and β-CD powder mixture
ples were collected in heparinized tubes at 5, 10, 20, 30,
containing the same amount of clathrate compound
45, 60, 90, 120, 180, 240, 360, and 480 min. The blood
were respectively loaded into HPMC capsules. The re-
samples were centrifuged at 4000 rpm for 10 min. The
lease was performed in water and phosphate-buffered
upper plasma was separated and kept at -20°C until use
saline (PBS) pH 6.8, respectively. This study used the
[38].
basket method in which the speed is 100 r/min and the
temperature is (37 ± 0.5) °C. A volume of 10 mL of solu- Preparation of plasma samples: Plasma sample was
tion was taken at 5, 10, 15, 20, 30, 45, and 60 minutes prepared by mixing 200 μL plasma and 200 μL β-naph-

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Table 1: Effect of different molar ratios of OMZ and β-CD, inclusion time and temperature on the encapsulation efficiency of OMZ-
CD (mean ± SD, n = 3).

Formulation OMZ : β-CD Inclusion time (h) Inclusion temperature (°C) EE (%)
1 1:01 3 30 41.82 ± 0.87
2 1:02 3 30 44.28 ± 1.71
3 1:03 3 30 34.62 ± 3.07
4 1:02 1 30 19.71 ± 2.75
5 1:02 3 30 44.28 ± 1.71
6 1:02 5 30 38.03 ± 1.54
7 1:02 3 30 44.28 ± 1.71
8 1:02 3 45 45.07 ± 1.29
9 1:02 3 60 47.10 ± 0.63

a b
OMZ

OMZ
β-CD

β-CD
Mixture

Mixture OMZ-CD

OMZ-CD
0 10 20 30 40 50 100 150 200 250 300 350
0.35
c d
0.30

OMZ
0.25
Womz•∆A

β-CD 0.20

0.15
Mixture

0.10
OMZ-CD
0.0 0.2 0.4 0.6 0.8 1.0
Womz

Figure 1: Property investigation of OMZ-CD a) X-ray diffraction of samples; b) DSC thermograms of samples; c) FITR of
samples; d) Determining of the inclusion ratio by the equimolar continuous change method.

thol methanol solution (10 μg/mL) as the internal stan- mixture of acetonitrile and water (55:45, v/v) was used
dard substance. After being vortexed for 2 min, the mix- as mobile phase at a flow rate of 1.0 mL/min. Method-
ture was centrifuged at 8000 rpm for 10 min to remove ological studies, e.g. precision of with-in and between
plasma proteins. The supernatant was injected into days and recovery were demonstrated to meet the re-
HPLC for analysis. quirements of the methodology.
High-performance liquid chromatography (HPLC): Pharmacokinetic analysis: DAS 2.0 software (Shutcm,
LC-10AT liquid chromatography (Shimadzu, Kyoto, Ja- Shanghai, China) is used to analyze data. The peak plas-
pan) was used for analysis. The tests were carried out ma of drug concentration (Cmax) and the time to reach
in a reversed-phase column (Inertsil® ODS-SP, 4.6 mm peak concentration (Tmax) were obtained from the plas-
× 250 mm, i.d. 5 μm, GL Sciences, Tokyo, Japan) at 35°C ma concentration–time curves of OMZ [39]. The linear
and under ultraviolet spectrophotometer at 302 nm. A trapezoidal rule was used to calculate the area under

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DOI: 10.23937/2469-584X/1510068 ISSN: 2469-584X

the plasma concentration-time curve (AUC). OMZ and β-CD.

Results The determination of inclusion ratio is showed in
Figure 1d. The WOMZ*△ A was used to plot the WOMZ.
Preparation of the OMZ-CD WOMZ referred to the molar fraction of OMZ in the
Effect of different molar ratios of OMZ and β-CD, in- mixture. ΔA referred to the difference in UV absorp-
clusion time and inclusion temperature on the EE (%) of tion intensity between OMZ before inclusion and
OMZ-CD are shown in Table 1. With the same inclusion OMZ after inclusion. The curve showed an arc. When
time and inclusion temperature, the EE (44.28 ± 1.71%) the molar ratio of OMZ to β-CD was 1:1, the value of
was the highest when the molar ratio of OMZ to β-CD WOMZ*△ A was the largest.
was set to 1:2 and the inclusion time for 3 hours. In- The result of saturated solubility of OMZ, physical
creasing of the temperature was beneficial to the im- mixture of OMZ and β-CD, and OMZ-CD in water and
provement of the EE. When the inclusion temperatures
PBS pH 6.86 buffer are showed in Figure 2a. The satu-
were 30 °C, 45 °C, and 60 °C, the EE were 44.28 ± 1.71%,
ration solubility of OMZ in water and PBS (pH 6.8) were
45.07 ± 1.29%, and 47.10 ± 0.63%, respectively.
75.38 ± 1.52 μg/mL and 80.26 ± 1.50 μg/mL respective-
Property investigation of OMZ-CD ly. The saturation solubility of physical mixture of OMZ
and β-CD was a little higher (121.66 ± 2.48 μg/mL in wa-
The pattern of X-ray diffraction, DSC and FTIR of
ter, 118.29 ± 0.32 μg/mL in PBS pH 6.86) than that of
OMZ, β -CD, physical mixture of OMZ and β -CD, and
OMZ. By contrast, the saturation solubility of OMZ-CD
OMZ-CD are showed in Figure 1a, Figure 1b, and Fig-
was increased by approximately 4.8 times and 3.5 times
ure 1c, respectively. The pattern of OMZ-CD was dif-
compared to that of OMZ in water and PBS (pH 6.8) re-
ferent from those of OMZ, β-CD, physical mixture of
spectively.
OMZ, and β-CD; while the pattern of physical mixture
of OMZ and β-CD was just a superposition of those of The plot of the content of OMZ-CD and micronized

a b
400
100
350
Water
pH6.86
Saturated solubility (µg/mL)

300 80
OMZ
Remaining ratio (%)

250 OMZ-CD
60
200
40
150

100 20

50
0
0
OMZ Mixture OMZ-cd 0 10 20 30 40
c Sample
d Time (min)
100
100
OMZ
80 OMZ-CD
80 Mixture
Cumulative Release (%)

Cumulative Release (%)

60
60
OMZ
OMZ-CD 40
40
Mixture

20 20

0 0

0 10 20 30 40 50 60 0 10 20 30 40 50 60
Time (min) Time (min)

Figure 2: Property investigation of OMZ-CD a) Saturated solubility of OMZ, physical mixture of OMZ and β-CD, and OMZ-CD
in water and pH 6.86 buffer; b) Acid resistance measurement of OMZ-CD and micronized OMZ; c) Dissolution profiles of OMZ
releasing from micronized OMZ, OMZ-CD powder and mixture of OMZ and β-CD powders in water; d) Dissolution profiles of
OMZ releasing from micronized OMZ, OMZ-CD powder and mixture of OMZ and β-CD powders in pH 6.86 media. Data are
shown as the means ± SD (n = 3).

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OMZ over time under simulated gastric acid conditions 6.8, the release of the three was lower than in water,
is shown in Figure 2b. OMZ was degraded very fast un- and the difference was significant. The fastest was
der acidic conditions, while the degradation rate re- OMZ-CD, followed by the mixture, and the slowest was
duced after being prepared as inclusion compound. Af- micronized drug substance.
ter a certain time both were close to 0. Fitting the data
by DAS 2.0 software (Shutcm, Shanghai, China), it was
Choice of antacids
found that the half-life of the micronized drug sub- Figure 3a and Figure 3b are the pH-time curves
stance was 4.00 ± 0.43 min, while it was 7.59 ± 0.83 min for the same mass of NaHCO3 and Na2CO3, MgO and
for OMZ-CD. The area under the curve of the latter was Mg(OH)2, respectively. Figure 3c is a pH-time curve
approximately 1.80 times than that of the former. of immobilized 400 mg MgO screened for 150 mg,
250 mg, and 350 mg NaHCO3, respectively. Figure 3d
The dissolution profiles of micronized OMZ, OMZ-CD
is a pH-time curve of immobilized 250 mg NaHCO3
powder, and a mixture containing the same amount of
screened for 300 mg, 400 mg, and 500 mg MgO, re-
OMZ and β-CD powders of the inclusion complex in wa-
spectively. Initially, the addition of an excess of ant-
ter and PBS pH 6.8 are shown in Figure 2c and Figure
acid caused a rapid increase of the pH of the solution
2d respectively. In water, the HPMC capsule ruptured
which stayed at a high value. As the hydrochloric acid
in about 5 min and then the drug began to release. The
was added, the excess antacid was completely atten-
release rate of OMZ-CD was significantly higher than
uated, and thereafter, the pH dropped rapidly.
that of micronized drug substances and mixtures, while
the difference between the latter two was not obvious. Physical characteristics of capsules
OMZ-CD could release over 80% in 15 min and nearly
The prescription information of both marketed
100% in 20 min. All the three could release more than
compound OMZ capsules and compound OMZ cap-
90% within 1 h. In phosphate-buffered saline (PBS) pH

a b
12
10 600mg Mg(OH)2
600mg NaHCO3 600mg MgO
600mg Na2CO3 10
800mg NaHCO3
8
800mg Na2CO3
8

6
6
pH

pH

4
4

2
2

0 0
-5 0 5 10 15 20 25 30 35 40
-10 0 10 20 30 40 50 60 70
t/min
t/min
c d
12 12
150mg NaHCO3
300mg MgO
10 250mg NaHCO3 10 400mg MgO
350mg NaHCO3 500mg MgO
8 8

6 6
pH

pH

4 4

2 2

0 0
0 10 20 30 40 50 60 0 10 20 30 40 50 60
t/min t/min

Figure 3: Choice of antacids a) The pH-time curves of NaHCO3 and Na2CO3; b) The pH-time curves of MgO and Mg(OH)2; c)
The pH-time curve of immobilized 400 mg MgO screened for 150 mg, 250 mg and 350 mg NaHCO3; d) The pH-time curve of
immobilized 250 mg NaHCO3 screened for 300 mg, 400 mg and 500 mg MgO.

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Table 2: Prescription information of self-made capsules and market capsule.

Formulation Self-made capsules Market capsules

Drug OMZ-CD 169 mg (OMZ 20 mg) OMZ 20 mg
Antacids 1 NaHCO3 250 mg NaHCO3 1100 mg
Antacids 2 MgO 400 mg /
Others / 40 mg
Total weight of contents 819 mg 1160 mg
Size of capsules 0# 00#

Table 3: Pharmacokinetics parameters obtained following oral administration of marketed capsules and the test to rabbits
(mean ± SD, n = 3).

Parameters Marketed tablets Test

Tmax (min) 30 23.33 ± 5.77

Cmax (ng/mL) 476.13 ± 44.84 686.06 ± 69.94*

t1/2 (min) 44.11 ± 1.79 52.41 ± 8.45

AUC0-τ (min·ng/mL) 39011.55 ± 6637.08 54180.11 ± 6483.16*

MRT0-τ (min) 78.48 ± 3.88 75.51 ± 1.16

Relative bioavailability (%) 100 138.88

*p < 0.05 vs. marketed capsules.

b 100
Test
Market sample
80
Release (%)

60

40

20

0 10 20 30 40 50 60
Time (min)

Figure 4: Studies on the compound capsule a) The physical characteristics of the homemade and the marketed compound
OMZ capsules; b) Dissolution profile of homemade and marketed compound OMZ capsules under simulated gastric acid
conditions. Data are shown as the means ± SD (n = 3).

sules we developed are showed in Table 2. The ap- mg of MgO into No. 0 HPMC capsules. By contrast,
pearance of the capsules is shown in Figure 4a. The market capsules are prepared by mixing 1100 mg
capsules we developed were prepared by mixing and NaHCO3 and suitable recipients and filling into a No.
filling 170 mg of OMZ-CD, 250 mg of NaHCO3, and 400 00 capsule.

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In vitro drug release of capsules uble [18]; the saturation solubility of OMZ in water and
PBS (pH 6.8) were 75.38 ± 1.52 μg/mL and 80.26 ± 1.50
The dissolution profile of commercial formulations
μg/mL (see Figure 2a). In an attempt to minimize these
and the formulations we developed under simulated
drawbacks, the aim of this work was to evaluate the ca-
gastric acid conditions are indicated in Figure 4b. Y-axis
pability of OMZ for the oral delivery of drug when asso-
indicates the ratio of the current drug content to the
ciated to CD.
complete release of the drug, expressed in percent-
age. Commercial sample released very fast in the early After being determined by the equimolar continu-
stage, then, slowed down and the drug content began ous change method [34-35], the result of inclusion ra-
to decrease after the maximum release was reached. tio measurement showed that OMZ and β-CD were 1:1
Finally, the drug content became 0. Same as the com- inclusion (see Figure 1d), which meant that one OMZ
mercial sample, the inclusion compound capsules re- molecule was linked to only one β-CD molecule, and
leased rapidly at first. When reached the maximum one β-CD molecule was also related to only one OMZ
level, the release stopped, then the drug content be- molecule. But in the preparation of OMZ-CD, when the
gan to decrease to 0. amount of β-CD was increased, the reaction equilibri-
um was promoted to move to the right, and thus the
In vivo pharmacokinetics molar ratio of 1:2 to 1:1 had better EE (see Table 1).
The plasma concentration-time curves after rabbits By contrast, when the molar ratio was 1:3, excessive
were fed marketed compound OMZ capsules and the β-CD was difficult to remove and the EE of the resulting
tests are shown in Figure 5. The main pharmacokinet- product was reduced. Though increasing the tempera-
ic parameters calculated from these data are shown in ture was beneficial to the improvement of the EE, but
Table 3. Commercial capsules showed a typical imme- higher temperatures made OMZ more unstable and
diate release curve, whereas the tests were more pro- the solution turned yellow, decreasing the entrapment
nounced. The average value of Cmax was 686.06 ± 69.94 rate. Thus, from both the perspective of energy con-
ng/mL after oral administration of the test, which was servation and stability of drug, 30 °C was selected for
more than that of marketed capsules. The t1/2 of the test the reaction temperature.
was 52.41 ± 8.45 min, while the value of marketed cap- EE increased as the inclusion time increased, but de-
sules was 44.11 ± 1.79 min. The relative bioavailability creased when the reaction time was too long. Stirring
of OMZ was 138.88% compared to marketed capsules. for a long time may destroy the weak intermolecular
Discussion force of OMZ-CD, resulting in reduced packaging effi-
ciency [36]. Consequently, OMZ-CD was prepared under
OMZ is a highly lipophilic compound with low oral the optimal conditions by stirring OMZ and β-CD at a
bioavailability that shows low stability related with rap- molar ratio of 1:2 at a constant temperature of 30°C for
id hydrolysis of its structure under acidic conditions 3 hours.
(half-life of the micronized drug substance was 4.00 ±
0.43 min) (see Figure 2b). Also, OMZ is very poorly sol- We used X-ray diffraction, DSC, and FTIR to char-

800
Plasma concentration (ng/mL)

Market sample
600 Test

400

200

0 100 200 300 400 500

Time (min)
Figure 5: Mean plasma concentration-time profiles of OMZ from the homemade preparations and the marketed
compound OMZ capsules following oral administration. Data are shown as the means ± SD (n = 3).

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DOI: 10.23937/2469-584X/1510068 ISSN: 2469-584X

acterize the generated OMZ-CD. The X-ray diffraction The commercial compound OMZ capsules were pre-
pattern of physical mixture of OMZ and β-CD showed pared by mixing large-dose antacids and suitable recip-
characteristic peaks at 2θ of 4.515, 9.019, 12.342, ients and filling into a No. 00 capsule, making it large,
12.778, 17.165, and 23.928 (see Figure 1a). All of these heavy, and difficult to swallow [30]. To this end, this
had appeared in the pattern of OMZ and β-CD, which study also aimed to reduce the use of antacids and re-
meant the mixture was simple powder of OMZ and duce the weight of the preparations by choosing other
β-CD. But in the pattern of OMZ-CD, most of the char- safe antacids.
acteristic peaks that consisted with OMZ disappeared.
The acid resistance of magnesium salt was higher
It showed that OMZ in the inclusion complex was not
than that of sodium salt (see Figure 3a and Figure 3b).
present in crystalline form but in amorphous state
However, sodium salt could generate a large number
[33].
of bubbles when it came in contact with the acid solu-
In Figure 1b, the DSC curve of OMZ showed that it tion, and quickly neutralized the acid while promoting
was a typical crystalline anhydrous material. The sharp dispersion. Therefore, the selected antacid was mainly
melting endotherm at 159.8 °C meant the melting magnesium salt to which was added a small amount of
point of the drug. The exothermic effect at 173.9 °C sodium salt to promote dispersion. MgO of the same
was due to its thermal decomposition [40]. The curve quality had a higher acid-Fighting effect than Mg(OH)2
of β-CD showed a broad endothermic effect around 60 (see Figure 3b). Compared with Na2CO3, NaHCO3 was
°C associated with crystal water losses [41]. The curve gentler with pH value (see Figure 3a). Ultimately, we
of the physical mixture of OMZ and β-CD showed that have chosen a mixture of MgO and NaHCO3 as antacid.
the characteristic peaks at 159.8 °C was still exist, In terms of screening of the amount of antacids,
meaning that OMZ had basically maintained its orig- when amount of NaHCO3 was set as 150 mg, the pH
inal crystallinity [42]. The disappearance of the OMZ value rose slowly and remained below 2.0 at 30 s af-
melting point in the curve of OMZ-CD suggested the ter administration (see Figure 3c). This may result in
formation of a true inclusion complex [43]. the unavoidable degradation of OMZ once contacted
In Figure 1c, OMZ had a complex absorption pattern with gastric acid in stomach, as the half-life of the
below 1600 cm-1. However, β-CD absorbed more in the OMZ-CD was only 7.59 ± 0.83 min (see Figure 2b). By
3500-2800 cm-1 region. No new peaks appeared in the contrast, the pH value rose faster to reach 6.0 at 30 s
spectra of binary systems, meaning that no chemical when the amount of NaHCO3 was 250 mg. According
bonds were created. The characteristic peaks of the to a previous study [28], our investigations showed
drug could still be observed in the spectrum of the that the peak time of plasma concentration in vivo is
physical mixture, which was the superposition of the about 30 min, and the time for 400 mg MgO to main-
characteristic peaks of OMZ and β-CD. The two sharp tain pH above 6 is more than 35 min (see Figure 3d).
peaks of OMZ at 1631.0 cm-1 and 1510.2 cm-1 which In order to minimize the dose, 400 mg of MgO and
were CH deformation, CC stretching (P, BI) and CH + 250 mg of NaHCO3 were selected as antacids. Thus,
NH deformation (BI) [44], were significantly reduced in the current study, we developed capsules with a
in the diffractogram of the inclusion complexes. The better swallow compliance, which had a small vol-
bending vibrations of the methoxy groups of OMZ at ume and less weight by mixing and filling 170 mg of
1204.6 cm-1 was decreased in the spectra of OMZ-CD OMZ-CD, 250 mg of NaHCO3, and 400 mg of MgO into
because of the restriction due to the inclusion of this No. 0 HPMC capsules. The total weight of the capsule
group within the CD cavity [33]. Therefore, it had been contents was 820 mg. However, the commercial cap-
demonstrated that OMZ-CD had formed. sule contents weigh up to 1160 mg and are filled with
No. 00 capsule (see Figure 4a and Table 2). Investi-
As a water-soluble auxiliary material, β-CD can im- gations on both in vitro drug release (see Figure 4b)
prove the surface wet ability of OMZ to increase the and in vivo pharmacokinetics (see Figure 5) showed
saturation solubility of OMZ in the physical mixture. As that compound OMZ capsules that we developed had
a result, the saturation solubility of the physical mix- a better release performance.
ture was slightly increased compared to that of the
drug (see Figure 2a). However, the saturation solubility With regard to in vitro drug release studies conduct-
of OMZ-CD was increased more. This could explain the ed on the compound capsule, the commercial sample
reason why inclusion compound let OMZ give a better released fast in the early stage due to the gas produc-
performance in in vitro drug release (see Figure 2c and tion of NaHCO3. However, due to the small amount of
Figure 2d). OMZ is an acidic drug so it was more diffi- simulated gastric fluid, the prescribed amount of drug
cult to release in a buffered salt solution than in water. substance could not be completely dissolved therein.
The difference in the saturation solubility of the three As the amount of solution increases, the release of the
substances led to a more differentiated dissolution be- drug substance increased. After the antacids were all
havior when they released in phosphate-buffered sa- neutralized, the pH decreased and the drug substance
line (PBS) pH 6.8. degraded under acidic conditions. Therefore, the curve

Geng et al. J Clin Gastroenterol Treat 2019, 5:068 • Page 9 of 11 •

DOI: 10.23937/2469-584X/1510068 ISSN: 2469-584X

appeared to rise first and then decreased. immediate release in the stomach, drug efficacy is pro-
duced within few minutes after taking the drug, which
Because of the large solubility enhance effect of
can greatly reduce the patient’s pain.
the prepared clathrate, OMZ in capsule that we devel-
oped could be completely dissolved under the simu- Acknowledgements
lated gastric acid conditions. As the commercial sam-
The authors gratefully acknowledge the support
ple, the initial gas production of NaHCO3 allowed the
from National Natural Science Foundation of China (No.
inclusion compound to release rapidly. The presence
81402859), Top-notch Academic Programs Project of
of MgO maintained a relatively high pH for a relatively
Jiangsu Higher Education Institutions (PPZY2015B164),
long period of time, so that the drug could maintain
Administration of Traditional Chinese Medicine of Zheji-
its maximum release over a long period of time. Simi-
ang Province (Program No. 2017ZA075).
larly, the pH decreased and the drug degraded under
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