706 Chem. Pharm. Bull. 65, 706–713 (2017) Vol. 65, No.

Regular Article

Formulation Optimization of Gastro-Retention Tablets of Paeonol and

Efficacy in Treatment of Experimental Gastric Ulcer
Xitong Zhang,a,b Yue Zhang,a,c Han Han,a Jun Yang,b Benliang Xu,a Bing Wang,*,a,c and
Tong Zhang*,a,c
a
 Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine; No. 1200,
Cailun Road, Pudong New District, Shanghai 201203, China: b Shanghai Xiangshan Hospital of Traditional Chinese
Medicine; No. 528, Middle Fuxing Road, Huangpu District, Shanghai 200020, China: and c School of Pharmacy,
Shanghai University of Traditional Chinese Medicine; No. 1200, Cailun Road, Pudong New District, Shanghai
201203, China.
Received December 18, 2016; accepted May 1, 2017; advance publication released online May 19, 2017

This study aims to develop a gastroretentive sustained-release drug delivery system of paeonol using
floating properties and to investigate its therapeutic effects in rat models. The gastric retention tablets of
paeonol (GRT-Ps) were prepared by a direct compression method, and the Box–Behnken design was used
to optimize its formulation. The optimized formulation containing 15% NaHCO3 and a 2 : 1 ratio of paeonol
and HPMC-K4M floated within 1 min and remained afloat for more than 8 h in the simulated gastric fluid
(200 mL, pH=1.2) and simultaneously showed the desired sustained drug release. Moreover, small tablets
(3 mm) were prepared according to the same formulation and the process technology of big tablets (8 mm). A
similar drug release behavior was observed between two kinds of tablets ( f 2=52), and then the evaluations
of efficacy and retention capacity in vivo were conducted with small tablets. In vivo retention studies showed
that the Tmax (2 h) of GRT-P in rat stomachs was significantly extended compared with the Tmax (0.5 h) of nor-
mal reference preparation. Compared with the model group, low and high doses of GRT-P could significantly
inhibit the increase of malondialdehyde (MDA) in serum. Studies showed that the higher MDA content in
inflammation tissue increases the inflammatory response. The ulcer inhibition rates of GRT-P in the high-
dose group were 59.0 and 64.1% in the ranitidine group. Results indicated that GRT-Ps had the potential for
a sustained drug release and an enhanced gastric residence time with relatively high drug concentrations in
the tissue distribution.
Key words paeonol; gastric retention tablet; sustained release; gastric ulcer; efficacy

Paeonol, also called peony phenol, is the active component release drug delivery systems effectively regulate drug release
of a traditional Chinese medicine, namely, moutan cortex into the system; however, drug bioavailability is low because
(Paeonia suffruticosa A NDREWS, Ranunculaceae).1) Paeonol of low drug concentration in local tissue. Therefore, gastric
has been extensively studied for its anti-inflammatory, anti- retention agents are significant in treating stomach diseases
oxidant, anti-atherosclerosis, anti-diabetic, and anti-mutagenic with the advantages of improving drug efficacy and reducing
effects.2,3) However, paeonol has significant growth-inhibitory drug toxicity.12)
and apoptosis-inducing effects in gastric cancer cells in vitro Preliminary experiments showed that paeonol has certain
and in vivo.4) Moreover, studies have shown that paeonol pre- inhibitory effects for Helicobacter pylori and gastric ulcer. We
vents inflammatory diseases of the alimentary canal, such as aimed to develop a sustained-release oral dosage of paeonol to
irritable gastric ulcer, with minimal side effects.5) However, increase the partial blood–drug concentration in the stomach.
studies on the ethanol-induced gastric ulcer effect of paeonol The sustained-release system can achieve effective therapeutic
are lacking. Currently, the listed paeonol dosages are adminis- drug concentrations in the systemic circulation over an ex-
tered via ordinary oral tablets and injection. However, paeonol tended period.13) In this study, we selected the floating system
has poor water solubility, easy oxidation, and a short biologi- to increase gastric residence time and to sustain drug release
cal half-life.6–8) The paeonol products are unable to prolong for developing gastric retention tablets of paeonol (GRT-P).
effective drug concentration in blood to influence the oral We designed the formulation of gastric retention and sustained
bioavailability of a drug. Therefore, the present study, which release for 8 h by considering gastric emptying time, gastric
is based on the properties of paeonol, has been designed to retention factors, and dietary habits.14)
develop gastric retention tablets using modern technology to
achieve prolonged presence in the stomach, thereby improv- Experimental
ing treatment of gastric ulcer. This approach has a profound Preparation of GRT-P Paeonol is volatile with low melt-
clinical significance in developing a novel sustained-release ing points, thereby causing difficulty in using the wet legal
delivery system with good local treatment for improving the system grain. We selected direct powder compression con-
therapeutic effect. sidering the high influence of the drug product surface prop-
Gastric retention preparation can extend drug release dura- erties on drug dissolution.15,16) Drug directly released from
tion, increase local treatment concentration, and improve drug powder after tablet disintegration, which has a considerable
absorption and bioavailability.9–11) Most oral sustained-control dispersion, can accelerate dissolution and can improve rela-
 To whom correspondence should be addressed.  e-mail: annabel_cn@163.com; zhangtdmj@hotmail.com
* 
© 2017 The Pharmaceutical Society of Japan
 Chem. Pharm. Bull.
Vol. 65, No. 8 (2017)707

tive bioavailability. Moreover, direct powder compression is lease enhancer and surfactant on the release of paeonol were
simple and does not require granulating and drying, thereby also investigated. The release mechanism was preliminarily
ensuring a stable quality of the finished product. The selec- determined through the morphological observation and change
tion of appropriate accessories for direct powder compression of structure.24)
is important. Auxiliary materials should have good liquidity, In Vitro Release Rule and Mechanism A relevant math-
compressibility, suitable bulk density, and large pharmaceuti- ematical model can be used in fitting the drug release curve
cal accommodation.17) Therefore, this study selected hydro- of preparation in vitro.25,26) In vitro average cumulative release
philic gel skeleton materials, hydroxypropyl methyl cellulose, rate and time of GRT-Ps were fitted according to the differ-
foaming agent sodium bicarbonate, flow aid powder silica gel, ent mathematical models; three release equations were fitted,
filler lactose, and microcrystalline cellulose as tablet accesso- namely, zero order, first order, and Higuchi equations, which
ries. All materials and accessories passed through sieve no. 80 were used to describe the mechanism of drug release of the
separately. The powder blend was then compressed into tablets tablets. The data obtained from in vitro drug release studies
using an 8 mm flat-face round tool on a single-punch tablet were used to calculate the correlation coefficient (r) between
machine (Cadmach, Ahmedabad, India). The tablet contained the cumulative amount of drug released and time. The best-
80 mg paeonol and maintained 200 mg tablet weight. The com- fitting model was considered concerning the one that had a
pression force was adjusted to obtain tablets with hardness in maximum r value. The three models are presented as follows:
a range of 4–5 kg/cm 2. We first mixed the active pharmaceuti-
cal ingredients and micro-powder silica gel to ensure paeonol Zero- order release equation : M t /M ∞ = K t
content uniformity in the tablets and then blended them again First- order release equation : ln(1 − M t /M ∞ ) = − k t
with lactose and microcrystalline with good liquidity; finally, Higuchi release equation : M t /M ∞ = K1/2
t
we blended all the ingredients.18)
Statistical Design and Analysis Recently, the response In addition, Korsmeyer–Peppas equation (Mt /M∞=Knt ) was
surface method experimental design has been widely used in used to determine the release mechanism of paeonol from tab-
screening for new drug delivery systems to ensure prescrip- lets. If 0.45< n<0.89, then the drug release mechanism con-
tion and process optimization.19) The Box–Behnken design firms Fick’s diffusion law of the synergistic effect of skeleton
(BBD), a response surface method, aims to establish the rela- dissolution and diffusion.
tive importance of two or more factors; this design indicates In Vitro Floating Ability Study The floating behavior of
the interaction between various factors that influence the mag- the tablets was visually determined in triplicate according to
nitude of the response.20–22) Short cycles and high precision the floating lag-time method described by ref. 27). A tablet
can establish a continuous variable surface model by evaluat- was placed briefly in a glass beaker containing 100 mL of
ing the influencing factors and their interactions in the process simulated gastric fluid and was maintained in a water bath at
through a method with advantages of few tests to determine 37±0.5°C. The floating lag time (the time that GRT-P floated
the most efficient level and to decrease the experimental group from the bottom to the surface of the liquid) and the total
number, which can save manpower and material resources. In floating duration (from the GRT-P on float to the tablet dis-
this study, according to single-factor experiments, three main solution disappearance or sinking time) were recorded.28) The
factors (contents of HPMC-K4M, NaHCO3, and Avicel) were design goal of floating lag time in vitro was less than 3 min,
selected, and their proper ranges were determined. The results and the tablets could maintain a floating state for more than
of the single factor study reduced the range of HPMC-K4M 8 h.10)
to between 15 and 30%, NaHCO3 between 15 and 22.5%, and In Vitro Drug Release Behavior Drug release studies
Avicel between 5 and 12.5%. A 17-run BBD, including 12 fac- on the prepared GRT-Ps were performed in triplicate con-
torial and 5 axial points, was applied to determine the optimal sistent with General Requirements 0931, Volume IV of the
prescription. Three variables were presented, namely, X1 (the Pharmacopoeia of the People’s Republic of China 2015 edi-
amount of HPMC-K4M), X2 (the amount of NaHCO3), and X3 tion.29) The tablets were placed in a 900 mL simulated gastric
(the amount of Avicel), along with three levels coded 1, 0, and fluid solution containing 0.25% sodium dodecyl sulfate (SDS)
−1 for high, intermediate, and low, respectively. The response at 37±0.5°C water bath with paddles rotated at a speed of
values were Y1: drug accumulative release at 2 h in vitro (%) 100 rpm. Samples (5 mL) were withdrawn from the dissolution
and Y2: drug accumulative release at 8 h in vitro (%). The fac- apparatus in each vessel after 2, 4, 6, and 8 h and were filtered
tors and the response surface analysis are listed in Table 1. through a cellulose acetate membrane (0.45 µm). The drug
Morphological Study on GRT-P The release behavior content was determined through the HPLC spectrophotometric
of paeonol from the matrix tablets was studied in vitro. A method at 274 nm.30) In each withdrawal, 5 mL of fresh me-
scanning electron microscopy (SEM) was used to inspect the dium was replaced into the dissolution flask.12,31)
porosity and morphology of the drug-released tablets after Assessment of Stomach Retention Effect Male Sprague-
they swelled in the release medium.23) The effects of the re- Dawley (SD) rats fasted for 12 h after receiving water and
were mildly anesthetized with ether. The 3 mm GRT-Ps was
administered intragastrically compared with the reference
Table 1. Response Surface Analysis of Factors and Levels
preparation of homemade conventional tablets. After 0.5, 2,
Level HPMC-K4M (X1, mg) NaHCO3 (X2, mg) Avicel (X3, mg) 4, 6, and 8 h treatments, the five rats were executed at each
time point. Stomach tissue was collected through dissection
−1 30 30 10 by immediately cutting open along the great curvature of
0 42.5 37.5 17.5
the stomach. Then, the stomach tissue was rinsed with 5 mL
1 55 45 25
physiological saline. If the whole tablets were visible, then
708 Chem. Pharm. Bull. Vol. 65, No. 8 (2017)

they were taken out of the stomach. The flashed gastric con- River Laboratory Animal Technology Co., Ltd. (Beijing,
tents were cryopreserved in −80°C. After the gastric tissue China). This study was approved by the Ethical Committee
was blotted with filter paper, precisely weighed, and cut, the of the Laboratory Animal Center, Shanghai University of
corresponding volume of physiological saline was added to the Traditional Chinese Medicine. The protocol approval number
tissue samples (1 g stomach tissue : 3 mL saline volume)32,33) is SYXK (Shanghai) 2014-0008, and the date of approval is
with the homogenate instrument to shear and homogenate, and June 27, 2014.
then the serum was set aside for −80°C cryopreservation. Two Statistical Analysis All the data were presented as
sets of samples with the lyophilizer were dried, and the dry mean±standard deviation (S.D.) or mean. Multiple compari-
solid samples were dissolved in 2 mL methanol. We filtered sons of means (ANOVA) were used to substantiate statistical
the supernatant obtained after centrifugation by 0.22 µm filter differences between groups, and Student’s t-test was used to
membrane filtration and determined its content through the compare two samples. The significance was tested at the 0.05
HPLC method. level of probability (p). Data analysis was performed with
Establishment of Gastric Ulcer Models A total of 40 SPSS software package (version 19.0, IBM, NY, U.S.A.) or
SD male rats weighing approximately 250–270 g were ran- Design-Expert software (version 8.0.6, Stat-Ease Inc., MN,
domly divided into five groups, namely, blank, model, posi- U.S.A.).
tive control ranitidine hydrochloride, low-dose, and high-dose
groups, according to weight. The drug doses were as follows: Results and Discussion
low-dose group: 24 mg·kg−1, high-dose group: 48 mg·kg−1, and Optimal Prescription Screening Results The BBD
ranitidine-positive control group: 25 mg·kg−1. After fasting method of the central composite design establishes the relative
with water for 12 h before models were established, all groups importance of two or more factors and indicates whether or
except the blank group were given 0.5 mL·100 g−1 of anhy- not the interaction occurs between factors, thereby showing
drous ethanol by lavaging mode. After establishing the model the factor that affects the magnitude of the response.20–22) We
for 2 h, each dose group was given the drug according to the used Design-Expert software (version 8.0.6, Stat-Ease Inc.,
aforementioned dosages by lavage, and the normal control and MN, U.S.A.) to determine multiple regression fittings of the
model groups were given 1·d−1 saline for 6 d. The rat gastric data in Table 2. Several statistical parameters were estimated,
volume was 1 mL·100 g−1. Then, 2 h after the last delivery, the including p value and multiple correlation coefficients (r)
rat abdomen was split to remove the abdominal aortic blood, provided by Design-Expert statistical software (version 8.0.6).
and then pylori and cardia were ligated to take the whole The results indicated that these full quadratic models were
stomach. The mice were cut along the greater curvature of the significant for all response values.
stomach, which was then washed with physiological saline. The model equation for the tablets in in vitro floating per-
According to the standard of Okabe ulcer index, the length centage at 2 h (%) is expressed as follows:
and width of ulcer surface were measured with a vernier
Y1 = 37.26 − 24.18A +13.06B + 6.06C − 9.43AB
caliper, calculated ulcer index, and ulcer inhibition rate; and
then a part of ulcer gastric tissue was sheared to determinate −2.93AC +1.05BC − 0.98A 2 +12.69B2 +15.2C 2
the content of hexosamine in the supernatant of tissue homog- The model equation for the tablets in in vitro floating per-
enate; furthermore, the residual gastric tissue was fixed in centage at 8 h (%) is expressed as follows:
4% formaldehyde to prepare pathological sections for further
Y2 = 67.16 − 14.54A + 3.56B+ 5.08C − 2.98AB
observation of ulcer formation and healing.34–36)
The abovementioned animals were obtained from Vital −2.5AC − 2.25BC − 5.22A 2 +12.23B2 +8.21C2

Table 2. Corresponding Surface Analysis Method and Result Analysis

HPMC-K4M NaHCO3 Avicel PH-102 2 h drug accumulative 8 h drug accumulative

Run order
(mg) (mg) (mg) release (%) release (%)

1 42.5 37.5 17.5 39.6 67

2 55 45 17.5 29 59.9
3 42.5 30 10 47.6 80.3
4 42.5 37.5 17.5 38.5 64.9
5 55 37.5 25 30.4 62.1
6 42.5 45 25 84.8 90.4
7 42.5 45 10 73.5 91.2
8 55 37.5 10 21.2 50.5
9 30 37.5 25 87.6 94.8
10 42.5 30 25 54.7 88.5
11 30 45 17.5 95.2 96.3
12 30 30 17.5 50.1 82.5
13 30 37.5 10 66.7 73.2
14 55 30 17.5 23.6 58
15 42.5 37.5 17.5 24.3 57.5
16 42.5 37.5 17.5 45.6 74.1
17 42.5 37.5 17.5 38.3 72.3
 Chem. Pharm. Bull.
Vol. 65, No. 8 (2017)709

Fig. 1. Contour and Surface Plots of 2 h Drug Release

The r values of the two models were 0.9834 and 0.9605. ly. Optimal formulations using X1=40, X2=30, and X3=24 mg
The p values for the lack-of-fit tests were 0.8722 and 0.6095, were prepared using the aforementioned method. The actual
indicating that the full quadratic model adequately fits the values and predicted responses generated by the mathematical
response surface. model are presented in Table 3.
Based on the aforementioned fitting mathematical model, Characterization of Tablets in SEM When sodium bi-
we depicted the corresponding contour map and independent carbonate mixes with gastric juices, carbon dioxide escapes
variable on the dependent variable of the three-dimensional from the film, and the tablet surface forms holes (Fig. 3),
(3D) surface figure37,38) by using Design-Expert (version 8.0.6) indicating that sodium bicarbonate plays a dual role as a pore
software. The results are illustrated in Figs. 1 and 2. Based on forming and a bleaching agent. Simultaneously, the powder
the numerical optimization and our design goals, the desirable material hydroxypropyl methyl cellulose, which has a minimal
range of responses were 20%<Y1<50% and Y2>90%. Accord- density, swells after a certain period in the release medium to
ing to the results of the software analysis, the overall model form a gel skeleton (Fig. 4) and begins to capture the carbon
reached a significant level (p<0.05), indicating that the fitting dioxide-produced holes, thereby widening the film; some drug
quadratic equation model was significant. One of the factors release channels are formed by the gel skeleton combining
is fixed at the center value, whereas the 3D maps and contour with the aforementioned holes, and the swelling layer con-
lines of Y1 and Y2 to other two factors are depicted respective- tinues to be dissolved simultaneously. The floating time is
710 Chem. Pharm. Bull. Vol. 65, No. 8 (2017)

Fig. 2. Contour and Surface Plots of 8 h Drug Release

Fig. 3. Surface SEM Images of GRT-P (A: Before Swelling, B: After Fig. 4. Cross-Section SEM Images of GRT-P (A: Before Swelling, B:
Swelling) After Swelling)
 Chem. Pharm. Bull.
Vol. 65, No. 8 (2017)711

extended when the drug release channel increases gradually, indicates the good slow-release effect of the gastric retention
and the preparations are released in a slow manner. In this dy- tablets (Table 4).
namic process, the tablets can continue to float in the release Peppas equation is lg Mt /M∞=0.4704 lg t+1.5341, n=0.4704.
medium because the density of GRT-P core is smaller than the Hence, the releasing mechanism of paeonol is a synergistic
release medium. effect of skeleton dissolution and diffusion.
In Vitro Release Properties and Mechanisms The Higu- In Vitro Floating Ability Study The experimental results
chi equation of the correlation coefficient r=0.9985 is higher show that the property in vitro floating of GRT-P has achieved
than the other r values; therefore, the optimal fitting model the desired objective, with the short bleaching time within
of the release law for GRT-P is the Higuchi equation, which 3 min and maintaining floating in vitro for more than 8 h.
In Vivo Gastric Retention Study The GRT-P and the
Table 3. Optimal Prescription of Actual Value Compared with Predicted
reference preparations of paeonol (RP-P) after distribution in
Value rat stomach tissue are illustrated in Fig. 5; the gastric contents
are depicted in Fig. 6. The experimental results show that the
Y1 Drug accumulative Y2 Drug accumulative distributions of GRT-P in the gastric contents and tissue of
release at 2 h (%) release at 8 h (%) rats are larger than the RP-P, with the Tmax of 2 and 0.5 h, re-
Predicted value 50.66 82.17 spectively; then, the drug–time curve of GRT-P has shown the
Actual value 51.14 90.95 obviously sustained-release effect of extending up to 8 h com-
Error rate 0.21 9.85 pared with RP-P. The area under curve (AUC) data also have
Error rate (%)=(Actual value−Forecast value)/Forecast value×100%. the same trend in the gastric contents and tissue of rats, with
the GRT-P having a higher gastric intake content and more
gastric tissue distribution than RP-P; this result indicates that
Table 4. Fitting Results of Release Equation the GRT-P can improve gastric treatment concentration and
enhance the treatment efficiency for gastric diseases.
Model Equation r
Preliminary Results of Pharmacodynamic Gastric Ulcer
Zero order release Y=10.778X+13.630 0.9519 Compared with the normal control group, the model group
First order release Y=0.1086X+3.6895 0.9846 showed a significant increase in the malondialdehyde (MDA)
Higuchi release Y=32.338X+0.5242 0.9985 content. Compared with the model group with p<0.01, the

Fig. 5. Stomach Tissue Medication in Curve Comparison (n=5)

Fig. 6. Gastric Content Medication in Curve Comparison (n=5)

712 Chem. Pharm. Bull. Vol. 65, No. 8 (2017)

low- and high-dose groups demonstrated that the gastric float-

ing tablets significantly inhibited the increase of MDA in the
serum (Fig. 7).
Compared with the model group, the ulcer index of the
high-dose and ranitidine groups of the GRT-P were signifi-
cantly lower (p<0.01); statistical significance was observed,
and no differences were found in ulcer index between the two
groups. The results are presented in Table 5.
Compared with the blank group, the model group showed
significantly decreased hexosamine content at p<0.01. How-
ever, differences were observed. The high-dose group had the
highest hexosamine content, indicating that the gastric reten-
tion tablets increased the hexosamine of gastric tissue and
had certain therapeutic effects in the ethanol-induced gastric
ulcers of the rat (Fig. 8).
Ethanol administration resulted in a significant epithelial
desquamation, hemorrhage, and inflammatory cell infiltration
in the mucosa. In the GRT-P high-dose group, the epithelial
desquamation was largely prevented. Moreover, a slight in-
Fig. 7. Effect of GRT-P on Serum MDA Content in Rats flammatory cell infiltration and limited hemorrhagic regions
* p<0.01 versus model group. were observed. The results showed that ethanol administration
resulted in severe damage to parietal cells, and the GRT-P
treatment prevented the damage (Fig. 9).

Conclusion
Gastroretentive drug delivery systems are important in the
delivery of drugs to the upper part of the gastrointestinal tract.
In this study, gastroretentive sustained-release paeonol tablets

Table 5. Inhibition Effect of GRT-P for Ethanol-Induced Gastric Ulcer

in Rats

Ulcer index Ulcer inhibition

Group Dose (mg/kg)
(points) rate (%)

Blank group — — —
Model group — 3.90±1.13 —
Low dose 24 3.00±0.76 23.10
High dose 48 1.60±0.92* 59.00
Fig. 8. Hexosamine Content of Rat Stomach Tissue Ranitidine group 25 1.40±0.92* 64.10
* p<0.01 versus blank model. * p<0.01 versus model group.

Fig. 9. Effects of GRT-P on Histological Evaluation in Ethanol-Induced Gastric Ulcer (HE Staining)
A: intact stomach, B: ethanol-induced ulcer, C: ranitidine group, D: GRT-P 48 mg/kg, E: GRT-P 24 mg/kg. Scale bar: 200 µm.
 Chem. Pharm. Bull.
Vol. 65, No. 8 (2017)713

were successfully prepared with the desired release rates and G.-H., Eur. J. Pharm. Sci., 101, 189–199 (2017).
floating durations. The preparation of the tablet formulation 16) Zong S. Y., Pu Y. Q., Xu B. L., Zhang T., Wang B., Int. Immuno-
pharmacol., 42, 32–38 (2017).
was stable, controllable, high-quality, highly sensitive, and
17) Acharya S., Patra S., Pani N. R., Carbohydr. Polym., 102, 360–368
characterized by simple detection. GRT-P had certain inhibito-
(2014).
ry effects on the gastric ulcer, with relatively high concentra- 18) Singh B., Garg B., Chaturvedi S. C., Arora S., Mandsaurwale R.,
tions of tissue distribution, and good sustained-release ability Kapil R., Singh B., J. Pharm. Pharmacol., 64, 654–669 (2012).
to improve the treatment of gastric local concentration, which 19) Venkata Srikanth M., Sreenivasa Rao N., Ambedkar Sunil S.,
achieved the goal of treating gastric disease. This dosage form Janaki Ram B., Ramana Murthy Kolapalli V., Acta Pharmaceutica
is promising for further in vivo studies, which can be used to Sinica B, 2, 60–69 (2012).
develop new paeonol dosage forms. 20) Naghibi Beidokhti H. R., Ghaffarzadegan R., Mirzakhanlouei S.,
Ghazizadeh L., Dorkoosh F. A., AAPS PharmSciTech, 2, 1–15
Acknowledgments This experimental work was finan- (2016).
cially supported by National Natural Science Foundation of 21) Shah B., Khunt D., Misra M., Padh H., Int. J. Biol. Macromol., 89,
206–218 (2016).
China (No. 81303233) and Shanghai Committee of Science
22) Ye Z., Wang W., Yuan Q., Ye H., Sun Y., Zhang H., Zeng X., Car-
and Technology (No. 13401900300).
bohydr. Polym., 147, 354–364 (2016).
23) Eisenächer F., Garbacz G., Mader K., Eur. J. Pharm. Biopharm., 88,
Conflict of Interest The authors declare no conflict of 778–786 (2014).
interest. 24) Rajinikanth P. S., Karunagaran L. N., Balasubramaniam J., Mishra
B., Chem. Pharm. Bull., 56, 1658–1664 (2008).
References 25) Tao Y., Lu Y., Sun Y., Gu B., Lu W., Pan J., Int. J. Pharm., 378,
1) Tao W., Wang H., Su Q., Chen Y., Xue W., Xia B., Duan J., Chen 30–36 (2009).
G., Psychiatry Res., 238, 116–121 (2016). 26) Hwang K. M., Cho C. H., Tung N. T., Kim J. Y., Rhee Y. S., Park E.
2) Sun G. P., Wang H., Xu S. P., Shen Y. X., Wu Q., Chen Z. D., Wei S., Eur. J. Pharm. Biopharm., 16, 30494–30495 (2017).
W., Eur. J. Pharmacol., 584, 246–252 (2008). 27) Jimenez-Castellanos M. R., Zia H., Rhodes C. T., Int. J. Pharm.,
3) Wu M., Gu Z., Evid. Based Complement. Alternat. Med., 6, 57–63 105, 65–70 (1994).
(2009). 28) Razavi M., Karimian H., Yeong C. H., Sarji S. A., Chung L. Y.,
4) Li N., Fan L. L., Sun G. P., Wan X. A., Wang Z. G., Wu Q., Wang Nyamathulla S., Noordin M. I., Development and Therapy, 9, 3125–
H., World J. Gastroenterol., 16, 4483–4490 (2010). 3139 (2015).
5) Arya P., Pathak K., Int. J. Pharm., 460, 1–12 (2014). 29) National Pharmacopoeia Committee, “Pharmacopoeia of People’s
6) Tsai T. H., Chou C. J., Chen C. F., J. Pharm. Sci., 83, 1307–1309 Republic of China [M]. Part 4.” Chemical Industry Press, Beijing,
(1994). 2015, General rule 0931: 121-3.
7) Ma L. Y., Xu X. D., Zhang Q., Miao J. H., Tang B. L., Eur. J. Drug 30) Xu B. L., Wang B., Pu Y. Q., Tao J. S., Cai Z. Z., Chinese Tradi-
Metab. Pharmacokinet., 33, 133–136 (2008). tional Patent Medicine, 34, 1892–1896 (2012).
8) Xie Y., Jiang Z. H., Zhou H., Ma W. Z., Wong Y. F., Liu Z. Q., Liu 31) Tadros M. I., Eur. J. Pharm. Biopharm., 74, 332–339 (2010).
L., BMC, 28, 1294–1302 (2014). 32) Kovačič N. N., Pislar M., Ilic I., Mrhar A., Bogataj M., Int. J.
9) Kim J. Y., Bae H. J., Choi J., Lim J. R., Kim S. W., Lee S. H., Park Pharm., 473, 552–559 (2014).
E. S., Arch. Pharm. Res., 37, 1053–1062 (2014). 33) Sumsakul W., Karbwang J., Na-Bangchang K., Exp. Parasitol., 161,
10) Kotreka U. K., Adeyeye M. C., Crit. Rev. Ther. Drug Carrier Syst., 54–61 (2016).
28, 47–99 (2011). 34) Song J. W., Seo C. S., Kim T. I., Moon O. S., Won Y. S., Son H. Y.,
11) Parikh D. C., Amin A. F., Expert Opin. Drug Deliv., 5, 951–965 Son J. K., Kwon H. J., Biol. Pharm. Bull., 39, 221–229 (2016).
(2008). 35) Chen H., Liao H., Liu Y., Zheng Y., Wu X., Su Z., Zhang X., Lai Z.,
12) Yin L., Qin C., Chen K., Zhu C., Cao H., Zhou J., He W., Zhang Q., Lai X., Lin Z. X., Su Z., Fitoterapia, 100, 110–117 (2015).
Int. J. Pharm., 452, 241–248 (2013). 36) El-Ashmawy N. E., Khedr E. G., El-Bahrawy H. A., Selim H. M.,
13) Badhan A. C., Mashru R. C., Shah P. P., Thakkar A. R., Dobaria N. Nutrition, 32, 849–854 (2016).
B., AAPS PharmSciTech, 10, 459–467 (2009). 37) Ghari T., Mortazavi S. A., Khoshayand M. R., Gilani K., J. Drug
14) Narendra C., Srinath M. S., Babu G., AAPS PharmSciTech, 7, E34 Del. Sci. Tech., 24, 352–360 (2014).
(2006). 38) Hao J., Gao Y., Zhao J., Zhang J., Li Q., Zhao Z., Liu J., AAPS
15) Yao J., Zhang Y., Hu Q., Zeng D., Hua F., Meng W., Wang W., Bao PharmSciTech, 16, 118–128 (2015).