International Journal of Pharmaceutics 579 (2020) 119185

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International Journal of Pharmaceutics

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Preparation and evaluation of captopril loaded gastro-retentive zein based T

porous floating tablets
⁎
Ali Razaa, Uzma Hayata, Hua-Jie Wanga,b, Jin-Ye Wanga,
a
School of Biomedical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
b
JiaxingYaojiao Medical Device Co. Ltd., 321 Jiachuang Road, Jiaxing 314032, China

A R T I C LE I N FO A B S T R A C T

Keywords: In this study, gastro-retentive porous floating tablets of captopril based on zein are reported using L-menthol as a
Zein porogen. Tablets were prepared by the direct compression method. Removing of L-menthol through sublimation
Porous floating tablets process generated pores in tablets, which decreased the density to promote floating over gastric fluid. Prepared
Gastroretentive drug delivery tablets showed no floating lag time and prolong total floating time (> 24 h). Drug release was found dependent
Sublimation
upon porosity of tablets, an increase in porosity of tablets resulted in increased drug release, so it can be tuned by
L-menthol
varying concentration of L-menthol. In addition to floating and sustained release properties, porous tablets
showed robust mechanical behavior in wet conditions, which can enable them to withstand real gastric en-
vironment stress. In vivo studies using New Zealand rabbits also confirmed the prolonged gastric retention (24 h)
and plasma drug concentration-time profile showed sustained release of captopril with higher Tmax and MRT as
compared to marketed immediate-release tablets. Overall, it was concluded that effective gastric retention can
be achieved using porous zein tablets using L-menthol as a porogen.

1. Introduction
Gastro-retentive drug delivery systems (GRDDS) provide prolonged
gastric retention and are considered a promising tool for the prepara-
tion of sustained-release oral formulations for certain drugs (Mandal
et al., 2016). Drugs, with narrow absorption window (gastric region),
lower solubility/stability in intestinal fluid or whose local effect at the
gastric site is required for higher efficacy, are considered as potential
candidates for GRDDS (Lopes et al., 2016; Rahim et al., 2015). These
drugs have poor bioavailability when incorporated in conventional
sustained-release formulations. Several types of GRDDS were reported,
including floating, mucoadhesive systems, swelling/expanding, sinking,
and magnetically controlled drug delivery systems (Tripathi et al.,
2019). Out of them, floating drug delivery systems (FDDS) are con-
sidered promising as they do not interfere or affect normal physiolo-
gical processes of stomach and have better patient compliance (Singh
and Kim, 2000; Tripathi et al., 2019). Floating drug delivery systems
are further classified into two types based on the mechanism of floating,
which are effervescent and non-effervescent FDDS (Singh and Kim,
2000). Effervescent based systems have a gas generating agent as a key
component of their composition, which reacts with gastric acid to
produce carbon dioxide gas that entrapped by matrix-forming compo-
nent leading to floating of the system (Loh and Elkordy, 2015; Prajapati
et al., 2013). Generally, such systems have a drawback of floating lag
time, which can cause premature removal of the floating system from
the stomach, and also acidity of the stomach may be varied which can
affect gas generation (Bardonnet et al., 2006; Oh et al., 2013;
Treesinchai et al., 2019). Conversely, non-effervescent FDDS do not
have floating lag time and compose of low-density polymers. However,
formulation of such systems requires higher concentrations of low-
density polymers which can increase the bulkiness of dosage forms
(Hwang et al., 2017). Porous tablets were also reported in which pores
were generated through sublimable agents such as camphor, ammo-
nium carbonate, and L-menthol to reduce the density of tablets for fa-
cilitating floating over gastric fluid (Huanbutta et al., 2016; Hwang
et al., 2017; Oh et al., 2013). Natural materials are considered ideal for
biomedical applications owing to their availability, biocompatibility,
and safety profile (Razavi, 2018).
Zein is a biodegradable, biocompatible protein obtained from the
corn and has “Generally regarded as safe (GRAS)” status from FDA
(Zhang et al., 2015). Our group reported several studies for biomedical
applications of zein (Dong et al., 2004; Gong et al., 2006; Raza et al.,
2019; Tu et al., 2009; Wang et al., 2017, 2009, 2007, 2005). Zein has
hydrophobic nature, is swellable in the aqueous medium, and has
matrix-forming ability to sustain encapsulated drugs (Berardi et al.,
2018). Different tablets have been reported based on zein (Berardi

⁎
Corresponding author.
E-mail address: jinyewang@sjtu.edu.cn (J.-Y. Wang).

https://doi.org/10.1016/j.ijpharm.2020.119185
Received 28 December 2019; Received in revised form 10 February 2020; Accepted 25 February 2020
Available online 26 February 2020
0378-5173/ © 2020 Published by Elsevier B.V.
A. Raza, et al. International Journal of Pharmaceutics 579 (2020) 119185

et al., 2017a; Georget et al., 2008; Guo and Shi, 2009; Katayama and 2.3. Physicochemical characterization
Kanke, 1992; Raza et al., 2019). In our previous report, we have pre-
pared effervescent zein floating tablets prepared through the com- 2.3.1. Morphological analysis using SEM
pression coating technique (Raza et al., 2019). These tablets had gas Morphology of tablets was observed using the scanning electron
generating agents (sodium bicarbonate and citric acid) and had a microscope (S-3400, Hitachi, Japan) at 100X magnification. Both the
floating lag time. Compression coating also limits its use for drugs with outer surface and inner surface were observed.
higher doses due to an increase in the bulkiness of tablets.
Despite numerous works reported on GRDDS, only limited studies 2.3.2. Weight variation
had shown in vivo success due to complex physiological behavior of in Weight variation of tablets was evaluated by measuring weights of
vivo environment (Pawar et al., 2012). Destructive gastric forces may be 10 tablets before and after removal L-menthol of using an analytical
a possible reason for in vivo failure of gastro-retentive floating tablets balance (AL104, Mettler Toledo, USA). Results were expressed as
that demand improvement of mechanical strength of tablets in wet mean ± SD.
conditions (Kim et al., 2019). Recently, Nguyen et al. (2019) used
Kollidon® SR (hydrophobic retarding agent) to enhance the mechanical 2.3.3. Hardness of tablets
strength of porous tablets. Furthermore, pharmaceutical applications of The hardness of 5 tablets (before and after sublimation) was mea-
porous tablets are still limited due to poor strength of tablets which can sured using a tablet hardness tester (YD-I, Tianjin Hengchuangda
be broken during processing and transportation. Technology Development Co, Ltd., China). The results were expressed
Here, we prepared zein based porous tablets without floating lag as tensile strengths, which were calculated using Eq. (1) (Fell and
time and having prolonged total floating time with sustained release of Newton, 1970).
the drug. The use of zein in porous tablets was hypothesized to provide
2F
higher mechanical strength to tablets in dry and wet conditions, which σ=
πdt (1)
can ensure tablets integrity during transportation and under gastric
stress. Captopril was used as a model drug for the preparation of where σ is tensile strength, F is crushing force (N), d is diameter of
floating tablets. Captopril is unstable in intestinal fluid and due to this tablets and t is thickness of tablets.
no sustained release formulation is available in the market despite its
higher dose frequency (Jiménez-Martínez et al., 2008). L-menthol was 2.3.4. Density of tablets
used as a porogen that is also a food-grade ingredient with GRAS status. Densities of tablets (after sublimation) were determined by dividing
Different concentrations of L-menthol were used to prepare different the weight of tablets by bulk volume of tablets as given in Eq. (2).
batches of tablets and influence on floating and drug release was Densities of 5 randomly selected tablets were determined from each
evaluated. formulation and results were presented as mean ± SD.
m
2. Materials and methods Density (g/cm3) =
d 2
π· ( ) ·t
2 (2)
2.1. Materials
where m, d and t are mass, diameter and thickness of tablets, respec-
tively.
Zein was purchased from WAKO Pure Chemical Industries Ltd.,
Japan. Captopril was procured from Shanghai Shu Can Industrial Co.,
Ltd., China. L-menthol was procured from Adamas-beta, China. All 2.3.5. Porosity
other reagents used were of analytical grade and used without any Porosities of all formulations (n = 3) were determined using the
further purification. Archimedes immersion technique as reported previously (Gong et al.,
2006; Mazón and De Aza, 2018). Briefly, the weight of dried tablets
(m1), after immersion in water under vacuum for 2 h (wet mass, m2)
2.2. Preparation of tablets
and weight of wet tablets in water (apparent weight, m3) were ob-
tained. Open/apparent porosity (Po) was calculated using Eq. (3).
Porous tablets were prepared using the direct compression method.
L-menthol crystals were crushed and passed through a sieve (sieve no. (m3 − m1 )
Po = × 100
60 with aperture size 300 μm). All materials as per compositions de- (m3 − m2 ) (3)
scribed in Table 1 were briefly mixed in pestle mortar followed by
further mixing in a polythene bag and passed through a sieve with an
aperture size of 300 μm. Tablets were compressed at weight given in 2.3.6. Content of captopril
Table 1 using a hydraulic press (80 kg/cm2 for 2 s) using 10 mm flat- Captopril content in tablets was determined after the sublimation
faced punches. Compressed tablets were placed in a vacuum oven for process. Tablets (n = 3) were crushed in pestle mortar and powder
24 h at 60 °C to allow sublimation of L-menthol. Tablets were weighed equivalent to 25 mg of captopril was taken and diluted in 0.1 N HCl in
to confirm the removal of L-menthol during the heating process. 100 mL of volumetric flask. Resultant dilution was stirred, while
heating at 40 °C for 30 min followed by filtering through a syringe filter
Table 1
(0.45 μm). The absorbance of samples was determined after further
Composition (in mg) of porous floating tablets. dilution with 0.1 N HCl (1:10) at 212 nm using a UV visible spectro-
photometer (U-3010, Hitachi, Japan) and captopril content was mea-
Composition (mg) Formulations
sured using calibration curve (R2 = 0.999).
F0 F1 F2 F3 F4
2.4. In vitro floating behavior
Zein 200 200 200 200 200
Captopril 50 50 50 50 50
L-menthol 25 50 75 100 125
Floating lag time (time required for tablets to start float after in-
Mg. Stearate 2.75 3 3.25 3.5 3.75 troduction into the medium) and total floating time (time until tablets
remain floating over medium) are important characteristics of floating
Total weight 277.75 303 328.25 353.5 378.75
Theoretical Weight after heating 252.75 253 253.25 253.5 253.75 drug delivery systems. To determine floating efficiency, the method
reported by Kim et al. with minor modifications (Fig. S1) (Kim et al.,

2
A. Raza, et al.
2018). Briefly, tablets were immersed into 1000 mL 0.1 N HCl in
1000 mL beaker with magnetic stirrer rotating at 150 rpm. The tem-
perature of the system was maintained at 37 °C. Floating behavior was
recorded for 24 h. Also, a floating behavior after applying stress was
evaluated using a method as reported previously (Eisenächer et al.,
2014). Briefly, 2.4 N force was applied for 6 s on wet tablets (n = 3)
after removing from dissolution medium (0.1 N HCl) at 2, 6, 12, and
24 h using 10 mm flat-faced in-house made probe (250 g weight). After
removing probe, tablets were again introduced into dissolution medium
and floating lag time was measured. 3 tablets were used for each for-
mulation and repeated stress was applied to the same tablets after de-
fined time intervals.
2.5. Swelling (water uptake) and erosion evaluation
The swelling ratio (water uptake) and erosion for porous tablets
(n = 3) were determined by the gravimetric method. The initial weight
of tablets (m1) was measured. After immersion in 200 mL of 0.1 N HCl,
tablets were removed after different time intervals (1, 2, 4, 6, 8, 10, 12,
and 24 h) and weighed (wet weight, m2) after removing excessive
medium from the surface. Furthermore, tablets were freeze-dried to
remove adsorbed medium and were weighed (m3). Water uptake (%)
and erosion (%) were calculated using Eqs. (4) and (5), respectively.
m − m1
Swelling index % = 2 × 100
m1 (4)
m − m3
% erosion = 1 × 100
m1 (5)
Water uptake by tablets was also visualized using fluorescent dye
Rhodamine G (0.1 mg/mL) in the dissolution medium. After the same
intervals as for swelling/erosion study, tablets were removed and
fluorescent images of cross-section were captured using a fluorescent
microscope (IX71, Olympus Optical Co., Ltd., Japan) to observe pene-
tration of water as red due to Rhodamine G.
2.6. Mechanical strength determination of wet tablets
Mechanical strength of tablets wetted in dissolution medium (0.1 N
HCl) was quantified using Modulator Compact Rheometer (MCR302,
Anton Paar, Austria). Tablets were removed from the dissolution
medium after 4, 8, and 12 h. A flat-faced 15 mm probe was penetrated
in wet tablets with a speed of 0.05 mm/s and the force-displacement
curve was obtained. Force (N) and work done (mJ) required to pene-
trate the probe up to 3 mm of tablets were calculated from curves and
compared. 3 tablets were used for each time point and results were
presented as mean ± SD.
2.7. In vitro drug release
In vitro drug release of floating tablets was determined in 1000 mL
of 0.1 N HCl in 1000 mL beaker. Agitation was produced with a mag-
netic stirrer at 150 rpm. The system was incubated at 37 °C during the
study (Raza et al., 2019). A simple approach based on the basic prin-
ciple of the official dissolution test method was used to avoid the ad-
herence of tablets with the shaft of the paddle (Gohel et al., 2004). 5 mL
of medium was withdrawn after different time intervals (1, 2, 4, 6, 8,
10, 12, and 24 h) and absorbance of withdrawn samples (diluted, if
required) was measured using the UV visible spectrophotometer at
212 nm after filtering through 0.45 μm syringe filter. Released captopril
content was calculated using the already established calibration curve
(R2 = 0.999). For each formulation, 3 randomly selected tablets were
used to evaluate in vitro drug release and results were expressed as
mean ± SD. The effect of pepsin was also evaluated on drug release
using F2. For this purpose, pepsin (3.2 g/L, 819 units/mg protein) was
added in 1000 mL of 0.1 N HCl and drug release quantification was
3
International Journal of Pharmaceutics 579 (2020) 119185
performed using the same dissolution test system. After predetermined
time points, 5 mL of dissolution medium was withdrawn and analyzed
using HPLC (L-2130, Hitachi, Japan) by a validated method with partial
modifications as reported previously (Naveed et al., 2013). Chromato-
graphic separation was done using reverse phase column C18 (Athena
C18, 4.6 ∗ 250 mm, 5 μm, Anpel Laboratory Technologies Inc., China)
with UV detection at 215 nm. Methanol: water: phosphoric acid
(55:45:0.05 v/v) mixture was used as a mobile phase with a flow rate of
0.5 mL/min. The concentration of captopril was calculated using the
calibration curve through peak area (R2 = 0.998). Dissolution profiles
were compared using the similarity index (f2) calculated using the
DDSolver plugin (Moore and Flanner, 1996; Zhang et al., 2010b). A
value of f2 greater than 50 showed a similarity between dissolution
profiles of two formulations. Drug dissolution data was further fitted for
zero order, first order, Higuchi and the Korsmeyer-Peppas model using
DDSolver plugin as per Eqs. (6)–(9), respectively (Zhang et al., 2010b).
Release exponent “n” in the Korsmeyer-Peppas model was used to
evaluate the mechanism of drug release. A value of “n” equal or less
than 0.45 show quasi Fickian diffusion, 0.45 for Fickian diffusion,
0.45–0.89 show non-Fickian diffusion, while a value greater than 0.89
shows case II transport (Korsmeyer et al., 1983).
Zero order Equation:
Mt
= ko t
M∞ (6)
First order Equation:
Mt
M∞
(
= 100 × 1 − e−k1 t ) (7)
Higuchi square root Equation:
Mt
= kh t1/2
M∞ (8)
Krosmeyer Pappas Equation:
Mt
= kp t n
M∞ (9)
where Mt/M∞ is amount of drug release in time t, k shows release rate
constants for corresponding model and n is release exponent.
2.8. In vivo pharmacokinetics
Pharmacokinetic study for floating tablets was performed on New
Zealand rabbits. Animals (3 rabbits, 2.5–2.6 kg) were procured from Jie
Si Jie Co., Ltd (Shanghai, China) and were acclimatized for one week
prior study. Animals study was conducted after the approval of the
Animals Ethics Committee, Shanghai Jiao Tong University. A cross-over
design was used for the study with a washout period of 7 days. The
study was performed on immediate-release captopril tablets (25 mg, 2
pills, Jiangsu Pengyao Pharmaceuticals Inc., China) and porous floating
tablets. 12 h fasting was allowed with free access to water before the
administration of tablets. Tablets were administered using “Pet Piller”
for proper swallowing. After administration of tablets, blood samples
(1 mL) were collected from marginal ear vein after 0.75, 1, 2, 3, 4, 6, 8,
12, and 16 h for immediate-release tablets and after 1, 2, 4, 6, 8, 12, 16,
20, 24, 36, and 48 h for floating tablets. Animals were allowed to eat
standard food (70 g each) at 12 and 24 h during the study, while free
access to water was provided during the complete study. Collected
blood was immediately transferred to Eppendorf tubes containing 10 µL
of EDTA (0.1 M) and 10 µL of ascorbic acid (0.1 M) to prevent oxidation
of captopril and centrifuged at 4000 rpm for 10 min to separate plasma.
Captopril was extracted from plasma and analyzed using HPLC as per
the previously reported method (Supplementary Methods S1) (Huang
et al., 2006; Li, Tan, & Zhou, 1996). Plasma concentration-time curves
were analyzed using PKSolver plug-in using the non-compartmental
approach to determine pharmacokinetic parameters (Zhang et al.,
A. Raza, et al. International Journal of Pharmaceutics 579 (2020) 119185

2010a).
2.9. In vivo radiographic study for evaluation of gastric retention
New Zealand rabbits (n = 3, 2.5–2.6 kg) were used for radiographic
study. Barium sulfate (10 %) was added in tablets and the same amount
of captopril was omitted. Tablets were administered to rabbits (12 h
fasting) and were fed at 12 h (70 g each), while allowed free access to
water during the study. X-ray radiographs were captured after 4, 8, 12,
and 24 h of administration of floating tablets (F2) under the same
parameters.
2.10. Statistical analysis
The comparison between different parameters of formulations was
done using Student’s t-test and a value of p < 0.05 was considered as
significant. For bioavailability comparison of formulations, area under
the plasma concentration-time curve was compared.
3. Results and discussion
3.1. Preparation and physico-chemical characterization of tablets
Floating tablets were prepared using the direct compression
method. The direct compression method is considered beneficial as
compared to the wet granulation technique because of simplicity, cost-
effectiveness, and continuous processing (Dai et al., 2019). Zein
without any other excipient can be used to prepare tablets by direct
compression method (Georget et al., 2008; Liu et al., 2005). Zein based
directly compressed tablets were reported to have lower density as
compared to tablets compressed after wet granulation or directly
compressed tablets containing calcium hydrogen phosphate (Georget
et al., 2008), therefore, the direct compression method was selected to
prepare floating tablets. Prepared tablets were treated with heat 60 °C
for 24 h to get porous tablets by removal of L-menthol through the
sublimation process. Weights of tablets before and after the sublimation
process were measured in for weight variation analysis and confirma-
tion of complete sublimation of L-menthol (Table 2). The porous
structure of the outer surface and cross-sectioned areas of tablets was
observed using SEM micrographs as shown in Fig. 1a. Porosity and bulk
densities of all formulations are given in Fig. 1b & c, respectively. With
an increase in the concentration of L-menthol in tablets, an increase in
porosity was observed that was due to more pore generation. Con-
versely, the bulk density of tablets was reduced with increase in por-
osity. All formulations showed bulk less than 1 with the highest value of
0.95 ± 0.04 g/cm3 for F0, while F4 showed the lowest density of
(0.67 ± 0.006 g/cm3). The bulk density with a value lesser than 1 g/
cm3 is necessary for the floating of tablets. Weights, diameter, thick-
ness, tensile strength, and content of captopril of porous tablets are
summarized in Table 2. Before the sublimation process, no significant
difference was found for the tensile strength of all formulations. The
tensile strength of all formulations was found to be increased sig-
nificantly (p < 0.05) after the sublimation process. These results were
found in agreement with the previous report in which a higher me-
chanical strength of zein conduits was observed after higher tempera-
ture treatment for the leaching process (Wang et al., 2017). Effect of
temperature of zein can be explained in light of the study reported by L.
Wang et al. that thermal treatment can break intrinsic disulfide linkages
and after treatment, zein molecules were cross-linked through new
disulfide bonds (Wang and Zhang, 2019). This re-arrangement of dis-
ulfide linkages were reported to occur at temperature 55–70 °C for
gluten proteins (Schofield et al., 1983). Higher tensile strength of ta-
blets after heat treatment might be due to this self-assembled structure.
Moreover, the tensile strength of F0 and F1 with low porosity was found
significantly higher (p < 0.05) than F2, F3, and F4, however, no sig-
nificant difference (p > 0.05) was found between F2, F3, and F4,
which could be explained by porosity variation. Higher tensile strength
of porous tablets is proposed to ensure tablet integrity during proces-
sing, transportation, and storage. Furthermore, the present facile pro-
duction method (direct compression and heating) shows promising
feature for large scale production.
3.2. In vitro floating behavior
Porous tablets showed immediate floating after immersion into
dissolution medium (0.1 N HCl) owing to their low density except for
F0, which did not float over the surface of the medium because of
higher density than other formulations (Fig. 2a). Porous tablets are
advantageous over effervescent based floating tablets due to lack of
floating lag time. Formulation F1-F4 showed total floating time over
24 h (Fig. 2a). Fig. 2b shows floating scores of porous tablets. F1-F4
showed a 10/10 score for 24 h, while F0 scored 0/10 due to non-
floating behavior. The scoring for porous zein tablets was better as
compared to previously reported HPMC/PEO based effervescent
floating tablets because they showed a lag time of more than 5 min to
get a level of 10/10 score that was due to floating lag time (Kim et al.,
2018). Under in vivo gastric conditions, tablets have to face stress
condition and a maximal force of 2.4 N may be exerted on tablets.
Therefore, floating tablets (F1-F4) were subjected to stress at 2.4 N
using a 10 mm flat-faced probe for 6 s followed by re-immersion into
the dissolution medium to observe floating behavior (Fig. 2c). F1 and
F2 showed robustness against stress conditions and exhibited a lower
floating lag time up to 24 h (10.3 s and 128 s, respectively) as shown in
Fig. 2d. F3 had intermediate strength as compared to F4 and F1/F2 with
floating lag time of about 2 h after 24 h, however, lag time less than
1 min was observed fir F3 after 12 h. F4 exhibited poor mechanical
stress withstanding because they were failed to float after 24 h
(Fig. 2d). Bulk densities of tablets after immersion in dissolution
medium were also measured which showed a relative constant bulk
density (< 1 g/cm3) after a brief increase in 1 h due to parallel increase

Table 2
Physico-chemical characteristics of porous floating tablets.
Formulations Before sublimation After sublimation Captopril
content$ (%)
Weight* (mg) Thickness* (mm) Diameter* (mm) Tensile Weight* (mg) Thickness* (mm) Diameter* (mm) Tensile
Strength# Strength#
(MPa) (MPa)

F0 276.5 ± 1.6 3.29 ± 0.07 10.08 ± 0.03 1.29 ± 0.05 254.7 ± 1.6 3.38 ± 0.02 10.14 ± 0.06 3.36 ± 0.19 97.2 ± 2.43
F1 304.8 ± 1.5 3.72 ± 0.11 10.06 ± 0.03 1.14 ± 0.06 256.6 ± 2.7 3.85 ± 0.12 10.17 ± 0.05 2.40 ± 0.32 97.4 ± 1.00
F2 327.8 ± 1.4 4.15 ± 0.07 10.11 ± 0.03 1.02 ± 0.06 255.3 ± 3.0 4.29 ± 0.03 10.19 ± 0.07 1.74 ± 0.19 96.7 ± 2.21
F3 354.1 ± 1.0 4.32 ± 0.07 10.08 ± 0.02 1.00 ± 0.09 254.0 ± 1.5 4.41 ± 0.11 10.18 ± 0.05 1.88 ± 0.17 95.8 ± 2.14
F4 378.8 ± 2.4 4.71 ± 0.04 10.05 ± 0.04 0.94 ± 0.25 252.7 ± 1.6 4.83 ± 0.04 10.11 ± 0.05 1.79 ± 0.14 95.7 ± 2.08

* n = 10.
#
n = 5.
$
n = 3.

4
A. Raza, et al.
Outer Inner
a b
F0
F1
F2
F3
F4
Fig. 1. Physical characteristics of floating porous tablets. (a) SEM micrographs of Outer and inner (cross-sectioned) areas of porous tablets (scale bar = 200 μm). (b)
Bulk densities of porous tablets (n = 3). (c) Porosity of porous tablets (n = 3).
in size with water uptake (Fig. S2). Overall, porosity can be considered
as a key factor for the mechanical stability of the matrix because an
increase in porosity can reduce the ability of tablets to withstand
against stress.
3.3. Swelling (water uptake) and erosion study
Water uptake (%) and erosion (%) of tablets with time were mea-
sured using the gravimetric method. Water uptake and erosion are
important parameters for determining the mechanism of drug release
and also responsible for floating behavior. Zein has hydrophobic nature
yet can swell in the aqueous medium. Guo & Shi, (2009) reported dry
coated zein tablets that exhibited initial swelling of about 80% and 4%
erosion which remained constant over time. Here, F4 with 61% porosity
showed significantly higher overall water uptake after 24 h as com-
pared to F1-F3 (Fig. 3a). Porosity facilitated the dissolution medium
uptake leading to a higher swelling ratio of F4. To visualize the water
uptake by tablets rhodamine G containing medium was used followed
by observation under a fluorescent microscope that also confirmed slow
penetration of medium in tablets with time. Furthermore, the erosion of
tablets was also evaluated after the freeze-drying of swelled tablets.
Zein is reportedly non-erodible in the aqueous medium; however, we
found erosion of tablets up to 17% at 24 h (Fig. 3b) that was might be
due to the release of the drug with time.
3.4. In vitro drug release
In vitro drug release profiles are given in Fig. 4a. A burst release of
drug was found in all formulations during 1 h, while a sustained release
of drug was observed with time. Porosity was found to be important in
controlling the release of captopril as the release rate was increased in
order of F4 > F3 > F2 > F1 with significant variation according to
5
International Journal of Pharmaceutics 579 (2020) 119185
1.0
0.8
Density (g/cm )
0.6
0.4
0.2
0.0
F0 F1 F2 F3 F4
Formulations
c 70
60
50
Porosity (%)
40
30
20
10
0
F0 F1 F2 F3 F4
Formulations
f2 values (Fig. 4a). Furthermore, the influence of the presence of pepsin
in the dissolution medium was also evaluated on F2 (Fig. 4b) that
showed no significant difference when compared with drug release
without pepsin (f2 = 55.02). Zein is resistant to digestive enzymes,
however, longer duration can enhance the degradation of zein (Nguyen
et al., 2019a; Wang et al., 2018). Limited exposed surface area to dis-
solution medium due to floating nature might be another reason for no
effect of pepsin on drug release. Captopril is freely soluble in 0.1 N HCl
and retardation of release is necessary for sustained release of captopril.
Zein can act as a retarding agent by the formation of a gelatinous layer
upon contact with the dissolution medium at 37 °C (Guo and Shi, 2009).
After 1 h of incubation of tablets in dissolution medium such a gelati-
nous layer can be observed (Fig. 4c).
To determine the mechanism of drug release from porous tablets, a
correlation was drawn between water uptake and erosion of tablets
with drug release as shown in Fig. 5a & b. A good correlation
(R2 = 0.960) was existed between drug release and water uptake
(%)/erosion (%) for all formulations. Water uptake is reportedly the
main mechanism of drug release as zein is non-erodible (Berardi et al.,
2017b, 2017a; Guo and Shi, 2009) and an increase in erosion was might
be due to release of drug from tablets as no eroded particles were ob-
served in the medium. Furthermore, water uptake was visualized by
adding Rhodamine 6G in dissolution medium (using F2) followed by
observation under the fluorescent microscope which showed gradual
penetration of water from the outer surface to core (Fig. 5c). Green core
(zein) after 24 h in F2 can reasonably explain 68.5% release of captopril
due to low penetration of water. Porosity is an important parameter for
drug release as reported by Guo and Shi, (2009). They found that zein
powder dry coating caused slow release (~10% in 12 h) as compared to
zein granules dry coating (~100% in 12 h) due to higher porosity of
coating layer. In the present study, the lack of interconnected porosity
may be responsible for the incomplete release of the drug even after
A. Raza, et al. International Journal of Pharmaceutics 579 (2020) 119185

F0
a F0 F1 F2 F3 F4 b F1
10 F2
F3
8 F4

Floating score
0h 6

2
24 h
0

0 5 10 15 20 25
Time (h)

c d
10000 2h
6h
12 h
Floating Lag Time (s)
1000 24 h

Non Floating
100

10

1
F1 F2 F3 F4
Time (h)
Fig. 2. In vitro floating behavior test. (a) Tablets floating status after 0 and 24 h of incubation in dissolution medium at 37 °C. (b) Floating score of all formulations in
1000 mL of medium under stirring conditions of 150 rpm (n = 3). (c) Images of tablets after removing from medium, applying stress of 2.4 N for 6 s and again
immersion of tablets in dissolution medium for observing floating tendency. (d) Floating lag times of tablets after applying stress of 2.4 N for 6 s at 2, 6, 12 and 24 h of
incubation in dissolution medium (n = 3).

24 h.
Drug release profiles were fitted for zero-order, first-order, Higuchi
and Korsmeyer-Peppas Model as shown in Table 3 and curve fitting is
shown in Fig. S3. No formulation presented a good fit for zero or first-
order release, while F3 was best fitted for the Higuchi model
(R2 = 0.960). All formulations exhibited best fitting for the Korsmeyer-
Peppas model with R2 values ranging from 0.994 to 0.999. Further-
more, all formulations followed quasi-Fickian diffusion for drug release
as indicated by the value of release exponent ‘n” that is less than 0.45,
which means mainly diffusion process was involved in the drug release
mechanism. Zein based matrices were previously reported to have re-
lease exponent less than 0.45 (Berardi et al., 2017b). In our previous
study, tablets with a lesser amount of zein in the coating layer had
quasi-Fickian diffusion (n < 0.45), however, tablets with a higher
amount of zein in the coating layer showed anomalous release
(n > 0.45) (Raza et al., 2019). Based on these studies, it can be

F1
200 F1
F2
20 F2
F3
F3
F4
160 F4
Water uptake (%)

15
Erosion (%)

120

10
80

5
40

0 0
0 5 10 15 20 25 0 5 10 15 20 25

Time (h) Time (h)

Fig. 3. Swelling (water uptake) (a) and erosion (b) of floating tablets with time (n = 3).

6
A. Raza, et al. International Journal of Pharmaceutics 579 (2020) 119185

Fig. 4. In vitro drug release from porous tablets. (a) Drug release profiles of all formulations in 1000 mL of 0.1 N HCl (n = 3). (b) Effect of pepsin (3.2 g/L) on drug
release from tablets of F2 (n = 3). (c) Tablet removed from dissolution medium after 1 h (c1) to observe gelatinous structure formation by self-assembly of zein (c2).
(c3) and (c4) are magnified images of highlighted sections of (c2).

a 100 b 100
r = 0.988
Cumulative drug release (%)

r = 0.961
Cumulative drug release (%)

80
80 r = 0.984
r = 0.971 r = 0.989
60 r = 0.967 F1
60 r = 0.992 F1 F2
F2 F3
F3 40 r = 0.987
40 F4
F4 Fitting for F1
Fitting for F1 Fitting for F2
Fitting for F2 20
20 Fitting for F3
Fitting for F3 Fitting for F4
Fitting for F4
0
0 0 2 4 6 8 10 12 14 16 18
0 40 80 120 160 200
Water uptake (%) Erosion (%)
c

Fig. 5. Investigation of drug release mechanism. (a) Correlation between cumulative drug release (%) and swelling/water uptake (%) (p < 0.05). (b) Correlation
between cumulative drug release (%) and erosion (%) (p < 0.05). (c) Visualization of water uptake by tablets using Rhodamine 6G containing medium followed by
observation under fluorescent microscope (green fluorescence shows zein and red fluorescence shows Rhodamine 6G). (For interpretation of the references to colour
in this figure legend, the reader is referred to the web version of this article.)

7
A. Raza, et al. International Journal of Pharmaceutics 579 (2020) 119185

Table 3
Fitting of drug release profiles with different release kinetic models.
Formulations Zero order model First order model Higuchi model Korsmeyer Peppas model

2 2 2
K0 R K1 R Kh R Kp R2 n

F1 2.97 ± 0.15 0.84 ± 0.0 0.05 ± 0.0 0.90 ± 0.0 12.21 ± 0.66 0.96 ± 0.0 20.01 ± 1.53 0.998 ± 0.0 0.29 ± 0.01
F2 4.15 ± 0.04 0.80 ± 0.02 0.09 ± 0.0 0.92 ± 0.01 17.22 ± 0.24 0.95 ± 001 28.88 ± 2.16 0.994 ± 0.0 0.28 ± 0.02
F3 4.69 ± 0.13 0.73 ± 0.02 0.13 ± 0.01 0.8 ± 0.01 19.80 ± 0.62 0.98 ± 0.01 41.58 ± 2.63 0.999 ± 0.0 0.18 ± 0.01
F4 5.46 ± 0.23 0.79 ± 0.04 0.18 ± 0.18 0.931 ± 0.03 22.70 ± 0.76 0.94 ± 0.24 41.66 ± 2.36 0.998 ± 0.00 0.24 ± 0.04

n = 3.

Fig. 6. Mechanical strength evaluation of wet

a b 20
F1-4 h tablets. (a) Images of different stages during
50
F1-8 h penetration of probe into tablets. (b) Mean
F1-12 h force distance curves (up to 3 mm penetration)
40 F2-4 h of floating tablets after removing from dis-
F2-8 h solution medium at 4, 8 and 12 h (n = 3). (c)
10 F2-12 h Force in Newton for probe to penetrate at 3 mm
30 F3-4 h
Force (N)

and work done (N. mm) for same level pene-

F3-8 h tration is given in (d).
F3-12 h
20 F4-4 h
0 F4-8 h
10 3.0 3.5 F4-12 h

0
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
Penetration (mm)
c 50 F1 d F1
F2
Penetration Work (N. mm)

40 F2
40 F3 F3
F4 F4
30 30
Force (N)

20 20

10
10

0
4 6 8 10 12 4 8 12
Time (h) Time (h)

F2 (Floating tablet) proposed that zein matrices, which have relatively free access or pe-
Plasma concentration (ng/ml)

Marketed immediate release tablet netration of dissolution medium show quasi-Fickian diffusion in-
1200 dependent of polymer relaxation, while in non-porous zein matrices
anomalous release is dominant.

800 3.5. Mechanical strength of wet tablets

Mechanical strength of wet tablets is an essential parameter for in

vivo successful gastric retention and sustained release of the drug
400 against real gastric stress (Eisenächer et al., 2014; Nguyen et al.,
2019b). Therefore, probe penetration method (Fig. 6a) was used for the
determination of the mechanical strength of wet tablets after removal
from the dissolution medium at 4, 8, and 12 h. Mean force-distance
0
0 5 10 15 20 25 30 35 40 curves at different time points of floating tablets are shown in Fig. 6b.
Forces required for 3 mm penetration and work done (N. mm or mJ) for
Time (h) penetration are shown in Fig. 6c & d, respectively, which showed a
Fig. 7. Plasma drug concentration profiles of marketed immediate release ta- reduction of mechanical integrity of tablets with time and porosity of
blets and porous floating tablets (F2) (n = 3). tablet, however; they could tolerate 2.4 N stress (maximal gastric stress)
without destruction. Zein has hydrophobic nature and formation of the
rubbery state in wet conditions by rearrangement of secondary struc-
ture attributes towards the better wet mechanical property of tablets for
a longer duration of time as compared to previously reported tablets

8
A. Raza, et al.
Table 4
Pharmacokinetic parameters of porous floating tablets (F2) and marketed immediate release tablets.
Formulations Parameters
t1/2 (h) Tmax (h)
F2 7.76 ± 0.77 4.66 ± 1.15*
Immediate release tablets 5.08 ± 0.55 0.75 ± 0
* Significant difference between F2 and immediate release tablets (p < 0.05) (n = 3).
Fig. 8. Radiographs of rabbits at (a) 4, (b) 8, (c) 12 and (d) 24 h after administration of barium sulfate (10%) loaded floating tablets (F2).
(Gong et al., 2006). For instance, Hwang et al., (2017) reported max-
imum work done of about 2 mJ after 8 h wetting with a force of less
than 0.5 N for hydroxyl methyl cellulose (HPMC) based porous floating
tablets. In another report, Thapa & Jeong, (2018) reported less than
6 N. mm (mJ) of work done for penetration of probe up to 8 h for
polyethylene oxide (PEO) based effervescent floating tablets. Overall,
zein based tablets showed good mechanical stability in wet conditions.
3.6. In vivo pharmacokinetics
Animal studies were carried out in rabbits. The selection of animals
for pre-clinical studies is crucial but it is difficult to consider all para-
meters in a single animal model (Hatton et al., 2015). For the gastric
emptying aspect, rodents may be considered best models but the size of
the dosage may influence the results (Hatton et al., 2015). In the pre-
sent study, tablets with 10 mm diameter were used for in vivo experi-
ments, which may be considered too big. However, several reported
studies used rabbits for evaluation of 10 mm or bigger tablets (Qi et al.,
2015; Saisivam et al., 2013). 9–11 mm tablets were reported to have
less than 4 h gastric emptying time in rabbits, which indicates such big
sized tablets can pass through the stomach without any non-physiolo-
gical gastric retention (Dev et al., 2011; Patel and Amin, 2011). In vivo
plasma concentration-time profiles of floating tablets (F2) and mar-
keted immediate-release tablets are shown in Fig. 7 and pharmacoki-
netic parameters are given in Table 4. F2 showed a typical sustained
release profile with significantly higher (p < 0.05) Tmax
(4.66 ± 1.15 h) as compared to that of immediate-release tablets
(0.75 ± 0 h). Additionally, higher mean residence time
(12.4 ± 1.1 h) was observed for F2 than immediate-release tablets
(6.38 ± 1.4 h). No significant difference was observed for the area
under curves for both formulations. The mean relative bioavailability
(F) of floating tablets to immediate-release tablets was 134.8%. Cap-
topril is unstable in intestinal higher pH so prolonged gastric retention
is required to formulate sustained-release tablets. Sustained release will
help to reduce dose frequency, which can promote patient compliance.
Higher MRT and Tmax for floating tablets indicate sustained release of
the drug. Sustained-release tablets were reported to have lower relative
bioavailability to immediate-release tablets (Qin et al., 2018; Rahim
et al., 2017). Here, 134.38% relative bioavailability can be explained by
the stability of captopril in gastric fluid. Due to shorter gastric residence
9
International Journal of Pharmaceutics 579 (2020) 119185
Cmax (ng) MRT (h) AUC0-t (μg/mL.h)
531.5 ± 120.1* 12.4 ± 1.1* 6.04 ± 2.03
1181.4 ± 54.3 6.38 ± 1.4 4.48 ± 0.52
time, incomplete absorption of captopril from immediate-release tablets
was a possible reason for lower bioavailability as reported in the case of
dihydromyricetin (Liu et al., 2019).
3.7. In vivo radiographic study
Gastric retention of floating tablets (F2) was evaluated in vivo by
capturing x-ray radiographs after the administration of barium sulfate
loaded tablets to New Zealand rabbits (Fig. 8). After 12 h, floating ta-
blets were observed in the stomach (3/3 rabbits), however, after 24 h,
tablet in one rabbit was not observed in the radiograph that was might
be due to degradation or elimination of tablet but in 2/3 rabbits, tablets
were observed at stomach position.
4. Conclusion
Floating based gastro-retentive drug delivery systems can be effec-
tively used for enhanced gastric retention. Porous tablets are com-
paratively a novel approach that offers no floating lag time, however,
poor mechanical strength is a major drawback for them leading to poor
handling and in vivo failure. In this study, zein based captopril loaded
porous tablets were prepared with an intrinsic low density without any
lag time for effective gastric retention. A simple preparation method
(direct compression) was used for the fabrication of tablets. Prepared
tablets exhibited higher mechanical strength after the sublimation
process. Drug release of tablets can be tuned by adjusting the porosity
of tablets, which can be controlled by the amount of L-menthol in ta-
blets. Hydrophobicity and rubbery texture of zein in aqueous medium
attributed to mechanical robustness of tablets, which is necessary to
withstand gastric stress. In vivo studies also confirmed enhanced gastric
retention (24 h) and sustained release of drug at the gastric site.
Overall, zein porous tablets showed successful in vivo gastric retention
for a prolonged period and application of this system can be extended to
other drugs suitable for gastro-retentive drug delivery systems.
CRediT authorship contribution statement
Ali Raza: Investigation, Writing - original draft, Visualization.
Uzma Hayat: Investigation, Visualization. Hua-Jie Wang:
Methodology, Writing - review & editing. Jin-Ye Wang: Supervision,
A. Raza, et al.
Project administration, Funding acquisition, Writing - review & editing,
Conceptualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgements
This work was supported by the Shanghai Municipal Science and
Technology Commission, China (13JC1403400, 15540723900,
18490740200), and Shanghai Municipal Education Commission, China
(Gaofeng Biomedical Engineering Grant, ZXGF082101), National Key
Research and Development Project, China (2019YFE0101200),
National High-End Foreign Experts Recruitment Plan, China
(G20190009056) and the Plan of Jiaxing Innovation and Elites Leading.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ijpharm.2020.119185.
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