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European Journal of Applied Sciences – Vol. 10, No. 2
Publication Date: April 25, 2022
DOI:10.14738/aivp.102.11992. Murata, Y., Kinoshita, M., Kofuji, K., & Maida, C. (2022). Preparation of Metoclopramide-loaded Film Dosage Forms using Natural
Polysaccharides. European Journal of Applied Sciences, 10(2). 128-136.
Services for Science and Education – United Kingdom
Preparation of Metoclopramide-loaded Film Dosage Forms using
Natural Polysaccharides
Yoshifumi Murata
Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan
Mayuko Kinoshita
Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan
Kyoko Kofuji
Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan
Chieko Maida
Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan
ABSTRACT
Natural polysaccharides are used as pharmaceutical or food ingredients. In this
study, film dosage forms (FDs) containing the model drug metoclopramide (MCP)
were prepared using sodium alginate or pectin as the film base, and the
preparations were modified using additives such as chitin. The dissolution profiles
of MCP from the FDs in a small volume of physiological saline were investigated. All
the forms immediately swelled, disintegrated in physiological saline, and were
transformed into a gelatinous substance. When the FD was prepared using sodium
alginate, MCP incorporated in the form gradually dissolved into the test solution. In
contrast, the drug immediately dissolved if the FD was prepared with pectin. The
MCP dissolution rate can be controlled by modification of the film base with suitable
additives. These results suggest that FDs prepared using these water-soluble
polysaccharides can be useful for administering medicines to persons that have
difficulty swallowing.
Keywords: Film dosage form; Metoclopramide; Sodium alginate; Pectin; Chitin; Alginic
acid.
INTRODUCTION
Natural polysaccharides are used as pharmaceutical or food ingredients because they are safe
to take orally, and because of their biological activities and polymeric characteristics [1, 2].
Alginic acid is an algal polysaccharide that consists of
-L-guluronic acid and
-D-mannuronic
acid. Alginic acid and its sodium salt (Alg-Na) are formulation additives used as tablet
disintegrators [3–5]. Alg-Na is also used orally to treat gastroesophageal reflux disease or
stomach ulcer because of its protective effect on the gastric mucosa [6–8]. Pectin is an anionic
polysaccharide composed of galacturonic acid, and the methyl ester is widely used as a food
additive as a gelling agent [9, 10]. Chitin is an abundant natural polysaccharide that consists of
N-acetyl-glucosamine and is generally extracted from crab or shrimp shell. Chitosan is the
cationic polysaccharide obtained by the deacetylation of chitin and is used in pharmaceutical
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Murata, Y., Kinoshita, M., Kofuji, K., & Maida, C. (2022). Preparation of Metoclopramide-loaded Film Dosage Forms using Natural Polysaccharides.
European Journal of Applied Sciences, 10(2). 128-136.
URL: http://dx.doi.org/10.14738/aivp.102.11992
preparations due to its unique physical properties resulting from electrostatic interactions [11,
12]. Chitosan is also an attractive material for drug development in the medicinal industry [13,
14].
Both Alg-Na and pectin immediately form a strong gel matrix in the presence of divalent cations
such as calcium ions. Gel beads prepared with calcium and Alg-Na or pectin have been studied
as vehicles for oral drug delivery [15–18]. Also, thin films can be simply prepared by using these
polysaccharides without the need for dissolution in organic solvents, controlling the pH, or
heating. When a film dosage form (FD) is prepared using a water-soluble polymer, the FD
rapidly swells, disintegrates, and transforms into a gelatinous substance in body fluids,
releasing the active compound incorporated into the polymer matrix. Therefore, FDs have
attracted interest as a dosage form not only for oral care, but also for patients who have
difficulty swallowing regular tablets [19–22]. However, the drugs incorporated in the FD should
be carefully selected because the drug loading capacity of the film matrix is typically low. We
previously reported the characteristics of FDs containing therapeutically active compounds
prepared with various polysaccharides [23, 24].
The dopamine receptor antagonist metoclopramide (MCP) has been used as an antiemetic and
gastroprokinetic [25, 26]. MCP is administered orally (approximately 10–20 mg per day) in
tablet or granule form, or as a syrup preparation, to patients of a wide range of ages. In the
present study, we prepared FDs containing the model drug MCP using Alg-Na or pectin as the
film base and modified the preparations using additives such as chitin. The drug release rates
from the FDs were investigated in a small amount of physiological saline.
MATERIALS AND METHODS
Materials
A high-molecular-weight polymer of Alg-Na, Alg-A (Nacalai Tesque, Inc. Kyoto, Japan), two low- molecular-weight polymers of Alg-Na, Alg-B and Alg-C (Kimica Co., Tokyo, Japan), and two
pectins, A-PT and C-PT (Sigma, St. Louis, MO, USA) were used as film bases, and several
polysaccharides were used as additives, as shown in Table 1. Nicotinic acid, sodium nicotinate
and nicotinamide (Wako Pure Chemical Industries, Ltd., Osaka, Japan) were also used as
additives. The model drug MCP, and hydroxylamine (HX), were purchased from Wako. The
water-soluble carbodiimide 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p- toluenesulfonate (CMEC) was purchased from Aldrich Chemical Co. (Milwaukee, WI, USA). All
other chemicals used were of reagent grade and obtained from commercial sources.
Table 1. Polysaccharides used for the preparation of film dosage forms
Name Manufacturer (species) Abbreviation Purposes
Sodium alginate Nacalai Tesque (300 cps) Alg-A Film base
Sodium alginate Kimica Co. (I-1G) Alg-B Film base
Sodium alginate Kimica Co. (IL-1G) Alg-C Film base
Pectin Sigma (apple pectin) A-PT Film base
Pectin Sigma (citrus pectin) C-PT Film base
Chitin Nacalai Tesque (powder) ----- Additive
Chitosan Kimica Co. (fine powder) ----- Additive
Alginic acid Wako (non-swelling) ----- Additive
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METHODS
FD preparation: FD was prepared using a casting method as follows: 1.5–2.0% (w/w) Alg-Na
or pectin was prepared as a film base solution in deionized water. MCP (10 mg) and/or additive
was added to 10 g of the base solution, then the mixture was thoroughly mixed by sonication
and poured (3 g each) into individual plastic Petri dishes (diameter, 54 mm). The dishes were
kept for 24 h at 40 °C, after which the formed circular films were transferred into a desiccator.
The thickness of each film was measured at 10 points using a micrometer (CLM1-15QM;
Mitutoyo, Kawasaki, Japan) with a set pressure of 0.5 N. Measurements were taken using three
films, and the mean thickness was calculated for each type of film.
Solubility of MCP: The solubility of MCP was measured in 10 mL of ion-exchanged water
containing 10 mg of additive. MCP was added to the test solution, and the mixture was shaken
at 37 °C for 24 h. The suspension was removed using a plastic syringe preheated to 37 °C, and
filtered using a syringe-driven filter unit (pore size: 0.45 μm). The solution was diluted with
methanol, mixed, and centrifuged (7,700 × g) (H-1300; Kokusan Co., Saitama, Japan) for 5 min.
The supernatant was then injected onto an HPLC column.
MCP assay: The HPLC system comprised a pump (LC-10AS; Shimadzu, Kyoto, Japan), a packed
column (150 mm × 4.6 mm, Cosmosil 5C18-MS-II, Nacalai Tesque, Inc.), a detector (UV-2075,
JASCO Co., Tokyo, Japan), and an auto-injector (SIL-10A; Shimadzu). The analysis was
conducted at ambient temperature using a mobile phase consisting of 20 mM phosphate buffer
(pH 2.2) and methanol (18:7) at a flow rate of 1.0 mL/min [27]. The detector wavelength was
set at 285 nm.
Drug dissolution test: The film was placed in a plastic dish and 10 mL of physiological saline
preheated at 37 °C was added. The dish was shaken at 300 rpm in an incubator (SI-300; As One
Co., Osaka, Japan) set at 37 °C. The medium (0.3 mL) was periodically removed using a plastic
syringe and filtered through a syringe-driven filter unit (pore size, 0.45 μm). An equal volume
(0.3 mL) of physiological saline at 37 °C was added to the dish in the incubator to maintain a
constant volume. The sample solution (80 μL) was placed in micro test tubes (1.5 mL), to which
720 μL of methanol was added to precipitate the polysaccharide dissolved from the dosage
form. Samples were mixed and centrifuged at 7,700 × g for 5 min and the supernatants were
injected onto the HPLC column. Each test was performed in triplicate.
Film disintegration test: The sample solution was obtained by the same method as described
in the drug dissolution test section. Next, aliquots (0.2 mL) of the filtered solution were
combined with 0.8 mL of ion-exchanged water in test tubes before vortexing. Each test was
performed in triplicate. The amount of Alg-Na in each sample solution (1 mL) was measured
using the method described below.
Colorimetric assay for alginate: The reagent solutions used were 20 mM HX in ion-exchanged
water and 0.1 M CMEC in 2% pyridine-HCl buffer (pH 5.0). Aliquots of HX and CMEC (1 mL each)
were added to 1 mL of the sample solution, followed by vortexing. Each mixture was incubated
at 40 °C for 20 min, after which 20 mM FeCl3 in 0.1 M HCl (3 mL) was added. The absorbance
of the solution was measured at 480 nm in a quartz cell (1 cm light path) using a
spectrophotometer (UV-1200; Shimadzu). Each absorbance value was normalized to that of a
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Murata, Y., Kinoshita, M., Kofuji, K., & Maida, C. (2022). Preparation of Metoclopramide-loaded Film Dosage Forms using Natural Polysaccharides.
European Journal of Applied Sciences, 10(2). 128-136.
URL: http://dx.doi.org/10.14738/aivp.102.11992
reagent blank. For each test, a calibration curve was constructed using a fresh set of Alg-Na
standards.
RESULTS AND DISCUSSION
Addition of drug and/or additive to the film base solution affected film formation. Circular films
(thickness: approximately 100
m) were formed when either 1.5% high-molecular-weight Alg- Na or 2–4% low-molecular-weight Alg-Na containing MCP was cast, as shown in Figure 1.
Although thin films could not be formed using 2% pectin containing MCP as the film base, FDs
were obtained by adding chitin or chitosan to the film bases.
The FD prepared using a water-soluble polysaccharide immediately swelled and disintegrated
in physiological saline, resulting in release of the drug incorporated in the form. Figure 2 shows
the dissolution profiles of MCP from FDs prepared using various types of Alg-Na. MCP gradually
dissolved after the form was brought in contact with the test medium. When the FDs were
prepared with 1.5% Alg-A, the amount of MCP dissolved from the form at 5 min was 0.35 ± 0.05
mg and at 20 min it was 0.55 ± 0.04 mg. For FDs prepared using 2–4% low-molecular weight
Alg-Na, approximately 0.5 mg of the drug dissolved at 20 min. Similar drug dissolution rates
were obtained from FDs prepared using 1.5% Alg-A containing 0.1% chitin or 0.1% chitosan,
as shown in Table 2.
Figure 1. Images of film dosage forms prepared with polysaccharides containing
metoclopramide
(a) 1.5% high-molecular-weight sodium alginate (Alg-A), (b) 2% low-molecular-weight sodium
alginate (Alg-B), (c) 2% apple pectin (A-PT), (d) 1.5% Alg-A containing 0.1% chitin, (e) 1.5%
Alg-A containing 0.1% alginic acid, and (f) 2% A-PT containing 0.2% chitin
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Figure 2. Dissolution profiles of metoclopramide (MCP) from film dosage forms prepared with
various types of Alg-Na
Each result represents the mean and standard deviation of three independent determinations.
Alg-A; high-molecular-weight sodium alginate, Alg-B; low-molecular-weight sodium alginate
(Kimica Co., I-1G), Alg-C; low-molecular-weight sodium alginate (Kimica Co., IL-1G)
Table 2. Effect of additive on the metoclopramide dissolution rate from film dosage forms
prepared with 1.5% Alg-A
Additive 5 min (mg) 20 min (mg)
0.1% Chitin 0.32 ± 0.01 0.50 ± 0.03
0.5% Chitin 0.37 ± 001 0.55 ± 0.01
0.1% Chitosan 0.33 ± 0.03 0.51 ± 0.02
0.5% Chitosan 0.44 ± 0.02 0.58 ± 0.01
The disintegration profiles of the films were assessed by measuring the amount of Alg-Na
dissolved in the test medium from each FD. Figure 3 shows the disintegration profiles of FDs
prepared with Alg-Na. For the FD prepared with 1.5% Alg-A, about 40% of Alg-Na dissolved in
the test solution after 5 min. For FDs prepared with Alg-A containing 0.1% chitin, 26% Alg-Na
dissolved after 5 min from the FD. In contrast, the FD prepared with 2% low-molecular weight
Alg-Na immediately disintegrated; for example, 75% Alg-Na dissolved after 5 min from the FD
prepared with 2% Alg-B. These results show that the disintegration profile of FD did not affect
the MCP dissolution rate from the form.
0
1
2
3
0 10 20 30
M
C
P (m
g)
Time (min)
1.5% Alg-A
2% Alg-B
4% Alg-C
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Murata, Y., Kinoshita, M., Kofuji, K., & Maida, C. (2022). Preparation of Metoclopramide-loaded Film Dosage Forms using Natural Polysaccharides.
European Journal of Applied Sciences, 10(2). 128-136.
URL: http://dx.doi.org/10.14738/aivp.102.11992
Figure 3. Dissolution profiles of sodium alginate (Alg-Na) from film dosage forms prepared
using Alg-Na
Each result represents the mean and standard deviation of three independent determinations.
Alg-A; high-molecular-weight sodium alginate, Alg-B; low-molecular-weight sodium alginate
Rapid drug dissolution profiles were observed for the FDs prepared using pectin, as shown in
Figure 4. In FDs prepared with 2% A-PT containing 0.2% chitin or 2% C-PT containing 0.2%
chitin, the amount of dissolved MCP from the FDs at 5 min were 2.44 ± 0.02 mg and 1.94 ± 0.09
mg, respectively. Rapid MCP dissolution was also observed for FDs prepared with Alg-Na
containing an additive such as alginic acid, as shown in Table 3. In addition, a similar drug
dissolution rate was obtained when the FD was prepared with 1.5% Alg-A containing 0.1%
nicotinic acid as an additive. However, there was no apparent change in the drug dissolution
rate when the FD comprised 1.5% Alg-A containing 0.1% sodium nicotinate or nicotinamide.
Figure 4. Dissolution profiles of metoclopramide (MCP) from film dosage forms prepared with
pectin containing chitin
0
20
40
60
80
100
0 10 20 30
R
ele
ase
d
Alg-N
a (%)
Time (min)
1.5% Alg-A
1.5% A-g-A + 0.1% Chitin
2% Alg-B
0
1
2
3
0 10 20 30
M
C
P (m
g)
Time (min)
2% A-PT + 0.2% Chitin
2% C-PT + 0.2% Chitin
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Each result represents the mean and standard deviation of three independent determinations.
A-PT; apple pectin, C-PT; citrus pectin
Table 3. Metoclopramide dissolution rate from film dosage forms prepared with 1.5% Alg-A
containing 0.1% additive
Additive 5 min (mg) 20 min (mg)
Alginic acid 1.09 ± 0.08 1.41 ± 0.11
Nicotinic acid 2.35 ± 0.27 2.59 ± 0.37
Sodium nicotinate 0.35 ± 0.01 0.60 ± 0.03
Nicotinamide 0.35 ± 0.03 0.68 ± 0.10
Table 4 shows the water-solubility of MCP at 37 °C. Solubility remained essentially unchanged
by the addition of chitin or chitosan, whereas the addition of alginic acid increased the solubility
of MCP. An incremental change in MCP solubility in physiological saline was also observed when
nicotinic acid, a weak acid, was added to the solution. In contrast, the drug solubility did not
change upon the addition of sodium nicotinate to the test solution. These results suggest that
changes in the MCP dissolution rate from the various FDs tested are likely due to the interaction
between the drug and components of the film base, such as pectin or an additive.
Table 4. Solubility of metoclopramide in water containing 0.1% additive at 37 °C
Additive Solubility (
g/mL)
Free 0.3
Chitin 0.2
Chitosan 0.2
Alginic acid 1.6
Nicotinic acid 2.8
Sodium nicotinate 0.2
CONCLUSION
FDs prepared with natural polysaccharides are considered useful for oral drug administration.
In this study, MCP-loaded FDs were prepared using natural polysaccharides as a film base or
an additive. The release rate of MCP from FDs and the disintegration profile of the dosage form
were then investigated using a small amount of physiological saline. FD prepared with Alg-Na
readily swelled and MCP incorporated in the form gradually dissolved. Disintegration of the FD
did not affect the MCP dissolution rate from the dosage forms. In contrast, the drug immediately
dissolved from FDs prepared with pectin. The MCP release rate is controllable by modifying the
film base with suitable additives. Our findings show that FDs prepared with Alg-Na or pectin
can be used to administer medicines to patients that have difficulty swallowing, because these
FDs rapidly disintegrate and solubilize even in restricted amounts of medium, such as saliva.
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Murata, Y., Kinoshita, M., Kofuji, K., & Maida, C. (2022). Preparation of Metoclopramide-loaded Film Dosage Forms using Natural Polysaccharides.
European Journal of Applied Sciences, 10(2). 128-136.
URL: http://dx.doi.org/10.14738/aivp.102.11992
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