Preparation and Characteristics of Film Dosage Form Natural Polysaccharides

doi:10.4236/pp.2011.23028

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Pharmacology & Pharmacy, 2011, 2, 194-198

doi:10.4236/pp.2011.23028 Published Online July 2011 (http://www.scirp.org/journal/pp)

Preparation and Characteristics of Film Dosage

from Natural Polysaccharides

Yoshifumi Murata1*, Kyoko Kofuji1, Norihisa Nishida2, Ryosei Kamaguchi2

1Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan; 2Morishita Jintan Co. Osaka Technocenter, Hirakata,

Japan.

Email: [email protected]

Received May 2nd, 2011; revised June 2nd, 2011; accepted June 10th, 2011.

ABSTRACT

We investigated preparation of film dosage form (FD) from natural polysaccharides using the casting method without

organic solvents, heating or pH control. Ferulic acid (FA) and catechin were employed as model compounds incorpo-

rated in the FD, and the release profile of each compound from the form was investigated in the limited medium. Film

formation was affected by the addition of the model compound to the polysaccharide solution. Rigid FD was obtained

with 2% low-molecular-weight alginate (L-ALG; thickness, 65 µm), and it ha rdened after the addition of 0.5% polyga-

lacturonic acid, although the thickness of the film did not change. The FDs immediately released the model compound,

and the forms dissolved in phosphate-buffered saline. FD modification did not affect the FA release rate except in the

early stage. FD would be a useful dosage f orm, especially for preve nting or treating l ocalized problems in the or al cavity.

Keywords: Film Dosage Form, Natura l Polysaccharide, Sodium Alginate , Ferulic Acid, Catechin

1. Introduction

Film has been noted as a dosage form in the fields of

medicine and cosmetics [1,2]. The film dosage form (FD)

adheres to a surface when a little liquid is present on it,

and then the drug or another active compound incorpo-

rated in the film is released. The FD design results in the

distribution of the drug across the region to which the

form is attached. However, FD swells and erodes if it is

prepared with aqueous-soluble materials. For example,

fast-dissolving film is quickly disintegrated by saliva

when it is used in the oral cavity [3,4]. Recently, this

film has attracted interest not only for oral care but for

patients with aphagia or dysphagia as well [5,6].

Polymer compounds are generally utilized as the film’s

base. Some water-soluble polymers are especially useful

because of the safety in which the film is prepared and

applied to humans. For example, gelatin polypeptide is

the most popular one for film formation and has been

used as the base for capsule preparation [7]. First, aque-

ous gelatin solution is prepared, and then, a cross- link-

ing agent such as glutaraldehyde is added to stabilize the

film. Agar, a polysaccharide has also been studied as a

potential material for film preparation. In general, agar

dissolves in water by heating, and the resultant solution

is then cooled and dried for film formation. In the case of

FD preparation, active compounds such as drugs are

added to the polymer solution. Therefore, the chemical

or thermal stability of the compound must be incorpo-

rated when FD is prepared using these polymers. On the

other hand, some polysaccharides can dissolve in aque-

ous solution without heat and form the film in dry sol-

vent. For example, neutral polysaccharides such as pul-

lulan (PUL) and acidic polysaccharides such as sodium

alginate (ALG) and sodium chondroitin sulfate (CHS)

are known film bases [8-11]. Although FD is readily

prepared using these aqueous polysaccharides, film for-

mation is affected in th e presence of additives, in cluding

drugs.

In this study, we investigated the preparation of FD

from natural polysaccharides without dissolving in or-

ganic solvents, heating, controlling the pH or adding a

plasticizer such as sorbitol, fatty acid or polyvinyl alco-

hol. Ferulic acid (FA) and catechin (CA) were employed

as mod el co mp o und s . FA is an an ti-o x id iz ing ag en t an d a

part of the human diet [12], and its physiological action

mitigates lifestyle-related diseases such as hypertension,

hyperlipidemia, and diabetes [13-15]. CA is a polyphenol

compound and a component of green tea that used for

beverages [16]. The model compound is expected to be

active following dissolution in body fluids such as saliva

Preparation and Characteristics of Film Dosage from Natural Polysaccharides195

upon oral FD administration [17,18]. Therefore, the re-

lease profile of each FD compound was investigated in

limited dissolution medium.

2. Experimental

2.1. Materials

Low-molecular-weight alginate (L-ALG) was obtained

from Alfa Aesar (Ward Hill, MA, USA), and high-mo-

lecular weight alginate (H-ALG), from Nacalai Tesque

Inc. (300 cps, Kyoto, Japan). Pullulan (PUL) was sup-

plied by Hayashibara Biochemical Laboratories (Okaya-

ma, Japan), and a polysaccharide produced by Bifido-

bacterium longum JBL05 (BPS) was supplied by Mor-

ishita Jintan (Osaka, Japan) [19]. CHS (C type) and

phos- phate-buffered saline (PBS; pH 7.4) were pur-

chased from Wako Pure Chemicals (Osaka, Japan). Chi-

tosan (CS; degree of deacetylation: 75% - 85%) was ob-

tained from Kimitsu Chem. Ind. (Tokyo, Japan). Hy-

droxypropyl methylcellulose acetate succinate (AS-HF

type; HPMC) was obtained from Shinetsu Chem. Co.

(Tokyo, Japan). A polygalacturonic acid (PGA) was

purchased from MP Biomedicals (Solon, OH, USA) and

another (pectic acid) from Wako Pure Chemical. FA was

purchased from Tsuno Food Ind. Co. Ltd. (Wakayama,

Japan). (+)-Catechin hydrate (CA) was purchased from

Spectrum Chemical MFG. Co. (New Brunswick, NJ,

USA). All other chemic al s we re of reagent grade.

2.2. FD Preparation

Each polysaccharide solution (0.5% - 4%) was prepared

using deionized water. A model compound was added to

the polysaccharide solution and mixed well, and 3.0 g of

the solution was poured into a p lastic Petri dish (diameter,

54 mm). After 24 h at 37˚C, the film formed on the dish

was transferred into a desiccator. Film formation was

judged to not have occurred if a film could not be re-

moved from the bottom of the dish.

2.3. Film Thickness and Rheological Properties

Film thickness was measured at 10 points on each film

using a micrometer (CLM1-15QM; Mitutoyo, Kawasaki,

Japan) with a set pressure of 0.5 N. Measurements were

made on 3 films, and the mean thickness was calculated.

The rheological properties of each film were determined

using a rheometer (SUN RHEO TEX SD-700#; Sun

Scientific Co., Tokyo, Japan) at room temperature. The

film was fixed on a vial (inner diameter, 1.4 mm; outer

diameter, 18.8 mm) using joining tape (Scotch mending

tape; Sumitomo 3M Ltd., Tokyo, Japan) and probed with

a cylindrical adapter (diameter, 5.0 mm). Stress and

strain were measured at the point at which the adapter

broke through the film. All tests were performed in trip-

licate.

2.4. X-Ray Diffractometry

X-ray diffractometry was carried out using an automatic

diffractometer (D8 DISCOVER with GADDS; Bruker

AXS K.K., Yokohama, Japan) with a voltage of 40 kV

and a current of 40 mA. The results of X-ray diffraction

were interpreted using a computer program (Bruker AXS

K.K.).

2.5. Dissolution Test

Physiological saline or PBS (pH 7.4) was used as the

dissolution test medium. A film was placed in a plastic

dish, and 10 mL of dissolution medium incubated at

37˚C was added. The dish was shaken at 300 rpm in a

shaker incubato r at 37 ˚C. An 80 µL aliquot was removed

periodically and placed in a micro test tube (1.5 mL) and

720 µL of methanol was added to precipitate the poly-

saccharide dissolved from the dosage form. The sample

was mixed and centrifuged (10,000 rpm, 5 min), and

then, the supernatant was injected into a high-perform-

ance liquid chromatography (HPLC) column. All tests

were performed in triplicate. The HPLC system had an

LC-6A pump (Shimadzu Co., Kyoto), a packed column

(150 mm × 4.6 mm; Cosmosil 5C18-MS-II; Nacalai Tes-

que, Kyoto), and a SPD-6A UV detector (Shimadzu Co.).

For determination of FA, HPLC was conducted at an

ambient temperature using an eluent containing 10

mmol/L phosphate buffer (pH 4.7) and methanol (8:2) at

a flow rate of 0.8 mL/min [20]. The detector wavelength

was set as 260 nm, and an eluent comprising 0.1% citric

acid and acetonitrile (87:13) was used to quantify CA;

the detector wavelength was then set to 280 nm [21].

3. Results and Discussions

To form circular film using the casting method, 1 - 4%

solution of each polysaccharide was prepared without

heating and poured into a Petri dish. The solvent was

then evaporated. The film formation was affected by

adding FA or CA to the polymer solution. Neither 4%

CHS nor 1.5% H-ALG adequately utilized the FD mate-

rials containing 3 mg FA. In addition, 4% CHS did not

form a circular film, while 1.5% H-ALG formed a fragile

film (Figure 1). On the other hand, 4% PUL formed a

rigid film for which the thickness and the stress were 51

± 2 µm and > 500 kPa, respectively. Additionally, 0.5%

BPS formed a soft film (thickness, 52 ± 2 µm; stress, ~

50 kPa). In the case of 2% L-ALG, a circular film

(thickness, 65 ± 1 µm) was obtained that could be modi-

fied through addition of other polysaccharides such as

PGA. Both 4% PUL and 2% L-ALG formed circular

films when CA was include in the film base (Figure 2).

Preparation and Characteristics of Film Dosage from Natural Polysaccharides

196

Figure 1. FDs prepared using various polysaccharides con-

taining FA (3 mg).

Figure 2. FDs prepared using various polysaccharides con-

taining CA (1.5 mg).

Table 1. FD thicknesses prepared using various polysac-

charides containing 3 mg FA.

Film base Additive Thickness (µm) SD (µm)

2% L-ALG 65 1

0.5% CS 96 6

1% CS 144 3

1% EC 87 2

1% HPMC 56 5

1% CHS 55 4

1% pectic acid 60 2

0.1% PGA 70 1

0.5% PGA 67 4

1% PGA 71 3

1.5% PGA 75 1

2% PGA 70 0

3% L-ALG 49 8

1.5% H-ALG 1% PGA 59 2

The actual drug contents calculated by the weights of

dried films were 6.6% (1.5% H-ALG), 4.2% (2% L-ALG)

and 2.5% (4% PUL), respectively.

Table 1 shows the thickness of the film prepared using

L-ALG or H-ALG as a film b ase. The thicknesses of the

films prepared with 2% L-ALG containing each poly-

saccharide except for 1% CS were < 100 µm. When FD

was prepared using 2% L-ALG thickened by the addition

of 0.5% CS; however, the increment of thickness did not

necessarily increase FD hardness (Figure 3). A more

rigid film was obtained by the addition of 0.5% PGA to

Figure 3. Rheological properties of FDs containing 3 mg FA.

Closed circle: 2% L-ALG; open circle: 2% L-ALG + 0.5%

CS; open square: 2% L-ALG + 0.5% PGA.

Figure 4. X-ray diffractograms. A: FA (powder); B: 1.5%

H-ALG film (FA free); C: 1.5% H-ALG film containing

FA.

2% L-ALG, although film thickness did not change.

Figure 4 shows the X-ray diffraction p attern s obtain ed

from FA powder and FDs prepared with 1.5% H-ALG;

FA exhibited a characteristic crystalline compound pat-

tern of diffraction. On the other hand, FD containing FA

showed a pattern which lacked the characteristic diffrac-

tion peaks of FA. This result shows that the crystal form

of FA is only slightly pr esent in FD.

FD is expected to release the compound contained in

the dosage form upon contact with saliva, which is se-

creted from the salivary glands at 0.5 - 0.6 L/day (1.5 -

2.0 mL/min when stimulated) [22]. In this study, a film

was soaked in 10 mL of PBS buffer (pH 7.4), and the

released amount of FA or CA was then measured. The

release profiles of FA from the FDs prepared using the

different polysaccharides are shown in Figure 5. All FDs

subsequently swelled in the dissolution medium and re-

leased FA incorporated in the FDs with disintegration. In

particular, FD prepared with H-ALG or BPS quickly

Preparation and Characteristics of Film Dosage from Natural Polysaccharides197

Figure 5. Release profiles of FA from FDs in PBS (pH 7.4).

Figure 6. The release profile of FA from FDs prepared with

2% L-ALG.

dissolved and released the total amount of FA at 5 - 10

min. When 2% L-ALG or 4% PUL was used, the FA was

released for about 30 min. A similar release profile was

obtained using FD prepared with 3% L-ALG. In FDs,

model compounds such as FA are dispersed in water-

soluble polymer matrices, and the FA particles may dis-

solve in the dissolution medium as the film erodes. The

release rate was affected by the property of the com-

pound incorporated in the FD. CA was also released

immediately; for example, the total amount contained in

the FD prepared with 2% L-ALG was released at 10 min

(data not shown). The release profile was attributed to

the high solubility of CA in th e dissolution medium, and

the rapid release rate was also observed from the FD

prepared with 4% PUL.

FD prepared with 2% L-ALG that was modified

through addition of CS, HPMC, or CHS did not affect

FA release (Figure 6). On the other hand, the initial re-

lease rate of FA was depressed when FD modified

through the addition of PGA. A similar additive effect

was observed in FD modified with pectic acid. Depres-

sion of the FA release rate through the addition of PGA

to 2% L-ALG was restricted at an extremely early stage,

Figure 7. Effect of PGA concentration on the release profile

of FA from FDs prepared with 2% L-ALG.

and the rapid release was observed after the film swelled

(Figure 7).

4. Conclusions

In this study, FDs were prepared using natural polysac-

charides without dissolving them into organic solvents,

heating them, controlling their pH, or adding plasticizers.

Some of these polysaccharides were able to incorporate

model compounds such as FA or CS, and all FDs imme-

diately released them as the forms eroded in the limited

dissolution medium. FD is a useful dosage form, espe-

cially for preventing or treating localized prob lems in the

oral cavity including dental caries and periodontal dis-

eases. However, the drug loading capacity of FD is typi-

cally very low; therefore, the compounds incorporated in

the FD should be carefully selected.

5. Acknowledgements

The authors would like to thank Dr. M Kimizu (Indus-

trial Research Institute of Ishikawa) for his help and ad-

vice on X-ray Diff r actometry experiment.

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