医薬品相互作用研究

Vol.43, No. 3（2019）53（199）医薬品相互作用研究
一
般論
文
43（3）53-59 （2019）

Characterization of Orally Disintegrating Films Containing Fluconazole
Mari MATSUMOTO a,b）, Katsuma ARAI c）, Akiko FUJITA d）Misaki TSUJI d）, Sachie HAYAKAWA b）,
Katsuhiko SAWAKAMI e）, Kentaro SAWAKAMI e）, Shigenari SHIDA c）, Yukio NOHARA c）, Kenji SUMIYA a,c）,
Kazuko MURATA a,c）, Yoshiko TAKEUCHI d）, Hirofumi TAKEUCHI d）, Ryo MURATA a,c*）
Graduate School of Science and Engineering, Iryo Sosei Universityb）
Department of Pharmacy, Iwakiyumoto Hospitalc）
Faculty of Pharmacy, Iryo Sosei Universityd）Laboratory of Pharmaceutical Engineering, Department of Drug Delivery Technology and Science,
Gifu Pharmaceutical Universitye）
Sawakami Pharmacya）（Received July 15, 2019; Revised August 26, 2019; Accepted August 26, 2019）
Patients with decreased swallowing function, such as children and the elderly, ﬁnd it diﬃcu lt to take tablets andcapsules, resulting in reduced compliance. An orally disintegrating ﬁlms (ODFs) are expected to be an excellent oral
dosage form for such patients because it rapidly disintegrates in the oral cavity and can be taken without or with asmall amount of water. In this study, ODF loaded with ﬂuconazo le (FLCZ) a synthetic antifungal agent was preparedusing hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC) as the ﬁlm base. The ODFs wereprepared using a ﬂat-bottom polypropylene weighing boat as the mold. The formulation characteristics were
evaluated with respect to their disintegrating, dissolving, mechanical, and morphological properties. And wecompared the changes in their physical properties caused by the loaded with FLCZ. Therefore, we suggested that is
eﬀective to use HPC, prepared using a weighing boat, as a base for an FLCZ-loaded ﬁlm.
Key Words: ﬂuconazole, orally disintegrating ﬁlm, hydroxypropyl cellulo se, hydroxypropyl methyl cellulose

Hydroxypropyl cellulose (HPC) and hydroxypropyl

Introduction
Oral dosage is the most common form of drug

methyl cellulose (HPMC) are water-soluble polymers

administration; however, patients with decreased

used as a ﬁlm base. ODFs with various drugs haveswallowing function, such as children and the

been prepared and their formulation properties andelderly, ﬁnd it diﬃcult to take tablets and capsules,

usefulness have been evaluated 3-7). ODFs containing

leading to reduced compliance. Drug-bearing

diﬀerent drugs in the same ﬁlm base have diﬀerent

formulations that rapidly disintegrate in the oral

formulation properties 3). In addition, even if the ﬁlm

cavity and can be taken without water or with abase is diﬀerent in the same drug, the formulation

small amount of water help such patients andproperties are diﬀerent, so it is important toimprove medication compliance. Orally

formulation design for preparing a formulation withdisinteg rat ing ﬁlms (ODFs) are expected to an

excellent disintegration characteristics and strength.

excellent oral dosage form because they rapidly

Fluconazole (FLCZ) is a synthetic antifungal agent

disintegrate in the oral cavity, and are durable andb e l o n g i n g t o t h e g r o u p o f t r i a z o l e s 8 ) . F LC Z i sportable owing to their thin, ﬂexible form .

available in various dosages forms in market like

1,2)

3)

Graduate School of Science and Engineering, Iryo Sosei University 5-5-1 Iino, Chuo-dai, Iwaki, Fukushima 970-8551, Japan.
Department of Pharmacy, Iwakiyumoto Hospital 6 Daiyama, Jyobanyumotomachi, Iwaki, Fukushima 972-8321, Japan.
c）Faculty of Pharmacy, Iryo Sosei University 5-5-1 Iino, Chuo-dai, Iwaki, Fukushima 970-8551, Japan.
d）Laboratory of Pharmaceutical Engineering, Department of Drug Delivery Technology and Science, Gifu Pharmaceutical University
1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
e）
Sawakami Pharmacy 3-6-5 Shimokubo, Misawa, Aomori 033-0023, Japan.
*Ryo Murata e-mail：r-murata@isu.ac.jp TEL：0246-29-5432 FAX：0246-29-5432
5-5-1 Iino, Chuo-dai, Iwaki, Fukushima 970-8551, Japan.
a）b）医薬品相互作用研究

54（200）Vol.43, No. 3（2019）

capsules, powder for oral suspension and others. And

was pro cured from Shin-E tsu Chemical ( Tokyo,

there are reports of mucoadhesive buccal ﬁlms

Japan). FLCZ was obtained from LKT. Labs. (St.

9,10)

,

vaginal ﬁlms 11).
In this study, orally disintegrating ﬁlms wereacquired from Pﬁzer (Tokyo, Japan).

prepared using HPC or HPMC as the ﬁlm base, andwe compared the changes in their physical

Methods

properties caused by the loaded with FLCZ. The

１. Film preparation

disintegration time, tensile strength, elongation, and

FLCZ was dissolved in ethanol. HPC was

bending number of times were measured. The

dissolved in ethanol and then mixed with an FLCZ

formulation characteristics were evaluated withsolution for HPC ﬁlm preparation. For the HPMC

respect to whether ﬁlms were loaded with FLCZ. The

ﬁlm preparation, HPMC was suspended in ethanol

release of FLCZ from the loaded ﬁlms was conﬁrmed,

and mixed with FLCZ, then diluted with a half

and their morphology was observed using a scanningvolume of water (containing an appropriate

electron microscope.

amount of glycerol dissolved). To prepare the ﬁlm,
FLCZ containing the dispersion was transferred toMaterials and Methods

a ﬂat-bottom polypropylene weighing boat (20 ×Materials

20 × 15 mm 3 ). The weighing boats were dried at

Hydroxypropyl cellulose (HPC) was obtained for
SL grade of NISSO HPC from Nippon Soda (Tokyo,

room temperature for 24 h. The ﬁlm formulations
are shown in Table 1.

Japan). Hydroxypropyl methylcellulose (HPMC)
Table 1. Film formulations

２. Evaluation ﬁlm thickness

Tosoh, Tokyo, Japan) at 40°C. The mobile phase

The thickness of each ﬁlm formulation was

was acetonitrile and water (1:4, v/v); ﬂow ratemeasured using a micrometer (Mitutoyo, Tokyo,

was 1.1 mL/min; and detection wavelength was

Japan). The thickness of each ﬁlm was calculated

260 nm. A sample of 20 μL was injected onas the mean of the four corners and the center.

column using Chromaster 5280 autosampler.

３. FLCZ content measurement

４. Evaluation of disintegration time

FLCZ was dissolved in water from the ﬁlm byDisintegration time was measured using the Petrisonicat ion at room temperature. The FLCZ

dish method described by Takeuchi et al 12) . The

concentration in the extract was evaluated bytime taken by a ﬁlm ﬂoating on water (50 mL) in a

HPLC. Reversed-phase chromatography was done

Petri dish (100 mm diameter) to completely

using a LaChrom Elite System (Hitachi, Tokyo,

disintegrate was recorded. In addition, forJapan). HPLC system consisting of a L-2130 pump,objective evaluation, disintegration time wasa L - 2 3 0 0 c o l u m n ov e n , a D -2500 in te g r a t o r, ameasured using a device developed for the oral

L-2400 UV-VIS detector. The HPLC analysis was
performed on a TSK GEL ODS-120H (4.6 × 150 mm,

Tokyo, Japan). Measurement method (Tricorptester医薬品相互作用研究

Vol.43, No. 3（2019）55（201）

method) of the disintegration test using the deviceof 1, 3, 5, 10, 20, and 30 min, 5 mL samples were

was developed by Takeuchi et al. They designed

withdrawn. The samples were ﬁltered through aan exclusive ﬁxture for ODFs, made an opening in

0 . 4 5 μ m m e m b r a n e ﬁ l t e r ( G L S c i e n c e , To k y o ,the center of the ﬁxture. A set of ﬁxtures, withJapan) and the amount of FLCZ released waswhich a sample ﬁlm is ﬁxed, was placed on thedetermined using HPLC. The analysis conditions ofstage. An artiﬁcial saliva solution, composed of

HPLC for FLCZ were as described above.

13)

1.44 g/L NaCl, 1.47 g/L KCl and 0.3% polysorbate
80, was used as the test medium. The medium was

８. Morphological observations

kept at 37°C in an incubator and dropped on a ﬁlm

The surface aspects (top and bottom) of anwith a ﬂow pump (dropping speed, 6 mL/min;

FLCZ-loaded ﬁlm were observed using a scanning

dropping height, 8 cm). The disintegration time,electron microscope (SEM) ( JSM-6010LA; JEOL,

deﬁned as the time until a ﬁlm tore and the test

Tokyo, Japan) operated at an acceleration voltage

medium passed through an opening of the ﬁxture,of 10 kV.

was automatically recorded using an opticalpassage sensor.

９. Statistical Analysis

５. Evaluation of tensile strength

deviation(S.D.),

andanalyzed

using

one-way

The results were expressed as mean ± standard

Mechanical properties were measured using acreep meter (RE-3305S, Yamaden, Tokyo, Japan).

statistical

diﬀerences

analysisof

werevariance

followed by the Tukey‒Kramer test for multiple

The ﬁlms were cut into 5 × 30 mm 2 pieces. The
ﬁlms were ﬁxed with two grips, which pulled at aanalyses were performed using Statcel 3 software

constant rate and stretched the ﬁlm until breakage(OMS Publishing Inc., Saitama, Japan).

occurred. A stress‒strain curve was created using
these results. The tensile strength and elongationa t b re ak o f the ﬁlms w ere calculated from thestress‒strain curve using the following formulas:Tensile strength (MPa) = fracture force (N) /cross section area (mm 2)
Elongation at break (%) = increase in length (mm)/ original length (mm) × 100

Results
The results of the measurements of ﬁlm
thickness are summarized in Fig 1. In the HPC ﬁlm,
thickness decreased with FLCZ loading, whereas in
the HPMC ﬁlm, the thickness increased with FLCZ
loading.

６. Evaluation of ﬁlm folding endurance
Folding endurance was measured using abending tester ( TCDM111LH, Yuasa, Okayama,
Japan). The ﬁlms were cut into 20 × 30 mm 2
pieces. The ﬁlms were repeatedly folded at thesame place, at a bending angle of 135 °and testing
speed of 90 rpm. The total number of times theﬁlms was folded before the ﬁlms cracked wasmeasured as the folding endurance value.

７. Evaluation of dissolution tests
Drug dissolution tests were performed using a
dissolution tester (NTR-6200AC, Toyama Sangyo,
Osaka, Japan). The tests were performed in 900
mL of water at 37.0°C, with a paddle stirring speedof 50 r.p.m. Without using a sinker, the ﬁlm was
ﬂoated on the medium and tested. At time intervals

Fig 1. Thickness of ﬁlm formulation
Film A: HPC ﬁlm unloaded; Film B: HPC ﬁlm loaded with FLCZ; Film C:
HPMC ﬁlm unloaded; and Film D: HPMC film loaded with FLCZ.
Values are presented as mean ± S.D. (n = 14). * p <0.005, ** p <0.01.

56（202）

医薬品相互作用研究

The results of content measurement are
p r e s e n t e d i n Ta b l e 2 . T h e F LC Z c o n t e n t i n t h e

Vol.43, No. 3（2019）was no statistically signiﬁcant diﬀerence ( P > 0.05)
in FLCZ content between the formulations.

formulations was approximately 92%, and there
Table 2. FLCZ content in the ﬁlms

The results of the disintegration test using the

break of HPC-based ﬁlms, result ing in g reater

Petri dish method are shown in Fig 2 (a) and thoseelongation than that noted in HPMC-based ﬁlms.

obtained using the Tricorptester method are shown

The results of the folding endurance test are

in Fig 2 (b). For HPC-based ﬁlms, loading w ith

shown in Fig 4. In the ﬁlm using HPC as a base, the

FLCZ reduced the disintegration time, whereas fornumber of folds formed before breaking was

HPMC-based ﬁlms, loading with FLCZ increased

increased by the addit ion of FLCZ; however, inthe disintegration time. For ﬁlms loaded with FLCZ,

HPMC-based, there was no signiﬁcant diﬀerence

the disintegration time of those prepared using

caused by the addition of FLCZ.

HPC was shorter than those prepared using HPMC.

The drug dissolution proﬁles of FLCZ-containing

The results of the measurements of tensile

formulations are presented in Fig 5. At 3 min afterstrength and elong at ion are shown in Fig 3. In

the start of the test, ﬁlm B released 74.0% of the

HPC-based ﬁlms, no signiﬁcant diﬀerence wasdrug load and ﬁlm D released 42.8%. Films B and D

observed in tensile strength, but elongat ion

released 80% of the drug within 5 min. There wasincreased with the addition of FLCZ. In

no statistically signiﬁcant diﬀerence between the

HPMC-based ﬁlms, no signiﬁcant diﬀerence wasﬁlm formulations; however, signiﬁcant diﬀerences

observed in tensile strength or elongation owing towere found in the dissolution rates of the two ﬁlm

the addition of FLCZ. HPC-based ﬁlms had weaker

formulations compared with the capsuletensile strength than HPMC-based ﬁlms; however,formulations.

the addition of FLCZ increased the elongation at

Fig 2. Evaluation of disintegration
Disintegration time was measured using the Petri dish method and Tricorptester method. (a) Petri dish method (n = 5),(b) Tricorptester method (n = 3). Film A: HPC ﬁlm unloaded; Film B: HPC f ilm loaded with FLCZ; Film C: HPMC ﬁlm
unloaded; and Film D: HPMC ﬁlm loaded with FLCZ. Values are pr esented as mean ± S.D. * P < 0.05, ** P < 0.01.

医薬品相互作用研究

Vol.43, No. 3（2019）57（203）

Fig 3. Eﬀect of FLCZ in ﬁlm on mechanical properties
Tensile strength and elongation at break were measured as mechanical properties using a creep meter. (a) Tensile strength(b) Elongation at break. Film A: HPC ﬁlm unloaded; Film B: HPC ﬁlm l oaded with FLCZ; Film C: HPMC ﬁlm unloaded; and Film
D: HPMC ﬁlm loaded with FLCZ. Values are presented as mean ± S.D. ( n = 3). * P < 0.05, ** P < 0.01.

Fig 4. Eﬀect of FLCZ in ﬁlm on folding endurance

Fig 5. Dissolution proﬁle of ﬁlm loaded with FLCZ

Folding endurance was measured with a bending meter. Film A: HPC
ﬁlm unloaded; Film B: HPC ﬁlm loaded with FLCZ; Film C: HPMC ﬁlm
unloaded; and Film D: HPMC ﬁlm loaded with FLCZ. Values arepresented as mean ± S.D. (n = 3). * P < 0.05, ** P < 0.01.

Film B: HPC ﬁlm loaded with FLCZ and Film D: HPMC ﬁlm loaded FLCZ.
Control experiment on dissolution rate was performed using Diﬂucan®
capsule (50 mg). Values are presented as mean ± S.D. (n = 3).

An SEM image is shown in Fig 6. This image

preparation at an in-hospital pharmacy without anshows that both ﬁlms B and D had smooth top

applicator was considered. In the casting method,

surfaces. The bottom of the ﬁlm was aﬀected by

the preparation solution is uniformly applied on athe shape of the mold surface, and it wasbase ﬁlm plate using an applicator, dried, and cut

conﬁrmed that the surface had several

to form a ﬁlm. In this work, using a polypropylene

irregularities.

weighing boat as a mold, the ﬁlm was formed on aweighing boat to shorten the cutting process.

Discussion and Conclusions
While developing ﬁlm preparation method,

To improve ODFs, they should be designed to
rapidly disintegrate. Although the disintegration

医薬品相互作用研究

58（204）Vol.43, No. 3（2019）

Fig 6. Scanning electron microscope observation of ﬁlms(a) Top of ﬁlm B, (b) Bottom of ﬁlm B, (c) Top of ﬁlm D, and (d) Bottom of ﬁlm D. Film B: HPC ﬁlm loaded with FLCZ and
Film D: HPMC ﬁlm loaded with FLCZ.

time is correlated with ﬁlm thickness, with the

did not signiﬁcantly aﬀect the release of FLCZ. The

addition of FLCZ, the thickness of the HPC

ﬁlm formulation was conﬁrmed to exhibit fasterdecreased and disintegration time reduced. The

capsules. Comparedi n ﬂ u e n c e o f F LC Z l o a d i n g o n ﬁ l m t h i c k n e s s i swith HPMC, HPC was evaluated to be superior inconsidered to be owing to the wettability of thedisintegration and dissolution because it exhibitedweighing boat when spreading the ﬁlm

a higher dissolution rate from 3 min after the start

preparation, and in HPC, the wettability isof the test.

improved by FLCZ loading.

The results of tests for the disintegrating,In addition to rapid disintegration, mechanicalmechanical, dissolving, and morphologicalstrength is also required. Tensile strength is one ofproperties suggested that is eﬀective to use HPC as

the indicators of the mechanical strength of aa base for the FLCZ-loaded ﬁlm prepared using aﬁlm 14), and elongation and folding endurance areweighing boat.

used to evaluate the properties of ﬁlm

ODF that rapidly disintegrates in the oral cavity

deformation, mechanical strength, and ﬂexibility. It

and can be taken without water or with a small

was evaluated using a tensile test and a folding

amount of water helps pat ients w ith decreased

endurance test to determine whether the ﬁlm canswallowing function, such as children and thewithstand the stress received when it is removed

e l d e r l y, a n d i m p r o v e m e d i c a t i o n c o m p l i a n c e .

from the mold or during storage. Although theMoreover, these ﬁlms have high durability andtensile strength of the HPC ﬁlm decreased with theportability owing to their thin, ﬂexible form. It is

addition of FLCZ, an increase in elongation and the

expected that these ﬁlms will be widely used as anumber of times of refraction resistance were

dosage form depending on patientʼs condition andconﬁrmed. It was also conﬁrmed that the HPC ﬁlmtaste preference.

wa s mo re ﬂe xible and easy to h andle th an the
H P M C ﬁ l m ; h o w e v e r, i t s t e n s i l e s t r e n g t h w a s
inferior to that of HPMC.
The dissolution test indicated that the ﬁlm baseConﬂict of interest
The authors declare no conﬂicts of interest.

医薬品相互作用研究

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