Journal of Controlled Release 99 (2004) 73 – 82

www.elsevier.com/locate/jconrel

Development of mucoadhesive patches for buccal

administration of ibuprofen
Luana Perioli a,*, Valeria Ambrogi a, Fausta Angelici a, Maurizio Ricci a,
Stefano Giovagnoli a, Marinella Capuccella b, Carlo Rossi a
a
Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy
b
Istituto Zooprofilattico dell’Umbria e delle Marche, Via G. Salvemini, 1, 06100 Perugia, Italy
Received 17 February 2004; accepted 15 June 2004
Available online 14 July 2004

Abstract

A new formulation for topical administration of drugs in the oral cavity has been developed using several film-forming and
mucoadhesive polymers. The films have been evaluated in terms of swelling, mucoadhesion and organoleptic characteristics.
The best film, containing polyvinylpyrrolidone (PVP) as film-forming polymer and carboxymethylcellulose sodium salt
(NaCMC) as mucoadhesive polymer, was loaded with ibuprofen as a model compound and in vitro and in vivo release studies
were performed. Statistical investigation of in vitro release revealed that the diffusion process was the main drug release
mechanism and the Higuchi’s model provided the best fit. In vivo studies showed the presence of ibuprofen in saliva (range 70 –
210 Ag/ml) for 5 h and no irritation was observed. These mucoadhesive formulations offer many advantages in comparison to
traditional treatments and can be proposed as a new therapeutic tool against dental and buccal diseases and disturbs.
D 2004 Elsevier B.V. All rights reserved.

Keywords: Mucoadhesion; Polymeric films; Ibuprofen; Buccal delivery; In vitro ex vivo and in vivo release

1. Introduction cavity. The advantage resides on the reduction of drug

dose because of its localization in the inflammatory
The present paper deals with the planning and process site. One particular problem that is common
realization of mucoadhesive polymeric films contain- to many drug delivery systems, aimed to the treatment
ing a non-steroidal anti-inflammatory drug (ibupro- of the oral cavity diseases, is the short residence time
fen) for the topical administration in the oral cavity. at the site of application. This problem may be
This new formulation was designed particularly for resolved by using bioadhesive polymers, i.e. polymers
anti-inflammatory and analgesic therapies in the oral that exhibit characteristic adhesive interactions with
biological membranes [1].
Recently, various bioadhesive mucosal dosage
* Corresponding author. Tel.: +39-07-5585-5133; fax: +39-07-
forms including adhesive tablets, gels, and, recently,
5585-5163. films have been developed [2]. However, buccal films
E-mail address: [email protected] (L. Perioli). are preferable over adhesive tablets in terms of flex-

0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2004.06.005
74 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82

ibility and comfort. In addition, they can circumvent 2.2. Fabrication of mucoadhesive drug free films
the relatively short residence time of oral gels on the
mucosa, which are easily washed and removed by Initially, films were prepared using only film-
saliva. Moreover, buccal films are also suitable for forming polymers. For their preparation the casting
protecting wound surfaces, thus reducing pain and method [4,5] was employed. The procedure consisted
increasing the treatment effectiveness [3]. in dissolving or dispersing polymers (40%) in water
In this study, new mucoadhesive films were and then ethanol was added at five different ratios
developed by using the casting method [4,5]. For (water solution/dispersion:ethanol): 1:5, 2:4, 3:3, 4:2,
this purpose, several film-forming polymers, as 5:1. A proper plasticizer (10% triethanolamine in the
Eudragit NE40D, Eudragit E100, Eudragit RSPO, case of the Eudragit polymers and 50% propylene
polyvinylpyrrolidone (PVP), and several mucoadhe- glycol in the case of PVP) was added.
sive polymers, as Carbopol 971, Carbomer 940, The mixtures were prepared with a magnetic
Polycarbophil, Methocel K4M, Methocel K15M stirrer (for Eudragit RSPO and E100) or mortar
and carboxymethylcellulose sodium salt (NaCMC), and pestle (for Eudragit NE40D and PVP) and cast
were used. onto a petri dish. The volume to be cast was
In order to prepare films having the appropriate determined so that a 10 mm thickness was obtained
characteristics, film-forming polymers were initially after casting the mixture. The petri dish was stored at
used alone and successively in combination with 4 jC for 24 h to remove all the air bubbles entrapped
mucoadhesive polymers. The films with the best and dried at 60 jC for 16 h. The films were
characteristics were selected for testing further their accurately observed and checked for possible imper-
in vitro, ex vivo and in vivo behavior. Ibuprofen was fections upon their removal from the petri dish. Then
eventually introduced in the film that showed the best a water solution of the mucoadhesive polymer (2%)
performances and its in vitro and in vivo release at three different ratios (mucoadhesive polymer so-
profiles were evaluated. lution/film-forming mixture): 1:5, 5:5, 5:10 was
added to the best film-forming polymer mixture.
Successively, the preparation procedure was repeated
2. Materials and methods as previously described.
Similarly, these new films were examined in order
2.1. Materials to select the film having the best characteristics
(Table 1).
Films were prepared using four film-forming
polymers and five mucoadhesive polymers. The 2.3. Swelling studies
film-forming polymers were: Eudragit NE40DR,
Eudragit E100R, Eudragit RSPOR (Röhm Pharma) Film swelling properties and erosion character-
and PVP (Plasdone K90R) (ISP Customer Service). istics were evaluated by determining the percentage
The mucoadhesive polymers were: hydroxypropyl of Hydration and Matrix Erosion or Dissolution
methylcellulose (HPMC) (Methocel K4M PREMI- (DS).
UM EPR) and Methocel K15M PREMIUM EPR) Each film was divided in portions of 4 cm2 (2
(Colorcon, England); NaCMC (Aldrich, USA); cm
2 cm) and cut, weighted (W1) and immersed in
Carbomer 940R (Galeno, Italy); Carbopol 971R simulated saliva fluid [3] at pH 6.75 for predeter-
NF and Polycarbophil (Noveon AA1R) (Noveon, mined periods of time (5, 15, 30, 45, 60, 120, 180,
USA). The plasticizers were triethanolamine (Röhm 240, 300 min). After immersion, the films were wiped
Pharma) and propylene glycol (Aldrich, USA). The off from the excess surface water using filter paper
model drug was ibuprofen (Sigma, Italy). Pig buccal and weighted (W2). The swollen films were dried at
mucosa was furnished by the Istituto Zooprofilattico 60 jC for 24 h and kept in the desiccator over 48
Sperimentale dell’Umbria e delle Marche (IZS), h and after drying the weighting was repeated (W3).
Perugia (Italy). All the other reagents were of the This experiment was performed in triplicate (n = 3,
highest purity available. a = 0.05).
 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82 75

Table 1
Composition and physical characterization of the selected films
Number Group Film-forming Mucoadhesive Film-forming Thickness (mm) Weighta (g)
(film-forming polymer polymer polymer mixture/ ( F 0.01) F ( F 0.001) F
polymer) aqueous mucoadhesive confidence confidence
mixture/EtOH polymer (n = 3; a = 0.05) (n = 3; a = 0.05)
(w/w) solution (w/w)
1 I (Eudragit NE40D) 1:5 HPMC K4M 5:10 0.18 F 0.01 0.0198 F 0.0016
2 2:4 HPMC K4M 5:10 0.12 F 0.03 0.0105 F 0.0025
3 2:4 HPMC K15M 5:10 0.05 F 0.01 0.0059 F 0.0009
4 II (Eudragit RSPO) 1:5 HPMC K4M 5:5 0.26 F 0.02 0.0174 F 0.0026
5 1:5 HPMC K15M 5:10 0.27 F 0.04 0.0247 F 0.0046
6 4:2 HPMC K4M 5:10 0.19 F 0.01 0.0221 F 0.0019
7 4:2 HPMC K15M 5:10 0.22 F 0.01 0.0254 F 0.0005
8 III (Eudragit E100) 1:5 NaCMC 5:5 0.23 F 0.03 0.0211 F 0.0014
9 1:5 NaCMC 5:10 0.17 F 0.01 0.0210 F 0.0010
10 IV (PVP) 1:5 NaCMC 5:5 0.25 F 0.04 0.0347 F 0.0021
11 1:5 NaCMC 5:10 0.14 F 0.01 0.0173 F 0.0016
12 2:4 NaCMC 5:5 0.20 F 0.02 0.0354 F 0.0012
13 2:4 NaCMC 5:10 0.13 F 0.01 0.0216 F 0.0027
14 3:3 NaCMC 5:1 1.23 F 0.04 0.0850 F 0.0034
15 3:3 NaCMC 5:10 0.13 F 0.03 0.0262 F 0.0009
16 3:3 HPMC K4M 5:10 0.16 F 0.01 0.0186 F 0.0009
17 3:3 HPMC K15M 5:10 0.16 F 0.01 0.0192 F 0.0004
a
Film portion of size 1 cm
1 cm.

Percentage of Hydration [6] and Matrix Erosion 2.5. Ex vivo mucoadhesion force
(DS) [5] were calculated by using the following
expressions: Ex vivo adhesion strength was assessed by a dyna-
mometer [8,9] using the above cited porcine mucosa.
% of Hydration ¼ ðW2  W1 Þ=W2
100 For mucoadhesive measurements, films were cut in
portions of 4 cm2 and pasted on a support, connected to
DS ¼ ðW1  W3 Þ=W1
100: the dynamometer (Lehrmittelban, Professor Dr. Maey,
Bonn, Germany) with cyanoacrylate glue. A piece of
2.4. Ex vivo mucoadhesion time porcine buccal mucosa was glued on a support and kept
in a vessel placed in a thermostatic bath at 37 jC
The ex vivo mucoadhesion time was performed ( F 0.1). The free side of the film was wetted with 50
(n = 3) after application of the films on freshly cut Al of simulated saliva fluid and pasted to the porcine
porcine buccal mucosa. The porcine buccal tissues buccal tissue by applying a light force with the finger
were fixed on the internal side of a beaker with tip for 20 s. The vessel was filled with simulated saliva
cyanoacrylate glue. Each film was divided in por- fluid at 37 jC and the measurement was started after 2
tions of 4 cm2 and cut, a side of each film was min. The maximum adhesive force is the average of
wetted with 50 Al of simulated saliva fluid and was three measurements (n = 3) and confidence intervals
pasted to the porcine buccal tissue by applying a were also determined at 0.05 significance level.
light force with the finger tip for 20 s. The beaker
was filled with 800 ml of the simulated saliva fluid 2.6. In vivo mucoadhesive performance of drug free
and was kept at 37 jC. After 2 min, a 150 rpm films
stirring rate was applied to simulate the buccal cavity
environment and film adhesion was monitored dur- In vivo studies were performed (in triplicate)
ing 8 h [7]. applying 2 cm2 (2 cm
1 cm) of each film on five
76 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82

healthy volunteer gums in order to assess: residence against the gum for 20 s without moistening the film
time, organoleptic characteristics, fragment loss, pos- before the application. The volunteers were not allowed
sible irritation, swelling and saliva level variations. to drink water or to eat food since half an hour before
Each film was pasted by applying a light force with the study. Drinking was allowed ad libitum starting
the finger tip for 20 s. from 30 min after administration of the film and fasting
was strictly observed throughout the experiment. How-
2.7. Fabrication of ibuprofen containing mucoadhe- ever, no drinking was allowed since 10 min before the
sive films collection of the salivary samples [11]. Care was taken
of the tongue to not contact the film since 10 min before
The drug loaded film was prepared by adding sampling in order to avoid abnormally high drug levels
ibuprofen to the final mixture to obtain a 1% or [12]. Time of residence, possible irritation, loss of
0.5% drug concentration. It was cast in a rectangular fragments, bad taste, dry mouth or excessive salivation
mould of 37.44 cm2 size. The volume to be cast was were evaluated in order to study the drug influence on
determined so that a 10 mm thickness was obtained the in vivo film behavior.
after casting the mixture. The mixture was stored at 4 Aliquots of saliva were collected after application
jC for 24 h, then was heated for 20 h at 60 jC. The of the film and at predetermined times. One milliliter
films thus obtained had, respectively, 0.91 mm thick- of each sample was diluted to 10 ml with simulated
ness (11.22 mg/cm2 of ibuprofen) and 0.52 mm saliva fluid and filtered through a Millipore cellulose
thickness (5.61 mg/cm2 of ibuprofen). acetate membrane filter (0.45 Am). Ibuprofen concen-
tration in each sample was determined by means of
2.8. In vitro release study from ibuprofen loaded films UV at kmax = 264 nm (n = 3).

A standard paddle apparatus (Steroglass, Perugia, 2.10. Statistical and kinetic analysis
Italy), as described in the Farmacopea Ufficiale della
Repubblica Italiana XI Ed. (F.U.XI) and properly The in vitro release profiles were tested for their
modified [10] was employed to evaluate drug release. kinetic behavior in order to establish the kind of
A portion of 6.24 cm2 (5.2 cm
1.2 cm) of film was mechanism possibly involved in ibuprofen release
used. A side of the film was attached with double from the film matrix. Data were analyzed using the
adhesive tape on the inert support and, after 2 min, the following equation [13]:
vessel was filled with simulated saliva fluid and
maintained at 37 jC while stirring at 50 rpm. Four Mt =Ml ¼ kt n
milliliter samples were collected at predetermined
time intervals and replaced with an equal volume of where Mt/Ml is the drug fraction released at time t, k
simulated saliva fluid. Ibuprofen concentration was is a constant depending upon structural and geometric
determined by a spectrophotometer (Jasco Ltd V-520, characteristics of the system, n is the diffusional
Great Dunmow, Essex, UK) at kmax = 264 nm and coefficient related to release mechanism. The n value
reported as an average of three measurements (n = 3, was varied from 0.5 to 1 and the statistical analysis
a = 0.05). was performed by calculating the correlation (r)
existing between the in vitro release and the model
2.9. In vivo drug release study and behavior of proposed at different n values.
ibuprofen loaded films

With the approval of the Ethic Committee of 3. Results and discussion

Aziende Sanitarie dell’Umbria (CEAS) and the written
consent released by the volunteers, in vivo release 3.1. Swelling-hydration and DS studies
studies were performed by applying an ibuprofen
containing film (6.24 cm2) to five healthy volunteer All the films hydrated very quickly, reaching 80%
gums. The volunteers were instructed to press the film hydration after just few minutes. Maximum hydration
 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82 77

(96 – 98%) was obtained with formulations containing time whereas the films from group III showed the
NaCMC (groups III and IV with the only exception of lowest mucoadhesion time. This difference depends
film 14 in which the NaCMC amount was low), upon several factors that affect the effectiveness of
whereas films containing HPMC K4M and K15M such a formulation. First of all, the employment of
showed a slightly lower hydration of 90 – 93%. These NaCMC favors hydration and the outward diffusion of
results inferred that NaCMC films exhibited higher the drug from the film matrix. Moreover, NaCMC,
capacity of water uptake than HPMC films as expected due to its solubility in water, results less effective as
on the basis of NaCMC higher water solubility. mucoadhesive polymer and it was demonstrated by
Some films (N 1, 3, 4, 6, 7, 16, 17) did not preserve the already cited lower mucoadhesion times of group
their integrity throughout the experiment and they III. In fact, when using HPMC, mucoadhesion time
showed fragmentation within 30 min after that maxi- always resulted high, because the polymer, although
mum hydration was reached. DS profiles, reported in manifesting decisively higher swelling is less water-
Fig. 1, were calculated from the comparison between affined and hence tends to retain its structure better
the initial and the final weights after immersion in a than NaCMC that, in turn, is better dissolved. Another
simulated saliva fluid. DS values were positive for the important factor to be considered is the kind of film-
majority of the films because of their low thickness and forming polymer used for the film preparation and the
consequent fragmentation. Film fragmentation was goodness and homogeneity of the polymer solution
clearly observed for groups I and II, while groups III mixtures. In fact, while Eudragit polymers are water
and IV behaved more regularly. In particular, from insoluble, PVP is water soluble and these character-
group IV DS profiles, fragmentation was already istics influenced miscibility with the mucoadhesive
evident at 100 min when HPMC instead of NaCMC polymer, the uniformity of the film as well as perme-
was employed. The highest losses were observed for ability to water of the film matrix. In spite of these
films containing HPMC as mucoadhesive polymer; for differences, ex vivo mucoadhesion times were not
some of these films fragmentation was so high that it drastically influenced by the polymer chemical and
was not possible to recover and handle the film from the physical characteristics. Groups I, II and IV showed
saliva fluid, even immediately after the beginning of very similar ex vivo mucoadhesion times regardless
the experiment (N 3, 6, 7, 16, 17). This higher fragility polymer and mixture ratios (Table 2). Only group III,
of the HPMC films could be due to the larger swelling as previously reported, resulted having lower ex vivo
in water of this polymer with respect to NaCMC. The mucoadhesive times.
consequence could be the formation of empty spaces
within the film matrix that could make this structure 3.2.2. In vivo mucoadhesion times of free drug
less resistant to mechanical stresses. patches
It was highlighted that swelling properties are Remarkable differences in term of in vivo mucoad-
probably more important when film integrity is eval- hesion times were instead observed among the films
uated. In fact, as already said, since HPMC have an investigated (Table 2). The highest residence time was
increased swelling capacity with respect to NaCMC, it detected for films N 2 and 15. Film behaviors were
is able of conditioning, to a larger extent than Eudragit monitored during the test. Groups II, III and IV showed
and PVP do, the mechanical and physical properties a lower in vivo mucoadhesion time with respect to the
of the films. This is also the reason for the regular DS ex vivo experiments with the exception of the film N
behavior of group III in which only films made of 15, for which the in vivo mucoadhesion time resulted
NaCMC were employed. identical to the ex vivo value. Similarly, group I had
almost identical in vivo – ex vivo mucoadhesion times
3.2. Mucoadhesive studies and, as for film N 15, film N 2 showed the highest value.
The more severe conditions that usually characterize in
3.2.1. Ex vivo mucoadhesion times of free drug vivo experiments may be the cause of such a decrease
patches in mucoadhesive time values. This effect resulted more
Film mucoadhesion times varied from 3 to 6.5 evident for groups IV and II. Water solubility may be
h (Table 2). Group II showed the highest adhesion the reason for the rapid decrease measured for group IV,
78 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82

Fig. 1. DS or Matrix Erosion of films (n = 3, a = 0.05).

in fact PVP as well as NaCMC are readily dissolved in vivo –ex vivo mucoadhesion times. Eudragit RSPO is
aqueous environment and, consequently, films made of water insoluble, but due to the presence of an internal
these polymers go through a fast disintegration and quaternary ammonium group, it is also the most water
reduction of the mucoadhesion time. Similarly, group permeable polymer among the Eudragit polymers
II, which contains Eudragit RSPO, had different in employed. Film adaptability to the gum was also
 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82 79

Table 2
Mucoadhesive characteristics of the films
Number Group (film-forming Ex vivo In vivo Ex vivo mucoadhesion
polymer) mucoadhesion mucoadhesion force (N) F conf.
time (h) time (h) (n = 3; a = 0.05)
1 I (Eudragit NE40D) 4 4.5 0.32 F 0.10
2 5 5 0.28 F 0.03
3 4 3.25 0.19 F 0.07
4 II (Eudragit RSPO) 6.5 4 0.28 F 0.03
5 6.5 2.75 0.30 F 0.06
6 6 2.25 0.31 F 0.05
7 6 2.25 0.33 F 0.05
8 III (Eudragit E100) 3 2 0.39 F 0.02
9 3 2.5 0.44 F 0.05
10 IV (PVP) 5 3.5 0.42 F 0.06
11 5 3.5 0.44 F 0.04
12 5 4.5 0.39 F 0.07
13 5.5 2.5 0.45 F 0.03
14 5.5 2.5 0.54 F 0.06
15 5 5 0.51 F 0.04
16 4 3.5 0.39 F 0.03
17 4 2.5 0.38 F 0.03

considered. Films with Eudragit were not very adapt- 15), on the contrary, showed good adaptability (Fig. 2)
able as they were poorly flexible and plastic. This because of the easy and rapid polymer hydration
behavior is clearly shown in Fig. 2 where film N 2 just immediately after application (c) and after gel forma-
applied (a) and after 2 h (b) is reported. PVP film (N tion (d). These findings correlated well with the behav-

Fig. 2. In vivo mucoadhesion behavior of film N 2, containing Eudragit NE40D and HPMC K4M, just applied (a) and after 2 h (b) and film N
15, containing PVP and NaCMC, just applied (c) and after 2 h (d).
80 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82

iors previously reported from DS, hydration and force, the film N 15, containing PVP and NaCMC
mucoadhesion studies. was selected for its characteristics that resulted suit-
able for buccal delivery formulations. Hence, this film
3.2.3. Ex vivo mucoadhesion force studies was loaded with a reference anti-inflammatory drug,
Mucoadhesion force values (Table 2) were between such as ibuprofen, to test its behavior as carrier for
0.19 and 0.54 N. Films from groups I and II and films ibuprofen sustained release in the oral cavity. For this
N 16 and 17 from group IV showed reduced mucoad- purpose, an ibuprofen containing film (1% of the
hesion forces. This behavior seemed to be dependent mixture before heating) was prepared and tested for
on the kind of mucoadhesive polymer used for film in vitro and in vivo drug release. In vitro release
preparation: HPMC films (groups I and II and N 16 profile showed a burst effect of the drug during the
and 17) showed lower mucoadhesive forces than first 10 min (35%), followed by a more sustained
NaCMC films. The same results were previously pattern. The release was completed after 4 h.
observed by other authors [3]. It is noteworthy to point In vivo drug release studies showed a good film
out that films with the highest mucoadhesion force hydration and drug levels in the saliva of about 50–
were N 10 –15 from group IV. They contained NaCMC 200 Ag/ml during the first 5 min. Moreover, the
and in particular PVP, which is known to possess good loaded film showed a complete film dissolution and
mucoadhesive properties [2,14]. Thus, it can be de- consequently a complete drug release after 150 min.
duced that PVP acts as co adjuvant by increasing the In addition, the application of the formulation caused
mucoadhesive properties of NaCMC as it was demon- gum irritation. The shorter in vivo dissolution time of
strated by the higher mucoadhesive forces generally drug loaded film in comparison to that of drug free
manifested by group IV films. The comparison of ex film, may be explained with the intense salivation and
vivo mucoadhesion times and mucoadhesive forces tongue movements due to the gum irritation.
revealed a good correlation between ex vivo data and For this reason, a film with the same polymeric
force values of group IV. This group, besides, having composition but containing half of the dose of ibu-
the longest ex vivo mucoadhesion times, also showed profen (0.5% of the mixture before heating) was
the highest mucoadhesive forces. Moreover, films with prepared. The ibuprofen concentration in the film
the same time value had also comparable force values. resulted 5.61 mg/cm2 (sodium salt). In vitro drug
However, when Eudragit polymers were employed release of this film showed that ibuprofen was rapidly
this correlation was decreased as shown by groups II released during the first 10 min (35%), and the release
and I, whose long ex vivo mucoadhesion times corre- was completed after 2 h and 30 min.
sponded to low force values. These findings reflect the In vivo studies (Fig. 3) showed that ibuprofen
different behavior of Eudragit polymers with respect to concentration in the saliva samples ranged between
PVP, which, in addition to its role as film-forming 70 and 210 Ag/ml and that the drug released in the
polymer, possesses non-neglectable mucoadhesive saliva was still detectable after 5 h from the end of the
properties that enhanced mucoadhesion. Finally, from release process. In this case no irritation was observed
Table 1 it resulted that thickness and mass weight of and probably less salivation and less tongue move-
the films did not influence their physical properties and ments permitted longer film presence.
their ex vivo and in vivo behavior. It was evident when From the kinetic and statistical point of view the in
comparing films 14 and 15 (group IV) and films 1 and vitro release profile of this film was fitted putting
3 (group I). In fact, their mucoadhesion times and increasing diffusion coefficient (n) values. The best
forces did not appear to be correlated to the measured correlation was obtained with n = 0.5 ( y = 0.0851x +
differences in size. 0.0525, r = 0.9934). This suggested that passive diffu-
sion (Fickian diffusion) was the drug release control-
3.3. Choice of the film with the best mucoadhesive ling mechanism. It can be interpreted as a Higuchi-like
properties behavior. In fact the Higuchi’s model (n = 0.5, drug
released < 70%) application to our system gave good
On the basis of the results obtained in terms of linearity and correlation expressed by the following
hydration, mucoadhesion time and mucoadhesion equation: y = 0.0953x + 0.0197 (r = 0.9978).
 L. Perioli et al. / Journal of Controlled Release 99 (2004) 73–82 81

Fig. 3. Ibuprofen concentration in the saliva samples from in vivo drug release studies (n = 5, a = 0.05).

From these results, it was clear that the Higuchi’s sufficient for therapeutic effect as it is located directly
model was appropriate to describe ibuprofen release on the site of the inflammation, if compared to tradi-
behavior. This kind of mechanism is in agreement with tional systemic therapies. Moreover, this buccal film is
swellable systems in which drug release is more very tolerable and comfortable because it is non-irritant
affected by the liquid penetration rate than by the and may be preferred over adhesive tablet in terms of
relaxation rate of the polymeric chains. These results elasticity, flexibility and capability to protect the
can be explained by the very low film thickness that wounded or inflamed surfaces.
characterizes these film matrices. In this case, this
particular device geometry permits the hydration to
prevail over the relaxation rate of the polymeric chains. Acknowledgements
In addition, in vivo/in vitro correlation over 150 min
of release was investigated. A satisfactory correlation The authors are very much grateful to Professor
that afforded to hypothesize a similar mechanism of Virgilio Gallai and Potito D’Errico, from the
drug release either in vivo or in vitro was observed. Neuroscience Department of the University of
Perugia, for their valuable suggestions and to Mr.
Marco Marani for the precious collaboration and
4. Conclusion technical assistance.

Good results were obtained both in vitro and in vivo

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