Vous êtes sur la page 1sur 10

23

Potential applications of chitosan in oral mucosal delivery


S. enel
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100-Ankara, Turkey
*Correspondence: ssenel@hacettepe.edu.tr
The accessibility of the oral cavity makes application of drugs easy and acceptable to the patient, while permitting easy removal in the event
of adverse reactions. Drugs penetrating the oral mucosa can be delivered systemically via direct entry into the systemic circulation thus avoiding
the hepatic frst-pass effect and degradation in the gastrointestinal tract. Due to the low permeability of the oral mucosa, new strategies are needed
to improve the delivery of drugs across the mucosa. In order to improve the availability of drugs across the oral mucosa, mucoadhesive systems
are applied to prolong the retention time of the delivery system on the mucosa. Furthermore, availability can be improved by using permeation
enhancers. Chitosan with its favorable properties such as bioadhesivity, biodegradability, biocompatibility and permeation enhancing activity,
offers great advantages over other polymers that are used for oral mucosal delivery. A wide choice of chitosan delivery systems such as solutions,
gels, sponges, flms, fbers, tablets and micro-/nanoparticles have been shown to be capable of delivering drugs into the oral cavity as well as
across the oral mucosa. In this review, applications of chitosan for oral mucosal delivery will be reviewed and the possibilities and limitations
discussed.
Key words: Chitosan Oral mucosa Oral mucositis Dental delivery.
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
For drugs which are usually ineffective when administered via
the oral route due to hydrophilic and enzymatic degradation in the
gastrointestinal tract, delivery through various mucosal routes such
as nasal, oral mucosal, rectal, vaginal, etc. has been widely applied
as an alternative delivery route. Over the last decade, the delivery of
drugs across the oral mucosa, especially buccal mucosa has gained
more importance, and there has been a signifcant increase in the
number of the buccal products [1] which are on the market. There are
many advantages of oral mucosa which make it an attractive site for
delivery. Firstly, it provides direct entry into the systemic circulation
hence avoiding the hepatic frst-pass effect and degradation in the
gastrointestinal tract. It is a readily accessible area, and allows self
application. The delivery can be terminated at any desired time. It is
not gender specifc, and patient compliance is reported to be very good.
However, there are also some disadvantages associated with this route
of drug delivery, mainly the low permeability and a smaller absorptive
surface area in comparison to the absorptive surface area of the small
intestines. Furthermore, salivation and resulting swallowing would
effectively remove the drug from the preferred absorptive region.
In order to overcome these limitations, new approaches are being
explored dealing with permeation enhancers, mucoadhesion, etc. for
better delivery which enables the delivery system to remain on the
application site longer and improve availability by also enhancing the
permeability of the oral mucosa. Due to its favorable properties such
as bioadhesion and penetration-enhancing effect, besides its bioactive
properties, in recent years, chitosan has become a very promising
compound in the development of oral mucosal systems.
After a short introduction to oral mucosa and delivery, this review
will focus more on chitosan and its applications in oral mucosal deliv-
ery and treatment. For further information on oral mucosal delivery,
the reader is asked to refer to the recently published review articles
[1-4].
I. STRUCTURE AND PERMEABILITY PROPERTIES
OF THE ORAL MUCOSA
The anatomy and functions of the oral mucosa have been extensively
reviewed in previous papers [5, 6], hence in this section the structure
of the oral mucosa and its properties will be described briefy only to
facilitate understanding how drugs, after applied to the oral mucosa,
cross the mucosa to reach to the blood capillaries.
The soft tissues lining the human oral cavity are covered with a
stratifying squamous epithelium. In regions subject to mechanical
forces associated with mastication (gingiva and hard palate), there is
a keratinizing epithelium which is similar to that of the epidermis of
the skin. The mucosa in these regions is known as masticatory mucosa.
The mucosal lining of the foor of the mouth (sublingual) and buccal
regions, which must be fexible so as to accommodate chewing or
speech, is termed the lining mucosa and is covered with a nonkeratiniz-
ing epithelium like the epithelium covering the esophagus or uterine
cervix. Specialized mucosa is found on the top surface of tongue and
is of lesser importance to drug permeation [5]. The masticatory mu-
cosa represents approximately 25%, the specialized mucosa (dorsum
of tongue) approximately 15%, and the lining mucosa approximately
60% of the total surface area of the oral lining [7]. Both the structure
and the relative area of the different types of mucosa would infuence
the penetration of substances across the oral lining.
The basic drug transport mechanism for oral epithelium is the same
as for other epithelia in the body. There are two major routes involved:
transcellular (intracellular) route and paracellular (intercellular). The
major pathway across the stratifed epithelium of large molecules is
via the paracellular spaces, and there is a barrier to penetration as a
result of modifcations to the intercellular substance in the superfcial
layers [8]. In non-keratinized epithelium, as cells reach the upper third
to quarter of the epithelium, membrane coating granules become evi-
dent at the superfcial aspect of the cells and appear to fuse with the
plasma membrane so as to extrude their contents into the intercellular
space. This discharge forms a barrier to the permeability of various
compounds. Furthermore, different compounds may penetrate the
epithelium at different rates, depending on the chemical nature of the
molecule and the type of tissue being traversed. Passive diffusion has
been shown to be the primary mechanism of transport of the drugs
across the buccal mucosa whereas carrier-mediated transport has been
reported to have a small role [1].

II. ORAL MUCOSAL DELIVERY SYSTEMS
In general, oral mucosal delivery systems are designed to provide
either unidirectional or multidirectional drug release. For unidirectional
release, they may be applied topically on the mucosa as a reservoir that
can release material either into the oral cavity (Figure 1a) or across the
mucosa (Figure 1b). In the frst case, there is no requirement for the
24
agents to penetrate the oral lining, and this may not even be desirable
whereas in the latter case, the drug is desired to penetrate across the
oral mucosa and reach the blood circulation. Agents can also be ap-
plied topically so as to treat local mucosal conditions that might range
from mucositis and the common mouth ulcer to rarer lesions, such as
the blistering or vesicular-bullous diseases (Fig. 1c). In this modality,
the target of drug action is likely to be the deeper proliferative cells
of the oral epithelium or the infammatory process in the underlying
connective tissue. In either case, the compound will have to penetrate
the superfcial barrier layers of the oral epithelium.
For rapid oral mucosal delivery, the drug may be presented as
lozenges, flms, sprays or compressed tablets having a fairly rapid
in-mouth disintegration time (15 min or less). Where prolonged or
reservoir action is required, the dosage form is usually bioadhesive
and the drug is release-controlled for slow absorption through the oral
mucosa or slow release into the oral cavity.
1. Bioadhesion
The ability to maintain the delivery system at a particular site for
an extended period of time is benefcial both for local disease treat-
ment and also for systemic drug bioavailability. Bioadhesive polymers
have been widely used to maintain an intimate and prolonged contact
of the formulation with the oral mucosa [3, 9]. The term bioadhesion
is defned as attachment of a synthetic or natural macromolecule to
mucus and/or an epithelial surface [10]. When adhesion occurs in a
biological setting it is often termed bioadhesion, furthermore if this
adhesion occurs on mucosal membranes it is termed mucoadhesion
[11]. In general the expressions bioadhesion and mucoadhesion
are often used interchangeably. Nagai was among the frst to pioneer
the bioadhesive drug delivery system in the early 1980s [12]. The frst
product developed by his group contains a steroidal anti-infammatory
agent, triamcinolone acetonide, and is still on the market for the treat-
ment of aphthous stomatitis (AFTACH by Teijin Pharma Ltd, Japan)
[13].
2. Penetration enhancement
Another approach to overcome the barrier properties of the buccal
mucosa for drugs is the incorporation of chemical compounds into the
formulations [14]. Substances that help to promote drug permeation
through the buccal epithelium are referred to as penetration enhancers,
permeation promoters, absorption enhancers [15]. Ideally chemicals
used as penetration enhancers should be safe and non-toxic, non-
irritant, pharmacologically and chemically inert and non allergenic.
In addition, the tissue should revert to its normal integrity and bar-
rier properties upon removal of the chemical. Penetration enhancers
can be divided into many categories according to their structure,
mechanism of action and the type of drugs whose permeation they
enhance. Penetration enhancers used for buccal delivery, the descrip-
tion of which is precluded due to the brevity of the current article,
have been extensively reviewed by several authors [16, 17]. Buccal
penetration enhancement is reported to result from agents being able
to (a) increase the partitioning of drugs into the buccal epithelium, (b)
extract (and not disrupt) intercellular lipids, (c) interact with epithelial
protein domains and/or (d) increase the retention of drugs at the buccal
mucosal surface [16].
III. CHITOSAN
Chitin, which is the most abundant polysaccharide in nature after
cellulose, is the major component of exoskeletons of crustaceans and
insects as well as of cell walls of some microorganisms, bacteria and
fungi. Chitosan is obtained by alkaline deacetylation of chitin, by
removal of acetyl groups from the molecular chain of chitin to give
amino groups (-NH
2
). It comprises copolymers of glucosamine and
N-acetyl glucosamine. Chitosan differs from cellulose at the C-2 car-
bon by having this amine group in place of a hydroxyl group. Hence,
unlike cellulose, chitosan possesses positive ionic charges.
The degree of acetylation represents the proportion of N-acetyl-
D-glucosamine units with respect to the total number of units and
can be used to differentiate between chitin and chitosan. Chitin with
a degree of deacetylation of 65-70% or above is generally known
as chitosan. The degree of deacetylation is an important property of
chitosan which defnes its physicochemical and biological properties
and hence determines its applications. While chitin is insoluble in most
organic solvents, chitosan is readily soluble in dilute acidic solutions
below pH 6.0. Its solubility and possession of free amino groups
which are active sites for many chemical reactions makes chitosan
more preferable than chitin.
Chitosan exhibits a variety of physicochemical and biological
properties resulting in numerous applications in felds ranging from
waste and water treatment, agriculture, textiles, cosmetics, nutritional
enhancement and food processing. Due to its biocompatibility, biode-
gradability and bioactivity it became a very attractive substance for
diverse applications as a biomaterial in pharmaceutical and medical
felds. As a non-toxic and non-allergenic bioadhesive polymer, chi-
tosan has been extensively studied for mucosal delivery of drugs and
vaccines as well as for its bioactive properties such as antimicrobial,
anti-infammatory, hemostatic, tumor inhibition, antiviral, tissue
regeneration, wound healing and immunogenic activities [18]. It has
also been shown to enhance the permeation of the compounds across
various mucosae such as buccal, nasal, intestinal and vaginal mucosa
[19-22].
Like its composition, the molecular weight of chitosan varies with
the raw material sources and the method of preparation. It is com-
mercially available from a number of suppliers in various grades of
purity, molecular weight, and degree of deacetylation. However, there
is still a lack in standardization of chitosan for pharmaceutical and
biomedical applications even though there is a monograph for chitosan
chloride in the European Pharmacopeia (EP 2008) and a monograph
for chitosan is being prepared for the United States Pharmacopoeia
(USP).
The major beneft of using chitosan within pharmaceutical ap-
plications is the possibility of adding various chemical groups, in
particular to the C-2 position allowing for the formation of novel
conjugates with additional functionalities. Using such modifcations,
Figure 1 - Drug release from oral mucosal delivery systems: a) unidi-
rectional-into the oral cavity; b) unidirectional-across the mucosa; and
c) multidirectional-into the oral cavity and oral mucosa.
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
25
the properties of chitosan may be tailored to suit the requirements of
specifc pharmaceutical-technological challenges.
The positive surface charge of chitosan allows it also to interact
with macromolecules like exogenous nucleic acids, negatively charged
mucosal surfaces, or even the plasma membrane. It has been shown
that chitosan and its degradation products are quickly eliminated via
the renal route following intraperitoneal administration to mice, thus
overcoming accumulation in the body [23]. In physiological conditions,
chitosan is thought to be degraded by lysosymes or by chitinases. While
chitin and chitin synthase do not exist in mammals, human chitinase
family members have recently been described. Chitinases are ubiquitous
chitin-fragmenting hydrolases. The frst human chitinase discovered
was chitotriosidase that is specifcally expressed by phagocytes, and
later the identifcation, purifcation, and subsequent cloning of a second
mammalian chitinase was reported [24]. This enzyme is characterized
by an acidic isoelectric point and therefore named acidic mammalian
chitinase (AMCase). In rodents and humans the enzyme is relatively
abundant in the gastrointestinal tract and is found to a lesser extent
in the lung.

Bioadhesive and penetration-enhancing
properties of chitosan
Chitosan has been proposed as a bioadhesive polymer for use in
oral mucosal drug delivery [11]. The bioadhesive property of chitosan
is mediated by ionic interaction between the positively charged chi-
tosan amino groups in chitosan and the negatively charged sialic acid
residues in mucus [9, 25]. A wide variety of bioadhesives have been
tested in the tissue culture model and the effect of mucin was also
examined. Whilst many gels were found to adhere for 1-5 h, chitosan
was shown to remain longer than a day [26]. Histologically, excellent
tissue wetting properties were observed in the presence of chitosan.
The absence of mucin, the control of gel hydration and swelling and
wetting characteristics were identifed as key factors for prolonged
adhesion.
Many studies have been reported on the penetration-enhancing
effect of chitosan across the buccal mucosa [2, 20, 27]. It has been
shown that the interaction between various types of bioadhesive poly-
mers and epithelial cells also has a direct infuence on permeability of
the tissue [28]. In this way, the penetration of large and hydrophilic
molecules across an epithelial barrier may be enhanced. Similarly, the
enhancing effect of chitosan on buccal permeability can be explained
by the bioadhesive nature of chitosan, which increases the retention
of the drug at its application site. Furthermore, as chitosan has been
shown to be capable of disrupting lipid micelles in the intestine [29],
the permeabilizing effect may also be attributed to its interference
with the lipid organization in the buccal epithelium, however, such a
mechanism has not been proven.
The bioadhesive and penetration-enhancing properties of chitosan
and its derivatives have been investigated in numerous in vivo and in
vitro models [30]. In vitro permeation studies are performed in diffusion
cells using excised tissues such as porcine and bovine [1, 31]. Buccal
cell cultures have also been used for in vitro permeation and bioadhe-
sion studies [32-34]. A lectin-binding inhibition technique, involving
an avidin-biotin complex and a colorimetric detection system was
developed to investigate the binding of chitosan to buccal epithelial
cells, without having to alter their physicochemical properties by the
addition of marker entities [35]. From the wide range of polymer
solutions screened, chitosan was found to give the greatest inhibition
of lectin binding to the surface of buccal cells, while methylcellulose,
gelatin, Carbopol 934P and polycarbophil also produced a substantial
reduction. Another technique has been described by Kockisch et al.
[36] to evaluate polymer adhesion to human buccal cells following
exposure to aqueous polymer dispersion, both in vitro and in vivo.
Adhering polymer was visualized by staining with 0.1% (w/v) of either
Alcian blue (60 min) or Eosin (10 min) solution, uncomplexed dye
being removed by 0.25 M sucrose washings. The extent of polymer
adhesion was quantifed by measuring the relative staining intensity
of control and polymer-treated cells by image analysis. Chitosan was
found to adhere to human buccal cells and following in vivo admin-
istration as a mouthwash it was shown to stay on the human buccal
mucosa for at least 1 h.
Various derivatives such as trimethylated chitosan [37], mono-N-
carboxymethyl chitosan [38], chitosan-EDTA conjugates [39], thiolated
chitosan [40] have been developed to improve its mucoadhesive and/
or permeation enhancing properties as well as to enhance its solubility.
It was shown that the mucoadhesive properties were also affected by
the charge of the polymer [41].
The mucoadhesive and penetration enhancement properties of
5-methyl-pyrrolidinone chitosan, two low-molecular-weight chitosans
and a partially reacetylated chitosan were studied ex vivo using por-
cine buccal mucosa. Acyclovir, as the model drug, was added to the
polymer solutions at 5% (w/w) concentration. Methyl-pyrrolidinone
chitosan was shown to exert the best mucoadhesive and penetration
enhancement properties and the penetration of acyclovir was found to
decrease by partial depolymerization of chitosan and disappear after
partial reacetylation [22].
It has been shown that the mucoadhesion and penetration-enhancing
properties of N-trimethyl chitosans (TMCs) depend on the degree of
quaternization and molecular weight [42]. The mucoadhesive properties
were found to increase with increasing degree of quaternization [42].
Similarly, the effect of partially substituted N,O-[N,N-diethylaminome-
thyl (diethyldimethylene ammonium)n]methyl chitosans, containing
different percentages of pendant quaternary ammonium groups, on
the permeation of rhodamine 123 (Rh-123), (hydrophobic marker of
the transcellular absorption route), and of fuorescein sodium (NaFlu),
(polar marker of the paracellular route), was investigated across the
excised porcine cheek epithelium. These chitosan derivatives, having
varying degrees of substitution were shown to enhance the paracellular
drug penetration across the buccal epithelium which was remarkably
higher than that of trimethylated chitosan whereas the transcellular
transport was substantially accelerated only by the most substituted
derivative [43].
IV. APPLICATIONS IN DRUG DELIVERY
Due to its bioadhesive property, permeation-enhancing property
and biocompatibility, chitosan is an excellent candidate for delivering
therapeutic compounds especially when prolonged release is desired.
Chitosan and its derivatives in various forms such as gels, flms,
sponges, tablets, micro-/nanoparticles have been used for the delivery
of drugs into the oral cavity as well as across the oral mucosa. The ex
vivo and in vivo studies published in the last decade on applications
of chitosan are summarized in Table I. In the following sections, the
application of chitosan as a delivery system will be reviewed focusing
more on formulation technologies.
1. Applications in the treatment of oral mucositis
In general, the use of bioadhesive gels reduces the frequency of
application and the amount of drug administered and can also improve
patient compliance and acceptance. Hence many studies have been
reported on gel formulations of chitosan and derivatives for drug
delivery.
Chitosan in gel form has been studied by several groups in the treat-
ment of oral mucositis, which is a particularly painful and debilitating
consequence of cancer therapy and occurs as a result of damage to the
oral mucosa by radiation or chemotherapy. For the mucositis patient, the
occlusion and lubrication of the chitosan gel is expected to reduce the
discomfort of the infammatory and ulcerative conditions. Associated
with atrophy and ulceration of the oral mucosa is an increased risk of
infection, particularly when there is immunosuppression. Therefore,
chitosan is an excellent candidate for the treatment of oral mucositis,
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
26
Table I - Applications of chitosan and its derivatives in oral mucosal drug delivery and treatment.
Dosage form Drug Chitosan type Other
additives
Activity Treatment Model Ref.
Gel TGF-b Chitosan-H (DD: 80%, MW:
1400 kDa, Dainishiseika Col-
our and Chem. MGF, Japan)
- Penetration
enhancer
Buccal drug
delivery
Wound healing Ex vivo (por-
cine mucosa)
20
Gel Hydrocortisone Chitosan-H (DD: 80%, MW:
1400kDa)
- Penetration
enhancer
Buccal drug
delivery
Antiinamma-
tory
Ex vivo (por-
cine mucosa)
26
Tablet Nicotine Protasan CL212 (DD: 73%,
MW: 272kDa)
Carbopol
974P
Magnesium
hydroxide
Buccal drug
delivery
Smoking ces-
sation
Human 30
Gel Nystatin Chitosan-H (DD: 80%, MW:
1400kDa)
Protasan CL 213 (DD:
84%, MW: 272kDa,
Pronova,Norway)
- Antifungal
Buccal and
gingival drug
delivery
Oral mucositis Hamster
Human
43
Film Ginsenoside
Rb1
Chitosan glycerol (Wako
Pure Chemical Industries,
Osaka, Japan)
Sodium
alginate
Buccal drug
delivery
Oral mucositis Hamster 44
Film patch AZMX (Astra-
Zeneca)
Chitosan (MW: 400 kDa) PVA, PEO,
PVP
sodium tauro-
cholate
Gingival drug
delivery
Model study Dogs 47
Tablet contain-
ing chitosan
microspheres
Chlorhexidine
diacetate
Chitosan (DD: 75-85%,
Aldrich,USA)
Mannitol
Sodium
alginate
Saccharine
Buccal drug
delivery
Antifungal Human 53
Blend lm Ornidazole Carboxymethyl-chitosan
(MW: 199.6 kDa, substituent
degree of carboxymethyled:
0.93)
PVA Buccal drug
delivery
Antimicrobial Rat
Rabbit
59
Gel Denbufylline Palmitoyl glycol chitosan SGDC
Carbopol 974
Buccal drug
delivery
Model study Rabbit 69
Disc Bromocriptine
mesylate/
pluronic F-127
solid dispersion
Chitosan Carbopol
974P
Buccal drug
delivery
Pathologic
hyperprol-
actinemia
Human 73
Patch Miconazole Chitosan NaCMC,
PVA, HEC,
HPMC, PVP
Buccal, gingival
drug delivery
Antifungal Human 78
Film Taurine Chitosan-H (DD: 80%, MW:
1400kDa)
Collagenous
membrane
Wound healing Periodontal
regeneration
Beagle dogs 63
Gel Demineralized
bone matrix
Protasan UP CL213
(DD: 84%, MW 252 kDa)
Collagenous
membrane
Tissue regenera-
tion
Periodontal
regeneration
Human 64
Scaffold Plasmid and
virus encoding
TGF-1 gene
Chitosan (DD: 85%, Sigma,
USA)
Collagen Tissue regenera-
tion
Gene delivery
Periodontal
regeneration
BALB/c 65
Sponge Platelet-derived
growth factor-
BB (PDGF-BB)
- - Bone healing Periodontal
regeneration
Rat 79
DD: degree of deacetylation; HEC (hydroxyethyl cellulose); HPMC (hydroxypropylmethyl cellulose); MW: molecular weight; NaCMC: sodium carboxyme-
thyl cellulose (NaCMC); polyethyleneoxide (PEO) PVA (polyvinyl alcohol); PVP (polyvinyl pyrrolidone); SGDC: sodium glycodeoxycholate;TGF-b:
transforming growth factor
offering not only delivery of therapeutic compounds but also exerting
antimicrobial activity as well as the ability to stimulate cell prolifera-
tion and tissue organization.
In a previous study [20], transforming growth factor-b (TGF-b),
which was chosen as a candidate compound that might protect or
promote the healing of the mucosal lining by having a direct effect on
epithelial proliferation in patients with oral mucositis, was incorporated
into chitosan gel [20]. To exert an effect after topical application, it
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
27
is essential that the compound reaches the proliferative (basal) com-
partment of the epithelium. Our results showed a six- to seven-fold
enhancement of permeability by chitosan for TGF-b to which the
oral mucosa was reported to be rather impermeable. Tissue section-
ing technique enabled the compound to be quantitated in different
strata at different time points, which provided information as to the
effectiveness of delivery of the bioactive peptide to the proliferating
cell compartments. The quantity of the drug in the superfcial layers
of the epithelium was found to increase in the presence of chitosan,
and also more TGF-b reached the deeper layer. The hydrophilicity of
the compound also seemed to have an effect, for there was relatively
greater penetration of TGF-b into the deeper tissue layers as compared
to our previous study using hydrocortisone, which is a water insoluble
compound [27].
In another study, we prepared gel and flm formulations using
chitosans at different molecular weights and in different solvents
[44]. Nystatin, which is considered as a prophylactic agent for oral
mucositis was incorporated into the formulations. The in vitro release of
nystatin from the formulations was found to decrease with the increas-
ing molecular weight of chitosan. The effect of the formulations was
investigated in vivo in hamsters with chemotherapy (5-fuorouracil)-
induced mucositis. Mucositis scores in groups treated with nystatin
incorporated into gel and suspension formulations were signifcantly
lower (p < 0.05) than those treated with the chitosan gel alone. Survival
of animals in the treated groups was higher than that in the control
group. The retention time and distribution of the gels in the oral
cavity were investigated in healthy volunteers. A faster distribution
of nystatin in the oral cavity was obtained using the nystatin suspen-
sion compared to the chitosan gels, but the nystatin saliva level also
decreased rapidly. Drug concentration above the minimum inhibitory
concentration (MIC) value for Candida albicans (0.14 g/mL) was
maintained for longer periods of time at the application site (90 min)
in the oral cavity.
Similarly, Watanabe et al. [45] studied the effect of ginsenoside
Rb1 isolated from ginseng on 5-fuorouracil-induced oral mucositis
in hamsters. Ginsenoside Rb1 was incorporated into chitosan-sodium
alginate flm. The flms were attached to the oral mucosa, and then the
healing process was examined by measuring the area of mucositis,
myeloperoxidase (MPO) activity and microscopic aspects. G-Rb1-
containing flms were shown to improve recovery which was found
to be dose-dependent whereas flms without ginsenoside Rb1 were
shown to have no effect in comparison to the control group.
In a study in which the functional (mucoadhesion, viscosity) and
bioactive (anti-infective, antioxidant and tissue repairing) properties of
various chitosans were assessed, and compared to those of hyaluronic
acid to fnd the best candidate for the treatment of oral mucositis,
high molecular weight chitosan ascorbate was found to be the most
effective among the other chitosans studied [46].

2. Applications in dental medicine
In dentistry, various applications of chitosan have been proposed
in which the physical, mechanical, chemical properties of this mate-
rial have been used. These studies were reviewed in a previous paper
published by the author [47]. Recently, there has been increased interest
in application of chitosan for its bioactive properties such as wound
healing, antimicrobial and tissue regeneration, in addition to the drug
delivery system in gel, flm, sponge, fber and particulate forms. In this
section, after reporting on recent studies on chitosan-based systems
for delivery in dental medicine, which are generally for local delivery,
application of chitosan in tissue regeneration will be reviewed.
2.1. Local drug delivery
Chitosan blends with hydrophilic polymers including polyviny-
lalcohol (PVA), polyethyleneoxide (PEO) and polyvinylpyrrolidone
(PVP), were investigated as candidates for oral gingival delivery
systems [48]. The bioavailabilty conferred by the chitosan blend
delivery systems, as concluded from dog studies, was shown to be
comparable to that based on chitosan alone, especially for those blends
involving high-molecular-weight hydrophilic polymers. The study
also indicated that chitosan blends were superior in other properties
compared to chitosan alone. These included improved comfort and
reduced irritation, ease of processing, improved flm quality, improved
fexibility, and enhanced dissolution.
Bupivacaine-loaded chitosan beads were prepared, and the in vitro
drug release was studied in different media [49]. Maximum release of
bupivacaine was obtained between 100 and 120 h, depending on the
presence of lysozyme in the release medium, the enzyme facilitating
the release process. A constant release rate of the drug, between 11
and 15 mg/h, was observed for 30 h. In order to prolong bupivacaine
release, the drug-loaded chitosan beads were coated with a poly (DL-
lactide-co-glycolide) flm. The resulting device allowed the drug to
be released in a sustained form; a constant release rate between 28.5
and 29.5 mg/h was obtained for 3 days, and the maximum release of
bupivacaine took place at day 9. The developed system was suggested
for use in the treatment of dental pain in the buccal cavity.
Film dosage form was developed for sustained delivery of a syn-
thetic favonoid derivative, iprifavone into the periodontal pocket [50].
For this purpose, monolayer composite systems made of iprifavone-
loaded poly(d,l-lactide-co-glycolide) (PLGA) micromatrices in a
chitosan flm form were obtained by emulsifcation/casting/evaporation
technique. Multilayer flms, made of three layers of polymers (chitosan/
PLGA/chitosan), were also prepared and compared to monolayer flms
for their in vitro characteristics. Signifcant differences in swelling,
degradation and drug release were observed depending on flm structure
and composition. The composite micromatricial flms were shown to
be a suitable dosage form to prolong iprifavone release for 20 days.
Topical delivery is the most widely accepted approach to prolong
drug concentrations of an antimicrobial agent in the oral cavity. As
most antifungals do not possess the inherent ability to bind to the oral
mucosa, this is best achieved through improved formulations. Besides
bioadhesive properties, chitosan has been shown to inhibit the adhesion
of Candida albicans to human buccal cells and exert antifungal activity
[51]. The antifungal agent, chlorhexidine gluconate (Chx), which has
also been shown to reduce C. albicans adhesion to oral mucosal cells,
was incorporated into chitosan gels (at 0.1 or 0.2% concentration) or
flm, and in vitro drug release and the antifungal activity of the gels and
flms in the presence and absence of Chx was studied [52]. Prolonged
release was observed with flm formulations. The highest antifungal
activity was obtained with 2% chitosan gel containing 0.1% Chx.
The antimicrobial activity of similar chitosan formulations in
gel and flm forms was investigated against a periodontal pathogen,
Porphyromonas gingivalis [53]. The viscosity, bioadhesive properties
and antimicrobial activity of chitosans at different molecular weights
and deacetylation degrees were assessed in the absence or presence
of Chx which was incorporated into the formulations at 0.1 and 0.2%
concentrations. The fow property of the gels was found to be suit-
able for topical application on the oral mucosa and to syringe into the
periodontal pocket. The bioadhesive properties of the formulations
were shown ex vivo using freshly excised porcine buccal mucosa.
Bioadhesion was found to be not affected by the incorporation of
Chx. Chitosan is shown to have an antimicrobial activity against P.
gingivalis, and this was found to be higher with high-molecular-weight
chitosan. The combination of chitosan with Chx showed a higher
activity when compared to that of Chx alone, which would provide
Chx application at lower concentrations thus avoiding its undesired
side effects. Chitosan-based flms and gels are suggested as promising
delivery systems for local therapy of periodontal diseases with their
bioadhesive property and antimicrobial activity.
Buccal tablets based on Chx-containing chitosan microspheres
were developed against buccal infections [54]. The antimicrobial
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
28
activity of the microparticles was investigated, and the incorpora-
tion of Chx into chitosan microparticles was shown to improve the
antimicrobial activity, particularly the highest against C. albicans.
Drug-free chitosan microparticles were shown to exert antimicrobial
activity as well due to the polymer itself. Buccal tablets were prepared
by direct compression of the microparticles with mannitol alone or
with sodium alginate. Following in vivo administration, the tablets
were shown to maintain prolonged release of the drug in the oral
cavity. In the control group, the mouth was rinsed with a commercial
mouthwash (Dentosan) containing 0.2% (w/v) Chx. For the chitosan
treated group, the drug was detected even after 3 h, whereas in the
control group, the salivary drug concentrations were very low, and
no drug was detected after 2 h.
Mucoadhesive microspheres for the controlled release of triclosan
in oral care formulations, specifcally dental pastes were prepared us-
ing chitosan, Gantrez MS-955, Carbopol 974P, polycarbophil [55].
Triclosan was rapidly released into a sodium lauryl sulfate-containing
buffer from all except for the chitosan microspheres. The loading
effciency was found to be highest with the chitosan microspheres.
For microspheres that were manufactured from Gantrez, Carbopol or
polycarbophil, the release was found to be zero-order kinetics whereas
with chitosan, the release profle was shown to ft the Baker and
Lonsdale model. Chitosan microspheres were suggested as promising
candidates for the sustained release of triclosan in the oral cavity.
The antibacterial and plaque-reducing action of water-soluble
chitosan has been shown when used as a mouth rinse reagent [56]. A
chitosan-containing chewing gum formulation was developed, which
could effectively suppress the growth of oral bacteria in saliva [57,
58]. Fifty healthy subjects, ranging in age from 19 to 32 years, were
recruited and allowed chew the gum for 5 min and then rested for
5 min. Each subject chewed a total of eight pieces of gum, which was
either supplemented with or without chitosan, for a total of 80 min.
The amount of oral bacteria was found to signifcantly decrease in
the chitosan group. In particular, the number of mutans streptococci
was maintained at about a 20% level in comparison to that before
gum chewing, even at 1 h after gum chewing. It was suggested that
a supplementation of chitosan to gum would be an effective method
for controlling the number of cariogenic bacteria in situations where
it is diffcult to brush ones teeth, such as when an individual is away
from home all day or participating in outdoor training.
Chitosan has been used for delivery into oral cavity of the essential
oils, which exert antibacterial/antifungal activity. Encapsulation with
chitosan was suggested to provide protection of the essential oils,
avoiding oxidation reactions, and also a sustained delivery [59].
The flms composed of poly(vinyl alcohol) (PVA) and carboxyme-
thyl-chitosan (CMCS) were prepared as local drug delivery system
by blending/casting method, and loaded with ornidazole (OD), which
is an effective compound in the treatment of susceptible protozoal
infections and prophylaxis of anaerobic bacterial infections [60]. The
blend flms were shown to exert pH-responsive swelling behavior, and
moderate drug release action, and also exhibit a little antimicrobial
activity against Escherichia coli and Streptococcus aureus strains.
Those characteristics of CMCS/PVA blend flms were reported to
be governed by the weight ratio of CMCS and PVA. Increasing the
content of PVA in blend flm was shown to decrease swelling and
decelerate the drug release whereas increasing the content of CMCS
was shown to enhance the antimicrobial activity. The biocompatibility
and bioactivity of the blend flm was also assessed using rabbit blood
and Wistar rats. No hemolysis, no toxicity to rat periodontia and no
cytotoxicity to the rat muscle were observed. After subcutaneously
implanting the blend drug flms in Wistar rats, the systems maintained
good retention at the application site and a high drug concentration
over a long period of time (5 days) which was longer than the period
of in vitro drug released (160 min). Results of the in vitro and in vivo
studies showed that CMCS/PVA blend drug flm was an excellent
candidate for local drug delivery system. It was suggested that the
PVA/CMCS drug flm would be absorbed over a long period of time
and that the wound would eventually be cicatrized by new forming
tissues.
2.2. Periodontal regeneration
Periodontal disease, which is characterized by infammation of
periodontal tissues, eventually leads to degeneration of the periodon-
tium. If periodontal disease is left untreated, tooth loss can occur. The
main aim of periodontal therapy is to repair the damaged periodontal
supporting tissues as a result of the infammatory disease process [61].
Recent studies have suggested that chitosan and its derivatives are
promising candidates as a supporting material for tissue engineering
applications owing to their porous structure, gel-forming properties,
ease of chemical modifcation, high affnity to in vivo macromolecules
[62].
The effect of chitosan on osteoblast and fbroblast cell attach-
ment was studied in vitro [63]. Mouse MC3T3-E1 osteoblasts and
3T3 fbroblasts were grown in the presence of serum on acid soluble
and water soluble chitosans. Cell attachment and immunofuorescent
analyses were performed at various time points to analyze initial
phenotypic profles. Our results suggested that chitosan supports the
initial attachment and spreading of osteoblasts preferentially over
fbroblasts, and that manipulation of the biopolymer can alter the level
of attachment and spreading.
An amino acid, taurine, which is considered to be benefcial for
regulating the infammation process, was incorporated into the chi-
tosan flm and the synergistic effects of taurine and chitosan in the
experimental defects at the vestibular bone of maxillary canine teeth
in dogs were investigated [64]. Cellular activity was observed both in
the mitochondria of fbroblasts and macrophages. These ultrastructural
alterations were thought to be the sign of the disturbed balance between
the generated oxidants and antioxidant defense mechanisms. Taurine
appeared to enhance the acceleration effect of chitosan on wound
healing at early periods. This effect may be considered benefcial in
tissue repair in destructive diseases like periodontitis.
The effect of chitosan on periodontal regeneration was investigated
in twenty chronic periodontitis patients [65]. Following initial therapy,
the patients were treated either with chitosan gel (1% w/v); chitosan gel
+ demineralized bone matrix or chitosan gel+collagenous membrane.
A fap was applied for control purposes. Clinical and radiographic
measurements were recorded at baseline, day 90 and day 180 after
surgery. Signifcant bone healing was observed when compared with
baseline indicating that chitosan gel alone or its combination with
demineralized bone matrix/collagenous membrane is promising for
periodontal regeneration.
The effects of many growth factors on periodontal tissue cells have
been assessed for their involvement in periodontal tissue engineering
using chitosan-based delivery systems [61]. Porous chitosan/collagen
scaffolds were prepared through a freeze-drying process, and loaded
with plasmid and adenoviral vector encoding human transforming
growth factor-b1 (TGF-b1) [66], and were assessed in vitro by analy-
sis of microscopic structure, porosity, and cytocompatibility. Human
periodontal ligament cells (HPLCs) were seeded in this scaffold, and
gene transfection was traced by green fuorescent protein (GFP). The
expression of type I and type III collagen was detected with RTPCR,
and then these scaffolds were implanted subcutaneously into athymic
mice. Results indicated that the pore diameter of the gene-combined
scaffolds was smaller than that of pure chitosan/collagen scaffold. After
implanted in vivo, EGFP-transfected HPLCs not only proliferated but
also recruited surrounding tissue to grow in the scaffold, demonstrating
the potential of chitosan/collagen scaffold combined Ad-TGF-b1 as a
good substrate candidate in periodontal tissue engineering.
Strong and macroporous scaffolds were developed via absorbable
fbers, biopolymer chitosan, and mannitol porogen [67]. MC3T3-E1
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
29
osteoblast-like cells were cultured on the specimens and inside the
calcium phosphate cement (CPC) composite paste carrier. The scaffold
strength was found to be more than doubled via reinforcement. The
cement injectability was increased from about 60% to nearly 100%.
Cell attachment and proliferation on the new composite matched those
of biocompatible controls. Cells were able to infltrate into the macro-
pores and anchor to the bone mineral-like nano-apatite crystals. For
growth factor delivery, CPC powder:liquid ratio and chitosan content
was reported to provide the means to tailor the rate of protein release
from CPC carrier.
N-[1-hydroxy-3-(trimethylammonium)propyl]chitosan chloride
(HTCC) was prepared, and the antibacterial activity of chitosan and
HTCC against oral pathogens, their proliferation activity and effects
on the ultrastructure of human periodontal ligament cells (HPDLCs)
were investigated [68]. Their results indicated that four oral strains
were susceptible to chitosan and HTCC with minimum inhibitory
concentrations (MICs) ranging from 0.25 to 2.5 mg/mL. Chitosan at
2000, 1000, 100, and 50 g/mL concentrations was shown to stimulate
the proliferation of human periodontal ligament cells (HPDLCs). On
the contrary, HTCC inhibited the proliferation at the same concentra-
tions but accelerated the proliferation of HPDLCs at relatively low
concentrations (10, 3, 1.5, 1, and 0.3 l g/mL).
3. Applications for systemic delivery
There are numerous applications of chitosan in oral mucosal de-
livery for systemic delivery as well [69]. Various dosage forms have
been developed for the delivery of drugs across oral mucosa to treat
various diseases.
A non-covalently cross-linked palmitoyl glycol chitosan (GCP)
hydrogel was assessed as an erodible controlled-release system for the
buccal delivery of hydrophilic macromolecules [70]. Samples of GCP
with different degrees of hydrophobicity were synthesized and porous
hydrogels were prepared by freeze-drying an aqueous dispersion of the
polymer in the presence or absence of either a model macromolecule
fuorescein isothiocyanatedextran (FITC-dextran, MW 4400) and/or
amphiphilic derivatives Gelucire 50/13 or vitamin E d-a-tocopherol
polyethylene glycol succinate. The hydration and erosion of the gels
were governed by the hydrophobicity of the gel and the presence of
the amphiphilic additives. GCP gels could be loaded with up to 27.5%
(w/w) of FITC-dextran by freeze-drying a dispersion of GCP in a
solution of FITC-dextran. The gels were bioadhesive but less than
that of hydroxypropylmethylcellulose, Carbopol 974NF. Furthermore,
these hydrogels were incorporated with a model hydrophobic drug,
denbufylline and sodium glycodeoxycholate (GDC) was also added
as a penetration enhancer [71]. The buccal absorption of denbufylline
was investigated in the rabbit model. Carbopol 974NF (CP), denbufyl-
line and GDC tablets were used as control. Denbufylline was found
to reduce the porosity, erosion and hydration of the gels while GDC
increased the hydration and erosion. All gels were mucoadhesive but
less so than the control CP tablets. Denbufylline was detected in 0.5
h after dosing with the GCP formulation, and delivery was sustained
for at least 5 h after dosing whereas with the CP tablets, drug delivery
was not sustained, and drug was detected in 1 h after dosing.
5-methylpyrrolidinone chitosan (MPC) flms were prepared as
carriers for the buccal delivery of protein drugs [72]. Myoglobin
(MHb) was chosen as the model protein. The results obtained show that
the modulation of MHb release was achieved only through chitosan
cross-linking; the best results in release rate control were obtained by
cross-linking performed at pH 6.5. Good bioadhesion properties were
maintained even with high cross-linking degrees; the swelling index of
MHb-loaded flms at different cross-linking degrees assessed at pH 7.4
and pH 6.4 were comparable to those of placebo flms. It was reported
that protein release could be controlled without affecting bioadhesion
by setting suitable tripolyphosphate cross-linking conditions for MPC
flms.
Films based on chitosan hydrochloride (HCS) and polyacrylic acid
sodium salt (PAA) were prepared for the delivery of acyclovir [73].
A commercial cream containing acyclovir and an aqueous acyclovir
suspension were used as references. The addition of PAA to HCS
produced a decrease in flm hydration. The addition of PAA to HCS
was found to decrease the drug release. All chitosan-based flms were
shown to enhance the permeation of acyclovir across porcine cheek
epithelium when compared to the suspension and the commercial
cream. The penetration enhancement properties were affected by the
mixing ratio of the two polymers.
The clinical effectiveness of a chitosan-based bioadhesive
unidirectional buccal bromocriptine mysylate/pluronic F127discs
was investigated in hyperprolactinemic patients [74]. A total of 42
patients were randomly divided into two groups. Group A comprised
21 patients who used unidirectional buccoadhesive bromocriptine
methylate discs once daily for 1 month. Group B included 21 patients
who used vaginoadhesive bromocriptine methylate discs once daily
for 1 month. Serum prolactin (PRL) levels were measured before
and after therapy in all cases. A signifcant reduction in serum PRL
levels was observed after 1 month of therapy in both groups showing
no signifcant difference between the groups. Buccal adhesive discs
were reported to have advantages over the vaginal disc such as being
gender nonspecifc, avoiding manipulating the vagina, which could be
inconvenient to some patients, being not dependent on cyclic estrogen
levels, and may easily be used during menstruation.
A new highly porous, fexible device was developed for buccal
peptide administration by a very simple and mild casting/freeze-drying
procedure, which consisted of a mucoadhesive chitosan layer containing
insulin and an impermeable protective layer made of ethylcellulose [75].
This structure was expected to provide unidirectional drug release to
the mucosa and avoid loss of drug due to washout with saliva. Insulin
release was reported to be modulated by varying certain formulation
variables (chitosan salt type and molecular weight, chitosan, solution
pH, insulin dose). It was suggested that electrostatic interaction could
occur between chitosan amino groups and the insulin carboxylic groups.
The affnity of chitosan sponges to mucin surfaces was related to the
swelling and solubility properties of the different salts of chitosan.
Antisense oligonucleotide-loaded chitosan nanoparticles were pre-
pared and the release of oligonucleotide from chitosan-tripolyphosphate
(TPP)/oligonucleotide nanoparticles investigated [76]. The interaction
between chitosan and oligonucleotide was confrmed by using capil-
lary zone electrophoresis (CZE). The release of oligonucleotides from
nanoparticles was found to be dependent on loading methods and pH
conditions. Chitosan/oligomer-TPP nanoparticles were reported to
show the lowest release percent of oligonucleotides with 41.3% at pH
7.0 among the loading methods. The released oligonucleotides from
chitosan/ oligonucleotide nanoparticles were suffciently stable for 12
h in the 20% saliva solution. The sustained release of oligonucleotide
from chitosan nanoparticles was suggested to be suitable for the local
therapeutic application in periodontal diseases.
Buccal bioadhesive tablet formulations of nicotine hydrogen tar-
tarate (NHT) for nicotine replacement therapy (NRT) were developed
using chitosan and carbomer at different ratios [31]. The release of NHT
from the tablets increased with the increasing amount of chitosan while
the bioadhesion decreased. In vivo studies were performed on healthy
non-smoker volunteers in comparison to a commercially available
transdermal patch. When compared to the transdermal patch, similar
plasma nicotine levels were obtained with the developed buccal tablet
but in a signifcantly shorter time (Cmax for buccal tablet: 3 h, and for
Cmax for transdermal patch: 11.5 h). The developed buccal formula-
tion was very promising for relieving acute craving and is suggested
for use in combination with the transdermal patch for NRT.
A matrix for buccal drug delivery composed of a different chitosan
salts and poloxamer 407 was prepared by lyophilization of the blend
and then compression into discs [77]. An experimental design (32)
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
30
was used to study the infuence of the type of chitosan salt and of
the relative amount of poloxamer on drug release capacity, swelling,
erosion, and mucoadhesiveness of matrices. It was shown that the
matrix properties depended signifcantly on both the relative amount
of poloxamer and chitosan salt type. The rank orders of chitosan salts
for the four processes assessed were reported as follows: drug release:
chitosan acetate > chitosan citrate > chitosan lactate; swelling: chitosan
lactate > chitosan acetate = chitosan citrate; erosion: chitosan citrate
> chitosan lactate > chitosan acetate; mucoadhesion: chitosan lactate
> chitosan acetate = chitosan citrate. Mucoadhesion was particularly
promoted when poloxamer 407 was present at about 30% (w/w). The
matrix composed of chitosan lactate and poloxamer 407 was reported
to show the best characteristics for buccal administration.
*
Chitosan is clearly an attractive bioadhesive polymer which has
great potential for improving the delivery of drugs into the oral cavity
as well as across the oral mucosa especially due to its biodegradabil-
ity, biocompatibility and low toxicity. With its chemical versatility, it
provides an excellent opportunity to tailor delivery systems with the
desired properties. Furthermore, chitosan itself has bioactive proper-
ties, for this reason it offers benefts in treatment as well. On the other
hand, standardization of chitosan and its derivatives remains the major
issue to be solved to optimize the possibility of its commercialization.
Nevertheless, this is not a diffcult obstacle to overcome, and with
the promising results obtained in human studies, chitosan appears
to have great potential in applications for oral mucosal delivery and
treatment.
REFERENCES
1. Pather S.I., Rathbone M.J., Senel S. - Current status and the
future of buccal drug delivery systems. - Expert Opin. Drug
Deliv., 5, 531-542, 2008.
2. Rossi S., Sandri G., Caramella C. - Buccal drug delivery: a chal-
lenge already won? - Drug Discovery Today, 2, 59-65, 2005.
3. Sudhakar Y., Kuotsu K., Bandyopadhyay A.K. - Buccal bioad-
hesive drug delivery, a promising option for orally less efcient
drugs. - J. Control. Rel., 114, 15-40, 2006.
4. Pather S.I., Rathbone M.J., Senel S. - Oral transmucosal drug
delivery. - In: Modied Release Drug Delivery Technology, M.J.
Rathbone, J. Hadgraft, M.S. Roberts, M.E. Lane Eds., Informa
Healthcare, New York, 2008, pp. 54-73.
5. Squier C.A., Senel S., Wertz P. - Oral (buccal) mucosal drug
delivery, promises and probabilities. - STP Pharma Prat., 10,
47-54, 2000.
6. Senel S., Kremer M., Nagy K., Squier C. - Delivery of bioac-
tive peptides and proteins across oral (buccal) mucosa. - Curr.
Pharm. Biotechnol., 2, 175-186, 2001.
7. Collins L.M., Dawes C. - The surface area of the adult human
mouth and thickness of the salivary lm covering the teeth and
oral mucosa. - J. Dent. Res., 66, 1300-1302, 1987.
8. Hoogstraate A.J., Senel S., Cullander C., Verhoef J.C., Jung-
inger H.E., Bodde H.E. - Effects of bile salts on transport rates
and routes of FITC-labelled compounds across porsine buccal
epithelium in vitro. - J. Control. Rel., 40, 211-221, 1996.
9. Lee J.W., Park J.H., Robinson J.R. - Bioadhesive-based dos-
age forms: the next generation. - J. Pharm. Sci., 89, 850-866,
2000.
10. Longer M., Robinson J. - Fundamental aspects of bioadhesion.
- Pharm. Int., 7, 114-117, 1986.
11. Andrews G.P., Laverty T.P., Jones D.S. - Mucoadhesive polymeric
platforms for controlled drug delivery. - Eur. J. Pharm. Biopharm.,
71, 505-518, 2009.
12. Ishida M., Machida Y., Nambu N., Nagai T. - New mucosal dos-
age form of insulin. - Chem. Pharm. Bull. (Tokyo), 29, 810-816,
1981.
13. www.teijin-pharma.co.jp/english/index.html. - Consulted July
29, 2009.
14. Senel S., Hincal A.A. - Drug permeation enhancement via
buccal route: possibilities and limitations. - J. Control. Rel., 72,
133-144, 2001.
15. Chattaraj S.C., Walker R.B. - Penetration enhancer classica-
tion. - In: Percutaneous Penetration Enhancers, E.W. Smith,
H.I. Maibach Eds., CRC Press, Boca Raton, 1995, pp. 5-20.
16. Nicolazzo J.A., Reed B.L., Finnin B.C. - Buccal penetration
enhancers, how do they really work? - J. Control. Rel., 105,
1-15, 2005.
17. Harmik S., Alka A., Farhan J.A., Roop K.K. - Critical evaluation
of permeation enhancers for oral mucosal drug delivery. - Drug
Dev. Ind. Pharm., Aug. 7, 2009.
18. Senel S., McClure S.J. - Potential applications of chitosan in
veterinary medicine. - Adv. Drug Deliv. Rev., 56, 1467-1480,
2004.
19. Illum L., Farraj N.F., Davis S.S. - Chitosan as a novel nasal de-
livery system for peptide drugs. - Pharm. Res., 11, 1186-1189,
1994.
20. Senel S., Kremer M.J., Kas S., Wertz P.W., Hincal A.A., Squier
C.A. - Enhancing effect of chitosan on peptide drug delivery
across buccal mucosa. - Biomaterials, 21, 2067-2071, 2000.
21. Thanou M., Verhoef J.C., Junginger H.E. - Chitosan and its
derivatives as intestinal absorption enhancers. - Adv. Drug Deliv.
Rev., 50, Suppl. 1, S91-101, 2001.
22. Sandri G., Rossi S., Ferrari F., Bonferoni M.C., Muzzarelli C.,
Caramella C. - Assessment of chitosan derivatives as buccal
and vaginal penetration enhancers. - Eur. J. Pharm. Sci., 21,
351-359, 2004.
23. Onishi H., Machida Y. - Biodegradation and distribution of water-
soluble chitosan in mice. - Biomaterials, 20, 175-182, 1999.
24. Boot R., Bloommaart E., Swart E., Vlugt K., Bijl N., Moe C.,
Place A., Aerts J. - Identication of a novel acidic mammalian
chitinase distinct from chitotriosidase. - J. Biological Chemistry,
276, 6770-6776, 2001.
25. Peppas N.A., Huang Y. - Nanoscale technology of mucoadhesive
interactions. - Adv. Drug Deliv. Rev., 56, 1675-1687, 2004.
26. Needleman I.G., Smales F.C. - In vitro assessment of bioadhe-
sion for periodontal and buccal drug delivery. - Biomaterials,
16, 617-624, 1995.
27. Senel S., Kremer M.J., Kas H.S., Wertz P.W., Hincal A.A., Squier
A.C. - Effect of chitosan in enhancing drug delivery across buccal
mucosa. - In: Advances in Chitin Science, Vol. IV, M.G. Peter,
A. Domard, R.A.A. Muzzarelli Eds., Universitat Potsdam, 2000,
pp. 254-258.
28. Luessen H.L., de Leeuw B.J., Langemeyer M.W., de Boer
A.B., Verhoef J.C., Junginger H.E. - Mucoadhesive polymers
in peroral peptide drug delivery. VI. Carbomer and chitosan
improve the intestinal absorption of the peptide drug buserelin
in vivo. - Pharm. Res., 13, 1668-1672, 1996.
29. Furda I. - Reduction of absorbtion of dietary lipids and cholesterol
by chitosan and its derivatives and special formulations. - In:
Chitosan Per os: From Dietary Supplement to Drug Carrier,
R.A. Muzzarelli Ed., Atec, Grottommare, 2000, pp. 41-63.
30. Smart J.D. - The basics and underlying mechanisms of mu-
coadhesion. - Adv. Drug Deliv. Rev., 57, 1556-1568, 2005.
31. Ikinci G., Senel S., Tokgozoglu L., Wilson C.G., Sumnu M. -
Development and in vitro/in vivo evaluations of bioadhesive
buccal tablets for nicotine replacement therapy. - Pharmazie,
61, 203-207, 2006.
32. Nielsen H.M., Rassing M.R. - TR146 cells grown on lters as
a model of human buccal epithelium. IV. Permeability of water,
mannitol, testosterone and beta-adrenoceptor antagonists.
Comparison to human, monkey and porcine buccal mucosa. -
Int. J. Pharm., 194, 155-167, 2000.
33. Portero A., Remunan-Lopez C., Nielsen H.M. - The potential of
chitosan in enhancing peptide and protein absorption across
the TR146 cell culture model, an in vitro model of the buccal
epithelium. - Pharm. Res., 19, 169-74, 2002.
34. www.mattek.com/pages/products/epioral.
35. Patel D., Smith A.W., Grist N., Barnett P., Smart J.D. - An in
vitro mucosal model predictive of bioadhesive agents in the oral
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
31
cavity. - J. Control. Rel., 61, 175-183, 1999.
36. Kockisch S., Rees G.D., Young A.S., Tsibouklis J., Smart J.D.
- A direct-staining method to evaluate the mucoadhesion of
polymers from aqueous dispersion. - J. Control. Rel., 77, 1-6,
2001.
37. Thanou M., Florea B.I., Langemeyer M.W., Verhoef J.C., Jung-
inger H.E. - N-trimethylated chitosan chloride (TMC) improves
the intestinal permeation of the peptide drug buserelin in vitro
(Caco-2 cells) and in vivo (rats). - Pharm. Res., 17, 27-31,
2000.
38. Thanou M., Nihot M.T., Jansen M., Verhoef J.C., Junginger
H.E. - Mono-N-carboxymethyl chitosan (MCC), a polyampholytic
chitosan derivative, enhances the intestinal absorption of low
molecular weight heparin across intestinal epithelia in vitro and
in vivo. - J. Pharm. Sci., 90, 38-46, 2001.
39. Bernkop-Schnurch A., Krajicek M.E. - Mucoadhesive polymers
as platforms for peroral peptide delivery and absorption: syn-
thesis and evaluation of different chitosan-EDTA conjugates. - J.
Control. Rel., 50, 215-223, 1998.
40. Bernkop-Schnurch A., Hornof M., Guggi D. - Thiolated chitosans.
- Eur. J. Pharm. Biopharm., 57, 9-17, 2004.
41. Bernkop-Schnurch A., Freudl J. - Comparative in vitro study of
different chitosan-complexing agent conjugates. - Pharmazie,
54, 369-71, 1999.
42. Sandri G., Rossi S., Bonferoni M.C., Ferrari F., Zambito Y.,
Di Colo G., Caramella C. - Buccal penetration enhancement
properties of N-trimethyl chitosan: Inuence of quaternization
degree on absorption of a high molecular weight molecule. - Int.
J. Pharm., 297, 146-155, 2005.
43. Zambito Y., Uccello-Barretta G., Zaino C., Balzano F., Di Colo
G. - Novel transmucosal absorption enhancers obtained by
aminoalkylation of chitosan. - Eur. J. Pharm. Sci., 29, 460-469,
2006.
44. Aksungur P., Sungur A., Unal S., Iskit A.B., Squier C.A., Senel
S. - Chitosan delivery systems for the treatment of oral mucosi-
tis: in vitro and in vivo studies. - J. Control. Rel., 98, 269-279,
2004.
45. Watanabe S., Suemaru K., Yamaguchi T., Hidaka N., Sakanaka
M., Araki H. - Effect of oral mucosal adhesive lms containing
ginsenoside Rb1 on 5-uorouracil-induced oral mucositis in
hamsters. - Eur. J. Pharmacol., 616, 281-286, 2009.
46. Puccio A., Rossi S., Ferrari F., Bonferoni M.C., Sandri G.,
Dacarro C., Grisoli P., Caramella C. - Chitosan as bioactive
polymer for the treatment of mucositis in cancer patients. - In:
9
th
International Conference of the European Chitin Society,
Venice, Italy, 2009, pp. 48-49.
47. Senel S., Kas H.S., Squier A.C. - Application of chitosan in
dental drug delivery and therapy. - In: Chitosan Per os: From
Dietary Supplement to Drug Carrier, R.A. Muzzarelli Ed., Atec,
Grottommare, 2000, pp. 241-256.
48. Khoo C.G., Frantzich S., Rosinski A., Sjostrom M., Hoogstraate
J. - Oral gingival delivery systems from chitosan blends with
hydrophilic polymers. - Eur. J. Pharm. Biopharm., 55, 47-56,
2003.
49. Bernardo M.V., Blanco M.D., Sastre R.L., Teijon C., Teijon
J.M. - Sustained release of bupivacaine from devices based
on chitosan. - Farmaco, 58, 1187-1191, 2003.
50. Perugini P., Genta I., Conti B., Modena T., Pavanetto F. - Peri-
odontal delivery of ipriavone: new chitosan/PLGA lm delivery
system for a lipophilic drug. - Int. J. Pharm., 252, 1-9, 2003.
51. Knapczyk J., Macura A.B., Pawlik B. - Simple tests demonstrat-
ing the antimycotic effect of chitosan. - Int. J. Pharm., 80, 33-38,
1992.
52. Senel S., Ikinci G., Kas S., Youse-Rad A., Sargon M.F., Hincal
A.A. - Chitosan lms and hydrogels of chlorhexidine gluconate
for oral mucosal delivery. - Int. J. Pharm., 193, 197-203, 2000.
53. Ikinci G., Senel S., Akincibay H., Kas S., Ercis S., Wilson C.G.,
Hincal A.A. - Effect of chitosan on a periodontal pathogen Por-
phyromonas gingivalis. - Int. J. Pharm., 235, 121-127, 2002.
54. Giunchedi P., Juliano C., Gavini E., Cossu M., Sorrenti M. - For-
mulation and in vivo evaluation of chlorhexidine buccal tablets
prepared using drug-loaded chitosan microspheres. - Eur. J.
Pharm. Biopharm., 53, 233-239, 2002.
55. Kockisch S., Rees G.D., Tsibouklis J., Smart J.D. - Mucoadhesive,
triclosan-loaded polymer microspheres for application to the oral
cavity: preparation and controlled release characteristics. - Eur.
J. Pharm. Biopharm., 59, 207-216, 2005.
56. Bae K., Jun S., Lee S., Paik D., Kim J. - Effect of water-soluble
reduced chitosan on Streptococcus mutans, plaque regrowth
and biolm vitality. - Clin. Oral Invest., 10, 102-107, 2006.
57. Hayashi Y., Ohara N., Ganno T., Ishizaki H., Yanagiguchi K. -
Chitosan-containing gum chewing accelerates antibacterial
effect with an increase in salivary secretion. - J. Dent., 35,
871-874, 2007.
58. Hayashi Y., Ohara N., Ganno T., Yamaguchi K., Ishizaki T.,
Nakamura T., Sato M. - Chewing chitosan-containing gum ef-
fectively inhibits the growth of cariogenic bacteria. - Arch. Oral
Biol., 52, 290-294, 2007.
59. Pedro A.S., Cabral-Albuquerque E., Ferreira D., Sarmento B.
- Chitosan: an option for development of essential oil delivery
systems for oral cavity care? - Carbohydrate Polymers, 76,
501-508, 2009.
60. Wang L., Chen X., Zhong D., Xu Q. - Study on poly(vinyl alco-
hol)/carboxymethyl-chitsaon blend lm as local drug delivery
system. - J. Material Sci., 18, 1125-1133, 2007.
61. Moioli E.K., Clark P.A., Xin X., Lal S., Mao J.J. - Matrices and
scaffolds for drug delivery in dental, oral and craniofacial tissue
engineering. - Adv. Drug Deliv. Rev., 59, 308-324, 2007.
62. Kim I.Y., Seo S.J., Moon H.S., Yoo M.K., Park I.Y., Kim B.C.,
Cho C.S. - Chitosan and its derivatives for tissue engineering
applications. - Biotechnol. Adv., 26, 1-21, 2008.
63. Fakhry A., Schneider G.B., Zaharias R., Senel S. - Chitosan
supports the initial attachment and spreading of osteoblasts
preferentially over broblasts. - Biomaterials, 25, 2075-2079,
2004.
64. Ozmeric N., Ozcan G., Haytac C.M., Alaaddinoglu E.E., Sargon
M.F., Senel S. - Chitosan lm enriched with an antioxidant agent,
taurine, in fenestration defects. - J. Biomed. Mater. Res., 51,
500-503, 2000.
65. Boynuegri D., Ozcan G., Senel S., Uc D., Uraz A., Ogus E.,
Cakilci B., Karaduman B. - Clinical and radiographic evalua-
tions of chitosan gel in periodontal intraosseous defects: a pilot
study. - J. Biomed. Mater. Res. B Appl. Biomater., 90, 461-466,
2009.
66. Zhang Y., Cheng X., Wang J., Wang Y., Shi B., Huang C., Yang X.,
Liu T. - Novel chitosan/collagen scaffold containing transforming
growth factor-beta1 DNA for periodontal tissue engineering. -
Biochem. Biophys. Res. Commun., 344, 362-369, 2006.
67. Xu H.H., Weir M.D., Simon C.G. - Injectable and strong nano-
apatite scaffolds for cell/growth factor delivery and bone regen-
eration. - Dent. Mater., 24, 1212-1222, 2008.
68. Ji Q.X., Zhong de Y., Lu R., Zhang W.Q., Deng J., Chen X.G. -
In vitro evaluation of the biomedical properties of chitosan and
quaternized chitosan for dental applications. - Carbohydr. Res.,
344, 1297-1302, 2009.
69. Salamat-Miller N., Chittchang M., Johnston T.P. - The use of
mucoadhesive polymers in buccal drug delivery. - Adv. Drug
Deliv. Rev., 57, 1666-1691, 2005.
70. Martin L., Wilson C.G., Koosha F., Tetley L., Gray A.I., Senel
S., Uchegbu I.F. - The release of model macromolecules may
be controlled by the hydrophobicity of palmitoyl glycol chitosan
hydrogels. - J. Control. Rel., 80, 87-100, 2002.
71. Martin L., Wilson C.G., Koosha F., Uchegbu I.F. - Sustained
buccal delivery of the hydrophobic drug denbufylline using
physically cross-linked palmitoyl glycol chitosan hydrogels. - Eur.
J. Pharm. Biopharm., 55, 35-45, 2003.
72. Colonna C., Genta I., Perugini P., Pavanetto F., Modena T., Valli
M., Muzzarelli C., Conti B. - 5-methyl-pyrrolidinone chitosan
lms as carriers for buccal administration of proteins. - AAPS
PharmSciTech, 7, 70, 2006.
73. Rossi S., Sandri G., Ferrari F., Bonferoni M.C., Caramella C. -
Buccal delivery of acyclovir from lms based on chitosan and
polyacrylic acid. - Pharm. Dev. Technol., 8, 199-208, 2003.
74. Darwish A.M., El-Sayed A.M., El-Harras S.A., Khaled K.A., Ismail
M.A. - Clinical efcacy of novel unidirectional buccoadhesive
vs. vaginoadhesive bromocriptine mesylate discs for treating
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010
32
pathologic hyperprolactinemia. - Fertil. Steril., 90, 1864-1868,
2008.
75. Portero A., Teijeiro-Osorio D., Alonso M.J., Remunan-Lopez
C. - Development of chitosan sponges for buccal administration
of insulin. - Carbohydrate Polymers, 68, 617-625, 2007.
76. Dung T.H., Lee S.R., Han S.D., Kim S.J., Ju Y.M., Kim M.S.,
Yoo H. - Chitosan-TPP nanoparticle as a release system of
antisense oligonucleotide in the oral environment. - J. Nanosci.
Nanotechnol., 7, 3695-3699, 2007.
77. Cafaggi S., Leardi R., Parodi B., Caviglioli G., Russo E., Bignardi
G. - Preparation and evaluation of a chitosan salt-poloxamer
407 based matrix for buccal drug delivery. - J. Control. Rel.,
102, 159-169, 2005.
78. Nafee N.A., Ismail F.A., Boraie N.A., Mortada L.M. - Mucoad-
hesive buccal patches of miconazole nitrate: in vitro/in vivo
performance and effect of ageing. - Int. J. Pharm., 264, 1-14,
2003.
79. Yoon J.P., Yong M.L., Si N.P., Seung Y.S., Chong P.C., Seung
J.L. - Platelet derived growth factor releasing chitosan sponge
for periodontal bone regeneration. - Biomaterials, 21, 153-159,
2000.
MANUSCRIPT
Received 3 August 2009, accepted for publication 24 September
2009.
Potential applications of chitosan in oral mucosal delivery
S. Senel
J. DRUG DEL. SCI. TECH., 20 (1) 23-32 2010

Vous aimerez peut-être aussi