Journal of Controlled Release 114 (2006) 15 – 40

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Review
Buccal bioadhesive drug delivery — A promising option
for orally less efficient drugs
Yajaman Sudhakar, Ketousetuo Kuotsu, A.K. Bandyopadhyay ⁎
Buccal Adhesive Research Laboratory, Division of Pharmaceutics, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
Received 4 December 2005; accepted 26 April 2006
Available online 7 July 2006

Abstract

Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs including
peptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoid
of untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensive
presystemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parentral route of administration is
the only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly,
have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the last
few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to
injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible
site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle
which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells.
Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high
bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the
optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging. With the right
dosage form design, local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution and
permeation. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical
properties of the drug and excipients. Advances in experimental and computational methodologies will be helpful in shortening the processing
time from formulation design to clinical use. This paper aims to review the developments in the buccal adhesive drug delivery systems to provide
basic principles to the young scientists, which will be useful to circumvent the difficulties associated with the formulation design.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Buccal delivery; Bioadhesive; Polymers; Formulation; Permeation enhancers; Evaluation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.1. Buccal mucosal structure and its suitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.2. Absorption pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.3. Barriers to penetration across buccal mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.1. Membrane coating granules or cored granules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.2. Basement membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.3. Mucus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.4. Saliva. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

⁎ Corresponding author. Tel.: +91 9831261813; fax: +91 033 30940712.

E-mail addresses: yajaman_pharma@yahoo.com (Y. Sudhakar), akbju@yahoo.com (A.K. Bandyopadhyay).

0168-3659/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2006.04.012
16 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40

2. Formulation design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.1. Pharmaceutical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.1.1. Buccal adhesive polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2. Physiological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.3. Pharmacological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.4. Permeation enhancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.4.1. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3. Muco/bioadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1. Bio/mucoadhesive forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1.1. Van der Waal's forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1.2. Hydrogen bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.3. Disulphide bridging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.4. Hydration forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.5. Electrostatic double-layer forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.6. Hydrophobic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.7. Steric forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.1.8. Covalent bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.2. Methods for measuring mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.2.1. Quantitative methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.2.2. Qualitative methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.3. Factors affecting bio/mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4. Developments in buccal adhesive drug delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.1. Commercial buccal adhesive drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.2. Research on buccal adhesive drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.2.1. Solid buccal adhesive formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.2.2. Semi-solid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.2.3. Liquid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
4.3. Delivery of proteins and peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.1. Determination of the residence time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.1.1. In vitro residence time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.1.2. In vivo residence time test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.2. Permeation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.2.1. In vitro methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.2.2. Ex vivo methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2.3. In vivo methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

1. Introduction clearance extensive in liver, which often leads to a lack of sig-

The main impediment to the use of many hydrophilic macro-
molecular drugs as potential therapeutic agents is their inadequate
and erratic oral absorption. The relatively recent evolution of
recombinant DNA research and modern synthetic and biotech-
nological methodologies allow the biochemist and chemist to
produce vast quantities of variety of peptides and proteins pos-
sessing better pharmacological efficacy. However, therapeutic
potential of these compounds lies in our ability to design and
achieve effective and stable delivery systems. The future chal-
lenge of pharmaceutical scientists will not only be polypeptide
cloning and synthesis, but also to develop effective nonparenteral
delivery of intact proteins and peptides to the systemic circulation.
Based on our current understanding of biochemical and phy-
siological aspects of absorption and metabolism of many bio-
technologically-produced drugs, they cannot be delivered
effectively through the conventional oral route. Because after
oral administration many drugs are subjected to presystemic
nificant correlation between membrane permeability, absorption,
and bioavailability [1]. Difficulties associated with parenteral
delivery and poor oral availability provided the impetus for ex-
ploring alternative routes for the delivery of such drugs. These
include routes such as pulmonary, ocular, nasal, rectal, buccal,
sublingual, vaginal, and transdermal. In absence of external sti-
muli to facilitate absorption, use of these alternative routes has had
limited success. Various strategies have been implemented to
promote the bioavailability of these drugs, including supplemen-
tal administration of enzyme inhibitors, use of absorption en-
hancers, novel formulation strategies, and reversible chemical
modifications [2].
Among the various transmucosal routes, buccal mucosa has
excellent accessibility, an expanse of smooth muscle and relatively
immobile mucosa, hence suitable for administration of retentive
dosage forms. Direct access to the systemic circulation through the
internal jugular vein bypasses drugs from the hepatic first pass
metabolism leading to high bioavailability. Other advantages such
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
as low enzymatic activity, suitability for drugs or excipients that
mildly and reversibly damages or irritates the mucosa, painless
administration, easy drug withdrawal, facility to include perme-
ation enhancer/enzyme inhibitor or pH modifier in the formulation
and versatility in designing as multidirectional or unidirectional
release systems for local or systemic actions etc, opts buccal
adhesive drug delivery systems as promising option for continued
research [3].
However, the effect of salivary scavenging and accidental
swallowing of delivery system; barrier property of buccal mu-
cosa stands as the major limitations in the development of
buccal adhesive drug delivery systems.
Our intent, therefore, is to discuss the implication of various
approaches for buccal adhesive delivery strategies applied for
the systemic delivery of orally less/in efficient drugs, in addition
to the widely used local drug delivery.
1.1. Buccal mucosal structure and its suitability
Buccal region is that part of the mouth bounded anteriorly and
laterally by the lips and the cheeks, posteriorly and medially by
the teeth and/or gums, and above and below by the reflections of
the mucosa from the lips and cheeks to the gums. Numerous
racemose, mucous, or serous glands are present in the submucous
tissue of the cheeks [4]. The buccal glands are placed between the
mucous membrane and buccinator muscle: they are similar in
structure to the labial glands, but smaller. About five, of a larger
size than the rest, are placed between the masseter and buccinator
muscles around the distal extremity of the parotid duct; their ducts
open in the mouth opposite the last molar tooth. They are called
molar glands [5]. Maxillary artery supplies blood to buccal mu-
cosa and blood flow is faster and richer (2.4 ml/min/cm2) than that
in the sublingual, gingival and palatal regions, thus facilitates
passive diffusion of drug molecules across the mucosa. The
thickness of the buccal mucosa is measured to be 500–800 μm
and is rough textured, hence suitable for retentive delivery sys-
tems [6]. The turnover time for the buccal epithelium has been
estimated at 5–6 days [7].
Buccal mucosa composed of several layers of different cells as
shown in Fig. 1. The epithelium is similar to stratified squamous
epithelia found in rest of the body and is about 40–50 cell layers
thick [5]. Lining epithelium of buccal mucosa is the nonkeratinized
stratified squamous epithelium that has thickness of approximately
500–600 μ and surface area of 50.2 cm2. Basement membrane,
lamina propria followed by the submucosa is present below the
epithelial layer [8]. Lamina propria is rich with blood vessels and
capillaries that open to the internal jugular vein. Lipid analysis of
buccal tissues shows the presence of phospholipid 76.3%, glu-
cosphingolipid 23.0% and ceramide NS at 0.72%. Other lipids
such as acyl glucosylated ceramide, and ceramides like Cer AH,
Cer AP, Cer NH, Cer AS, and EOHP/NP are completely absent [9].
The primary function of buccal epithelium is the protection of
the underlying tissue. In nonkeratinized regions, lipid-based
permeability barriers in the outer epithelial layers protect the
underlying tissues against fluid loss and entry of potentially
harmful environmental agents such as antigens, carcinogens,
microbial toxins and enzymes from foods and beverages [10].
17
Fig. 1. Cross-section of buccal mucosa.
1.2. Absorption pathways
Studies with microscopically visible tracers such as small
proteins [11] and dextrans [12] suggest that the major pathway
across stratified epithelium of large molecules is via the inter-
cellular spaces and that there is a barrier to penetration as a result of
modifications to the intercellular substance in the superficial
layers. However, rate of penetration varies depending on the
physicochemical properties of the molecule and the type of tissue
being traversed. This has led to the suggestion that materials uses
one or more of the following routes simultaneously to cross the
barrier region in the process of absorption, but one route is pre-
dominant over the other depending on the physicochemical pro-
perties of the diffusant [13].
➢ Passive diffusion
◦ Transcellular or intracellular route (crossing the cell
membrane and entering the cell)
◦ Paracellular or intercellular route (passing between the
cells)
➢ Carrier mediated transport
➢ Endocytosis
The flux of drug through the membrane under sink condition
for paracellular route can be written as Eq. (1)
Dp e
Jp ¼ Cd ð1Þ
hp
Where, Dp is diffusion coefficient of the permeate in the inter-
cellular spaces, hp is the path length of the paracellular route, ε is the
area fraction of the paracellular route and Cd is the donor drug
concentration.
Similarly, flux of drug through the membrane under sink
condition for transcellular route can be written as Eq. (2).
ð1−eÞDc Kc
Jc ¼ Cd ð2Þ
hc
18 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Where, Kc is partition coefficient between lipophilic cell mem-
brane and the aqueous phase, Dc is the diffusion coefficient of
the drug in the transcellular spaces and hc is the path length of
the transcellular route [14].
In very few cases absorption also takes place by the process of
endocytosis where the drug molecules were engulfed by the
cells. It is unlikely that active transport processes operate within
the oral mucosa; however, it is believed that acidic stimulation of
the salivary glands, with the accompanying vasodilatation, faci-
litates absorption and uptake into the circulatory system [15].
The absorption potential of the buccal mucosa is influenced by
the lipid solubility and molecular weight of the diffusant. Ab-
sorption of some drugs via the buccal mucosa is found to increase
when carrier pH is lowered and decreased with an increase of pH
[16]. However, the pH dependency that is evident in absorption of
ionizable compounds reflects their partitioning into the epithelial
cell membrane, so it is likely that such compounds will tend to
penetrate transcellularly [17]. Weak acids and weak bases are
subjected to pH-dependent ionization. It is presumed that ionized
species penetrate poorly through the oral mucosa compared with
non-ionized species. An increase in the amount of non-ionized
drug is likely to increase the permeability of the drug across an
epithelial barrier, and this may be achieved by a change of pH of the
drug delivery system. It has been reported that pH has effect on the
buccal permeation of drug through oral mucosa [18]. The diffusion
of drugs across buccal mucosa was not related to their degree of
ionization as calculated from the Henderson–Hasselbalch equation
and thus it is not helpful in the prediction of membrane diffusion of
weak acidic and basic drugs [19].
In general, for peptide drugs, permeation across the buccal
epithelium is thought to be through paracellular route by passive
diffusion. Recently, it was reported that drugs that have a mono-
carboxylic acid residue could be delivered into systemic circulation
from the oral mucosa via its carrier [20]. The permeability of oral
mucosa and the efficacy of penetration enhancers have been inves-
tigated in numerous in vivo and in vitro models. Various kinds of
diffusion cells, including continuous flow perfusion chambers,
Ussing chambers, Franz cells and Grass–Sweetana, have been used
to determine the permeability of oral mucosa [21]. Cultured epi-
thelial cell lines have also been developed as an in vitro model for
studying drug transport and metabolism at biological barriers as
well as to elucidate the possible mechanisms of action of pene-
tration enhancers [22,23]. Recently, TR146 cell culture model was
suggested as a valuable in vitro model of human buccal mucosa for
permeability and metabolism studies with enzymatically labile
drugs, such as leu-enkefalin, intended for buccal drug delivery [24].
1.3. Barriers to penetration across buccal mucosa
The barriers such as saliva, mucus, membrane coating granules,
basement membrane etc retard the rate and extent of drug ab-
sorption through the buccal mucosa. The main penetration barrier
exists in the outermost quarter to one third of the epithelium [8].
1.3.1. Membrane coating granules or cored granules
In nonkeratinized epithelia, the accumulation of lipids and
cytokeratins in the keratinocytes is less evident and the change in
morphology is far less marked than in keratinized epithelia. The
mature cells in the outer portion of nonkeratinized epithelia be-
come large and flat, retain nuclei and other organelles and the
cytokeratins do not aggregate to form bundles of filaments as seen
in keratinizing epithelia. As cells reach the upper third to quarter of
the epithelium, membrane-coating granules become evident at the
superficial aspect of the cells and appear to fuse with the plasma
membrane so as to extrude their contents into the intercellular
space. The membrane-coating granules found in nonkeratinizing
epithelia are spherical in shape, membrane-bounded and measure
about 0.2 μm in diameter [25]. Such granules have been observed
in a variety of other human nonkeratinized epithelia, including
uterine cervix [26] and esophagus [27]. However, current studies
employing ruthenium tetroxide as a post-fixative indicate that in
addition to cored granules, a small proportion of the granules in
nonkeratinized epithelium do contain lamellae, which may be the
source of short stacks of lamellar lipid scattered throughout the
intercellular spaces in the outer portion of the epithelium. In
contrast to the intercellular spaces of stratum corneum, those of the
superficial layer of nonkeratinizing epithelia contain electron lu-
cent material, which may represent nonlamellar phase lipid, with
only occasional short stacks of lipid lamellae.
1.3.2. Basement membrane
Although the superficial layers of the oral epithelium represent
the primary barrier to the entry of substances from the exterior, it is
evident that the basement membrane also plays a role in limiting the
passage of materials across the junction between epithelium and
connective tissue. A similar mechanism appears to operate in the
opposite direction. The charge on the constituents of the basal
lamina may limit the rate of penetration of lipophilic compounds that
can traverse the superficial epithelial barrier relatively easily [28].
1.3.3. Mucus
The epithelial cells of buccal mucosa are surrounded by the
intercellular ground substance called mucus with the thickness
varies from 40 μm to 300 μm [29]. Though the sublingual glands
and minor salivary glands contribute only about 10% of all saliva,
together they produce the majority of mucus and are critical in
maintaining the mucin layer over the oral mucosa [30]. It serves as
an effective delivery vehicle by acting as a lubricant allowing cells
to move relative to one another and is believed to play a major role
in adhesion of mucoadhesive drug delivery systems [31]. At buccal
pH, mucus can form a strongly cohesive gel structure that binds to
the epithelial cell surface as a gelatinous layer [8]. Mucus mole-
cules are able to join together to make polymers or an extended
three-dimensional network. Different types of mucus are produced,
for example G, L, S, P and F mucus, which form different network
of gels. Other substances such as ions, protein chains, and enzymes
are also able to modify the interaction of the mucus molecules and,
as a consequence, their biophysical properties [32].
Mucus is composed chiefly of mucins and inorganic salts
suspended in water. Mucins are a family of large, heavily gly-
cosylated proteins composed of oligosaccharide chains attached
to a protein core. Three quarters of the protein core are heavily
glycosylated and impart a gel like characteristic to mucus. Mucins
contain approximately 70–80% carbohydrate, 12–25% protein
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
and up to 5% ester sulphate [33]. The dense sugar coating of
mucins gives them considerable water-holding capacity and also
makes them resistant to proteolysis, which may be important in
maintaining mucosal barriers [4].
Mucins are secreted as massive aggregates by prostaglandins
with molecular masses of roughly 1 to 10 million Da. Within these
aggregates, monomers are linked to one another mostly by non-
covalent interactions, although intermolecular disulphide bonds
also play a role in this process. Oligosaccharide side chains con-
tain an average of about 8–10 monosaccharide residues of five
different types namely L-fucose, D-galactose, N-acetyl-D-glucos-
amine, N-acetyl-D-galactosamine and sialic acid. Amino acids
present are serine, threonine and proline [34]. Because of the
presence of sialic acids and ester sulfates, mucus is negatively
charged at physiological salivary pH of 5.8–7.4 [8].
At least 19 human mucin genes have been distinguished by
cDNA cloning-MUC1, 2, 3A, 3B, 4,5AC, 5B, 6–9, 11–13, and
15–19. Mucin genes encode mucin monomers that are synthesized
as rod-shaped apomucin covers that are post translationally modi-
fied by exceptionally abundant glycosylation. Two distinctly dif-
ferent regions are found in mature genes. The amino- and carboxy-
terminal regions are very lightly glycosylated, but rich in cysteines,
which are likely, involved in establishing disulfide linkages within
and among mucin monomers. A large central region formed of
multiple tandems repeats of 10 to 80 residue sequences in which up
to half of the amino acids are serine or threonine. This area becomes
saturated with hundreds of O-linked oligosaccharides also found
on mucins, but much less abundantly [4].
Mucins are characterized not only by large molecular masses
but also by large molecular mass distributions, as seen by analytical
ultra centrifugation, and by the powerful technique of size
exclusion chromatography coupled to multi-angle laser light sca-
ttering [35,36]. In solution, mucins adopt a random-coil confor-
mation [37], occupying a time averaged spheroidal domain as
shown by hydrodynamics and critical-point-drying electron mi-
croscopy. Mucins, which are different, are the submaxillary mu-
cins, with a lower carbohydrate content and different structure [38].
1.3.4. Saliva
The mucosal surface has a salivary coating estimated to be
70 μm thick [39], which act as unstirred layer. Within the saliva
there is a high molecular weight mucin named MG1 [40] that can
bind to the surface of the oral mucosa so as to maintain hydration,
provide lubrication, concentrate protective molecules such as
secretory immunoglobulins, and limit the attachment of micro-
organisms. Several independent lines of evidence suggest that
saliva and salivary mucin contribute to the barrier properties of oral
mucosa [41]. The major salivary glands consist of lobules of cells
that secrete saliva; parotids through salivary ducts near the upper
teeth, submandibular under the tongue, and the sublingual through
many ducts in the floor of the mouth. Besides these glands, there
are 600–1000 tiny glands called minor salivary glands located in
the lips, inner cheek area (buccal mucosa), and extensively in other
linings of the mouth and throat [42]. Total output from the major
and minor salivary glands is termed as whole saliva, which at
normal conditions has flow rate of 1–2 ml/min [43]. Greater
salivary output avoids potential harm to acid-sensitive tooth enamel
19
by bathing the mouth in copious neutralizing fluid [44]. With
stimulation of salivary secretion, oxygen is consumed and
vasodilator substances are produced; and the glandular blood
flow increases, due to increased glandular metabolism [45]. Saliva
is composed of 99.5% water in addition to proteins, glycoproteins
and electrolytes. It is high in potassium (7 × plasma), bicarbonate
(3 × plasma), calcium, phosphorous, chloride, thiocyanate and urea
and low in sodium (1/10 × plasma). The normal pH of saliva is 5.6–
7. Saliva contains enzymes namely α-amylase (breaks 1–4
glycosidic bonds), lysozyme (protective, digests bacterial cell
walls) and lingual lipase (break down the fats) [46].
Saliva serves multiple important functions. It moistens the
mouth, initiates digestion and protects the teeth from decay. It also
controls bacterial flora of the oral cavity. Because saliva is high in
calcium and phosphate, it plays a role in mineralization of new
teeth repair and precarious enamel lesions. It protects the teeth by
forming “protective pellicle”. This signifies a saliva protein coat on
the teeth, which contains antibacterial compounds. Thus, problems
with the salivary glands generally result in rampant dental caries.
Lysozyme, secretory IgA, and salivary peroxidase play important
roles in saliva's antibacterial actions. Lysozyme agglutinates bac-
teria and activates autolysins. Ig A interferes with the adherence of
microorganisms to host tissue. Peroxidase breaks down salivary
thiocyanate, which in turn, oxidizes the enzymes involved in
bacterial glycolysis. However, salivary flow rate may play role in
oral hygiene. Intraoral complications of salivary hypofunction may
cause candidiasis, oral lichen planus, burning mouth syndrome,
recurrent aphthous ulcers and dental caries. A constant flowing
down of saliva within the oral cavity makes it very difficult for
drugs to be retained for a significant amount of time in order to
facilitate absorption in this site [44,45]. The other important factor
of great concern is the role of saliva in development of dental
caries. Salivary enzymes act on natural polysaccharidic polymers
that hasten the growth of mutants of streptococci and other plaque
bacteria leading to development of dental caries.
In general, intercellular spaces pose as the major barrier to
permeation of lipophilic compounds, and the cell membrane
which is lipophilic in nature acts as the major transport barrier for
hydrophilic compounds because it is difficult to permeate through
the cell membrane due to a low partition coefficient [13].
Permeabilities between different regions of the oral cavity vary
greatly because of the diverse structures and functions. In general,
the permeability is based on the relative thickness and degree of
keratinization of these tissues in the order of sublingual > buc-
cal > palatal. The permeability of the buccal mucosa was estimated
to be 4–4000 times greater than that of the skin [47].
2. Formulation design
Buccal adhesive drug delivery systems with the size 1–3 cm2
and a daily dose of 25 mg or less are preferable. The maximal
duration of buccal delivery is approximately 4–6 h [3].
2.1. Pharmaceutical considerations
Great care needs to be exercised while developing a safe
and effective buccal adhesive drug delivery device. Factors
20 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Table 1
Properties and characteristics of some representative bioadhesive polymers
Bioadhesives Properties
Polycarbophil (polyacrylic acid crosslinked with • Mw 2.2 × 105
divinyl glycol) • η 2000–22,500 cps (1% aq. soln.)
• κ 15–35 mL/g in acidic media (pH 1–3) 100 mL/g in
neutral and basic media
• φ viscous colloid in cold water
• Insoluble in water, but swell to varying degrees in
common organic solvents, strong mineral acids, and
bases.
Carbopol/carbomer (carboxy polymethylene) • Pharmaceutical grades: 934 P, 940 P, 971 P and 974 P.
empirical formula: (C3H4O2)x (C3H5–Sucrose)y • Mw 1 × 106–4 × 106
• η 29,400–39,400 cps at 25 °C with 0.5% neutralized
aqueous solution.
• κ 5 g/cm3 in bulk, 1.4 g/cm3 tapped.
• pH 2.5–3.0
• φ water, alcohol, glycerin
• White, fluffy, acidic, hygroscopic powder with a slight
characteristic odour.
Sodium carboxymethyl cellulose SCMC (cellulose • It is an anionic polymer made by swelling cellulose
carboxymethyl ether sodium salt) empirical with NaOH and then reacting it with monochloroacetic
formula: [C6H7O2(OH)3x (OCH2–COONa)x]n acid.
• Grades H, M, and L
• Mw 9 × 104–7 × 105
• η 1200 cps with 1.0% soln.
• ρ 0.75 g/cm3 in bulk
• pH 6.5–8.5
• φ water
• White to faint yellow, odorless, hygroscopic powder or
granular material having faint paper-like taste.
Hydroxypropyl cellulose partially substituted • Grades: Klucel EF, LF, JF, GF, MF and HF
polyhydroxy propylether of cellulose HPC • Mw 6 × 104–1 × 106
(cellulose 2-hydroxypropyl ether) empirical • η 4–6500 cps with 2.0% aq. soln.
formula: (C15H28O8)n • pH 5.0–8.0
• ρ 0.5 g/cm3 in bulk
• Soluble in water below 38 °C, ethanol, propylene
glycol, dioxane, methanol, isopropyl alcohol, dimethyl
sulphoxide, dimethyl formamide etc.
• Insoluble in hot water
• White to slightly yellowish, odorless powder.
Characteristics
• Synthesized by lightly crosslinking of 0.5–1%
w/w divinyl glycol
• Swellable depending on pH and ionic strength.
• Swelling increases as pH increases.
• At pH 1–3, absorbs 15–35 ml of water per gram but
absorbs 100 ml per gram at neutral and alkaline pH.
• Entangle the polymer with mucus on the surface of
the tissue
• Hydrogen bonding between the nonionized
carboxylic acid and mucin.
• Synthesized by cross-linker of allyl sucrose or
allyl pentaerythritol
• Excellent thickening, emulsifying, suspending,
gelling agent.
• Common component in bioadhesive dosage forms.
• Gel looses viscosity on exposure to sunlight.
• Unaffected by temperature variations, hydrolysis,
oxidation and resistant to bacterial growth.
• It contributes no off-taste and may mask the
undesirable taste of the formulation.
• Incompatible with Phenols, cationic polymers,
high concentrations of electrolytes and resorcinol.
• Emulsifying, gelling, binding agent
• Sterilization in dry and solution form, irradiation
of solution loses the viscosity.
• Stable on storage.
• Incompatible with strongly acidic solutions
• In general, stability with monovalent salts is very
good; with divalent salts good to marginal; with
trivalent and heavy metal salts poor, resulting in
gelation or precipitation.
• CMC solutions offer good tolerance of water
miscible solvents, good viscosity stability over the
pH 4 to pH 10 range, compatibility with most water
soluble nonionic gums, and synergism with HEC
and HPC.
• Most CMC solutions are thixotropic; some are
strictly pseudoplastic.
• All solutions show a reversible decrease in viscosity at
elevated temperatures. CMC solutions lack yield value.
• Solutions are susceptible to shear, heat, bacterial,
enzyme, and UV degradation.
• Good bioadhesive strength.
• Cell immobilization via a combination of ionotropic
gelation and polyelectrolyte complex formation (e.g.,
with chitosan) in drug delivery systems and dialysis
membranes.
• Best pH is between 6.0 and 8.0.
• Solutions of HPC are susceptible to shear, heat,
bacterial, enzymatic and bacterial degradation.
• It is inert and showed no evidence of skin irritation
or sensitization.
• Compatible with most water-soluble gums and resins.
• Synergistic with CMC and sodium alginate.
• Not metabolized in the body.
• It may not tolerate high concentrations of
dissolved materials and tend to be salting out.
• It is also incompatible with the substituted
phenolic derivatives such as methyl and propyl
parahydroxy benzoate.
• Granulating and film coating agent for tablet
• Thickening agent, emulsion
• Stabilizer, suspending agent in oral and topical
solution or suspension
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Table 1 (continued )
Bioadhesives Properties
Hydroxypropylmethyl Cellulose HPMC (cellulose • Methocel E5, E15, E50, E4M, F50, F4M, K100, K4M,
2-hydroxypropylmethyl ether) empirical formula: K15M, K100M.
C8H15O6–(C10H18O6)n–C8H15O5 • Mw 8.6 × 104
• η E15–15 cps, E4M–400 cps and K4M–4000 cps
(2% aqueous solution.)
• φ Cold water, mixtures of methylene chloride and
isopropylalcohol.
• Insoluble in alcohol, chloroform and ether.
• Odorless, tasteless, white or creamy white fibrous or
granular powder.
Hydroxyethyl Cellulose non-ionic polymer made • Available in grades ranging from 2 to 8,00,000 cps at 2%.
by swelling cellulose with NaOH and treating with • Light tan or cream to white powder, odorless and
ethylene oxide. tasteless. It may contain suitable anticaking agents.
• ρ 0.6 g/mL
• pH 6–8.5
• φ in hot or cold water and gives a clear, colorless
solution.
Xanthan gum xanthan gum is an anionic • It is soluble in hot or cold water and gives visually
polysaccharide derived from the fermentation of hazy, neutral pH solutions.
the plant bacteria Xanthamonas campestris • It will dissolve in hot glycerin.
• Solutions are typically in the 1500 to 2500 cps range at
1%; they are pseudoplastic and especially shear-thinning.
In the presence of small amounts of salt, solutions shows
good viscosity stability at elevated temperatures.
• Solutions possess excellent yield value.
Guar gum (galactomannan polysaccharide) empirical • Obtained from the ground endosperms of the seeds of
formula: (C6H12O6)n consists chiefly of a high Cyamposis tetyragonolobus (family leguminosae).
molecular weight hydrocolloid polysaccharide • MW approx. 220,000
composed of galactan and mannan units combined • η 2000–22500 Cps (1% aqueous solution.)
through glycosidic linkages • Forms viscous colloidal solution when hydrated in
cold water. The optimum rate of hydration is between pH
7.5 and 9.0.
Hydroxypropyl Guar non-ionic derivative of guar. • Φ in hot and cold water
Prepared by reacting guar gum with propylene • Gives high viscosity, pseudoplastic solutions that show
oxide. reversible decrease in viscosity at elevated temperatures.
• Lacks yield value.
Chitosan a linear polysaccharide composed of • Prepared from chitin of crabs and lobsters by N-
randomly distributed β-(1-4)-linked D- deacetylation with alkali.
glucosamine (deacetylated unit) and N-acetyl-D- • Φ dilute acids to produce a linear polyelectrolyte with
glucosamine (acetylated unit). a high positive charge density and forms salts with
inorganic and organic acids such as glutamic acid,
hydrochloric acid, lactic acid, and acetic acid.
• The amino group in chitosan has a pKa value of ∼6.5,
thus, chitosan is positively charged and soluble in acidic
to neutral solution with a charge density dependent on
pH and the %DA-value.
21
Characteristics
• Mixed alkyl hydroxyalkyl cellulosic ether
• Suspending, viscosity-increasing and film-
forming agent
• Tablet binder and adhesive ointment ingredient
• E grades are generally suitable as film formers
while the K grades are used as thickeners.
• Stable when dry.
• Solutions are stable at pH 3.0 to 11.0
• Incompatible to extreme pH conditions and
oxidizing materials.
• Solutions are pseudoplastic and show a reversible
decrease in viscosity at elevated temperatures.
• HEC solutions lack yield value.
• Solutions show only a fair tolerance with water
miscible solvents (10 to 30% of solution weight).
• Compatible with most water-soluble gums and resins.
• Synergistic with CMC and sodium alginate.
• Susceptible for bacterial and enzymatic degradation.
• Polyvalent inorganic salts will salt out HEC at
lower concentrations than monovalent salts.
• Shows good viscosity stability over the pH 2 to pH
12 ranges.
• Used as suspending or viscosity builder
• Binder, film former.
• Xanthan gum is more tolerant of electrolytes, acids
and bases than most other organic gums.
• It can, nevertheless, be gelled or precipitated with
certain polyvalent metal cations under specific
circumstances.
• Solutions show very good viscosity stability over
the pH 2 to 12 range and good tolerance of water-
miscible solvents.
• It is more compatible with most nonionic and
anionic gums, featuring useful synergism with
galactomannans.
• It is more resistant to shear, heat, bacterial,
enzyme, and UV degradation than most gums.
• Stable in solution over a pH range of 1.0–10.5.
• Prolonged heating degrades viscosity.
Bacteriological stability can be improved by the
addition of mixture of 0.15% methyl paraben or
0.1% benzoic acid.
• The FDA recognizes guar gum as a substance
added directly to human food and has been affirmed
as generally recognized as safe.
• Incompatible with acetone, tannins, strong acids,
and the alkalis. Borate ions, if present in the
dispersing water, will prevent hydration of guar.
• Used as thickener for lotions and creams, as tablet
binder, and as emulsion stabilizer.
• Compatible with high concentration of most salts.
• Shows good tolerance of water miscible solvents.
• Better compatibility with minerals than guar gum.
• Good viscosity stability in the pH range of 2 to 13.
• More resistance to bacterial and enzymatic degradation.
• Mucoadhesive agent due to either secondary
chemical bonds such as hydrogen bonds or ionic
interactions between the positively charged amino
groups of chitosan and the negatively charged sialic
acid residues of mucus glycoproteins or mucins.
• Possesses cell-binding activity due to polymer
cationic polyelectrolyte structure and to the negative
charge of the cell surface.
• Biocompatible and biodegradable.
• Excellent gel forming and film forming ability.
(continued on next page)
22 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Table 1 (continued )
Bioadhesives Properties
Carrageenan an anionic polysaccharide, extracted • Available in sodium, potassium, magnesium, calcium
from the red seaweed Chondrus crispus. and mixed cation forms.
• Three structural types exist: Iota, Kappa, and
Lambda, differing in solubility and rheology.
• The sodium form of all three types is soluble in both
cold and hot water.
• Other cation forms of kappa and Iota are soluble only
in hot water.
• All forms of lambda are soluble in cold water.
Sodium Alginate consists chiefly of the alginic acid, • Purified carbohydrate product extracted from brown
a polyuronic acid composed of β-D-mannuronic seaweed by the use of dilute alkali.
acid residues. empirical formula: (C6H7O6Na)n • Occurs as a white or buff powder, which is odorless
anionic polysaccharide extracted principally from and tasteless.
the giant kelp Macrocystis Pyrifera as alginic acid • pH 7.2
and neutralized to sodium salt. • η 20–400 Cps (1% aqueous solution.)
• φ Water, forming a viscous, colloidal solution.
• Insoluble in other organic solvents and acids where the
pH of the resulting solution and acids where the pH of
the resulting solution falls below 3.0.
Poly (hydroxy butyrate), Poly (e-caprolactone) • Biodegradable
and copolymers • Properties can be changed by chemical modification,
copolymerization and blending.
Poly (ortho esters) • Surface eroding polymers. • Application in sustained drug delivery and
ophthalmology.
Characteristics
• Widely used in controlled delivery systems such as
gels, membranes, microspheres.
• Chitosan enhance the transport of polar drugs
across epithelial surfaces. Purified qualities of
chitosans are available for biomedical applications.
Chitosan and its derivatives such as trimethylchitosan
(where the amino group has been trimethylated)
have been used in non-viral gene delivery.
Trimethylchitosan, or quaternised chitosan, has
been shown to transfect breast cancer cells. As the
degree of trimethylation increases the cytotoxicity
of the derivative increases. At approximately 50%
trimethylation the derivative is the most efficient at
gene delivery. Oligomeric derivatives (3–6 kDa) are
relatively non-toxic and have good gene delivery
properties.
• All solutions are pseudoplastic with some degree
of yield value. Certain ca-Iota solutions are
thixotropic. Lambda is non-gelling, Kappa can
produce brittle gels; Iota can produce elastic gels.
All solutions show a reversible decrease in viscosity
at elevated temperatures. Iota and Lambda
carrageenan have excellent electrolyte tolerance;
kappa's being somewhat less. Electrolytes will
however decreases solution viscosity. The best
solution stability occurs in the pH 6 to 10. It is
compatible with most nonionic and anionic water-
soluble thickeners. It is strongly synergistic with
locust bean gum and strongly interactive with
proteins. Solutions are susceptible to shear and
heat degradation.
• Excellent thermoreversible properties.
• Used also for microencapsulation.
• Safe and nonallergenic.
• Incompatible with acridine derivatives, crystal
violet, phenyl mercuric nitrate and acetate, calcium
salts, alcohol in concentrations greater than 5%, and
heavy metals.
• Stabilizer in emulsion, suspending agent, tablet
disintegrant, tablet binder.
• It is also used as haemostatic agent in surgical
dressings
• Excellent gel formation properties
• Biocompatible
• Microstructure and viscosity are dependent on the
chemical composition.
• Used as immobilization matrices for cells
and enzymes, controlled release of bioactive
substances, injectable microcapsules for treating
neurodegenerative and hormone deficiency
diseases.
• Lacks yield value.
• Solutions show fair to good tolerance of water
miscible solvents (10–30% of volatile solvents; 40–
70% of glycols)
• Compatible with most water-soluble thickeners
and resins.
• Its solutions are more resistant to bacterial and
enzymatic degradation than many other organic
thickeners.
• Used as a matrix for drug delivery systems, cell
microencapsulation.
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Table 1 (continued )
Bioadhesives Properties
Poly (cyano acrylates) • Biodegradable depending on the length of the alkyl • Used as surgical adhesives and glues.
chain.
Polyphosphazenes • Can be tailored with versatile side chain functionality • Can be made into films and hydrogels.
Poly (vinyl alcohol) • Biocompatible
Poly (ethylene oxide) • Highly biocompatible.
Poly (hydroxytheyl methacrylate) • Biocompatible
Poly (ethylene oxide-b-propylene oxide) • Surfactants with amphiphilic properties.
influencing drug release and penetration through buccal
mucosa, organoleptic factors, and effects of additives used
to improve drug release pattern and absorption, the effects of
local drug irritation caused at the site of application are to be
considered while designing a formulation.
2.1.1. Buccal adhesive polymers
Polymer is a generic term used to describe a very long
molecule consisting of structural units and repeating units
connected by covalent chemical bonds. The term is derived
from the Greek words: polys meaning many, and meros
meaning parts [4]. The key feature that distinguishes
polymers from other molecules is the repetition of many
identical, similar, or complementary molecular subunits in
these chains. These subunits, the monomers, are small
molecules of low to moderate molecular weight, and are
linked to each other during a chemical reaction called
polymerization. Instead of being identical, similar monomers
can have varying chemical substituents. The differences
between monomers can affect properties such as solubility,
flexibility, and strength. The term buccal adhesive polymer
covers a large, diverse group of molecules, including
substances from natural origin to biodegradable grafted co-
polymers and thiolated polymers.
Bioadhesive formulations use polymers as the adhesive
component. These formulations are often water soluble and
when in a dry form attract water from the biological surface
and this water transfer leads to a strong interaction. These
polymers also form viscous liquids when hydrated with water
that increases their retention time over mucosal surfaces and
may lead to adhesive interactions. Bioadhesive polymers
should possess certain physicochemical features including
hydrophilicity, numerous hydrogen bond-forming groups,
flexibility for interpenetration with mucus and epithelial
tissue, and visco-elastic properties [48].
2.1.1.1. Ideal characteristics.
✓ Polymer and its degradation products should be non-toxic,
non-irritant and free from leachable impurities.
✓ Should have good spreadability, wetting, swelling and
solubility and biodegradability properties.
23
Characteristics
• Potentially used in drug delivery.
• Applications in drug delivery.
• Gels and blended membranes are used in drug
delivery and cell immobilization.
• Its derivatives and copolymers are used in various
biomedical applications.
• Hydrogels have been used as soft contact lenses,
for drug delivery, as skin coatings, and for
immunoisolation membranes.
• Used in protein delivery and skin treatments.
✓ pH should be biocompatible and should possess good
viscoelastic properties.
✓ Should adhere quickly to buccal mucosa and should
possess sufficient mechanical strength.
✓ Should possess peel, tensile and shear strengths at the
bioadhesive range.
✓ Polymer must be easily available and its cost should not
be high.
✓ Should show bioadhesive properties in both dry and
liquid state.
✓ Should demonstrate local enzyme inhibition and penetra-
tion enhancement properties.
✓ Should demonstrate acceptable shelf life.
✓ Should have optimum molecular weight.
✓ Should possess adhesively active groups.
✓ Should have required spatial conformation.
✓ Should be sufficiently cross-linked but not to the degree
of suppression of bond forming groups.
✓ Should not aid in development of secondary infections
such as dental caries.
2.1.1.2. Some representative polymers:
2.1.1.2.1. Hydrogels. Hydrogels, often called as “wet”
adhesives because they require moisture to exhibit the
adhesive property. They are usually considered to be cross
linked water swollen polymers having water content ranging
from 30% to 40% depending on the polymer used. These are
hydrophilic matrices that absorb water when placed in an
aqueous media. This may be supplied by the saliva, which
may also act as the dissolution medium. They are structured
in such a manner that the crosslinking fibers present in their
matrix effectively prevent them from being dissolved and thus
help them in retaining water. When drugs are loaded into
these hydrogels, as water is absorbed into the matrix, chain
relaxation occurs and drug molecules are released through the
spaces or channels within the hydrogel network. Polymers
such as polyacrylates (carbopol and polycarbophil), ethylene
vinyl alcohol, polyethylene oxide, poly vinyl alcohol, poly
(N-acryloylpyrrolidine), polyoxyethylenes, self cross linked
gelatin, sodium alginate, natural gums like guar gum, karaya
gum, xanthan gum, locust bean gum and cellulose ethers like
methyl cellulose, hydroxypropyl cellulose, hydroxy propyl
24 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
methyl cellulose, sodium carboxy methyl cellulose etc. form
part of the family of hydrogels [49].
2.1.1.2.2. Copolymers. Researchers are currently working
on carrier systems containing block copolymers rather than
using single polymeric system. Copolymerization with two or
more different monomers results in chains with varied
properties. A block copolymer is formed when the reaction is
carried out in a stepwise manner, leading to a structure with long
sequences or blocks of one monomer alternating with long
sequences of the other. These networks when composed of
hydrophilic and hydrophobic monomers are called polymer
micelle. These micelles are suitable for enclosing individual
drug molecules. Their hydrophilic outer shells help to protect
the cores and their contents from chemical attack by aqueous
medium. Most micelle-based systems are formed from poly
(ethylene oxide)-b-polypropylene-b-poly (ethylene oxide) tri-
block network.
There are also graft copolymers, in which entire chains of one
kind (e.g., polystyrene) are made to grow out of the sides of
chains of another kind (e.g., polybutadiene), resulting in a
product that is less brittle and more impact-resistant. Thus, block
and graft copolymers can combine the useful properties of both
constituents and often behave as quasi-two-phase systems [50].
2.1.1.2.3. Multifunctional polymers. These are the bioad-
hesive polymers having multiple functions. In addition to the
possession of bioadhesive properties, these polymers will also
serve several other functions such as enzyme inhibition, per-
meation enhancing effect etc. Examples are polyacrylates, po-
lycarbophil, chitosan etc.
2.1.1.2.4. Thiolated polymers. These are the special class
of multifunctional polymers also called thiomers. These are
hydrophilic macromolecules exhibiting free thiol groups on the
polymeric backbone. Due to these functional groups various
features of well established polymeric excipients such as poly
(acrylic acid) and chitosan were strongly improved [51]. Thi-
olated polymers designated thiomers are capable of forming
disulphide bonds with cysteine-rich subdomains of mucus gly-
coproteins covering mucosal membranes [52]. Consequently, the
bridging structure most commonly used in biological systems is
utilized to bind drug delivery systems on the mucosal membranes.
By immobilization of thiol groups the mucoadhesive properties of
poly (acrylicacid) and chitosan, was improved to 100-fold to 250-
fold [53,54].
Thiomers are capable of forming intra- and interchain
disulphide bonds within the polymeric network leading to strongly
improved cohesive properties and stability of drug delivery sys-
tems such as matrix tablets. Due to the formation of strong covalent
bonds with mucus glycoproteins, thiomers show the strongest
mucoadhesive properties of all so far tested polymeric excipients
via thioldisulphide exchange reaction and an oxidation process.
Zinc dependent proteases such as aminopeptidases and carbox-
ypeptidases are inhibited by thiomers. The underlying mechanism
is based on the capability of thiomers to bind zinc ions and this
property is highly beneficial for oral administration of protein and
peptide drugs. They also exhibit permeation-enhancing effects for
the paracellular uptake of drugs based on a glutathione-mediated
opening process of the tight junctions [55,56].
2.1.1.2.5. Milk protein. A particular example is a milk
protein concentrate containing a minimum of 85% of proteins
such as Prosobel L85, LR85F at concentration of 15% to 50%,
preferably 20% to 30% in a bioadhesive tablet showed good
bioadhesive property [57].
2.1.1.2.6. In general.
➢ Cationic and anionic polymers bind more effectively than
neutral polymers.
➢ Anionic polymers with sulphate groups bind more
effectively than those with carboxylic groups.
➢ Polyanions are better than polycations in terms of binding
potential and toxicity.
➢ Water-insoluble polymers give greater flexibility in
dosage form design compared to rapidly or slowly dis-
solving water-soluble polymers.
➢ Degree of binding is proportional to the charge density on
the polymer.
Some of the properties and characteristics of buccal adhesive
polymers are listed in Table 1.
2.1.1.3. Factors governing drug release from a polymer. For
a given drug the release kinetics from the polymer matrix
could be governed predominantly by the polymer morphology
and excipients present in the system. Drug release from a
polymeric material takes place either by the diffusion or by
polymer degradation or by a combination of the both.
Polymer degradation generally takes place by the enzymes
or hydrolysis either in the form of bulk erosion or surface
erosion [58].
2.1.1.3.1. Polymer morphology. The polymer matrix
could be formulated as macro or nanospheres, gel film or an
extruded shape (cylinder, rod etc). Also the shape of the ex-
truded polymer can be important to the drug release kinetics. It
has been shown that zero order release kinetics can be achieved
using hemispherical polymer form.
2.1.1.3.2. Excipients. The main objective of incorporating
excipients in the polymer matrix is to modulate polymer degra-
dation kinetics. Studies carried out have shown that by in-
corporating basic salts as excipients slow down the degradation
and increases the stability of protein polymers. Similarly hydro-
philic excipients can accelerate the release of drugs although
they may also increase the initial burst effect.
2.2. Physiological considerations
Physiological considerations such as texture of buccal
mucosa, thickness of the mucus layer, its turn over time, effect
of saliva and other environmental factors are to be considered in
designing the dosage forms [59]. Saliva contains moderate
levels of esterases, carbohydrases, and phosphatases that may
degrade certain drugs. Although saliva secretion facilitates the
dissolution of drug, involuntary swallowing of saliva also
affects its bioavailability. Hence development of unidirectional
release systems with backing layer results high drug bioavail-
ability [60].
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
2.3. Pharmacological considerations
Drug absorption depends on the partition coefficient of the
drugs. Generally lipophilic drugs absorb through the transcel-
lular route, where as hydrophilic drugs absorb through the
paracellular route. Chemical modification may increase drug
penetration through buccal mucosa. Increasing nonionized
fraction of ionizable drugs increases drug penetration through
transcellular route. In weakly basic drugs, the decrease in pH
increases the ionic fraction of drug but decreases its
permeability through buccal mucosa [61]. Electrostatic
interactions of drugs such as tetracycline, hydrogen bonding
with drugs like urea and hydrophobic interactions with drugs
like testosterone with mucin will decrease rate of absorption
[62]. Residence time and local concentration of the drug in
the mucosa, the amount of drug transported across the
mucosa into the blood are the responsible factors for local or
systemic drug delivery. Optimization by a suitable formula-
tion design hastens drug release from the dosage form and
taken up by the oral mucosa. Drugs such as buprenorphine,
testosterone, fentanyl, nifedipine and several peptides such as
insulin, thyrotropin-releasing hormone, and oxytocin have
been tried to deliver via the buccal route. However the
relative bioavailabilities of peptides by the buccal route were
still low due to its poor permeation and enzymatic barrier of
buccal mucosa but can be improved by the incorporation of
penetration enhancers and/or enzyme inhibitors [63]. Previous
drug absorption studies have demonstrated that oral mucosal
absoption of amines and acids at constant concentration are
proportional to their partition coefficients. Similar dependen-
cies on partition coefficients were obtained from acyclovir, β-
adrenoreceptor blocking agents, substituted acetanilide, and
others [18].
2.4. Permeation enhancers
Membrane permeation is the limiting factor for many drugs
in the development of buccal adhesive delivery devices. The
epithelium that lines the buccal mucosa is a very effective
barrier to the absorption of drugs. Substances that facilitate the
permeation through buccal mucosa are referred as permeation
enhancers [64]. As most of the penetration enhancers were
originally designed for purposes other than absorption
enhancement, a systemic search for safe and effective
penetration enhancers must be a priority in drug delivery. The
goal of designing penetration enhancers, with improved
efficacy and reduced toxicity profile is possible by under-
standing the relationship between enhancer structure and the
effect induced in the membrane and of course, the mechanism
of action. However, the selection of enhancer and its efficacy
depends on the physicochemical properties of the drug, site of
administration, nature of the vehicle and other excipients. In
some cases usage of enhancers in combination has shown
synergistic effect than the individual enhancers. The efficacy of
enhancer in one site is not same in the other site because of
differences in cellular morphology, membrane thickness,
enzymatic activity, lipid composition and potential protein
25
interactions are structural and functional properties. Penetration
enhancement to the buccal membrane is drug specific [65].
Effective penetration enhancers for transdermal or intestinal
drug delivery may not have similar effects on buccal drug
delivery because of structural differences; however, enhancers
used to improve drug permeation in other absorptive mucosae
improve drug penetration through buccal mucosa. These
permeation enhancers should be safe and non-toxic, pharma-
cologically and chemically inert, non-irritant, and non-aller-
genic [66]. However, examination of penetration route for
transbuccal delivery is important because it is fundamental to
select the proper penetration enhancer to improve the drug
permeability. The different permeation enhancers available are
[66–68].
➢ Chelators: EDTA, citric acid, sodium salicylate, methoxy
salicylates.
➢ Surfactants: sodium lauryl sulphate, polyoxyethylene,
Polyoxyethylene-9-laurylether, Polyoxythylene-20-cety-
lether, Benzalkonium chloride, 23-lauryl ether, cetylpyr-
idinium chloride, cetyltrimethyl ammonium bromide.
➢ Bile salts: sodium glycocholate, sodium deoxycholate,
sodium taurocholate, sodium glycodeoxycholate, sodium
taurodeoxycholate.
➢ Fatty acids: oleic acid, capric acid, lauric acid, lauric acid/
propylene glycol, methyloleate, lysophosphatidylcholine,
phosphatidylcholine.
➢ Non-surfactants: unsaturated cyclic ureas.
➢ Inclusion complexes: cyclodextrins.
➢ Others: aprotinin, azone, cyclodextrin, dextran sulfate,
menthol, polysorbate 80, sulfoxides and various alkyl
glycosides.
➢ Thiolated polymers: chitosan-4-thiobutylamide, chitosan-
4-thiobutylamide/GSH, chitosan-cysteine, Poly (acrylic
acid)-homocysteine, polycarbophil-cysteine, polycarbo-
phil-cysteine/GSH, chitosan-4-thioethylamide/GSH, chit-
osan-4-thioglycholic acid.
2.4.1. Mechanisms of action
Mechanisms by which penetration enhancers are thought to
improve mucosal absorption are as follows [69,70]
➢ Changing mucus rheology: Mucus forms viscoelastic
layer of varying thickness that affects drug absorption.
Further, saliva covering the mucus layers also hinders the
absorption. Some permeation enhancers' act by reducing
the viscosity of the mucus and saliva overcomes this
barrier.
➢ Increasing the fluidity of lipid bilayer membrane: The
most accepted mechanism of drug absorption through
buccal mucosa is intracellular route. Some enhancers
disturb the intracellular lipid packing by interaction with
either lipid packing by interaction with either lipid or
protein components.
➢ Acting on the components at tight junctions: Some
enhancers act on desmosomes, a major component at
the tight junctions there by increases drug absorption.
26 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
➢ By overcoming the enzymatic barrier: These act by
inhibiting the various peptidases and proteases present
within buccal mucosa, thereby overcoming the enzymatic
barrier. In addition, changes in membrane fluidity also
alter the enzymatic activity indirectly.
➢ Increasing the thermodynamic activity of drugs: Some
enhancers increase the solubility of drug there by alters
the partition coefficient. This leads to increased thermo-
dynamic activity resulting better absorption.
Surfactants such as anionic, cationic, nonionic and bile
salts increases permeability of drugs by perturbation of
intercellular lipids whereas chelators act by interfering with
the calcium ions, fatty acids by increasing fluidity of
phospholipids and positively charged polymers by ionic
interaction with negative charge on the mucosal surface
[71–76]. Chitosan exhibits several favorable properties such
as biodegradability, biocompatibility and antifungal/antimicro-
bial properties in addition to its potential bioadhesion and
absorption enhancer [77,78].
3. Muco/bioadhesion
Bioadhesion is the phenomenon between two materials,
which are held together for extended periods of time by
interfacial forces [79]. It is generally referred as bioadhesion
when interaction occurs between polymer and epithelial surface;
mucoadhesion when occurs with the mucus layer covering a
tissue. Generally bioadhesion is deeper than the mucoadhesion.
However, these two terms seem to be used interchangeably. It is
interesting that the interaction between the layers adsorbed from
whole saliva resembles the one previously reported between
layers of adsorbed gastric mucins, which points to a strong
contribution to the interaction of high molecular weight
glycoproteins.
3.1. Bio/mucoadhesive forces
The common nature of all adhesive events, interfacial
phenomena and forces that are involved in bioadhesion are
strongly related to those considered in classical colloid and
surface science. Intermolecular forces are electromagnetic
forces which act between molecules or between widely
separated regions of a macromolecule. These are fundamen-
tally electrostatic interactions or electrodynamic interactions.
Such forces may be either attractive or repulsive in nature.
They are conveniently divided into two classes: short-range
forces, which operate when the centers of the molecules are
separated by 3 angstroms or less and long-range forces, which
operate at greater distances. Generally, if molecules do not tend
to interact chemically, the short-range forces between them are
repulsive. These forces arise from interactions of the electrons
associated with the molecules and are also known as exchange
forces. Molecules that interact chemically have attractive
exchange forces; these are also known as valence forces.
Mechanical rigidity of molecules and effects such as limited
compressibility of matter arise from repulsive exchange forces.
Long-range forces, or van der Waal's forces as they are also
called, are attractive and account for a wide range of physical
phenomena, such as friction, surface tension, adhesion and
cohesion of liquids and solids, viscosity, and the discrepancies
between the actual behavior of gases and that predicted by the
ideal gas law [80].
Many theories have been proposed to explain the forces that
underpin bioadhesion. They are
❖ Electronic theory
❖ Adsorption theory
❖ Wetting theory
❖ Diffusion theory
❖ Fracture theory, etc. [81].
However, there is yet to be a clear explanation. As
bioadhesion occurs between inherently different mucosal
surfaces and formulations that are solid, semisolid and liquid,
it is unlikely that a single, universal theory will account for all
types of adhesion observed. In biological systems it must be
recognized that, owing to the amphiphilicity of many biological
macromolecules, orientation effects can often occur at inter-
faces. These are crucially important and have in fact been
reported to be so dramatic as to change overall long-range
interactions from being purely repulsive to their becoming
attractive [82]. For any type of charged surface, such as
biosurfaces, it is common to distinguish between pure
electrostatic repulsive forces, which oppose adhesion, and
attractive forces, which, if the surfaces come close enough,
will strive to bring the interacting bodies together. This balanced
relationship between repulsive and attractive interactions is
expressed in the DLVO theory [83]. In biological systems,
interactions can be more complex, as they often take place in
high ionic strength aqueous media and in the presence of
macromolecules. Therefore electrostatic contributions may be
less important, at least at long range, in favor of force
components such as steric forces, hydrophobic interactions,
and hydration forces.
3.1.1. Van der Waal's forces
The attractive forces included in the DLVO theory are nor-
mally termed van der Waal's forces and will arise in a number of
ways. These may be further divided into the following three
components [84,85]:
(i) London dispersion forces: These are also called as dis-
persion forces. These originate out of the electronic
motions in paired molecules and give rise to attractive
interactions. These forces involve the attraction between
temporarily induced dipoles in nonpolar molecules (often
disappear within a second) [86]. This polarization can be
induced either by a polar molecule or by the repulsion of
negatively charged electron clouds in nonpolar molecules.
These results when two atoms belonging to different
molecules are brought sufficiently close together. These
interactions involve a force of about 0.5–1 K cal/mole.
London Dispersion forces exist between all atoms [87].
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
(ii) Dipole–dipole interactions: These are also called Keesom
interactions after Willem Hendrik Keesom who produced
the first mathematical description in 1921, are the forces
that occur between two molecules with permanent
dipoles. These work in a similar manner to ionic inter-
actions, but are weaker because only partial charges are
involved. These are due to attraction between polar
groups. These have force of 1–7 K cal/mole. Dipole–
dipole interactions also come from partial charges another
order of magnitude weaker [88].
(iii) Debye type forces: These are the interactions between
permanent and induced dipoles. Permanent dipoles can
induce a transient electric dipole in non-polar molecules
and produce dipole induced dipole interactions. These
interactions involve a force of about 1–3 K cal/mole [86].
The non-retarded van der Waal's force is inversely pro-
portional to the square of the distance between two spherical
particles, where the proportionality constant is the Hamaker
constant, which has the dimension of energy, can be used to
describe the strength of the van der Waal's interaction and is
dependent on the properties of the involved particles and on the
medium where the interaction takes place [89].
3.1.2. Hydrogen bonding
Hydrogen bonding is basically an electrostatic interaction
that arises when a hydrogen atom bound to an electronegative
atom, e.g., nitrogen, oxygen, or fluorine, interacts with another
electronegative atom [90]. The result is a dipolar molecule. The
hydrogen atom has a partial positive charge and hence can
interact with another highly electronegative atom in an adjacent
molecule. This results in a stabilizing interaction that binds the
two molecules together. The force is short range and highly
directional. In a more hydrophobic environment, hydrogen
bonds become significant and are essential in the formation of
stable structures. Bond energy serves as a measure of strength of
bonds. Magnitude of bond energy for hydrogen bond is between
10 and 20 kJ/mol [91]. Role of hydrogen bonding in interaction
between mucoadhesive and mucin at gastric pH was studied by
Tobyn et al. [92]. The bonding is stronger and is directional. The
directional nature of hydrogen bonding requires the two
molecules to adopt a specific relative geometry [93].
3.1.3. Disulphide bridging
A disulfide bond (SS-bond), also called a disulfide bridge, is
a strong covalent bond between two sulfhydryl (–SH) groups.
Oxidation of the thiol group yields a disulfide (S–S) bond [94].
This bond is very important to the folding, structure, and
function of proteins [95]. Due to the formation of strong
covalent bonds with mucus glycoproteins, thiomers show the
strongest mucoadhesive properties of all so far tested polymeric
excipients via thioldisulphide exchange reaction and an
oxidation process [96] as shown in Fig. 2.
3.1.4. Hydration forces
A type of short-range (< 1 nm) repulsive interaction,
suggested as originating from the binding of water molecules
27
to polar surface sites, has been observed between phospholipids
[97] and solid surfaces under certain conditions [98]. This
hydration force is believed to be particularly important in
biological systems, since it prevents contact even in the absence
of charge–charge repulsion.
3.1.5. Electrostatic double-layer forces
A charged surface is always surrounded by a cloud of counter
ions (double-layer), which balances the surface charge. When
two surfaces with the same charge approach each other, a
repulsive force will arise due to the overlap of the double layers.
This is the origin of the electrostatic double-layer forces, which
can be described by the so-called Poisson–Bolzmann equation.
These forces decay exponentially with the surface separation,
with a decay length that decreases with increasing ionic
strength in the surrounding medium. It should be noted that
specific dispersion force-induced ion adsorption could some-
times dominate at charged interfaces, thereby making it
virtually impossible to distinguish between the contributions
of electrostatic and dispersion forces [89]. In biological fluids,
which generally carry a large net negative charge, contribute
significantly to the decay length already at low concentrations
[90]. Thus, the decay length in saliva is likely to be less than
the value of approximately 1.0 nm calculated from its salt
composition. Any increase in ionic strength, increases
adhesion to negatively charged surfaces; this was assigned to
less repulsion between the surface and the adhering cells [91].
3.1.6. Hydrophobic interactions
Hydrophobic effect is another particularly important phenom-
enon with respect to bioadhesion related to the presence of water.
It is the property that nonpolar molecules like to self-associate in
the presence of aqueous solution. It has been assigned to the
tendency of water molecules to form ordered structures in
proximity to non-polar molecular domains and may give rise to
attractive interactions between non-polar residues such as
hydrocarbon side chains. The hydrophobic effect is usually
described in the context of protein folding, protein–protein
interactions, nucleic acid structure, and protein–small molecule
interactions. In the case of protein folding, it is used to explain
why many proteins have a hydrophobic core which consists of
hydrophobic amino acids, such as alanine, valine, leucine,
isoleucine, phenylalanine, and methionine grouped together;
often coiled-coil structures form around a central hydrophobic
axis. The energetics of DNA tertiary structure assembly were
determined by Eric Kool to be mostly caused by the hydrophobic
effect, as opposed to Watson–Crick base pairing [99].
The hydrophobic effect can be nullified to a certain extent by
lowering the temperature of the solution to near zero degrees; at
such temperatures, water prefers to be in an ordered structure
and the order generated by hydrophobic patches is no longer as
energetically unfavorable. This is neatly demonstrated by the
increased solubility of benzene in water at temperatures lower
than room temperature. On the macroscopic level, long-range
attractive forces have been observed between hydrophobic
surfaces formed by adsorption or deposition of amphiphilic
molecules and are believed to be non-equilibrium forces
28 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Fig. 2. Formation of covalent bonds between thiolated polymers and mucin glycoproteins.
[93,97]. It should be noted that the origin of the long-range
attractive forces between hydrophobic surfaces is controversial,
but their occurrence has been related to instability of the
deposited monolayer [100]. Strength of these interactions is
about 0.37 kcal/mol [86].
3.1.7. Steric forces
Repulsive steric interactions or steric forces appear as the
result of the increasing concentration of molecular segments
that occurs when surfaces bearing for example bound macro-
molecules come close to each other and therefore considered to
be important in biological systems. The maximum possible
number of molecular contacts between an adhesive and its
substrate may be greatly restricted by the steric aspects of
molecular geometry [80].
3.1.8. Covalent bonds
Like metallic bonds, covalent bonds are characterized by the
electrons that are shared between the engaged atoms. Covalent
bonds operate only over short interatomic distances (1–
2 × 10− 1 nm). They tend to decrease in strength with increasing
bond-length, and are oriented at well-defined angles. Unless
chemical reactions take place, based on the formation or
breakup of for example disulphide bridges, covalent bonds are
unlikely to be important in bioadhesion processes under
physiological conditions.
On the basis of molecular interactions, the interaction between
two molecules is composed of attraction and repulsion. Attractive
interactions arise from weak forces such as van der Waal's forces,
electrostatic attraction, hydrogen bonding, hydrophobic interac-
tions and/or strong forces, which are covalent in nature. Repulsive
interactions occur because of electrostatic and steric repulsion.
For muco/bioadhesion to occur, the attractive interactions should
be larger than nonspecific repulsion [101].
Steps involved in the process of bio/mucoadhesion are
(i) Spreading, wetting, swelling and dissolution of bio/
mucoadhesive polymer at the interface, initiates intimate
molecular contact at the interface between the polymer
and the epithelial/mucus layer.
(ii) Interdiffusion and interpenetration between the chains of
the adhesive polymer and the mucus/epithelial surface
resulting physical cross links or mechanical interlocking.
(iii) Adsorption: The orientation of the polymers at the interface
so that adhesive bonding across the interface is possible.
(iv) Formation of secondary chemical bonds between the
polymer chains and mucin molecules.
3.2. Methods for measuring mucoadhesion
These tests are important during the design and development
of a mucoadhesive release system to study compatibility, sta-
bility, surface analysis and bioadhesive bond strength. These
tests are broadly classified in to qualitative methods and quan-
titative methods.
3.2.1. Quantitative methods
These are also called macroscopic methods. The majority of the
quantitative bio and/or mucoadhesion measurement methods
found in the literature are based on measuring the force required
to break the adhesive bond between the model membrane and the
adhesive. Depending on the direction in which the adhesive is
being separated from the substrate, peel, shear, and tensile forces
can be measured.
3.2.1.1. Determination of peel strength. The peel adhesion
tests are mainly used for buccal and transdermal patches [102].
The test is based on the calculation of energy required to detach
the dosage form from the substrate material (usually excised
buccal mucosa) attached through the bioadhesive material in the
direction as shown in Fig. 3.
Fracture Energy (G)
Pð1−Cos hÞ
G¼ ¼ W -ð1 þ kÞ
w
Where P is the peel force;
w is the peel width;
W° is the intrinsic work of adhesion and k is the proportionality
constant that accounts for hysteretic losses.
Peel work is the sum of the following components
➢ Surface energy that results from the creation of two free
surfaces (energy of dewetting) also referred to as the
intrinsic work of adhesion (or cohesion)
➢ Bulk energy that dissipates into the stripping member
➢ Strain energy in the newly detached strip
Intrinsic work of adhesion (or cohesion) is independent of
the following:
◦ Peel rate (speed)
◦ Peel angle
◦ Thickness of the adhesive
◦ Thickness of the stripping member
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Fig. 3. Representation of peel, shear and tensile forces.
Values of intrinsic work of adhesion vary from 0.07 J/m squared
for hydrocarbon van der Waal's interactions, 2 J/m squared for a
system with covalent bonding as part of the adhesion. The work of
fracture can be several orders of magnitude greater than the
intrinsic work of adhesion [4].
3.2.1.2. Determination of shear strength. Shear stress, τ is
the force acting tangentially to a surface divided by the area of
the surface. It is the force per unit area required to sustain a
constant rate of fluid movement. Mathematically, shear stress
can be defined as:
s ¼ F=A
where,
τ shear stress
F force
A area of the surface subjected to the force.
If a fluid is placed between two parallel plates spaced 1.0 cm
apart, and a force of 1.0 dyn is applied to each square centimeter of
the surface of the upper plate to keep it in motion, the shear stress
in the fluid is 1 dyn/cm2 at any point between the two plates [4].
Shear stress measures the force that requires causing the
bioadhesive to slide with respect to the mucus layer in a direction
parallel to their plane of contact as shown in Fig. 3.
Sam et al. studied the mucoadhesiveness of Ca polycarbophil,
sodium CMC, HPMC using homogenized mucus from pig in-
testine as model substrate by modified wilhelmy plate surface
tension apparatus [103]. Similarly, Smart et al. studied mucoad-
hesive strength of CP 934, Na CMC, HPMC, gelatin, PVP, acacia,
PEG, pectin, tragacanth and sodium alginate was measured by the
force required to pull the plate out of the solution is determined
under constant experimental conditions by using mucus from
guinea pig intestine as model substrate by Wilhelmy plate method,
where a glass plate suspended from a microbalance, which was
dipped in a temperature-controlled mucus sample [104]. Instead
of biological substrates, Ishida et al. [105] used glass plates as
model substrate by shearing stickiness apparatus and Gurney et al.
[106] used polymethylmethacrylate to study shear stress of
carbapol and sodium CMC by Instron model 1114, respectively.
3.2.1.3. Determination of tensile strength. Tensile stress is also
termed Maximum Stress or Ultimate Tensile Stress. The resistance
29
of a material to a force tending to tear it apart, measured as the
maximum tension the material can withstand without tearing.
Tensile strength can be defined as the strength of material
expressed as the greatest longitudinal stress it can bear without
tearing apart. As it is the maximum load applied in breaking a
tensile test piece divided by the original cross-sectional area of the
test piece, it is measured as Newtons/sq.m. Specifically, the tensile
strength of a material is the maximum amount of tensile stress that
it can be subjected to before failure. The definition of failure can
vary according to material type and design methodology.
There are three typical definitions of tensile strength:
▪ Yield Strength — The stress a material can withstand
without permanent deformation.
▪ Ultimate Strength — The maximum stress a material can
withstand.
▪ Breaking Strength — The stress coordinate on the stress–
strain curve at the point of rupture.
Methods using the tensile strength usually measure the force
required to break the adhesive bond between a model membrane
and the test polymers.
Lehr et al. [103] determined tensile strength of flat-faced
buccal adhesive tablets, with a diameter of 5.5 mm containing
50 mg of the mucoadhesive material is to be tested for its shear
stresses by clamping the model mucosal surface between two
plates, one having a U-shaped section cut away to expose the test
surface. The tablet was attached to a Perspex disc, and then placed
into contact with the exposed mucosa at the base of the U shaped
cut. 1.5 g weight was used to consolidate the adhesive joint for
2 min, and the plates were oriented from horizontal to vertical and
Perspex disc attached to the underside of the balance, which was
linked to a microcomputer for data collection. A shear stress was
applied by lowering the plates and model mucosa at a rate of 2 mm
min− 1 until adhesive joint failure occurred (Fig. 4).
Many researchers studied shear strength of polymers such as
polyacrylic acid, hydroxy propylcellulose, carbapol 934,
HPMC etc. using buccal mucosa as substrate by using different
instruments such as tensile tester, modified pan balance etc.
3.2.1.4. Colloidal gold staining method. Park [107] proposed
the colloidal gold staining technique for the study of bioadhesion.
The technique employs red colloidal gold particles, which were
adsorbed on mucin molecules to form mucin–gold conjugates,
which upon interaction with bioadhesive hydrogels develops
a red color on the surface. This can be quantified by measuring
at 525 nm either the intensity on the hydrogel surface or the
conjugates.
3.2.1.5. Direct staining method. It is a novel technique 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 or Eosin solution; and the uncomplexed
dye was removed by washing with 0.25 M sucrose. The extent of
polymer adhesion was quantified by measuring the relative
staining intensity of control and polymer treated cells by image
30 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Fig. 4. Schematic representation of apparatus for measuring tensile strength.
analysis. Carbopol 974 P, polycarbophil and chitosan were found
to adhere to human buccal cells from 0.10% w/w aqueous dis-
persions of these polymers. Following in vivo administration as a
mouthwash, these polymers persisted upon the human buccal
mucosa for at least one hour. This method is only suitable for
assessing the liquid dosage forms, which are widely employed to
enhance oral hygiene and to treat local disease conditions of the
mouth such as oral candidacies and dental caries [108].
3.2.2. Qualitative methods
These methods are useful for preliminary screening of the
respective polymer for its bio or mucoadhesion, compatibility
and stability. However, these methods are not useful in mea-
suring the actual bioadhesive strength of the polymers. They are
3.2.2.1. Viscometric method. Katarina Edsman [109] has
studied the dynamic rheological measurements on gels containing
four different carbopol polymers and the corresponding mixtures
with porcine gastric mucin and bovine submaxillary mucin. The
method does not give the same ranking order when two different
comparison strategies were used. The results were contrast to the
results obtained with the tensile strength measurements.
Hassan [110] developed a simple viscometric method to
quantify mucin–polymer bioadhesive bond strength. Viscosities
of 15% w/w porcine gastric mucin dispersion were measured
with Brookfield's viscometer. In absence or presence of selected
neutral, anionic and cationic polymer, viscosity components and
the forces of bioadhesion were calculated. He observed a
positive rheological synergism when chitosan solutions pre-
pared in pH 5.5 acetate buffers and in 0.1 M Hcl, were mixed
with a fixed amount of porcine gastric mucin. The mixtures with
mucin showed a viscosity greater than the sum of polymer and
mucin viscosities.
Mortazavi and Smart [111] investigated the effect of carbopol
934 P on rheological behavior of mucus gel and role of mucus and
effect of various factors such as ionic concentration, polymer mo-
lecular weight, its concentration and the introduction of anionic,
cationic and neutral polymers on mucoadhesive mucus interface.
Carla Caramella et al. [112] investigated the influence of
polymer concentration and polymer: mucin weight ratio on
chitosan–mucin interaction, assessed by means of viscosimetric
measurements. Two hydration media, distilled water and 0.1 M
Hcl were used. Chitosan solutions were prepared at concentra-
tions greater than the characteristic entanglement concentration
and mixed with increasing amounts of porcine gastric mucin.
Viscosity measurements were performed on the polymer–mucin
mixtures and on polymer and mucin solutions having the same
concentrations as in the mixtures. The formation of chitosan–
mucin interaction products was determined on the basis of the
changes in low shear viscosity and high shear viscosity of the
mixtures as a function of polymer: mucin weight ratio. Rheo-
logical synergism parameter was also calculated. The results
obtained suggest that two different types of rheological interaction
occur between chitosan and mucin in both media, depending on
polymer concentration and polymer: mucin weight ratio.
3.2.2.2. Analytical ultracentrifuge criteria for mucoadhesion.
These methods are useful in identifying the material that is able to
form complexes with the mucin. The assay can be done for change
in molecular mass using sedimentation equilibrium, but this has an
upper limit of less than 50 MDa. Since complexes can be very large,
a more sensible assay procedure is to use sedimentation velocity
with change in sedimentation coefficient, s, as their marker for
mucoadhesion. Where mucin is available in only miniscule
amounts, a special procedure known as Sedimentation Fingerprint-
ing can be used for assay of the effect on the mucoadhesive. UV
absorption optics is used as the optical detection system. However,
in this case the mucoadhesive is invisible, but the pig gastric mucin
at the concentrations normally employed is visible. The sedimen-
tation ratio (scomplex/smucin), the ratio of the sedimentation coef-
ficient of any complex involving the mucin to that of pure mucin
itself, is used as the measure for mucoadhesion [113].
3.2.2.3. Atomic force microscopy. This method is based on the
changes in surface topography when the polymer bound on to
buccal cell surfaces. Unbound cells shows relatively smooth
surface characteristics with many small craters like pits and
indentations spread over cell surfaces, while polymer bound
cells will loose crater and indentation characteristics and gained
a higher surface roughness.
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
3.2.2.4. Electrical conductance. Bremakar used modified
rotational viscometer to determine electrical conductance of various
semi-solid mucoadhesive ointments and found that the electrical
conductance was low in the presence of adhesive material.
3.2.2.5. Fluorescent probe method. In this method the
membrane lipid bilayered and membrane proteins were labeled
with pyrene and fluorescein isothiocyanate, respectively. The
cells were mixed with the mucoadhesive agents and changes in
fluorescence spectra were monitored. This gave a direct indication
of polymer binding and its influence on polymer adhesion [114].
3.2.2.6. Lectin binding inhibition technique. The method
involves an avidin–biotin complex and a colorimetric detection
system to investigate the binding of bioadhesive polymers to
buccal epithelial cells without having to alter their physico-
chemical properties by the addition of marker entities. The
lectin cancanavalian A has been shown to specifically bind to
sugar groups present on the surface of buccal cells. If polymers
bind to buccal cells, they will mask the surface glycoconjugates,
thus reducing or inhibiting cancanavalian A binding [115].
3.2.2.7. Thumb test. This is a very simple test used for the
qualitative determination of peel adhesive strength of the
polymer and is useful tool in the development of buccal
adhesive delivery systems. The adhesiveness is measured by the
difficulty of pulling the thumb from the adhesive as a function
of the pressure and the contact time. Although the thumb test
may not be conclusive, it provides useful information on peel
strength of the polymer.
3.3. Factors affecting bio/mucoadhesion
Numerous studies have indicated that there is a certain
molecular weight at which bioadhesion is optimum. The optimum
molecular weight for the maximum bioadhesion depends on the
type of polymers. It dictates the degree of swelling in water, which
in turn determines interpenetration of polymer molecules within
the mucus. It seems that the bioadhesive force increases with the
molecular weight up to 100,000 and beyond this level there is not
much effect [106]. For the best bioadhesion to occur, the con-
centration of polymer must be at optimum. Flexibility of polymer
chain is also important for interpenetration and entanglement
[116,117]. As water-soluble polymers become cross-linked, the
mobility of the individual polymer chain decreases. As the cross
linking density increases, the effective length of the chain, which
can penetrate into the mucus layer, decreases even further and
mucoadhesive strength is reduced. Besides molecular weight or
chain length, spatial conformation of a molecule is also important.
Despite a high molecular weight of 19,500,000 for dextrans, they
have similar adhesive strength to that of polyethylene glycol with
a molecular weight of 200,000. The helical conformation of
dextran may shield many adhesively active groups, primarily
responsible for adhesion, unlike PEG polymers, which have a
linear conformation. Swelling is not only related to the polymer
itself, and also to its environment. Interpenetration of chains is
easier as polymer chains are disentangled and free of interactions.
31
Swelling depends both on polymer concentration and the
presence of water. When swelling is too great, a decrease in
bioadhesion occurs [116].
pH was found to have significant effect on mucoadhesion as
observed in studies of polyacrylic polymers cross-linked with
carboxyl groups. pH influences the charge on the surface of both
mucus and the polymers. Mucus will have a different charge
depending on pH because of differences in dissociation of
functional groups on the carbohydrate moiety and amino acids of
the polypeptide backbone. It was observed that the pH of the
medium was critical for the degree of hydration of highly cross
linked polyacrylic acid polymers, increasing between pH 4 and 5,
continuing to increase slightly at pH 6 and 7 and decreasing at
more alkaline pH levels [118]. To place a solid bioadhesive
system, it is necessary to apply a defined strength. Whatever the
polymer may be, the adhesion strength increases with the applied
strength and duration of its application, up to an optimum [119].
The initial contact time between mucoadhesive and the mucus
layer determine the extent of swelling and the interpenetration of
polymer chains. Along with the initial pressure, the initial contact
time can dramatically affect the performance of a system. The
mucoadhesive strength increases as the initial contact time
increases [101]. Dehydration of the mucosa, causes by water
movement from the mucosa to the dry powder, may have resulted
in adhesion between the two surfaces [120]. A low interfacial
tension value for the bioadhesive tissue increases the possibility
of obtaining adhesive bonds [121]. Addition of highly water-
soluble additive reduces the water content when the material
dissolves, and thus makes the water unavailable for the
bioadhesive material, and subsequently decreases bioadhesion
[122]. The duration of adhesion depends on the amount of water
at the interface. Excessive water reduces the duration of adhesion.
However the magnitude of this change is not the same for all the
materials. It is believed that faster the rate of absorption of water,
the shorter is the time required for the material to obtain initial
adhesion and maximum adhesive strength. But rapid water
absorbency may cause the shortening of the duration of adhesion
[123]. Previous drug absorption studies have demonstrated that
buccal absorption through oral mucosa for drugs such as
morphine sulphate, nicotine, flecainide, sotalol, propanolol and
others changed with changing pH [18].
4. Developments in buccal adhesive drug delivery
Retentive buccal mucoadhesive formulations may prove to be
an alternative to the conventional oral medications as they can be
readily attached to the buccal cavity retained for a longer period of
time and removed at any time. Buccal adhesive drug delivery
systems using matrix tablets, films, layered systems, discs, micro
spheres, ointments and hydrogel systems has been studied and
reported by several research groups. However, limited studies exist
on novel devices that are superior to those of conventional buccal
adhesive systems for the delivery of therapeutic agents through
buccal mucosa. A number of formulation and processing factors
can influence properties and release properties of the buccal ad-
hesive system. There are numerous important considerations that
include biocompatibility (both the drug/device and device/
32 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40

environment interfaces), reliability, durability; environmental sta- Table 2

bility, accuracy, delivery scalability and permeability are to be Commercial name Bioadhesive Company Dosage
considered while developing such formulations. While biocom- polymer form
patibility is always an important consideration, other considerations Buccastem PVP, Xanthum gum, Rickitt Tablet
vary in importance depending on the device application. Bioadhe- Locust bean gum Benckiser
sive formulations designed for buccal application should exhibit Suscard HPMC Forest Tablet
Gaviscon liquid Sodium alginate Rickitt Oral liquid
suitable rheological and mechanical properties, including pseudo-
Benckiser
plastic or plastic flow with thixotrophy, ease of application, good Orabase Pectin, gelatin ConvaTech Oral paste
spreadability, appropriate hardness, and prolonged residence time Corcodyl gel HPMC Glaxosmithkline Oromucosal
in the oral cavity. These properties may affect the ultimate perfor- gel
mance of the preparations and their acceptance by patients [124]. Corlan pellets Acacia Celltech Oromucosal
pellets
An ideal buccal adhesive system must have the following
Fentanyl Oralet™ Lexicomp Lozenge
properties: Miconaczole Bioalliance Tablet
Lauriad
✓ Should adhere to the site of attachment for a few hours, EmezineTM BDSI's
✓ Should release the drug in a controlled fashion, BEMA Fentanyl BDSI's
Straint™ SR Ardana
✓ Should provide drug release in an unidirectional way
Zilactin Zila Buccal film
toward the mucosa, Luborant Sodium CMC Antigen Artificial
✓ Should facilitate the rate and extent of drug absorption, saliva
✓ Should not cause any irritation or inconvenience to the Saliveze Sodium CMC Wyvern Artificial
patient and saliva
Tibozole Tibotec Tablet
✓ Should not interfere with the normal functions such as
talking, drinking etc.

4.1. Commercial buccal adhesive drug delivery systems
Recent reports suggest that the market share of buccal
adhesive drug delivery systems are increasing in the American
and European market with the steady growth rate of above 10%.
Some of the commercially available buccal adhesive formula-
tions are listed in Table 2.
4.2. Research on buccal adhesive drug delivery systems
4.2.1.2. Microparticles. Bioadhesive microparticles offer the
same advantages as tablets but their physical properties enable
them to make intimate contact with a lager mucosal surface
area. In addition, they can also be delivered to less accessible
sites including the GI tract and upper nasal cavity. The small
size of microparticles compared with tablets means that they are
less likely to cause local irritation at the site of adhesion and the
uncomfortable sensation of a foreign object within the oral
cavity is reduced.

Several buccal adhesive delivery devices were developed at
the laboratory scale by many researchers either for local or
systemic actions. They are broadly classified in to
❖ Solid buccal adhesive dosage forms
❖ Semi-solid buccal adhesive dosage forms
❖ Liquid buccal adhesive dosage forms
4.2.1. Solid buccal adhesive formulations
Dry formulations achieve bioadhesion via dehydration of the
local mucosal surface.
4.2.1.1. Tablets. Several bioadhesive tablet formulations were
developed in recent years either for local or systemic drug
delivery. Tablets that are placed directly onto the mucosal
surface have been demonstrated to be excellent bioadhesive
formulations. However, size is a limitation for tablets due to the
requirement for the dosage form to have intimate contact with
the mucosal surface. These tablets adhere to the buccal mucosa
in presence of saliva. They are designed to release the drug
either unidirectionally targeting buccal mucosa or mutidirec-
tionally in to the saliva. Table 3. represents some of the research
done so far in the development of buccal adhesive tablets.
4.2.1.3. Wafers. Bromberg et al. [160] described a conceptually
novel periodontal drug delivery system that is intended for the
treatment of microbial infections associated with peridontitis. The
delivery system is a composite wafer with surface layers posses-
sing adhesive properties, while the bulk layer consists of anti-
microbial agents, biodegradable polymers and matrix polymers.
4.2.1.4. Lozenges. Bioadhesive lozenges may be used for the
delivery of drugs that act topically within the mouth including
antimicrobials, corticosteroids, local anaesthetics, antibiotics
and antifungals. Conventional lozenges produce a high initial
release of drug in the oral cavity, which rapidly declines to
subtherapeutic levels, thus multiple daily dosing is required. A
slow release bioadhesive lozenge offers the potential for pro-
longed drug release with improved patient compliance. Codd
and Deasy investigated bioadhesive lozenges as a means to
deliver antifungal agents to the oral cavity [161].
4.2.2. Semi-solid dosage forms
4.2.2.1. Gels. Gel forming bioadhesive polymers include cross-
linked polyacrylic acid that has been used to adhere to mucosal
surfaces for extended periods of time and provide controlled release
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40 33

Table 3 release of drug at the absorption site. A limitation of gel formu-

Buccal adhesive tablets lations lies on their inability to deliver a measured dose of drug to
Drug Bioadhesive polymer Excipients References the site. They are therefore of limited use for drugs with narrow
Ketoprofen Chitosan and sodium [125] therapeutic window. He et al. [162] designed a novel, hydrogel-
alginate based, bioadhesive, intelligent response system for controlled drug
Nifedipine Chitosan, polycarbophil, [126] release. This system combined several desirable facets into a single
sodium alginate, gellan gum
Propranolol CP, HPMC, PC, SCMC, [127]
formulation; a poly (hydroxyethyl methacrylate) layer as barrier,
PAA poly (methacrylic acid-g-ethylene glycol) as a biosensor and poly
Propranolol HPMC, CP 934 [128] (ethyleneoxide) to promote mucoadhesion.
Propranolol HPMC, PC [129]
Diltiazem CP, HPMC, PC, SCMC, [130] 4.2.2.2. Patches/films. Flexible films may be used to deliver
PAA
drugs directly to a mucosal membrane. They also offer advantages
Diltiazem CP 934 and PVP K-30 Citric acid and [81]
PEG 4000 over creams and ointments in that they provide a measured dose of
Metaclopromide CP, HPMC, PC, SCMC, [127] drug to the site. Buccal adhesive films are already in use com-
PAA mercially for example, Zilactin used for the therapy of canker
Nystatin Carbomer, HPMC Lactose [131] sores, cold sores and lip sores. These were represented in Table 4.
Verapamil HPC-M, CP 934 [132,133]
Triamcilone HPC, CP-934 [134]
Triamcilone HPMC, PADH [135] 4.2.3. Liquid dosage forms
Lidocaine CP-934, HPC-H [136] Viscous liquids may be used to coat buccal surface either as
Metronidazole CP-934, HPMC [137] protectants or as drug vehicles for delivery to the mucosal surface.
Sodium fluoride Modified starch, PAA [138] Traditionally, pharmaceutically acceptable polymers were used to
Miconazole Modified starch, CP-934 [139]
enhance the viscosity of products to aid their retention in the oral
Pentazocine CP-934P, HPMC [140]
Chlorpheneramine Hakea gum [141] cavity. Dry mouth is treated with artificial saliva solutions that are
Calcitonin Hakea gum [141] retained on mucosal surfaces to provide lubrication. These
Omeprazole Sodium alginate, Magnesium [142] solutions contain sodium CMC as bioadhesive polymer.
HPMC, CP-934P, PC oxide
Nicotine HPC, CP-934P, PVP [143]
4.3. Delivery of proteins and peptides
Clotrimazole CP 974P, HPMC K4M [144]
Nicotine hydrogen Aionic, cationic and pH increasing [145]
tartrate nonionic additive The buccal mucosa represents a potentially important site for
Citrus oil and Cross linked PAA and [146] controlled delivery of macromolecular therapeutic agents, such
magnesium salt HPC as peptides and protein drugs with some unique advantages such
Buspirone Hcl CP 974 HPMCK4M [147]
Omeprazole Sodium alginate and MgO and [148]
as the avoidance of hepatic first-pass metabolism, acidity and
HPMC croscaramellose protease activity encountered in the gastrointestinal tract.
sodium
Hydrocortisone HPMC (methocelk4m), [149] Table 4
acetate carbapol934P, Buccal adhesive patches/films
polycarbiphyl
Drug Bioadhesive polymer Excipients Reference
Ergotamine PVA Witepsol W-35 [150]
tartrate and cod liver oil Plasmid DNA Noveon, eudragit S-100 [163]
extract B-galactosidase Noveon, eudragit S-100 [163]
Hydralazine Hcl CP 934P and CMC [151] Ipriflavone PLGA, chitosan [164]
Prednisolone Polycarbophil and CP [152] Chlorhexidine Chitosan [165]
934P gluconate
Buprenorphine HEMA and Polymeg [153] Chlorpheneramine Polyoxyethylene [166]
Morphine Carbomer and HPMC [154] maleate
sulphate Protirelin HEC, HPC, PVP, PVA [167,168]
Piribedit [155] Buprenorphine CP-934, PIB and PIP [169]
Nimesulide [156] Isosorbide HPC, HPMCP Glycerrhizinic [170]
Cetylpyridinium [157] dinitrate acid
chloride Lidocaine HPC, CP [171]
Thiocolchicoside [158] Miconazole nitrate SCMC, chitosan, PVP [172]
Propranolol CP-934P, HPMC K4M [159] PVA, HEC and HPMC
Nifedipine Sodium alginate Mannitol, PEG 6000 [173]
Abbrevations: CP: carbapol, HPMC: hydroxypropylmethylcellulose, PC:
Acyclovir [P (AA-co-PEG)] Sodium glycocholate [174]
polycarbophil, SCMC: sodium carboxymethylcellulose, PAA: polyacrylic
acid, HPC: hydroxypropyl cellulose, PVP: poly (vinylpyrrolidone), PADH: Abbrevations: CP: carbapol, HPMC: hydroxypropylmethylcellulose, PC:
poly (acrylicacid-2-5-dimethyl 1-5 hexadiene). polycarbophil, SCMC: sodium carboxymethylcellulose, PVP: poly (vinylpyrro-
lidone), PLGA: poly (D,L-lactide co-glycolide), HPMCP: hydroxypropylmethyl
cellulosephthalate, PIB: polyisobutylene, PIP: polyisoprene, [P (AA-co-PEG)]:
of drugs. Gels have been widely used in the delivery of drugs to the copolymers of polyacrylic acid and polyethylene glycol monomethylether
oral cavity. Advantages of gel formulations include their ability to monomethacrylate, HPC: hydroxypropylcellulose, HEC: hydroxyethylcellulose,
form intimate contact with the mucosal membrane and their rapid PVA: polyvinylalcohol.
34 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40

Another interesting advantage is its tolerance (in comparison
with the nasal mucosa and skin) to potential sensitizers. A variety
of proteins/peptides with or without penetration enhancer were
studied by different scientists using different animal models like
dogs, rabbits, rats, pigs and humans. Some of those develop-
ments were represented in Table 5.
5. Evaluation
In addition to the routine evaluation tests such as weight
variation, friability, hardness, content uniformity, in vitro dis-
solution for tablets; tensile strength, film endurance, hygroscop-
icity etc for films and patches; viscosity, effect of aging etc for gels
and ointments; buccal adhesive drug delivery devices are also to
be evaluated specifically for their mucoadhesive strength and
permeability.
5.1. Determination of the residence time
5.1.1. In vitro residence time
It was determined using a modified USP disintegration appa-
ratus as shown in Fig. 5. The disintegration medium composed of
800 ml isotonic phosphate buffer pH 6.75 maintained at 37 °C. A
segment of rabbit intestinal mucosa, 3 cm long, was glued to the
surface of a glass slab, vertically attached to the apparatus. The
mucoadhesive tablet was hydrated from one surface using 15 ml
IPB and then the hydrated surface was brought into contact with
the mucosal membrane. The glass slab was vertically fixed to the
apparatus and allowed to move up and down so that the tablet was
completely immersed in the buffer solution at the lowest point and
was out at the highest point. The time necessary for complete
erosion or detachment of the tablet from the mucosal surface was
recorded [189].
5.1.2. In vivo residence time test
The experiment was conducted on four human healthy
volunteers of 25–50 years old. Plain bioadhesive tablets with
optimized properties were selected for the in vivo evaluation. The
bioadhesive tablet was placed on the buccal mucosa between the
cheek and gingiva in the region of the upper canine and gently
pressed onto the mucosa for about 30 s. The tablet and the inner
upper lip were carefully moistened with saliva to prevent the
sticking of the tablet to the lip. The volunteers were asked to
monitor the ease with which the system was retained on the mucosa
and note any tendency for detachment. The time necessary for
complete erosion of the tablet was simultaneously monitored by
carefully observing for residual polymer on the mucosa. In ad-
dition, any complaints such as discomfort, bad taste, dry mouth or
increase of salivary flux, difficulty in speaking, irritation or mucosal
lesions were carefully recorded. Repeated application of the bio-
adhesive tablets was allowed after a two days period for the same
volunteer [189].
5.2. Permeation studies
During the preformulation studies, buccal absorption/perme-
ation studies must be conducted to determine the feasibility of this
route of administration for the candidate drug and to determine the
type of enhancer and its concentration required to control the rate
of permeation of drugs. These studies involve methods that would
examine in vitro, ex vivo and/or in vivo buccal permeation profile
and absorption kinetics of the drug.
5.2.1. In vitro methods
Deasy [157] used an apparatus consisting of a water jacket and
an internal compartment containing 50 ml of simulated saliva as
dissolution medium to study the release of cetylpyridinium chlo-
ride tablet by placing in the metal die sealed at the lower end by
paraffin wax to ensure the drug release from one end alone. The
medium was stirred with a rotating stirrer at 250 rpm. Ishida [171]
conducted dissolution studies with similar apparatus with slight
modification of providing a water jacket for the maintenance
of temperature for dosage forms of lidocaine. Nagai [190] used
Toyamp-Sangyo TR-553 dissolution tester to measure the

Table 5
Buccal adhesive formulations for proteins/peptides
Protein/peptide drug Dosage form Enhancer Animal model % increase in bioavailability Ref.
Buserelin Patch SGDC Pig, rat 12.7% [175]
Calcitonin Tablet No enhancer Rabbits 37% [176]
Captopril Tablet SGDC Humans [177]
Colony stimulating factor (G-SCF) Patch No enhancer Dogs Two fold increase in [178]
pharmacological action.
Enalapril Solution No enhancer Human No significant increase [179]
Glucagon like peptide Tablet STC Human 4–23% [180]
Gonadotropin releasing hormone Tablet SC, SDC, STC, STDC Dog SDC > SC > STC > STDC [181]
Interferon Solution No enhancer Mice Marked increase [182]
Insulin Liposomes No enhancer Rat No significant increase [183]
Lisinopril Solution No enhancer Human No significant increase [179]
Lutinizing hormone releasing hormone Tablet SDC 5% Dog 237% [184]
Octreotide acetate Azone, SC, EDTA, STC Dog Azone > SC > EDTA > STC [185]
Oxytocin Patch No enhancer Rabbit Slight increase [186]
Protrelin (TRH) Patch Citric acid, Sodium- Human, rats Increase in plasma [187]
5-methoxy salicylate thyrotropin concentration
Recombinant human interferon alpha B/D hybrid Solution No enhancer Rabbit, rat 0.005% [188]
 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
Fig. 5. Schematic diagram of the apparatus used for the determination of
residence time. S: glass slab; D: disintegration apparatus; B: glass beaker; M:
mucosal membrane; T: mucoadhesive tablet; IBP: Isotonic phosphate buffer.
dissolution rate of disk like dosage forms by keeping in a rotating
basket at 100 rpm in 900 ml of purified water. The same apparatus
was used for the evaluation of oral mucosal dosage forms of
insulin. Hughes and Gehris [191] described a novel dissolution
testing system that is capable of characterizing buccal dissolution.
It comprises of a single, stirred, continuous flow-through filtration
cell that includes a dip tube designed to remove finely divided solid
particles. Filtered solution is removed continuously and used to
analyze for dissolved drug.
5.2.2. Ex vivo methods
Most of the ex vivo studies examining drug transport across
buccal mucosa uses buccal tissues from animal models. Im-
mediately after sacrificing the animals the buccal mucosal tissue
is surgically removed from the oral cavity. The membranes are
stored in Krebs buffer at 4 °C until mounted in the diffusion cells
for the ex vivo permeation experiments. Preservation of the
dissected tissue is an important issue that will affect the studies.
There is no standard means by which the viability or the integrity
of the dissected tissue can be assessed. The most meaningful
method to assess tissue viability is the actual permeation experi-
ment itself, if the drug permeability does not change during the
time course of the study under the specific experimental con-
ditions of pH and temperature, then the tissue is considered
viable.
Dowty [192] studied tissue viability by using ATP levels in
rabbit buccal mucosa. He reported a 50% drop in the tissue
ATP concentration during the initial 6 h of the experiment
without a corresponding drop in tissue permeability. Despite
certain gradual changes, the buccal tissue seems to remain
viable for a rather long period of time. Hence, a decrease in
ATP levels does not assure a drop in permeability character-
istics of the tissue.
Buccal cell cultures have also been suggested as useful in
vitro models for buccal drug permeation and metabolism.
However, to utilize these culture cells for buccal drug transport,
the number of differentiated cell layers and the lipid composition
of the barrier layers must be well characterized and controlled
[193–195].
35
5.2.3. In vivo methods
5.2.3.1. Selection of animal species. Apart from the specific
methodology used to study buccal drug permeation characteristics,
special attention is warranted to the selection of experimental
animal species for such experiments. Many researchers have used
small animals including rats and hamsters for permeability studies
[196,197]. But unlike humans, most laboratory animals have totally
keratinized oral lining, hence not suitable. The rat has a buccal
mucosa with a very thick, keratinized surface layer. The rabbit is the
only laboratory rodent that has non-keratinized mucosal lining
similar to human tissue. But, the sudden transition to keratinized
tissue at the mucosal margins makes it hard to isolate the desired
non-keratinized region [198].
Among the larger experimental animals monkeys are practical
models because of the difficulties associated with its mainte-
nance. Dogs [199,200] are easy to maintain and less expensive
than monkeys [201] and their buccal mucosa is non-keratinized
and has a close similarity to that of the human buccal mucosa.
Pigs also have non-keratinized buccal mucosa similar to that of
human and their inexpensive handling and maintenance costs
make them a highly suitable animal model for buccal drug
delivery studies. In fact, the oral mucosa of pigs resembles that of
human more closely than any other animal in terms of structure
and composition [202].
5.2.3.2. Buccal absorption test. Beckett and Triggs [203]
developed a method to measure the kinetics of drug absorption.
It is carried out by swirling of a 25 ml sample of the test solution
for 15 min by human volunteers followed by the expulsion of the
solution. The amount of drug remaining in the expelled volume
is then determined to assess the amount of drug absorbed. The
drawbacks of this method are inability to localize the drug
solution within a specific site of the oral cavity, accidental
swallowing of a portion of the sample solution and the salivary
dilution of the drug.
5.2.3.3. Modified buccal absorption test. Gonzalez-Younes et
al. [204] developed this method by correcting for salivary
dilution and accidental swallowing, but these modifications also
suffer from the inability of site localization.
5.2.3.4. Perfusion system. A circulating perfusion chamber
attached to the upper lip of anesthetized dogs by cyanoacrylate
cement and the drug solution is circulated through the device for
a predetermined period of time. Sample fractions are collected
from the perfusion chamber and blood samples are drawn at
regular intervals [205].
5.2.3.5. Buccal perfusion cell apparatus. Rathbone [206]
developed an apparatus that provides continuous monitoring of
drug loss as a function of time offers larger area for drug transfer
and has no leakage problem. He used several methods to study the
rate and extent of drug loss from human oral cavity. These include
the buccal absorption test, disk methods and perfusion cells.
These methods have provided information on the mechanism by
which drugs are transported across oral cavity membranes and
36 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40
suggest that passive diffusion or carrier mediated transport
systems may be involved.
In vivo buccal permeation of FITC labeled dextran 4400 and
the peptide drug buserelin was investigated in pigs. The delivery
device consisted of an application chamber with a solution of
FD4 or buserelin, and was attached to the buccal mucosa for
four hours using an adhesive patch. The randomized crossover
study including intravenous administration and buccal delivery
without and with 10 mM sodium glycodeoxycholate as an
absorption enhancer was performed in pigs [207].
Tanaka et al. [208] studied the absorption of salicylic acid
through the hamster cheek pouch. Ointments containing salicylic
acid were applied to the cheek pouch of hamster and the influence
of the type of base on drug absorption was examined.
6. Conclusion
The need for research into drug delivery systems extends
beyond ways to administer new pharmaceutical therapies. The
safety and efficacy of current treatments may be improved if their
delivery rates, biodegradation, and site specific targeting can be
predicted, monitored and controlled. From both a financial and
global healthcare perspective, finding ways to administer
injectable medications is costly and some time leads to serious
hazardous effects. Hence inexpensive multiple dose formulations
with better bioavailabilities are needed. Improved methods of
drug release through transmucosal and transdermal methods
would be of great significance, as by such routes, the pain factor
associated with parenteral routes of drug administration can be
totally eliminated. Buccal adhesive systems offer innumerable
advantages in terms of accessibility, administration and with-
drawal, retentivity, low enzymatic activity, economy and high
patient compliance. Since the introduction of Orabase in 1947,
when gum tragacanth was mixed with dental adhesive powder to
apply penicillin to the oral mucosa; the market share of bioad-
hesive drug delivery systems is increasing. The growth rate for
transmucosal drug delivery systems is expected to increase 11%
annually through 2007. Worldwide market revenues are at $3B
with the U.S. at 55%, Europe at 30% and Japan at 10%.
Adhesion of buccal adhesive drug delivery devices to
mucosal membranes leads to an increased drug concentration
gradient at the absorption site and therefore improved bioavail-
ability of systemically delivered drugs. In addition, buccal
adhesive dosage forms have been used to target local disorders at
the mucosal surface (e.g., mouth ulcers) to reduce the overall
dosage required and minimize side effects that may be caused by
systemic administration of drugs. Researchers are now looking
beyond traditional polymer networks to find other innovative
drug transport systems. Much of the development of novel
materials in controlled release buccal adhesive drug delivery is
focusing on the preparation and use of responsive polymeric
system using copolymer with desirable hydrophilic/hydrophobic
interaction, block or graft copolymers, complexation networks
responding via hydrogen or ionic bonding and new biodegradable
polymers especially from natural edible sources. At the current
global scenario, scientists are finding ways to develop buccal
adhesive systems through various approaches to improve the
bioavailability of orally less/inefficient drugs by manipulating the
formulation strategies like inclusion of pH modifiers, enzyme
inhibitors, permeation enhances etc. Novel buccal adhesive
delivery systems, where the drug delivery is directed towards
buccal mucosa by protecting the local environment is also gaining
interest. Currently solid dosage forms, liquids and gels applied to
oral cavity are commercially successful. The future direction of
buccal adhesive drug delivery lies in vaccine formulations and
delivery of small proteins/peptides. Microparticulate bioadhesive
systems are particularly interesting as they offer protection to
therapeutic entities as well as the enhanced absorption that result
from increased contact time provided by the bioadhesive
component. Exciting challenges remain to influence the bioavail-
ability of drugs across the buccal mucosa. Many issues are yet to
be resolved before the safe and effective delivery through buccal
mucosa. Successfully developing these novel formulations
requires assimilation of a great deal of emerging information
about the chemical nature and physical structure of these new
materials.
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