BUCCUL DRUG DELIVERY – A REVIEW

Abstract-

Buccal delivery of drugs provides an attractive alternative to the oral route of drug
administration, particularly in overcoming deficiencies associated with the latter mode of
administration. Problems such as high first-pass metabolism and drug degradation in the harsh
gastrointestinal environment can be circumvented by administering the drug via the buccal route.
Moreover, buccal drug absorption can be promptly terminated in case of toxicity by removing
the dosage form from the buccal cavity. It is also possible to administer drugs to patients who
cannot be dosed orally to prevent accidental swallowing. Therefore adhesive mucosal dosage
forms were suggested for oral delivery, which included adhesive tablets, adhesive gels and
adhesive patches. 185, and many other dosage forms with various combinations of polymers,
absorption enhancers were tried and evaluated. In addition to this studies have been conducted
on the development of controlled or slow release delivery systems for systemic and local therapy
of diseases in the oral cavity.(1,13,14)

Keywords- buccal patches, buccal tablets, permeation enhancers, mucoadhesive polymers

Contents

1. Introduction

1.1Overview of the oral mucosae

1.2 Routes of drug absorption
1.3 Buccal mucosa as a site for drug delivery
1.3.1 Factors affecting drug delivery via buccul route

2. Buccal drug delivery system

2.1 Structure and Design of buccul dosage forms
2.1.1 Matrix based
2.1.2 Reservior based
2.2 Related researches on mucoadhesive polymers and delivery systems
3. Conclusion

Introduction the buccal route. Moreover, buccal drug

Buccal delivery of drugs provides an
attractive alternate to the oral route of drug
administration, particularly in over coming
deficiencies associated with the latter mode
of dosing. Problems such as high first - pass
metabolism and drug degradation in the
harsh gastrointestinal environment can be
circumvented by administering the drug via
absorption can be promptly terminated in
case of toxicity by removing the dosage
form from the buccal cavity. It is also
possible to administer drugs to patients who
cannot be dosed orally. Therefore, adhesive
mucosal dosage forms were suggested for
oral delivery that included adhesive tablets
adhesive gels and adhesive patches.

1
However, buccal films are preferable over
adhesive tablets in terms of flexibility and
comfort.
Overview of the Buccal Mucosa
The buccal mucosa is composed of an
outermost layer of stratified squamous
epithelium.Below this lies a basement
membrane, a lamina propria followed by the
submucosa as the innermost layer.The
epithelium of the buccal mucosa is about 40-
50 cell layers thick.
The buccal mucosa measures at 500-800 µm
in thickness and it is not keratinized,hence
do not contain acylceramides and only have
small amounts of ceramide. They also
contain small amounts of neutral but polar
lipids, mainly cholesterol sulfate and
glucosyl ceramides.
It is currently believed that the permeability
barrier in the oral mucosa is a result of
intercellular material derived from the so-
called ‘membrane coating granules’ (MCG).
When cells go through differentiation,
MCGs start forming and at the apical cell
surfaces they fuse with the plasma
membrane and their contents are discharged
into the intercellular spaces at the upper one
third of the epithelium. For non-keratinized
epithelia, the major MCG lipid components
are cholesterol esters, cholesterol, and
glycosphingolipids. Outer epithelium is
considered to be the rate limiting step to
mucosal penetration.
The cells of the oral epithelia are surrounded
by mucus, the principle components of
which are complexes made up of proteins
and carbohydrates. This matrix may actually
play a role in cell-cell adhesion, as well as
acting as a lubricant. Along the same lines,
the mucus is also believed to play a role in
bioadhesion of mucoadhesive drug delivery
systems. At physiological pH the mucus
2
network carries a negative charge (due to the
sialic acid and sulfate residues) which may
play a role in mucoadhesion. At this pH
mucus can form a strongly cohesive gel
structure that will bind to the epithelial cell
surface as a gelatinous layer.
The salivary pH ranges from 5.5 to 7
depending on the flow rate. At high flow
rates, the sodium and bicarbonate
concentrations increase leading to an
increase in the pH. The daily salivary
volume is between 0.5 to 2 liters and it is
this amount of fluid that is available to
hydrate oral mucosal dosage forms. A main
reason behind the selection of hydrophilic
polymeric matrices as vehicles for oral
transmucosal drug delivery systems is this
water rich environment of the oral
cavity.(13)
Buccal routes of drug absorption
There are two possible routes of drug
absorption through the squamous stratified
epithelium of the oral mucosa:
i. Transcellular (intracellular, passing
through the cell) and
ii. Paracellular (intercellular, passing
around the cell).
Permeation across the buccal mucosa has
been reported to be mainly by the
paracellular route through the intercellular
lipids produced by membrane-coating
granules.
The buccal mucosa is a potential site for the
controlled delivery of hydrophilic
macromolecular therapeutic agents
(biopharmaceuticals) such as peptides,
oligonucleotides and polysaccharides.
However, these high molecular weight drugs
usually have low permeability leading to a
low bioavailability, and absorption
enhancers may be required to overcome this.
The buccal mucosa also contains proteases
that may degrade peptide-based drugs. In
addition, the salivary enzymes may also
reduce stability.
Disease states where the mucosa is damaged
would also be expected to increase
permeability. This would be particularly true
in conditions that result in erosion of the
mucosa such as lichen planus, pemphigus,
viral infections and allergic reactions.
Buccal Mucosa as a Site for Drug
Delivery
Buccal mucosa is less permeable and is thus
not able to give a rapid onset of absorption
(i.e., more suitable for a sustained release
formulation). It has an expanse of smooth
muscle and relatively immobile mucosa
which makes it a more desirable region for
retentive systems used for oral transmucosal
drug delivery. Thus the buccal mucosa is
more fitted for sustained delivery
applications, delivery of less permeable
molecules, and perhaps peptide drugs.
One of the major disadvantages associated
with buccal drug delivery is the low flux
which results in low drug bioavailability.
Various compounds have been investigated
for their use as buccal penetration enhancers
in order to increase the flux of drugs through
the mucosa. Drugs investigated for buccal
delivery using various permeation/
absorption enhancers range in both
molecular weight and physicochemical
properties. Small molecules such as butyric
acid and butanol, ionizable low molecular
weight drugs such as acyclovir, propranolol,
and salicylic acid, large molecular weight
hydrophilic polymers such as dextrans, and
a variety of peptides including octreotide,
leutinizing hormone releasing hormone
(LHRH), insulin, and a-interferon have all
been studied.
3
A series of studies on buccal permeation
of buserelin and fluorescein isothiocyanate
(FITC) labelled dextrans reported the
enhancing effects of di- and tri-hydroxy bile
salts on buccal penetration. Their results
showed that in the presence of the bile salts,
the permeability of porcine buccal mucosa
to FITC increased by a 100-200 fold
compared to FITC alone. The mechanism of
penetration enhancement of FITC-labelled
dextrans by sodium glycocholate (SGC) was
shown to be concentration dependent. Below
10 mM SGC, buccal permeation was
increased by increasing the intercellular
transport and at 10 mM and higher
concentrations by opening up a transcellular
route. Gandhi and Robinson investigated the
mechanisms of penetration enhancement of
transbuccal delivery of salicylic acid. They
used sodium deoxycholate and sodium
lauryl sulfate as penetration enhancers, both
of which were found to increase the
permeability of salicylic acid across rabbit
buccal mucosa.(14)
Factors Affecting Drug Delivery Via
Buccal Route
The rate of absorption of hydrophilic
compounds is a function of the molecular
size. Smaller molecules (75-100 Da)
generally exhibit rapid transport across the
mucosa, with permeability decreasing as
molecular size increases. For hydrophilic
macromolecules such as peptides,
absorption enhancers have been used to
successfully alter the permeability of the
buccal epithelium, causing this route to be
more suitable for the delivery of larger
molecules.
Only the nonionized forms of molecules
have the ability to cross-lipoidal membranes
in significant amounts. The more lipid
soluble a compound is, the higher its
permeability. The permeabilities for these
compounds are direct functions of their oil-
water partition coefficients. The partition
coefficient is a useful tool to determine the
absorption potential of a drug. In general,
increasing a drug’s polarity by ionization
or the addition of hydroxyl, carboxyl, or
amino groups, will increase the water
solubility of any particular drug and cause a
decrease in the lipid-water partition
coefficient. Conversely, decreasing the
polarity of a drug (e.g. adding methyl or
methylene groups) results in an increased
partition coefficient and decreased water
solubility. The partition coefficient is also
affected by pH at the site of drug
absorption. With increasing pH, the partition
coefficient of acidic drugs decreases, while
that of basic drugs increases. The partition
coefficient is also an important indicator of
drug storage in fat deposits. Obese
individuals can store large amounts of lipid-
soluble drug in fat stores. These drugs are
dissolved in the lipid and are a reservoir of
slow release from these fat deposits.
The ionization of a drug is directly related to
both its pKa and pH at the mucosal surface.
Limitations Of Buccal Drug Delivery
Depending on whether local or systemic
action is required the challenges faced while
delivering drug via buccal drug delivery can
be enumerated as follows.
1. For local action the rapid elimination
of drugs due to the flushing action of
saliva or the ingestion of foods stuffs
may lead to the requirement for
frequent dosing.
2. The non-uniform distribution of
drugs within saliva on release from a
solid or semisolid delivery system
could mean that some areas of the
oral cavity may not receive effective
levels.
3. For both local and systemic action,
patient acceptability in terms of taste,
irritancy and ‘mouth feel’ is an issue.
4
For systemic delivery the relative
impermeability of oral cavity mucosa with
regard to drug absorption, especially for
large hydrophilic biopharmaceuticals, is a
major concern.(13,14)
BUCCAL DRUG DELIVERY SYSTEM
Structure And Design Of Buccal Dosage
Form
Buccal Dosage form can be of
1. Matrix type: The buccal patch designed
in a matrix configuration contains drug,
adhesive, and additives mixed together
2. Reserviour type: The buccal patch
designed in a reservoir system contains a
cavity for the drug and additives separate
from the adhesive. An impermeable backing
is applied to control the direction of drug
delivery; to reduce patch deformation and
disintegration while in the mouth; and to
prevent drug loss.
Additionally, the patch can be constructed to
undergo minimal degradation in the mouth,
or can be designed to dissolve almost
immediately. Transmucosal drug delivery
systems can be bi-directional or
unidirectional. Bi-directional (Figure 1)
patches release drug in both the mucosa and
the mouth while, Unidirectional (Figure 2)
patches release the drug only into the
mucosa. (13)
Figure 1 : Buccal Patch designed for
Bidirectional drug release
Figure 2: Buccal Patch designed for
Unidirectional drug release
Related research on mucoadhesive
polymers and delivery systems
Keiko Tsutsumi studied that buccal
administration of ergotamine tartrate (ET)
combined with polyvinyl alcohol (PVA) gel
brought about higher plasma concentration
of ET compared with that of oral
administration of capsules in guinea-pigs.
Tmax of ET in plasma of buccal
administration was significantly smaller than
that of oral administration. For the buccal
dosage form of ET, the bioadhesive tablet
system (BTS) was newly developed. It
consisted of a reservoir of drug and an
adhesive region. BTS showed better
absorption of ET compared with PVA gel in
guinea pigs. Among several pharmaceutical
bases in the reservoir of BTS, Witepsol W-
35 was most effective.(7)
Bioavailability enhancement: This can be
achieved by using different types of
polymers and various other techniques that
will help in increasing the permeability. In a
study, flexible buccal patches were
developed using water soluble polymer,
hydroxypropyl methylcellulose (HPMC E
15) and hydroxypropyl cellulose (HPC JF).
The bioavailability of carvedilol from buccal
patches has increased 2.29 folds when
compared to that of oral solution. HPMC
E15 LV showed better results.(1)
Thiocolchicoside, a muscle-relaxant agent,
is administered by the oral, intra-muscular
and topical route. After oral administration
the extent of bioavailability compared with
intra-muscular administration is low, due to
a first pass effect. In this paper, the delivery
of thiocolchicoside through oral mucosa is
studied to improve the bioavailability. Two
dosage forms, a bioadhesive disc and a fast
dissolving disc for buccal and sublingual
administration of thiocolchicoside,
respectively, were designed. The fast
dissolving (sublingual) form resulted in a
5
quick uptake of 0.5 mg of thiocolchicoside
within 15 min whereas with the adhesive
buccal form the same dose can be absorbed
over an extended period of time.(8)
Optimizing release characteristics for
hydrophobic drugs: It has been shown that
the incorporation of cyclodextrins in a PEO-
based hydrophilic matrix intended for the
delivery of poorly soluble drugs can be a
suitable strategy to optimize the release
features of the system while maintaining
good bioadhesive properties. Cyclodextrins
are responsible for an increase in the erosion
rate of the tablet and an improved
dissolution of the drug inside the polymeric
matrix. This latter effect is the crucial factor,
which determines the increase of release rate
from the tablets in solution as well as a
twenty-fold increase in the amount of
carvedilol permeated through porcine buccal
mucosa. This systems turns to be of great
potential as buccal delivery system in view
of the possibility of tailoring release features
while maintaining good bioadhesive
properties.(2)
Improved buccal transport for peptides
and proteins: To improve the buccal
transport new absorption promoters should
be developed to be sufficiently active and at
the same time causing no side effects like
irritation or unpleasant taste. Many
substances can function as absorption
promoter, the most popular being detergents
such as bile acids salts, sodium lauryl
sulfate, etc. But many detergents have some
side effects.We have found that lysalbinic
acid, a product of the alkaline hydrolysis of
egg albumin and a mild detergent, meets
those requirements. The preparation and
some physicochemical properties of
lysalbinic acid are described. Hamster cheek
pouch was used as a model for the
penetration process studies lysalbinic acid
was shown to increase significantly an oral
mucosa permeability for _-interferon and
insulin. So this substance of the natural
origin can be applied as an absorption
enhancer for the buccal delivery of peptide
drugs.(3)
chitosan–TGA conjugate in combination
with glutathione represents a promising
candidate for a safe buccal drug delivery
system of PACAP with enhanced buccal
adhesion and permeation(11).
Improved patient compliance: Buccal
administration could be an alternative, non-
invasive delivery route for many drugs given
parenterall, like Naltrexone hydrochloride
(NLX).(4) which is being used in opioid
dependent patients who have undergone
intoxication.
The present study done by Jaehwi Lee, Ian
W. Kellaway suggest that PEG 200
enhances the action of the lipophilic
permeation enhancer oleic acid and that the
combination of oleic acid and PEG 200 as a
co-enhancer can be a useful tool to improve
the membrane permeability in the buccal
delivery of peptide drugs using a cubic
liquid crystalline phase of glyceryl
monooleate and water.(10)
Nagai et al. studied the applicability of
hydroxypropyl cellulose (HPC) as a
mucoadhesive agent, they found this high
viscosity grade material to be a suitable
adhesive for topical mucus membranes.
They reported the combination of HPC and
carbopol 934P (CP) to produce a preferable
material for mucoadhesive dosage forms.
HPC tablets showed a slight adhesion but
dissolved easily on the gel bed. On the other
hand, CP tablets showed strong adhesion but
the swollen CP tablets seemed too hard. The
combination of HPC and CP provided the
mucoadhesion and adequate softness to
prepare the tablets. The adhesive force of the
HPC-CP tablet was affected by the mixing
ratio of HPC and CP. The adhesion force
showed a minimum value at the mixing ratio
of 3:2 (HPC:CP) due to the formation of an
6
inter-polymer complex between HPC and
CP in the acidic pH range. Complex
formation between CP and HPC seemed to
suppress the interaction between molecules
of hydrogel and the mucus membrane, and
the adhesion force was therefore most
reduced at a mixture ratio of 1:4 (HPC/CP).
(13)
In a study, a bioadhesive tablet formulation
for buccal delivery was designed using a
mixture of hydroxypropyl methylcellulose
and carbomer, incorporated with a
penetration enhancer, sodium
glycodeoxycholate (GDC). In vitro
bioadhesion property of the formulated
tablet was examined and histological study
was carried out to examine an in vivo
interaction between the tablet and tissue.
GDC did not affect the adhesiveness of the
tablet which makes it an acceptable
excipient for a buccal bioadhesive drug
delivery system. Histological changes such
as loss of upper cell layers and formation of
vacuoles as well swelling in the cells were
observed in the buccal epithelium, after 4 h
contact with the tablets containing GDC.(5)
Watanabe et al. reported on hydrogels
formed by the combination of natural gums,
xantham gum, and locust bean gum, which
are applicable in buccal delivery systems.
Xantham gum is a natural gum obtained
through fermentation of glucose by
Xanthamonas campestris. Locust bean gum
and xantham gum alone cannot form a
hydrogel. However, when a mixture of these
gums is dissolved in a neutral medium at
90°C and then cooled with ice for 30 min, a
clear, strong hydrogel is formed. The gel
strength of the hydrogels was affected by the
mixing ratio of the gums, and the addition of
sucrose improved the sustained release
properties of the hydrogels. The hydrogel
consisting of xantham gum and locust bean
gum showed only a low mucoadhesion, but
it can be applied to a buccal delivery system
because of its safety, gel strength, sustained
release properties and good feel in the
mouth.(13)
This study of silymarin encapsulated
liposomes revealed an amelioration in the
encapsulation efficiency upon increasing
amount of added drug in the preparation.
Addition of cholesterol beyond a certain
limit produced a decrease in encapsulation
efficiency. Studying the effect of certain
additives and their interactions using two
full 23 factorial designs enabled the
determination of certain enhancement or
decrease in encapsulation efficiency
according to the additive. Addition of stearyl
amine as a positively charge inducer was
capable of enhancing the encapsulation
efficiency. Tween 20, Tween 80 and
dicetylphophate in one molar ratio decreased
the encapsulation efficiency. Molar ratios of
some ingredients were explored to
determine best encapsulation efficiency. In
vitro permeation study through chicken
cheek pouch of hybrid liposomes containing
L:Ch:SA:T 20 of 9:1:1:0.5 molar ratio
showed superior permeation results
compared with neutral or positively charged
liposomes.(12)
Poly(ethyleneoxide) (PEO) is a effective buccal permeation/absorption
biocompatible eroding polymer available in
a number of molecular weights, which is
receiving growing attention as sustained-
release bioadhesive platform due to its
safety, ease. Depending on the molecular
weight of PEO, different dissolution and
water swelling rates, viscoelastic behaviour
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7
of the swollen gel as well as extent and
duration of bioadhesion can be achieved.
PEO has been used in oral sustained-release
tablets Proper modulation of drug release
rate has been attained by tailoring molecular
weight and its distribution.(9)
Conclusion
The buccal mucosa offers several
advantages for controlled drug delivery for
extended periods of time. The mucosa is
well supplied with both vascular and
lymphatic drainage and first-pass
metabolism in the liver and pre-systemic
elimination in the gastrointestinal tract are
avoided. The area is well suited for a
retentive device and appears to be
acceptable to the patient. With the right
dosage form design and formulation, the
permeability and the local environment of
the mucosa can be controlled and
manipulated in order to accommodate drug
permeation. Buccal drug delivery is a
promising area for continued research with
the aim of systemic delivery of orally
inefficient drugs as well as a feasible and
attractive alternative for non-invasive
delivery of potent peptide and protein drug
molecules. However, the need for safe and
enhancers is a crucial component for a
prospective future in the area of buccal drug
delivery.
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