1

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

1.1 Overview 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

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

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. Therefore, adhesive

mucosal dosage forms were suggested for

oral delivery that included adhesive tablets

adhesive gels and adhesive patches.

2

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

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.

3

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.

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

4

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.

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

5

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

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

6

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

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

7

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

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

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

effective buccal permeation/absorption

enhancers is a crucial component for a

prospective future in the area of buccal drug

delivery.

REFERENCES:

1. Vamshi, Vishnu Yamsani1,2, Ramesh Gannu1, Chandrasekhar Kolli1, M.E.Bhanoji Rao2,

Madhusudan Rao Yamsani1*; Development and in vitro evaluation of buccoadhesive

8

carvedilol tablets. Acta Pharm. 57 (2007) 185-197 original research paper

10.2478/v10007-007-0015-7.

2. Brunella Cappello a, Giuseppe De Rosa a, Lucia Giannini a, Maria Immacolata La

Rotonda a, Giuseppe Mensitieri b, Agnese Miro a, Fabiana Quaglia a, Roberto Russo c;

Cyclodextrin-containing poly(ethyleneoxide) tablets for the delivery of poorly soluble

drugs: Potential as buccal delivery system; International Journal of Pharmaceutics 319

(2006) 63–70, 25 April 2006

3. P.L. Starokadomskyy ., I.Ya. Dubey; New absorption promoter for the buccal delivery:

Preparation and characterization of lysalbinic acid; . International Journal of

Pharmaceutics 308 (2006) 149–154; 28 December 2005

4. Libero Italo Giannola a,*,1, Viviana De Caro a, Giulia Giandalia a, Maria Gabriella

Siragusa a, Claudio Tripodo b, Ada Maria Florena b, Giuseppina Campisi c,1 Release of

naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system

design; , Universita`di Palermo, Italy, 3 March 2007

5. S. S¸ enel a,*, Y. C¸ apan a, M.F. Sargon b, C.B. Giray c, A.A. Hýncal a Histological and

bioadhesion studies on buccal bioadhesive tablets containing a penetration enhancer

sodium glycodeoxycholate; . International Journal of Pharmaceutics 170 (1998) 239–245;

17 April 1998.

6. Keiko Tsutsumi a, Yasuko Obata a,*, Tsuneji Nagai a, Thorsteinn Loftsson b, Kozo

Takayama a ; Buccal absorption of ergotamine tartrate using the bioadhesive tablet system

in guinea-pigs; International Journal of Pharmaceutics 238 (2002) 161–170; 10 February

2002.

7. A.P. Munasur a, V. Pillay b, D.J. Chetty c, T. Govender a,; Statistical optimisation of the

mucoadhesivity and characterisation of multipolymeric propranolol matrices for buccal

therapy; . International Journal of Pharmaceutics 323 (2006) 43–51; 2 June 2006

8. M. Artusi a, P. Santi a, P. Colombo a,_, H.E. Junginger b ; Buccal delivery of

thiocolchicoside: in vitro and in vivo permeation studies; LACDR, Leiden/Amsterdam

Center for Drug Research, Division of Pharmaceutical Technology, Leiden University, 27

September 2002.

9. Jaehwi Lee, Ian W. Kellaway *; Combined effect of oleic acid and polyethylene glycol

200 on buccal permeation of [D-Ala2, D-Leu5]enkephalin from a cubic phase of glyceryl

monooleate; International Journal of Pharmaceutics 204 (2000) 137–144; 15 June 2000.

10. Nina Langoth a,., Jochen Kalbe b, Andreas Bernkop-Schn¨urch c; Development of a

mucoadhesive and permeation enhancing buccal delivery system for PACAP (pituitary

adenylate cyclase-activating polypeptide); International Journal of Pharmaceutics 296

(2005) 103–111; 8 April 2005

11. Nina Langoth a, Jochen Kalbe b, Andreas Bernkop-Schnürch a,; Development of buccal

drug delivery systems based on a thiolated polymer; International Journal of

Pharmaceutics 252 (2003) 141–148; 18 November 2002

12. M.S. El-Samaligy, N.N. Afifi, E.A. Mahmoud.; Increasing bioavailability of silymarin

using a buccal liposomal delivery system: Preparation and experimental design

investigation; International Journal of Pharmaceutics 308 (2006) 140–148; 13 December

2005.

13. Amir H Shojaei, Buccal Mucosa As A Route For Systemic Drug Delivery: A Review;J

Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 1 (1):15-30, 1998

9

14. Raj Birudaraj,Ravichandran Mahalingam,Xiaoling Li,Bhaskara R. Jasti; Advances in

Buccal Drug Delivery ; Current Status In Buccal Drug Delivery System; Vol. 5 Issue 2

,2007