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The basics and underlying mechanisms of mucoadhesionB

John D. Smart*

School of Pharmacy and Biomolecular Sciences, University of Brighton, Lewes Road, Brighton BN2 4GJ, UK

Received 30 July 2004; accepted 12 July 2005

Abstract

Mucoadhesion is where two surfaces, one of which is a mucous membrane, adhere to each other. This has been of interest in

the pharmaceutical sciences in order to enhance localised drug delivery, or to deliver ddifficultT molecules (proteins and

oligonucleotides) into the systemic circulation. Mucoadhesive materials are hydrophilic macromolecules containing numerous

hydrogen bond forming groups, the carbomers and chitosans being two well-known examples. The mechanism by which

mucoadhesion takes place has been said to have two stages, the contact (wetting) stage followed by the consolidation stage (the

establishment of the adhesive interactions). The relative importance of each stage will depend on the individual application. For

example, adsorption is a key stage if the dosage form cannot be applied directly to the mucosa of interest, while consolidation is

important if the formulation is exposed to significant dislodging stresses. Adhesive joint failure will inevitably occur as a result

of overhydration of a dosage form, or as a result of epithelia or mucus turnover. New mucoadhesive materials with optimaladhesive properties are now being developed, and these should enhance the potential applications of this technology.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Mucoadhesion; Mucoadhesives; Bioadhesion; Bioadhesives; Mucosal delivery; Carbomers

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557

2. Mucous membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557

3. Mucoadhesives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557

3.1. Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1557

3.2. Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558

4. The mucoadhesive/mucosa interaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

4.1. Chemical bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

4.2. Theories of adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559

0169-409X/$ - see front matterD 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.addr.2005.07.001

B This review is part of the Advanced Drug Delivery Reviews theme issue on Mucoadhesive Polymers: Strategies, Achievements and Future

Challenges, Vol. 57/11, 2005.

* Tel./fax: +44 1273 642091.

E-mail address: [email protected].

Advanced Drug Delivery Reviews 57 (2005) 15561568

www.elsevier.com/locate/addr

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4.3. Mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1560

4.3.1. The contact stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1560

4.3.2. The consolidation stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562

5. Removal mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15646. Some factors affecting mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1564

7. Liquid and semisolid adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565

7.1. Water soluble polymer adsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565

7.2. Retention of liquids and gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565

8. New materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565

9. Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1566

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1566

1. Introduction

Bioadhesion may be defined as the state in which

two materials, at least one of which is biological in

nature, are held together for extended periods of time

by interfacial forces. In the pharmaceutical sciences,

when the adhesive attachment is to mucus or a

mucous membrane, the phenomenon is referred to as

mucoadhesion [1].

Over the last two decades mucoadhesion has

become of interest for its potential to optimise loca-

lised drug delivery, by retaining a dosage form at the

site of action (e.g. within the gastrointestinal tract) or

systemic delivery, by retaining a formulation in inti-

mate contact with the absorption site (e.g. the nasal

cavity). The need to deliver dchallengingT molecules

such as biopharmaceuticals (proteins and oligonucleo-

tides) has increased interest in this area. Mucoadhe-

sives materials could also be used as therapeutic

agents in their own right, to coat and protect damaged

tissues (gastric ulcers or lesions of the oral mucosa) or

to act as lubricating agents (in the oral cavity, eye and

vagina).

This review will consider the basic mechanisms by

which mucoadhesives can adhere to a mucous mem-brane in terms of the nature of the adhering surfaces

and the forces that may be generated to secure them

together.

2. Mucous membranes

Mucous membranes (mucosae) are the moist sur-

faces lining the walls of various body cavities such

as the gastrointestinal and respiratory tracts. They

consist of a connective tissue layer (the lamina

propria) above which is an epithelial layer, the sur-face of which is made moist usually by the pre-

sence of a mucus layer. The epithelia may be either

single layered (e.g. the stomach, small and large

intestine and bronchi) or multilayered/stratified

(e.g. in the oesophagus, vagina and cornea). The

former contain goblet cells which secrete mucus

directly onto the epithelial surfaces, the latter con-

tain, or are adjacent to tissues containing, specia-

lised glands such as salivary glands that secrete

mucus onto the epithelial surface. Mucus is present

as either a gel layer adherent to the mucosal surface

or as a luminal soluble or suspended form. The

major components of all mucus gels are mucin

glycoproteins, lipids, inorganic salts and water, the

latter accounting for more than 95% of its weight,

making it a highly hydrated system [2]. The mucin

glycoproteins are the most important structure-form-

ing component of the mucus gel, resulting in its

characteristic gel-like, cohesive and adhesive proper-

ties. The thickness of this mucus layer varies on

different mucosal surfaces, from 50 to 450 Am in

the stomach [3,4], to less than 1 Am in the oral

cavity [5]. The major functions of mucus are that ofprotection and lubrication (they could be said to act

as anti-adherents).

3. Mucoadhesives

3.1. Materials

The most widely investigated group of mucoad-

hesives are hydrophilic macromolecules containing

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numerous hydrogen bond forming groups [610], the

so-called dfirst generationT mucoadhesives. Their

initial use as mucoadhesives were in denture fixative

powders or pastes [7]. The presence of hydroxyl,carboxyl or amine groups on the molecules favours

adhesion. They are called dwetT adhesives in that

they are activated by moistening and will adhere

non-specifically to many surfaces [12]. Once acti-

vated, they will show stronger adhesion to dry inert

surfaces than those covered with mucus. Unless

water uptake is restricted, they may overhydrate to

form a slippery mucilage. Like typical hydrocolloid

glues, if the formed adhesive joint is allowed to dry

then, they can form very strong adhesive bonds.

Typical examples are carbomers, chitosan, sodiumalginate and the cellulose derivatives (Fig. 1).

These were used initially largely as they were avail-

able doff-the-shelfT with regulatory approval, but in

the last few years, new enhanced materials have been

developed.

3.2. Formulations

First generation mucoadhesive polymers present

significant formulation challenges, being hydrophilic,with limited solubility in other solvents while forming

high viscosity, often pH sensitive, aqueous solutions

at low concentrations. Dry polymers also become

adhesive on exposure to moisture, and so readily

cohere, or adhere to manufacturing equipment or

delivery devices. Mucoadhesives have been formu-

lated into tablets, patches, or microparticles, typically

with the adhesive polymer forming the matrix into

which the drug is dispersed, or the barrier through

which the drug must diffuse [10,12]. Mucoadhesive

ointments and pastes consist of powdered bioadhesivepolymers incorporated into a hydrophobic base. Solu-

tions tend to be viscous due to the nature of the

mucoadhesive materials. Other proposed mucoadhe-

sive formulations include gels, vaginal rods, pessaries

and suppositories [12].

a) Poly(acrylic acid), R = allylsucrose or allyl pentaerythritol

(Carbopols); or divinyl glycol(polycarbophil)

b) Chitosan

c) Sodium alginate

d) Cellulose derivatives e.g.

Sodium carboxylmethylcelluloseR1, R4 = CH2OH; R2, R3, R5 = OH;

R6=OCH2CO2-Na

+

Hydroxypropylmethylcellulose

R1=CH2OCH3; R2=OH,R3=OCH2CHOHCH3; R4=CH2OH;

R5,R6=OCH3

n

n

n

n

Fig. 1. The structure of some common dfirst generationT mucoadhesive polymers.

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4. The mucoadhesive/mucosa interaction

4.1. Chemical bonds

For adhesion to occur, molecules must bond across

the interface. These bonds can arise in the following

way [13].

(1) Ionic bondswhere two oppositely charged

ions attract each other via electrostatic interac-

tions to form a strong bond (e.g. in a salt

crystal).

(2) Covalent bondswhere electrons are shared, in

pairs, between the bonded atoms in order to

dfill

Tthe orbitals in both. These are also strong

bonds.

(3) Hydrogen bondshere a hydrogen atom, when

covalently bonded to electronegative atoms

such as oxygen, fluorine or nitrogen, carries a

slight positively charge and is therefore is

attracted to other electronegative atoms. The

hydrogen can therefore be thought of as being

shared, and the bond formed is generally weaker

than ionic or covalent bonds.

(4) Van-der-Waals bondsthese are some of the

weakest forms of interaction that arise from

dipoledipole and dipole-induced dipole attrac-

tions in polar molecules, and dispersion forces

with non-polar substances.

5) Hydrophobic bondsmore accurately described

as the hydrophobic effect, these are indirect

bonds (such groups only appear to be attracted

to each other) that occur when non-polar groups

are present in an aqueous solution. Water mole-

cules adjacent to non-polar groups form hydro-

gen bonded structures, which lowers the system

entropy. There is therefore an increase in the

tendency of non-polar groups to associate witheach other to minimise this effect.

4.2. Theories of adhesion

There are six general theories of adhesion, which

have been adapted for the investigation of mucoadhe-

sion [11,14,15].

The electronic theory suggests that electron trans-

fer occurs upon contact of adhering surfaces due to

differences in their electronic structure. This is pro-

posed to result in the formation of an electrical double

layer at the interface, with subsequent adhesion due to

attractive forces.

The wetting theory is primarily applied to liquidsystems and considers surface and interfacial ener-

gies. It involves the ability of a liquid to spread

spontaneously onto a surface as a prerequisite for

the development of adhesion. The affinity of a liquid

for a surface can be found using techniques such as

contact angle goniometry to measure the contact

angle of the liquid on the surface, with the general

rule being that the lower the contact angle, the

greater the affinity of the liquid to the solid. The

spreading coefficient (SAB) can be calculated from

the surface energies of the solid and liquids usingthe equation:

SAB cB cA cAB

where cA is the surface tension (energy) of the

liquid A, cA is the surface energy of the solid B

and cAB is the interfacial energy between the solid

and liquid. SAB should be positive for the liquid to

spread spontaneously over the solid.

The work of adhesion (WA) represents the energy

required to separate the two phases, and is given by:

WA cA cB cAB:

The greater the individual surface energies of the

solid and liquid relative to the interfacial energy, the

greater the work of adhesion.

The adsorption theory describes the attachment

of adhesives on the basis of hydrogen bonding

and van der Waals forces. It has been proposed

that these forces are the main contributors to the

adhesive interaction. A subsection of this, the che-

misorption theory, assumes an interaction across

the interface occurs as a result of strong covalent

bonding.The diffusion theory describes interdiffusion of

polymers chains across an adhesive interface. This

process is driven by concentration gradients and is

affected by the available molecular chain lengths and

their mobilities. The depth of interpenetration depends

on the diffusion coefficient and the time of contact.

Sufficient depth of penetration creates a semi-perma-

nent adhesive bond.

The mechanical theory assumes that adhesion

arises from an interlocking of a liquid adhesive (on


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setting) into irregularities on a rough surface. How-

ever, rough surfaces also provide an increased sur-

face area available for interaction along with an

enhanced viscoelastic and plastic dissipation ofenergy during joint failure, which are thought to be

more important in the adhesion process than a

mechanical effect [15].

The fracture theory differs a little from the other

five in that it relates the adhesive strength to the forces

required for the detachment of the two involved sur-

faces after adhesion. This assumes that the failure of

the adhesive bond occurs at the interface. However,

failure normally occurs at the weakest component,

which is typically a cohesive failure within one of

the adhering surfaces.

4.3. Mucoadhesion

Due its relative complexity, it is likely that the

process of mucoadhesion cannot be described by

just one of these theories. In considering the mechan-

ism of mucoadhesion, a whole range dscenariosT for

in-vivo mucoadhesive bond formation are possible

(Fig. 2). These include:

(1) Dry or partially hydrated dosage forms contact-

ing surfaces with substantial mucus layers (typi-

cally particulates administered into the nasal

cavity).

(2) Fully hydrated dosage forms contacting surfaces

with substantial mucus layers (typically particu-

lates of many dFirst GenerationT mucoadhesives

that have hydrated in the luminal contents on

delivery to the lower gastrointestinal tract).

(3) Dry or partially hydrated dosage forms contact-

ing surfaces with thin/discontinuous mucus

layers (typically tablets or patches in the oral

cavity or vagina).(4) Fully hydrated dosage forms contacting surfaces

with thin/discontinuous mucus layers (typically

aqueous semisolids or liquids administered into

the oesophagus or eye).

It is unlikely that the mucoadhesive process will be

the same in each case.

In the study of adhesion generally, two steps in the

adhesive process have been identified [16], which

have been adapted to describe the interaction between

mucoadhesive materials and a mucous membrane

(e.g. [1,17]) (Fig. 3).

Step 1 Contact stage: An intimate contact (wetting)occurs between the mucoadhesive and mucous

membrane.

Step 2 Consolidation stage: Various physicochemi-

cal interactions occur to consolidate and

strengthen the adhesive joint, leading to pro-

longed adhesion.

4.3.1. The contact stage

The mucoadhesive and the mucous membrane

have initially come together to form an intimate

contact. In some cases these two surfaces can bemechanically brought together, e.g. placing and

holding a delivery system within the oral cavity,

eye or vagina. In others the deposition of a particle

is encouraged via the aerodynamics of the organ.

For example within the nasal cavity or bronchi of

the respiratory tract deposition onto the dstickyT

mucus coat is encouraged by processes such as

inertial impaction, in order to dfilter outT particles

from the airstream [18]. The gastrointestinal tract is

an example of an inaccessible mucosal surface

where the adhesive material cannot be placed

directly onto the target mucosal surface, or delivered

to the surface by organ design. In general, adhesion

and possible blockage of the gastrointestinal tract

would be potentially catastrophic. For larger parti-

cles, peristalsis and other gastrointestinal movement

would help to force the dosage form into contact

with the mucosa. However little evidence of suc-

cessful adhesion of larger dosage forms has yet

been reported in the literature, other than the poten-

tially dangerous case of oesophageal adhesion [19].

For smaller particles in suspension, adsorption onto

the gastrointestinal mucosa would be an essential prerequisite for the adhesion process. Other exam-

ples where an adsorption step would be required

would be the administration of nanoparticle suspen-

sions to the precorneal region, or mouthwashes

containing microparticles.

The principles of the DLVO theory (described in

the 1940s by Derjaguin and Landau, and separately

by Verwey and Overbeek to explain the stability of

colloids [18]) have been used to describe the phy-

sicochemical processes involved in the adsorption of


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bacteria onto surfaces [20,21]. The theory may

therefore also be used in the consideration of the

adsorption process for small particles. Within the

body a particle will move due to Brownian motion,

the flow of liquids within a body cavity and body

movements such as peristalsis. If a particle

approaches a surface it will experience both repul-

sive and attractive forces. Repulsive forces arise

from osmotic pressure effects as a result of the

interpenetration of the electrical double layers, steric

effects and also electrostatic interactions when the

surface and particle carry the same charge. Attrac-

tive forces arise form van der Waals interactions,

surface energy effects and electrostatic interactions if

the surface and particles carry opposite charges. The

relative strength of these opposing forces will vary

depending on the nature of the particle, the aqueousenvironment, and the distance between the particle

and surface. For example, the smaller the particle,

the greater the surface-area-to-volume ratio and

therefore the greater the attractive forces. Particles

can be weakly held at a secondary minimum (circa

10 nm separation), a region where the attractive

forces are balanced by the repulsive forces allowing

the particles to be easily dislodged. For stronger

adsorption to occur, particles have to overcome a

repulsive barrier (the potential energy barrier) to get

Particle Particle

a) Dry or partially hydrated dosage forms

contacting surfaces with substantial mucus

layers (e.g. aerosolised particles deposited

in the nasal cavity).

b) Fully hydrated dosage forms contacting

surfaces with substantial mucus layers (e.g.

particle suspensions in the gastrointestinal

tract).

c) Dry or partially hydrated dosage forms

contacting surfaces with thin/

discontinuous mucus layers (e.g. a tablet

placed onto the oral mucosa).

d) Fully hydrated dosage forms contacting

surfaces with thin/discontinuous mucus

layers (e.g. aqueous microparticles

administered into the vagina).

Hydrated

layer

Mucus layer

Tablet Gel

Mucus layer

Fig. 2. Some scenarios where mucoadhesion can occur.

Contactstage

Consolidationstage

Mucosawithmucus

Dosageform

Interactionarea

Fig. 3. The two stages in mucoadhesion.


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closer to the surface (circa 1 nm). If this barrier is

sufficiently small, or if the particle has sufficient

energy, then adsorption into the primary minimum

can occur. This type of adsorption would berequired to allow a strong adhesive bond to form.

This situation is made more complex by the fact

that the surface in question is usually a mucus gel

rather than a solid, and the particles in-vivo may

become hydrated and/or coated with biomolecules,

significantly altering their physicochemical properties

[2224]. The adhesive interaction necessary to retain

a dosage form may only need to be weak if the

forces promoting displacement are also small. A

consideration of many physicochemical models of

liquids at solid interfaces suggests that the liquidadjacent to the interface is stationary, with the rate

of flow increasing with distance from the surface

[25]. Many texts also refer to the presence of an

unstirred water layer at the surface of the gastroin-

testinal mucosae [26]. Mucous membranes typically

have a highly irregular topography on both the

macroscopic and microscopic level so it is possible

for small particulates to become lodged in these

surface folds and crevasses. Small particles may

therefore be subjected only to minor dislodging

stresses so only small adhesive interactions would

be required to keep them in place. This might

explain how apparently inert materials have been

reported to be mucoadhesive (e.g. [2729]).

4.3.2. The consolidation stage

It has been proposed that if strong or prolonged

adhesion is required, for example with larger for-

mulations exposed to stresses such as blinking or

mouth movements, then a second dconsolidationT

stage is required. Mucoadhesive materials adhere

most strongly to solid dry surfaces [30] as long as

they are activated by the presence of moisture.Moisture will effectively plasticize the system allow-

ing mucoadhesive molecules to become free, con-

form to the shape of the surface, and bond

predominantly by weaker van der Waal and hydro-

gen bonding. In the case of cationic materials such

as chitosan, electrostatic interactions with the nega-

tively charged groups (such as carboxyl or sulphate)

on the mucin or cell surfaces are also possible. The

mucoadhesive bond is by nature very heterogenous

making it extremely difficult to use spectroscopic

techniques to identify the type of bonds and groups

involved although hydrogen bonds have been iden-

tified as being important [1,31]. Polymer/mucosae

interactions have been investigated by evaluatingsurface energies [3234]. Although of interest,

these studies have met with varying degrees of

success, which is unsurprising considering the het-

erogeneous nature of mucosal surfaces and biopoly-

mer solutions relative to the normally pure solvents

and surfaces required in surface energy measure-

ments. Polymers and biopolymers in solution tend

to rapidly accumulate at interfaces producing a sig-

nificant reduction in the surface energy. It is also

noticeable when undertaking tensiometer studies

with these systems that the high affinity of materialslike carbomers for water almost appears to have a

dsuction-likeT effect, helping to hold to formulation

onto a solid surface [30]. For surfaces with only

limited amounts of mucus, a dry mucoadhesive

polymer will almost certainly collapse the mucus

layer by extracting the water component of the

gel, allowing the polymer molecules the freedom

to interact by hydrogen bonding with the epithelial

surface [17].

However, when a substantial mucus layer is

present then the anti-adherent properties of mucus

will need to be overcome if a strong adhesive joint

is to be formed. In this case the adhesive joint can

be considered to contain three regions (Fig. 4), the

mucoadhesive, the mucosa and an interfacial region,

consisting at least initially of mucus. To achieve

strong adhesion, a change in the physical properties

of the mucus layer will be required otherwise it

will readily fail on application of a dislodging

stress.

There are essentially two theories as to how gel

strengthening/consolidation occurs. One is based on

a macromolecular interpenetration effect, which hasbeen dealt with in a theoretical basis by Peppas and

Mucoadhesive dosage form

Mucus layer

The mucosa

Fig. 4. The three regions within a mucoadhesive joint.


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Sahlin [15]. In this theory, based largely on the

diffusion theory described by Voyutskii [35] for

compatible polymeric systems, the mucoadhesive

molecules interpenetrate and bond by secondary

interactions with mucus glycoproteins (Fig. 5). Evi-

dence for this is provided by an ATIR FTIR study

by Jabbari et al. [36]. In their study a thin cross-

linked film of poly(acrylic acid) was formed on an

ATR crystal. A mucin solution was placed into

contact with this film and ATR-FTIR spectra col-

lected over a period of time. Deconvolution of these

spectra revealed a peak after 6 min at 1550 cm1

(which manifested itself as a small shoulder in the

original spectrum) which was attributed to mucin

dimeric carboxylic CMO stretching and it was pro-

posed that this indicated the presence of interpene-

trating mucin molecules within the poly(acrylic

acid) film. Another study [37] suggested that evi-

dence of substantial interpenetration was apparent

for poly(acrylic acid)s labeled with fluoresceina-

mine. This was size dependent but even the largest

polymer (polycarbophil) showed penetration to a

depth of 60 Am after 4 h. However, the model

mucus used was a commercial mucin which is

thought to be degraded and therefore of limitedvalue as a model of native mucus [38,39]. The

porcine intestinal mucosa also used in this study

had been frozen prior to experimentation, a proce-

dure likely to result in significant damage to the

mucus gel layer. Further indirect evidence for inter-

penetration is based on the rheological effects of

mixing mucus with mucoadhesive gels [40,41].

Rheological synergism, an increase in the resistance

to elastic deformation (i.e. mucus gel strengthening)

is evident, and this would undoubtedly help conso-

lidate the adhesive joint.The second theory is the dehydration theory [17].

When a material capable of rapid gelation in an

aqueous environment is brought into contact with a

second gel water movement occurs between gels

until equilibrium is achieved. A polyelectrolyte gel,

such as a poly(acrylic acid) will have a strong affinity

for water, therefore a high dosmotic pressureT and a

large swelling force [42,43]. When brought into con-

tact with a mucus gel it will rapidly dehydrate that

gel and force intermixing and consolidation of the

mucus joint (Fig. 6) until equilibrium is reached. The

movement of water from mucus into a poly(acrylic

acid) film was observed by Jabbari et al. [36]. A

mucus gel, on dehydration, goes from having lubri-

cant to the opposite adhesive properties, as observed

in studies by Mortazavi and Smart [44,45].

The latter theory explains why mucoadhesion

arises very quickly, within a matter of seconds,

while the former requires two large macromolecules

to interpenetrate several Am within a short time.

The rheological synergy study suggests that as soon

Fig. 5. The interpenetration theory; three stages in the inteaction

between a mucoadhesive polymer and mucin glycoprotein.

Mucoadhesive dosage form

DehydratedMucus layer

The mucosa

Hydrating region in dosageform

Direction of watermovement

Fig. 6. The dehydration theory of mucoadhesion.


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testing. The presence of metal ions, which can inter-

act with charged polymers, may also affect the adhe-

sion process.

7. Liquid and semisolid adhesion

7.1. Water soluble polymer adsorption

Mucoadhesive polymers (chitosan, polycarbophil

and Carbopol 934) in dilute solutions were shown to

bind to buccal cells in-vitro [57], and to bind and be

retained in vivo for over 2 h [58]. The mechanism by

which this occurs is that of polymer adsorption at an

interface, where polymers will naturally collect toreduce the surface energy and can then bind by the

formation of many weak bonds, mimicking the natural

role of mucins in saliva. The scenario is complicated

by the presence of mucins on the mucosae, which

means that polymers are adsorbing onto a hydrated

gel. In the case of cationic polymers like chitosan, the

positive charge will favour binding to a negatively

charged surface although, in-vivo binding to soluble

luminal mucins may inhibit this effect [59].

7.2. Retention of liquids and gels

More concentrated mucoadhesive dispersions have

been shown to be retained on mucosal surfaces for

extended periods [60,61]. The process by which

polymeric dispersions spread and are retained on

mucosae will depend principally on the surface

energy of the solid and liquid (a positive spreading

coefficient), along with the rheology of the liquid.

The dispersion will need to be sufficiently mobile to

allow spreading and interaction while not being so

mobile as to be readily dislodged. Systems that allow

in-situ gelation will clearly favour retention in thiscase [62,63]. The interaction of the liquid or semi-

solid with biological fluids in terms of the rate and

extend of mixing and dissolution, will also be key

factors influencing retention.

8. New materials

In order to overcome the limitations of first gen-

eration doff-the-shelfT mucoadhesive materials, new

types of materials have been investigated that allow

specificity, or prolong and strengthen the mucoadhe-

sion process. In some cases, existing mucoadhesive

polymers have been modified, while in others, newmaterials are developed.

One approach to produce improved mucoadhe-

sives has been to modify existing materials. For

example thiol groups (by coupling cysteine, thiogly-

colic acid, cysteamine) have been placed into a range

of mucoadhesive polymers such as the carbomers,

chitosans and alginates by Bernkop-Schnurch et al.

[6467]. The concept is that in-situ they will form

disulphide links not only between the polymers them-

selves thus inhibiting overhydration and formation of

the slippery mucilage, but also with the mucin layer/mucosa itself, thus strengthening the adhesive joint

and leading to improved adhesive performance. This

interesting approach appears to be meeting with some

success.

The incorporation of ethyl hexyl acrylate into a

copolymer with acrylic acid in order to produce a

more hydrophobic and plasticized system was con-

sidered by Shojaei et al. [68]. This would reduce

hydration rate while allowing optimum interaction

with the mucosal surface, and the mucoadhesive

force was found to be greater with the copolymer

than with poly(acrylic acid) alone.

The grafting of polyethylene glycol (PEG) onto

poly(acrylic acid) polymers and copolymers has also

been investigated [6971]. These copolymers were

shown to have favourable adhesion relative to poly

(acrylic acid) alone, in that the polyethylene glycol

is proposed to promote interpenetration with the

mucus gel [72]. Poly(acrylic acid)/PEG complexes

have also been developed as mucoadhesive materi-

als [73].

Poloxomer gels have been investigated as they are

reported to show phase transitions from liquids tomucoadhesive gels at body temperature and will

therefore allow in-situ gelation at the site of interest

[63]. Pluronics have also been chemically combined

with poly(acrylic acid)s to produce systems with

enhanced adhesion [74] and retention in the nasal

cavity [75].

Dihydroxyphenylalanine (DOPA), an amino acid

found in mussel adhesive protein that is believed to

lend to the adhesive process, has also been combined

with pluronics to enhance their adhesion [76].


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Glyceryl monooleate/water liquid crystalline

phases have also been found to be mucoadhesive

using a range of mucosal surfaces, although the

mechanism will differ somewhat from that of othermucoadhesives [77].

Lectins are proteins or glycoproteins that have

been considered second-generation bioadhesives,

and differ significantly from the polymeric systems

described above. There is a range of lectins avail-

able that interact with specific sugar residues via

relatively weak (secondary) interactions and have

been considered for use in targeted drug delivery

[78].

9. Conclusions and future prospects

The mechanism by which a mucoadhesive bond is

formed will depend on the nature of the mucous

membrane and mucoadhesive material, the type of

formulation, the attachment process and the subse-

quent environment of the bond. It is apparent that a

single mechanism for mucoadhesion proposed in

many texts is unlikely for all the different occasions

when adhesion occurs. However, an understanding of

the mechanism of mucoadhesion in each instance will

assist the development of the new, enhanced systems

required for the delivery of the products of the bio-

technology revolution.

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