Mucoadhesive Drug Delivery System - Project Paper

Mucoadhesive Drug Delivery Systems
1. INTRODUCTION
The effect of a drug can now be reinforced as a result of the development of new release
systems. Controlled release consists of techniques that make the active chemical agents
available for a target, providing an adequate release rate and duration to produce the desired
effect. The main controlled drug delivery systems currently available include matrices,
pellets, floating systems, liposomes, microemulsions, liquid crystals, solid dispersions,
nanosuspensions, transdermal systems, cyclodextrin inclusion complexes, osmotic pumps and
bioadhesive systems (1).
Bioadhesion can be defined as the state in which two materials, at least one of which is
biological in nature, are maintained together for a prolonged time period by means of
interfacial forces (2). During the 1980s, this concept began to be applied to drug delivery
systems. It consists of the incorporation of adhesive molecules into some kind of
pharmaceutical formulation intended to stay in close contact with the absorption tissue,
releasing the drug near to the action site, thereby increasing its bioavailability and promoting
local or systemic effects.
The potential use for mucoadhesive systems as drug carriers lies in its prolongation of the
residence time at the absorption site, allowing intensified contact with the epithelial barrier
(3). On the other hand, adhesion of preparations onto mucous membrane can be impaired by
the mucociliary clearance system. This clearance, a natural defense mechanism of the body
against the deposition of impurities onto the mucous membrane, can also remove the
preparation. Thus, by using bioadhesive molecules, it is possible to retain the preparation at
the action site and to direct the drug to a specific site or tissue. Other features associated with
the development of controlled drug delivery systems using bioadhesive molecules include a
decrease in drug administration frequency and an increase in patient compliance to the
therapy (4). Therefore, a bioadhesive system controlling drug release could improve the
treatment of diseases, helping to maintain an effective concentration of the drug at the action
site (5).
Mucous membrane is the main administration site for bioadhesive systems, although the need
for new bioadhesive formulations for dermal administration has also been reported when
prolonged cutaneous action is desired. A prolonged effect upon the dermal administration of

creams, solutions, and lotions is unexpected, since such preparations can be easily removed
from the skin by moisture, temperature, and physical movements (6).
1.1. Mucous Membranes
Mucous membranes (mucosae) are the moist surfaces 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 surface of which is made
moist usually by the presence of a mucous layer. The epithelia may be either single layered
(e.g. the stomach, small and large intestines and bronchi) or multilayered/stratified (e.g. in the
esophagus, vagina and cornea). The former contain goblet cells which secrete mucous
directly onto the epithelial surfaces; the latter contain, or are adjacent to tissues containing,
specialized glands such as salivary glands that secrete mucous onto the epithelial surface.
Mucous is present either as a gel layer adherent to the mucosal surface or as a luminal soluble
or suspended form. The major components of all mucous gels are mucin glycoproteins, lipids,
inorganic salts and water, the latter accounting for more than 95% of their weight, making
them a highly hydrated system (2).
Figure 1: Mucous membrane structure
1.2. Functions of Mucous Layer

1. Protective: resulting particularly from its hydrophobicity.
2. Barrier: The role of the mucous layer as a barrier in tissue absorption of the drugs and
influence the bioavailability.
3. Adhesion: Mucous has strong cohesion properties.
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4. Lubrication: It is to keep the mucous from the goblet cell is necessary to compensate
for the removal of the mucous layer due to digestion, bacterial degradation and
solubilization of mucin molecules (7).
1.3. Advantages of Mucoadhesive Drug Delivery Systems
Easy of administration and termination of therapy in emergency.
Permits localization of the drug for a prolonged period of time.
Can be administered to unconscious and trauma patients.
Significant reduction in dose can be achieved, there by reducing dose, dose dependent
side effects, and eliminates peak-valley profile.
It offers a passive system for drug absorption.
It allows for the local modification of tissue permeability, inhibition of protease

activity or reduction in immunogenic response. Thus, selective uses of therapeutic
agents like peptides, proteins and ionized species can be achieved.
Flexibility in physical state, shape, size and surface.
Maximized absorption rate due to intimate contact with the absorbing membrane and
decreased diffusion barriers.
It satisfies several futures of the controlled release system.
The oral mucosa lacks prominent mucous secreting goblet cells and therefore there is
no problem of diffusion limited mucous build up beneath the applied dosage form.
The presence of saliva ensures relatively large amount of water for drug dissolution
unlike in case of rectal and transdermal routes.
An increase in the drug concentration gradient due to the intense contact of particles
with the mucosal.
A direct contact with intestinal cells that is the first step before particle absorption
Offers an excellent route, for the systemic delivery of drugs with high first pass
metabolism, thereby offering a greater bioavailability.
A significant reduction in dose can be achieved there by reducing dose related side
effects.
Drugs which are unstable in the acidic environment are destroyed by enzymatic or
alkaline environment of intestine can be administered by this route. Eg. Buccal
sublingual, vaginal
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Drugs which show poor bioavailability via the oral route can be administered
conveniently.
It offers a passive system of drug absorption and does not require any activation.
The presence of saliva ensures relatively large amount of water for drug dissolution
unlike in case of rectal and transdermal routes.
Systemic absorption is rapid.
This route provides an alternative for the administration of various hormones, narcotic
analgesic, steroids, enzymes, cardiovascular agents etc.
The buccal mucosa is highly perfused with blood vessels and offers a greater
permeability than the skin.
Less dosing frequency.
Shorter treatment period.
Increased safety margin of high potency drugs due to better control of plasma levels.
Maximum utilization of drug enabling reduction in total amount of drug administered.
Improved patient convenience and compliance due to less frequent drug

administration.
Reduction in fluctuation in steady state levels and therefore better control of disease
condition and reduced intensity of local or systemic side effects. Basic assumption is
drug should absorbed throughout GI tract
Limited gastric residence time which ranges from few minutes to 12 hours which lead
to unpredictable bioavailability and time to achieve maximum plasma level (8) (9).
1.4. Limitations
Drugs which are unstable at buccal pH cannot be administered.
Drugs which irritate the mucosa or have a bitter or unpleasant

taste or an obnoxious odor cannot be administered by this route.
Only drug with small dose requirement can be administered.
Only those drugs which are absorbed by passive diffusion can be

administered by this route.
Eating and drinking may become restricted.
There is an ever present possibility of the patient swallowing the

dosage form.
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Over hydration may leads to slippery surface and structural

integrity of the formulation may get disrupted by this swelling
and hydration of the bioadhesive polymers.
Drugs contained in the swallowed saliva follows the pre-oral and advantages of
buccal route are lost (8) (10).
2. MECHANISM OF MUCOADHESION
The concept of mucoadhesion is one that has the potential to improve the highly variable
residence times experienced by drugs and dosage forms at various sites in the gastrointestinal
tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the
mucosa should enhance absorption(11).The mechanisms responsible in the formation of
bioadhesive bonds are not fully known, however most research has described bioadhesive
bond formation as a three step process:2.1. Wetting and swelling of polymer.
2.2. Interpenetration between the polymer chains and the mucosal membrane.
2.3. Formation of Chemical bonds between the entangled chains.
2.1. Wetting and swelling of polymer
The wetting and swelling step occurs when the polymer spreads over the surface of the
biological substrate or mucosal membrane in order to develop an intimate contact with the
substrate.This can be readily achieved for example by placing a bioadhesive formulation such
as a tablet or paste within the oral cavity or vagina. Bioadhesives are able to adhere to or
bond with biological tissues by the help of the surface tension and forces that exist at the site
of adsorption or contact. Swelling of polymers occurs because the components within the
polymers have an affinity for water (2).
Figure 2: Wetting and Swelling of Polymer
2.2. Interpenetration between the polymer chains and the mucosal membrane
The surfaces of mucosal membranes are composed of high molecular weight polymers
known as glycoproteins. In this step interdiffusion and interpenetration take place between
the chains of mucoadhesive polymers and the mucous gel network creating a great area of
contact (11). The strength of this bond depends on the degree of penetration between the two
polymer groups. In order to form strong adhesive bonds, one polymer group must be soluble
in the other
and
both
polymer
types
must
be of similar
chemical
structure (2).
Figure 3: Inter diffusion and Interpenetration of Polymer and Mucous
2.3. Formation of Chemical bonds between the entangled chains

In this step entanglement and formation of weak chemical bonds as well as secondary bonds
between the polymer chains mucin molecule. The typesof bonding formed between the chains
includes primary bonds such as covalent bonds and weaker secondary interactions such as
van der Waals Interactions and hydrogen bonds. Both primary and secondary bonds are
exploited in the manufacture of bioadhesive formulations in which strong adhesions between
polymers are formed (2).
Figure 4: Entanglement of Polymer and Mucous by Chemical bonds
3. MUCOADHESION THEORIES OF POLYMER ATTACHMENT

Although the chemical and physical basis of mucoadhesion are not yet well understood, there
are six classical theories adapted from studies on the performance of several materials and
polymer-polymer adhesion which explain the phenomenon.
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3.1. The Wetting theory

The wetting theory applies to liquid systems which present affinity to the surface in order to
spread over it. This affinity can be found by using measuring techniques such as the contact
angle. The general rule states that the lower the contact angle, the greater is the affinity. The
contact angle should be equal or close to zero to provide adequate spreadability. The
spreadability coefficient, S
0, can be calculated from the difference between the surface
AB
energies B and A and the interfacial energy AB, as indicated in the equation given below (2).
This theory explains the importance of contact angle and reduction of surface and interfacial
energies to achieve good amount of mucoadhesion.
S AB = B - A - AB
Figure 5: Influence of contact angle on mucoadhesion
3.2. The Diffusion theory

Diffusion theory describes the interpenetration of both polymer and mucin chains to a
sufficient depth to create a semi-permanent adhesive bond. It is believed that the adhesion
force increases with the degree of penetration of the polymer chains. This penetration rate
depends on the diffusion coefficient, flexibility and nature of the mucoadhesive chains,
mobility and contact time. According to the literature, the depth of interpenetration required

to produce an efficient bioadhesive bond lies in the range 0.2-0.5 m. This interpenetration
depth of polymer and mucin chains can be estimated by the following equation:
l = (tD b)
where t is the contact time and D b is the diffusion coefficient of the mucoadhesive material in
the mucous. The adhesion strength for a polymer is reached when the depth of penetration is
approximately equivalent to the polymer chain size. In order for diffusion to occur, it is
important that the components involved have good mutual solubility, that is, both the
bioadhesive and the mucous have similar chemical structures. The greater the structural
similarity, the better is the mucoadhesive bond (5).
Figure 6: Secondary interaction between mucoadhesive device and of mucous
3.3. The Fracture theory

This is perhaps the most used theory in studies on the mechanical measurement of
mucoadhesion. It analyzes the force required to separate two surfaces after adhesion is
established. This force, sm, is frequently calculated in tests of resistance to rupture by the ratio
of the maximal detachment force, Fm, and the total surface area, A0 , involved in the adhesive
interaction.
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Sm= Fm / A0
Since the fracture theory is concerned only with the force required to separate the parts, it
does not take into account the interpenetration or diffusion of polymer chains. Consequently,
it is appropriate for use in the calculations for rigid or semi-rigid bioadhesive materials, in
which the polymer chains do not penetrate into the mucous layer (2) (12).
Figure 7: Fractures occurring for mucoadhesion
3.4. The electronic theory

This theory describes adhesion occurring by means of electron transfer between the mucous
and the mucoadhesive system, arising through differences in their electronic structures. The
electron transfer between the mucous and the mucoadhesive results in the formation of
double layer of electrical charges at the mucous and mucoadhesive interface. The net result of
such a process is the formation of attractive forces within this double layer (13).
3.5. The adsorption theory
In this instance, adhesion is the result of various surface interactions (primary and secondary
bonding) between the adhesive polymer and mucous substrate. Primary bonds due to
chemisorptions result in adhesion due to ionic, covalent and metallic bonding, which is
generally undesirable due to their permanencySecondary bonds arise mainly due to van der
Waals forces, hydrophobic interactions and hydrogen bonding. Whilst these interactions
require less energy to "break", they are the most prominent form of surface interaction in
mucoadhesion processes as they have the advantage of being semi-permanent bonds (14).
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All these numerous theories should be considered as supplementary processes involved in the
different stages of the mucous/substrate interaction, rather than individual and alternative
theories. Each and every theory is equally important to describe the mucoadhesion process.
There is a possibility that there will be initial wetting of the mucin, and then diffusion of the
polymer into mucin layer, thus causing the fracture in the layers to effect the adhesion or
electronic transfer or simple adsorption phenomenon that finally leads to the perfect
mucoadhesion. 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 subsequent 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.
3.6. The Mechanical theory
Mechanical theory considers adhesion to be due to the filling of the irregularities on a rough
surface by a mucoadhesive liquid. Moreover, such roughness increases the interfacial area
available to interactions thereby aiding dissipating energy and can be considered the most
important phenomenon of the process (15). It is unlikely that the mucoadhesion process is the
same for all cases and therefore it cannot be described by a single theory. In fact, all theories
are relevant to identify the important process variables.
The mechanisms governing mucoadhesion are also determined by the intrinsic properties of
the formulation and by the environment in which it is applied. Intrinsic factors of the polymer
are related to its molecular weight, concentration and chain flexibility. For linear polymers,
mucoadhesion increases with molecular weight, but the same relationship does not hold for
non-linear polymers. It has been shown that more concentrated mucoadhesive dispersions are
retained on the mucous membrane for longer periods, as in the case of systems formed by in
situ gelification. After application, such systems spread easily, since they present rheological
properties of a liquid, but gelify as they come into contact the absorption site, thus preventing
their rapid removal. Chain flexibility is critical to consolidate the interpenetration between
formulation and mucous (16).
Environment-related factors include pH, initial contact time, swelling and physiological
variations. The pH can influence the formation of ionizable groups in polymers as well as the
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formation of charges on the mucous surface. Contact time between mucoadhesive and
mucous layer determines the extent of chain interpenetration. Super-hydration of the system
can lead to build up of mucilage without adhesion. The thickness of the mucous layer can
vary from 50 to 450m in the stomach to less than 1m in the oral cavity. Other physiological
variations can also occur with diseases. None of these mechanisms or theories alone can
explain the mucoadhesion which occurs in an array of different situations. However, the
understanding of these mechanisms in each instance can help toward the development of new
mucoadhesive products. (2)
4. FACTORS AFFECTING MUCOADHESION

4.1. Polymer related factors
4.1.1. Molecular weight
4.1.2. Concentration of active polymer
4.1.3. Flexibility of polymer chains
4.1.4. Special confirmation
4.1.5. Swelling
4.1.6. Hydrogen bonding capacity
4.1.6.1. Hydration
4.1.6.2. Charge
4.1.6.3. Concentration
4.2. Environment related factors
4.2.1. pH of polymer - substrate interface
4.2.2. Applied strength
4.2.3. Initial contact time
4.3. Physiological factors
4.3.1 Mucin turns over
4.3.2 Disease state
4.1. Polymer-Related Factors
4.1.1. Molecular weight
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The optimum molecular weight for maximum bioadhesion depends upon type of
mucoadhesive polymer at issue. It is generally understood that the threshold required for
successful bioadhesion is at least 100 000 molecular weight. For example, polyethylene
glycol (PEG), with a molecular weight of 20 000, has little adhesive character, whereas PEG
with 200 000 molecular weight has improved, and PEG with 400 000 has superior adhesive
properties. The fact that mucoadhesiveness improves with increasing molecular weight for a
linear polymer implies two things:
(1) Interpenetration is more critical for a low-molecular-weight polymer to be a good
mucoadhesive, and
(2) Entanglement is important for high-molecular-weight polymers. Adhesiveness of a
nonlinear structure, by comparison, follows a quite different trend. The adhesive
strength of dextran, with a high molecular weight of 19 500 000 is similar to that of
PEG, with a molecular weight of 200 000. The reason for this similarity may be that
the helical conformation of dextran may shield many of the adhesive groups, which
are primarily responsible for adhesion, unlike the conformation of PEG (17).
4.1.2. Concentration of active polymer
There is an optimum concentration for a mucoadhesive polymer to produce maximum
bioadhesion. In highly concentrated system, beyond the optimum level, however, the
adhesive strength drops significantly because the coiled molecules become separated from
the medium so that the chain available for interpenetration becomes limited (18).
4.1.3. Flexibility of polymer chains
Mucoadhesion starts with the diffusion of the polymer chains in the interfacial region.
Therefore, it is important that the polymer chains contain a substantial degree of flexibility in
order to achieve the desired entanglement with the mucous. The increased chain
interpenetration was attributed to the increased structural flexibility of the polymer upon
incorporation of polyethylene glycol. In general, mobility and flexibility of polymers can be
related to their viscosities and diffusion coefficients, as higher flexibility of a polymer causes
greater diffusion into the mucous network (19).
4.1.4. Spatial conformation
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 adhesive
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strength similar to that of PEG, 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 (17).
4.1.5. Swelling
Swelling characteristics are related to the mucoadhesive itself and its environment. Swelling
depends on the polymer concentration, the ionic strength, and the presence of water. During
the dynamic process of bioadhesion, maximum bioadhesion in vitro occurs with optimum
water content. Overhydration results in the formation of a wet slippery mucilage without
adhesion (17).
4.1.6. Hydrogen bonding capacity
Hydrogen bonding is another important factor in mucoadhesion of a polymer. Desired
polymers must have functional groups that are able to form hydrogen bonds, and flexibility of
the polymer is important to improve this hydrogen bonding potential. Polymers such as
poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylic acid), as well as all
their copolymers, have good hydrogen bonding capacity (19).
4.1.6.1. Hydration
Hydration is required for a mucoadhesive polymer to expand and create a proper
macromolecular mes of sufficient size, and also to induce mobility in the polymer chains in
order to enhance the interpenetration process between polymer and mucin. Polymer swelling
permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding
and/or electrostatic interaction between the polymer and the mucous network. However, a
critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and
mucoadhesion occurs (19).
4.1.6.2. Charge
Some generalizations about the charge of bioadhesive polymers have been made previously,
where nonionic polymers appear to undergo a smaller degree of adhesion compared to
anionic polymers. Strong anionic charge on the polymer is one of the required characteristics
for mucoadhesion (19). Some cationic polymers are likely to demonstrate superior
mucoadhesive properties, especially in a neutral or slightly alkaline medium. Additionally,
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some cationic high-molecular-weight polymers, such as chitosan, have shown to possess
good adhesive properties. There is no significant literature about the influence of the charge
of the membrane on the mucoadhesion but the pH of the membrane affects the mucoadhesion
as it can influence the ionized or un-ionized forms of the polymers (20).
4.1.6.3. Concentration
The importance of this factor lies in the development of a strong adhesive bond with the
mucous, and can be explained by the polymer chain length available for penetration into the
mucous layer. When the concentration of the polymer is too low, the number of penetrating
polymer chains per unit volume of the mucous is small and the interaction between polymer
and mucous is unstable. In general, the more concentrated polymer would result in a longer
penetrating chain length and better adhesion. However, for each polymer, there is a critical
concentration, above which the polymer produces an "unperturbed" state due to a
significantly coiled structure. As a result, the accessibility of the solvent to the polymer
decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher
concentrations of polymers do not necessarily improve and, in some cases, actually diminish
mucoadhesive properties. One of the studies addressing this factor demonstrated that high
concentrations of flexible polymeric films based on polyvinylpyrrolidone or poly(vinyl
alcohol) as film-forming polymers did not further enhance the mucoadhesive properties of the
polymer (21).
4.2. Environment-Related Factors
4.2.1. pH of polymersubstrate interface
pH can influence the formal charge on the surface of the mucous as well as certain ionizable
mucoadhesive polymers. Mucous will have a different charge density depending on pH due
to the difference in dissociation of functional groups on the carbohydrate moiety and the
amino acids of the polypeptide backbone. Some studies had shown that the pH of the medium
is important for the degree of hydration of cross-linked polycyclic acid, showing consistently
increased hydration from pH 4 through pH 7, and then a decrease as alkalinity or ionic
strength increases, for example polycarbophil does not show a strong mucoadhesive property
above pH 5 because uncharged, rather than ionized, carboxyl group reacts with mucin
molecule, presumably through numerous hydrogen bonds. However, at higher pH, the chain
is fully extended due to electrostatic repulsion of the carboxyl ate anions (17).
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4.2.2. Applied strength

To place a solid mucoadhesive system, it is necessary to apply a defined strength. Whatever
the polymer, poly (acrylic acid/divinyl benzene) or carbopol 934, the adhesion strength
increases with the applied strength or with the duration of its application, up to an optimum.
The pressure initially applied to the mucoadhesive tissue contact site can affect the depth of
interpenetration. If high pressure is applied for a sufficiently long period of time, polymers
become mucoadhesive even though they do not have attractive interactions with mucin (17).
4.2.3. Initial contact time
Contact time between the mucoadhesive and mucous layer determines the extent .of swelling
and interpenetration of the mucoadhesive polymer chains. More mucoadhesive strength
increases as the initial contact time increases (17).
4.3. Physiological Factors

4.3.1. Mucin turnover
The natural turnover of mucin molecules from the mucous layer is important for at least two
reasons. Firstly, the mucin turnover is expected to limit the residence time of the
mucoadhesives on the mucous layer. No matter how high the mucoadhesive strength, they are
detached from the surface due to mucin turnover. The turnover rate may be different in the
presence of mucoadhesives, but no information is available on this aspect. Secondly, mucin
turnover results in substantial amounts of soluble mucin molecules. These molecules interact
with mucoadhesives before they have chance to interact with the mucous layer. Surface
fouling is unfavorable for mucoadhesion to the tissue surface. Mucin turnover may depend on
the other factors such as the presence of food. The gastric mucosa accumulates secreted
mucin on the luminal surface of the tissue during the early stages of fasting. The accumulated
mucin is subsequently released by freshly secreted acid or simply by the passage of ingested
food; the exact turnover rate of the mucous layer remains to be determined. Lehr et al.
calculated a mucin turnover time of 47270 min. The ciliated cells in the nasal cavity are
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known to transport the mucous to the throat at the rate of 5 mm/min. The mucociliary
clearance in the tracheal region has been found to be at the rate of 410 mm/min (17).
4.3.2. Disease state
The physiochemical properties of the mucous are known to change during disease conditions
such as the common cold, gastric ulcers, ulcerative colitis, cystic fibrosis, bacterial, and
fungal infections of female reproductive tract, and inflammatory conditions of the eye. The
exact structural changes taking place in mucous under these conditions are not clearly
understood. If mucoadhesives are to be used in the disease states, the mucoadhesive property
needs to be evaluated under the same conditions (17)
5. POLYMERS USED FOR MUCOADHESIVE DRUG DELIVERY

Mucoadhesive polymers are water-soluble and water insoluble polymers, which are swellable
networks, jointed by cross-linking agents. These polymers possess optimal polarity to make
sure that they permit sufficient wetting by the mucous and optimal fluidity that permits the
mutual adsorption and interpenetration of polymer and mucous to take place. Mucodhesive
polymers that adhere to the musin-epithelial surface can be conveniently divided into three
broad classes:
1. Polymers that become sticky when placed in water and owe their mucoadhesion to
stickiness.
2. Polymers that adhere through nonspecific, noncovalent interactions those are
primarily electrostatic in nature (although hydrogen and hydrophobic bonding may be
significant).
3. Polymers that bind to specific receptor site on tile self surface. All three polymer
types can be used for drug delivery (22).
5.1. Characteristics of an ideal mucoadhesive polymer
1. Polymer must have a high molecular weight upto 100.00 or more this is necessary to
promote the adhesiveness between the polymer and mucous (23).
2. long chain polymers-chain length must be long enough to promote the
interpenetration and it should not be too long that diffusionbecomes a problem
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3. Degree of cross linking- it influences chain mobility and resistance to dissolution.
Highly cross linked polymers swell in presence of water and retain their structure.
Swelling favours controlled release of the drug and increases the polymer/mucous
interpenetration. But as the cross linking increases, the chain mobility decreases
which reduces the mucoadhesive strength (24).
4. Spatial conformation.
5.
Flexibility of polymer chain- this promotes the interpenetration of the polymer within
the mucous network.
6. Optimum hydration- excessive hydration leads to decreased mucoadhesive strength

due to formation of a slippery mucilage.
7. Optimum Ph mucoadhesion is optimum at low pH conditions but at higher pH
values a change in the conformation occurs into a rod like structure making those
more available for inter diffusion and interpenetration.
8. Concentration of the polymer- an optimum concentration is required to promote the
mucoadhesive strength (25).
9. High viscosity
10. The polymer and its degradation products should be nontoxic and should be non
absorable from the gastrointestinal tract.
11. It should be nonirritant to the mucous membrane.
12. It should preferably form a strong noncovalent bond with the mucin-epithelial cell
surfaces.
13. It should adhere quickly to most tissue and should possess some site-specificity.
14. It should allow daily incorporation to the drug and offer no hindrance to its release.
15. The polymer must not decompose on storage or during the shelf life of the dosage
form.
16. The cost of polymer should not be high so that the prepared dosage form remains
competitive (26).
5.2. Classification of Mucoadhesive Polymers
5.2.1. Synthetic polymers
a) Cellulose derivatives (methylcellulose, ethylcellulose, hydroxy-ethylcellulose,
Hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy
methylcellulose.
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b) Poly (acrylic acid) polymers (carbomers, polycarbophil).
c) Poly (hydroxyethyl methylacrylate).
d) Poly (ethylene oxide).
e) Poly (vinyl pyrrolidone).
f) Poly (vinyl alcohol).
5.2.2. Natural polymers
a) Tragacanth
b) Sodium alginate
c) Karaya gum
d) Guar gum
e) Xanthan gum
f) Lectin
g) Soluble starch
h) Gelatin
i) Pectin
j) Chitosan (22).
5.2.3. Hydrophilic Polymers
These are the water-soluble polymers that swell indefinitely in contact with water and
eventually undergo complete dissolution, e.g. Methyl Cellulose, Hydroxyl Ethyl Cellulose,
Hydroxyl Propyl Methyl Cellulose, Sodium Carboxy Methyl Cellulose, Carbomers, Chitosan
and Plant gums (22).
5.2.4. Hydrogels
These are water swellable materials, usually a cross-link polymer with limited swelling
capacity, e.g. poly (acrylic acid co acrylamide) copolymers, carrageenan, sodium alginate,
guar gum and modified guar gum, etc (22).
5.2.5. Thermoplastic Polymers
These polymers include the non-erodible neutral polystyrene and semi-crystalline bioerodible polymers, which generate the carboxylic acid groups as they degrade, e.g.
polyanhydrides and polylactic acid. Various synthetic polymers used in mucoadhesive
formulations include polyvinyl alcohol, polyamides, polycarbonates, polyalkylene glycols,
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polyvinyl ethers, esters and halides, polymethacrylic acid, polymethylmethacrylic acid,
Methyl Cellulose, Hydroxyl Propyl Cellulose, Hydroxyl Propyl Methyl Cellulose, and
Sodium Carboxy Methyl Cellulose. Various biocompatible polymers used in mucoadhesive
formulations include cellulose-based polymers, ethylene glycol polymers and its copolymers,
oxyethylene polymers, polyvinyl alcohol, polyvinyl acetate and esters of hyaluronic acid.
Various biodegradable polymers used in mucoadhesive formulations are poly (lactides), poly
(glycolides), poly (lactide-co-glycolides), polycaprolactones, and polyalkyl cyanoacrylates.
Polyorthoesters, polyphosphoesters, polyanhydrides, polyphosphazenes are the recent
additions to the polymers (27).
5.3. Newer second generation polymers
They have the following advantages

- More site specific hence called cytoadhesives.
- Are least effected by mucous turn over rates.
- Site specific drug delivery is possible.
5.3.1. Thiolated polymers:
The presence of free thiol groups in the polymeric skeleton helps in the formation of
disulphide bonds with that of the cysteine-rich sub-domains present in mucin which can
substantially improve the mucoadhesive properties of the polymers (e.g. poly (acrylic acid)
and chitosan) in addition to the paracellular uptake of the bioactive agents [76-80]. Various
thiolated polymers include chitosaniminothiolane, poly(acrylic acid)cysteine, poly(acrylic
acid)homocysteine,
chitosanthioglycolic
acid,
chitosanthioethylamidine,
alginate
cysteine, poly(methacrylic acid)cysteine and sodium carboxymethylcellulosecysteine (28)

5.3.2. Lectin-based polymers
Lectins are proteins which have the ability to reversibly bind with specific sugar /
carbohydrate residues and are found in both animal and plant kingdom in addition to various
microorganisms. Many lectins have been found to be toxic and immunogenic which may lead
to systemic anaphylaxis in susceptible individuals on subsequent exposure (28). The specific
affinity of lectins towards sugar or carbohydrate residues provides them with specific cytoadhesive property and is being explored to develop targeted delivery systems. Lectins
20

extracted from legumes have been widely explored for targeted delivery systems. The various
lectins which have shown specific binding to the mucosa include lectins extracted from Ulex
europaeus I, soybean, peanut and Lens culinarius (29). The use of wheat germ agglutinin has
been on the rise due to its least immunogenic reactions, amongst available lectins, in addition
to its capability to bind to the intestinal and alveolar epithelium and hence could be used to
design oral and aerosol delivery systems (30)
5.3.3. polyox WSRA
Class of high molecular weight polyethylene molecular weright polyethylene oxide

homopolymers having the following properties:
- water soluble
- hydrophillic nature
- high molecular weight
- functional group for hydrogen bondimg
- biocompatible and non toxic
- can be formulated into tablets, films, gels, microcapsules, syrups (31).
6. COMMON SITES OF APPLICATION FOR MUCOADHESIVE DRUG

DELIVERY SYSTEMS
The primary objectives of mucoadhesive dosage forms are to provide intimate contact of the
dosage form with the absorbing surface and to increase the residence time of the dosage form
at the absorbing surface to prolong drug action. Due to mucoadhesion, certain water-soluble
polymers become adhesive on hydration and hence can be used for targeting a drug to a
particular region of the body for extended periods of time. The mucosa lines a number of
regions of the body including the gastrointestinal tract, the urogenital tract, the airways, the
ear, nose, and eye. These represent potential sites for attachment of any mucoadhesive system
and hence, the mucoadhesive drug delivery system may include the following (32).
1. Gastrointestinal delivery system.
2. Nasal delivery system.
3. Ocular delivery system.
4. Buccal delivery system.
21

5. Vaginal delivery System.
6. Rectal delivery system.
6.1. Gastrointestinal drug delivery system
The idea of mucoadhesives began with the clear need to localize a drug at certain sites in the
GI tract. Therefore, a primary objective of using mucoadhesive systems orally would be
achieved by obtaining a substantial increase in residence time of the drug for local drug effect
and to permit once-daily dosing. A number of mucoadhesive-based dosage forms, including
sustained release tablets, semisolid forms, powders, and micro- and/or nanoparticles in the GI
tract, have been widely studied. Nonetheless, successful systems that will be retained in the
GI tract of humans for a desirable time have not yet been developed (33).
Matharu and Sanghavi used carbopol 934P and poly (acrylic acid) cross linked with 0.001%
ethlene glycol to prepare mucoadhesive tablets for captopril (34). Decrosta et al. also used
carbopol 934P as mucoadhesive substance to prepare captopril sustained-release tablets.
Captopril mixed with carbopol 934P and stearic acid (as lubricant), tableted, could sustain the
release of the drug for up to 16 h or more (35).
6.2. Nasal drug delivery system
Histologically, the nasal mucosa provides a potentially good route for systemic drug delivery.
With a surface area of 150 cm2, a highly dense vascular network, and a relatively permeable
membrane structure, the nasal route has good absorption potential. One of the most important
features of the nasal route is that it avoids first-pass hepatic metabolism, thereby reducing
metabolism (27). Nasal delivery has been obtained using solutions, powders, gels and
microparticles. The most commonly employed intranasal APIs are solutions containing
sympathomimetic vasoconstrictors for immediate relief of nasal congestion. In addition to
local effects, intranasal route of drug administration has also been used to achieve a distal
systemic effect. Polymeric components such as hydroxyl propylcellulose, chitosan, carbomer,
NaCMC, hyaluronic acid and polyacrylic acid have all shown promise as mucoadhesive
agents for use in controlled drug delivery to pulmonary and nasal sites. Such polymeric
delivery platforms may be used either alone or as synergistic combination systems. One of
the most interesting, the use of intranasal drug delivery for the induction of antibody
responses in serum, as well as local and distal mucosal secretions, due to absorption through
the nasal associated lymphoid tissue (36).
22
6.3. Ocular drug delivery system

Mucin is secreted by conjunctival globlet cells, but there are no globlet cells on the cornea.
On this basis, a mucoadhesive polymer will firmly attach to conjunctival mucous but only
loosely, if at all, to corneal mucous.Opthalmic dosage forms can be improved by increasing
the time the active ingredients remain in contact with eye tissues. There are several
mucoadhesive dosage forms that have been developed to this end: liquid systems, in situ
gelling systems, dispersed, systems and solid systems (37). Pre-application these systems are
in the liquid state and are easily administered, whereas post-application they are transformed
in highly viscous networks. Mucoadhesive polymers would be expected only to attach to
conjunctival mucous in vivo, but migration may result in ausing deposition of semisolid
within the corneal area, ringing with it a detrimental effect on visual acuity (36).
6.4. Buccal drug delivery system
Because of the presence a smooth and relatively immobile surface for placement of a
mucoadhesive dosage form, the buccal region appears to be more suitable for sustained
delivery of therapeutic agents using mucoadhesive systems. The buccal and sublingual routes
avoid firstpass metabolism. These regions consist of a nonkeratinized epithelium, resulting in
a somewhat more permeable tissue than the skin. Therefore, drugs with a short biological
half-life requiring a sustained release effect and exhibiting poor permeability, sensitivity to
enzymatic degradation, or poor solubility may be good candidates to be delivered via the oral
cavity. Relevant mucoadhesive dosage forms for the oral cavity include gels, patches, tablets,
and
ointments
(38).
First-generation
mucoadhesives,
such
as
sodium
carboxy
methylcellulose, hydroxypropylcellulose examined for the treatment of periodontal disease

and the controlled delivery of macromolecular therapeutic agents, such as peptides, proteins
and polysaccharides (39).
6.5. Vaginal drug delivery system
Recently, vaginal mucoadhesive preparations have been developed as a new type of
controlled release form for the treatment of both topical and systemic diseases. For drugs that
are susceptible to gut or hepatic metabolism or which cause GI side effects, vaginal delivery
may offer a number of advantages over the other routes of administration. The greatest
advantage of such dosage forms is the possibility of maintaining them in the vagina for
extended periods of time including daytime and nighttime, thereby enabling lower dosing
23

frequencies. The vagina is a fibromuscular tube connecting the uterus to the exterior of the
body. The surface area of the vagina is increased by numerous folds in the epithelium and by
microridges covering the epithelial cell surface. Among the polymers, polyacrylic acid and
hydroxypropyl methyl cellulose are the ideal excipient in mucoadhesive strength. In general,
traditional vaginal dosage forms include solutions, suspensions, gels, microparticles,
suppositories, creams, foams, and tablets and all have a relatively short contact time.
Robinson et al. reported on a system of treatment using a gel containing the mucoadhesive
polycarbophil that remained on vaginal tissue for 3-4 days and hence served as a platform for
delivery of drug such as progesterone (40).
6.6. Rectal drug delivery system
Another way to deliver the drug by using mucoadhesive polymers is through the mucous
membrane of the rectum. Hydrogels administered rectally have proven to be useful for drug
delivery. Hydrogels such as using hydroxy ethyl methacrylate crosslinked with ethylene
glycol dimethacrylate and including antipyrine and theophyiline as model drugs provided
rate-controlled drug delivery (36).
7. DIFFERENT MUCOADHESIVE DOSAGE FORMS

7.1. Solid dosage forms
7.1.1. Tablets
Tablets are small, flat, and oval, with a diameter of approximately 5-8 mm. Unlike the
conventional tablets, mucoadhesive tablets allow for drinking and speaking without major
discomfort. They soften, adhere to the mucosa, and are retained in position until dissolution
and/or release is complete. Mucoadhesive tablets, in general, have the potential to be used for
controlled release drug delivery, but coupling of mucoadhesive properties to tablet has
additional advantages, for example, it offers efficient absorption and enhanced bioavailability
of the drugs due to a high surface to volume ratio and facilitates a much more intimate
contact with the mucous layer. Mucoadhesive tablets can be tailored to adhere to any mucosal
tissue including those found in stomach, thus offering the possibilities of localized as well as
systemic controlled release of drugs. The application of mucoadhesive tablets to the mucosal
tissues of gastric epithelium is used for administration of drugs for localized action.
Mucoadhesive tablets are widely used because they release the drug for a prolonged period,
24

reduce frequency of drug administration and improve the patient compliance. The major
drawback of mucoadhesive tablets is their lack of physical flexibility, leading to poor patient
compliance for long-term and repeated use. (41).
Bioadhesive vaginal tablets are relatively easy and inexpensive to manufacture. They are
characterized by a greater irritation effect and a smaller contact area with mucosa in
comparison with mucoadhesive gels, but on the other hand, they should show a more
prolonged residence time at the application site. Different tablets have been investigated for
their capability to adhere to cow vaginal mucosa and their swelling properties (42). They
consisted of Carbopol 934, polyvinylpyrrolidone, pectin, and ethylene maleic anhydride
resins and their mixtures. The most favorable formulation was that based on a mixture of
Carbopol 934 and pectin in a 2:1 weight ratio, which showed the highest bioadhesive strength
and swelling volume and the lowest vaginal pH reduction.n Polycarbophil-based bioadhesive
tablets of metronidazole were tested for adhesion on bovine submaxillary mucin (43). To
achieve more effective treatment of vaginal candidosis, ketoconazole was formulated in
bioadhesive tablets that increase the time of contact of drug with the vaginal mucosa and thus
its therapeutic effect. The tablets were based on sodium carboxymethylcellulose (NaCMC),
polyvinylpyrrolidone, or HPMC (44).
7.1.2. Microparticles
Physical properties of microparticles enable them to make intimate contact with a lager
mucosal surface area. They 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 (45). Application of bioadhesive microspheres
to the mucosal tissues of ocular cavity, gastric and colonic epithelium is used for
administration of drugs for localized action. Prolonged release of drugs and a reduction in
frequency of drug administration to the ocular cavity can highly improve the patient
compliance (46). The latter advantage can also be obtained for the drugs administered
intranasally due to the reduction in mucociliary clearance of drugs adhering to nasal mucosa.
Microspheres prepared with bioadhesive and bioerodible polymers undergo selective uptake
by the M cells of Peyer patches in gastrointestinal (GI) mucosa. This uptake mechanism has
been used for the delivery of protein and peptide drugs, antigens for vaccination and plasmid
DNA for gene therapy. Moreover, by keeping the drugs in close proximity to their absorption
25

window in the GI mucosa, the bioadhesive microspheres improve the absorption and oral
bioavailability of drugs like furosemide and riboflavin (46).
7.1.3. Wafers
Drug delivery system intended for the treatment of microbial infections associated with
peridontitis. The delivery system is composite wafer with surface layers possessing adhesive
properties, while the bulk layer consists of antimicrobial agents, biodegradable polymers and
matrix polymers (47).
7.1.4. Lozenges
Lozenges used topically within the mouth including antimicrobials, corticosteroids, local
anesthetics, antibiotics and antifungals. Conventional lozenges produce a high initial release
of drug in oral cavity, which rapidly declines to sub-therapeutic levels, thus multiple daily
dosing is required. A slow release bioadhesive lozenge offers potential for prolonged drug
release with improved patient compliance. Codd and Deasy investigated bioadhesive
lozenges as a means to deliver antifungal agents to the oral cavity (48).
7.2. Semi-solid dosage forms

7.2.1. Gels
Crosslinked polyacrylic acid is a gel forming bioadhesive polymers adhere to mucosal
surfaces for extended periods of time and provide controlled release release of drug at the
absorption site. A limitation of gels is their inability to deliver a measured dose of drug to the
site. A novel, hydrogel based, bioadhesive, intelligent response system for controlled drug
release. This system combined several desirable facets into a single formulation; a poly
(hydroxyethyl methacrylate) layer as barrier, poly (methacrylic acid-g-ethylene glycol) as a
biosensor and poly (ethyleneoxide) to promote mucoadhesion (49).
The application of mucoadhesive gels provides an extended retention time in the oral cavity,
adequate drug penetration, as well as high efficacy and patient acceptability. A major
application of adhesive gels is the local delivery of medicinal agents for the treatment of
periodontitis, which is an inflammatory and infectious disease that causes formation of
pockets between the gum and the tooth, and can eventually cause loss of teeth. It has been
26

suggested that mucoadhesive polymers might be useful for periodontitis therapy when
incorporated in antimicrobial-containing formulations that are easily introduced into the
periodontal pocket with a syringe (50).
Recently, a new bioadhesive gel, Acidform (Conrad, Arlington, VA, USA), was designed with
acid-buffering and viscosity-retaining properties to maintain the acidic vaginal milieu (the
low pH inactivates many pathogens and spermatozoa), to form a protective layer over the
vaginal epithelium (minimizing the contact with pathogenic organism), and to provide longterm vaginal retention. Acid-buffering, bioadhesive, viscosity retaining, and spermicidal
properties of Acidform were compared in vitro with those of marketed formulations (51).
7.2.2. Patches or Films
Patches are laminates consisting of an impermeable backing layer, a drug-containing
reservoir layer from which the drug is released in a controlled manner, and a mucoadhesive
surface for mucosal attachment. Patch systems are similar to those used in transdermal drug
delivery. Two methods used to prepare adhesive patches include solvent casting and direct
milling. In the solvent casting method, the intermediate sheet from which patches are
punched is prepared by casting the solution of the drug and polymer(s) onto a backing layer
sheet, and subsequently allowing the solvent(s) to evaporate. In the direct milling method,
formulation constituents are homogeneously mixed and compressed to the desired thickness,
and patches of predetermined size and shape are then cut or punched out. An impermeable
backing layer may also be applied to control the direction of drug release, prevent drug loss,
and minimize deformation and disintegration of the device during the application period (52).
Patches or films may be used to deliver drugs directly to a mucosal membrane. They also
offer advantages over creams and ointments in that they provide a measured dose of drug to
the site. Buccal adhesive films are already in use commercially for example, Zilactin used for
the therapy of canker sores, cold sores and lip sores (53).
Bioadhesive films based on mixtures of chitosan and polyacrylic acid and intended for
vaginal delivery of acyclovir were recently developed in our laboratory. Such films showed
good mucoadhesive properties and the capability, depending on the polymer-mixing ratio, of
enhancing drug penetration into pig vaginal mucosa. Moreover, they were capable of
27

prolonging drug release and were characterized by elastic properties, which make them
resistant towards mechanical stress (54).
7.3. Liquid dosage forms
In case of ocular drug delivery need to increase the viscosity and reduce the drainage rate and
subsequently increase the therapeutic rate. Mucosal surface coat by viscous liquids either
protectants or drug vehicles for delivery to the mucosal surface. Cellulose derivative,
acrylates, chitosan, thiomers are use as a effective mucoadhesive polymer for liquid dosage
form. Traditionally, pharmaceutically acceptable polymers used to enhance the viscosity of
products to aid their retention in the oral cavity. Dry mouth is treated with artificial saliva
solutions that are retained on mucosal surfaces to provide lubrication. These solutions contain
sodium CMC as bioadhesive polymer (55).
8. TECHNIQUES FOR THE DETERMINATION OF MUCOADHESION

The evaluation of bioadhesive properties is fundamental to the development of novel
bioadhesive delivery systems. These tests are also important to screen large number of
materials and their mechanisms. Numerous methods have been developed for studying
mucoadhesion. Since no standard apparatus is available for testing bioadhesive strength, an
inevitable lack of uniformity between test methods has arisen. Nevertheless, the main testing
modes are recognized
8.1. In vitro Methods
8.1.1. Tensile test
8.1.2. Shear strength
8.1.3. Peel strength
8.1.4. Rheological methods
8.1.5. Falling Liquid Film Method
28

8.1.6. In Vitro residence time
8.2. In vivo Methods
8.1. In vitro Methods
8.1.1. Tensile strength
The most popular technique used for the determination of force of separation in bioadhesive
testing is the application of force perpendicularly to the tissue/adhesive interface, during
which a state of tensile stress is set up (56).
The force most frequently evaluated in such tests is rupture tensile strength. Generally, the
equipment used is a texture analyzer or a universal testing machine. In this test, the force
required to remove the formulation from a model membrane is measured, which can be a disc
composed of mucin, a piece of animal mucous membrane, generally porcine nasal mucous or
intestinal mucous from rats. Based on results, a force-distance curve can be plotted which
yields the force required to detach the mucin disc from the surface with the formulation, the
tensile work (area under the curve during the detachment process), the peak force and the
deformation to failure. This method is more frequently used to analyze solid systems like
microspheres, although there are also studies on semi-solid materials (57).
Figure 8: Measurement of mucoadhesive tensile strength with an automatic surface tensiometer.
8.1.2. Shear strength

Mucoadhesion strength can also be measured in terms of shear strength. This test measures
the force required to separate two parallel glass slides covered with the polymer and with a
29

mucous film (58). This can also be done using Wilhemys model, in which a glass plate is
suspended by a microforce balance and immersed in a sample of mucous under controlled
temperature. The force required to pull the plate out of the sample is then measured under
constant experimental conditions. Although measures taken by this method are reproducible,
the technique involves no biological tissue and therefore does not provide a realistic
simulation of biological conditions (59).
Figure 9: Apparatus to determine mucoadhesion in vitro, using Wilhemys technique.
8.1.3. Peel Test

The peel test is based on the calculation of energy required to detach the patch from the
substrate. The peel test is of limited use in most bioadhesive systems. However, it is of
value when the bioadhesive system is formulated as a patch (60).
30
Figure 10: Simplified representation of a typical test set-up used to determine peel strength of bioadhesive
films.
8.1.4. Rheological methods

Rheological techniques that study the flow and deformation of materials may be useful in
predicting the mucoadhesive ability of a polymeric formulation. A simple rheological
approach for polymer solutions and gels was first suggested by Hassan and Gallo (61).
In this method, rheological interaction between a polymer gel and mucin solution was
determined. It was shown that a polymer gel and mucin solution mixture exhibited larger
rheological response than the sum of the values of polymer and mucin. However, a wide
variation in results is found in the literature that utilizes rheological methods for
mucoadhesion determination, which may be attributable to differences in mucin type and
concentration, as well as polymer concentrations. Therefore, Hagerstrom recommend that the
rheological method should not be used as a stand-alone method for studying the
mucoadhesive properties of the polymer gels (62).
8.1.5. Falling Liquid Film Method

In this method the chosen mucous membrane is placed in a stainless steel cylindrical tube,
which has been longitudinally cut. This support is placed inclined in a cylindrical cell with a
temperature controlled at 37 C. An isotonic solution is pumped through the mucous
membrane and collected in a beaker (63).Subsequently, in the case of particulate systems, the
amount remaining on the mucous membrane can be counted with the aid of a coulter counter.
For semi-solid systems, the non adhered mucoadhesive can be quantified by high
performance liquid chromatography. In this later case, porcine stomach, intestinal and buccal
mucous were tested, and also jejunum from rabbits. The validation of this method showed
that the type of mucous used does not influence the results. The release systems tested were
precursors of liquid crystals constituted by monoglycerides. This methodology allows the
31

visualization of formation of liquid-crystalline mesophase on the mucous membrane after the
flowing of the fluids and through analysis by means of polarized light microscopy (57).
Figure 11: Schematic representation of in vitro model of Falling Liquid Film Method.
8.1.6. In vitro residence time

It carried out by using modified USP disintegration apparatus as shown in. The disintegration
medium composed of 800 ml isotonic phosphate buffer pH 6.75 maintained at 37 C.
Segment of rabbit intestinal mucosa, 3 cm long, was stick to the surface of a glass slab,
vertically attached to the apparatus. The mucoadhesive tablet was hydrated from one surface
using 15 ml isotonic phosphate buffer 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 thetablet from the mucosal surface was recorded (64).
32
Figure 12: Schematic diagram of the apparatus used for determination of residence time.
S: glass slab; D: disintegration apparatus M: mucosal membrane; T: mucoadhesive tablet;
IBP: isotonic phosphate buffer
8.2. In vivo Methds

In vivo aspects of mucoadhesive testing have recently been reported to monitor the
mucoadhesion on tissue surface such as the GIT or the buccal cavity. However, there are only
a limited number of in vivo studies reported in the literature in vitro work because of the time,
cost, and ethical constrains. The most common in vivo techniques to monitor mucoadhesion
include GI transit times of bioadhesive-coated particles and drug release from in situ
bioadhesive devices.
33

Ch'ng studied the in vivo transit time for bioadhesive beads in the rat GIT. A 51Cr-labeled
bioadhesive was inserted at selected time intervals; the GITs were removed. The GIT of the
rat was then cut into 20 equal segments and the radioactivity was measured.
Davis investigated the noninvasive in vivo technique to determine the transit of mucoadhesive
agent. Therefore, in this study a formulation was used containing a gamma-emitting
radionuclide. The release characteristics and the position polymer could be examined by
gamma scintigraphy. In recent times, magnetic resonance imaging (MRI) is another
noninvasive technique that is widely used. Christian Kremser used MRI to detect the time
and location of release of mucoadhesive formulation using dry Gd-DOTA powder. (65)
9. RECENT ADVANCES IN MUCOADHESIVE DRUG DELIVERY

SYSTEMS
For optimal buccal mucoadhesion, Shojaei and Li have designed, synthesised and
characterised a copolymer of PAA and PEG monoethylether monomethacrylate (PAA-coPEG) (PEGMM). By adding PEG to these polymers, many of the shortcomings of PAA for
mucoadhesion, outlined earlier, were eliminated. Hydration studies, glass transition
temperature, mucoadhesive force, surface energy analysis and effect of chain length and
molecular weight on mucoadhesive force were studied. The resulting polymer has a lower
glass transition temperature than PAA and exists as a rubbery polymer at room temperature.
Copolymers of 12 and 16-mole %PEGMM showed higher mucoadhesion than PAA. The
effects of hydration on mucoadhesion seen by the copolymers revealed that film containing
lower PEGMM content, which had higher hydration levels, had lower mucoadhesive
strengths. The 16-mole %PEGMM had the most favourable thermodynamic profile and the
highest mucoadhesive forces. Polymersinvestigated in this study also showed that the
molecular weight and chain length had little or no effect on the mucoadhesive force (66).
Novel polymers of PAA complexed with PEGylated drug conjugate were investigated by
Lele, et al. Only a carboxyl group containing drugs such as indomethacin could be loaded
into the devices made from these polymers. An increase in the molecular weight of PEG in
these copolymers resulted in a decrease in the release of free indomethacin, indicating that
drug release can be manipulated by choosing different molecular weights of PEG (67).
34
A new class of hydrophilic pressure-sensitive adhesives (PSAs) that share the properties of
both hydrophobic PSAs and bioadhesives has been developed by Corium Technologies.
These Corplex adhesive hydrogels have been prepared by non-covalent (hydrogen bond)
cross-linking of a film-forming hydrophilic polymer (for example PVP) with a short-chain
plasticizer (typically PEG) bearing complementary reactive hydroxyl groups at its chain ends.
Owing to the appreciable length and flexibility of PEG chains, a relatively large space can be
provided for a stoichiometric complex and a carcass-like structure. The specific balance
between enhanced cohesive strength and large free volume in PVPPEG miscible blends
influences their PSA behaviour. Properties of these hydrophilic PSA hydrogels prepared by
the carcass-like cross-linking method can be modified using a polymer with complementary
reactive groups to form ladder-like cross-links with PVP.
Thus, these Corplex PSA hydrogels have a broad range of unique adhesive/cohesive
properties that enable topical and drug delivery systems to be applied to either skin or
mucosa. An AB block copolymer of oligo(methyl methacrylate) and PAA has been
synthesised for prolonged mucosal drug delivery of hydrophobic drugs. These block
copolymers form micelles in an aqueous medium, which was confirmed by a fluorescence
probe technique using pyrene. A model drug, doxorubicin hydrochloride, when incorporated
into these micelles, results in its release being prolonged at a slower rate (68).
Polymers with thiol groups were also investigated as a new generation of mucoadhesive
polymers. A study conducted by Bernkop-Schnurch, et al. demonstrated that introduction of a
sulphahydryl group increased the adhesive properties of mucoadhesive polymers. In this
study, cysteine was attached covalently to polycarbophil by using carbodiimide as a mediator,
forming amide bonds between the primary amino group of the amino acid and the carboxylic
acid moieties of the polymer. The results showed that there was considerable improvement in
the overall behaviour of adhesion and adhesive properties when tested on porcine intestinal
mucosa at a pH level above five (69).
In addition, mucoadhesive microspheres were studied recently by Bogataj, et al. for
application in the urinary bladder. The microspheres were prepared by a solvent evaporation
method using Eudragit RL or hydroxypropylcellulose as matrix polymers. In another study,
microspheres with a Eudragit RS matrix polymer and different mucoadhesive polymers, i.e.
35

chitosan hydrogen chloride, sodium salt of carboxymethyl cellulose and polycarbophil were
prepared and found to be useful as platforms for oral peptide delivery, with a high capacity of
binding to bivalent cations, which are essential cofactors for intestinal proteolytic enzymes
(70).
10. CONCLUSION
With the great influx of new molecules stemming from drug research, mucoadhesive systems
may play an increasing role in the development of new pharmaceuticals. The focus of
pharmaceutical research is being steadily shifted from the development of new chemical
entities to the development of novel drug delivery system (NDDS) of existing drug molecule
to maximize their effect in terms of therapeutic action and patient protection. Mucoadhesive
drug delivery systems offer unique carrier system for many pharmaceuticals and can be
tailored to adhere to any mucosal tissue, including those found in oral cavity and
gastrointestinal tract.
Current use of mucoadhesive polymers to increase contact time for a wide variety of drugs
and routes of administration has shown dramatic improvement in both specific therapies and
more general patient compliance. Mucoadhesive polymers may provide an important tool to
improve the bioavailability of the active agent by improving the residence time at the delivery
site. The various sites where mucoadhesive polymers have played an important role include
buccal cavity, nasal cavity, rectal lumen, vaginal lumen and gastrointestinal tract.
Development of novel mucoadhesive delivery systems are being undertaken so as to
understand the various mechanism of mucoadhesion and improved permeation of active
agents.
The most widely studied and accepted polymers for mucoadhesion have been the hydrophilic,
high molecular weight, anionic molecules like carbomers. Recently the focus has been on the
novel second generation polymers like the thiolated polymers, lectins and lecithin. The
second generation mucoadhesive polymer is enormous, since they have revolutionized the
concept of mucoadhesion through new findings arising from basic research on these new
compounds.
Novel mucadhesive delivery system, where the drug delivery is directed towards mucous by
protecting the local environment is also gaining interest. The future direction of
36

mucoadhesive drug delivery lies in vaccine formulations and delivery of small proteins and
peptides. Microparticulate mucodhesive 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.
Although significant advances have been made in the field of mucoadhesives, there are still
many challenges ahead in this field of particular importance is the development of universally
acceptable standard evaluation methods and development of newer site directed polymers.
Efforts have been initiated on these lines in the form of novel techniques for evaluation of
mucoadhesive strength of tablets to specific cell types. Polymeric science needs to be
explored to find newer mucoadhesive polymers with the added attributes of being
biodegradable, biocompatible, mucoadhesive for specific cells or mucosa and which could
also function as enzyme inhibitors for the successful delivery of proteins and peptides.
37
11. REFERENCE
1) Wise DL. Handbook of pharmaceutical controlled release technology. Marcel
Dekker, New York, 2000; p. 890.
2) Smart JD. The basics and underlying mechanisms of mucoadhesion. Advance Drug
Delivery Reviews, 2005; v.57 (11), p.1556- 1568.
3) Ganga S. Mucosal drug delivery a review, Pharmaceutical reviews, 2007, v. 5 (6).
4) Woodley, J. Bioadhesion, new possibilities for drug administration? Clinical
Pharmacokinetics, 2001; v.40 (2), p.77-84.
5) Huang Y, Leobandung W, Foss A, Peppas NA. Molecular aspects of muco- and
bioadhesion: tetheres structures and site-specific surfaces. Journal of Controlled
Release, 2000; v.65 (1), p.63-71.
6) Shin SC, Lee JW, Yang KH, Lee CH. Preparation and evaluation of bioadhesive
benzocainegels for enhanced local anesthetic effects. International Journal of
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Mucoadhesive Drug Delivery Systems

Mucoadhesive Drug Delivery Systems

Figure 1: Mucous membrane structure

1.2. Functions of Mucous Layer

Mucoadhesive Drug Delivery Systems

Easy of administration and termination of therapy in emergency.

Permits localization of the drug for a prolonged period of time.

Can be administered to unconscious and trauma patients.

It offers a passive system for drug absorption.

It allows for the local modification of tissue permeability, inhibition of protease

Flexibility in physical state, shape, size and surface.

It satisfies several futures of the controlled release system.

Mucoadhesive Drug Delivery Systems

Systemic absorption is rapid.

Less dosing frequency.

Shorter treatment period.

Maximum utilization of drug enabling reduction in total amount of drug administered.

Improved patient convenience and compliance due to less frequent drug

Drugs which are unstable at buccal pH cannot be administered.

Drugs which irritate the mucosa or have a bitter or unpleasant

Only drug with small dose requirement can be administered.

Only those drugs which are absorbed by passive diffusion can be

Eating and drinking may become restricted.

There is an ever present possibility of the patient swallowing the

Mucoadhesive Drug Delivery Systems

Over hydration may leads to slippery surface and structural

Mucoadhesive Drug Delivery Systems

Figure 2: Wetting and Swelling of Polymer

Mucoadhesive Drug Delivery Systems

Figure 3: Inter diffusion and Interpenetration of Polymer and Mucous

2.3. Formation of Chemical bonds between the entangled chains

Figure 4: Entanglement of Polymer and Mucous by Chemical bonds

3. MUCOADHESION THEORIES OF POLYMER ATTACHMENT

Mucoadhesive Drug Delivery Systems

3.1. The Wetting theory

0, can be calculated from the difference between the surface

Figure 5: Influence of contact angle on mucoadhesion

3.2. The Diffusion theory

Mucoadhesive Drug Delivery Systems

Figure 6: Secondary interaction between mucoadhesive device and of mucous

3.3. The Fracture theory

Mucoadhesive Drug Delivery Systems

Figure 7: Fractures occurring for mucoadhesion

3.4. The electronic theory

Mucoadhesive Drug Delivery Systems

Mucoadhesive Drug Delivery Systems

4. FACTORS AFFECTING MUCOADHESION

Mucoadhesive Drug Delivery Systems

Mucoadhesive Drug Delivery Systems

Mucoadhesive Drug Delivery Systems

Mucoadhesive Drug Delivery Systems

4.2.2. Applied strength

4.3. Physiological Factors

Mucoadhesive Drug Delivery Systems

5. POLYMERS USED FOR MUCOADHESIVE DRUG DELIVERY

Mucoadhesive Drug Delivery Systems

6. Optimum hydration- excessive hydration leads to decreased mucoadhesive strength

Mucoadhesive Drug Delivery Systems

Mucoadhesive Drug Delivery Systems

They have the following advantages

5.3.1. Thiolated polymers:

cysteine, poly(methacrylic acid)cysteine and sodium carboxymethylcellulosecysteine (28)

Mucoadhesive Drug Delivery Systems