Review Article

Review on Mucoadhesive Drug Delivery System:

Novel Approaches in Modern Era
Arshad Bashir Khan*, Rajat Mahamana, Emili Pal
Department of Pharmaceutics, Krupanidhi College of Pharmacy, #12/1, Chikkabellandur, Carmelaram Post, Bangalore- 560035,
Karnataka, India.

ABSTRACT
Purpose: This review article has been written with a purpose of providing extensive information regarding the theoretical
considerations, mucoadhesive polymers and evaluation of mucoadhesive drug delivery system. It would be beneficial
to the researchers working in this field. Approach: The anatomy and physiology of the mucosa is briefly discussed,
followed by the elucidation of various theories of mucoadhesion. The properties of various mucoadhesive polymers
have been discussed. The potential advantages and disadvantages have also been highlighted. Findings: The success
and degree of mucoadhesion is influenced by various polymer-based properties such as the degree of cross-linking,
chain length and the presence of various functional groupings. Conclusion: Mucoadhesive drug delivery system offer
close contact with the absorption tissue, the mucous membrane, releasing the drug at the site of action leading to an
increase in bioavailability and greater local and systemic effects.
Key words: Bioadhesion, Buccal Mucoadhesive drug delivery, Mucoadhesive theories, Mucoadhesion, mucosa.

INTRODUCTION
Oral delivery has so far been the most Mucoadhesive substances could also be used Received Date : 29-10-2014
common and preferred route of adminis- as therapeutic agents in their own right, to Revised Date : 12-12-2014
Accepted Date : 17-12- 2014
tration for most of the therapeutic agents. coat and protect and soothe the injured tis-
The popularity of the oral route has been sues (gastric ulcers or lesions of the oral DOI: 10.5530/rjps.2014.4.2
attributed to the patient acceptance, ease mucosa) or as lubricants (in the oral cavity, Address for
of administration, accurate dosing, cost eye and vagina).5
correspondence
Dr. Arshad Bashir Khan,
effective manufacturing method, least ste- Associate Professor,
rility constraints, flexible design of dosage Department of
forms and generally improved shelf-life of MECHANISM OF MUCOADHESION Pharmaceutics,
Krupanidhi College of
the product.1,2 Mucoadhesion is a complex process involv- Pharmacy,
#12/1, Chikkabellandur,
Mucoadhesive drug delivery has been a ing wetting, adsorption and interpenetra- Carmelaram Post,
topic of interest in the design of drug deliv- tion of polymer chains. Mucoadhesion is Bangalore - 560035,
ery systems to lengthen the residence time established in the following stages:
Karnataka, India.
Phone No: +919740379897
of the dosage form at the site of application E-mail: arbakh@gmail.com
or absorption and to facilitate intimate con- • Contact stage: Intimate physical con-
tact of the formulation with the underlying tact between a bioadhesive/Mucoadhesive
absorption surface, so as to improve and material and a membrane (wetting or swell-
enhance the bioavailability of drug. Muco- ing phenomenon).
adhesive controlled drug delivery systems
are beneficial, since they give a controlled • Consolidation stage: Penetration of the
drug release over a period of time and can bioadhesive/Mucoadhesive into underlying
also be utilized for localizing the drug to a the tissue or into the surface of the mucous
specific site in the body.3,4 membrane (interpenetration).6 www.rjps.in

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 Arshad et al.: Review on Mucoadhesive Drug Delivery System

Mucoadhesion and bioadhesion mucin glycoproteins are the most important structure-
Mucoadhesion may be defined as a state in which two forming component of the mucus gel, which provide
components, of which one is of biological source, are the mucous with its characteristic gel-like, cohesive and
joined together for prolonged periods of time by the adhesive properties. The thickness of this mucus layer
aid of interfacial forces. ‘Bioadhesion’ broadly includes varies at different mucosal surfaces, from 50 to 450 μm
adhesive interactions with any biological or biologically in the stomach, to less than 1 μm in the oral cavity. The
derived substance, whereas ‘Mucoadhesion’ is used major functions of mucus include protection and lubri-
when the bond is formed with a mucosal surface, while cation (anti adherents).10-12
the term cytoadhesive means adhesion to cells. Muco- Composition of mucus layer
adhesive drug delivery systems are also a sub- type of
gastro- retentive drug delivery systems. In the formu- Mucus is translucent and viscous secretion which forms
lation of oral controlled-release dosage forms, signifi- a thin, continuous gel layer sticking to the mucosal epi-
cant benefits may follow from the use of mucoadhesive thelial surface. Mucus glycoprotiens are high molecular
polymers providing brief adhesion between the drug weight proteins possessing attached oligosaccharide
delivery system and the mucous or epithelial cell surface units containing, L-fucose, D-galactose, N-acetyl-D-glu-
of the alimentary canal. The bond between polymer and cosamine, N-acetyl-D-galactosamine and Sialic acid10-12
mucous membrane involves secondary forces, such as Functions of mucous layer
hydrogen bonds or Van der Waals forces. Mucoadhe-
• Mucous layer is protective because of its hydropho-
sives may, therefore, be regarded as a specific class of
bicity.
bioadhesives.
• It influences the bioavailability of drugs as it acts as a
Mucoadhesive/biodhesive drug delivery system can be barrier in tissue absorption of drugs and other sub-
applied to the following systems: strates.
• Buccal delivery system • It strongly bonds with the epithelial cell surface as a
continuous gel layer.
• Oral delivery system
• It plays a major role in the lubrication of the mucosal
• Vaginal delivery system membrane and maintenance of its moisture.10-12
SITES FOR MUCOADHESIVE DRUG DELIVERY
• Rectal delivery system SYSTEM
• Nasal delivery system The common sites for mucoadhesive drug delivery sys-
tems include oral cavity, eye conjunctiva, vagina, nasal
• Ocular delivery system6-9 cavity and gastrointestinal tract.
• The buccal cavity has a very limited surface area of
MUCOUS MEMBRANES
around 50 cm2 but the accessibility of the site makes it a
Mucous membranes (mucosae) are the moist surfaces, preferred location for delivering therapeutic agents. Deliv-
lining the walls of various body cavities such as the gas- ery through this site avoids hepatic first-pass metabolism
trointestinal and respiratory tracts. They consist of a in addition to the local treatment of the oral infections.
connective tissue layer (the lamina propria) above which The sublingual mucosa is relatively more permeable than
is an epithelial layer, the upper part of which is made the buccal mucosa; hence formulations for sublingual
moist usually due to the presence of a mucus layer. The delivery are formulated to release the active agent immedi-
epithelia may be either single layered (e.g. the stomach, ately. The mucoadhesive formulation is of importance for
small and large intestine and bronchi) or multilayered/ the delivery of active agents to the buccal mucosa where
stratified (e.g. in the oesophagus, vagina and cornea). the active agent has to be released in a controlled manner.
The former contain goblet cells which secrete mucus Hence, the buccal cavity is more suitable for mucoadhe-
directly onto the epithelial surfaces, the latter contain, sive drug delivery.
or are adjacent to tissues containing, specialized glands
such as salivary glands that secrete mucus onto the epi- • Nasal cavity also offers a potential site for the
thelial surface. Mucus is present as either a gel layer designing of formulations using mucoadhesive polymers.
sticking to the mucosal surface or as a soluble or sus- The nasal mucosa has a surface area of about150-200 cm2
pended lumenal entity. The primary components of all but the residence time of a particulate matter in the nasal
mucus gels are mucin glycoproteins, lipids, inorganic mucosa varies between 15 and 30 min. This short time is
salts and water, the latter comprising more than 95% due to the increased activity of the mucociliary layer due
of its weight, making it a highly hydrated system. The to stimulation by foreign particles.
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 Arshad et al.: Review on Mucoadhesive Drug Delivery System

• Ophthalmic mucoadhesive drug delivery is also of • Drugs, which are unstable at buccal pH, cannot be
great interest. Due to the continuous formation of tears administered by this route.
and blinking of eye lids there is a rapid removal of the • Only drugs with small dose requirements can be
active medicament from the ocular cavity, which results administered.
in the poor bioavailability of the active agents which can • Drugs may be swallowed along with the saliva and
be reduced by delivering the drugs using ocular inserts or lose the advantages of buccal route.
patches. • Only those drugs, which are absorbed by passive dif-
fusion, can be administered by this route.
• The vaginal and the rectal lumen have also been
• Eating and drinking may become restricted.
explored for the delivery of the active agents both sys-
• In case of vaginal drug delivery, the drug has to be
temically and locally. The active agents meant for the sys-
stable in the acidic vaginal pH.
temic delivery by this route of administration bypasses
• The vaginal formulation may interfere with sexual
the hepatic first-pass metabolism. Quite often the delivery
intercourse.
systems suffer from migration within the vaginal/rectal
• The vaginal formulation may leak and cause messi-
lumen which might affect the delivery of the active agent
ness.
to the specific location. This can be overcome by applying
• The vaginal formulation may be contraindicated in
the principles of mucoadhesion.
case of pregnancy.
• Gastrointestinal tract is also a potential site which • In case of ocular formulations, the formulation may
has been explored since long for the development of cause uneasiness and blurring.
mucoadhesive based formulations. The manipulation of • It may get dislodged.
the transit time of the delivery systems in a particular area • In case of nasal formulations, the presence of the
of the gastrointestinal system by using mucoadhesive formulation may stimulate sneezing and subsequent
polymers has evinced a great interest among researchers dislodgement of the formulation.
around the world.13-20 • The formulation may irritate the sensitive nasal
mucosa.
ADVANTAGES OF MUCOADHESIVE DRUG • Over hydration may lead to the formation of slip-
DELIVERY SYSTEM pery surface and structural integrity of the formula-
Mucoadhesive delivery system offers several advantages tion may get disrupted by the swelling and hydration
over conventional drug delivery systems which are as of the bioadhesive polymers.6,21,22
follows: THEORIES OF MUCOADHESION
• Prolongs the residence time of the dosage form at Many theories have been hypothesized for explaining
the site of absorption, hence increases the bioavail- mucoadhesion, although the chemical and physical basis
ability. of mucoadhesion is not yet clearly understood. There
• Excellent accessibility, rapid onset of action possible. are six classical theories which have resulted from stud-
• Rapid absorption because of enormous blood sup- ies on the performance of several materials and poly-
ply and good perfusion rates. mer- polymer adhesion. The contact angle and time of
• An alternative to oral route, whereby the drug is pro- contact plays a significant role in mucoadhesion. Figure
tected from degradation in the acidic environment of
1 depicts the various theories of mucoadhesion.
the GIT.
• Better patient compliance. Wetting theory
• Moreover, rapid cellular recovery and healing of the The ability of a bioadhesive or mucous to spread and
local site. develop intimate contact with its corresponding sub-
• Reduced dosing frequency. strate is a major factor in bond formation. The affinity
• Shorter treatment period. between the liquid systems and the mucus membrane
• Increased safety margin of high potency drugs due to can be determined by measuring the contact angle. As a
better control of plasma levels. general rule, lower the contact angle, greater is the affin-
• Maximum utilization of drug enabling reduction in ity. The contact angle should be equal or close to zero to
total amount of drug administered.6,21,22 provide adequate spreadability. Figure 2 is a schematic
DISADVANTAGES diagram showing influence of contact angle between
• Drugs, which irritate the oral mucosa, have a bitter the formulation and mucous membrane.23-25
or unpleasant taste, odour, cannot be administered The spreadability coefficient, SAB, can be calculated
by this route. from the difference between the surface energies
130 RGUHS J Pharm Sci | Vol 4 | Issue 4 | Oct–Dec, 2014
 Arshad et al.: Review on Mucoadhesive Drug Delivery System

Figure 1: Theories of Mucoadhesion.

Figure 2: A schematic diagram showing the influence of contact angle between device and mucous membrane on bioadhesion.
[Reproduced from: Carvalho FC, Bruschi, ML, Evangelista RC, Gremiao MP. Daflon. Mucoadhesive drug delivery systems. Braz. J. Pharm. Sci. [online]. 2010, vol.46, n.1
[cited 2015-01-12], pp. 1-17. Available from: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502010000100002&lng=en&nrm=iso>. ISSN 1984-8250.
http://dx.doi.org/10.1590/S1984-82502010000100002.]

γB and γA and the interfacial energy γAB, as indicated bond strength increases with the enhancement in the
in equation: degree of the penetration. Diffusion coefficient, flex-
SAB = γB - γA - γAB ibility and nature of mucoadhesive chains, mobility
and contact time of polymer chains are the factors on
Greater the individual surface energy of mucus and
which the degree of penetration depends. The depth of
device in relation to the interfacial energy, greater is the
interpenetration required to produce a firm bioadhesive
adhesion work, WA.
bond lies in the range 0.2–0.5 μm. This interpenetration
WA= γA + γB - γAB depth of polymer and mucin chains can be found out by
Diffusion theory the following equation
The phenomenon of the interpenetration and entangle- The interpenetration depth, l = (tDb) ½
ment of the bioadhesive polymer chains and mucous Where t is the contact time and Db is the diffusion coef-
polymer chains is explained by the diffusion theory. The ficient of the mucoadhesive material in the mucus. The
RGUHS J Pharm Sci | Vol 4 | Issue 4 | Oct–Dec, 2014 131
 Arshad et al.: Review on Mucoadhesive Drug Delivery System

Figure 3: The secondary interactions resulting from inter-diffusion of polymer chains of bioadhesive device and of mucus.
[Reproduced from: Carvalho FC, Bruschi, ML, Evangelista RC, Gremiao MP. Daflon. Mucoadhesive drug delivery systems. Braz. J. Pharm. Sci. [online]. 2010, vol.46, n.1
[cited 2015-01-12], pp.1-17. Available from: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502010000100002&lng=en&nrm=iso>. ISSN 1984-8250.
http://dx.doi.org/10.1590/S1984-82502010000100002.]

adhesion strength for a polymer is reached when the Electronic theory

depth of penetration is approximately equivalent to the The electronic theory depends on the assumption that
polymer chain size. In order for diffusion to occur, it the bioadhesive material and the target biological mate-
is important that the components involved have good rial have different electronic surface characteristics.
mutual solubility, that is, both the bioadhesive and the Based on this, when two surfaces come in contact with
mucus have similar chemical structures. The greater each other, electron transfer occurs in an attempt to
the structural similarity, the better is the mucoadhesive balance the Fermi levels, resulting in the formation of
bond. Figure 3 shows interactions between polymer a double layer of electrical charge at the interface of
chains and mucous membrane.26,27 the bioadhesive and the biologic surface. The bioadhe-
Fracture theory sive force is believed to be present due to the attractive
forces across this double layer.26,29
The most widely used theory in studies on the mechani-
cal measurement of mucoadhesion, is the fracture the- Adsorption theory
ory. It analyses the force needed to separate two surfaces This theory states that the bioadhesive bond formed
after adhesion is established. The work fracture has been between an adhesive substrate and the tissue is due
found to be more when the polymer network fibres are to the weak Van der Waals forces and hydrogen bond
longer or if the degree of cross-linking within such a formation. It is one of the most widely accepted the-
system is decreased. This theory helps in the determina-
ories of bioadhesion. Table 1 indicates types of bond
tion of fracture strength (σ) following the separation of
formed.26,29
two surfaces via its relationship to the Young’s modulus
of elasticity (E), the fracture energy (ε) and the critical FACTORS AFFECTING MUCOADHESION6,21,30
crack length (L) through the following equation. Figure Table 2 points out various polymer related factors, envi-
4 shows regions of mucoadhesive bond rupture.11,28 ronment related factors and physiological factors which
affects mucoadhesion.
POLYMER RELATED FACTORS6,21,30

Mechanical theory Molecular weight

Mechanical theory proposes that the adhesion is due to The interpenetration of polymer molecules into the
the filling of the irregularities on a rough surface by a mucus layer is variable, for low molecular weight poly-
mucoadhesive liquid. The roughness enhances the inter- mers penetration is more than high molecular weight
facial area available to interactions thereby aiding dis- polymers because entanglements are favored in high
sipation of energy.24 molecular weight polymers.

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Figure 4: Regions where the mucoadhesive bond rupture can occur.

[Reproduced from: Carvalho FC, Bruschi, ML, Evangelista RC, Gremiao MP. Daflon. Mucoadhesive drug delivery systems. Braz. J. Pharm. Sci. [online]. 2010, vol.46, n.1
[cited 2015-01-12], pp.1-17. Available from: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502010000100002&lng=en&nrm=iso>. ISSN1984-8250.
http://dx.doi.org/10.1590/S1984-82502010000100002.]

Table 1: Mucoadhesive/ mucosa interactions.28,30 For a linear polymer, the bioadhesive property is directly
proportional to the molecular weight. For example-
Types of chemical
bonds
Process of bonding Polyethylene glycol (PEG) having molecular weight of
Ionic bonds Two oppositely charged ions attract
20,000 has little adhesive character, whereas PEG hav-
each other via electrostatic interaction to ing molecular weight of 2,00,000 has enhanced adhesive
form a strong bond (e.g. in a salt crystal) property, and PEG having molecular weight 4,00,000
Covalent bonds Electrons are shared in pairs between has superior adhesive property. But in case of nonlinear
the bonded atoms in order to fill the polymer, the bio adhesiveness may or may not depend
orbitals in both. These are strong bonds
on molecular weight. This is mainly because the helical
Hydrogen bonds Hydrogen atom covalently bonds to
electronegative atom such as oxygen,
or coiled structures of such polymer may shield some
fluorine or nitrogen, carries a slight of the adhesive group, which are mainly responsible for
positive charge and is therefore the adhesive property. For example, the adhesive prop-
attracted to other electronegative atoms.
erty of dextran having a molecular weight of 9,50,000
The hydrogen can therefore be thought
of as being shared and the bond formed is similar to that of PEG having a molecular weight of
is generally weaker than ionic and 2,00,000, due to helical structures of dextran that may
covalent bond shield many of adhesive groups.
Van der Waals These are some of the weakest forms of
bonds interaction that arise from dipole-dipole Concentration of polymer
and dipole-induced dipole attractions in
polar molecules, and dispersion forces
There is an optimum concentration for a mucoadhesive
with non polar substances polymer to produce maximum bioadhesion. In highly
Hydrophobic Indirect bonds that occur when non concentrated system, beyond the optimum level, the
bonds polar groups are present in an aqueous adhesive strength drops significantly because the coiled
solution. molecules become separated from the medium so the

Table 2: Factors affecting mucoadhesion.

Polymer related factors Environment related factors Physiological factors
•Molecular weight •pH of polymer-substrate •Mucin turnover
•Concentration of polymer interface •Disease state
•Flexibility of polymer chains •Applied strength •Rate of renewal of mucosal
•Spatial confirmation •Initial contact time cells
•Swelling •Moistening •Concomitant diseases
•Hydrogen bonding capacity •Presence of metal ions •Tissue movement
•Cross linking density
•Charge

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chain available for interpenetration become limited. It Charge

affects the availability of long polymer chains for pene- The bioadhesive property of ionic polymer is always
tration into the mucus layer. Thus it is important mainly higher than that of non-ionic polymer. In neutral or
for liquid and viscous drug delivery system. The impor- slightly alkaline medium, the cationic polymer shows
tance of this factor lies in the development of strong superior mucoadhesive property. It has been proven
adhesive bond with the mucus and can be explained by that, cationic high molecular weight polymer such as
the polymer chain length available for penetration into chitosan possess good bioadhesive property.
the mucus layer. When the concentration of polymer is
too low, the number of penetrating polymer chains per ENVIRONMENT RELATED FACTORS
unit volume of the mucous is small and the interaction pH of polymer-substrate interface
between polymers and mucous is unstable.
pH influences the charge on the surface of both mucus
Flexibility of polymer chains and polymers. Mucus will have a different charge den-
For an effective bioadhesion, the polymer chain should sity depending on pH, because of difference in dissocia-
effectively diffuse into the mucus layer. For achieving tion of functional groups on carbohydrate moiety and
such diffusion, the polymer chain should have sufficient amino acids of the polypeptide backbone, which may
flexibility which depends on the viscosity and diffusion affect adhesion.
coefficient. Higher flexibility of polymer causes greater Applied strength
diffusion into mucus network.
While placing a buccal mucoadhesive drug delivery sys-
Spatial confirmation tem, sufficient strength should be applied in order to
Bioadhesive force is also dependent on the conforma- provide a good bioadhesive property. Even though there
tion of polymers, i.e., helical or linear. The helical con- is no attractive forces between polymer and mucus, then
formation of polymers may shield many active groups, application of high pressure for sufficient long time
primarily responsible for adhesion, thus reducing the make the polymer become bioadhesive with mucus.
mucoadhesive strength of the polymer. Initial contact time
Swelling or hydration Contact time between the bioadhesive and mucus layer
Proper hydration to mucoadhesive polymer is essen- determines the extent of swelling and interpenetration
tial to create macromolecular mesh of sufficient pore of the bioadhesive polymer chains. Moreover, bio-
size and also induces mobility, which are necessary for adhesive strength increases as the initial contact time
enhancing the interpenetration. increases.
Moistening
Hydrogen bonding capacity
Moistening is required to allow the mucoadhesive poly-
Hydrogen bonding is another important factor for
mer to spread over the surface and create a macromolec-
mucoadhesion of a polymer. For mucoadhesion to
ular network of sufficient size for the interpenetration
occur, desired polymers must have functional groups
of polymer and mucin molecules to increase the mobil-
that are able to form hydrogen bonds. Ability to form
ity of polymer chains. However there is a critical level
hydrogen bonds is due to the presence of (COOH, OH
of hydration for mucoadhesive polymers characterized
etc.). Flexibility of the polymer is important to improve
by optimum swelling and bioadhesion.
its hydrogen bonding potential. Polymers such as polyvi-
nyl alcohol, hydroxylated methacrylate and poly (meth- Presence of metal ions
acrylic acid) as well as all their co-polymers are having Interaction with charged groups of polymer and/or
good hydrogen bonding capacity. mucous can decrease the number of interaction sites
Cross linking density and the tightness of mucoadhesive bonding.
The cross linking density indicates the number of aver- PHYSIOLOGICAL FACTORS
age molecular weight of the cross linked polymer, which
Mucin turnover
determines the average pore size. When the cross link-
ing density is higher, then the pore size becomes small, High mucin turnover is not beneficial for the mucoad-
so that diffusion of water into the polymer network hesive property because of following reasons:
occurs at a lower rate, thus there is only an insufficient • The high mucin turn over limits the residence time of
swelling of polymer resulting in decreased penetration bioadhesive polymer as it detaches from the mucin
of polymer into the mucin. layer, even though it has a good bioadhesive property.
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• High mucin turn over may produce soluble mucin There are two broad classes of mucoadhesive polymers
molecule, thus molecule interact with the polymer, hydrophilic polymer and hydrogels. In the large classes
before they interact with mucin layer. of hydrophilic polymers those containing carboxylic
Hence there will not be sufficient mucoadhesion. group exhibit the best mucoadhesive properties, poly
vinyl pyrrolidone (PVP), Methyl cellulose (MC), Sodium
Disease state
carboxymethylcellulose (SCMC) Hydroxypropyl cellu-
The physicochemical property of mucus may alter dur- lose (HPC) and other cellulose derivative. Hydrogels are
ing some disease state, such as common cold, gastric the class of polymeric biomaterial that exhibit the basic
ulcers, ulcerative colitis, bacterial and fungal infections characteristics of hydrogel to swell by absorbing water
etc. Thus alteration in the physiological state may affect interacting by means of adhesion with the mucus that
the bioadhesive property. covers epithelia i.e.
Rate of renewal of mucosal cells
• Anionic group- Carbopol, Polyacrylates and their
cross linked modifications
Rate of renewal of mucosal cells varies extensively from • Cationic group- Chitosan and its derivatives
different types of mucosa. It limits the persistence of • Neutral group- Eudragit- NE30D etc.
bioadhesive systems on mucosal surfaces. Table 3 contains example of various natural, synthetic,
Concomitant diseases biocompatible and biodegradable polymers.
Concomitant diseases can alter the physicochemical Characteristics of an ideal mucoadhesive polymer
properties of mucous or its quantity (for example, hypo • The polymer and its degradation products should be
and hyper secretion of gastric juice), increases in body nontoxic and should be non absorbable from the GI tract.
temperature, ulcer disease, colitis, tissue fibrosis, allergic
rhinitis, bacterial or fungal infection and inflammation. • It should be nonirritant to the mucus membrane.

Tissue movement • It should preferably form a strong non covalent

bond with the mucin–epithelial cell surfaces.
Tissue movement occurs on consumption of liquid and
food, speaking, peristalsis in the GIT and it affects the • It should adhere quickly to most tissue and should
mucoadhesive system especially in case of gastro reten- possess some site specificity.
tive dosage forms.6,21,30
• It should allow easy incorporation of the drug and
MUCOADHESIVE POLYMERS21,31-34 should offer no hindrance to its release.
Mucoadhesive polymers are water-soluble and water
• The polymers must not decompose on storage or
insoluble polymers, which are swellable networks,
during the shelf life of the dosage form.
joined by cross-linking agents. These polymers possess
optimal polarity to make sure that they permit sufficient • The cost of polymer should not be high so that the
wetting by the mucus and optimal fluidity that permits prepared dosage form remains competitive.
the mutual adsorption and interpenetration of polymer
and mucus to take place. Molecular characteristics

Table 3: Examples of mucoadhesive polymers.31-34

Natural Synthetic Biocompatible Biodegradable
Sodium alginate Polyvinyl alcohol, Polyamides, Esters of Poly (lactides),
Pectin polycarbonates, Polyalkylene hyaluronic acid, Poly(glycolides),
Tragacanth glycols, Polyvinyl Poly(lactide-co-
Gelatin Polyvinyl ethers, acetate, glycolides),
Carrageenan Esters and halides, Ethylene glycol Polycaprolactones,
Polymethacrylic acid, Polymethyl Polyalkyl
methacrylic acid, cyanoacrylates.
Methylcellulose, Ethyl cellulose, Polyorthoesters,
Hydroxypropyl cellulose, Polyphosphoesters,
Hydroxypropyl Methylcellulose, Polyanhydrides,
Sod. Carboxymethylcellulose Polyphosphazenes
Chitosan
Polyethylene oxide

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• Strong hydrogen bonding groups (-OH, -COOH). coprotein that bind reversibly to specific carbohydrate
• Strong anionic charges. residues (Onishi and Machida, 1999). After binding to
• Sufficient flexibility to penetrate the mucus network the cell the lectins may either remain on the cell surface
or tissue crevices. or may be taken inside the cell via endocytosis. Hence
• Surface tension characteristics suitable for wetting they allow a method for site specific and controlled drug
mucus/mucosal tissue surface. delivery. The lectins have many advantages but they also
• High molecular weight. have the disadvantage of being immunogenic.
NEW GENERATION OF MUCOADHESIVE MUCOADHESIVE DOSAGE FORMS32-34
POLYMER21,31-34
The primary objectives of mucoadhesive dosage forms
The new generation of mucoadhesives can adhere are to provide intimate contact of the dosage form with
directly to the cell surface, rather than to mucous. They the absorbing surface and to increase the residence time
interact with the cell surface by means of specific recep- of the dosage form at the absorbing surface to prolong
tors or covalent bonding instead of non-specific mecha- drug action. Due to mucoadhesion, certain water-solu-
nisms, which are characteristic of the previous polymers. ble polymers become adhesive on hydration and hence
Examples of such polymers are the incorporation of can be used for targeting a drug to a particular region
l-cysteine into thiolated polymers and the target-specific, of the body for extended periods of time. The mucosa
lectin mediated adhesive polymers. These classes of poly- lines a number of regions of the body including the
mers hold promise for the delivery of a wide variety of gastrointestinal tract, the urogenital tract, the airways,
new drug molecules, particularly macromolecules, and the ear, nose, and eye. These represent potential sites for
create new possibilities for more specific drug–receptor attachment of any mucoadhesive system and hence, the
interactions and improved targeted drug delivery. mucoadhesive drug delivery system may include the fol-
Co-polymers/Interpolymer complex lowing: Gastrointestinal delivery system, Nasal delivery
system, Ocular delivery system, Buccal delivery system,
A block copolymer is formed when the reaction is car- Vaginal delivery System, Rectal delivery system.
ried out in a stepwise manner, leading to a structure
with long sequences or blocks of one monomer alter- EVALUATION STUDIES OF MUCOADHESIVE
nating with long sequences of the other. There are also DRUG DELIVERY SYSTEM
graft co-polymers, in which entire chains of one kind
In vitro/ex vivo tests35-43
(e.g., polystyrene) are made to grow out of the sides of
chains of another kind (e.g. polybutadiene), resulting in • Methods determining tensile strength
a product that is less brittle and more impact-resistant. • Methods determining shear stress
Hydrogen bonding is a major driving force for inter • Adhesion weight method
polymer interactions. • Fluorescent probe method
• Flow channel method
Thiolated polymers (Thiomers) • Mechanical spectroscopic method
These are hydrophilic macromolecules exhibiting free • Falling liquid film method
thiol groups on the polymeric backbone. Based on • Colloidal gold staining method
thiol/disulfide exchange reactions and/or a simple • Viscometer method
oxidation process disulfide bonds are formed between • Thumb method
such polymers and cysteine-rich subdomains of mucus • Adhesion number
glycoproteins building up the mucus gel layer. So far, • Electrical conductance
the cationic thiomers, chitosan–cysteine, chitosan– thio- • Swelling properties
butylamidine as well as chitosan–thioglycolic acid, and • In vitro drug release studies
the anionic thiomers, poly (acylic acid)–cysteine, poly • Mucoretentability studies
(acrylic acid)–cysteamine, carboxymethylcellulose– cys- In vivo methods
teine and alginate - cysteine, have been generated. Due
• Use of radioisotopes
to the immobilisation of thiol groups on mucoadhesive
• Use of gamma scintigraphy
based polymers, their mucoadhesive properties are 2 to
• Use of pharmacoscintigraphy
140 fold improved.
• Use of electron paramagnetic resonance (EPR)
Lectins oximetry
Lectins are naturally occurring proteins that are useful in • X - ray studies
biological recognition involving cells and proteins. Lec- • Isolated loop technique
tins are a class of structurally diverse proteins and gly- In vitro method

136 RGUHS J Pharm Sci | Vol 4 | Issue 4 | Oct–Dec, 2014

 Arshad et al.: Review on Mucoadhesive Drug Delivery System

Methods determining tensile strength inder which is coated with freshly excised porcine intes-
In tensile and shear experiments, the stress is uniformly tinal mucosa to which polymer discs were attached. The
distributed over the adhesive joint, whereas in the peel cylinder is placed in a dissolution apparatus and rotated
strength stress is focused at the edge of the joint. Thus at 125 RPM. It is analysed every 30 mins for the attach-
tensile and shear measure the mechanical properties of ment of the polymers discs.
the system, whereas peel strength measures the peeling Falling liquid film method
force.
In this method the mucous membrane is placed in a
Texture profile analyzer is a commercial instrument stainless steel cylindrical tube, which has been longitudi-
which is used to measure the force required to remove nally cut. This support is placed inclined in a cylindrical
bioadhesive films from excised tissue in vitro. For this cell with a temperature controlled at 37º. An isotonic
test, a piece of animal mucous membrane was taken and solution is pumped through the mucous membrane and
tested for the force required to take away the formula- collected in a beaker. Subsequently, in the case of par-
tion from a model membrane which consists of disc ticulate systems, the amount remaining on the mucous
composed of mucin. The texture analyzer, operating membrane can be counted with the aid of a coul-
in tensile test mode and coupled with a sliding lower ter counter. For semi-solid systems, the non-adhered
platform, was also used to determine peel strength of mucoadhesive can be quantified by high performance
similar formulations. On a movable platform the animal liquid chromatography .This methodology allows the
skin was placed and on top of it the bioadhesive film visualization of formation of liquid-crystalline meso-
was placed, which was later on pulled vertically to deter- phase on the mucous membrane after the flowing of
mine the peel strength. Figure. 5 and 6 are diagrams the fluids and through analysis by means of polarized
of texture profile analyzer and determination of peel light microscopy.
strength.
Fluorescent probe method
Methods determining shear stress
In this method the membrane lipid bilayer and mem-
The measurement of the shear stress gives a direct cor- brane proteins are labeled with pyrene and fluorescein
relation to the adhesion strength. In a simple shear stress isothiocyanate, respectively. The cells are mixed with the
measurement based method two smooth, polished plexi mucoadhesive agents and changes in fluorescence spec-
glass boxes are selected; one block is fixed with adhe- tra were monitored. This gives an indication of polymer
sive Araldite® on a glass plate, which is fixed on leveled binding and its influence on polymer adhesion.
table. The level is adjusted with the spirit level. To the
upper block, a thread is tied and the thread is passed Flow Channel method
down through a pulley, the length of the thread from The method was conducted in an attempt to under-
the pulley to the pan was 12 cm. At the end of the stand structural requirements for bioadhesion in order
thread a pan of fixed is attached. More weights can be to design improved bioadhesives polymers for oral use.
added to it. A recent method involves the measurement The membrane lipid bilayer and membrane proteins
of mucoadhesion by use of a stainless steel rotating cyl- were labeled with pyrene and fluorescence isothiocya-

Figure 5: Texture profile analyzer in bioadhesion test mode Figure 6: Determines peel strength of bioadhesive films
Reproduced from:Shaikh R, Raj Singh TR, Garland MJ, Woolfson AD, Donnelly RF. Mucoadhesive drug delivery systems. Journal of Pharmacy and Bioallied Sciences 2011;
3(1):89-100. doi:10.4103/0975-7406.76478.

RGUHS J Pharm Sci | Vol 4 | Issue 4 | Oct–Dec, 2014 137

 Arshad et al.: Review on Mucoadhesive Drug Delivery System

nate, respectively. The cells were then mixed with candi- hesive ointments and found that the electrical conduc-
date bioadhesives and the change in florescence spectra tance was low in the presence of adhesive material.
was monitored. This gave an indication of polymer
Mucoadhesive Strength
binding and its influence on polymer adhesion.
Mucoadhesive strength of the dosage form can be mea-
Swelling index sured on the modified physical balance.The apparatus
The extent of swelling can be measured in terms of % consists of a modified double beam physical balance in
weight gain by the dosage form. The swelling index is which the right pan is replaced by a glass slide with cop-
calculated using following formula. per wire and additional weight, to make the right side
weight equal with left side pan. A Teflon® block of
fixed diameter and height is fabricated with an upward
portion of 2 cm height and 1.5 cm diameter on one
side. This is kept in beaker filled with buffer media 0.1N
Where, S.I = Swelling index
HCl pH 1.2, which is then placed below right side of
Wt = Weight of tablet at time t the balance. Goat or rat stomach mucosa can be used
Wo = Weight of tablet before placing in the beaker as a model membrane and buffer media 0.1N HCl pH
1.2 can be used as moistening fluid. The one side of the
Colloidal gold staining method
dosage form is attached to the glass slide of the right
Colloidal gold staining technique is proposed for the arm of the balance and then the beaker is raised slowly
study of bioadhesion. The technique employs red col- until contact between goat mucosa and mucoadhesive
loidal gold particles, which are adsorbed on mucin mol- dosage form is established. A preload of 10 g is placed
ecules to form mucin–gold conjugates, which upon on the slide for 5 min (preload time) to establish adhe-
interaction with bioadhesives hydrogels develops a red sion bonding between mucoadhesive dosage form and
color on the surface. This can be quantified by measur- goat or rat stomach mucosa. The preload and preload
ing either the intensity on the hydrogel surface or the time are kept constant. After the completion of preload
conjugates at 525 nm. time, preload is removed from the glass slide and water
is then added in the plastic bottle in left side arm by
Viscometric method peristaltic pump at a constant rate of 100 drops per min.
A simple viscometric method is used to quantify mucin– The addition of water is stopped when mucoadhesive
polymer bioadhesive bond strength. Viscosities of 15% dosage form is detached from the goat or rat stomach
w/v porcine gastric mucin dispersion in 0.1M HCl (pH 1) mucosa. The weight of water required to detach muco-
or 0.1M acetate buffer (pH 5.5) is measured with a Brook- adhesive dosage form from stomach mucosa is noted as
field viscometer in the absence or presence of selected mucoadhesive strength in grams. Figure 7 is mucoadhe-
neutral, anionic, and cationic polymers. Viscosity compo- sion test assembly.
nents and the forces of bioadhesion are calculated.
Thumb method
This is a very simple test used for the qualitative deter-
mination of peel adhesive strength of the polymer and
is useful tool in the development of buccal adhesive Stability Studies
delivery systems. The adhesiveness is measured by the The success of an effective formulation can be evaluated
difficulty of pulling the thumb from the adhesive as a only through stability studies. The purpose of stability
function of the pressure and the contact time. testing is to obtain a stable product which assures its
safety and efficacy up to the end of shelf life at defined
Adhesion number
storage conditions and peak profile. ICH guidelines can
Adhesion number for mucoadhesive microspheres be followed in this regard.
is determined as the ratio of the number of particles
Measurement of the Residence Time/In Vivo Techniques
attached to the substrate to the total number of applied
particles, expressed as a percentage. The adhesion strength Measurements of the residence time of mucoadhesive
increases with an increase in the adhesion number. at the application site provide quantitative information
on their mucoadhesive properties. The GI transit times
Electrical conductance of many mucoadhesive preparations have been exam-
The rotational viscometer was modified to determine ined using radioisotopes and the fluorescent labeling
electrical conductance of various semi-solid mucoad- techniques.
138 RGUHS J Pharm Sci | Vol 4 | Issue 4 | Oct–Dec, 2014
 Arshad et al.: Review on Mucoadhesive Drug Delivery System

Figure 7: Mucoadhesion test assembly

[Reproduced from: Giradkar KP, Channawar MA, Kajale AD, Sridhar E, Kamble RS, Bakde BV, et al. Design development and in vitro evaluation of bioadhesive dosage form
for buccal route. Int J Pharm Res Dev 2006; 2(6):1-20]

Table 4: Commercial mucoadhesive drug delivery system.44,45

Drug Mucoadhesive polymers Application site Name and form
Triamcinolone acetonide Hydroxypropylcellulose, Oral cavity Attach tablet
Carbopol934
Nitroglycerine Carbopol934
Prochlorperazine maleate Synchron (modified HPMC) Buccal Susadrin tablet
Beclomethasonedipropionate Ceronia, Xanthum Gum Buccal Buccastem tablet
Hydroxypropyl cellulose Oral cavity Salcoat powder spray
Sodium CMC, pectin, and Oral cavity Orabase gel
Beclomethasonedipropionate gelatin in polyethylene mineral
oil base
Aluminium hydroxide Sodium CMC,Pectin,and gelatin Oral cavity Orahesive bandage
in polyisobutylene spread onto
polyethylene film
Hydroxypropyl cellulose Oral cavity Rhinocoat powder
Polyacrylic acid Vaginal Replen gel
Sucrose octasulfate Gastrointestinal ulcers Sucralfate

GI Transit using Radio-Opaque Tablets distribution of radioactivity in the genital tract after
It is a simple procedure involving the use of radio- administration of technetium-labeled HYAFF tablets.
opaque markers, e.g. barium sulfate, encapsulated in Dimensions of the stomach part of the sheep can be
mucoadhesive tablets to determine the effects of muco- outlined and imaged using labeled gellan gum, and the
adhesive polymers on GI transit time. Feces collection data collected are subsequently used to compare the
(using an automated feces collection machine) and X-ray distribution of radio labeled HYAFF formulations. The
inspection provide a non-invasive method of monitor- retention of mucoadhesive-radio labeled tablets based
ing total GI residence time without affecting normal GI on HYAFF polymer was found to be more for the dry
motility. Mucoadhesives labeled with Cr-51, Tc- 99m, powder formulation than for the pessary formulation
In-113m, or I-123 have been used to study the transit after 12 h of administration to stomach epithelium. The
of the tablets in the GI tract. combination of the sheep model and the gamma scin-
tigraphy method has been proved to be an extremely
Gamma Scintigraphy Technique useful tool for evaluating the distribution, spreading,
Distribution and retention time of the mucoadhe- and clearance of administered stomach mucoadhesive
sive tablets can be studied using the gamma scintigra- tablets. Table 4 contains information about some com-
phy technique. A study has reported the intensity and mercially available mucoadhesive drug delivery systems.
RGUHS J Pharm Sci | Vol 4 | Issue 4 | Oct–Dec, 2014 139
 Arshad et al.: Review on Mucoadhesive Drug Delivery System

CONCLUSION Development And In Vivo Evaluation In Humans. J Control Release.

Res. 2003; 89(3): 419-28.
The mucoadhesive drug delivery system is a very prom- 16. Sultana Y, Aqil M, Ali A. Ocular Inserts for Controlled Delivery of
ising approach for delivering the drugs which have nar- Pefloxacin Mesylate: Preparation and Evaluation. Acta Pharm. Res.
2005; 55(3): 305-14.
row absorption window at the target site to maximize 17. Wagh VD, Inamdar B, Samanta MK. Polymers Used In Ocular Dosage
their usefulness. With the introduction of a large num- Form and Drug Delivery Systems. Asian J Pharm. Res. 2008; 2(1): 12-
ber of new drug molecules from drug discovery, muco- 7.
18. Elhadi SSA, Mortada ND, Awad GAS, Zaki NM, Taha RA. Development
adhesive drug delivery will play an even more important of In Situ Gelling and Mucoadhesive Mebeverine Hydrochloride Solution
role in delivering these molecules. Improvements in for Rectal Administration. Saudi Pharm. J. Res. 2003; 11(4): 150-71.
mucoadhesive based oral delivery and, in particular, 19. Choi HG, Oh YK, Kim CK. In Situ Gelling and Mucoadhesive Liquid
Suppository Containing Acetaminophen: Enhanced Bioavailability. Int.
the development of novel, highly-effective and mucosa J. Pharm. Res. 1998; 165(1): 23-32.
compatible polymers, are creating new commercial and 20. Schnürch AB. Mucoadhesive Systems in Oral Drug Delivery. Drug
clinical opportunities. Discov Today Res. 2005; 2(1): 83-7.
21. Madhav NVS, Ojha A, Tyagi Y, Negi M. Mucoadhesion: a novelistic
platform for drug delivery system. Int J Pharm. 2014; 2(9): 246-58.
CONFLICT OF INTEREST 22. Patel AR, Patel DA, Chaudhry SV. Mucoadhesive buccal drug delivery
system. Int J of Pharm and Life Sci. 2011; 2(6): 848-56.
The authors declare that there is no conflict of interest. 23. Tangri P, Madhav NVS. Oral mucoadhesive drug delivery systems: a
review. Int J of Biopharm. 2011; 2(1): 36-46.
24. Asija R, Kumawat JK, Sharma D. Mucoadhesive drug delivery system:
ACKNOWLEDGEMENT a review. J of Drug Dis and Therapeutics. 2013; 12(1): 1-8.
25. Naskar S, Roy SK, Kuotsu K. Drug delivery based on buccal adhesive
The authors are thankful to the Head of Department, systems - a review. Int J of Pharm and Bio Sci. 2013; 4(3): 240-56.
Pharmaceutics, the Principal, and the management of 26. Desmukh GD, Varma MM, Manjunath SY. Critical review on buccal
mucoadhesive drug delivery system. Am J Pharm Tech Res. 2011; 1(1):
Krupanidhi College of Pharmacy, for their support.
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27. Patil SM, Kulkarni SS. Review on buccal mucoadhesive drug delivery
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