36

Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

ISSN 0976 - 1047

2229 - 7499

International Journal of Biopharmaceutics

Journal homepage: www.ijbonline.com

IJB
ORAL MUCOADHESIVE DRUG DELIVERY SYSTEMS: A REVIEW
Pranshu Tangri*,1, N.V. Satheesh Madhav1
1
DIT- Faculty of Pharmacy, Mussoorie Diversion road, Bhagwantpura, Makkawala,
Dehradun-248001, Uttarakhand, India.
ABSTRACT
This article focuses on defining the principles of bioadhesive delivery systems based on hydrogels to biological
surfaces that are covered by mucus. An overview of the last decade’s discoveries on mucoadhesion and applications of
mucoadhesive hydrogels as drug carriers is given. Techniques that are frequently used to study the adhesion forces and
physicochemical interactions between hydrogel, mucus, and the underlying mucosa are reviewed. Mucoadhesion can be
defined as a state in which two components, of which one is of biological origin are held together for extended periods of
time by the help of interfacial forces mucoadhesion is the attachement of the drug along with a suitable carrier to the
mucous membrane. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of
polymer chains. Thereafter, several researchers have focused on the investigations of the interfacial phenomena of
mucoadhesion with the mucus. The polymers used for formulation of mucoadhesive drug delivery systems are poly acrylic
acid derivatives, chitosan and newer second generation polymers. Mucoadhesive drug delivery systems with its various
advantages have a lot of potential in formulating dosage forms for various chronic diseases.

Key words: Mucoadhesion, Bioadhesion, Oral mucosa, Mucin, Mucus, Hydrogels.

INTRODUCTION
BIOADHESION/MUCOADHESION substance, and mucoadhesion is used when the bond is
The term bioadhesion refers to any bond formed formed with a mucosal surface.
between two biological surfaces or a bond between a
biological and a synthetic surface. In case of bioadhesive MECHANISM OF MUCOADHESION
drug delivery, the term bioadhesion is used to describe As stated, mucoadhesion is the attachment of the
the adhesion between polymers, either synthetic or drug along with a suitable carrier to the mucous
natural and soft tissues or the gastrointestinal mucosa. In membrane. Mucoadhesion is a complex phenomenon
cases where the bond is formed with the mucus the term which involves wetting, adsorption and interpenetration
mucoadhesion may be used synonymously with of polymer chains. Mucoadhesion has the following
bioadhesion. Mucoadhesion can be defined as a state in mechanism (Andrews GP et al., 2000),
which two components, of which one is of biological 1. Intimate contact between a bioadhesive and a
origin, are held together for extended periods of time by membrane (wetting or swelling phenomenon) (Chowdary
the help of interfacial forces. Generally speaking, KPR et al., 2000; Gandhi RB et al., 1988).
bioadhesion is a term which broadly includes adhesive 2. Penetration of the bioadhesive into the tissue or into
interactions with any biological or biologically derived the surface of the mucous membrane (interpenetration)
*Corresponding Author (Chowdary KPR et al., 2000; Gandhi RB et al., 1988).
Residence time for most mucosal routes is less than an
Pranshu Tangri hour and typically in minutes, it can be increased by the
E-mail: prianshu_tangri@yahoo.co.in addition of an adhesive agent in the delivery system
 37
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

which is useful to localize the delivery system and Electronic theory

increases the contact time at the site of absorption (Yang The electronic theory depends on the
X et al., 1998). The exact mechanism of mucoadhesion is assumption that the bioadhesive material and the target
not known but an accepted theory states that a close biological material have different electronic surface
contact between the mucoadhesive polymer and mucin characteristics. Based on this, when two surfaces come in
occurs which is followed by the interpenetration of contact with each other, electron transfer occurs in an
polymer and mucin. The adhesion is prolonged due to the attempt to balance the Fermi levels, resulting in the
formation of van der vaals forces, hydrogen bonds and formation of a double layer of electrical charge at the
electrostatic bonds. interface of the bioadhesive and the biologic surface. The
Theories of mucoadhesion (Andrews GP et al., 2000) bioadhesive force is believed to be present due to the
Wettability theory attractive forces across this double layer (Derjaguin BV
Electronic theory et al., 1966).
Fracture theory Fracture theory
Adsorption theory This is by-far the most accepted theory on
Diffusion theory bioadhesion. It explains the forces required to separate
Wettability theory the two surfaces after adhesion has taken place. It
The ability of bioadhesive or mucus to spread measures the maximum Tensile stress(sm) produced
and develop intimate contact with its corresponding during detachment as follows ((Mathiowitz E et al.,
substrate is an important factor in bond formation. The 2010),
wetting theory was developed predominantly in regard to s m = Fm/Ao
liquid adhesives, uses interfacial tensions to predict Where Fm and Ao represent the maximum force of
spreading and in turn adhesion (Peppas NA et al., 1985; detachment and the total surface area respectively. In a
Mikos AG et al., 1989; Baszkin A et al., 1990). The uniform single-component system, fracture strength (sf),
study of surface energy of polymers and tissues to predict which is equal to the maximum stress of detachment(sm),
mucoadhesive performance has been given considerable is proportional to the fracture energy (gc), Youngs
attention (Lehr CM et al., 1993; Kaelble DH et al., modulus of elasticity (E) and the critical crack length (c)
1977). of the fracture site as follows (Kammer HW, 1983),
The contact angle (Q) which should ideally be s f = (gcE/c)1/2
zero for adequate spreading is related to interfacial fracture energy can be obtained by the sum of the
tensions (g) as per the Youngs equation, reversible work of adhesion, Wr (work done to produce
new fracture surfaces) and the irreversible work of
g tg = g bt + gbg cos Q adhesion, Wi (work of plastic deformation),
g c = Wr + Wi
Where the subscripts t,g and b represent tissue, Adsorption theory
gastrointestinal contents and bioadhesive polymer This theory states that the bioadhesive bond
respectively, for spontaneous wetting to occur formed between an adhesive substrate and the tissue is
(Mathiowitz E et al., 2010; Ranga Rao KV et al., 1988) due to the weak van der waals forces and hydrogen bond
gtb ≥ gbt + gbg formation. It is one of the most widely accepted theories
the spreading coefficient, Sb/t can be given by, of bioadhesion (Good RJ, 1977; Tabor D, 1977).
Sb/t = gtg - gbt - gbg Diffusion theory
For the bioadhesion to take place the spreading The concept of the interpenetration and
coefficient must be positive, hence it is advantageous to entanglement ob the bioadhesive polymer chains and
maximize the interfacial tension at the tissue-GI contents mucous polymer chains is supported by the diffusion
interface and minimizing the surface tension at the other theory. The bond strength increases with the increase in
two interfaces. The interfacial tension can be measured the degree of the penetration. This penetration is
by methods like the Wilhelmy plate method (Reinhart CT dependent on the concentration gradients and the
et al., 1984; Bateup BO, 1989). It has been shown that diffusion coefficients. It is believed that interpenetration
the BG-tissue interfacial tension can be calculated as, in the range of 0.2-0.5µm is required to produce effective
g bt = gb + gt – 2F(gbgt)1/2 bond strength. The penetration depth (l) can be estimated
Where the values of F (interaction parameter) can be by (Mikos AG et al., 1986),
found in published papers (Wu S et al., 1970; Good RJ et l = (tDb)1/2
al., 1975) thus by the wetting theory it is possible to where t is the time of contact and Db is the diffusion
calculate spreading coefficients for various bioadhesives coefficient of the bio adhesive material in the mucus.
over biological tissues and predict the intensity of the
bioadhesive bond.
 38
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

Factors affecting mucoadhesion (Ch’ng HS et al., basal layers to the superficial layers. The turnover time
1985) for the buccal epithelium has been estimated at 5-6 days
The mucoadhesion of a drug carrier system to (Wertz PW et al., 1991), and this is probably
the mucous membrane depends on the below mentioned representative of the oral mucosa as a whole. The oral
factors. mucosal thickness varies depending on the site: the
 polymer based factors buccal mucosa measures at 500-800 µm, while the
Molecular weight of the polymer mucosal thickness of the hard and soft palates, the floor
Concentration of polymer used of the mouth, the ventral tongue, and the gingivae
Flexibility of polymer chains measure at about 100-200 µm. The composition of the
Swelling factor epithelium also varies depending on the site in the oral
Stereochemistry of polymer cavity. The mucosae of areas subject to mechanical stress
 physical factors (the gingivae and hard palate) are keratinized similar to
pH at polymer substrate interface the epidermis. The mucosae of the soft palate, the
Applied strength sublingual, and the buccal regions, however, are not
Contact time keratinized (Squier CA et al., 1991). The keratinized
 physiological factors epithelia contain neutral lipids like ceramides and
Mucin turnover rate acylceramides which have been associated with the
Diseased state barrier function. These epithelia are relatively
ADVANTAGES OF ORAL MUCOADHESIVE impermeable to water. In contrast, non-keratinized
DRUG DELIVERY epithelia, such as the floor of the mouth and the buccal
- Prolongs the residence time of the dosage form at the epithelia, do not contain acylceramides and only have
site of absorption. small amounts of ceramide (Galey WR et al., 1976;
- Due to an increased residence time it enhances Gandhi RB et al., 1994). They also contain small
absorption and hence the therapeutic efficacy of the drug amounts of neutral but polar lipids, mainly cholesterol
- Excellent accessibility sulfate and glucosyl ceramides. These epithelia have been
- Rapid absorption because of enormous blood supply found to be considerably more permeable to water than
and good blood flow rates keratinized epithelia.
- increase in drug bioavailability due to first pass Permeability
metabolism avoidance The oral mucosae in general are somewhat leaky
- Drug is protected from degradation in the acidic epithelia intermediate between that of the epidermis and
environment in the GIT intestinal mucosa. It is estimated that the permeability of
- Improved patient compliance- ease of drug the buccal mucosa is 4-4000 times greater than that of the
administration skin. As indicative by the wide range in this reported
- faster onset of action is achieved due to mucosal value, there are considerable differences in permeability
surface between different regions of the oral cavity because of
Oral mucosa and mucin the diverse structures and functions of the different oral
Oral mucosa mucosae. In general, the permeabilities of the oral
Within the oral mucosal cavity, the buccal mucosae decrease in the order of sublingual greater than
region offers an attractive route of administration for buccal, and buccal greater than palatal (Harris D et al.,
systemic drug delivery. The mucosa has a rich blood 1982). This rank order is based on the relative thickness
supply and it is relatively permeable (Gandhi RE et al., and degree of keratinization of these tissues, with the
1988). sublingual mucosa being relatively thin and non-
Oral histology keratinized, the buccal thicker and non-keratinized, and
The oral mucosa is composed of an outermost the palatal intermediate in thickness but keratinized. It is
layer of stratified squamous epithelium. Below this lies a currently believed that the permeability barrier in the oral
basement membrane, a lamina propria followed by the mucosa is a result of intercellular material derived from
submucosa as the innermost layer. The epithelium is the so-called ‘membrane coating granules’ (MCG)
similar to stratified squamous epithelia found in the rest (Gandhi RB et al., 1994). This barrier exists in the
of the body in that it has a mitotically active basal cell outermost 200µm of the superficial layer. Permeation
layer, advancing through a number of differentiating studies have been performed using a number of very
intermediate layers to the superficial layers, where cells large molecular weight tracers, such as horseradish
are shed from the surface of the epithelium (Harris D et peroxidase (Squier CA et al., 1984) and lanthanum
al., 1982). The epithelium of the buccal mucosa is about nitrate (Hill MW et al., 1979). When applied to the outer
40-50 cell layers thick, while that of the sublingual surface of the epithelium, these tracers penetrate only
epithelium contains somewhat fewer. The epithelial cells through outermost layer or two of cells. When applied to
increase in size and become flatter as they travel from the the submucosal surface, they permeate up to, but not into,
 39
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

the outermost cell layers of the epithelium. According to 1994; Edgar WM et al., 1992). Up to 70% of the total
these results, it seems apparent that flattened surface cell mucin found in saliva is contributed by the minor
layers present the main barrier to permeation, while the salivary glands. At physiological pH the mucus network
more isodiametric cell layers are relatively permeable. carries a negative charge (due to the sialic acid and
Aside from the MCGs, the basement membrane may sulfate residues) which may play a role in mucoadhesion.
present some resistance to permeation as well, however At this pH mucus can form a strongly cohesive gel
the outer epithelium is still considered to be the rate structure that will bind to the epithelial cell surface as a
limiting step to mucosal penetration. The structure of the gelatinous layer. Another feature of the environment of
basement membrane is not dense enough to exclude even the oral cavity is the presence of saliva produced by the
relatively large molecules. salivary glands. Saliva is the protective fluid for all
tissues of the oral cavity. It protects the soft tissues from
Table No.1 List of compounds used as oral mucosal abrasion by rough materials and from chemicals. It
permeation enhancers allows for the continuous mineralisation of the tooth
Permeation Enhancer enamel after eruption and helps in remineralisation of the
(Siegel IA et al., 1981) enamel in the early stages of dental caries (Aungst BJ et
23-lauryl ether al., 1989). Saliva is an aqueous fluid with 1% organic
Aprotinin and inorganic materials. The major determinant of the
Azone salivary composition is the flow rate which in turn
Benzalkonium chloride depends upon three factors: the time of day, the type of
Cetylpyridinium chloride stimulus, and the degree of stimulation (Peppas NA et al.,
Cetyltrimethylammonium bromide 1985; Edgar WM et al., 1992). The salivary pH ranges
Cyclodextrin from 5.5 to 7 depending on the flow rate. At high flow
Dextran sulfate rates, the sodium and bicarbonate concentrations increase
Lauric acid leading to an increase in the pH. The daily salivary
volume is between 0.5 to 2 liters and it is this amount of
Lauric acid/Propylene glycol
fluid that is available to hydrate oral mucosal dosage
Lysophosphatidylcholine
forms. A main reason behind the selection of hydrophilic
Menthol polymeric matrices as vehicles for oral transmucosal drug
Methoxysalicylate delivery systems is this water rich environment of the
Methyloleate oral cavity.
Oleic acid Buccal Routes of Drug Absorption
Phosphatidylcholine There are two permeation pathways for passive
Polyoxyethylene drug transport across the oral mucosa: paracellular and
Polysorbate 80 transcellular routes. Permeants can use these two routes
Sodium EDTA simultaneously, but one route is usually preferred over
Sodium salicylate the other depending on the physicochemical properties of
Sodium taurodeoxycholate the diffusant. Since the intercellular spaces and
Sulfoxides cytoplasm are hydrophilic in character, lipophilic
compounds would have low solubility in this
Environment environment. The cell membrane, however, is rather
The cells of the oral epithelia are surrounded by lipophilic in nature and hydrophilic solutes will have
an intercellular ground substance, mucus, the principle difficulty permeating through the cell membrane due to a
components of which are complexes made up of proteins low partition coefficient. Therefore, the intercellular
and carbohydrates. These complexes may be free of spaces pose as the major barrier to permeation of
association or some maybe attached to certain regions on lipophilic compounds and the cell membrane acts as the
the cell surfaces. This matrix may actually play a role in major transport barrier for hydrophilic compounds
cell-cell adhesion, as well as acting as a lubricant, (Squier CA et al., 1986).
allowing cells to move relative to one another (Tabak LA Buccal Mucosa as a Site for Drug Delivery
et al., 1982). Along the same lines, the mucus is also Even though the sublingual mucosa is relatively
believed to play a role in bioadhesion of mucoadhesive more permeable than the buccal mucosa, it is not suitable
drug delivery systems (Peppas NA et al., 1985). In for an oral transmucosal delivery system. The sublingual
stratified squamous epithelia found elsewhere in the region lacks an expanse of smooth muscle or immobile
body, mucus is synthesized by specialized mucus mucosa and is constantly washed by a considerable
secreting cells like the goblet cells, however in the oral amount of saliva making it difficult for device placement.
mucosa, mucus is secreted by the major and minor Because of the high permeability and the rich blood
salivary glands as part of saliva (Rathbone M et al., supply, the sublingual route is capable of producing a
 40
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

rapid onset of action making it appropriate for drugs with penetration enhancers, both of which were found to
short delivery period requirements with infrequent dosing increase the permeability of salicylic acid across rabbit
regimen. Due to two important differences between the buccal mucosa. Their results also supported that the
sublingual mucosa and the buccal mucosa, the latter is a superficial layers and protein domain of the epithelium
more preferred route for systemic transmucosal drug may be responsible for maintaining the barrier function
delivery (Harris D et al., 1982; Squier CA et al., 1984). of the buccal mucosa. Table No.1 shows a list of
First difference being in the permeability characteristics compounds used as oral mucosal permeation enhancers.
of the region, where the buccal mucosa is less permeable Mucin
and is thus not able to give a rapid onset of absorption Mucin is a family of high molecular weight,
(i.e., more suitable for a sustained release formulation). heavily glycosylated proteins produced by many
Second being that, the buccal mucosa has an expanse of epithelial tissues. Some mucins remain membrane bound
smooth muscle and relatively immobile mucosa which while others are secreted to the mucosal surface or are
makes it a more desirable region for retentive systems secreted to be a part of the saliva (Zhang J et al., 1994).
used for oral transmucosal drug delivery. Thus the buccal Structure
mucosa is more fitted for sustained delivery applications, Mucins composed of two regions, The amino
delivery of less permeable molecules, and perhaps acid an dcarbonyl terminal regions, rich in cysteine and a
peptide drugs. large central region composed of 10-80 residue
Similar to any other mucosal membrane, the sequences made up of serine or threonine (Zhang J et al.,
buccal mucosa as a site for drug delivery has limitations 1994).
as well. One of the major disadvantages associated with Secretion
buccal drug delivery is the low flux which results in low Mucin is secreted by the stimulation of
drug bioavailability. Various compounds have been MARCKS (myristylated alanine rich C kinase substrate)
investigated for their use as buccal penetration enhancers which coordinates the secretion from the vesicles within
in order to increase the flux of drugs through the mucosa the epithelial cells. The fusion of the vesicles to the
(Squier CA et al., 1986). Since the buccal epithelium is plasma membrane causes release of mucin, this
similar in structure to other stratified epithelia of the viscoelastic product combined with other secretions is
body, enhancers used to improve drug permeation in called mucus (Zhang J et al., 1994).
other absorptive mucosae have been shown to work in Role of mucus
improving buccal drug penetration (Siegel IA et al., The surface epithelium of the stomach and
1985). Drugs investigated for buccal delivery using intestine are exposed to the highly acidic concentration of
various permeation/absorption enhancers range in both HCl and proteolytic enzymes like pepsin. But still it
molecular weight and physicochemical properties. Small retains its integrity due to the mucus secreted by the
molecules such as butyric acid and butanol (Shojaei A.H goblet cells located in the stomach, duodenum, and the
et al., 1996), ionizable low molecular weight drugs such transverse colon. This mucus contains mucin, an
as acyclovir, propranolol, and salicylic acid, large oligosaccharide with terminal sialic acid (pka= 2.6),
molecular weight hydrophilic polymers such as dextrans, which neutralizes the hcl and withstands the effect of
and a variety of peptides including octreotide, leutinizing pepsin. These surface adhesive properties of mucin are
hormone releasing hormone (LHRH), insulin, and a- being utilized in the development of mucoadhesive drug
interferon have all been studied. A series of studies (Oh delivery systems.
CK et al., 1990) on buccal permeation of buserelin and Mechanism
fluorescein isothiocyanate (FITC) labelled dextrans The drugs coated with a mucoadhesive polymer
reported the enhancing effects of di- and tri-hydroxy bile binds to the mucus and hence is retained on the surface
salts on buccal penetration. Their results showed that in epithelium for an extended duration. The drug molecules
the presence of the bile salts, the permeability of porcine in turn are constantly released from the polymer over an
buccal mucosa to FITC increased by a 100-200 fold extended duration of time.
compared to FITC alone. The mechanism of penetration Polymers used for mucoadhesive drug delivery
enhancement of FITC-labelled dextrans by sodium (Andrews GP et al., 2000)
glycocholate (SGC) was shown to be concentration The rheology of the mucoadhesion is a typical
dependent (Galey WR et al., 1976). Below 10 mM SGC, topic and it deals with a number of forces, factors of the
buccal permeation was increased by increasing the components, state of the material, its derived properties.
intercellular transport and at 10 mM and higher Based on the rheological aspects, we can categorize the
concentrations by opening up a transcellular route. mucoadhesive polymers into two broad categories,
Gandhi and Robinson (Siegel IA et al., 1985) materials which undergo matrix formation or hydrogel
investigated the mechanisms of penetration enhancement formation by either a water swellable material or a water
of transbuccal delivery of salicylic acid. They used soluble material.
sodium deoxycholate and sodium lauryl sulfate as
 41
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

Mucoadhesive drug delivery systems are based 6) Flexibility of polymer chain- this promotes the
on the adhesion of a drug/ carrier to the mucous interpenetration of the polymer within the mucus network
membrane. To promote this adherence an suitable carrier (Imam ME et al., 2003).
is required. These carriers generally polymers are 7) Concentration of the polymer- an optimum
classified as, concentration is required to promote the mucoadhesive
Hydrophillic polymers strength. It depends however, on the dosage form. For
Contains carboxylic group and possess excellent solid dosage form the adhesive strength increases with
mucoadhesive properties. increase in the polymer concentration. But in case of
These are pvp (poly vinyl pyrrolidine) semi solod dosage forms an optimum concentration os
Mc (methyl cellulose) essential beyond which the adhesive strength decreases
Scmc (sodium carboxy metyhyl cellulose) (Ugwoke MI et al., 2005).
Hpc (hydroxyl propyl cellulose) 8) Charge and degree of ionization- the effect of
Hydrogels polymer charge on mucoadhesion was clearly shown by
Hydrophillic polymers Bernkop-Schnurch and Freudl. In this work, various
These swell when in contact with water and adhere to tne chemical entities were attached to chitosan and the
mucus membrane. These are further classified according mucoadhesive strength was evaluated. Cationic chitosan
to their charge hcl showed marked adhesiveness when compared to the
Anionic polymers - carbopol, polyacrylates control. The attachement of EDTA an anionic group
Cationic polymers - chitosan increased the mucoadshesive strength significantly.
Neural/ non ionic polymers - eudragit analogues DTPA/chitosan system exhibited lower mucoadhesive
(Semalty A et al., 2005) strength than cationic chitosan and anionic EDTA
They can also be classified as, chitosan complexes because of low charge. Hence the
Synthetic polymers mucoadhesive strength can be attributed as
Natural polymers anion>cation>nonionic (Bernkop-Schnurch A et al.,
Synthetic polymers - cellulose derivatives, carbopols, etc. 1999).
Natural polymers - tragacanth, pecyin, gelatin sodium 9) Optimum hydration- excessive hydration leads to
alginate, acacia. decreased mucoadhesive strength due to formation of a
Ideal muco polymer Characteristics slippery mucilage (Mortazavi SA et al., 1993).
A mucoadhesion promotoing agent or the 10) Optimum Ph – mucoadhesion is optimum at low pH
polymer is added to the formulation which helps to conditions but at higher pH values a change in the
promote the adhering of the active pharmaceutical conformation occurs into a rod like structure making
ingredient to the oral mucosa. The agent can have such those more available for inter diffusion and
additional properties like swelling so as to promote the interpenetration. At very elevated pH values, positively
disintegration when in contact with the saliva. charged polymers like chitosan form polyelectrolyte
As understood earlier, that various physical and complexes with mucus and exhibit strong mucoadhesive
chemical exchanges can affect the polymer/ mucus forces (Peppas N et al., 2004).
adhesion, so as polymer should be carefully selected with 11) High applied strength and initial contact time.
the following properties in mind. 12) It should non toxic, economic, biocompatible
1) polymer must have a high molecular weight upto preferably biodegradable.
100.00 or more. Table no. 2 shows the relative strength of the
This is necessary to promote the adhesiveness between various mucoadhesive polymers
the polymer and mucus (Huang Y et al., 2000). The polymers that are used in mucoadhesive drug
2) Long chain polymers-chain length must be long delivery were categorised by Park and Robinson as,
enough to promote the interpenetration and it should not - Polymers that become sticky when placed in an
be too long that diffusion becomes a problem (Sudhakar aquous media and owe their bioadhesion to stickiness
Y et al., 2006). - polymers that adhere through non specific, non
3) High viscosity. covalent electrostatic interactions
4) Degree of cross linking- it influences chain mobility - Polymers that bind to specific receptors.
and resistance to dissolution. Highly cross linked
polymers swell in presence of water and retain their Polymers used for oral mucoadhesive drug delivery
structure. Swelling favours controlled release of the drug PAA derivatives carbomer- carbopol 934
and increases the polymer/mucus interpenetration. But as noveon- polycarbophil
the cross linking increases, the chain mobility decreases These are polymers of acrylic acid cross linked with
which reduces the mucoadhesive strength (Sudhakar Y et polyalkenyl ethers or divinyl glycol. They are produced
al., 2006). from primary polymer particles of about 0.2 - 0.6 micron
5) Spatial conformation.
 42
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

Table No. 2 Related research on mucoadhesive polymers and delivery systems (Satoh K et al., 1989; Guo JH, 1994;
Veillard MM et al., 1987; Leung SS et al., 1990; Nair M et al., 1996; Li X et al., 1996)
Bioadhesive Polymer(s) Studied Investigation Objectives
HPC and CP Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination
HPC and CP Measured Bioadhesive property using mouse peritoneal membrane
CP, HPC, PVP, CMC Studied inter polymer complexation and its effects on bioadhesive strength
CP and HPMC Formulation and evaluation of buccoadhesive controlled release delivery systems
Tested mucosal adhesion on patches with two-ply laminates with an
HPC, HEC, PVP, and PVA
impermeable backing layer and hydrocolloid polymer layer
Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-
HPC and CP
CP freeze dried mixture as core base
CP, PIP, and PIB Used a two roll milling method to prepare a new bioadhesive patch formulation
Xanthum gum and Locust bean gum Hydrogel formation by combination of natural gums
Chitosan, HPC, CMC, Pectin, Evaluate mucoadhesive properties by routinely measuring the detachment force
Xantham gum, and Polycarbophil form pig intestinal mucosa
Hyaluronic acid benzyl esters,
Evaluate mucoadhesive properties
Polycarbophil, and HPMC
Hydroxyethylcellulose Design and synthesis of a bilayer patch (polytef-disk) for thyroid gland diagnosis
Design of a unidirectional buccal patch for oral mucosal delivery of peptide
Polycarbophil
drugs
Poly(acrylic acid) and Synthesized and evaluated crosslinked polymers differing in charge densities and
Poly(methacrylic acid) hydrophobicity
Number of Polymers including HPC, Measurement of bioadhesive potential and to derive meaningful information on
HPMC, CP, CMC. the structural requirement for bioadhesion
Adhesion strength to the gastric mucus layer as a function of crosslinking agent,
Poly(acrylic acid-co-acrylamide)
degree of swelling, and carboxyl group density
Effects of PAA molecular weight and crosslinking concentration on swelling and
Poly(acrylic acid)
drug release characteristics
Poly(acrylic acid-co-methyl
Effects of polymer structural features on mucoadhesion
methacrylate)
HEMA copolymerized with
Polymeg® (polytetramethylene Bioadhesive buccal hydrogel for controlled release delivery of buprenorphine
glycol)
Poly(acrylic acid-co-butylacrylate Relationships between structure and adhesion for mucoadhesive polymers
CMC, Carbopol 974P, Carbopol EX-
55, Pectin (low viscosity), Chitosan Mucoadhesive gels for intraoral delivery
chloride,
CMC, CP, Polyethylene oxide,
Polymethylvinylether/Maleic Buccal mucoadhesive device for controlled release anticandidal device - CMC
anhydride (PME/MA), and tablets yielded the highest adhesive force
Tragacanth
Buccal mucoadhesive tablets with optimum blend ratio of 80:20 PC to HPMC
HPMC and Polycarbophil (PC)
yielding the highest force of adhesion
PVP, Poly(acrylic acid) Transmucosal controlled delivery of isosorbide dinitrate
Poly(acrylic acid-co-poly
ethyleneglycol) copolymer of acrylic To enhance the mucoadhesive properties of PAA for buccal mucoadhesive drug
acid and poly ethyleneglycol delivery
monomethylether monomethacryalte
Poly acrylic acid and poly ethylene To enhance mucoadhesive properties of PAA by interpolymer complexation
glycol through template polymerization
Drum dried waxy maize starch
(DDWM), Carbopol 974P, and Bioadhesive erodible buccal tablet for progesterone delivery
sodium stearylfumarate
Abbreviations: CP = Carbopol 934P, HPC = Hydroxy propyl cellulose, PVP = Poly(vinyl pyrrolidone), CMC = Sodium carboxymethyl cellulose, HPMC
= Hydroxy propyl methyl cellulose, HEC = Hydroxy ethyl cellulose, PVA = Poly(vinyl alcohol), PIB = Poly(isobutylene), PIP = Poly(isoprene).
 43
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

diameter. Each primary particle exists as a network deacetylated gallan gum.The presence of the thiol group
structure of polymer cahains interconnected by cross increases the residence time by promoting covalent bonds
links. Carbopol polymers along with pemulen and with the cystiene residues in mucus. The disulphide
noveon polymers are all cross linked. They swell in water bonds may also alter the mechanism of drug release from
upto 1000 times their original volume to form a gel when the delivery system due to increased rigidity and cross
exposed to a pH of 4.0 to 6.0. The glass transition linking.
temperature is about 105c. Due to presence of e.x. chitosan iminothiolane
carboxylate group and a pka of 6.0 to 0.5, repulsion PAA homocystiene
between the negative charges occurs leading to increased Paa cystiene
swelling and hence increased mucoadhesive strength of Alginate cystiene
the polymer. Polyox WSR (Bottenberg P et al., 1991)
Today, a large number of companies are using carbopol A class of high molecular weight polyethylene
polymers because of the following merits molecular weight polyethylene oxide homopolymers
- Good tabletting formulation flowability. having the following properties,
- Long drug release profiles - Water soluble
- Can give drug releases profiles similar to carbopol hydrophillic nature
971oNF, with better handling characterstics. - High molecular weight
- Are safe and effective for oral administration - Functional group for hydrogen bondimg
- Arebioadhesive and providing increased - Biocompatible and non toxic
bioavailability - Can be formulated into tablets, films, gels,
- Are approved by many pf the world pharmacopoeias microcapsules, syrups.
- Protect protien and peptides from degradation and Novel polymers (Shojaei AM et al., 1997)
hence increase the bioavailability of proteins or peptide - Tomato lectin showed that it has binding selectivity to
based formulations the small intestine epithelium.
Chitosan (Hassan EE et al., 1990) - Shajaei and Li have designed and characterized a co
It is a cationic polymer (polysaccharide), it is polymer of PAA and PEG monoethylether mono
produced by the deacetylation of chitin. Chitosan is methacrylate (PAA-co-PEG) for exhibiting optimal
gaining importance in the development of mucoadhesive buccal adhesion.
drug delivery system because of its good - Lele et al., investigated novel polymers of PAA
biocompatibility, biodegradability and non toxic nature. complexed with PEGylated drug conjugate.
It binds to the mucosa via ionic bonds between the amino - A new class of hydrophilic pressure sensitive adhesives
group and salicylic acid residues. Chitosan being linear (PSA) have been developed by corium technologies.
provides greater polymer chain flexibility. Onishi and Corplex have been prepared by non covalent hydrogen
Machida showed that chitosan and its metaboloized bonding crosslinking of a film forming hydrphillic
derivatives are quickly eliminated by the kidney. polymer with a short chain plasticizer having reactive OH
Newer second generation polymers (Andrews GP et al., groups at chain ends.
2000) - Langath N et al., investigated the benefit of thiolated
They have the following advantages polymers for the development of buccal drug delivery
- More site specific hence called cytoadhesives. systems.
- Are least effected by mucus turnover rates., - Bogataj et al., Al prepared and studied Mucoadhesive
- Site specific drug delivery is possible. microspheres for application in urinary bladder
Lectins (Clark MA et al., 2000) - Alur HH et al., studied rthe transmucosal sustained
Lectins are naturally occurring proteins that are delivery of chlorphenazine maleate in rabbits using a
useful in biological recognition involving cells and novel natural mucoadhesive gum from hakea as an
proteins. Lectins are a class of structurally diverse excipient in buccal tablets. The gum provided sustained
proteins and glycoprotein that bind reversibly to specific releawse and sufficient mucoadhesion.
carbohydrate residues. Methods of evaluation
After binding to the cell the lectins may either remain on Mucoadhesive polymers can be evaluated by
the cell surface or may be taken inside the cell via testing their adhesion strength by both in vitro and in
endocytosis., they hence allow a method for site specific vivo tests.
and controlled drug delivery. The lectins have many In vitro tests / exvivo (Gupta A et al., 1992)
advantages but they also have the disadvantage of being The importance is layed on the elucidation of the exact
immunogenic. mechanisms of bioadhesion. These methods are,
Thiolated polymers (Bernkop-Schnurch A et al., 2005) - methods determining tensile strength
These are thiomers which are derived from - methods determining shear stress
hydrophilic polymers such as polyacrylates, chitosan or - adhesion weight method
 44
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

- fluorescent probe method

- flow channel method treatment of periodontal diseases, but now the trend is
- mechanical spectroscopic method shifting towards the effective utilization of these systems
- falling liquid film method to the delivery of peptides, proteins and polysaccharides
- colloidal gold staining method (Andrews GP et al., 2000).
- viscometer method The buccal cavity has additional advantages of
- thumb method high patient compliance. Orabase, a first generation
- adhesion number mucoadhesive paste has been used as barrier system for
- electrical conductance mouth ulcers. Semisolids offer more ease in
- swelling properties administration, but tablets have also been formulated.
- in vitro drug release studies Tablets include matrix devices or multilayered systems
- mucoretentability studies containing a mucoadhesive agent. The tablet is kept
In vivo methods (Cafaggi S et al., 2005) under the upper lip to avoid clearance mechanism of the
- use of radioisotopes salivary gland. Buccostem, an adhesive antiemetic tablet
- use of gamma scintigraphy containing prochlorperazine is usually administered in
- use of pharmacoscintigraphy this manner (Altaf MA et al., 2008).
- use of electron paramagnetic resonance(EPR) oximetry Buccal mucoadhesive dosage forms may be
- X ray studies classified into three types,
- Isolated loop technique - A single layer device with multidirectional drug
Mucoadhesion studies by Novel Madhav-Shankar release.
Mucoretentive Study Apparatus - A dosage form with impermeable backing layer which
Novel Madhav-Shankar Mucoretentive Study is superimposed on top of an drug loaded bioadhesive
Apparatus is a novel self designed apparatus by Madhav layer, creating a double layered device and preventing
& Shankar 2009, it provides a unique platform for loss from the top surface of the dosage form into the oral
mounting the tissue for the mucoretentive study of the cavity.
dosage device and it produced reproducible data. The - Unidirectional release device, the drug is releasesd
apparatus assembled as shown in the figure no.1. The only from the side adjacent to the buccal mucosa.
study can be conducted by placing a bioplate 2mm
diameter, 3 cm away from the narrow open end with the CONCLUSION
help of a loop. The ringer solution is then allowed to pass The phenomenon of mucoadhesion can be used
at a rate of 5ml/min. The solution continuously allowed as a model for the controlled drug delivery approaches
to flow until dislodgement of bioplate. The time of for a number of drug candidates. The various advantages
dislodgement of bioplate is registered (Satheesh Madhav of the oral mucoadhesive drug delivery systems like
NV et al., 2008). prolongation of the residence time of the drug which in
turn increases the absorption of the drug are important
Fig. no. 1. Novel Madhav-Shankar Mucoretentive factors in the oral bioavailability of many drugs. The
Study Apparatus (Satheesh Madhav NV et al., 2008). factors which are determinant in the overall success of
the mucoadhesive drug delivery are the polymer
physicochemical properties and the in-vivo factors such
as the mucin turnover rate, mucin flow. A number of both
in-vitro and in-vivo techniques have been developed for
the evaluation of the mucoadhesive drug delivery
systems. Mucoadhesive dosage forms extend from the
simple oral mucosal delivery to the nasal, vaginal, ocular
and rectal drug delivery systems. The most widely
studied and accepted polymers for mucoadhesion have
been the hydrophilic, high molecular weight, anionic
RECENT APPLICATIONS IN ORAL molecules like carbomers. Recently the focus has been on
MUCOADHESIVE DRUG DELIVERY the novel second generation polymers like the thiolated
Oral mucoadhesive drug delivery has polymers, lectins and lecithins.
widespread applications for many drugs which on oral Despite the huge amount of work been done on
administration result in poor bioavailability and are this drug dekivery platform, the focus has been primarily
rapidly degraded by the oral mucoadhesive drug delivery on the formulation of gastroretentive dosage forms,
provides advantages of high accessibility and low hence, work must be done to exploit this drug delivery
enzymatic activity. Earlier the hydrophilic polymers like system for various other approaches like drug targeting
SCMC, HPC and polycarbophil were used for the and site specific drug delivery systems.
 45
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

REFERENCES
Altaf MA, Charyulu N. Ionic gelation controlled drug delivery systems for gastric-mucoadhesive microcapsules of
captopril. Indian J Pharm Sci, 2008; 70: 655-8.
Andrews GP, Thomas P, Laverty TP, David S, Jones SD. Mucoadhesive polymeric platforms for controlled drug delivery.
Eur. J. Pharm. Biopharm. 2009; 71: 505-518.
Aungst BJ, Rogers NJ. Comparison of the effects of various transmucosal absorption promoters on buccal insulin delivery.
Int. J. Pharm. 1989; 53: 227-235.
Baszkin A, Proust JE, Monsengo P, Boissonnade MM. Wettability of polymers by mucion aqueous solutions. Biorheology.
1990; 27: 503-514.
Bateup BO. Surface chemistry and adhesion. Int J Adhes Adhesive. 1989; 7: 233-239.
Berkop-Schnurch A. Thiomers: a new generation of mucoadhesive polymers. Adv. Drug deliv. Rev. 2005; 57: 1569- 1582.
Bernkop-Schnurch A, Freudl J. Comparative in vitro study of different chitosan-complrxing agent conjugates. Pharmazie,
1999; 54: 369-371.
Cafaggi S, Leardi R, Parodi B, Caviglioli G, Russo E, Bignardi G. Preparation and evaluation of a chitosan salt-poloxamer
407 based matrix for buccal drug delivery. J. Control. Release. 2005; 102: 159-169.
Ch’ng HS, Park H Kelly P, Robinson JR. Bioadhesive polymers as platform for oral controlled drug delivery. II: Synthesis
and evaluation of some swelling water insoluble bioadhesive polymers. J. Pharm. Sci. 1985; 74: 399-405.
Chowdary KPR, Srinivas L. Mucoadhesive drug delivery systems: A review of current status. Indian Drugs. 2000; 37(9):
400-406.
Clark MA, Hirst B, Jepson M. Lectin mediated mucosal delivery of drugs and microparticles. Adv. Drug Deliv. Rev. 2000;
43: 207-223.
Derjaguin BV, Toporov YP, Muller VM, Aleinkova IN. On the relationship between the molecular component of the
adhesion of elastic particles to a solid surface. J Colloid Interface Sci. 1966; 58: 528-533.
Edgar WM. Saliva: its secretion, composition and functions. Br. Dent. J. 1992; 172: 305-312.
Galey WR, Lonsdale HK, Nacht S. The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water.
J. Invest. Dermat. 1976; 67: 713-717.
Gandhi RB, Robinson JR. Bioadhesion in drug delivery. Ind. J. Pharm. Sci. 1988; 50(3): 145-152.
Gandhi RB, Robinson JR. Oral cavity as a site for bioadhesive drug delivery. Adv. Drug Del. Rev. 1994; 13: 43-74.
Gandhi RE. Robinson JR. Bioadhesion in drug delivery. Ind. J. Pharm. Sci. 1988; 50: 145-152.
Good RJ. Spreading pressure and contact angle. J Colloid Interface Sci. 1975; 52: 308-313.
Good RJ. Surface energy of solids and liquids. Thermodynamics, molecular forces, and structure. J Colloid Interface Sci.
1977; 59: 398-419.
Guo JH. Investigating the surface properties and bioadhesion of buccal patches. J. Pharm. Pharmacol. 1994; 46: 647-650.
Gupta A, Garg S, Khar RK. Measurement of bioadhesive strenghs of mucoadhesive buccal tablets: Design of in-vitro
assembly. Indian Drugs. 1992; 30(4): 152-155.
Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. J. Pharm. Sci. 1992; 81: 1-10.
Hassan EE, Gallio JM. A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive boind
strength. Pharm, Res. 1990; 7: 491-495.
Hill MW, Squier CA. The permeability of oral palatal mucosa maintained in organ culture, J. Anat. 128 (1979) 169-178.
Huang Y, Leobandung W, Foss A, Peppas NA. Molecular aspects of mucoadhesion and bioadhesion: tethered structures and
site specific surfaces. J. Control. Release. 2000; 65: 63-71.
Imam ME, Hornof M, Valenta, Reznicek G, Bernkop- Schnurch A. Evidence for the interpretation of mucoadhesive
polymers into the mucus gel layer. STP Pharma. Sci. 2003; 13: 171-176
Kaelble DH, Moacanin J. A surface energy analysis of bioadhesion. Polymer. 1977; 18: 475-482.
Kammer HW. Adhesion between polymers. Acta Polym. 1983; 34: 112.
Lehr CM, Bodde HE, Bowstra JA, Junginger HE. A surface energy analysis of mucoadhesion. II: Prediction of
mucoadhesive performance by spreading coefficients. Eur J Pharm Sci. 1993; 1: 19-30.
Lele BS, Hoffman AS. Mucoadhesive Drug Carriers Based on Complexes of poly (acrylic acid) and PEGylated Drugs
having Hydrolysable PEG-anhydride-drug Linkages. J. Control. Release. 2000; 69: 237-248.
Leung SS, Robinson JR. Polymer structure features contributing to mucoadhesion: II. J. Control. Release. 1990; 12: 187-
194.
Li X, Shojaei AH. Novel copolymers of acrylic acid and poly ethylene glycol monomethylether monomethacrylate for
buccoadhesion: In vitro assessment of buccoadhesion and analysis of surface free energy. Proceed. Int. Symp.
Control. Rel. Bioact. Mater. 1996; 23: 165-166.
Mathiowitz E, Chickering DE III, Lehr CM. Bioadhesive Drug Delivery Systems, Fundamentals, Novel Approaches, and
Development. Marcel Dekker, Inc. New York, 2010.
 46
Pranshu Tangri et al. / International Journal of Biopharmaceutics. 2011; 2(1): 36-46.

Mikos AG, Peppas NA. Measurement of the surface tension of mucin solutions. Int J Pharm. 1989; 3: 1-5.
Mikos AG, Peppas NA. Systems for controlled release of drugs. V. Bioadhesive systems. STP Pharmacol. 1986; 2: 705-
716.
Mortazavi SA, Smart J. An investigation into the role of water movement and mucus gel dehydration in mucoadhesion. J.
Control. Rel. 1993; 25: 197-203.
Oh CK, Ritschel WA. Biopharmaceutic aspects of buccal absorption of insulin, Meth. Find Exp. Clin. Pharmacol. 1990; 12:
205-212.
Peppas N, HuangY. Nanoscale technology of mucoadhesive interactions. Adv. Drug Deliv. Rev. 2004; 56: 1675-1687.
Peppas NA, Buri PA. Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissue. J. Controlled
Release. 1985; 2: 257-275.
Peppas NA, Buri PA. Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues. J. Control. Rel.
1985; 2: 257-275.
Ranga Rao KV, Buri P. Bioadhesion and factors affecting the bioadhesion of microparticles. In: M. Szycher, ed. High
Performance Biomaterials. Lancaster, PA: Technomic Publishing Company, 1988: 259-268.
Rathbone M, Drummond B, Tucker I. Oral cavity as a site for systemic drug delivery. Adv. Drug Del. Rev. 1994; 13: 1-22.
Reinhart CT, Peppas NA. Solute diffusion in swollen membranes. Part II. Influence of crosslinking on diffusive properties. J
Membr Sci. 1984; 18: 227-239.
Satheesh Madhav NV, Uma Shankar MS. A smart biopolymeric material from Arachis hypogea seeds for formulation of
amikacin loaded bioplates. Indian patent application filed. 2008; 95.
Satoh K, Takayama K, Machida Y, Suzuki Y, Nakagaki M, Nagai T. Factors affecting the bioadhesive property of tablets
consisting of hydroxypropyl cellulose and carboxyvinyl polymer. Chem. Pharm. Bull. 1989; 37: 1366-1368.
Semalty A, Bhojwani Mona, Bhatt GK, Gupta GD, Shrivastav AK. Design and Evaluation of Mucoadhesive Buccal Films
of Diltiazem Hydrochloride. Indian J. Pharm. Sci. 2005; 67(5): 548-52.
Shojaei AH, Li X. In vitro permeation of acyclovir through porcine buccal mucosa, Proceedings of International
Symposium on Controlled Release of Bioactive Materials. 1996; 23: 507-508.
Shojaei AM, LI X. Mechanism of Buccal Mucoadhesion of Novel Copolymersof Acrylic Acid and Polyethylene Glycol
Monomethylether Monomethacrylate. J. Control. Release. 1997; 47: 151-61.
Siegel IA, Gordon HP. Surfactant-induced increase of permeability of rat oral mucosa to non-electolytes in vivo, Arch. Oral
Biol. 1985; 30: 43-47.
Squier CA, Hall BK. The permeability of mammalian non-keratinized oral epithelia to horseraddish peroxidase applied in
vivo and in vitro, Arch. Oral Biol. 1984; 29: 45-50.
Squier CA, Cox P, Wertz PW. Lipid content and water permeability of skin and oral mucosa. The J. Invest. Dermat. 1991;
96: 123-126.
Squier CA, Wertz PW. Structure and Function of the Oral Mucosa and Implications for Drug Delivery, in, M.J. Rathbone,
(Eds) Oral Mucosal Drug Delivery, ,Marcel Dekker, Inc., New York, 1986: 1-26.
Sudhakar Y, Kuotsu K, BandyopadhyayAK. Buccal bioadhesive drug delivery – a promising option for orally less efficient
drugs. J. Control. Release. 2006; 114: 15-40.
Tabak LA, Levine MJ, Mandel ID, Ellison SA. Role of salivary mucins in the protection of the oral cavity. J. Oral Pathol.
1982; 11: 1-17.
Tabor D. surface forces and surface interactions. J Colloid Interface Sci. 1977; 58: 2-13.
Ugwoke MI, Agu RU, Verbeke N, Kinget R. Nasal mucoadhesive drug delivery: background, applications, trends and future
perspectives. Adv. Drug delivery. Rev. 2005; 57: 1640-1665.
Veillard MM, Longer MA, Martens TW, Robinson JR. Preliminary studies of oral mucosal delivery of peptide drugs. J.
Control. Release. 1987; 6: 123-131.
Wertz PW, Squier CA. Cellular and molecular basis of barrier function in oral epithelium. Crit. Rev. Ther. Drug Carr. Sys.
1991; 8: 237-269.
Wu S. Surface and interfacial tensions of polymer melts. II. Poly(methyl methacrylate), poly(n-butyl methacrylate), and
polystyrene. J Phys Chem. 1970; 74: 632-638.
Yang X, Robinson JR. In: Okano T, ed. Biorelated functional polymers and gels : controlled release and applications in
biomedical engineering, San Diego, Academic Press, 1998: 135.
Zhang J, Niu S, Ebert C, Stanley TH. An in vivo dog model for studying recovery kinetics of the buccal mucosa permeation
barrier after exposure to permeation enhancers: apparent evidence of effective enhancement without tissue damage. Int. J.
Pharm.1994; 101: 15-22.