2. Introduction
• Definition : Adhesion can be defined as the bond produced
by contact between a pressure - sensitive adhesive and a
surface.
• Ability to stick,adhere or hold
• Bioadhesion is defined as an ability of a material to adhere
to a biological tissue for an extended period of time In the
case of polymer attached to the mucin layer of a mucosal
tissue, the term “mucoadhesion” is used.
3. Different routes of targeting Bdds
They are :1)Buccal
delivery system
2)Sub lingual
delivery system
Depending upon 3)Vaginal delivery
the route of system
Types of Drug administration of 4)Rectal delivery
delivery systems: the mucoadhesive system
drugs they are 5)Nasal delivery
different types . system
6)Ocular delivery
system
7)Gastro intestinal
delivery system
4. MECHANISM OF MUCOADHESION
Mucoadhesive Inner layers called mucosa Inner epithelial
Cell lining Covered with viscoelastic fluid.
Secreted by Goblet cells Composed of water and mucin (an
anionic polyelectrolyte ) Other components include proteins,
lipids and mucopolysaccharides ,electrolytes
Thickness varies from ≈40–50 μm to ≈300 μm
Mucus is composed mainly of Water (>95%) Glycoproteins
of exceptionally high molecular weight Mineral salts -1 %
Free proteins – 0.5 to 1%
7. Factors affecting Mucoadhesion
Polymer related factors:
Molecular weight
Concentration of active polymer
Flexibility of polymer chains
Environment related factors :
pH of polymer - substrate interface
Applied strength
Initial contact time
Swelling
Physiological factors:
mucin trun over
Disease state
8. Theories of mucoadhesion
The Theories include :-
(a) The electronic theory.
(b) The wetting theory.
(c) The adsorption theory.
(d) The diffusion theory.
(e) The mechanical theory.
(f) The cohesive theory.
(g) Fracture theory.
The phenomena of bioadhesion occurs by a complex
mechanism .There are seven theories have been proposed
till date
9. Electronic theory: Proposes transfer of electrons amongst the
surfaces due to difference in their electrical structure resulting in the
formation of an electrical double layer thereby giving rise to attractive
forces.
Wetting theory: Postulates that if the contact angle of liquids on the
substrate surface is lower, then there is a greater affinity for the liquid
to the substrate surface.
If two such substrate surfaces are brought in contact with each other in
the presence of the liquid, the liquid may act as an adhesive amongst
the substrate surfaces.
10. The diffusion theory: Assumes the diffusion of the polymer chains,
present on the substrate surfaces, across the adhesive interface
thereby forming a networked , semipermeable structure. The
extent depth to which the polymer chain penetrate the mucus
depend on diffusion coefficient &time of contact .
11. Fracture theory : This theory attempts to relete the difficulty of
separation of two surfaces after adhesion .
Adhesion Strength = (E ԑ/L )1/2
E =Young’s modulus of elasticity
ԑ = Fracture energy
L = Critical crack length when two surfaces are separated
12. Cohesive theory :proposes that the phenomena of bioadhesion
are mainly due to the intermolecular interactions amongst like-
molecules.
Mechanical theory :explains the diffusion of the liquid adhesives
into the micro-cracks and irregularities present on the substrate
surface thereby forming an interlocked structure which gives rise
to adhesion. Surface roughness =d/h
Adsorption theory:After initial contact of the material adhere to
surface due to forces acting between the atoms in the two
surfaces later result in formation of bonds(primary & secondary)
due to the presence of intermolecular forces.
hydrogen bonding and Van der Waal’s forces, for the adhesive
interaction amongst the substrate surfaces.
13. Mechanisms of Bioadhesion :The mechanisms responsible in
the formation of bioadhesive bonds are not fully known,
however most research has described bioadhesive bond
formation as a three step process.
Step1: Wetting and swelling of polymer
Step2: Interpenetration between the polymer chains and the
mucosal membrane
Step3: Formation of chemical bonds between the entangled
chains.
Process of bioadhesion can be classified,
Chemical (electronic and adsorption theories)
Physical (wetting, Diffusion and cohesive theory)
16. Bio/muco-adhesive systems: bind to the gastric epithelial cell
surface or mucin, which extends the GRT of drug delivery system
in the stomach.
The ability to provide adhesion of a drug delivery system to the
gastrointestinal wall provides longer residence time in a particular
organ site, thereby producing an improved effect in terms of local
action or systemic effect.
Binding of polymers to the mucin/epithelial surface can be
divided into three categories:
1. Hydration-mediated adhesion:Certain hydrophilic polymers
tend to imbibe large amount of water and become sticky, thereby
acquiring bioadhesive properties.
17. 2. Bonding-mediated adhesion:The adhesion of polymers to a
mucus/epithelial cell surface involves various bonding
mechanisms.
Physical-mechanical bonds can result from the insertion of the
adhesive material into the folds or crevices of the mucosa.
Chemical bonds may be either covalent (primary) or ionic
(secondary) in nature.
Secondary chemical bonds consist of dispersive interactions (i.e.,
Vander Waals interactions) and stronger specific interactions such
as hydrogen bonds.
3. Receptor-mediated adhesion: Certain polymers bind to specific
receptor sites on the cell surfaces, thereby enhancing the gastric
retention of dosage forms.
Various investigators have proposed different mucin-polymer
interactions, such as:
18. Wetting and swelling of the polymer to permit intimate contact
with the biological tissue.
Interpenetration of bioadhesive polymer chains and entanglement
of polymer and mucin chains.
Formation of weak chemical bonds.
Sufficient polymer mobility to allow spreading.
Water transport followed by mucosal dehydration .
The bioadhesive coated system when comes in contact with the
mucus layer, various non-specific or specific interactions occurs
between the complimentary structures and these interactions last
only until the turnover process of mucin
the drug delivery system should release its drug contents during
this limited adhesion time, in order for a bioadhesive system to be
successful.
21. Characteristics of Bioadhesive polymers
Flexibility- important because it controls the extent of the
interpenetration between the polymers and mucosal/epithelial
surfaces.
Hydrophilicity – Polymers that are hydrophilic in nature are able
to form strong adhesive bonds with mucosal membranes because
the mucus layer contains large amounts of water.
Hydrogen bonding – Hydrogen bonding between the entangled
polymer chains forms strong adhesive bonds, therefore the
presence of hydrogen bond – forming groups such as OH and
COOH groups are vital in large quantities.
High molecular weight – Polymers with a high molecular weight
are desirable because they provide more bonding sites.
Surface tensions – Surface tensions are needed to spread the
bioadhesive polymer into the mucosal layer epithelial surface.
22. CHARACTERISTICS OF AN IDEAL MUCOADHESIVE POLYMER
Rapid adherence to mucosa.
Exhibit strong interaction with the mucin epithelial tissue.
Minimum impact on drug release.
Good spreadability, wetting, swelling and solubility and
biodegradability properties.
Unaffected by the hydrodynamic conditions, food and pH
changes.
Easy to incorporate in various dosage forms.
Possess peel, tensile and shear strengths at the bioadhesive range.
Show bioadhesive properties in both dry and liquid state.
Demonstrate local enzyme inhibition and penetration
enhancement properties.
23. Bioadhesion and drug absorption
Drug absorption is the process by which a drug leaves its site of
administration and enters the general circulation.
A drug has to cross several cell membranes before reaching its
target tissue or organ.
These membranes act as barriers which control the transport of
drugs and other molecules across cells.
The general structure of a cell/plasma membrane consists of a
matrix of proteins surrounded by a phospholipid bilayer.
Drugs may cross a cell membrane by passive diffusion, facilitated
passive diffusion, active transport or pinocytosis.
Drug absorption is determined by physicochemical properties of
drugs, their formulations (e.g. tablet,capsule,solution) and routes
of administration such as oral, parenteral and rectal.
24. i)Passive Diffusion:Diffusion is the tendency of molecules to
spread into an available
ii)Facilitated passive diffusion:This is when molecules are
transported across membranes cells with the help of carrier
proteins.
iii)Active Transport:it is the movement of molecules and ions
against their concentration gradients, from lower to higher
concentrations.
iv)Pinocytosis:Pinocytosis (a form of endocytosis) allows a cell to
engulf large molecules and fluid that may be present in the
extracellular region.
Pinocytosis plays a role in the transport of protein drugs.
25. Passive Diffusion Facilitated passive diffusion
Active Transport
Pinocytosis
27. TECHNIQUES FOR EVALUATING BIOADHESIVE
PROPERTIES
INVITRO STUDIES
1) Tensile stress measurement
a) Wilhelmy plate technique: The Wilhelmy plate technique is
traditionally used for the measurement of dynamic contact
angles. The instrument measures the bioadhesive force
between mucosal tissue and the dosage form .
By using the CAHN software system, parameters such as
fracture strength, deformation to failure and work of adhesion
can be analysed.
28. b)Electromagnetic force transducer (EMFT): uses a calibrated
electromagnet to detach a magnetic loaded polymer DDS from a
tissue sample .
It has the unique ability to record remotely and simultaneously
the tensile force information as well as high magnification video
images of bioadhesive interactions at near physiological
conditions.
EMFT measures tissue adhesive forces by monitoring the
magnetic force required to exactly oppose the bioadhesive force.
29. 2)Shear stress measurement:The shear stress technique measures the
force that causes a mucoadhesive to slide with respect to the mucous
layer in a direction parallel to their plane of contact .
o Adhesion tests based on the shear stress measurement involve two
glass slides coated with polymer and a film of mucus.
o Mucus forms a thin film between the two polymer coated slides, and
the test measures the force required to separate the two surfaces.
3)Rheological approach:The rheological properties of the
mucoadhesive interface (i.e. of the hydrated gel) are influenced by the
occurrence of interpenetration step in the process of bioadhesion.
30. o Chain interlocking, conformational changes and chemical interaction,
which occur between bioadhesive polymer and mucin chains, produce
changes in the rheological behaviour of the two macromolecular species.
4)Colloidal gold staining method:This technique employs red colloidal
gold particles, which are stabilized by the adsorbed mucin molecule by
forming mucin–gold conjugates .
o Upon interaction with mucin–gold conjugates, bioadhesive hydrogels
develop a red colour on the surface.
o Thus, the interaction between them can easily be quantified, either by
the measurement of the intensity of the red colour on the hydrogel
surface or by the measurement of the decrease in the concentration of
the conjugates from the absorbance changes at 525 nm.
31. 5)Viscometeric method:A simple viscometric method was used to
quantify mucin–polymer bioadhesive bond strength Viscosities of 15
%w/v porcine gastric mucin dispersion in 0.1M HCl (pH 1) or 0.1M
acetate buffer (pH 5.5) were measured with a Brookefield viscometer
in the absence or presence of selected neutral, anionic, and cationic
polymers.
Viscosity components and the forces of bioadhesion were calculated.
6)Fluorescent probe method:Park and Robinson studied polymer
interaction with the conjunctival epithelial cell membrane using
fluorescent probes .
The study was done in an attempt to understand structural
requirements for bioadhesion in order to design improved bioadhesive
polymers for oral use.
32. The membrane lipid bilayer and membrane proteins were labelled
with pyrene and fluorescein isothiocyanate, respectively.
The cells were then mixed with candidate bioadhesive, and the
changes in fluorescence spectra were monitored.
This gave a direct indication of polymer binding and its influence
on polymer adhesion.
33.
34. INVIVO TECHNIQUES
GI transit using radio-opaque technique:It involves the use of
radio-opaque markers, e.g., barium sulfate, encapsulated in
bioadhesive DDS to determine the effects of bioadhesive polymers
on GI transit time.
Faeces collection (using an automated faeces collection machine)
and x-ray inspection provide a non-invasive method of
monitoring total GI residence time without affecting normal GI
motility.
Mucoadhesives labelled with Cr-51, Tc-99m, In-113m, or I-123 have been
used to study the transit of the DDS in the GI tract .
Gamma scintigraphy technique:It is a valuable tool used in the
development of pharmaceutical dosage forms.
With this methodology, it is possible to obtain information non-
invasively.
35. o This technique gives information in terms of:
o oral dosage forms across the different regions of GI
tract
o the time and site of disintegration of dosage forms
o the site of drug absorption
o also the effect of food
o disease
o size of the dosage form on the in vivo performance of
the dosage forms.
36. Advantages :
Mucoadhesive dosage forms have three distinct advantages when
compared to conventional dosage forms.
These dosage forms are readily localized in the region applied to
improve and enhance the bioavailability of drugs.
These dosage forms facilitate intimate contact of the formulation
with the underlying absorption surface.
This allows modification of tissue permeability for absorption of
macromolecules ,such as peptides and proteins.
Mucoadhesive dosage forms also prolong the residence time of the
dosage form at the site of application and absorption to permit
once or twice a day dosing.
37. Disadvantages :
Medications administered orally do not enter the blood stream
immediately after passage through the buccal mucosa.
Instead they have to be swallowed and then have to pass through a
portion of the GIT before being absorbed.
So the action is not very rapid in the GIT as compared when the
drug is administered through buccal route.
Many drugs affect liver metabolism and also cause destruction via
first pass metabolism of other drugs.
One of the side effects of many antibiotics is the destruction of
normal GI flora resulting in diarrhea.
The absorption of mucoadhesive drugs is adversely affected by the
presence of food.
Tetracyclines, in particular, complicates the administration of this
class of antibiotics via the oral route.
Mucoadhesive drugs cannot bypass liver metabolism.
38. CONCLUSION
Improvements in bioadhesive-based drug delivery and, in
particular, the delivery of novel, highly-effective and mucosa-
compatible polymer, are creating new commercial and clinical
opportunities for delivering narrow absorption window drugs at
the target sites to maximise their usefulness.
Mucoadhesive drug delivery systems are being studied from
different angles, including development of novel mucoadhesives,
design of the device, mechanisms of mucoadhesion and
permeation enhancement.
39. REFERENCES
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bioadhesion. In: Mathiowitz E, Chickering DE, Lehr CM (eds).
Bioadhesive drug delivery systems: Fundamentals, novel approaches,
and developments, New York: Marcel Dekker, 1999, pp 1–10.
o Ahuja A, Khar RK, Ali J. Mucoadhesive drug delivery systems. Drug Dev
Ind Pharm, 1997; 23 (5): 489–515.
o Park K, Robinson JR. Bioadhesive polymers as platforms for oral
controlled drug delivery: method to study bioadhesion. Int J Pharm,
1984; 19: 107–127.
o Smart JD, Kellaway IW, Worthington HEC. An in vitro investigation of
mucosa-adhesive materials for use in controlled drug delivery. J
Pharm Pharmacol, 1984; 36: 295–299.
o Peppas NA, Buri P. Surface, interfacial and molecular aspects of
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