An overview of Bio/Mucoadhesive drug delivery system covering various aspects like advantages, approaches, mechanism of mucoadhesion, various theories, various testing methods and examples of marketed preparations.

1. Presented by:
Swapnil singh
M.S. (Pharm.) Semester II
Dept. of Pharmaceutics
NIPER Mohali

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 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 the state in which two
materials, at least one of which is biological in
nature, are held together, if it is mucus then called as
mucoadhesion

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 These dosage forms are readily localized in the region applied
to improve and enhance bioavailability of drugs
 Facilitate intimate contact of the formulation with the
underlying absorption surface
 Allows modification of tissue permeability for absorption of
macromolecules, such as peptides and proteins
 Prolongs residence time at the site of application thus
decreases dosing frequency
 Local delivery to the intestine and proximal small intestine
 Effective for delivery of drugs with narrow absorption
window

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 Buccal delivery system
 Sub-lingual delivery system
 Nasal delivery system
 Occular delivery system
 Gastro intestinal delivery system
 Rectal delivery system
 Vaginal delivery system

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 Rapid adherence to the mucosal layer without any
change in the physical property of the delivery matrix
 Minimum interference to th release of the active
agent
 Biodegradable without producing any byproducts
 Enhance the penetration of the active agent

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 Mucoadhesive inner layers called mucosa inner
epithelial cell lining is covered with viscoelastic fluid
 Secreted by Goblet cells lining the epithelia or by
special exocrine glands
 Composed of water and mucin (an anionic
polyelectrolyte)
 Thickness varies from 40 µm to 300 µm
 General composition of mucus
Water…………………………………..95%
Glycoproteins and lipids……….0.5-5%
Mineral salts………………………..1%
Free proteins…………………………0.5-1%

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 Complex high molecular weight macromolecule
consisting of a polypeptide backbone to which
carbohydrate chains are attached
 The mucus which covers the epithelial surface has
various roles:
 Protective
 Barrier
 Adhesion
 Lubrication

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Mucus secreting cells
Structure of mucin

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 The mechanism responsible in the formation of
mucoadhesive bonds are not fully known, however
most researcher has described it as a three step
process
 Step 1 : Wetting and swelling of the
polymer(contact stage)
 Step 2 : Interpenetration between the polymer
chains and the mucosal membrane
 Step 3 : Formation of bonds between the
entangled chains (both known as consolidation
stage)

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 Wetting and swelling step occurs when polymer
spreads over the surface of mucosal membrane to
develop intimate contact
 Swelling of polymer occur because the components
of polymer have an affinity for water

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 In this step the mucoadhesive polymer chain and the
mucosal polymer chains intermingle and entangles to
form adhesive bonds
 Strength of bonds depends upon the degree of
penetration of the two polymer groups
Interpenetration of mucoadhesive and mucous polymer chains

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 This step involves formation of weak chemical bonds
between the entangled polymer chains
 Bonds includes primary bonds such as covalent
bonds and secondary interactions such as
vanderWaals and hydrogen bonds

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 Electronic theory
 Wetting theory
 Adsorption theory
 Diffusion theory
 Fracture theory
 Mechanical theory
 Cohesive theory

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Electronic theory
 This theory considers that both mucoadhesive
and biological materials possess opposing electrical
charges; when both materials come in contact with
each other they form double electronic layer at
interface leading to mucoadhesion
Wetting theory
 Best applied to liquid or low viscosity
bioadhesives
 Postulates that if the contact angle of liquids on
the substrate surface is lower, then there is a great
affinity for the liquid to the substrate surface. This
affinity can be measured by contact angle

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 Wetting theory calculates the contact angle and work
of adhesion (Wa), given by Dupre’s eq.
 Ƴb & Ƴt are surface tension of polymer and substrate
respectively and Ƴbt is interfacial tension
 The adhesive work done is a sum of the surface
tensions of the two adherent phases, less the
interfacial tensions apparent between both phases
t

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Horizontal resolution of the forces gives the Young eq.
Where, Ƴbt, Ƴba, and Ƴta are surface tension between
tissue and polymer, polymer and air, and tissue and
air respectively
 If the vector Ƴta greatly exceeds Ƴbt + Ƴba, that is:
 then θ will approach zero and wetting will be
complete
A liquid bioadhesive spreading over a typical soft tissue surface

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Adsorption theory
The mucoadhesive device adheres to mucus by
secondary chemical interactions such as vanderWaals,
hydrogen bonding or hydrophobic interaction
Such forces are considered most important in adhesive
interaction because, although they are individually
weak, a great number of interactions can result in
strong adhesion
Diffusion theory
Diffusion theory describes that polymeric chains
from the bioadhesive interpenetrate into glycoprotein
mucin chains and reach a sufficient depth within the
opposite matrix to allow formation of a
semipermanent bond

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The depth of 0.2-0.5 µm is required to produce an
efficient mucoadhesive bond

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Fracture theory:
This theory describes the force required for the
separation of two surfaces after adhesion
Where σ is the fracture strength, ε fracture energy, E
young modulus of elasticity, and L the critical crack
length
It is used for rigid or semi-rigid bioadhesive materials,
in which the polymer chains do not penetrate into
the mucus layer

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 Mechanical theory
Mechanical theory considers adhesion to be due
to the filling of the irregularities on a rough surface
by a mucoadhesive liquid. Moreover, such roughness
increases the interfacial area available to interactions
 Cohesive theory
It proposes that the phenomena of bioadhesion
are mainly due to the intermolecular interactions
amongst like-molecules

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 Polymer related factors:
Molecular weight
Conc. of polymer
Flexibility of polymer chains
Presence of functional group
Spatial conformation
Cross linking density
 Environment related factors:
pH of polymer substrate interface
Applied strength
 Physiological factors:
Mucin turn over
Disease state

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They are water soluble and water insoluble polymers
which are swellable networks joined by cross linking
agent
Characteristic of ideal polymer
 Degradation products should be non toxic and non
absorbable from GIT
 Good spreadibility, wetting, swelling and
biodegradable properties
 Optimum molecular weight
 Non irritant to mucous membrane
 Form a strong non-covalent bond with mucin
epithelial cell surface

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 Adhere quickly to moist tissue
 Allow easy incorporation of the drug
 Stable, cost effective and approved by regulatory
authorities

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 According to source
Natural and semisynthetic Synthetic
Agarose Carbopol
Chitosan Polycarbophil
Gelatin Polyacrylic acid
Hyaluronic acid Methacrylic acid
Carrageenan Polyacrylates
Pectin PVA
CMC PVP
Thiolated CMC Ethylhexa acrylate
Sodium CMC Thiolated polymer
Hydroxyethylcellulose
Hydroxypropylcellulose
HPMC

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 According to water solubility
 According to charge
Soluble Insoluble
CMC, Sodium CMC, HEC, HPMC,
MC, PVA, PVP, etc.
Carbopol, Polycarbophil,
Polyacrylic acid, PEG, etc.
Charged Uncharged
Aminodextran, Chitosan,
Carbopol, SodiumAlginate,
Pectin, SodiumCMC, etc.
Starch, HPC, PEG, PVA, PVP, etc.

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Route Formulation
Oral(Buccal and Sublingual) Tablet, patch, gel, ointment
Nasal Gel, microspheres, dry powder
Ocular Insert, gel
Gastrointestinal Gel, tablet, microsphere,
capsule
Skin/Transdermal Patch, liposome
Vaginal Gel, microsphere, tablet
Rectal Gel

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In vitro studies
1) Tensile stress measurement
a) Wilhelmy’s plate technique: Traditionally used
to measure dynamic contact angle, measures
bioadhesive force between mucosal tissue and
dosage form
By using CAHN software fracture strength and work
of adhesion can be analysed
Apparatus to determine
mucoadhesion in vitro, using
Wilhemy’s technique

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2) Everted gut sac procedure(ex vivo)
Can be applied to liposomes, microspheres and
nanoparticles

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3) Colloidal gold staining method: Employs red colloidal
gold particles stabilised by adsorbed mucin forming
mucin-gold conjugates
 Upon interaction with conjugates bioadhesive
hydrogel develop red colour on surface
 Interaction can be quantified by :
Measuring red colour intensity on Hydrogel
 Measuring decrease in concentration of
conjugates at 525nm

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Tests measuring mucoadhesive strength
 Depending on the direction in which the
mucoadhesive is separated from the substrate,iti s
possible to obtain the detachment, shear, and
rupture tensile strengths
 The force most frequently evaluated in such tests is
rupture tensile strength
 Generally, the equipment used is a texture analyzer
In this test,
 The force required to remove the formulation from a
model membrane is measured

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Bioadhesion test using the texture analyzer
Microbalance method
Wilhemy’s plate technique, or the microforce balance
technique, can also be modified in order to measure
the specific adhesion force of microparticles

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The general problem of adhesion force and from the
rheological methods is that the mucoadhesive response is
seen macroscopically while the interactions occur at a
microscopic level
Following methods are used to study molecular interactions
a) Dielectric Spectroscopy: Study of material response to the
application of an electrical field
the impedance or permittivity of the sample is obtained and
the property of charges changing in the system can be
determined
b) Zeta potential: Mucin particles are suspended in an
appropriate buffer and mixed with a solution of the polymer,
If the zeta potential value of the mucin particles changes,
this can suggest greater affinity between polymer and mucin
particles

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c) Optical biosensor: One molecule is immobilized
other remains in solution, The molecules in solution,
when binding to the immobilized molecules, alter the
refraction index of the medium and this change is
detected by the screening of a laser beam
d) Falling Liquid Film Method :
In the case of particulate systems, the amount
remaining on the mucous membrane can be counted
with the aid of a coulter counter, For semi-solid
systems, the non adhered mucoadhesive can be
quantified by high performance liquid
chromatography
This methodology allows the visualization of formation of liquid-
crystalline mesophase on the mucous membrane

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In vivo Techniques
1) GI transit using radio-opaque technique: It involves
use of radio opaque markers, e.g., barium sulphate,
encapsulated in BDDS
Mucoadhesive labelled with Cr51, Tc99, In113 Have
been also used
2)Gamma scintigraphy: Information are obtained
noninvasively
Provides various information like:
 Dosage form across different regions of GI tract
 Time and site of disintegration
 Site of absorption
 Effect of food and disease

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 Flavia Chiva Carvalho, Marcos Luciano Bruschi, Raul Cesar
Evangelista, Maria Palmira Daflon Gremiao ; Mucoadhesive
drug delivery systems; Brazilian Journal of Pharmaceutical
Sciences vol. 46, 2010;1-18.
 Formulation and in vitro evaluation of mucoadhesive buccal
tablets of Timolol maleate;Int J Pharm Biomed Res 2010, 1(4),
129-134
 Smart, J. D., Kellaway, I. W., Worthington, H. E. C., An in-vitro
investigation of mucosa-adhesive materials for use in
controlled drug delivery, J. Pharm. Pharmacol., 1984,295-299
 Pranshu tangri: mucoadhesive drug delivery: mechanism and
methods of evaluation, Int J. of Pharma and biosciences: vol.
2, 2011, 458-461

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