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MUCOADHESIVE DRUG
DELIVERY
PRESENTED BY :
MR. NILESH TRIBHUVAN
(PHARMACEUTICS)
GUIDED BY :
Dr.M.R. BHALEKAR
AISSMS COLLEGE OF PHARMACY
CONTENTS
Introduction
Mucosal membrane
Mucoadhesive polymers
Mechanism of mucoadhesion
Theories of mucoadhesion
Factors affecting mucoadhesion
Transmucosal routes
Types of mucoadhesive formulations
Methods of evaluation of mucoadhesion
References
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INTRODUCTION (1)
In biological systems, four types of bioadhesion could be
distinguished:
1. Adhesion of a normal cell on another normal cell.
2. Adhesion of a cell with a foreign substance.
3. Adhesion of a normal cell to a pathological cell.
4. Adhesion of an adhesive to a biological substance.
For drug delivery purpose, the term bioadhesion implies
attachment of a drug carrier system to a specific biological
location.
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Adhesion can be defined as the bond produced by contact
between a pressure sensitive adhesive and a surface.
Presence of amine and carboxyl groups particularly favours
adhesion
Bioadhesion is defined as the state in which two materials, at
least one of which being of a biological nature, are held together
for an extended period of time by interfacial forces.
It is also defined as the ability of a material (synthetic or
biological) to adhere to biological tissue for an extended period
of time .
The biological surface can be epithelial tissue or it can be the
mucus coat on the surface of a tissue. If adhesive attachment is to
a mucus coat ,the phenomenon is referred to as mucoadhesion.
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Mucoadhesive drug delivery system is a system which utilizes the
property of mucoadhesion of certain polymers which become
adhesive on hydration and hence can be used for targeting a drug to
a particular region of the body for extended periods of time.
Mucoadhesion is an interfacial phenomenon in which two materials
at least one of which is biological, is held together by means of
interfacial forces.
The attachment could be between an artificial material and
biological substrate such as adhesion between a polymer and a
biological membrane.
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ADVANTAGES
1)Mucosal DDS has major advantage to bypass first pass hepatic
metabolism, increasing the bioavailability of drugs.
2) The drug is protected from degradation due to pH and digestive
enzymes of the middle gastrointestinal tract.
3) As mucosal membranes are relatively permeable, it allows a rapid
onset of action.
4) Mucosal membrane particularly the nasal mucosa offers potential
for a rapid absorption of drugs with plasma profile closely
duplicating that from an intravenous bolus injection. This is
especially useful in emergency situations.
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5) In controlled release drug delivery
6) These dosage forms are readily localized in the region applied
to improve and enhance the bioavailability of drugs.
7) Targeted & localized drug delivery
8) 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.
9) Avoidance of drug degradation
10) High drug flux through the absorbing tissue
11) Reduction in fluctuation of plasma level.
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A.PHYSIOLOGY OF MUCOUS MEMBRANE
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Fig 1: Regions in mucus layer 9/12/2012 3:40:26 PM
B. MUCUS (NATURE, STRUCTURE AND
COMPOSITION)
Nature of Mucus Secretion
Mucus is translucent and viscid secretion which forms a thin ,
continuous gel blanket adherent to the mucosal epithelial surface.
Mucus is secreted by the goblet cells lining the epithelia or by
special exocrine glands with mucus cells .
Normally the mucus is clear, visco-elastic and adhesive.
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General composition of mucus :
Water……………………….95%
Glycoprotiens and lipids….0.5-5%
Mineral salts……………….1%
Free proteins………………0.5-1%
These units contain an average of about 8-10
monosaccharide residues of five different types.
They are:
a) L-fucose
b) D-galactose
c) N-acetyl-D-glucosamine
d) N-acetyl-D-galactosamine
e) Sialic acid
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Structure and Composition of Mucus
Complex-high molecular weight macromolecule consisting of a
polypeptide (protein) backbone to which carbohydrate side
chains are attached.
Fig 2: Generic structure of mucin monomer
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Mucus forms flexible, threadlike strands that are internally
cross linked by disulphide bond.
Fig 3: Disulphide bond present in mucus
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Key macromolecular components are a class of glycoprotein known
as Mucins.
The mucus layer which covers the epithelial surface has various
roles:
1)Protective
2)Barrier
3)Adhesion
4)Lubrication
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Mucosal membrane
These are moist membranes that line passage-ways
and structures in the body that lead to the external
environment such as the mouth, nose, respiratory
tract, gastrointestinal tract and vagina.
They secrete a viscous fluid known as mucus,
which acts as a protective barrier and also
lubricates the mucosal membrane.
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The amount of drug absorbed depends on the drug concentration,
vehicle of drug delivery, mucosal contact time, venous drainage of
the mucosal tissue, pH of the absorption site, size of drug molecule
and relative lipid solubility.
Parameters such as diffusion coefficient, partition coefficient and
thickness of the tissue are inherent properties of drug and mucosa.
Other parameters such as surface area, duration of drug delivery
and concentration are controlled by the dosage form and
formulation.
Free drug concentration is key issue, if drug is bound with other
components in formulation it is not available for transmucosal
delivery and bioavailability will be reduced.
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Transmucosal drug absorption
There are two routes involved in drug permeation across
epithelial membranes :
1)Paracellular route
2)Transcellular route
Paracellular is the transport of molecules around or
between cells.Tight junctions exist between cells.
The intercellular tight junction is the major barrier to
paracellular transport of macromolecules and polar
compounds.
Poly(acrylic acid)derivatives such as carbomer and
chitosans have been studied for their possible uses as
absorpion enhancers that cause the loosening of tight
junctions.
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MUCOADHESIVE POLYMERS (4)
A muco(bio)adhesive polymer is a natural or synthetic
polymer capable of producing adhesive interaction with
biological membrane which , is thus called as
mucoadhesive polymer
There are two broad classes of mucoadhesive polymers:
1)Hydrophilic polymers , ex: HPMC ,carbomer etc.
2)Hydrogels ex: Chitosan, carageenan , guar gum, sodium
alginate , etc.
3)Thermoplastic polymers :
a)Non erodible neutral polystyrene
b)Semi crystalline bioerodible polymers: poly
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anhydrides and poly lactic acid.
MUCOADHESIVE POLYMERS
Polymers adheres to the mucin epithelial surface can be
divided into three broad categories:
1)Polymers that become sticky when placed in water and owe
their mucoadhesion to stickiness,
2)Polymers that adhere through non specific ,non covalent
interactions which are primarily electrostatic in
nature(although hydrogen and hydrophobic bonding may
be significant)
3)Polymers that bind to specific receptor sites on the cell
surface.
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REQUIREMENTS OF POLYMERS
The polymer and its degradation products should be non
toxic and non absorbable from GI tract.
Non irritant to the mucus membrane.
Preferably form a strong non covalent bond with the mucin
epithelial cell surfaces.
Adhere quickly to moist tissue and should posses some site
specificity.
Allow easy incorporation of the drug and offer no
hindrance to its release.
Must not decompose on storage or during the shelf life of
the dosage form .
The cost should not be high so that the prepared dosge form
remains competitive.
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Mucoadhesive interactions
Ionic bonds
Covalent bonds
Van der waals bonds
Hydrogen bonds
Hydrophobic bonds
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Theories of mucoadhesion
1. 1) Electronic theory
2. 2 )Adsorption theory
3. 3 )Wetting theory
4. 4 )Diffusion theory
5) Fracture theory
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Mucoadhesive Drug Delivery Systems
The term mucoadhesion is used to describe adhesion interactions
between polymers and mucus or mucosal surfaces.
Mechanisms of mucoadhesion
The mechanisms responsible in the formation of mucoadhesive bonds
are not fully known, however most research has described
mucoadhesive bond formation as a three step process.
Step 1 : Wetting and swelling of polymer
Step 2 : Interpenetration between the polymer chains and the mucosal
membrane
Step 3 : Formation of chemical bonds between the entangled chains
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Mechanism of Mucoadhesion
Step 1
The wetting and swelling step occurs when the polymer
spreads over the surface of the biological substrate or mucosal
membrane in order to develop an intimate contact with the
substrate. This can be readily achieved for example by placing
a mucoadhesive formulation such as a tablet or paste within
the oral cavity or vagina.
Swelling of polymers occur because the components within
the polymers have an affinity for water.
Fig 4
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Mechanism of Mucoadhesion
Step 2
The surface of mucosal membranes are composed of high
molecular weight polymers known as glycoproteins. In
step 2 of the mucoadhesive bond formation, the
mucoadhesive polymer chains and the mucosal polymer
chains intermingle and entangle to form semi permeable
adhesive bonds.
The strength of these bonds depends on the degree of
penetration between the two polymer groups. In order to
form strong adhesive bonds, one polymer group must be
soluble in the other and both polymer types must be of
similar chemical structure.
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The interpenetration of polymer
chains
mucoadhesive
polymer chains
Mucus
polymer chains
Fig 5
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Mechanism of Mucoadhesion
Step 3
This step involves the formation of weak chemical bonds
between the entangled polymer chains. The types of
bonding formed between the chains include primary bonds
such as covalent bonds and weaker secondary interactions
such as van der Waals Interactions and hydrogen bonds.
Both primary and secondary bonds are exploited in the
manufacture of mucoadhesive formulations in which
strong adhesions between polymers are formed.
Step 3
Fig 6
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Factors affecting Mucoadhesion (13)
1. Polymer related factors:
i) Molecular weight
ii) Concentration of active polymer
iii) Flexibility of polymer chains
iv) Spacial confirmation
v) Cross linking density
vi) Charge
vii) Hydration
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2. Environment related factors:
i) pH of polymer - substrate interface
ii) Applied strength
iii) Initial contact time
iv) Swelling
3. Physiological factors:
i) Mucin turn over
ii) Disease states
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Enhancement of transmucosal agent transport
Non enhanced drug delivery is based solely on diffusion.
Hydrophilic ionic drugs diffuse through intercellular space, while
hydrophobic are able to pass through cellular membranes
Permeation of drugs throghout epithelial barriars could be
promoted by penetration enhancers such as physical or chemical
methods.
Enhancer efficacy depends upon the physicochemical properties
of drug, the administration site and nature of the vehicle.
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Various chemical enhancers used across epithelial tissues; among
them chelators (eg: sodium EDTA or salicylates), surfactants
(eg: sodium Dodecylsulfate), bile salts (eg: sodium deoxycholate,
sodium Glycocholate), fatty acids (eg: oleic acid, lauric acid)
and non surfactants(eg: cyclodextrins)
Different mechanical penetration enhancements such as electro
osmosis , electrophoresis, electroporation.
Electrophoretic enhancement is mostly used, most effective for
water soluble ionized compounts. Rate of migration is limited by
maximum electric current which can be applied across
mucosa(below 0.5 mA/ cm2 )
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Pharmaceutical consideration and formulation
aspects
An ideal transmucosal drug delivery system must meet several
prerequisites to be successful
1) It should rapidly attach to the mucosal surface and maintain a
strong interaction to prevent displacement.
Contact time should also be sufficiently long at the target site
normally longer than that needed for complete drug release.
2) Bioadhesion performance should not be impacted by
surrounding environmental pH.
Drug release from a polymeric material takes place either by
diffusion or by polymer degradation or by their combination.
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TRANSMUCOSAL ROUTES
Drug absorption through a mucosal surface is generally efficient
because the stratum corneum epidermidis, the major barrier to
absorption across the skin, is absent.
Mucosal surfaces are usually rich in blood supply, providing
the means for rapid drug transport to the systemic circulation
and avoiding, in most cases, degradation by first-pass hepatic
metabolism.
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Transmucosal Routes includes:
1. Nasal Transmucosal Administration
2. Oral Transmucosal Administration
Buccal
Sublingual
3. Rectal Transmucosal Administration
4. Vaginal Transmucosal Administration
5. Ocular Transmucosal Administration
6. Gastrointestinal Transmucosal Administration
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Types of Mucoadhesive Formulations
1. Solid Bioadhesive Formulations:
Tablets : Dry formulation such as tablets are able to form strong interactions
with mucosal surfaces by attracting water from the mucosal surface.
Inserts: These include ocular inserts such as eye drops and eye gels
Lozenges: Mucoadhesive lozenges containing antibiotics and local
anaesthetics can be used topically to treat conditions affecting the
mouth.
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Types of Mucoadhesive Formulations (5)
2. Semi-solid mucoadhesive Formulations
Gels : Mucoadhesive polymers that are able to form gels include polyacrylic
acid which adheres to mucosal surfaces in a cross-linked form.
Gel formulations are used to target several parts of the body including the eye,
vagina and oral cavity.
Films: Mucoadhesive films that are flexible in nature can be used to directly
deliver drugs to specific mucosal membranes.
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Types of Mucoadhesive Formulations
3. Liquid Bioadhesive Formulations
Viscous liquids: Viscous liquids containing mucoadhesive polymers such as
carboxymethyl cellulose may be used to protect mucosal membranes from
damage and irritation.
Gel-forming liquids: These formulations are administered as liquids but undergo
a change in their form in response to conditions such as temperature and pH.
Such formulations are used for the controlled-release of drugs into the eye.
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38
Targets for Mucoadhesive Formulations
Table 1: Sites to which mucoadhesive formulations are targeted
Body site Systems Formulation
Eye Occular drug delivery system Hypotears , Gel Tears and
Pilogel
Nasal cavity Nasal drug delivery systems Rhinocort , Beconase ,
Oral cavity Dental gels / buccal systems Corlan, Daktarin ,
Buccastem
Vagina Local vaginal delivery systems Aci-Jel, Crinone
Rectum Local/systemic rectal delivery Anacal, Germoloid
systems
Methods for evaluation of mucoadhesion
1)In vitro methods
Shear stress method
Detachment force measurement (Modified balance method)
Fluorescent probe method
Flow channel method
Falling liquid film method
Adhesion number
2)In vivo methods
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Fig.7. Measurement of mucoadhesive tensile strength with
an automatic surface tensiometer.
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Fig 8. Mucoadhesion by modified balance method
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Fig 9.Apparatus for falling liquid film method.
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REFERENCES
1)James Swarbik ,James C. Boylan,″ Encyclopedia of
Pharmaceutical Technology″,vol 10,page no: 133
2) N.K.Jain , ″Controlled and novel drug delivery ″, C.B.S.
publisher and distributers,1st edition, page no:353-380
3) Yie W.Chien, ″Novel drug delivery system ″, second
edition, vol.50,Marcel Dekker and Inc. New york, hang
kong, page no:-197-228
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4) http:// www.pharmainfo.net/reviews/mucoadhesive-
polymers-review , accessed on 14/4/2010
5) http:/www.pharmainfo.net , accessed on 15/4/2010
6) http:/www.ualberta.ca/csps/JPPS1/A Shojaei/ buccal review
7)http:/ www.aapspharmscitech.org/view , accessed on
18/4/2010
8) Gavin P. Andrews , Thomas P. Laverty and David S. Jones
European Journal of Pharmaceutics and Biopharmaceutics
Volume 71, Issue 3, March 2009, Pages 505-518
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