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.
2. 2
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
3. 3
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
4. 4
Buccal delivery system
Sub-lingual delivery system
Nasal delivery system
Occular delivery system
Gastro intestinal delivery system
Rectal delivery system
Vaginal delivery system
5. 5
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
6. 6
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%
7. 7
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
10. 10
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)
11. 11
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
12. 12
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
13. 13
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
14. 14
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Mechanical theory
Cohesive theory
15. 15
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
16. 16
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
17. 17
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
18. 18
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
19. 19
The depth of 0.2-0.5 µm is required to produce an
efficient mucoadhesive bond
20. 20
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
21. 21
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
22. 22
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
23. 23
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
24. 24
Adhere quickly to moist tissue
Allow easy incorporation of the drug
Stable, cost effective and approved by regulatory
authorities
26. 26
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.
28. 28
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
29. 29
2) Everted gut sac procedure(ex vivo)
Can be applied to liposomes, microspheres and
nanoparticles
30. 30
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
31. 31
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
32. 32
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
33. 33
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
34. 34
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
35. 35
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
38. 38
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