Mucoadhesive Drug Delivery System - Project Paper
Mucoadhesive Drug Delivery System - Project Paper
Mucoadhesive Drug Delivery System - Project Paper
1. INTRODUCTION
The effect of a drug can now be reinforced as a result of the development of new release
systems. Controlled release consists of techniques that make the active chemical agents
available for a target, providing an adequate release rate and duration to produce the desired
effect. The main controlled drug delivery systems currently available include matrices,
pellets, floating systems, liposomes, microemulsions, liquid crystals, solid dispersions,
nanosuspensions, transdermal systems, cyclodextrin inclusion complexes, osmotic pumps and
bioadhesive systems (1).
Bioadhesion can be defined as the state in which two materials, at least one of which is
biological in nature, are maintained together for a prolonged time period by means of
interfacial forces (2). During the 1980s, this concept began to be applied to drug delivery
systems. It consists of the incorporation of adhesive molecules into some kind of
pharmaceutical formulation intended to stay in close contact with the absorption tissue,
releasing the drug near to the action site, thereby increasing its bioavailability and promoting
local or systemic effects.
The potential use for mucoadhesive systems as drug carriers lies in its prolongation of the
residence time at the absorption site, allowing intensified contact with the epithelial barrier
(3). On the other hand, adhesion of preparations onto mucous membrane can be impaired by
the mucociliary clearance system. This clearance, a natural defense mechanism of the body
against the deposition of impurities onto the mucous membrane, can also remove the
preparation. Thus, by using bioadhesive molecules, it is possible to retain the preparation at
the action site and to direct the drug to a specific site or tissue. Other features associated with
the development of controlled drug delivery systems using bioadhesive molecules include a
decrease in drug administration frequency and an increase in patient compliance to the
therapy (4). Therefore, a bioadhesive system controlling drug release could improve the
treatment of diseases, helping to maintain an effective concentration of the drug at the action
site (5).
Mucous membrane is the main administration site for bioadhesive systems, although the need
for new bioadhesive formulations for dermal administration has also been reported when
prolonged cutaneous action is desired. A prolonged effect upon the dermal administration of
Significant reduction in dose can be achieved, there by reducing dose, dose dependent
side effects, and eliminates peak-valley profile.
Maximized absorption rate due to intimate contact with the absorbing membrane and
decreased diffusion barriers.
The oral mucosa lacks prominent mucous secreting goblet cells and therefore there is
no problem of diffusion limited mucous build up beneath the applied dosage form.
The presence of saliva ensures relatively large amount of water for drug dissolution
unlike in case of rectal and transdermal routes.
An increase in the drug concentration gradient due to the intense contact of particles
with the mucosal.
A direct contact with intestinal cells that is the first step before particle absorption
Offers an excellent route, for the systemic delivery of drugs with high first pass
metabolism, thereby offering a greater bioavailability.
A significant reduction in dose can be achieved there by reducing dose related side
effects.
Drugs which are unstable in the acidic environment are destroyed by enzymatic or
alkaline environment of intestine can be administered by this route. Eg. Buccal
sublingual, vaginal
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Drugs which show poor bioavailability via the oral route can be administered
conveniently.
It offers a passive system of drug absorption and does not require any activation.
The presence of saliva ensures relatively large amount of water for drug dissolution
unlike in case of rectal and transdermal routes.
This route provides an alternative for the administration of various hormones, narcotic
analgesic, steroids, enzymes, cardiovascular agents etc.
The buccal mucosa is highly perfused with blood vessels and offers a greater
permeability than the skin.
Increased safety margin of high potency drugs due to better control of plasma levels.
Reduction in fluctuation in steady state levels and therefore better control of disease
condition and reduced intensity of local or systemic side effects. Basic assumption is
drug should absorbed throughout GI tract
Limited gastric residence time which ranges from few minutes to 12 hours which lead
to unpredictable bioavailability and time to achieve maximum plasma level (8) (9).
1.4. Limitations
Drugs contained in the swallowed saliva follows the pre-oral and advantages of
buccal route are lost (8) (10).
2. MECHANISM OF MUCOADHESION
The concept of mucoadhesion is one that has the potential to improve the highly variable
residence times experienced by drugs and dosage forms at various sites in the gastrointestinal
tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the
mucosa should enhance absorption(11).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:2.1. Wetting and swelling of polymer.
2.2. Interpenetration between the polymer chains and the mucosal membrane.
2.3. Formation of Chemical bonds between the entangled chains.
2.1. Wetting and swelling of polymer
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 bioadhesive formulation such
as a tablet or paste within the oral cavity or vagina. Bioadhesives are able to adhere to or
bond with biological tissues by the help of the surface tension and forces that exist at the site
of adsorption or contact. Swelling of polymers occurs because the components within the
polymers have an affinity for water (2).
2.2. Interpenetration between the polymer chains and the mucosal membrane
The surfaces of mucosal membranes are composed of high molecular weight polymers
known as glycoproteins. In this step interdiffusion and interpenetration take place between
the chains of mucoadhesive polymers and the mucous gel network creating a great area of
contact (11). The strength of this bond 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 (2).
AB
energies B and A and the interfacial energy AB, as indicated in the equation given below (2).
This theory explains the importance of contact angle and reduction of surface and interfacial
energies to achieve good amount of mucoadhesion.
S AB = B - A - AB
l = (tD b)
where t is the contact time and D b is the diffusion coefficient of the mucoadhesive material in
the mucous. The adhesion strength for a polymer is reached when the depth of penetration is
approximately equivalent to the polymer chain size. In order for diffusion to occur, it is
important that the components involved have good mutual solubility, that is, both the
bioadhesive and the mucous have similar chemical structures. The greater the structural
similarity, the better is the mucoadhesive bond (5).
Sm= Fm / A0
Since the fracture theory is concerned only with the force required to separate the parts, it
does not take into account the interpenetration or diffusion of polymer chains. Consequently,
it is appropriate for use in the calculations for rigid or semi-rigid bioadhesive materials, in
which the polymer chains do not penetrate into the mucous layer (2) (12).
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All these numerous theories should be considered as supplementary processes involved in the
different stages of the mucous/substrate interaction, rather than individual and alternative
theories. Each and every theory is equally important to describe the mucoadhesion process.
There is a possibility that there will be initial wetting of the mucin, and then diffusion of the
polymer into mucin layer, thus causing the fracture in the layers to effect the adhesion or
electronic transfer or simple adsorption phenomenon that finally leads to the perfect
mucoadhesion. The mechanism by which a mucoadhesive bond is formed will depend on the
nature of the mucous membrane and mucoadhesive material, the type of formulation, the
attachment process and the subsequent environment of the bond. It is apparent that a single
mechanism for mucoadhesion proposed in many texts is unlikely for all the different
occasions when adhesion occurs.
3.6. The 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 thereby aiding dissipating energy and can be considered the most
important phenomenon of the process (15). It is unlikely that the mucoadhesion process is the
same for all cases and therefore it cannot be described by a single theory. In fact, all theories
are relevant to identify the important process variables.
The mechanisms governing mucoadhesion are also determined by the intrinsic properties of
the formulation and by the environment in which it is applied. Intrinsic factors of the polymer
are related to its molecular weight, concentration and chain flexibility. For linear polymers,
mucoadhesion increases with molecular weight, but the same relationship does not hold for
non-linear polymers. It has been shown that more concentrated mucoadhesive dispersions are
retained on the mucous membrane for longer periods, as in the case of systems formed by in
situ gelification. After application, such systems spread easily, since they present rheological
properties of a liquid, but gelify as they come into contact the absorption site, thus preventing
their rapid removal. Chain flexibility is critical to consolidate the interpenetration between
formulation and mucous (16).
Environment-related factors include pH, initial contact time, swelling and physiological
variations. The pH can influence the formation of ionizable groups in polymers as well as the
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12
4.1.6.1. Hydration
Hydration is required for a mucoadhesive polymer to expand and create a proper
macromolecular mes of sufficient size, and also to induce mobility in the polymer chains in
order to enhance the interpenetration process between polymer and mucin. Polymer swelling
permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding
and/or electrostatic interaction between the polymer and the mucous network. However, a
critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and
mucoadhesion occurs (19).
4.1.6.2. Charge
Some generalizations about the charge of bioadhesive polymers have been made previously,
where nonionic polymers appear to undergo a smaller degree of adhesion compared to
anionic polymers. Strong anionic charge on the polymer is one of the required characteristics
for mucoadhesion (19). Some cationic polymers are likely to demonstrate superior
mucoadhesive properties, especially in a neutral or slightly alkaline medium. Additionally,
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17
Flexibility of polymer chain- this promotes the interpenetration of the polymer within
the mucous network.
The presence of free thiol groups in the polymeric skeleton helps in the formation of
disulphide bonds with that of the cysteine-rich sub-domains present in mucin which can
substantially improve the mucoadhesive properties of the polymers (e.g. poly (acrylic acid)
and chitosan) in addition to the paracellular uptake of the bioactive agents [76-80]. Various
thiolated polymers include chitosaniminothiolane, poly(acrylic acid)cysteine, poly(acrylic
acid)homocysteine,
chitosanthioglycolic
acid,
chitosanthioethylamidine,
alginate
Lectins are proteins which have the ability to reversibly bind with specific sugar /
carbohydrate residues and are found in both animal and plant kingdom in addition to various
microorganisms. Many lectins have been found to be toxic and immunogenic which may lead
to systemic anaphylaxis in susceptible individuals on subsequent exposure (28). The specific
affinity of lectins towards sugar or carbohydrate residues provides them with specific cytoadhesive property and is being explored to develop targeted delivery systems. Lectins
20
ointments
(38).
First-generation
mucoadhesives,
such
as
sodium
carboxy
25
27
30
Figure 10: Simplified representation of a typical test set-up used to determine peel strength of bioadhesive
films.
31
Figure 11: Schematic representation of in vitro model of Falling Liquid Film Method.
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Figure 12: Schematic diagram of the apparatus used for determination of residence time.
S: glass slab; D: disintegration apparatus M: mucosal membrane; T: mucoadhesive tablet;
IBP: isotonic phosphate buffer
A new class of hydrophilic pressure-sensitive adhesives (PSAs) that share the properties of
both hydrophobic PSAs and bioadhesives has been developed by Corium Technologies.
These Corplex adhesive hydrogels have been prepared by non-covalent (hydrogen bond)
cross-linking of a film-forming hydrophilic polymer (for example PVP) with a short-chain
plasticizer (typically PEG) bearing complementary reactive hydroxyl groups at its chain ends.
Owing to the appreciable length and flexibility of PEG chains, a relatively large space can be
provided for a stoichiometric complex and a carcass-like structure. The specific balance
between enhanced cohesive strength and large free volume in PVPPEG miscible blends
influences their PSA behaviour. Properties of these hydrophilic PSA hydrogels prepared by
the carcass-like cross-linking method can be modified using a polymer with complementary
reactive groups to form ladder-like cross-links with PVP.
Thus, these Corplex PSA hydrogels have a broad range of unique adhesive/cohesive
properties that enable topical and drug delivery systems to be applied to either skin or
mucosa. An AB block copolymer of oligo(methyl methacrylate) and PAA has been
synthesised for prolonged mucosal drug delivery of hydrophobic drugs. These block
copolymers form micelles in an aqueous medium, which was confirmed by a fluorescence
probe technique using pyrene. A model drug, doxorubicin hydrochloride, when incorporated
into these micelles, results in its release being prolonged at a slower rate (68).
Polymers with thiol groups were also investigated as a new generation of mucoadhesive
polymers. A study conducted by Bernkop-Schnurch, et al. demonstrated that introduction of a
sulphahydryl group increased the adhesive properties of mucoadhesive polymers. In this
study, cysteine was attached covalently to polycarbophil by using carbodiimide as a mediator,
forming amide bonds between the primary amino group of the amino acid and the carboxylic
acid moieties of the polymer. The results showed that there was considerable improvement in
the overall behaviour of adhesion and adhesive properties when tested on porcine intestinal
mucosa at a pH level above five (69).
In addition, mucoadhesive microspheres were studied recently by Bogataj, et al. for
application in the urinary bladder. The microspheres were prepared by a solvent evaporation
method using Eudragit RL or hydroxypropylcellulose as matrix polymers. In another study,
microspheres with a Eudragit RS matrix polymer and different mucoadhesive polymers, i.e.
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10. CONCLUSION
With the great influx of new molecules stemming from drug research, mucoadhesive systems
may play an increasing role in the development of new pharmaceuticals. The focus of
pharmaceutical research is being steadily shifted from the development of new chemical
entities to the development of novel drug delivery system (NDDS) of existing drug molecule
to maximize their effect in terms of therapeutic action and patient protection. Mucoadhesive
drug delivery systems offer unique carrier system for many pharmaceuticals and can be
tailored to adhere to any mucosal tissue, including those found in oral cavity and
gastrointestinal tract.
Current use of mucoadhesive polymers to increase contact time for a wide variety of drugs
and routes of administration has shown dramatic improvement in both specific therapies and
more general patient compliance. Mucoadhesive polymers may provide an important tool to
improve the bioavailability of the active agent by improving the residence time at the delivery
site. The various sites where mucoadhesive polymers have played an important role include
buccal cavity, nasal cavity, rectal lumen, vaginal lumen and gastrointestinal tract.
Development of novel mucoadhesive delivery systems are being undertaken so as to
understand the various mechanism of mucoadhesion and improved permeation of active
agents.
The most widely studied and accepted polymers for mucoadhesion have been the hydrophilic,
high molecular weight, anionic molecules like carbomers. Recently the focus has been on the
novel second generation polymers like the thiolated polymers, lectins and lecithin. The
second generation mucoadhesive polymer is enormous, since they have revolutionized the
concept of mucoadhesion through new findings arising from basic research on these new
compounds.
Novel mucadhesive delivery system, where the drug delivery is directed towards mucous by
protecting the local environment is also gaining interest. The future direction of
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37
11. REFERENCE
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Journal of Pharmaceutical Science, 2003; v.92, p.1869-1881.
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39
JK,
Tambwekar
K,
Garg
S.
Bioadhesive
microspheres
41
at
poly(acrylic
acid)=mucin
interface
using
ATR-FTIR
42
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