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Mucoadhesive Polymers - A Review

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Ajay Semalty

Ajay Semalty

Mucoadhesion is the relatively new and emerging concept in drug delivery.
Mucoadhesion keeps the delivery system adhering to the mucus membrane. Transmucosal
drug delivery systems show various merits over conventional drug delivery
systems.

Mucoadhesive polymers facilitate the mucoadhesion by their specific properties.
This article reviews desirable properties of mucoadhesive polymers and the
latest advancement in the field.

Introduction

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 effective in terms of
therapeutic action and patent protection1,2. Moreover the
development of NDDS are going to be the utmost need of pharmaceutical industry
especially after enforcement of Product Patent3,4.

The development of NDDS has been made possible by the various compatible polymers
to modify the release pattern of drug5,6. In the recent years the
interest is growing to develop a drug delivery system with the use of a mucoadhesive
polymer that will attach to related tissue or to the surface coating of the
tissue for the targeting various absorptive mucosa such as ocular, nasal,
pulmonary, buccal, vaginal etc. This system of drug delivery is called as
mucoadhesive drug delivery system7,8.

Transmucosal
delivery of therapeutic agents is a popular method because membranes are
relatively permeable, allowing for the rapid uptake of a drug into the systemic
circulation and avoiding the first pass metabolism9,10. The
efficient uptake offers several benefits over other methods of delivery and
allows drugs to circumvent some of the body’s natural defense mechanism11-13.
The market share of transmucosal drug delivery system has been increasing, with
an estimated US market
share of US$179 million in year 200014. Transmucosal products can be
designed to be administered via the oral / buccal route using mucoadhesive,
quick dissolve tablets and solid lozenge formulations and via vaginal or
urethral route using suppositories. All these transmucosal delivery systems are
formulated with one or more mucoadhesive polymers as an essential component for
mucoadhesion and the subsequent success of the delivery system.

Mucoadhesive Polymers10-19

There are two broad classes of mucoadhesive polymers: hydrophilic polymer
and hydrogels. In the  large classes of
hydrophilic polymers those containing carboxylic group exhibit  the best mucoadhesive properties, poly vinyl
pyrrolidone (PVP) , Methyl cellulose (MC), Sodium carboxy methylcellulose
(SCMC) Hydroxy propyl cellulose (HPC) and other cellulose derivative.

Hyrogels
are the class of polymeric biomaterial 
that exhibit  the basic
characteristics of an hydrogels to swell by absorbing water interacting by
means of adhesion with the mucus that covers epithelia i.e.

· Anionic group-       Carbopol, Polyacrylates and their crosslinked modifications

· Cationic group-      Chitosan and its derivatives

· Neutral group-        Eudragit- NE30D etc.

Important Factors of Mucoadhesion

High molecular weight (up to 100,000), High viscosity (up to an optimum),
Long chain polymers, Optimum concentration of polymeric adhesive, Flexibility
of polymer chain, Spatial confirmation, Optimum cross-linked density of polymer,
Charge and degree of ionization of polymer (anion >cation >unionized),
Optimum medium pH, Optimum hydration of the polymer, High applied strength
and duration of its application and High initial contact time, are some basic
properties which a polymer must have to show a good mucoadhesive profile20.

Besides the above factors, some
physiological factors, like mucin turnover and disease status also affect the
mucoadhesion. The mucin turnover is expected to limit the residence time of the
mucoadhesives on the mucus layer. No matter, how high the mucoadhesive
strength, mucoadhesives are detached from the surface due to mucin turnover.
The physiochemical properties of the mucus are known to change during diseases
conditions such as common cold, gastric ulcers, ulcerative colitis, cystic
fibrosis, bacterial and fungal infections of the female reproductive tract and
inflammatory conditions of the eye, thereby changing the degree of mucoadhesion.

In a study, mucoadhesive force of
various polymers was studied and the results were found as shown in Table 2.

Next Generation Mucoadhesive Polymers

With the disappointment in the merger
of mucoadhesive systems into pharmaceuticals in the site-specific drug delivery
area, there has been an increasing interest from researchers in targeting
regions of the GIT using more selective compounds capable of distinguishing
between the types of cells found in different areas of the GIT. Loosely termed
“cytoadhesion,” this concept is specifically based on certain materials that
can reversibly bind to cell surfaces in the GIT22. These next
generation of mucoadhesives function with greater specificity because they are
based on receptor-ligand-like interactions in which the molecules bind strongly
and rapidly directly onto the mucosal cell surface rather than the mucus itself23.

One such class of compounds that has
these unique requirements is called lectins. Lectins are proteins or
glycoproteins and share the common ability to bind specifically and reversibly
to carbohydrates. They exist in either soluble or cell-associated forms and
possess carbohydrate-selective and recognizing parts. They are found mostly in
plants, to a lesser extent in some vertebrates (referred to as endogenous
lectins), and can also be produced from bacteria or invertebrates24.
Lectin-based drug delivery systems have applicability in targeting epithelial
cells, intestinal M cells, and enterocytes. The intestinal epithelial cells
possess a cell surface composed of membrane-anchored glycoconjugates. It is
these surfaces that could be targeted by lectins, thus enabling an intestinal
delivery concept.

One lectin which has been studied to
considerable extent in vitro binding and uptake is tomato lectin (TL),
which has been shown to bind selectively to the small intestine epithelium. In
one study, using the everted gut sac model, this lectin was bound to
polystyrene microspheres. Uptake of (TL) into the serosal fluid was reported as
eight-fold higher than the control (BSA)25. Furthermore,
BSA-coupled microspheres were shown to have slower uptake than TL-coupled
microspheres by a factor of two. In another study, specific binding by tomato
lectin-coated polystyrene microspheres (0.98 mm) to enterocytes in vitro was
examined26. fluorescently labelled polystyrene microspheres were
coated with TL, and incubated in a CaCo-2 cell line. It was observed that the
lectin-coated microspheres were resistant to repeat washings compared to the
control (BSA-microsphere).

For optimal buccal mucoadhesion, Shojaei and Li have designed, synthesized
and characterized a copolymer of PAA and PEG monoethylether monomethacrylate(PAA-co-PEG)
(PEGMM)27. By adding PEG to these polymers, many of the shortcomings
of PAA for mucoadhesion, outlined earlier, were eliminated. Hydration studies,
glass transition temperature, mucoadhesive force, surface energy analysis
and effect of chain length and molecular weight on mucoadhesive force were
studied. The resulting polymer has a lower glass transition temperature than
PAA and exists as a rubbery polymer at room temperature. Copolymers of 12
and 16-mole% PEGMM showed higher mucoadhesion than PAA. The effects of hydration
on mucoadhesion seen by the copolymers revealed that film containing lower
PEGMM content, which had higher hydration levels, had lower mucoadhesive strengths.
The 16-mole%PEGMM had the most favourable thermodynamic profile and the highest
mucoadhesive forces. Polymers investigated in this study also showed that
the molecular weight and chain length had little or no effect on the mucoadhesive
force28.

Lele, et al, investigated novel polymers of PAA
complexed with PEGylated drug conjugate29. Only a carboxyl group
containing drugs such as indomethacin could be loaded into the devices made
from these polymers. An increase in the molecular weight of PEG in these
copolymers resulted in a decrease in the release of free indomethacin,
indicating that drug release can be manipulated by choosing different molecular
weights of PEG.

A new class of hydrophilic pressure-sensitive adhesives
(PSAs) that share the properties of both hydrophobic PSAs and bioadhesives has
been developed by CoriumTechnologies30. 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
plasticiser (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 PVP–PEG 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 synthesized for prolonged mucosal drug delivery of hydrophilic
drugs31. These block copolymers from micelles in an aqueous medium,
which was confirmed by 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. 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 polymers32.
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. Langoth, N. et al., investigated the benefit of
thiolated polymers (thiomers) for the development of buccal drug delivery systems.
The matrix tablet based on this thiomer showed good stability, mucoadhesion and
controlled drug release (for leuenkephalin over 24 hrs)33.

In addition, mucoadhesive microspheres were studied recently by Bogataj, et
al. for application in the urinary bladder34. 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.chitosan hydrogen chloride,
sodium salt of carboxymethyl cellulose and polycarbophil were prepared and
found to be useful as platforms for oral peptide delivery, with a high capacity
of binding to bivalent cations, which are essential cofactors for intestinal
proteolytic enzymes35.

Alur, H.H.
et al., studied the transmucosal sustained delivery of Chlopheniramine maleate
in rabbits using a novel natural mucoadhesive gum (from Hakea), as an excipient
in  buccal tablets36. It was
concluded that the gum not only sustained the release of drug but also provided
sufficient mucoadhesion to tablets for clinical application.

Summary  

Transmucosal drug delivery systems, are gaining popularity day by day in
the global pharma industry and a burning area of further research and development.
To summarize, polymers with certain specific characters like high molecular
weight and viscosity, long chain length, flexibility of chain length etc.
are needed for the design of transmucosal drug delivery systems.

There is no doubt that mucoadhesion has moved into a new area with these
new specific targeting compounds (Tomato lectins, Corplex™ adhesive hydrogels
etc.) with researchers and drug companies looking further into potential involvement
of more smaller complex molecules, proteins and peptides, and DNA for future
technological advancement in the ever-evolving drug delivery arena.

References

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Table 2: Rank order of mucoadhesive force for various polymers21

Test
Polymer

Mean % AdhesiveForce

Standard
Deviation

Poly(acrylic
acid)

Tragacanth

Poly(methyl
vinylether co-maleic angydride)

Poly(ethylene
oxide)

Methylcellulose

Sodium
alginate

HPMC

Karaya
gum

MEC

Soluble
starch

Gelatin

Pectin

PVP

PEG

PVA

Poly(hydroxy
ethylmethacrylate)

Hydroxypropylcellulose

185.0

154.4

147.7

128.6

128.0

126.2

125.2

125.2

117.4

117.2

115.8

100.0

97.6

96.0

94.8

88.4

87.1

10.3

7.5

9.7

4.0

2.4

12.0

16.7

4.8

4.2

3.1

5.6

2.4

3.9

7.6

4.4

2.3

13.3

About Authors

*For correspondence

E-mail: semaltyajay@yahoo.co.in

Ajay Semalty

Ajay Semalty

He has
done post graduation in pharmacy (M. Pharm.) with specialization in
Pharmaceutics. He is life member of IPA, APTI and ISTE. He has published
research papers in journals of repute and attended conferences at national
level. Presently working as Lecturer in Dept. of Pharmaceutical Sciences, H.N.B. Garhwal University
Srinagar-246174, Uttaranchal (INDIA).

Mona Semalty

She has
done M. Pharm. with specialization in Pharmaceutics. She is life member of IPA.
She has published research papers in journals of repute and attended
conferences at national level. Presently working as Lecturer in Dept. of
Pharmaceutical Sciences, H.N.B. Garhwal University Srinagar-246174, Uttaranchal (INDIA).

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