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International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S330
Polymers in designing the mucoadhesive
films: A comprehensive review
Rohan Mukhopadhyay1, Subhajit Gain1, Surajpal Verma1*, Bhupendra Singh1,
Manish Vyas2, Meenu Mehta3, Anzarul Haque4
Departments of 1Quality Assurance, 2Ayurveda and 3Pharmacognosy, School of Pharmaceutical Sciences,
Lovely Professional University, Phagwara – 144 411, Punjab, India, 4Department of Pharmaceutical Analysis,
College of Pharmacy, Prince Sattam Bin Abdulaziz University, Kharj, KSA
Abstract
Considering the compliance of patients and ease of administration, the oral cavity is profoundly chosen to deliver
drugs. This article focuses on mucoadhesive buccal drug delivery system providing sustained release of the drug.
The drug of choice for buccal delivery is those which undergoes high first-pass metabolism or undergo acid
degradation. This review article aims to focus on various aspects of buccal films, factors affecting mucoadhesion and
its evaluating parameters. Different theories involved in mucoadhesion process and along with the polymers that are
involved in developing different categories of films have been focused. Factors influencing the polymers involved
flexibility, molecular weight, charge, etc., are also considered in this review. Most commonly used polymers in the
development of mucoadhesive films are lectins, starch, pectins, and cellulose derivatives, etc. Several agents such
as penetration enhancers and mucoadhesive agents are employed to develop an ideal film. These dosage forms are
formulated using two processes, namely film casting method and hot-melt extrusion method. The developed films
are evaluated based on multiple parameters such as surface pH, flatness, tensile strength, and peel strength. This
review gives an overall view of different polymers that are used to develop the mucoadhesive films and compare
their degree of mucoadhesion along with their parametric tests to evaluate the developed films.
Key words: Film casting method, hot-melt extrusion method, lectins, Mucoadhesive buccal drug delivery system,
pectins, penetration enhancers
Address for correspondence:
Dr. Surajpal Verma, School of Pharmaceutical Sciences,
Lovely Professional University, Phagwara – 144 411,
Punjab, India. Phone: +91-9878464676.
E-mail: surajpal.15834@lpu.co.in/surajpal_1982@
yahoo.co.in
Received: 10-05-2018
Revised: 11-06-2018
Accepted: 23-06-2018
INTRODUCTION
Mucoadhesive buccal patch has
gained attention and development
has been skyrocketing over the past
few decades. As a dosage form, patches have
grabbed the views of pharma sectors as a novel,
convenient, and patient-compatible.[1] The oral
mucosa has an enriched supply of blood and
is relatively permeable. This delivery of the
drug through buccal route escapes first-pass
metabolism and has a reduced enzymatic activity
when compared to gastrointestinal (GI) tract.[2]
Human Oral Cavity
In humans, the approximate surface area of the
oral mucosa is100 cm2. The oral mucosa can be
differentiated as the masticatory mucosa which
is 25% of total oral mucosa having a thickness
of 100–200 µm. The lining mucosa covers
60% of the total area and has a thickness of
500–800 µm. It is present in lips, cheeks, oral cavity floor,
etc. [Figure 1].[3]
Mechanisms of Drug Transportation through
Buccal Mucosa
Transportation of drugs involves mainly two basic routes
[Table 1]: Transcellular or intracellular which demands to
cross the cellular membrane with lipid and polar domain, but
paracellular or intercellular transport is accomplished through
passive diffusion through extracellular lipid domain.[4]
REVIEW ARTICLE
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S331
Theories of Mucoadhesion
Mucoadhesion can be classified broadly into three categories:
Type1mucoadhesion includes aggregation of platelets and
healing of the wound (biological phases interaction only).
Adhesion of Type 2 category involves a biological phase and
a simulated substrate. Adhesion of an artificial material to
a substrate of biological nature is described as Type 3, for
example, synthetic hydrogels adhesion to soft tissues.
Basic mechanism that is involved in mucoadhesion is as
follows:
1. Close contact existing between a membrane and
bioadhesive.
2. Piercing of bioadhesive into tissue or mucous
membrane.[5]
To explain the mechanism of mucoadhesion, multiple
theories have been proposed:
Wetting theory
This theory hypothesizes the penetration of adhesives into
the irregularities and gets itself anchored on the surface. It
is applicable to liquid or mucoadhesive system having low
viscosity. This theory explains the ability of spreadability of
mucoadhesive polymer on biological surfaces. Measuring
the contact angle, the affinity toward the surface can be
determined.[6]
Adsorption theory
As per this theory, two different types of chemical bonding,
i.e. H-bonding and Van der Waals forces play an important
role in adhesive interactions. Chemisorption theory explains
the interaction across the interface takes place due to strong
covalent bonding.[7]
Electronic theory
Structural properties and electronic structures differ with
different surfaces. Electronic differences in the structure are
the backbone of this theory. Transfer of electrons between
the polymers and epithelium mucous membrane leads to a
formation of the bond. Electronic charges are developed in
a bilayer fashion between mucoadhesive system and mucus
which leads to the development of attractive force between
two surfaces through electronic double-layer.[8]
Fracture theory
This theory explains that the existing bonds of adhesion
between the systems are related to the force that is needed to
detach the two surfaces. This hypothesis correlates the amount
of force required to separate polymer from the mucus is related
to the strength of their adhesive bonding. Through the following
equation, we can determine fracture strength (σ) and establish
a relationship between the separations of two surfaces.
σ = √(E*ε)/L
Where E represents Young’s modulus of elasticity, ɛ
represents the energy of fracture, and
L represents the critical length of crack.[9]
Diffusion interlocking theory
According to this theory, the diffusion is dependent on time. In
this process, diffusion takes place in two ways where the rate
of penetration depends on coefficients of diffusion of both the
polymers interacting at the junction. Various factors influencing
the process of diffusion are chain flexibility, molecular weight,
the density of cross-linking, and temperature [Figure 2]. An
interpenetration layer of 0.2–0.5 µm is needed to extend a firm
bond. The required time (t) for the highest degree of adhesion
during interpenetration among two substrates can be calculated
using L (interpenetration depth) and Db (the coefficient of
diffusion).[10]
t=L2/Db
Mechanical theory
As per this theory, the adhesion takes place due to the rough
surface being filled with a mucoadhesive fluid. Although
these irregularities increase the area of interface that area is
free to interact. But it is considered as the most influential
step in the process.[11]
Factors Influencing the Mucoadhesion Action
Mucoadhesion depends not only on the bioadhesive polymer
but also the medium as well in which the polymer will adhere
to. Factors influencing the polymeric mucoadhesive properties
are molecular weight, the capacity of hydrogen bonding, chain
flexibility, the density of cross-linking, concentration, hydration,
and charge of a polymer, which is described as below:
Figure 1: Structure of oral cavity
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S332
FACTORS RELATING TO POLYMERS
Molecular Weight
With increments of polymers molecular weight over 100,000
the bioadhesive quality of the polymer increments, therefore.
A relationship exists between polyoxyethylene polymer’s
bioadhesive quality and their resulting atomic weights,
varying in the scope of 200,000–7,000,000 and the same has
been accounted for by Tiwari et al.[12]
Flexibility
Start of bioadhesion takes place when polymer diffuses
into the interfacial locale. In this way, it is a need that the
chains of the polymer have a significant level of flexibility to
accomplish the coveted association with the mucus.[13]
Hydrogen Bonding Capacity
It is an important factor that is involved in the mucoadhesion
process of a polymer. Park and Robinson have reported that
the polymers of desired quality must possess functional
groups that can have the ability to form hydrogen bonds to
have desired mucoadhesion.[14] Through further study, it has
been revealed that the flexibility of polymer is a crucial aspect
that improves the hydrogen bonding potential. A sustainable
hydrogen bonding capacity is exhibited by polymers and
copolymers such as hydroxylated methacrylate [Figure 3].[15]
Cross-linking Density
The average size of pores in the polymers, the average
polymeric molecular weight having cross-link and the cross-
linking density are the three most important interrelated
structural parameters required for a network of polymer.
Thus, it is rational that as the density of cross-linking
increases, the diffusion of water into the polymer decreases
thus causing the polymer to swell insufficiently. Flory
reported that at equilibrium, polymer’s limit of the swelling
has an inverse relationship with the polymer’s extent of
cross-linking.[16,17]
Charge
Several rational ideas about the charge that is possessed by
the bioadhesive polymers have been previously established,
the degree of adhesion to nonionic polymers as compared to
anionic polymers is relatively smaller. The anionic charge of
the polymer must be strong enough for mucoadhesion to take
place. Superior mucoadhesive properties are exhibited by
some cationic polymers significantly in a medium which is
neutral or slightly alkaline.
Figure 2: Differentiation of polymers based on several parameters
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S333
Concentration
This is an important factor which is responsible for
developing a firm adhesive bond with the mucus. Low
polymer concentration lowers the density of penetrating
polymer chains in the mucus and there takes place an
unstable interaction between polymer and mucus. In general,
the highly concentrated polymer would prompt be shaping a
more extended infiltrating chain length with higher adhesion.
High polymer concentration does not ensure improved
properties of mucoadhesion, and in some cases, it actually
reverses the action.[18]
Hydration (swelling)
Hydration is necessary to extend mucoadhesive polymers,
and a legitimate macromolecular mesh of required size is
created which helps in inducing mobility in the chains of
polymer which aids in the process of interpenetration existing
between mucin and polymer. Swelling of the polymer allows
a mechanical inclusion by uncovering the sites of bioadhesion
for hydrogen bonding or electrostatic communication among
the polymer and the mucous system. Nevertheless, for perfect
swelling and bioadhesion to take place, an optimum level of
hydration is needed in the mucoadhesive polymer.[19]
Optimum pH
At conditions of low pH, ideal mucoadhesion takes place,
but at higher pH range, a conformational change occurs. At
a higher pH range, polymers having a positive charge like
chitosan form polyelectrolyte complexes with mucus while
exhibiting greater forces of mucoadhesion.[20]
Optimum Polymer Chain Length
The polymers should have optimum chain length. The length
ought to have the capacity to advance the interpenetration
and short to the degree which encourages diffusion.[21]
NATURE OF POLYMERS
Polymers Based on Charge
Numerous polymers possessing charge have proved to be
crucial in the development of mucoadhesive formulations
with sustained release. Derivatives of polyacrylic acid (PAA)
showed enhanced mucoadhesive properties as compared to
cellulose derivatives. Ionic complex with the counter-ionic
drug molecules may be formed with the ionic polymers to
develop mucoadhesive property exhibiting drug delivery
matrix. Cationic polysaccharide chitosan has been used in
some mucoadhesive formulations for its unique properties
such as mucoadhesion, biocompatibility, and non-toxicity.[22,23]
Anionic polymers
Polymers like carboxymethyl cellulose are popularly
deployed for developing mucoadhesive drug delivery.
Anionic polymers are highly used and are a very popular
choice in the pharmaceutical sector. Mucoadhesive polymers
of these types exhibit high strength of mucoadhesion and
a minimum level of toxicity. As these types of polymers
possess functional groups such as carboxyl and sulfate
which, in turn, result in general negative charge at pH which
is higher than its pKa value. Since strong hydrogen bonds
are formed between mucosal mucin layer and these polymers
that’s responsible for outstanding mucoadhesive properties.
Cationic polymers
Of all the mucoadhesive polymers of cationic nature, chitosan
is the most popular and widely studied and are involved in
developing several formulations in pure or in derivatized
forms. Through deacetylation of chitin, the cationic
polysaccharide chitosan is formed. The unique properties of
chitosan make it functional in different fields and are also
used as an eliciting agent, antipathogenic agent, film-forming
agent, as well as in cosmetics.[24,25]
Non-ionic polymers
Mucoadhesives are created utilizing polymers of non-
ionic nature such as methylcellulose (MC), hydroxypropyl
methylcellulose (HPMC), and poly(vinyl pyrrolidone)
(PVP). Out of a few classifications of polymers, non-ionic
have demonstrated the best mucoadhesive quality.[26,27]
Release profile of HPMC 15cps grade is better compared to
HPMC K100LV and HPMC K4M [Figure 2].
Polymers Based on Generation
First generation mucoadhesives
These hydrophilic molecules are natural or synthetic in
nature which contains various organic functional groups that
can generate bonds of hydrogen such as hydroxyl, amino, and
carboxyl groups, which never specifically cohere to different
surfaces. Polymers of this class can further be classified into
three subcategories: Anionic, cationic, and nonionic. Since
cationic molecules are negatively charged at physiological
pH, so these molecules can interact the mucous surface.
Mucoadhesion occurs in cationic polymers (e.g. chitosan)
as the electrostatic interactions that take place between the
polymers amino groups and the mucins sialic groups in the
mucus layer.
Second-generation mucoadhesive materials
Multifunctional materials are used in novel mucoadhesive
systems. An impeccable polymer should display the capacity
to fuse with both the water-soluble and lipid soluble drugs,
demonstrate mucoadhesive attributes in both of its solid
and liquid structures, repress local enzymes or enhance
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S334
absorption, be particular for a cell site or region, invigorate
endocytosis and in conclusion to have a more extensive
safety range (Lee et al., 2000). These are multifunctional
novel mucoadhesive systems which can be named as
second-generation polymers. They act as an alternate option
to non-specific bioadhesives as they can cohere to cell or
mucous surface having specific chemical structures on them.
Molecules similar to invasins, lectins, antibodies, and those
acquired by means of adding thiols to know molecules are
considered in this group [Figure 4].[28,29]
MUCOADHESIVE POLYMERS
Lectins
From a couple of years back, lectins have gotten tremendous
consideration in pharma world for its common potential to
tie particularly with moieties of free sugar or with sugar
residues of polysaccharides, glycolipids, or glycoproteins
which can be either free or bound (as in membranes of
cell). Lectins are a decent choice for oral delivery, as
they provide moderately great protection from acids and
enzymes as well. In any case, binding is possible only just
if the comparing sugar moieties are available or accessible
on the mucosal epithelium. But there are no homogeneous
events of interactions with particular sugar moieties in the
GIT.[30]
Acrylates
Mucoadhesive polymers such as hydroxypropyl cellulose
(HPC), chitosan, and the derivatives of PAA have picked
up prevalence in an extensive variety of formulations. PAA
is considered as one of the most efficient mucoadhesive
polymers among these mucoadhesives. Its high solubility
in water makes it an important carrier for a sustained drug
release. Due to the hydrogen bonding being so strong, strong
complexation between PVP and PAA could be employed
for the preparation of mucoadhesive microspheres. Both
the water-soluble polymers PVP and PAA, on coming in
contact with each other they precipitate after forming a
complex.[31]
Hyaluronic acid
It is anionic in nature and is found all through epithelial,
connective, and neural tissues. The size of the polymers can
range between 5000 and 20,000,000 Da. It is a significant
component present in the synovial fluid and is in charge of
increasing the fluid viscosity. With decreasing molecular
weight of HA, the performance of mucoadhesion enhances
simultaneously.
Gellan gum (GG)
Water-soluble polymers with gel-forming ability when
applied to the delivery site are presently the matter of
interest. The advantages of these polymers outnumber the
other polymers as the liquid form are applied at the delivery
site and swelling causes a strong gel to form and thereby
increasing the formulation’s residence time. GG, a microbial
polysaccharide is produced by water-soluble bacterium
Sphingomonas elodea. Gums alternate to GG (xanthan gum
and karaya gum) have been studied for the controlled delivery
of formulations.[32]
Alginate
Alginate belongs to the category of anionic mucoadhesive
polymer which through carboxyl hydroxyl interactions with
mucin glycoproteins forms strong hydrogen bonds. It’s a
linear, polysaccharide which is soluble in water has gained
attention for applications in different pharmaceutical and
biotechnological fields. Mucoadhesive microbeads have
been produced from the derivatives of thiolated sodium
alginate for the treatment of periodontal pockets locally,
and prolonged release has been observed post-application
which reflects its potential in the treatment of periodontal
disorders.[33]
Poloxamers
Poloxamers like polymers are used on a wide scale in the
pharmaceutical sector for their like high viscous nature which
also offers for a choice of vehicles for controlled release drug
delivery and its high range similarity with a broad-spectrum
of drugs and excipients in formulation developments, which
makes it a good choice of vehicle for delivery of drug through
different administration routes. For its thermoreversible
polymeric property, this polymer is useful in mucoadhesive
formulations.[34]
Pectin
Pectin is a polysaccharide, anionic in nature is specifically
a heteropolysaccharide that is predominantly seen in
primary cell walls. Due to the presence of carboxyl groups
significantly in the structure, it possesses mucoadhesiveness
which causes its interaction with mucus. On hydration,
pectin forms hydrogel possessing high viscosity and thereby
facilitating mucoadhesion.[35]
Starch
Due to their hydrophilic nature and biocompatibility,
polysaccharides, namely starch, alginate, chitosan, and
other cellulose derivatives have been generally utilized as
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S335
systems to deliver mucoadhesive drugs.[36] Starch (amylum), a
polysaccharide formed through glucose units in a large number
and connected together through glycosidic bonds. The starch’s
ability to absorb moisture makes it fit to shape a mucoadhesive
gel-like framework. This phenomena of absorption lead
to the mucosal membrane dehydration which brings about
the drug moiety transportation through paracellular tight
intersections.[37] As bioadhesive drug carriers, spray-dried
starch or Carbopol 974P showed notable improvement for
drug carriers in terms of the mucoadhesive capacity when
contrasted with equal physical blends without exhibiting
any irritational sign. This further recommended starch as a
biocompatible and safe bioadhesive transporter.[38] In addition,
with polymer such as Carbopol 974P and HPMC, the matrix
of starch indicated an increment in the drug discharge for a
model medication of propranolol hydrochloride.[39]
PEG
Another polymer in the mucoadhesive category which is
both safe and nonimmunogenic, likewise non-antigenic
and has been approved by FDA is PEG. It has high water
solubility and has quick in vivo clearance and relies on
its molecular weight.[40] The hydrogen bond forming
capacity with residues of sugar on glycosylated proteins
is the reason behind unique mucoadhesive properties of
PEG.[41] Incorporation of linear PEG chains to matrices
of hydrogel increases the degree of adhesiveness to the
mucous membrane because of the interpenetration of chain
that occurs at the mucus/hydrogel interface has also been
reported.[42]
Sulfated polysaccharide
Sulfated derivatives of polysaccharides have been taken
into account, and high focus has been given on both
its biological and chemical properties from the past
decade.[43] Biological activities have been studied for the
sulfated polysaccharides to look for its anticoagulant,
antioxidant, and antithrombotic activities.[44] The sulfated
polysaccharides show increased water solubility and
exhibit changes in the chain conformation, bringing
in the modification in their biological properties.
Further, the effects of the sulfated polysaccharide and
cyclophosphamide in combination were also examined,
and the sulfated form of chitosan and chitin were proved
to be reliable carriers for delivering several therapeutic
agents over a mucosal membrane.[45]
Carrageenan
Carrageenan consists of gelatin quality polysaccharides
and is obtained from the extract of the red seaweed plant.
Carrageenan is commonly preferred by the vegans and
vegetarians when compared to gelatin. It fills various needs in
conventional drug, which incorporates security from herpes
simplex and personal lubrication and is utilized as a part of
the treatment of the HIV. It is likewise a powerful antivirus
for treating the common cold. Increment in sulfated ester
diminishes the temperature of solvency of the carrageenan
and manufactures poor strength gels. In the pharmaceutical
industry, it is employed in various medicaments as a
mucoadhesive material.[46]
Gelatin
Gelatin, a polyelectrolyte whose net charge relies both on the
pH and the sort of gelatin utilized. Type A gelatin is separated
through acidic hydrolysis from collagen, with an isoelectric
point extending in the vicinity of 7 and 9. However, gelatin
of type B is acquired through alkaline hydrolysis having an
isoelectric point in the vicinity of 4.7 and 5.3. It has been
reported that aminated microspheres of gelatin possess higher
ability of gastric mucoadhesion than gelatin microspheres
used alone. Higher number of amino group indicates the
better flexibility of chain.[47]
Chitosan
Chitosan is a polysaccharide which is made out of
copolymers such as N-acetyl glucosamine and glucosamine.
It is insoluble at neutral or higher pH, then again it forms a
salt with different organic and inorganic acids. Chitosan is a
polymer which is biocompatible and non-toxic in nature. It
is having numerous applications in the delivery of drugs and
shows enhanced absorption for macromolecular drugs which
are hydrophilic in nature. It is also used as an excipient in
formulation development. In a swollen state, it serves as an
excellent mucoadhesive polymer when studied on mucosa
of the porcine intestine. Chitosan is a promising carrier
for colon targeted drug delivery because of its insolubility
at pH >6.5, a similar condition found in the ileum and
jejunum of the GIT on the other hand colonic pH ranges
between 5.5 and 6.0. Hence, at colonic pH, chitosan gets
solubilized subsequently with the release of the drug moiety
(Ludwig, 2005). Chitosan alongside with its metabolized
derivatives is promptly disposed of through kidney. The
mucoadhesive properties of chitosan are determined by
the structure as its degree and sort of interaction with
mucin relies on its structure. Electrostatic binding is the
primary interaction that takes place among chitosan and
mucin. To enhance the chitosan’s mucoadhesive properties
and to make it appropriate for controlled drug delivery,
different adjustments have been done in various ways.[48]
The polymeric solution of chitosan is prepared using 1.5%
(V/V) acetic acid in distilled water under occasional stirring
for 48 h. The final viscous solution of chitosan is filtered
through nylon gauze to eliminate suspended particles and
debris. The drug release profile is enhanced using a water-
soluble hydrophilic polymer PVP K-30 into the chitosan
solution under constant stirring.
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S336
Cellulose derivatives
Diverse polysaccharides along with their derivatives, for
example, chitosan, hyaluronic acid, guar gum, and so forth have
discovered numerous applications in different mucoadhesive
delivery systems. Polymers belonging to this category were
additionally investigated for mucoadhesive delivery into the
eye. NaCMC shows excellent ocular mucoadhesive property
among all mucoadhesive cellulose derivates. Many studies
uncovers that the surface-dynamic property of the cellulose
and its derivatives helps in its film-forming capability.[49,50]
Polymer profile
Formulation design
Conventional dosage forms fail to guarantee the therapeutic
drug levels in mucosal and in the circulation when a drug is
administered through mucosal and transmucosal route. This
happens due to the physiological removal mechanisms that
are involved in the oral cavity (mechanical stress and washing
impact of salivation), which dislodges the drug away from the
active mucosal site, bringing about a shorter time of exposure
and unforeseeable drug distribution at the site of action. For
having the desired therapeutic action, it is fundamental to
expand and enhance the contact between the mucosa and
active substance. To fulfil the requirements of therapeutics,
designed formulations for administration in the buccal region
should have the mentioned functional agents: Agents for
mucoadhesion, to keep up a firm and delayed contact of the
formulation with the absorption site; penetration enhancers,
to upgrade the penetration of medication crosswise over
mucosa or into the most profound epithelium layers; and
enzyme inhibitors, to finally prevent the degradation of drug
through enzymes of mucosa.
Mucoadhesive agents
Depending on the kind of dosage form utilized, buccal
mucoadhesion is possible in different situations. Swelling
along with polymer hydration play the crucial role in case
of partially hydrated or dry formulations. Mucus dehydration
and polymer hydration simultaneously could enhance the
cohesive properties of mucous that aids in the process of
mucoadhesion. Swelling is the driving factor behind chain
flexibility of polymer and interpenetration between mucin
chains and polymer. The coefficient of spreading and the
capacity of forming bonds of physical or chemical nature with
mucin elevates when dosage forms of completely hydrated
nature are taken into consideration. Henceforth, depending
on the formulation type, polymers with varying properties
need to be considered.[51]
The polymers that are frequently used in less hydrated buccal
dosage forms include polyvinyl alcohol (PVA), HPMC, and
HPC. When tested in the total hydrated state, the polymers,
for example, PAA, chitosan, and its derivatives, HPC, PVA,
and gelatine have shown to interact with buccal mucosa.[52]
In recent studies, it has been revealed that cubic and lamellar
liquid crystals of glyceryl monooleate have indicated
properties of mucoadhesion and it looks to be feasible to use
those as carriers to deliver peptides in buccal cavity.[53] In the
past few years, as specific bioadhesives lectins have been
contemplated for oral drug delivery.[54]
Penetration enhancers
To upgrade the retention of drugs which have poor solubility
and especially large molecules which are hydrophilic in
nature, permeation enhancers in recent years have become
the center of focus.[55] For a drug to enter the systemic
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S337
circulation, penetration enhancers are employed to show its
therapeutic action. Their nature must be non-irritant and must
demonstrate a reversible impact which means that after the
drug has been completely absorbed, barrier properties of the
epithelium should be able to recover. The common classes
included in buccal penetration enhancers are fatty acids (lauric
acid, oleic acid, and extract of cod liver oil) which disrupt the
packing of intercellular lipids, surfactants and bile salts (by
extracting membrane protein or lipids, through fluidizing the
membrane, through reverse micellizing the membrane, and
making aqueous channels), a zone (through creating a fluid-
like region in intercellular lipids), and alcohols (through
reorganization of the lipid domains and through changing the
conformation in protein).[56,57]
At present, chitosan along with its different derivatives is
previously known for their properties of mucoadhesion and
has also exhibited to be the potential penetration enhancers
for transmucosal absorption of the drug.[58] Due to the brief
broadening of the tight junctions existing between the cells,
the penetration properties of chitosan through mucosae
(intestinal and nasal) are intensified.[59] It must be brought
to the attention that different in vitro methods and ex vivo
methods have been carried out to estimate and characterize the
penetration enhancement properties of the different materials,
but the in vivo conditions are not simulated appropriately.
The establishment of new standardized biological models
that serve as a substitute for animal studies is need of the
hour for the evaluation of different materials and compare
them [Figure 2].
Absorption enhancement mechanism
In general, permeation enhancers act through the following
ways:
1. Elevating the cell membrane’s fluidity.
2. Extricating intercellular and intracellular lipids.
3. Disruption of lipid structure.
4. Cellular proteins alteration.
5. Increase the drug’s thermodynamic activity.
6. Overcoming barriers of enzymes, especially for protein
drugs and peptides.
7. Alteration of the rheology of surface mucin.
Effective in enhancing the absorption of large molecules,
some proteins in vitro penetration was about 1–3 % but on
adding an appropriate enhancer enhanced the value to 10%.
Table 1: Comparison between theories of Mucoadhesion
Theory Mechanism behind bioadhesion Comments
Wetting theory Bioadhesive polymer’s ability to develop by
spreading close contact with the membrane of
mucus
Spreading coefficient of polymer must be positive
Adsorption theory Chemical bonds are formed due to surface
forces
Profound primary forces: Covalent bonding, ionic
bonding, hydrogen bonding, and van der Waal’s
forces.
Electronic theory Appealing electrostatic forces between mucin
system of glycoprotein and the material of
bioadhesion
Exchange of electron happens between the
development of a two‑fold charged electric layer
at the interface between two surfaces
Fracture theory Analysis of the maximum tensile stress that
is produced amid separation of the mucosal
surfaces
Independent of physical entanglement between
mucin strand and bioadhesive polymer chain,
hence ideal to study about the bioadhesion of
hard polymer, which needs an adaptable chain
Diffusion
interlocking theory
Physical entrapment of mucin strands and the
flexible chains of polymer
For highest diffusion and higher bioadhesive
quality, dissolvability parameters (δ) of both the
bioadhesive polymer and the mucus glycoprotein
must be comparative
Selection of solvent system
Preparation of polymeric
solution/suspension
Casting of polymeric solution/suspension
Drying of the casted solution/suspension
in hot air oven (40-50 °C)
Peeling, Cutting, and packing of prepared
film
Solubility of drug and polymer
Drug and polymer compatibility in
the solvent system
Viscosity of polymeric solution
Miscibility of drug and polymer
Temperature during mixing
Air entrapment
Viscosity of the solution/suspension
Drying temperature
Drying time
Moisture control
Selection of packing container
Moisture control
•
•
•
•
•
•
•
•
•
•
•
•
Figure 3: Steps involved in the film casting process and the
critical parameters involved
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S338
Enzyme inhibitors
The simultaneous administration of a drug and enzyme inhibitor
is an alternate approach for enhancing the drugs and peptides
absorption buccally. Protein containing drugs get stabilized by
enzyme inhibitors, such as aprotinin, puromycin, and some bile
salts through different mechanisms, which includes alteration
of the enzyme activities, changing the peptides or proteins
conformation or providing the drug less accessibility to
enzymatic degradation.[60] Few mucoadhesive polymers such
as poly and chitosan derivatives inhibit the activity of enzymes
even if not present in buccal mucosa. Enzyme autolysis with
loss of enzyme activity takes place through conformational
changes caused when a polyacrylic acid (carbomer) can bind
the essential enzyme cofactors calcium and zinc.[61] In the past
few years, the derivatives of a polymer having thiol groups
on poly(acrylates) or chitosan have been proved to improve
inhibitory properties of polymer-enzyme.[62]
Preparation of buccal delivery films
The two major manufacturing processes involved in the
development of mucoadhesive buccal films are film casting
process and hot-melt extrusion technique.
Film casting
Based on the literature, the method of film casting is surely the
most explored and frequently used process for manufacturing
films. This is mainly due to the easy steps involved in the
process and the inexpensive system setup that incurs at the
research on a laboratory scale.
The whole process involves at least six different steps to
develop a film:
1. Casting solution preparation.
2. Removal of air from the solution.
3. Transfer of solution into the mold.
4. Drying the casting solution.
5. Cutting the final dosage form containing the required
amount of drug.
6. Packaging.
Amid the film manufacturing process, the prime significance
is given to the solution or suspension’s rheological properties,
content uniformity, air bubbles entrapment, and the remaining
solvents present in the final form of dose. Air bubbles are
acquainted incidentally with the fluid amid the steps of
mixing in the manufacturing process and evacuation of air
is a crucial step for reasons like homogeneity.[63] Films cast
from solutions containing airshow a nonuniform surface and
heterogeneous thickness. Presence of organic solvents is a
major concern while manufacturing films for buccal delivery.
Due to several health problems and undesired hazard exerted
by organic solvents on the environment, its used is generally
criticized.[64]
Uniformity of content has always been a noteworthy test since
the introduction of buccal films. Schmidt in one of his earliest
attempts to enhance the drug uniformity in formulated films
proposed that the monolayered nature is mainly responsible
for the nonuniformity of the films. He further postulated a
multi-step technique for manufacturing multi-layered films.
On the other hand, Yang et al. proposed that self-aggregation
is a primary reason for films to show poor uniformity,
and the drying process was important in preventing the
aggregation of the film formulation ingredients. Adding a
viscous agent like gel formers was proposed to avoid non-
uniformity of films.[65] The solvent-casting method is used
for manufacturing films containing heat-sensitive API’s
since the required temperatures for the solvent removal are
relatively low.
Hot-melt extrusion technique
In this method, a molten blend of required ingredients is
forced through an orifice to produce a material of high
homogeneity in varying shapes and sizes.[66] This method is
used to manufacture the controlled-release formulations such
as matrix tablets and pellets[67] and orally disintegrating films
as well.[68] However, few articles have reported using this
technique to manufacture the mucoadhesive buccal films.
Extensive research has been conducted by Repka et al.’s
on the use of this technique for manufacturing these films
and thereby comparing different possible matrix formers
and additives for processing the blend.[69,70] In a previous
publication, it has been reported that films exclusively
Table 2: List of permeation enhancers
S. No. Permeation enhancers
1 2,3‑Lauryl ether
2 Benzalkonium chloride
3 Aprotinin
4 Dextran sulfate
5 Glycol
6 Sodium EDTA
7 Sodium glycocholate
8 Polysorbate 80
9 Polyoxyethylene
Figure 4: The practical steps involved in hot‑melt extrusion
technique
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S339
containing HPC could not be produced, however on adding
the plasticizers, such as PEG 8000 or triethyl citrate made
it possible for manufacturing flexible, thin, and stable HPC
films for a longer period of time.[71] Further study revealed
that with an increased molecular weight, there was a steep
decrease in the release of the films which allows zero-order
drug release [Figure 4].
There are several factors influencing the ideal buccal delivery
film formulation, yet three critical parameters have been
examined broadly in the literature of mucoadhesive buccal
films such as properties of mucoadhesion, enhancement
of permeation, and controlled release of the drug. The vast
majority of the polymers that are utilized in mucoadhesives
are essentially water-soluble polymers that swell and permits
chain interactions to occur with the buccal mucosa’s mucin.
Polymers belonging to the poly (acrylic acid) families have
been exhaustively used as mucoadhesives, as they belong
to the mucoadhesives of first-generation.[72] These polymers
must be hydrated so that they can exhibit their mucoadhesive
properties; however, the phenomenon is limited by a critical
degree of hydration. Overhydration takes place above this
critical value which further leads to the slippery mucilage
formation lacking mucoadhesive properties. It has been
accounted for that the mucoadhesive quality of films got
upgraded with an increase in the chitosan part. The authors
recommended that with an expansion in the concentration of
chitosan, the quantity of amine groups expands that interact
with the negatively charged (carboxyl, sulfate, etc.) groups
present on the buccal epithelium surface.[73] At present,
formulated mucoadhesive films are utilized as platforms
to convey nanoparticles through the oral route.[74] A large
portion of the polymers for mucoadhesion investigated in the
literature are apparently hydrophilic in nature or exhibit some
crucial features for mucoadhesion. Although on repeated
experiment, it has been found that different insoluble grades
of eudragit exhibit some properties of mucoadhesion when
used separately or when combined with other water-soluble
polymers.[75] It has also been proposed that the plasticizer
plays an important role in increasing the mucoadhesion. The
study assumed that the best mucoadhesive characteristics are
exhibited by the ionizable polymers,[76] which on combination
with low-swellable properties would enhance compliance of
patients.
Printing technologies
Latest technologies such as 3D printing could be employed
to produce mucoadhesive films. It could be used extensively
to meet the needs of the individual patient. This will possibly
make both ends meet in the pharmaceutical industry to
fulfill the future demand of customized medicine. These
technologies are gaining popularity for its high flexibility
and cost-effectiveness. From the pharmaceutical industry
point of view, printing technologies are commonly used for
identifying or labeling the pharmaceutical dosage forms, thus
optimizing the product to be readily identified and to prevent
any counterfeit production. This approach has been recently
used for the drug loading of pharmaceutical dosage forms.
A combination of both inkjet and flexographic technologies
has been practiced as well. The inkjet printing is used for
printing of API on a different substrate, and the flexographic
printing is employed for coating the drug loaded-substrate
with a polymeric thin film. All these techniques contribute
to produce the film with high homogeneous distribution and
accurate dosage of the drug throughout the films. The accuracy
of dose and uniform distribution of the drug substances in the
films are responsible for several reasons, such as properties of
coating mass, like density or viscosity, which are influenced
inherently by the amount and characteristics of the processed
drug substances. To summarize, printing a drug on dosage
form is the latest breakthrough in film development and
proved to be a powerful tool to manufacture dosage form
with excellent uniformity, unique speed-ability, and high
stability.[77]
EVALUATION PARAMETERS
Surface pH
The developed mucoadhesive film is put on a Petri plate
previously containing 4 mL of distilled water then it undergoes
swelling at room temperature (25 ± 1°C) for a duration of 1 h.
After that, pH of the film is measured by putting the terminal
electrode of pH meter on its swelled surface.
Flatness
Mucoadhesive film of distinct size (1 cm2) is put up against a
plane surface, and it is cut vertically in several pieces (strips),
and the length is measured subsequently. Percent constriction
is calculated using the following formula. A constriction of
zero percentage infers 100% flatness.
Constriction (%) = {(L1 −L2)/L1} * 100
Here, L1 represents the initial length of the film and L2
represents the final length of the strip.
Flatness (%)= 100−constriction (%).
Drug content
Small pieces are cut from the mucoadhesive film and are
dissolved in 0.1 N NaOH (100 mL) with the assistance
of magnetic stirrer. At that point, the solution undergoes
filtration through a syringe filter of size 0.45 µm. From the
prepared stock solution, a sample of 10 µg/mL concentration
is prepared, and scanning is done by ultraviolet (UV)–vis
spectrophotometer at 242 nm (λmax). For blank control,
placebo mucoadhesive films are used generally. The content
of drug is calculated from the absorbance measured.
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S340
Swelling study
In the wake of guaranteeing the initial weight and diameter of
the film, the samples on the agar plate surface were permitted
to swell that was placed in an incubator kept at a temperature
of 37°C. The increment in the weight and breadth of the films
(n = 3) was measured at pre-set time intervals of (1–5 h). The
swelling percent (%S) was determined using the given equation:
Xt – Xo
%S 100
Xo
= ×
where Xt represents the swollen patch’s weight or diameter of
after a time t, and Xo represents the initial weight or diameter
of the film at zero time.
Determination of the in vitro residence time
A USP disintegration apparatus is modified to estimate
the time for in vitro residence. The composition of the
disintegration medium is 800 ml of isotonic phosphate buffer
(IPB) having pH 6.75 and kept up at37°C. A 3 cm long
portion of rabbit intestinal mucosa is stuck to the glass section
surface attached to the apparatus in a vertical position. The
mucoadhesive film undergoes hydration with IPB of 15 µl
with pH 6.75. The slab of glass is settled to the mechanical
assembly vertically and permitted to move at the same time
up and down to completely immerse the film at the lowest
point in the buffer solution and is out again at the highest
point. The time needed to completely detach the film from the
surface of mucosa is recorded (mean of triplicate trials). Once
more, controlling the media composition, pH, temperature,
or substrate nature will decide the in vitro residence time.
Despite the fact that the estimation of the in vitro residence
time gives information to upgrade the formulation, it does
not reveal the actual strength of the mucoadhesive bond. The
strength of mucoadhesion is estimated as the highest force
needed to withdraw the film from the substrate.
Estimation of mechanical properties of
mucoadhesive films
Alongside the imperative parameters such as the strength of
mucoadhesion and residence time of buccal films, a critical
role is played by the mechanical properties of dosage forms
physical integrity. Most pertinent to the study of mucoadhesive
buccal films are the tensile strength, elongation at break, and
the Young’s modulus.
Tensile strength test
Between two discs of polyoxymethylene, an aqueous
dispersion sample of a mucoadhesive polymer was placed.
The upper disc is movable whereas the disc of the lower
end is stationary, settled on a machine frame. The strength
needed to perpendicularly detach the mucoadhesive cups
from buccal mucosa of freshly removed bovine is termed as
tensile strength. The stress is distributed uniformly over the
mucoadhesive joint in this test. Mucus membrane the large
intestine of a pig is attached to the upper movable disc. After
computing the highest force and work for detachment, it is
in this way inferred that the tensile strength relies on the
concentration used as well as the sort of polymer utilized.
Tensile strength = (Force at failure/Cross-sectional area of
the film)
Elongation at Break
(Increase in length at break/Initial film length)*100
In general, elongation is increased with an increase in
the quantity of acceptable plasticizing agents in a given
formulation.
Young’s modulus
The firmness or the deformation process of the film in the
region of elasticity is evaluated using this parameter. It is
the initial of elastic distortion and is calculated from the
proportion of corresponding strain and stress applied. It can
also be determined from the slope of the stress-strain curve:
Young’s modulus = (Slope of stress-strain curve)/(Film
thickness * Cross-head speed)
It is realized that the fragile and slight polymers have a
little rigidity, low Young’s modulus, and short lengthening
at break; however, a sensitive and solid polymer exhibits a
direct elasticity, low Young’s modulus, and a high extension
at break.
Peel strength test
The measure of power or energy needed to separate the
mucoadhesive formulation tangentially from the freshly
extracted buccal mucosa of bovine. In this test, the edge
of the adhesive system is mainly focused on the stress.
To estimate the mechanical property of the created
mucoadhesive formulations, the tests considered are tensile
strength and shear strength. On the other hand, resistance
toward the peeling power is determined by the peel strength
test. The test for tensile strength is the most normally utilized
mucoadhesive assessment strategy as extracted from the
literature.
Ex vivo mucoadhesion time
The time for mucoadhesion is studied utilizing a mucoadhesive
film. A pH 6.6 phosphate buffer (800 ml) is utilized as a
Mukhopadhyay, et al.: Applications of polymers in mucoadhesive films
International Journal of Green Pharmacy • Apr-Jun 2018 (Suppl) • 12 (2) | S341
medium for disintegration kept up at 37°C. Cheek mucosa
of porcine, 3 cm in length joined to the glass surface which
is vertically connected to the mechanical assembly. The
film is then hydrated with 15 μl phosphate buffer from one
surface, and it is carried into with the mucosal film’s contact.
To completely submerge the film in the buffer solution, the
apparatus is permitted to climb and down. The time needed
to entirely separate the film from the surface of the mucosa is
taken in the record.
Mucoadhesive force determination
The mucoadhesive power of the adhesive polymeric systems
is tested with a tensile tester utilizing a plastic (PVC) plate.
Plastic plates and polymeric films of the predetermined area
(1 cm2 and thickness of 0.8 mm) were cut, and after wetting
with water, the film was positioned over the plastic plate
surface. Under the force of fingertip, it was put in touch with
the plate for 2 min before the measurement. The peak force
was measured that is needed to segregate the film from the
attached surface of the plastic plate.
In vivo mucoadhesion study
Due to the cost included, time required and other moral
worries, there is an acute shortage of in vivo study reports
in the literature. The mucoadhesive formulation’s in vivo
performance depends on the interfacial mechanisms as
well as on the characteristics of the entire mucoadhesive
compound such as the mucosa, the dosage form, and the
interface connecting them.[78]
CONCLUSION
Mucoadhesive buccal film is a novel and promising drug
delivery system which may be mono/multi-layered. The
process of mucoadhesion involves various phenomenons
such as adsorption, electronic interaction, wetting, fracture,
diffusion interlocking, and mechanical. Different kind of
polymers used in the preparation of films, such as ionic and
non-ionic which are further classified on the generation wise.
The selection of the polymers depends on the types of the
active pharmaceutical ingredient, method of preparation and
also the storage conditions. To design a film, we need certain
additives such as mucoadhesive agents, penetration enhancers,
and enzyme inhibitors. There are two techniques involved in
the manufacturing of a film that is film casting process and hot-
melt extrusion process. Due to ease of operation, film casting
method is widely used. Nowadays, 3D printing technology is
introduced to manufacture a film precisely. The developed films
undergo rigorous quality control evaluations tests to check the
quality of the films before it could be marketed. Mucoadhesive
films possess a great potential to replace the existing formulation
in certain disease conditions such as cardiac heart failure
(BELBUCA), asthma, gastroesophageal reflux disease, nausea
and vomiting caused by cancer chemotherapy, hyperacidity
(Gas-X), decongestant (Sudafed PE), opioid dependence
(Suboxone), severe pain (Onsolis), migraine (Zolmitriptan
Rapidfilm), and constipation (Pedis-Lax).
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Source of Support: Nil. Conflict of Interest: None declared.