Department of Pharmaceutics,

STES’s Smt. Kashibai Navale College of Pharmacy, Kondhwa.

 Content

 Introduction
 Principles of Bioadhesion/ Mucoadhesion
 Concepts
 Advantages and Disadvantages
 Transmucosal Permeability
 Formulation Considerations of Buccal Delivery
Systems.
 Mucoadhesive drug delivery systems

 Delivery of drugs via the absorptive mucosa in various easily

accessible body cavities, like the ocular, nasal, buccal, rectal
and vaginal mucosa.

 It has the advantage of bypassing the hepato-

gastrointestinal first-pass elimination associated with oral
administration.

 Various mucoadhesive polymers are being used to formulate

mucoadhesive drug delivery systems.
 Mucoadhesive drug delivery systems utilizes the property
of mucoadhesion/bioadhesion of certain polymers,
which become adhesive on hydration and hence, can be
used for targeting a drug to the particular region of the
body for extended period of time.

 It can be exploited for the noninvasive systemic

delivery of organic and peptide-based drugs, with rapid
absorption as well as sustained drug action.
 Mucosal membranes can be useful sites with good
accessibility for easy application of drug delivery systems,
especially for those with bio(muco)adhesive properties.

 Mucoadhesive drug delivery systems facilitate the

possibility of avoiding either destruction by
gastrointestinal contents or hepatic first-pass inactivation
of drug.
Mucoadhesive/bioadhesive drug delivery system can be
applied to the following systems:

Buccal delivery system

Oral delivery system
Vaginal delivery system
Rectal delivery system
Nasal delivery system
Ocular delivery system
 Structure of the mucosa of the oral cavity

Mucous membranes (mucosae) are the moist

surfaces, lining the walls of various body cavities
such as the gastrointestinal and respiratory tracts.

They consists of a connective tissue layer (the

lamina propria) above which is an epithelial layer, the
upper part of which is made moist usually due to the
presence of a mucous layer.
The epithelia may be either single layered (e.g. the stomach,
small and large intestine and bronchi) or
multilayered/stratified (e.g. in the oesophagus, vagina and
cornea).

The former contain goblet cells which secrete

mucous directly onto the epithelial surfaces, the latter
contain, or are adjacent to tissues containing, specialized
glands such as salivary glands that secrete mucous
onto the epithelial surface.
Mucous is present as either a gel layer sticking to the
mucosal surface or as a soluble or suspended luminal entity.

The primary components of all mucous gels are mucin

glycoproteins, lipids, inorganic salts and water, the latter
comprising more than 95% of its weight, making it a highly
hydrated system.

The mucin glycoproteins are the most important structure

forming component of the mucous gel, which provide the
mucous with its characteristic gel-like, cohesive and adhesive
properties.
The thickness of this mucous layer varies at different
mucosal surfaces, from 50 to 450 μm in the stomach, to
less than 1 μm in the oral cavity.

The major functions of mucous include protection and

lubrication (anti-adherents).
Structure of the mucosa of the oral cavity
 Permeability of the mucosa of the oral cavity

 The oral mucosa in general is somewhat leaky epithelia

intermediate between that of the epidermis and intestinal
mucosa.

 It is estimated that the permeability of the buccal mucosa

is 4-4000 times greater than that of the skin.

 In general, the permeabilities of the oral mucosae

decrease in the order of sublingual greater than buccal
and buccal greater than palatal.
 This rank order is based on the relative thickness and
degree of keratinization of these tissues, with the
sublingual mucosa being relatively thin and non-
keratinized, the buccal thicker and non-keratinized, and
the palatal intermediate in thickness but keratinized.
 Environment of the mucosa of the oral cavity

 The cells of the oral epithelia are surrounded by an

intercellular ground substance, mucus, the principle
components of which are complexes made up of proteins
and carbohydrates.

 These complexes may be free of association or some

maybe attached to certain regions on the cell surfaces.
 This matrix may actually play a role in cell-cell adhesion,
as well as acting as a lubricant, allowing cells to move
relative to one another.

 Along the same lines, the mucus is also believed to play

a role in bioadhesion of mucoadhesive drug delivery
systems.
 Composition of Mucus Layer

Mucus is a translucent and viscid secretion which forms a

thin, contentious gel, mean thickness of this layer varies
from about 50-450 µm in humans secreted by the cells
lining the epithelia.

It has the following general composition. –

 Water -95%
 Glycoprotein and lipids – 0.5-3.00%
 Mineral salts – 1%
 Free proteins – 0.5-1.0%
 Functions of Mucus Layer

1. Protective: resulting particularly from its hydrophobicity.

2. Barrier: The role of the mucus layer as a barrier in tissue
absorption of the drugs and influence the bioavailability.
3. Adhesion: Mucus has strong adhesion properties.
4. Lubrication: It is to keep the mucus from the goblet cell is
necessary to compensate for the removal of the mucus
layer due to digestion, bacterial degradation and
solubilisation of mucin molecules.
 Need of Mucoadhesive

For sustained release of drug.

To target drug delivery and also for localized drug
delivery.
To bypass or minimize hepatic first pass metabolism so
that drug degradation can be avoided.
For prolonged therapeutic effect.
For high and rapid drug movement through the absorbing
tissue.
To reduce in fluctuation of steady state plasma level.
 Role of Saliva

1. Saliva is composed of 99% water and is complex fluid

containing organic and inorganic material. Secretion of
saliva is highest during working hours.
2. Protective fluid for all tissues of the oral cavity.
3. Continuous mineralization / demineralization of the tooth
enamel.
4. Moisten the oral cavity
 Concept of Bioadhesion

 The term ‘bioadhesive’ describes materials that bind or

adhere to the biological substrates.

 ‘Bioadhesive’ can be defined as a material that is capable of

interacting with biological material and being retained on
them or holding them together for extended period of time.

 Bioadhesion is the state in which two materials (at least one

of which is biological in nature), are held together for a
extended period of time by interfacial forces.
 These drug delivery system utilize property of bioadhesion
of certain water soluble polymers, which become adhesive
on hydration and hence can be used for targeting particular
sites.

 The term bioadhesion implies attachment of drug-carrier

system of specific biological location. This biological
surface can be epithelial tissue or the mucous coat on the
surface of tissue.

 If adhesive attachment is to mucous coat then phenomenon

is referred as mucodhesion.
 Bioadhesion’ may occur via 3 ways:

i). Bioadhesion in-between biological layers without the

involvement of artificial materials.

ii). Cell adhesion into the culture dishes or adhesion to a

variety of substances, such as woods, metals, and other
synthetic substances.

iii).Adhesion of artificial substances to the biological

substrates like the adhesion of hydrophilic polymers to skin or
other soft tissues.
 Different strategies have been adopted for controlled
mucosal delivery and are based on:

1. Prolonging the duration of absorption process.

2. Developing unidirectional delivery systems

3. Preparing user-friendly mucosal delivery systems.

 Mechanism of Mucoadhesion
Mucoadhesion is a complex process involving wetting,
adsorption and interpenetration of polymer chains.
Mucoadhesion is established in the following stages:

 Contact stage: Intimate physical contact between a

Bioadhesive/Mucoadhesive material and a membrane
(wetting or swelling phenomenon).
 Consolidation stage: Penetration of the
Bioadhesive/Mucoadhesive into underlying the tissue or
into the surface of the mucous membrane
(interpenetration).
 Six theories have been proposed to explain the
fundamental mechanism of bioadhesion
/mucoadhesion:

1. Electronic theory
2. Adsorption theory
3. Wetting theory
4. Diffusion theory
5. Fracture theory
6. Mechanical theory
1.Electronic theory-

 (Attractive electrostatic forces in-between glycoprotein

mucin network and the bioadhesive/mucoadhesive
polymers.)

 When both mucoadhesive and biological materials come

into contact, they transfer electrons leading to the building
of a double electronic layer at the interface, where the
attractive forces within this electronic double layer
determines the mucoadhesive strength.
2.Adsorption theory-

 (Surface forces (covalent bonds, ionic bonds, hydrogen

bonds, and van der Waal’s forces) resulting in chemical
bonding.)

 The mucoadhesive device adheres to the mucus by

secondary chemical interactions, such as in van der Waals
and hydrogen bonds, electrostatic attraction or
hydrophobic interactions.
 Such forces have been considered the most important in
the adhesive interaction phenomenon because, although
they are individually weak, a great number of interactions
can result in an intense global adhesion.
3.Wetting theory-

 (Ability of bioadhesive/mucoadhesive polymers to spread

and develop immediate attachment with the mucous
membranes.)

 The wetting theory applies to liquid systems which present

affinity to the surface in order to spread over it.

 This affinity can be measure by contact angle.

 The general rule states that the lower the contact angle then
the greater the affinity The contact angle should be equal or
close to zero to provide adequate spreadability.
 The spreadability coefficient, SAB, can be calculated from
the difference between the surface energies yB and yA and
the interfacial energy yAB, as indicated in equation,

SAB=yB-yA-yAB

 The greater the individual surface energy of mucus and

device in relation to the interfacial energy, the greater the
adhesion work, WA, i.e, the greater the energy needed to
separate the two phases

WA=yA+yB-yAB
4.Diffusion theory-

 (Physical entanglement of mucin strands and the flexible

polymeric chain.)

 Diffusion theory describes the interpenetration of both

polymer and mucin chains to a sufficient depth to create a
semi-permanent adhesive bond.

 It is believed that the adhesion force increases with the

degree of penetration of the polymer chains.
 This penetration rate depends on the diffusion coefficient,
flexibility and nature of the mucoadhesive chains,
mobility and contact time.
 This interpenetration depth of polymer and mucin chains
can be estimated by the following equation.

I=(tDb)1/2

Where, t – Contact Time

Db – Diffusion Coefficient of the mucoadhesive material in
the mucus.

 The adhesion strength foe a polymer is reached when the

depth of penetration is approximately equivalent to the
polymer chain size.
5.Fracture theory-

 (Analyses the maximum tensile stress developed during

detachment of mucoadhesive/bioadhesive drug delivery
systems from the mucosal surfaces.)

 It analyses the force required to separate two surfaces after

adhesion is established. The force Sm is frequently
calculated in tests of resistance to rupture by the ratio of the
maximal detachment force, Fm and the total surface area
A0.
Sm=Fm/A0
6.Mechanical theory-

 This theory consider 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.
 Advantages of Mucosal Drug Delivery System

 Mucosal drug delivery offers several advantages over

other controlled release systems:

 These systems allow the developing of contact in-between

the dosage forms and the mucosa
(mucoadhesion/bioadhesion).

 High drug concentration can be maintained at the

absorptive surface for a prolonged period.
 Painless and ease of administration.

 Low enzymatic activity and avoid of first pass metabolism.

Targeting and localization of the dosage form at a specific
site.

 Termination of therapy is possible.

 Drugs which are unstable in acidic environment of stomach

or destroyed by the alkaline environment of intestine can
be given other mucosal route.
 Drug shows poor bioavailability by oral route can be
administered by other mucosal route.

 It follows passive diffusion, and does not require any

activation.

 Thin mucin film exist on the surface of oral cavity provides

opportunity to retain delivery system in contact with
mucosa for prolonged period of time with the help of
mucoadhesive compounds.
 The buccal membrane is sufficiently large to allow
delivery system to be placed at different sites on the same
membrane for different occasion, if the drug or other
excipients cause reversible damage or irritate mucosa.
(Dosage forms can be immobilized specifically at any part
of the oral mucosa, buccal mucosa, sublingual or gingival
mucosa, etc)

 The presence of saliva ensures large amount of water for

dissolution of drug unlike in case of rectal and
transdermal route.
 Disadvantages of Mucosal Drug Delivery System

 Small mucosal surface for contact.

 Lack of flexibility of dosage forms.

 Difficult to achieve high drug release rates required for

some drugs.

 Extent and frequency and frequency of attachment may

cause local irritation.
 Over hydration may lead to formulation slippery surface
and structural integrity of the formulation may get
disrupted by the swelling and hydration of the bioadhesion
polymer.

 Eating and drinking may become restricted.

 Drug which irritates mucosa or have a bitter or unpleasant

taste or an obnoxious odour cannot be administered by this
route.

 Costly drug delivery system.

 Only drug which are absorbed by passive diffusion can
be administered by this route.

 Only small dose drug can be administered.

 In case of buccal tablet there is possibility that patient

may swallow the tablet.

 Unfortunately, the back of standardized techniques often

leads to unclear result.
 Formulation Consideration for Mucosal Drug Delivery
System
 In case of both mucosal (local) and transmucosal
(systemic) administration, conventional dosages are not
able to assure therapeutic level.

 Mucosal drug delivery systems contains active drug along

with the following functional agents:

(1) Mucoadhesive polymers

(2) Penetration enhancers
(3) Enzyme inhibitors.
(a) Mucoadhesive Polymers: The polymer hydration and
consequently the mucous cohesive properties that promote
mucoadhesion (MA), Swelling should favour polymer
chain flexibility and interpenetration b/w polymer and
mucin chains.

 These can be broadly categorized as:

I. Synthetic polymers

II. Natural polymers.

(I) Synthetic polymers:
(a) Cellulose derivatives: Methylcellulose (MC), Hydroxy
ethylcellulose (HEC), Hydroxyl propylcellulose (HPC),
Hydroxy propyl methylcellulose (HPMC), Sodium
carboxy methylcellulose (NaCMC), etc.
(b)Poly (Acrylic acid) polymers: Carbomers, Polycarbophil.
(c) Poly vinyl alcohol (PVA).

(II) Natural polymers:

Chitosan, gum tragacanth, sodium alginate, xanthan gum,
locust bean gum, gellan gum, etc.
 Ideal Characteristics of Mucoadhesive Polymers

 A mucoadhesion promotoing agent or the polymer is

added to the formulation which helps to promote the
adhering of the active pharmaceutical ingredient to the
oral mucosa.

 The agent can have such additional properties like

swelling so as to promote the disintegration when in
contact with the saliva.
1) Polymer must have a high molecular weight up to 100.00
or more. This is necessary to promote the adhesiveness
between the polymer and mucus.

2) Long chain polymers-chain length must be long enough to

promote the interpenetration and it should not be too long
that diffusion becomes a problem.

3) High viscosity.
4) Degree of cross linking- it influences chain mobility and
resistance to dissolution. Highly cross linked polymers
swell in presence of water and retain their structure.
Swelling favours controlled release of the drug and
increases the polymer/mucus interpenetration

5) Spatial conformation.

6) Flexibility of polymer chain- this promotes the

interpenetration of the polymer within the mucus
network.
7) Concentration of the polymer- an optimum
concentration is required to promote the
mucoadhesive strength. It depends however, on the
dosage form.

8) Charge and degree of ionization- the effect of polymer

charge on mucoadhesion was clearly shown by
Bernkop-Schnurch and Freudl. Cationic chitosan HCl
showed marked adhesiveness when compared to the
control.
The attachment of EDTA an anionic group increased the
mucoadhesive strength significantly. DTPA/chitosan system
exhibited lower mucoadhesive strength than cationic chitosan
and anionic EDTA chitosan complexes because of low charge.
Hence the mucoadhesive strength can be attributed as
anion>cation>non-ionic.

9) Optimum hydration- excessive hydration leads to decreased

mucoadhesive strength due to formation of a slippery
mucilage.
10) Optimum pH – mucoadhesion is optimum at low pH
conditions but at higher pH values a change in the
conformation occurs into a rod like structure making those
more available for inter diffusion and interpenetration. At
very elevated pH values, positively charged polymers like
chitosan form polyelectrolyte complexes with mucus and
exhibit strong mucoadhesive forces.

11) It should non toxic, economic, biocompatible preferably

biodegradable.
(b) Penetration Enhancers (PE): PE is also required
when a drug has to reach the systemic circulation to
exert its action. Must be non-irritant and have a
reversible effect. Recently, chitosan and its derivatives,
polymers already known for MA properties help for
transportion of drug through paracellular pathway.

List of Permeation Enhancer: Benzalkonium chloride,

Dextran sulfate, Fatty acid, Propylene glycol, Menthol,
Phosphatidylcholine, Polysorbate 80, Sodium EDTA.
c) Enzyme inhibitors: Drug + enzyme inhibitors=
improving the buccal absorption of drugs, particularly
peptides.

Examples: 1. Aprotinin 2. Bestatin 3. Puromycin bile salts

stabilise protein drugs by different mechanism (effecting the
activity of the enzymes, altering the conformation of the
protein.
 Classification of Mucoadhesive Polymers

I. Based on Specificity:

(a) The specific bioadhesive polymers: These have the

ability to adhere specific chemical structures within the
biological molecules, e.g. Lectins, fimbrin.

(b) The non-specific bioadhesive polymers: These have the

ability to bind with boththe cell surfaces and the mucosal
layer, e.g. Polyacrylic acid, cyanoacrylates.
II. Based on Origin:

(a) Synthetic Polymers

For example: Cellulose derivatives: Methyl cellulose, ethyl
cellulose, hydroxyethyl cellulose.Polyacrylic acid
polymers: Polymethylacrylate, polyvinylpyrrolidone,
polyvinyl alcohol.

(b) Natural Polymers

For example: Tragacanth, sodium alginate, karaya gum, guar
gum, xanthan gum, lectin, soluble starch, gelatin, pectin,
chitosan.
III. According to their Charge:

(a) Anionic polymers: carbopol, polyacrylates.

(b) Cationic polymers: chitosan.
(c) Neural/non-ionic polymers: eudragit analogues.

IV. Based on Solubility:

(a) Water soluble polymers

(b) Water insoluble polymers
 Mucosal drug delivery systems can be classified as:
1. Non-attached mucosal drug delivery systems
2. Attached or immobilized mucosal drug delivery
systems

1. Non-attached mucosal drug delivery systems:

 These systems are being formulated to be absorbed

through the mucosa within the oral cavity.

 Examples: Sublingual tablets, Fast dissolving tablets

(Melt-in-mouth or orally disintegrating tablets), etc.
2. Attached or immobilized mucosal drug delivery systems:

 These systems are being formulated to be remained

attached onto the mucosal surface by the adhesive
properties.

 These systems are also known as mucoadhesive systems.

 Examples: Buccal drug delivery systems, rectal DDS,

vaginal DDS, nasal DDS, etc.
 Factors Affecting Mucoadhesion

The mucoadhesion of a drug carrier system to the mucous

membrane depends on the below mentioned factors.

I. Polymer Based Factors:

 Molecular weight of the polymer

 Concentration of polymer used of polymer chain
 Swelling factor
 Stereochemistry of polymer.
II. Physical Factors:

 pH at polymer substrate interface

 Applied strength
 Contact time.

III. Physiological Factors:

 Mucin turnover rate

 Diseased state.
 Applications of Mucosal Drug Delivery System

Mucoadhesive Dosage Forms are available in various

following forms summarized intable:

1) Tablets:

 Tablets are small, flat and oval, with a diameter of

approximately 5-8 mm. Unlike the conventional tablets,
mucoadhesive tablets allow for drinking and speaking
without major discomfort.
 They soften, adhere to the mucosa, and are retained in
position until dissolution and/or release is complete.

 Mucoadhesive tablets, general, have the potential to be

used for controlled release drug delivery, but coupling of
mucoadhesive properties to tablet has additional
advantages, for example, it offers efficient absorption and
enhanced bioavailability of the drugs due to a high surface
to volume ratio and facilitates a much more intimate
contact with the mucous layer.
 Mucoadhesive tablets can be tailored to adhere to any
mucosal tissue including those found in stomach, thus
offering the possibilities of localized as well as systemic
controlled release of drugs.

 The application of mucoadhesive tablets to the mucosal

tissues of gastric epithelium is used for administration of
drugs for localized action.
 Mucoadhesive tablets are widely used because they
release the drug for a prolonged period, reduce
frequency of drug administration and improve the
patient compliance.

 The major drawback of mucoadhesive tablets is their

lack of physical flexibility. leading to poor patient
compliance for long-term and repeated use.
2) Films:

 Mucoadhesive films may be preferred over adhesive

tablets in terms of flexibility and comfort.

 In addition, they can circumvent the relatively short

residence time of oral gels on the mucosa, which are
easily washed away and removed by saliva.

 Moreover, in the case of local delivery for oral diseases,

the films also help to protect the wound surface, thus help
to reduce pain, and treat the disease more effectively.
 An ideal film should be flexible, elastic, and soft, yet
adequately strong to withstand breakage due to stress from
mouth movements.

 It must also possess good mucoadhesive strength in order

to be retained in the mouth for the desired duration of
action.

 Swelling of film, if it occurs, should not be too extensive

in order to prevent discomfort.
3) Patches:

 Patches are laminates consists of an impermeable backing

layer, a drug- containing reservoir layer from which the drug
is released in a controlled manner, and a mucoadhesive
surface for mucosal attachment.

 Patch systems are similar to those used in transdermal drug

delivery.

 Two methods used to prepare adhesive patches includes

solvent casting and direct milling.
 In the solvent casting method, the intermediate sheet from
which patches are punched is prepared by casting the
solution of the drug and polymers onto a backing layer
sheet, and subsequently allowing the solvents to
evaporate.

 In the direct milling method, formulation constituents are

homogeneously mixed and compressed to the desired
thickness, and patches of predetermined size and shape are
then cut or punched out.
 An impermeable backing layer may also be applied to
control the direction of drug release, prevent drug loss,
and minimize deformation and disintegration of the
device during the application period.

4) Gels and Ointments:

 Semisolid dosage forms, such as gels and ointments,

have the advantage of easy dispersion throughout the
oral mucosa.
 However, drug dosing from semisolid dosage forms may
not be as accurate as from tablets, patches, or films. Poor
retention of the gels at the site of application has been
overcome by using mucoadhesive formulations.

 Certain mucoadhesive polymers, for example, sodium

carboxymethylcellulose, carbopol, hyaluronic acid and
xanthan gum, undergo a phase change from liquid to
semisolid.

 This change enhances the viscosity, which results in

sustained and controlled release of drugs.
 Hydrogels are also a promising dosage form for buccal
drug delivery.

 They are formed from polymers that are hydrated in an

aqueous environment and physically entrap drug molecules
for subsequent slow release by diffusion or erosion.

 The application of mucoadhesive gels provides an

extended retention time in the oral cavity, adequate drug
penetration, as well as high efficacy and patient
acceptability.
 A major application of adhesive gels is the local delivery of
medicinal agents for the treatment of periodontitis, which is
an inflammatory and infectious disease that causes
formation of pockets between the gum and the tooth, and
can eventually cause loss of teeth.

 It has been suggested that mucoadhesive polymers might be

useful for periodontitis therapy when incorporated in
antimicrobial containing formulations that are easily
introduced into the periodontal pocket with a syringe.
 HPMC has been used as an adhesive ointment ingredient.
Additionally, a highly viscous gel is developed from
carbopol and hydroxypropylcellulose for ointment dosage
forms that could be maintained on the tissue for up to 8
hours.
 Evaluation

(1) Tensile Stress Measurement:

(a) Wilhelmy plate technique:

The Wilhelmy plate technique is traditionally used for the
measurement of dynamic contact angles. The instrument
measures the bioadhesive force between mucosal tissue and
the dosage form. By using the CAHN software system,
parameters such as fracture strength, deformation to failure
and work of adhesion can be analysed.
(b) Electromagnetic force transducer (EMFT) uses a
calibrated electromagnet detach a magnetic loaded polymer
DDS from a tissue sample.

 It has the unique ability to record remotely and

simultaneously the tensile force information as well as high
magnification video images of bioadhesive interactions at
near physiological conditions.

 EMFT measures tissue adhesive forces by monitoring the

magnetic force required to exactly oppose the bioadhesive
force.
(2) Shear Stress Measurement:

 The shear stress technique measures the force that causes

a mucoadhesive to slide with respect to the mucous layer
in a direction parallel to their plane of contact.

 Adhesion tests based on the shear stress measurement

involves two glass slides coated with polymer and a film
of mucous. Mucous forms a thin film between the two
polymer coated slides, and the test measures the force
required to separate the two surfaces.
(3) Rheological Approach

 The rheological properties of the mucoadhesive interface

(i.e. of the hydrated gel) are influenced by the occurrence of
the interpenetration step in the process of bioadhesion.

 Chain interlocking, conformational changes and chemical

interaction, which occur between bioadhesive polymer and
mucin chains, produce changes in the rheological behaviour
of the two macromolecular species.
 Falling Liquid Film Method:

 In this method, the biological membrane is placed at an

inclination of a tygon tube flute.

 The adhesion of particles to this surface is monitored by

passing the particle suspension over the surface.

 By comparing the fraction of particles adherent to the

tissue, the adhesion strength of different polymers can be
determined.
(4) Colloidal Gold Staining Method

 This technique employs red colloidal gold particles, which

are stabilized by the adsorbed mucin molecule by forming
mucin-gold conjugates.
 Upon interaction with mucin-gold conjugates, bioadhesive
hydrogels develops a red colour on the surface.
 Thus, the interaction between them can easily be
quantified, either by the measurement of the intensity of the
red colour on the hydrogel surface or by the measurement
of the decrease in the concentration of the conjugates from
the absorbance changes at 525 nm.
(5) Viscometeric Method

 A simple viscometric method is used to quantify mucin-

polymer bioadhesive bond strength viscosities of 15% w/v
porcine gastric mucin dispersion in 0.1 M HCl (pH 1) or
0.1 M acetate buffer (pH 5.5) are measured with a
Brookefield viscometer in the absence or presence of
selected neutral, anionic, and cationic polymers.

 Viscosity components and the forces of bioadhesion are

calculated.
(6) Fluorescent Probe Method

 Fluorescent probe method is used to study polymer

interaction with a conjunctival epithelial cell membrane.

 The experiment consists of adding a fluorescent lipo

soluble probe, pyrene, which localizes in the lipid bilayer
of the cell membrane, to a suspension of cultured human
conjunctival epithelial cells.
 The cells are then mixed with various bioadhesive
polymers. The addition of a polymer, which binds to the
cell membrane, resulted in compression of the lipid
bilayer, causing a change in fluorescence proportional to
polymer binding.

 Measurement of pyrene fluorescence provides a

quantitative way to compare the interaction of polymers
with the cell membrane.
(7) Thumb Test

 It is a simple method which can be used to identify

mucoadhesives.

 The adhesiveness is quantitatively measured by the

difficulty of pulling the thumb from the adhesive as a
function of the pressure and the contact time.

 Although the thumb test may not be conclusive, it provides

useful information on mucoadhesive potential.
 In-vivo Techniques:

 Measurement of biological response of living organism

locally or systemically after administration of MDDS is
evaluated.

 For exmaple: Nitroglycerin, an organic nitrate for treatment

of angina pectoris, is the most commonly used drug applied
to the oral mucosa and its systemic pharmacological effects
are monitored to measure drug absorption.
(8) Buccal Absorption Test (Swirl and spit test)

 Buffered drug solution, of known volume and

concentration, is placed in the subject's mouth and is
swirled in the mouth for a defined length of time.

 The solution is then expelled and assayed. The amount of

drug absorbed is determined by the difference between the
amounts of drug introduced and recovered.
(9) In-vivo Perfusion Studies

 Perfusion experiments are done by attaching the perfusion

chambers to the oral mucosa of an anesthetized dog.

 Drug solutions are circulated through the device and

collected at different time intervals.
(10) GI Transit using Radio-opaque Technique

 It involves the use of radio-opaque markers, e.g., barium

sulfate, encapsulated in bioadhesive DDS to determine
the effects of bioadhesive polymers on GI transit time.

 Faeces collection (using an automated faeces collection

machine) and X-ray inspection provide a non-invasive
method of monitoring total GI residence time without
affecting normal GI motility.
(11) Gamma Scintigraphy Technique
 It is a valuable tool used in the development of
pharmaceutical dosage forms. With this methodology, it is
possible to obtain information non-invasively. This
technique gives information in terms of
 oral dosage forms across the different regions of GI tract
 the time and site of disintegration of dosage forms
 the site of drug absorption
 also the effect of food
 disease
 size of the dosage form on the in-vivo performance of the
dosage forms.
 Transmucosal Permeability

 The mucosal lining of the oral cavity is referred to as the

oral mucosa.

 The oral mucosa comprises the buccal, sublingual,

gingival, palatal and labial mucosa.

 The unique environment of the transmucosal route offers

its potential as an effective route for the delivery of a
variety of drugs.
 Due to rich blood supply, higher bioavailability, lymphatic
drainage and direct access to systemic circulation, the
transmucosal route is suitable for drugs, which are
generally susceptible to acid-hydrolysis in the
gastrointestinal tract or extensively metabolized in liver.

 In addition, oral mucosa facilitates an advantage of

retaining drug delivery systems in contact with the
absorptive mucosal surface for a longer period (i.e,
Mucoadhesion) and thus, optimizing the drug concentration
gradient across the mucosal membrane with the reduction
of differential pathways.
 Thus, the delivery of drugs through the transmucosal
route has attracted particular attention due to its potential
for high patient compliance and unique physiological
features.

 The drugs to be administered through the transmucosal

route need to be released from the dosage forms to the
effective delivery site (e.g., buccal or sublingual area) and
pass through the mucosal layers to enter the systemic
circulation
 Certain physiological features of the transmucosal route play
significant roles in this process, including pH, enzyme
activity, fluid volume and the permeability of oral mucosa.

 Mucosal routes provide the potential pathways to bypass

hepatogastrointestinal first-pass elimination following oral
administration.

 Transmucosal drug delivery has the potential to achieve

greater systemic bioavailability for orally metabolized
drugs, including organic and peptide-based pharmaceuticals.
 The secretion of saliva is also an important determinant
for the performance of transmucosal drug delivery.
 The main mechanisms responsible for the penetration
of various molecules include:
 Simple diffusion (paracellular or transcellular)
 carrier-mediated diffusion
 active transport
 pinocytosis or endocytosis.

 However, there is little research on to what extent this

phenomenon affects the efficiency of oral transmucosal
delivery from different drug delivery systems and thus,
further research needs to be conducted to better
understand this effect.
 There are two routes potentially involved in drug
permeation across epithelial membranes:
I. Transcellular route
II. Paracellular route
1)Paracellular route:
 For hydrophilic compounds
 This compound is difficult to penetrate into the lipophilic
cell membrane
 Intercellular space is preferred route for drug transport
 Drug movement in this route (JH)can be written as,
(JH)=DH € Co
hH
Where, €=Fraction of surface area of paracellular route
DH =Diffusion coefficient
Hh = pathlength of paracellular route
Co = donar side drug concentration
2)Transcellular route:
 For lipophilic compound
 Drug molecule move across both lipophilic cell
membrane and hydrophilic cytoplasm as well as
intercellular space.
 The permeability of lipophilic compound across the
epithelial cell membrane is typically high.
 Drug flux is transcellular route (JL) can be expressed as:
(JL)= (1-€) DH Kp Co
hL
Where, Kp-partition coefficient between lipophilic and
hydrophilic region, hL-pathlength of transcellular route
 Drug delivery across the oral mucosal membranes is
termed transmucosal drug delivery.

 It can be divided into three main categories of

transmucosal drug delivery based on the characteristics of
the oral cavity:

I. Sublingual delivery: Administration of drugs via the

sublingual mucosa (the membrane of the ventral surface
of the tongue and the floor of the mouth) to the systemic
circulation.
II. Buccal delivery: Administration of drugs via the buccal
mucosa (the lining of the cheek) to the systemic
circulation. (Drugs are delivered through mucosal
membrane into systemic circulation by placing drug in
between cheeks and gums.)

II. Local delivery: For the treatment of conditions of the

oral cavity, principally ulcers, fungal conditions and
periodontal disease, gingival disease, bacterial and fungal
infections, dental stomatitis, etc.
Formulation Considerations of Buccal Delivery Systems

 Transmucosal administration of drugs across the buccal

lining is defined as buccal drug delivery.

 The mucosa of the buccal area has a large, smooth and

relatively immobile surface, which provides a large
contact surface (Fig).

 The large contact surface of the buccal mucosa

contributes to rapid and extensive drug absorption.
 Buccal drug
delivery was first
introduced by
Orabase in 1947,
when gum
tragacanth was
mixed with dental
adhesive powder to
supply penicillin to
the oral mucosa.
Fig: Schematic diagram of buccal mucosa
 Recent years, buccal drug delivery has proven particularly
useful and offers several advantages over other drug
delivery systems including:

 Bypass of the gastrointestinal tract and hepatic portal

system, increasing the bioavailability of orally
administered drugs that otherwise undergo hepatic first-
pass metabolism.

 Convenience of administration as compared to injections

or oral medications.
 Improved patient compliance due to the elimination of
associated pain with injections. Administration of drugs in
unconscious or incapacitated patients.

 Sustained drug delivery.

 Increased ease of drug administration; and ready

termination of delivery by detaching the dosage form.
 Buccal drug delivery occurs in a tissue that is more
permeable than skin and is less variable between patients,
resulting in lower inter-subject variability.

 Because of greater mucosal permeability, buccal drug

delivery can also be used to deliver larger molecules such
as low molecular weight heparin.

 In addition, buccal DDS could potentially be used to

deliver drugs that exhibit poor or variable bioavailability,
and bioavailability will be enhanced for drugs that
undergo significant first-pass metabolism.
 Because drug absorbed from the oral cavity avoids both
first-pass metabolism and enzymatic/acid degradation in
the gastrointestinal tract, buccal administration could be
of value in delivering a growing number of potent
peptide and protein drug molecules.
 In addition, buccal delivery of such drug molecules is a
promising area for continued research with the aim of
alternative non-invasive delivery.

 The novel type buccal dosage forms include:

 Buccal mucoadhesive tablets

 Buccal patches and films
 Semisolids (ointments and gels) and powders
 Buccal mucoadhesive tablets:

 Buccal mucoadhesive tablets are dry dosage forms that

have to be moistened prior to placing in contact with
buccal mucosa.

 Buccal patches and films:

 Buccal patches and films consist of two laminates, with an

aqueous solution of the adhesive polymer being cast onto
an impermeable backing sheet, which is then cut into the
required round or oval shape.
 These also offer advantages over creams and ointments in
that they provide a measured dose of drug to the site.

 Recent years, buccal patches and films have received the

greatest attention for buccal delivery of drugs.

 They present a greater patient compliance compared with

tablets owing to their physical flexibility that causes only
minor discomfort to the patient.
 Semisolids (ointments and gels):

 Bioadhesive gels or ointments have less patient

acceptability than solid bioadhesive dosage forms, and
most of the dosage forms are used only for localized
drug therapy within the oral cavity.
 Structure and design of buccal patches

 Buccal patches are of two types on the basis of their

release characteristics:

I. Unidirectional buccal patches

II. Bidirectional buccal patches

 Unidirectional patches release the drug only into the

mucosa, while bidirectional patches release drug in both
the mucosa and the mouth.
 Buccal patches are structurally of two types:

I. Matrix type
II. Reservoir type

I. Matrix type: Fig : Schematic representation of the matrix-

type buccal patch design
 The buccal patch is designed in a matrix configuration
contains drug, adhesive, and additives mixed together
(Fig.).
II. Reservoir type:

 The buccal patch designed in a reservoir system contains

a cavity for the drug and additives separate from the
adhesive.

 An impermeable backing is applied to control the

direction of drug delivery; to reduce patch deformation
and disintegration while in the mouth; and to prevent
drug loss.
 Composition of buccal patches

 Drugs:

 The selection of suitable drug for the design of buccal

drug delivery systems should be based on
pharmacokinetic properties of the drugs to be
administered.

 Drug used for rapid release/prolonged release and for

local systemic effect is suitable candidate for buccal
delivery.
 The drug should have following characteristics for the
designing of effective buccal patches:

i. The conventional single dose of the drug should be small.

ii. The drugs having biological half-life between 2-8 hr are

good candidates for controlled drug delivery.

iii. Tmax of the drug shows wider-fluctuations or higher

values when given orally.
ii. Through oral route drug may exhibit first pass effect or
pre-systemic drug elimination.

v. The drug absorption should be passive when given orally.

vi. Buccal adhesive drug delivery systems with the size 1–3
cm2 and a daily dose of 25 mg or less are preferable.
 Polymers (adhesive layer):

 Bioadhesive polymers play a major role in the designing of

buccal patches.

 Bioadhesive polymers are from the most diverse class and

they have considerable benefits upon patient health care
and treatment.

 Drug release from a polymeric material takes place either

by the diffusion or by polymer degradation or by a
combination of the both.
 These polymers enable retention of dosage form at the
buccal mucosal surface and thereby provide intimate
contact between the dosage form and the absorbing
tissue.

 Polymer degradation generally takes place by the

enzymes or hydrolysis either in the form of bulk erosion
or surface erosion.
 An ideal bioadhesive polymer for buccal patches
should have following characteristics:

i. The polymer should be inert and compatible with the

buccal environment.

ii. It should allow easy incorporation of drug in to the

formulation.

iii. The polymer and its degradation products should be

non-toxic absorbable from the mucous layer.
iv. It should demonstrate acceptable shelf life.

v. It should form a strong non covalent bond with the mucin

or epithelial surface and should possess sufficient
mechanical strength.

vi. The pH of the polymer should be biocompatible and

should possess good viscoelastic properties.
vii. It should adhere quickly to moist tissue surface and
should possess the site specificity.

viii. The polymer must not decompose on storage or during

the shelf life of the dosage form.

ix. It must have high molecular weight and narrow

distribution.
x. The polymer should be easily available in the market and
economical.

xi. The polymer should have good spreadability, wetting,

swelling and solubility and biodegradability properties.

xii. It should demonstrate local enzyme inhibition and

penetration enhancement properties.
 Backing layer:

 Backing layer plays a major role in the attachment of

buccal patches to the mucus membrane.

 The materials used as backing membrane should be inert,

and impermeable to the drug and penetration enhancer.

 Such impermeable membrane on buccoadhesive patches

prevents the drug loss and offers better patient
compliance.
 The commonly used materials in backing membrane
include water insoluble polymers such as ethylcellulose,
Eudrajit RL and RS, etc.
 Penetration enhancer:

 Substances that facilitate the permeation through buccal

mucosa are referred as permeation enhancers.

 Selection of the appropriate permeation enhancer and its

efficacy depends on the physicochemical properties of
the drug, site of administration, nature of the vehicle and
other excipients.

 Permeation enhancers used for designing buccal patches

must be nonirritant and have a reversible effect.
 To increases the permeation rate of the membrane of co-
administrated drug penetration enhancer are added.
Without causing toxicity and damaging the membrane
they improve the bioavailability of drugs that have poor
membrane penetration.

 The epithelium should recover its barrier properties after

the drug has been absorbed.

 The most common classes of buccal penetration enhancers

include fatty acids that act by disrupting intercellular lipid
packing, surfactants, bile salts, and alcohols.
 Plasticizers:

 To impart appropriate plasticity of the buccal patches,

suitable plasticizers are required to add in the formulation
of buccal patches.

 Typically, the plasticizers are used in the concentration of

0-20 % w/w of dry polymer.

 The selection of plasticizer depends upon the

compatibility with the polymer and type of solvent
employed in the casting of film.
 Plasticizer is an important ingredient of the film, which
improves the flexibility of the film and reduces the
bitterness of the film by reducing the glass transition
temperature of the film.

 Plasticizers should be carefully selected because improper

use of the plasticizers affects the mechanical properties of
the film.

 Widely used plasticizers in buccal patches and films are

PEG100, 400, propylene glycol, glycerol, castor oil etc.
 Taste masking agents:

 Taste masking agents or taste masking methods should

be used in the formulation if the drugs have bitter taste,
as the bitter drugs makes the formulation unpalatable,
especially for pediatric preparations.

 Thus, before incorporating the drugs in the buccal

patches, the taste needs to be masked.
 Various methods can be used to improve the palatability
of the formulation, such as complexation technology,
salting out technology, etc.
 Mechanism of buccal absorption

 Buccal absorption leads systemic or local action via the

buccal mucosa and it occurs by passive diffusion of the
non ionized species, a process governed primarily by a
concentration gradient, through the intercellular spaces of
the epithelium.

 The passive transport of non-ionic species across the

lipid membrane of the buccal cavity is the primary
transport mechanism.
 The buccal mucosa has been said to be a lipoidal
barrier to the passage of drugs, as is the case with
many other mucosal membrane and the more
lipophillic the drug molecule, the more readily it is
absorbed.
 Factors Affecting Buccal Absorption

 The oral cavity is a complex environment for drug

delivery as there are many interdependent as well as
independent factors which reduce the absorbable
concentration at the site of absorption.

I. Membrane Factors
II. Environmental Factors
I. Membrane Factors:

 This involves degree of keratinization, surface area

available for absorption, mucus layer of salivary pellicle,
intercellular lipids of epithelium, basement membrane
and lamina propria.

 In addition, the absorptive membrane thickness, blood

supply/lymph drainage, cell renewal and enzyme content
will all contribute to reducing the rate and amount of
drug entering the systemic circulation.
II. Environmental Factors:

(a) Saliva:

 The thin film of saliva coats throughout the lining of

buccal mucosa and is called salivary pellicle or film.

 The thickness of salivary film is 0.07-0.10 mm.

 The thickness, composition and movement of this film

affect the rate of buccal absorption.
(b) Salivary glands:

 The minor salivary glands are located in epithelial or deep

epithelial region of buccal mucosa.

 They constantly secrete mucus on surface of buccal

mucosa.

 Although, mucus helps to retain mucoadhesive dosage

forms, it is potential barrier to drug penetration.
 Manufacturing methods of buccal patches

 Manufacturing processes involved in making buccal

patches, are namely-

 Solvent Casting
 Hot Melt Extrusion
 Direct Milling
1. Solvent casting:

 In this method, all patch excipients including the drug co-

dispersed in an organic solvent and coated onto a sheet of
release liner.

 After solvent evaporation a thin layer of the protective

backing material is laminated onto the sheet of coated
release liner to form a laminate that is die-cut to form
patches of the desired size and geometry.
2. Hot melt extrusion:

 In hot melt extrusion blend of pharmaceutical

ingredients is molten and then forced through an
orifice to yield a more homogeneous material in
different shapes such as granules, tablets, or films.

 Hot melt extrusion has been used for the manufacture

of controlled release matrix tablets, pellets and
granules, as well as oral disintegrating films.
 However, only a hand full article has reported the
use of hot melt extrusion for manufacturing
mucoadhesive buccal patches.
3. Direct milling:

 In this, patches are manufactured without the use of

solvents.

 Drug and excipients are mechanically mixed by direct

milling or by kneading, usually without the presence of
any liquids.

 After the mixing process, the resultant material is rolled

on a release liner until the desired thickness is achieved.
 The backing material is then laminated as previously
described.

 While there are only minor or even no differences in

patch performance between patches fabricated by the
two processes, the solvent-free process is preferred
because there is no possibility of residual solvents and
no associated solvent-related health issues.
 Advantages of buccal drug delivery systems

 Sustained drug delivery.

 Increased ease of drug administration.

 Excellent accessibility.

 Drug absorption through the passive diffusion.

 Rapid onset of action.

 Versatility in designing as multidirectional or
unidirectional release systems for local or systemic
actions, etc.

 Low enzymatic activity, suitability for drugs or excipients

that mildly and reversibly damages or irritates the
mucosa, painless administration, easy drug withdrawal,
facility to include permeation.

 The drug is protected from degradation due to pH and

digestive enzymes of the middle gastrointestinal tract.
 A relatively rapid onset of action can be achieved
relative to the oral route, and the formulation can be
removed if therapy is required to be discontinued.

 Though less permeable than the sublingual area, the

buccal mucosa is well vascularized, and drugs from the
buccal systems can be rapidly absorbed into the venous
system underneath the oral mucosa.

 High blood supply and good blood flow rate cause

rapid absorption.
 Flexibility in physical state, shape, size and surface.

 Transmucosal delivery occurs is fewer variables between

patients, resulting in lower inter-subject variability as
compared to transdermal patches.

 Nor painful neither irritations.

 The residence time of dosage form at the site of absorption

is prolong, hence increases the bioavailability.

 Improved patient compliance.

 Disadvantages of Buccal Drug Delivery System

Prolonged contact of the drug possessing ulcerogenic

property.

For the in vitro screening of drugs the oral mucosal

delivery is lack of good model. This is the major drawback
of this drug delivery.

Patient acceptability in terms to taste, irritancy and mouth

feel is to be checked.
As compared to the sublingual membrane the buccal
membrane is low permeability. Also has smaller surface
area.

The dissolution of drug due to continuous secretion of

saliva.
 Limitations of buccal drug delivery systems

 Depending on whether local or systemic action is

required the challenges faced while delivering drug via
buccal drug delivery can be enumerated as follows:

 For local action the rapid elimination of drugs due to the

flushing action of saliva or the ingestion of foods stuffs
may lead to the requirement for frequent dosing.
 The non-uniform distribution of drugs within saliva on
release from a solid or semisolid delivery system could
mean that some areas of the oral cavity may not receive
effective levels.

 For both local and systemic action, patient acceptability

in terms of taste, irritancy and ‘mouth feel’ is an issue.
 Types of Bioadhesive Formulations

1. Solid Bioadhesive Formulations

 Tablets : Dry formulations such as tablets are able to form

strong interactions with mucosal surfaces by attracting
water from the mucosal surface. An example is
Buccastem® which is used in the treatment of nausea,
vomiting and vertigovertigo. It is administered to the
buccal mucosa (inside of the cheeks).
 Inserts: These include ocular inserts such as eye drops and
eye gels. An example is Pilogel® which is used in the
treatment of glaucoma (raised pressure in the eye). Pilogel®
contains the bioadhesive agent carbomer 940,which
minimises irritation and prevents the loss of product by
keeping the gel in place.

 Lozenges: Bioadhesive lozenges containing antibiotics and

local anaesthetics can be used topically to treat conditions
affecting the mouth. Research has shown that bioadhesive
lozenges are able to release drugs in a controlled manner by
prolonging the drug release.
2. Semi-solid bioadhesive Formulations

 Gels : Bioadhesive polymers that are able to form gels

include polyacrylic acid which adheres to mucosal
surfaces in a cross-linked form. Gel formulations are used
to target several parts of the body including the eye,
vagina and oral cavity. An advantage of gels is that they
are able to form a very close contact with mucosal
membranes and rapidly release drugs at their site of
absorption.
 Films: Bioadhesive films that are flexible in nature can
be used to directly deliver drugs to specific mucosal
membranes. They form a very close contact with the
membrane and are able to deliver an accurate dose of
drug to the site ofabsorption. An example of a
bioadhesive film is Zilactin® which is used in the
treatment of cold sores and mouth ulcers
3. Liquid Bioadhesive Formulations

 Viscous liquids: Viscous liquids containing bioadhesive

polymers such as carboxymethyl cellulose may be used to
protect mucosal membranes from damage and irritation.
They can also be used to deliver drugs to specific sites. An
example is artificial tears, a carbomer solution used to
treat dry eyes.
 Gel-forming liquids: These formulations are
administered as liquids but undergo a change in their form
in response to conditions such as temperature and pH.
Such formulations are used for the controlled-release of
drugs into the eye.
 Hypotears® and Sno Tears® Eye drops are used for dry
eye and tear deficiency and they generally lubricate the
eyes. They both contain the polymer polyvinyl alcohol
(PVA) which increases tear production and protects the eye
from further irritation.

 GelTears® and Viscotears® Liquid gel eye drops are used

for dry eye conditions contain carbomer 980 (polyacrylic
acid). Carbomers lubricate the eye by clinging to the
surface of the eye. This can help reduce the frequency of
their application into the eye.
 Pilogel® Is an eye gel used in the treatment of
glaucoma. It contains the high molecular weight
polymer polyacrylic acid. The polymer increases the
viscosity of the gel which provides a prolonged
retention of the gel in the eye.
THANK YOU…