Mishra Amul et al
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ISSN; 2411-1376
Review Article
Title: Buccal Drug Delivery System: A Review Mishra Amul*, Bharkatiya Meenakshi and Marothia Deepak, Patel harshna Dept. of Pharmaceutics, B. N. Institute of Pharmaceutical Sciences, Udaipur (Raj) ____________________________________________________________________________ Corresponding Author:
Dr. Mishra Amul Contact: +919414738107
[email protected]
Article Statistics Received: 14th Jan 2015 Revised: 10th Feb 2016 Accepted: 1st Apr 2016 ISSN; 2411-1376
Abstract: Bioadhesion can be defined as a phenomenon of interfacial molecular attractive forces in the midst of the surfaces of the biological substrate and the natural or synthetic polymers, which allows the polymer to adhere to the biological surface for an extended period of time. [1-4] Bioadhesive polymeric systems have been used since extent in the development of products for various biomedical applications which include denture adhesives and surgical glue. Considerable attention has been focused in recent years on the delivery of drugs through the oral mucosa which have a high first pass metabolism or degrade in the gastrointestinal tract. Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Unlike oral drug delivery, which presents a hostile environment for drugs, especially proteins and polypeptides, due to acid hydrolysis and the hepatic first-pass effect, the mucosal lining of buccal tissues provides a much milder environment for drug absorption. Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site. Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. Buccal dosage forms can be of Matrix or Reservoir types. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. Keywords: Buccal Drug Delivery, Mucoadhesion, Bio-adhasive Polymers, Evaluation, Backing Membrane, Penetration Enhancers
Site this Article: Mishra Amul*, Bharkatiya Meenakshi and Marothia Deepak and Patel harshna, Buccal Drug Delivery System: A Review, journal de afrikana, 2016, 3(1); 157-176.
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Introduction:
depending on the particular drug, a better
Mucoadhesive polymers are synthetic or
enzymatic flora for drug absorption. Within
natural macromolecules which are capable
the oral mucosal cavity, delivery of drugs is
of attaching to mucosal surfaces. The
classified into three categories. [1]
concept of mucoadhesive polymers has been introduced into the pharmaceutical literature
1) Sublingual delivery: This is systemic
more than 40 years ago and nowadays it has
delivery of drugs through the mucosal
been accepted as a promising strategy to
membranes lining the floor of the mouth.
prolong the residence time and to improve
2)
the specific localization of drug delivery
administration
systems on various membranes. Amongst
membranes
the various routes of drug delivery, oral
mucosa), and
route is perhaps the most preferred to the
3) Local delivery:
patient and the clinician alike. However,
into the oral Cavity.
peroral
administration
of
drugs
Buccal
delivery: through
lining
the
Which
is
drug
the
mucosal
cheeks
(buccal
This is drug delivery
has
disadvantages such as hepatic first pass
Mechanism of Mucoadhesion:
metabolism
degradation
Several theories have been put forward to
within the GI tract, that prohibit oral
explain the mechanism of polymer–mucus
administration of certain classes of drugs
interactions that lead to muco adhesion. To
especially peptides and proteins.
start with, the sequential events that occur
and
enzymatic
during bio adhesion include an intimate Consequently, other absorptive mucosae are
contact between the bio adhesive polymer
considered as potential sites for drug
and the biological tissue due to proper
administration. Transmucosal routes of drug
wetting of the bio adhesive surface and
delivery (i.e., the mucosal linings of the
swelling of the bio adhesive. Following this
nasal, rectal, vaginal, ocular, and oral cavity)
is the penetration of the bio adhesive into the
offer
peroral
tissue crevices, interpenetration between the
administration for systemic drug delivery.
muco adhesive polymer chains and those of
These advantages include possible bypass of
the mucus. Subsequently low chemical
first pass effect, avoidance of pre-systemic
bonds can become operative. Hydration of
elimination within the GI tract, and,
the polymer plays a very important role in
distinct
advantages
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bio adhesion. There is a critical degree of hydration
required
for
optimum
bio
unidirectional
adhesion. If there is incomplete hydration, the active adhesion sites are not completely
toward
the
Should facilitate the rate and extent of drug absorption,
water weakens the adhesive bond as a result of an overextension of the hydrogen bonds.
way
mucosa,
liberated and available for interaction. On the other hand, an excessive amount of
Should provide drug release in an
Should not cause any irritation or inconvenience to the patient and
During hydration, there is a dissociation of
Should not interfere with the normal functions such as talking, drinking[5]
hydrogen bonds of the polymer chains. The polymer–water interaction becomes greater
Advantages Of Buccal Drug Delivery
than
System
the
polymer-polymer
interaction,
thereby making the polymer chains available
1) Bypass the gastrointestinal tract and
for mucus penetration. Following polymer
hepatic
hydration
chain
bioavailability of orally administered drugs
segments of the muco adhesive polymer
that otherwise undergo hepatic first-pass
with the mucus occurs. The factors critical
metabolism. In addition the drug is protected
for this model of muco adhesion are the
from degradation due to pH and digestive
diffusion coefficient of the polymer, contact
enzymes of the middle gastrointestinal tract.
time and contact pressure. The polymer
2) Improved patient compliance due to the
diffusion coefficient is influenced by the
elimination
molecular mass between cross-links, and is
injections;
inversely related to the cross-linking density.
unconscious
intermingling
between
[2, 3, 4]
portal
of
system,
associated
administration or
increasing
pain of
incapacitated
the
with
drugs
in
patients;
convenience of administration as compared to injections or oral medications.
An Ideal Properties/ Characteristics of
3) Sustained drug delivery.
Buccal Adhasive Drug Delivery System
4) A relatively rapid onset of action can be
Should
adhere to the site of
attachment for a few hours,
Should
release
controlled fashion,
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the
drug
achieved relative to the oral route, and the formulation can be removed if therapy is
in
a
required to be discontinued. 5) Increased ease of drug administration.
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6)
Though
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less
permeable
than
the
4) Swallowing of saliva can also potentially
sublingual area, the buccal mucosa is well
lead to the loss of dissolved or suspended
vascularized, and drugs can be rapidly
drug
absorbed into the venous system underneath
removal of the dosage form.
the oral mucosa.
These are some of the problems that are
7) In comparison to TDDS, mucosal
associated with buccal drug delivery
and,
ultimately,
the
involuntary
surfaces do not have a stratum corneum. Thus, the major barrier layer to transdermal
Limitations
drug delivery is not a factor in trans mucosal
Administration
routes of administration.
1) Drugs which are unstable at buccal pH
8) Trans mucosal delivery occurs is less
cannot be administered.
variable between patients, resulting in lower
2) Eating and drinking may become
inter subject variability as compared to
restricted.
transdermal patches.
3) There is an ever present possibility of the
9) The large contact surface of the oral
patient swallowing the dosage form.
cavity contributes to rapid and extensive
4) Over hydration may leads to slippery
drug absorption.
surface and structural integrity of the
of
Buccal
Drug
formulation may get disrupted by this Disadvantages of Buccal Drug Delivery
swelling and hydration of the bioadhesive
System
polymers.
1)
Low
permeability
of
the
buccal
5) Drugs which irritate the mucosa or have a
membrane: specifically when compared to
bitter or unpleasant taste or an obnoxious
the sublingual membrane.
odor cannot be administered by this route.
2) Smaller surface area. The total surface
6) Only drug with small dose requirement
area of membranes of the oral cavity
can be administered.
available for drug absorption is 170 cm2 of
7) Only those drugs which are absorbed by
2
which ~50 cm represents non-keratinized
passive diffusion can be administered by this
tissues, including the buccal membrane.
route.
3) The continuous secretion of saliva (0.5–2
8). Drugs contained in the swallowed saliva
l/day) leads to subsequent dilution of the
follows the pre-oral and advantages of
drug.
buccal route are lost.
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Theories of Mucoadhasives:
(i) primary bonds that are somewhat
1. Diffusion Theory: The essence of this
permanent and therefore undesirable in bio
theory is that chains of the adhesive and the
adhesion
substrate interpenetrate one another to a
(ii) vander Waals, hydrogen, hydrophobic
sufficient depth to create a semi permanent
and
adhesive bond. The penetration rate depends
secondary chemical bonds.
on
the
diffusion
coefficient
of
electrostatic
forces,
which
form
both
interacting polymers, and the diffusion co-
4. Wetting Theory: Primary application to
efficient is known to depend on molecular
liquid bio adhesive system, the wetting
weight
In
theory emphasizes the intimate contact
addition, segment mobility, flexibility of the
between the adhesive and mucus. Thus, a
bioadhesive polymer, mucus glycoprotein,
wetting surface is controlled by structural
and the expanded nature of both network are
similarity, degree of cross linking of the
important parameters that need to be
adhesive polymer, or use of a surfactant.
considered.[5]
The work of adhesion [expressed in terms of
and
cross-linking
density.
surface and interfacial tension (Y) being 2. Electronic Theory:
The adhesive
defined as energy per cm2 released when an
polymer and mucus typically have different
interface is formed.] [6]
electronic characteristics. When these two
According to Dupres equation work of
surface come in contact, a double layer of
adhesion is given by
electrical charge forms at the interface, and
Wa = YA + YB – YAB
then adhesion develops due to the attractive
Where A & B refer to the biological
force fro m electron transfer across the
membranes
electrical double layer.
formulation respectively
and
the
bio
adhesive
The work of cohesion is given by: 3. Adsorption Theory:
The adsorption
Wc = 2YA or YB
theory of bio adhesion proposes that
For a bioadhesive material B spreading on a
adhesion of a polymer to a biological tissue
biological
results from:
coefficient is given by:
substrate,
the
spreading
SB/A = YA – (YB+YAB)
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SB/A should be positive for a bioadhesive
molecular weight of bio adhesive
material to adhere to a biological membrane.
polymer. Molecular flexibility
5. Fracture: Fracture theory of adhesion is related to
It is important for interpenetration
separation of two surfaces after adhesion.
and enlargement. As water soluble
The fracture strength is equivalent to
polymers become cross linked, the
adhesive strength as given by
mobility of the individual polymer
G = (Eε. /L) ½
chain decreases. As the cross linking
Where: E- Young’s modules of elasticity, ε-
density
Fracture energy, L- Critical crack length
length of chain which can penetrate
when two surfaces are separated
into the mucus layer decreases even
increases,
the
effective
further and muco- adhesive strength is reduced.
Bioadhasive Polymers: Bioadhesive polymers have properties to get
Concentration of active polymer
adhered to the biological membrane and
There
hence capable of prolonging the contact time
optimum concentration of
of the drug with a body tissue. The use of
corresponding
bio adhesive polymers can significantly
adhesion.
improve the performance of many drugs.
system, the adhesive strength drops
This
significantly.
improvement
ranges
from
better
treatment of local pathologies to improved
is
to
an
the
polymer best
bio
In highly concentrated
Polymer chain length
bioavailability and controlled release to
The polymer molecule must have an
enhance patient compliance. [7,8]
adequate length.
Factors Affecting Bioadhesion
2. Environment Related Factors
1) Polymer-Related Factors
pH
Polymer molecular weight
pH was found to have a significant
The optimum molecular weight for
effect of muco adhesion are observed
the maximum bio adhesion depends
in studies of poly acrylic polymer
on the type of polymers. The bio
cross linked with COOH group. pH
adhesive forces increases with the
influences the charge on the surface
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of both mucus and the polymers.
polymer is important to improve this
Mucus will have a different chart
hydrogen bonding potential.
density depending on pH because of differences
in
dissociation
functional
groups
of
Some
generalizations
about
the
the
charge of bio adhesive polymers
carbohydrate moiety and amino acids
have been made previously, where
of
nonionic polymers appear to undergo
polypeptide
carbophil
show
on
Charge
backbone. Poly the
maximum
a
smaller
degree
of
adhesion
adhesive strength at pH 3, the
compared to anionic polymers. It has
adhesive
decreases
been shown that some cationic
gradually as the pH increases upto 5
polymers are likely to demonstrate
poly carbophil does not show any
superior muco adhesive properties,
muco adhesive property above pH 5.
especially in a neutral or slightly
This study, the first systematic
alkaline medium 9. Additionally,
investigation of the mechanism of
some cationic high-molecular-weight
muco adhesion, clearly shows that
polymers, such as chitosan, have
the protonated carboxyl group rather
shown to possess good adhesive
than ionized carboxyl group react
properties.
strength
with mucin molecules presumably by
Hydration (swelling)
numerous simultaneous hydrogen bond.
Hydration is required for a muco
[9]
adhesive polymer to expand and
Hydrogen bonding capacity Hydrogen
bonding
is
create a proper “macromolecular another
mesh” of sufficient size, and also to
important factor in muco adhesion of
induce mobility in the polymer
a polymer. Park and Robinson found
chains in order to enhance the
that in order for muco adhesion to
interpenetration
occur, desired polymers must have
process
polymer and mucin.
between
[10, 11]
functional groups that are able to form hydrogen bonds 8. They have
Permeation enhancers:
also confirmed that flexibility of the
Permeation enhancers are substances added to pharmaceutical formulation in order to
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increases the membrane permeation rate or
9-Lauryl ether, Polyoxythylene-20-
absorption rate of a co-administered drug.
cetylether, Benzalkonium chloride,
They are used to improve bioavailability of
Fatty acids : Oleic acid, Capric acid,
drugs
with
normally
poor
Lauric
membrane
acid/
propylene
glycol,
permeation properties without damaging the
Methyloleate, Lysophosphatidylcholine,
membrane and causing toxicity. Enhancer
Phosphatidylcholi
efficacy depends on the physiochemical
Chelators: EDTA, Citricacid, Sodium salicylate, Methoxy salicylates
properties of the drug, administration site, nature of the vehicle and whether enhancer
Non-surfactants: Unsaturated cyclic ureas
is used alone or in combination. [12] Categories and examples of membrane
Inclusion complexes: Cyclodextrins Others:
permeation enhancers
deoxycholate,
Polysorbate 80, Sulfoxides and various
Sodium
taurocholate,
Sodium
glycodeoxycholate,
Sodium
Azone,
Cyclodextrin, Dextran sulfate, Menthol,
Bile salts: Sodium glycocholate, Sodium
Aprotinin,
alkyl
glycosides.
Thiolated
polymers:Chitosan-4-thiobutylamide, Chitosan-
glycodeoxycholate,
4-
Chitosan-cysteine,
Surfactants : Sodium lauryl sulphate,
thiobutylamide/gsh, Chitosan-
4-
thiobutylamide/gsh,
Polyoxyethylene, Polyoxyethylene-
Table: 1 List of Active Ingredients delivered via a buccal route Sr. No. 1 2 3 4 5 6 7 8 9 10 11 12
Active Ingredients Metronidazole Nifedipine Propranolol Danazol Nicotine Omeprazole Carbamazepine Arecoline Protirelin Piroxicam Terbutaline sulphate Theophylline
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Active Ingredients Chitosan Testosterone Zinc sulphate Morphine sulphate Acyclovir Metoprolol tartrate Lignocaine Oxytocin Diclofenac sodium Pentazocine Ergotamine tartrate Hydrocortisone acetate
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Basic Components Of Buccal Bioadhesive
Through oral route drug may exhibit
Drug Delivery System
first pass effect or pre systemic drug
The basic components of buccal bio
elimination.
adhesive drug delivery system are
1. Drug substance
The drug absorption should be passive when given orally.
2. Bioadhesive polymers 3. Backing membrane
2. Bioadhesive Polymers
4. Penetration enhancers
The first step in the development of
5. Adhesives
buccoadhesive dosage forms is the selection and characterization of appropriate bio
1. Drug Substance
adhesive polymers in the formulation."
Before formulating buccoadhcsivc drug
Bioadhesive polymers play a major role in
delivery systems, one has to decide whether
buccoadhesive drug delivery systems of
the
rapid
drugs. Polymers arc also used in matrix
for
devices in which the drug is embedded in
local/systemic effect. The selection of
the polymer matrix, that controls the
suitable
of
duration of release of drugs. Bioadhesive
buccoadhesive drug delivery systems should
polymers arc by for the most diverse class
be based on pharmacokinetic properties. The
and they have considerable benefits upon
drug should have following characteristics:
patient health care and treatment. The drug
[13]
is released into the mucous membrane by
intended,
action
release/prolonged
drug
is
release
for
the
for and
design
The conventional single dose of the
means of rate controlling layer or core layer.
drug should be small.
Bioadhesive polymers adhere to the mucin/
The drugs having biological half-life
epithelial surface are effective and lead to
between candidates
2-8
hours
for
are
good
significant improvement in the oral drug
controlled
drug
delivery. [16]
delivery.
Tmax of the drug shows widerfluctuations or higher values when given orally. [14,15]
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Synthetic
An ideal polymer for buccoadhesive drug
delivery systems should have following
polymers
scmisynthctic
Ex. : PVA, PEG, HPMC, PVP,
Characteristics.
and
It should be inert and compatible
carbomers etc[18]
with the environment
The polymer and its degradation
3. Backing Membrane
products
Backing membrane plays a major role in the
should
be
non-toxic
absorbable from the mucous layer.
attachment of bio adhesive devices to the
It should adhere quickly to moist
mucus membrane. The materials used as
tissue surface and should possess some site
backing membrane should be inert, and
specificity.
impermeable to the drug and penetration
The polymer must not decompose on
enhancer. Such impermeable membrane on
storage or during the shelf life of the dosage
buccal bioadhesive patches prevents the
form.
drug
The
polymer
should
be
easily
available in the market and economical.
It should allow easy incorporation of
loss
and
offers
in backing membrane include carbopol, magnesium stearate, HPMC, HPC, CMC, polycarbophil etc. [19]
Criteria followed in polymer selection
4. Penetration Enhancers
It should form a strong non covalent
bond with the mucin/epithclial surface
Penetration
enhancer’s
arc
used
in
buccoadhesive formulations to improve the
It must have high molecular weight
and narrow distribution.
patient
compliance. The commonly used materials
drug in to the formulation[17]
better
release of the drug. They aid in the systemic delivery of the drug by allowing the drug to
It should be compatible with the
penetrate more readily into the viable
biological membrane.
tissues. The commonly used penetration
The polymers that are commonly used as
enhancers are sodium lauryl sulphate, CPC,
bio adhesives in pharmaceutical applications
polysorbate -80, laureth -9, sodium fusidate,
are:
polmitoyl
Natural polymers
carnitine,
azone,
sodium
glycocholate, dimethyl formamide etc. [20]
Ex. : Gelatin, sodium alginate.
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3. Buccal
5. Bioadhesives Bio adhesives are the substances that are capable of interacting with the biological
Bioadhesive
Semisolids(ointments and gels) 4. Buccal Bioadhesive Powders
material and being retained on them or holding them together for extended period of
1. Buccal Bioadhesive Tablets
time. Bioadhesive can be used to apply to
Buccal bio adhesive tablets are dry dosage
any mucous or non mucous membranes and
forms, that are to be moistened prior to
it also increases intimacy and duration of
placing in contact with buccal mucosa.
contact of the drug with the absorbing
Double and multilayered tablets are already
membrane.
[20, 21]
The commonly used bio
formulated using bio adhesive polymers and
adhesives are sodium alginate, carbomers,
excipients. The two buccal bio adhesive
polycarbophil, HPMC, HPC, gelatin etc.
tablets
commercially
available
buccoadhesive tablets in UK are "Bucastem" The
bioadhesivc
should
have
the
It should be inert and compatible
1) Nitroglycerin bioadhesive tablets for the treatment of anginapectories.[22]
It should adhere to the mucus
2) Sumatriptan
membrane aggressively.
Suscard
Examples:
with biological environment.
"
It should not produce any residue on
mucosa layer.
and
buccaP'(Prochloroperazine).
following characters,
(Nitroglycerine)
succinate
buccal
adhesive tablet which is effective in
It should preferably form a strong
the acute treatment of mygrain and cluster headache. [23]
non-covalent bond with mucin/ epithelial cell surface.
3) Verapamil HCl buccal tablet with compressed verapamil HCl (15ml)
Classification of Buccal Bioadhesive
muco adhesive polymer like sodium
Dosage Forms
alginate and HPC - EXF with
1. Buccal Bioadhesive Tablets
standard tablet excepitints.
2. Buccal Bioadhesive Patches and Films
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2. Buccal Bioadhesive Patches And
4. Buccal
Films
Bioadhesive
Powder
Dosage Forms
Buccal bio adhesive patches consists of two
Buccal bioadhesive powder dosage forms
poly laminates or multilayered thin film
are a mixture of bioadhesive polymers and
round or oval as consisting of basically of
the drug and are sprayed onto the buccal
bio
mucosa. [26]
adhesive
polymeric
layer
and
impermeable backing layer to provide
Evaluation of bi-layered tablets:
unidirectional flow of drug across buccal
All the above batches were evaluated for
mucosa. Buccal bio adhesive films arc
average thickness, average weight and
formulated by incorporating the drug in
weight
alcohol solution of bio adhesive polymer.
swelling index, surface pH, in vitro drug
Example:
release, mucoadhesive strength, residence
1) Isosorbid dinitrate in the form of
variation,
hardness,
friability,
time and in vivo bioavailability studies.
unidirectional errodible buccal film
1.Weight variation:
are developed and characterised for
Collect 10 tablets from each formulation of
improving bioavailability.
varying concentration of natural polymer.
2) Buccal film of salbutamol sulphate and terbutalin sulphate
for
the
treatment of asthma.
Weigh the tablets individually from all the selected formulations; calculate the average weight and comparing the individual tablet
3) Buccoadhesive film of clindamycin used for pyorrhoea treatment. [24]
weights to the average.[27] 2.Thickness: Collect 3 tablets from each batch of
3. Buccal
Bioadhesivc
Semisolid
formulation and the thickness of the tablets were measured with the help of vernier
Dosage Forms Buccal bioadhesive semisolid dosage forms
caliper. The average thickness is calculated.
consists of finally powdered natural or
3.Friability
synthetic
Friability of the tablets was determined by
polymer
dispersed
in
a
polyethylene or in aqueous solution.
using Roche friabilator. From each batch, 6
Example: Arabase. [25]
tablets were weighed accurately which was W1 then placed in the friabilator and rotated at 25 rpm for 4 min. After completing the
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rotation weight of tablets were weighed
7. In-vitro mucoadhesion studies:
which is W2. The percentage friability was
Mucoadhesive strength of the buccal tablets
determined. [28]
was measured on the “Modified Physical
4.Hardness:
Balance method” which is shown in figure
Monsanto hardness tester was used for this
6.
purpose. The hardness of five tablets in each
membrane as the model mucosal membrane.
batch was measured and the average
The fresh porcine buccal mucosa was cut
hardness was calculated.
into pieces and washed with phosphate
The
method
used
porcine
buccal
buffer pH 6.8. The both pans were balanced 5. In vitro swelling studies:
by adding an appropriate weight on the left-
The swelling rate of buccoadhesive tablets
hand pan. A piece of mucosa was tied to the
are evaluated using 2% w/v agar gel plate.
surface of the beaker and placed below the
For each formulation, 3 tablets are weighed
left
and average weight of each 3 tablets are
phosphate buffer pH 6.8. The tablet was
calculated (W1). The tablets are placed with
stuck to the lower side of left pan with glue.
the core facing the gel surface in Petridishes
Previously weighed beaker was placed on
which are placed in an incubator at 37 ±
the right hand pan and water (equivalent to
0.1°. The tablets are removed at time
weight) was added slowly to it until the
intervals of 0.5, 1, 2, 3, 4, 5 and 6 hours,
tablet detach from the mucosal surface. The
excess water on surface is absorbed using
both pans were balanced by adding an
filter paper and swollen tablets are weighed.
appropriate weight on the left- hand pan.
The average weight (W2) is determined and
The weight required to detach the tablet
then swelling index is calculated using the
from
formula. [29]
bioadhesive strength. The experiment was
% Swelling index = ((W2-W1)/W1) ×100
pan
the
which
was
mucosal
moistened
surface
with
gave
the
performed in triplicate and average value was calculated. [30]
6. Determination of surface pH of tablets: Buccoadhesive tablets are left to swell for
Force of adhesion = (mucoadhesive
2hrs on surface of agar plate. The surface
strength/100) × 9.81.
pH is measured using pH paper placed on core surface of the swollen tablet.
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8. In vivo residence time:
10. Surface pH:
The in-vivo residence time was examined in
The method used to determine the surface
human volunteers. The placebo buccal
pH of the formulation was similar to that
tablets were prepared and given to the
used by Bottenberg et al. a combined glass
human volunteers and advised to administer
electrode was used for the purpose. The
the tablet in the buccal region. The time
tablets were allowed to swell by keeping
required for the tablet to detach from the
them in contact with 1 mL of distilled water
buccal region is determined as residence
for 2 hrs and pH was noted by bringing the
time. [31]
electrode in contact with the surface of tablet and allowing it to equilibrate for 1 min.
9. In vitro release studies: The United pharmacopoeia (USP) type ІІ dissolution apparatus was used to study the
11. Ex vivo Permeation Study:
release of drug from buccal tablets. Tablets
In this study, porcine buccal mucosa was
were supposed to release the drug from one
used as a membrane. Diffusion studies were
side only; therefore an impermeable backing
carried out, to evaluate the permeability of
membrane was placed on the other side of
drug across the porcine buccal mucosal
the tablet. The tablet was further fixed to a
membrane, by using glass surface Franz
2x2 cm glass slide with a solution of
diffusion cell. Porcine buccal mucosa was
cyanoacrylate adhesive. In vitro drug release
obtained from local slaughter house and
studies were carried out in 500 ml of
used within 2 hrs of slaughter. The tissue
phosphate buffer solution pH 6.6 for 8h
was stored in phosphate buffer pH 7.4
using TDT 08L dissolution apparatus at 50
solution upon collection. The epithelium
rpm and 37±0.5oc. At predetermined time
was separated from underlying connective
intervals samples were withdrawn and
tissues with surgical scissors clamped
replaced with fresh medium. The samples
between donor and receiver chamber of
were filtered, diluted suitably then analyzed
diffusion cells for permeation studies. The
spectrometrically.
smooth surface of mucosa should face the
All
performed in triplicate. [32]
dissolution
were
donor chamber and receiver chamber was filled with phosphate buffer of 7.4 pH. Whole assembly was placed in water bath
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maintained at 37±10C. Buccal epithelium
The strip was pulled by the top clamp at a
was allowed to stabilization for period of
rate of 300 mm/min till it broke. The force
1hr and hydrodynamic in receiver chamber
and elongation were measured when the film
was maintained by stirring with magnetic
broke.
bead at 50 rpm. After the stabilization of
The following equations were used to
buccal epithelium, the patch was kept on
calculate mechanical properties of the film:
buccal epithelium and 3ml of phosphate buffer of 6.8 pH was added in donor chamber. The sample of 1 ml were withdrawn at the time interval of 1 hour upto 8hrs and replaced with equal volume of
2.Folding endurance
fresh
sink
Three films of each formulation of size 2x2
condition was maintained throughout the
cm were cut. Folding endurance was
study. The withdrawn sample was diluted to
determined by repeatedly folding one film at
5ml.The amount of drug was determined by
the same place till it broke or folded upto
UV-VIS Spectrophotometer. [32,33]
300 times at the same place. The number of
12. In vivo oral bioavailability studies
times the film could be folded at the same
Albino white rabbits weighing about 1.5-
place without breaking gave the value of
2Kg were used for oral bioavailability
folding endurance. [34]
studies. All the rabbits were fasted overnight
3. Measurement of film thickness
before the experiments but had free access
The thickness of the film was measured
to water.
using a Screw gauge micrometer at 10
EVALUATION OF BUCCAL FILM:
different spots from each batch. The mean
1. Measurement
and standard deviation were calculated.
dissolution
medium.
of
The
mechanical
4. Mass uniformity
properties: Mechanical properties of the film were
The assessment of mass uniformity was
evaluated using Universal testing machine
done by weighing 10 randomly selected
(Instron, India). The film strip in dimension
films from each batch. The test was
of 50x15 mm, free from air bubbles or
performed on three
physical imperfections was held between
formulation
two clamps positioned at a distance of 5 cm.
deviation were determined. [35]
© journal de afrikana
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then
films
mean
from each
and
standard
171
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journal de Afrikana, 2016, 3(1); 157-176
5. Drug content uniformity
determined for three films of one type of
5 films were weighed and dissolved in 100
formulation. [36]
ml isotonic phosphate buffer pH 6.8 using
9. In vitro residence time
magnetic stirrer. The solution was filtered
The in vitro residence time was determined
and after suitable dilution analyzed for drug
using
spectrometrically.
apparatus. 800 ml of isotonic phosphate
6. Surface pH
buffer (IPB) maintained at 370 was used as a
The agar plate was prepared by dissolving
medium. The segment of rabbit intestinal
2% w/v agar in isotonic phosphate buffer pH
mucosa of 3 cm length was glued vertically
6.8 and pouring the solution into the
to the glass slab. Then this glass slab was
petridish till gelling at room temperature.
attached to the apparatus vertically. The film
Buccal films were allowed to swell on the
was hydrated on one surface using 50 µl IPB
surface of agar plate for 2 h. The surface pH
and then this hydrated surface was applied
was measured using pH indicator paper, the
to the rabbit mucosa with little pressure. The
change in colour determined after 90s and
glass slab was then allowed to move up and
compared with the standard colour scale.
down
7. Viscosity
immersed in the buffer solution at the lowest
The viscosity of the solution used for buccal
and highest point. The time required for
films were determined using Brookfield
complete erosion or detachment of the film
viscometer.
from the mucosal surface was recorded.
8. Film swelling:
10. In vitro release study
The film swelling studies were conducted
The release of drug from the buccal film was
using two media, namely, distilled water and
determined using Keshary-Chein diffusion
simulated saliva fluid. The Buccal film was
cell. The diffusion medium was phosphate
weighed and placed in a pre-weighed wire
buffer pH 6.8, maintained at 370. The
mesh with sieve opening 800 mµ. The mesh
parchment paper was soaked in phosphate
containing a film sample was submerged
buffer pH 6.8 for 1h and then air-dried. It
into 15 ml medium. Increase in weight of
was mounted between the donor and
the film was determined at preset time
receptor compartment and film was placed
intervals until a constant weight was
on it. Both the compartments were clamped
observed. The degree of swelling was
together. The phosphate buffer pH 6.8 was
© journal de afrikana
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a
so
modified
that
USP
patch
disintegration
was
completely
172
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journal de Afrikana, 2016, 3(1); 157-176
filled in the receptor compartment (11ml
the film separated from the mucosal surface,
capacity) and stirred using magnetic stirrer.
the total weight on the pan minus 5 g is the
At different time intervals samples were
force required to separate the film from the
withdrawn and replaced with an equal
mucosa. This gives the bioadhesive strength
volume of buffer. The samples were
of the film in grams. [39]
analyzed spectrphotometrically. [38]
13. In vivo mucoadhesion studies
11. In vitro bioadhesion strength
The in vivo mucoadhesion of the buccal
To evaluate the bioadhesion strength the
films were determined in healthy human
tensile strength required to detach the
volunteers. The volunteers were asked to
bioadhesive
apply the film by gently pressing it in the
film
from
mucosa
was
measured.
buccal mucosa for 30 s. The volunteers were
12. Measurement of adhesion force
advised to perform their normal activity
The two sides of the balance were balanced
except eating food. They were asked to note
with 5 g weight on the right hand side. The
down the retention time of the film as well
rabbit intestine excised and washed was tied
as various criteria related to acceptability of
tightly with the protrusion in the block. The
the film for example irritation of mucosa,
block was then lowered into the glass
taste, dryness of mouth, comfort, salivary
container, which was then filled with
secretion etc.
isotonic phosphate buffer (pH 6.8) kept at 37+10, such that the buffer just reaches the
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