Buccal drug delivery system is part of mucoadhesive drug delivery system and their principal and formulation ,mechanisam of adhesion to mucosa ,use of polymers in BDDS and permiability enhancers and evaluation parameters of buccal tablets and patchs
Avoid first pass effect,
1. Presentation by.
A sreedhar reddy
M Pharmacy (pharmaceutics)
BUCCAL DRUG DELIVERY SYSTEM
SRI VENKATESHWARA UNIVERSITY
2. MUCOADHESIVE DRUG DELIVERY SYSTEMS
Mucoadhesive drug delivery systems are delivery systems, which utilized the property of bio adhesion of
certain polymers, which become adhesive on hydration and hence can be used for targeting a drug to
particular region of the body for extended period of time
The ability to maintain a delivery system at a particular location for an extended period of time has great
appeal for both local as well as systemic drug bioavailability.
It provides the possibility of avoiding either destruction by gastrointestinal contents or hepatic first-pass
inactivation of drug.
The mucoadhesive drug delivery system includes the following:
• 1. Buccal drug delivery systems
• 2. Sublingual drug delivery systems
• 3. Rectal drug delivery systems
• 4. Vaginal drug delivery systems
• 5. Ocular drug delivery systems
• 6. Nasal drug delivery systems
3.
4. BUCCAL DRUG DELIVERY SYSTEM
DEFINITION: Delivery of drug through buccal mucosa of oral cavity is Called Buccal drug
delivery system. buccal mucosa lines the inner region of cheeks(drug enters from mucosa site to
systemic circulation).
In BDDS the product is placed in between upper gingiva and cheek to treat local and systemic
conditions
Advantages:
Advantages
Avoid first
pass effect
Avoid acid
and
enzymatic
degradatio
n
Permeatio
n is faster
respect
to skin and
TDDS
Drug
release
prolong
period of
time
Drug
absorption
by passive
diffusion
For
unconscio
us or
comatose
patients
5. Disadvantages:
Drugs which are unstable at buccal ph cannot be
administered
Eating and drinking may become restricted
Drug required with small dose can only be
administered
Drugs which have a bitter taste or unpleasant taste or
an obnoxious odor or irritate the mucosa cannot be
administered by this route.
7. Buccal environment
It has four parts and its thickness is 500-800mm
Epithelium: is the major barrier for lipophilic drug.it has initially square shaped cells which
further grows in the elliptical cells which are permeable for hydrophilic drugs. It may be
keratinized or non keratinized
Mostly non keratinized epithelium is permeable to drug very easily due to absence of acyl
ceramide and only small amounts of ceramides. Also they contain small amount of neutral but
polar lipids hence more permeable to formulation
Lamina propria: Barrier for hydrophilic drug
Hence highly hydrophilic and highly lipophilic drugs are not suitable for BDDS
Salivary secretion: it is secreted by parotid sub maxillary and sub lingual gland. Saliva secretion
contain 99 percent water and 1 percent of salts and mucine , albumin enzymes
8. Role of mucus
•made up of proteins and carbohydrates.
•Cell-cell adhesion
•Lubrication
•bio adhesion of mucoadhesive drug delivery systems
Role of saliva
•protective fluid for all tissues of the oral cavity.
•Continuous mineralization/ demineralization of the tooth enamel.
•To hydrate oral mucosal dosage forms.
Permeability of drugs through buccal mucosa / route of drug absorption.
There are two possible routes of drug absorption through the squamous stratified epithelium of the oral
mucosa:
I. Transcellular (intracellular, passing through the cell)
ii. Paracellular (intercellular, passing around the cell).
9. Permeation across the buccal mucosa has been reported to be mainly by the paracellular route through the
intercellular lipids.
The buccal mucosa is a potential site for the controlled delivery of hydrophilic macromolecular therapeutic
agents (biopharmaceuticals) such as peptides, oligonucleotides and polysaccharides. However, these high
molecular weight drugs usually have low permeability leading to a low bioavailability, and absorption
enhancers may be required to overcome this.
The buccal mucosa also contains proteases that may degrade peptide-based drugs. In addition, the salivary
enzymes may also reduce stability.
Disease states where the mucosa is damaged would also be expected to increase permeability. This would be
particularly true in conditions that result in erosion of the mucosa such as viral infections and allergic
reactions.
10. In Buccal drug delivery Drug is formulated as
1. Matrix type: the buccal patch designed in a matrix configuration contains drug, adhesive, and additives
mixed together.
2. 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.
Additionally, the patch can be constructed to undergo minimal degradation in the mouth, or can be
designed to dissolve almost immediately.
Based on their geometry:
Type 1: single layer device with multidirectional release. Significant drug loss due to swallowing.
Type 2: impermeable baking layer is superimposed; preventing drug loss into the oral cavity.
Type 3: unidirectional release device, drug loss is minimal. Achieved by coating every phase except contact
site.
11. Factors affecting
1. Polymer related factors
2. Drug related factors
3. patient related factors
1) Polymer related factor:
Polymers usually diffuse into the mucosal layer and thereafter adhere to the layer by forming intermolecular
entanglements.
• Molecular weight:
with the increase in the molecular weight (mw) of the polymer chain there is an increase in the
mucoadhesiveness of a polymer. In general, polymers having MW ≥ 100, 000 have been found to have
adequate mucoadhesive property for biomedical applications. A typical example is polyethylene glycol (PEG).
PEG of 20,000 MW shows negligible mucoadhesive property while PEG of 200,000 MW exhibits improved
mucoadhesiveness; and the PEG of 400,000 MW has got excellent mucoadhesiveness.
12. • Polymer chain:
polymer chain length plays an important role in bioadhesiveness. With the increase in the chain length of the
polymers there is an increase in the mucoadhesive property of the polymer.
• Flexibility:
• flexible polymer chains helps in the better penetration and entanglement of the polymer chains with that of
mucosal layer thereby improving the bio adhesive property. The flexibility of the polymer chains is
generally affected by the crosslinking reactions and the hydration of the polymer network. Higher the
crosslinking density, lower is the flexibility of the polymer chains.
• Functional group: the functional groups responsible for interactions which include hydroxyl, carboxyl and
amino groups. Various polymers which have the ability to form strong hydrogen bonds include poly (vinyl
alcohol), acrylic derivates, celluloses and starch. In addition to this, presence of charged functional groups in
the polymer chain has a marked effect on the strength of the bio adhesion. E.g. Anionic polyelectrolytes
have been found to form stronger adhesion when compared with neutral polymers.
• Environmental factors: pH influences the charge on the surface of both mucus and the polymers. Mucus
will have a different charge depending on pH because of differences in dissociation of functional groups on
the carbohydrate moiety and amino acids of the polypeptide backbone. E.g. Chitosan (cationic
polyelectrolyte) shows strong mucoadhesion in presence of alkaline medium
13. 2) Drug related factors:
molecular weight of the drug should be less than 1000dalton. Even the lipophilicity of the drug also affect the
formulation.
3) Patient related factors:
salivary secretion rate, pH of buccal cavity, eating /drinking habit.
Theories of mucoadhesion
The phenomena of bio adhesion occurs by a complex mechanism. Till date, six theories have been proposed
which can improve our understanding for the phenomena of adhesion and can also be extended to explain the
mechanism of bio adhesion.
The theories include:
A. The electronic theory,
B. The wetting theory,
C. The adsorption theory,
D. The diffusion theory,
E. The fracture theory
14. The electronic theory proposes transfer of electrons amongst the surfaces resulting in the formation of an
electrical double layer thereby giving rise to attractive forces.
The wetting theory postulates that if the contact angle of liquids on the substrate surface is lower, then
there is a greater affinity for the liquid to the substrate surface. If two such substrate surfaces are brought in
contact with each other in the presence of the liquid, the liquid may act as an adhesive amongst the substrate
surfaces.
The adsorption theory proposes the presence of intermolecular forces, viz. Hydrogen bonding and van der
waal’s forces, for the adhesive interaction amongst the substrate surfaces.
The diffusion theory assumes the diffusion of the polymer chains, present on the substrate surfaces, across
the adhesive interface thereby forming a networked structure.
Fracture theory analyses the maximum tensile stress develop during detachment of the BDDS from
mucosal surfaces.
15. Mechanism of mucoadhesion
The mechanism responsible in the formation of mucoadhesive bond
step 1: wetting and swelling of the polymer(contact stage)
step 2: interpenetration between the polymer chains and the mucosal membrane
step 3: formation of bonds between the entangled chains (both known as consolidation stage)
• STEP 1: WETTING AND SWELLING STEP occurs when polymer spreads over the surface of mucosal
membrane to develop intimate contact swelling of polymer occur because the components of polymer have an
affinity for water
16. STEP 2: in this step the mucoadhesive polymer chain and the mucosal polymer chains intermingle and
entangles to form adhesive bonds .Strength of bonds depends upon the degree of penetration of the two
polymer groups
Step 3 this step involves formation of weak chemical bonds between the entangled polymer chains bonds
includes primary bonds such as covalent bonds and secondary interactions such as vander waals and hydrogen
bonds.
17. Basic components of buccal drug delivery system
The basic components of buccal drug delivery system are
1. Drug substance
2. Bio adhesive polymers
3. Backing membrane
4. Permeation enhancers
1) Drug substance:
before formulating mucoadhesive drug delivery systems, one has to decide whether the intended, action is for rapid
release/prolonged release and for local/systemic effect.
The selection of suitable drug for the design of buccoadhesive drug delivery systems should be based on
pharmacokinetic properties. The drug should have following characteristics.
• The conventional single dose of the drug should be small.
• The drugs having biological half-life between 2-8 hrs. are good candidates for controlled drug delivery.
• Molecular weight should be less than 1000dalton.
• Through oral route drug may exhibit first pass effect or presystemic drug elimination. (Drug that degrades in
GIT).
• The drug absorption should be passive when given orally.
• The drug should be non-irritant to mucosa.
18. 2. Bio adhesive polymer:
an ideal polymer for buccoadhesive drug delivery systems should have following characteristics.
1. It should be inert and compatible with the environment
2. The polymer and its degradation products should be non-toxic absorbable from the mucous layer.
3. It should adhere quickly to moist tissue surface and should possess some site specificity.
4. The polymer must not decompose on storage or during the shelf life of the dosage form.
5. The polymer should be easily available in the market and economical.
6. It should allow easy incorporation of drug in to the formulation.
Criteria followed in polymer selection
1. It should form a strong non covalent bond with the mucine/epithelial surface
2. It must have high molecular weight and narrow distribution
3. It should be compatible with the biological membrane.
20. 4. Backing membrane:
backing membrane plays a major role in the attachment of bio adhesive devices 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 buccal bio adhesive patches prevents the drug loss and offers better patient
compliance. The commonlyUsed materials in backing membrane include Carbopol, magnesium stearate,
HPMC, HPC, CMC, polycarbophil etc.
5. Permeation enhancers:
substances that facilitate the permeation through buccal mucosa are referred as permeation enhancers.
Selection of enhancer and its efficacy depends on the physicochemical properties of the drug, site of
administration, nature of the vehicle and other excipients.
Mechanisms of action of permeation:
1. Changing mucus rheology: by reducing the viscosity of the mucus and saliva overcomes this barrier.
2. Increasing the fluidity of lipid bilayer membrane: disturb the intracellular lipid packing by interaction with
either lipid packing by interaction with either lipid or protein components.
21. 3. Acting on the components at tight junctions: by inhibiting the various peptidases and proteases present
within buccal mucosa, thereby overcoming the enzymatic barrier. In addition, changes in membrane fluidity
also alter the enzymatic activity indirectly.
4. Increasing the thermodynamic activity of drugs: some enhancers increase the solubility of drug there by
alters the partition coefficient
Permeation enhancers:
22. Manufacturing methods of buccal patches/ films
manufacturing processes involved in making mucoadhesive buccal patches/films, namely solvent casting, and
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. 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.
23. Evaluations parameters of buccal drug delivery system
1. Surface pH: buccal patches are left to swell for 2 hrs. on the surface of an agar plate. The surface ph is
measured by means of a pH paper placed on the surface of the swollen patch.
2. Thickness measurements: the thickness of each film is measured at five different locations (center and four
corners) using an electronic digital micrometer.
3. Swelling study: buccal patches are weighed individually (designated as W1), and placed separately in 2%
agar gel plates, incubated at 37°C ± 1°C, and examined for any physical changes. At regular 1hr time intervals
until 3 hours, patches are removed from the gel plates and excess surface water is removed carefully using the
filter paper. The swollen patches are then reweighed (W2) and the swelling index (SI) is calculated using the
following formula.
SI = W2-W1/W1*100
4. Folding endurance: the folding endurance of patches is determined by repeatedly folding 1 patch at the
times without breaking.
5. Disintegration time: there are two methods for determining the DT of buccal path or film.
• Slide frame method: the film/patch is kept on the slide. Place a drop of water on it. Note the time when hole
is observed in the film.
24. • Petri dish method: the patch/film is place in the petri dish and add 2ml water. Note the time in when the
film/patch is dissolved.
• tablet : disintegration was performed using DT apparatus taking 6 tablets randomly for 4 hours for buccal
tablet and 2min for sublingual tablet.
6. Water absorption capacity test:
circular patches/films, with a surface area of 2.3 cm2 are allowed to swell on the surface of agar plates
prepared in simulated saliva and kept in an incubator maintained at 37°C ± 0.5°c. At various time intervals
(0.25, 0.5, 1, 2, 3, and 4 hours), samples are weighed (wet weight) and then left to dry for 7 days in a
desiccators over anhydrous calcium chloride at room temperature then the final constant weights are recorded.
Water uptake (%) is calculated using the following equation.
Water uptake (%) = (Ww - Wf)/Wf x 100
Where, Ww is the wet weight
Wf is the final weight. The swelling of each film is measured
25. 7. Permeation study of buccal patch:
the receptor compartment is filled with phosphate buffer pH 6.8, and the hydrodynamics in the receptor
compartment is maintained by stirring with a magnetic bead at 50 rpm. Samples are withdrawn at
predetermined time intervals and analyzed for drug content.
8. Ex-vivo mucoadhesion time:
the ex-vivo mucoadhesion time performed after application of the buccal patch on freshly cut buccal mucosa
(sheep and rabbit). The fresh buccal mucosa is tied on the glass slide, and a mucoadhesive patch is wetted with
1 drop of phosphate buffer pH 6.8 and pasted to the buccal mucosa by applying a light force with a fingertip
for 30 secs. The glass slide is then put in the beaker, which is filled with 200 ml of the phosphate buffer pH
6.8, is kept at 37°C ± 1°C. After 2 minutes, a 50-rpm stirring rate is applied to simulate the buccal cavity
environment, and patch adhesion is monitored for 12 hrs. The time for changes in color, shape, collapsing of
the patch, and drug content is noted.
26. 9. Measurement of mechanical properties:
mechanical properties of the films (patches) include tensile strength and elongation at break is evaluated using
a tensile tester.
Film strip with the dimensions of 60 x 10 mm and without any visual defects cut and positioned between two
clamps separated by a distance of 3 cm. Clamps designed to secure the patch without crushing it during the
test, the lower clamp held stationary and the strips are pulled apart by the upper clamp moving at a rate of 2
mm/sec until the strip break. The force and elongation of the film at the point when the strip break is recorded.
The tensile strength and elongation at break values are calculated using the formula.
T = M x g/ b x t kg/mm2
Where,
• M - is the mass in gm,
• g - is the acceleration due to gravity 980 cm/sec 2 ,
• b - is the breadth of the specimen in cm,
• t - is the thickness of specimen in cm
27. Tensile strength (kg/mm2 ) is the force at break (kg) per initial cross- sectional area of the specimen (mm2 ).
it measures the strength of patches as diametric tension or tearing force. It is measured in g or N/m2.
It shows the strength of patches to various stresses and can be measured by using simple calibrated vertical
spring balance
10.In vitro drug release:
the united states pharmacopeia (USP) XXIII-B rotating paddle method is used to study the drug release from
the bilayer and multilayered patches.
The dissolution medium consisted of phosphate buffer pH 6.8. The release is performed at 37°C ± 0.5°C, with
a rotation speed of 50 rpm. The backing layer of buccal patch is attached to the glass disk with instant adhesive
material. The disk is allocated to the bottom of the dissolution vessel. Samples (5 ml) are withdrawn at
predetermined time intervals and replaced with fresh medium. The samples filtered through Whatman filter
paper and analyzed for drug content after appropriate dilution.
11. The in-vitro buccal permeation through the buccal mucosa (sheep and rabbit) is performed using Franz
type glass diffusion cell at 37°c± 0.2°c. Fresh buccal mucosa is mounted between the donor and receptor
compartments. The buccal patch is placed with the core facing the mucosa and the compartments clamped
together.
28. 12. Stability study in human saliva:
the stability study of patches was performed in natural human saliva. Human saliva was collected from
humans (ages 18-50 years) and filtered. Patches were placed in separate petri-dishes containing 5 ml of human
saliva and put in a temperature-controlled oven at 37°C ± 0.2°C for 6 hours. At regular time intervals (0, 1, 2,
3, and 6 hours), patches were examined for changes in color and shape, collapse, and drug content
29. Reference:
• Yie W.Chien novel drug delivery system vol-50
• Ms PRACHI JOSHI novel drug delivery
• MUHAMMAD UMAR JAVAID CENTRAL SOUTH UNIVERSITY | CSU · SCHOOL OF CHEMISTRY AND CHEMICAL ENGINEERING
• PHD CHEMISTRY