buccal drug delivery

1. 1

2. INDEX
• TYPES OF BUCCAL DRUG DELIVERY SYSTEM
• EVALUATION OF BUCCAL TABLETS
• EVALUATION OF BUCCAL FILMS/PATCHES
• EVALUATION OF BUCCAL SEMI-SOLID DOSAGE FORMS
• EXAMPLES FOR REPORTED BUCCOADHESIVE DRUG DELIVERY SYSTEM
2

3. 1. BUCCAL BIOADHESIVE TABLETS
 These tablets are usually prepared by direct compression, but wet granulation
can also be used.
 Double and multilayered tablets are already formulated using bioadhesive
polymers and excipients.
 The two buccal bioadhesive tablets commercially available in UK are Bucastem
(Nitroglycerine) and Suscard buccaP (Prochloroperazine).
 EX : METAPROLOL TARTARATE
3

4. BUCCAL BIOADHESIVE PATCHES AND FILMS
• Buccal bioadhesive patches consists of two poly- laminates or multilayered
thin film round or oval ,consisting of basically a bioadhesive polymeric layer
and impermeable backing layer to provide unidirectional flow of drug across
buccal mucosa.
• Buccal bioadhesive films are formulated by incorporating the drug in alcohol
solution of bioadhesive polymer.
• Example:
1) Isosorbide dinitrate in the form of unidirectional erodible buccal film are
developed and characterized for improving bioavailability.
2) Buccal film of salbutamol sulphate and terbutalin sulphate for the
treatment of asthma.
3) Buccoadhesive film of clindamycin used for pyorrhea treatment.
4

5. BUCCAL BIOADHESIVE SEMISOLID DOSAGE FORMS
• Buccal bioadhesive semisolid dosage forms consist of finely powdered
natural or synthetic polymer dispersed in aqueous solution.
• Example: TESS BUCCAL PASTE (for mouth ulcers)
BUCCAL BIOADHESIVE POWDER DOSAGE FORMS
• Buccal bioadhesive powder dosage forms are a mixture of bioadhesive
polymers and the drug that are sprayed onto the buccal mucosa.
5

6. EVALUATION OF BUCCAL TABLETS (IN-VITRO)
Thickness :
• The thickness of buccal tablets was determined using digital micrometer.
• Ten individual tablets from each batch were used and the results averaged.
Weight variation :
Weight variation was performed for 20 tablets from each batch using an
electronic balance and average values were calculated .
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7. Hardness :
• Hardness was conducted for 3 tablets from each batch using Monsanto
hardness tester and average values were calculated.
Assay :
Ten tablets were weighed and grounded in a mortar and pestle to get fine
powder.
powder equivalent to the mass of one tablet was dissolved in methanol by
sonication for 30 min and filtered through filter paper.
The drug content was analyzed spectrophotometrically at 274nm using an
UV spectrophotometer.
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8. Disintegration test : (USP NF 2004)
• Test is performed for buccal tablets which are not having backing.
• six tablets were taken randomly from each batch and placed in USP
disintegration apparatus (baskets type).
• Apparatus was run for 4 hr and the basket was lift from the fluid, observe
whether all of the tablets have disintegrate.
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9. TISSUE ISOLATION STUDIES
porcine buccal tissue from domestic pigs was obtained from a local slaughter house and
used within 3 hours of slaughter.
Pigs were 6.5 ± 0.5 months of age at the time of death.
Or the animals were killed by electro shock followed by exsanguinations.
The tissue was stored in pH 6.6 phosphate buffer at 4 degree Celsius after collection.
Excesses of connective and adipose tissue (epithelium ) were trimmed away until 0.8mm
thick slides were obtained and allowed to equilibrate for approximately one hour in
receptor buffer (acidic buffer) at room temperature to regain lost elasticity and ex vivo
drug permeation study on the tissue was performed using Franz diffusion cell.
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10. •Fourier transform infrared spectroscopy
The samples were crushed with KBr to make pellets
under hydraulic preassure of 10 tons, and then the
FTIR spectra were recorded between 400 and
4000𝑐𝑚−1.
To investigate the possibility of any chemical
interaction between drug and polymers used in
the preparation.
Differential scanning calorimetric analysis
The samples were heated from 0-300 degrees at a
heating rate of 10 degrees per meters under argon
atmosphere using a microcalorimeter and then
thermograms were obtained.
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11. MUCO/BIOADHESIVE TEST
(MODIFIED BALANCE METHOD)
• Modified physical balance method was used for determining the ex-vivo
bioadhesive strength.
• Fresh Porcine buccal mucosa obtained from a local slaughterhouse was
stored in pH 6.6 phosphate buffer at 4 degrees Celsius upon collection. The
experiment was performed within 3 hours of procurement of the mucosa.
• The porcine buccal mucosa was fixed to the stainless steel piece with
cyanoacrylate adhesive and placed in a beaker, then pH 6.6 phosphate
buffer was added into the beaker up to the upper surface of the porcine
buccal mucosa to maintain buccal mucosal viability during the experiment.
• Then the tablet was attached to the upper clamp of the apparatus and the
beaker was raised slowly to establish contact between porcine buccal
mucosa and the tablet. 11

12. • A preload of 50 gm was placed on the clamp for 5 mins to establish
adhesive bond between the tablet and porcine buccal mucosa.
• After completion of preload time, preload was removed from the clamp
and water was added into the beaker from burette at a constant rate.
• The weight of water required to detach the tablet from porcine buccal
mucosa was noted as mucoadhesive strength and experiment was
repeated with fresh mucosa in an identical manner.
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13. Surface pH study
 The buccal tablets were placed in glass tubes and allowed to swell in contact
with pH 7.4 phosphate buffers (12ml).
 Thereafter, surface pH was measured by using pH paper placed on the surface
of the swollen tablets. The mean of three readings was recorded.
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Palatability study
 It is conducted on the basis of taste, after bitterness and physical
appearance.
 All the batches are rated A, B and C grades as per the criteria.
 When the formulation scores at least one A grade, formulation is considered
as average.
 scores two A grade then considered as good and the one with all three A
grade considered good buccal formulation.

14. Swelling index:
• The extent of swelling can be measured in terms of % weight gain by the
dosage form.
• The swelling index is calculated using following formula
S.I= Wt – Wo
Wo
• Where,
S.I = Swelling index
Wt = Weight of tablet at time t
Wo = Weight of tablet before placing in the beaker
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15. In vitro drug release of buccal tablets
• The United States Pharmacopeia (USP) rotating paddle method (16) was used
to study the drug release from the buccal tablets.
• The dissolution medium consisted of 500 mL of phosphate buffer pH 6.8. The
release was performed at 37degree Celsius ± 0.5 degree Celsius, with a rotation
speed of 50 rpm.
• The backing layer of buccal tablet was attached to the glass slide with instant
adhesive, (cyanoacrylate adhesive). The slide was placed in to the bottom of
the dissolution vessel.
• Samples (5 mL) were withdrawn at predetermined time intervals and replaced
with fresh medium.
• Dissolution for the conventional marketed product was conducted without
glass slide.
• The samples were filtered through filter paper and analyzed after appropriate
dilution by UV spectrophotometer at 274 nm.
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16. Stability of buccal tablets
• Stability studies of buccal tablets were performed for optimized
formulation in normal human saliva.
• The human saliva was collected from humans and filtered through filter
paper. Buccal tablets were placed in separate Petri dishes containing 5
mL of human saliva and placed in a temperature-controlled oven for 8 hr
at 37°C ± 0.2°C.
• At regular time intervals (0, 2, 4, 6 and 8 hr), the buccal tablets were
examined for change in color, surface area and integrity.
• The experiments were repeated in triplicate (n = 3) in a similar manner.
16

17. Residence time:
• Take a slide, stick a mucosa on it with gum.
• Place our dosage form on it with few droplets of PBS with p.H (6.8), allow
it to stick on it.
• Now make it inclined & at constant rate add PBS 6.8 drop wise on it
without moving the slide.
• Note the time till dosage form detaches from mucosa.
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18. Residence time
• Locally modified USP disintegration apparatus was used.
• DT media: 800 mL PBS pH 6.8 at 37 °C.
• The buccal tissue was glued to the surface of a glass slab, vertically
attached to the apparatus.
• The buccal tablet was hydrated from one surface using 0.5 mL of PBS pH
6.8, and then the hydrated surface was brought into contact with the
mucosal membrane.
• The glass slab was vertically fixed to the apparatus and allowed to run in
such a way that the tablet was completely immersed in the buffer
solution at the lowest point and was out at the highest point.
• The time necessary for complete erosion or detachment of the tablet
from the mucosal surface was recorded
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19. Ex vivo permeation study
• In this study, porcine buccal mucosa was used as a membrane.
• Diffusion studies were carried out, to evaluate the permeability of drug
across the porcine buccal mucosal membrane, by using glass surface Franz
diffusion cell.
• Porcine buccal mucosa was obtained from local slaughter house and used
within 2 hrs of slaughter. The tissue was stored in phosphate buffer pH 7.4
solution upon collection.
• The epithelium was separated from underlying connective tissues with
surgical scissors clamped between donor and receiver chamber of diffusion
cells for permeation studies. The smooth surface of mucosa should face the
donor chamber and receiver chamber was filled with phosphate buffer of
7.4 pH.
• Whole assembly was placed in water bath maintained at 37±10ºC.
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20. • Buccal epithelium was allowed to stabilization for period of 1hr and
hydrodynamic in receiver chamber was maintained by stirring with
magnetic bead at 50 rpm.
• After the stabilization of buccal epithelium, the patch was kept on buccal
epithelium and 3ml of phosphate buffer of 6.8pH 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 fresh dissolution medium.
• The sink condition was maintained throughout the study. The withdrawn
sample was diluted to 5ml.
• The amount of drug was determined by UV-VIS Spectrophotometer.
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21. • In-vivo oral bioavailability studies:
• Albino white rabbits weighing about 1.5-2Kg were used for oral
bioavailability studies.
• All the rabbits were fasted overnight before the experiments but had free
access to water.
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22. EVALUATION OF BUCCAL PATCHES/FILMS
Film Weight and Thickness
• The weight of each prepared film was measured using a digital
balance among the three films of every formulation and the average
weight was calculated.
• Similarly the thickness of each film was measured using a micrometer
screw gauge at different points of the film and the average was
calculated.
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23. Folding Endurance
• Folding endurance of the films was premeditated by repeatedly folding
one film at the same place till it broke or folded up to 300 times
manually.
• The number of times the film could be folded at the same place until it
breaks gives you value of folding endurance.
Surface pH
Surface pH of the films can be determined by allowing three films of
each formulation to swell for two hours on an agar plate surface.
pH was measured by means of pH paper positioned on the surface of
the swollen film and a mean was calculated.
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24. Swelling Index
• The films were weighed individually and placed on the surface of an agar
plate kept in an incubator maintained at 37±0.2°c and the samples were
allowed to swell.
• An increase in the weight of the film was noted in regular intervals of
time and the weight was calculated.
• The percent swelling, %S was calculated using the following equation:
Percent Swelling (%S) = (X t - X o /X o ) x 100
Where, X t = the weight of the swollen film after time t
X o = the initial film weight at zero time.
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25. Moisture Content
• The prepared films are weighed individually and kept in a desiccator
containing calcium chloride at room temperature for 24 h.
• After a specified interval, the films are to be weighed again until they show
an unvarying weight.
• The % moisture content was calculated By using the following formula,
% moisture content = initial weight- final weight/ initial weight × 100
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26. Water Vapour Transmission Rate (Wvt)
• About 1 g of calcium chloride was taken in the vial which is used as
transmission cell and the polymeric films measuring 2 𝑐𝑚2
area were fixed
over the brim with the help of an adhesive.
• The initial weight of the cells was noted by weighing them accurately. Finally,
they are placed in a closed desiccator containing saturated solution of
potassium chloride and were taken out and weighed at standard intervals.
• The water vapour transmitted rates were calculated by using the following
formula.
• Wvt = WL/S
• Where, W = water vapour transmitted in mg.
• L is the thickness of the film in mm.
• S is exposed surface area in 𝑐𝑚2.
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27. In- Vitro Release Study
• Dissolution studies are carried out in a USP dissolution apparatus using 900
ml of dissolution medium at 37 ± 0.5ºC, rotated at constant speed of 50
rpm.
• An aliquot of the sample is periodically withdrawn at suitable time intervals
and the volume is replaced with fresh dissolution medium.
• The sample is analyzed at specified nm by UV-visible spectrometer
spectrophotometrically and amount of drug release at various time
intervals were calculated.
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28. •In-vitro release study
• The release of drug from the buccal film was determined using Keshary-Chein
diffusion cell.
• The diffusion medium was phosphate buffer pH 6.8, The parchment paper was
soaked in phosphate buffer pH 6.8 for 1h and then air-dried.
• It was mounted between the donor and receptor compartment and film was
placed on it.
• Both the compartments were clamped together.
• The phosphate buffer pH 6.8 was filled in the receptor compartment (11ml
capacity) and stirred using magnetic stirrer.
• At different time intervals samples were withdrawn and replaced with an
equal volume of buffer.
• The samples were analyzed spectrphotometrically.
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29. In-Vitro Residence Time
• The in vitro residence time is performed using disintegration apparatus
maintained at a temperature of 37 ± 2°C using 900 ml of the disintegration
medium.
• The portion of the porcine buccal mucosa, each of 3 cm length, is glued to the
glass piece surface, which is then vertically attached to the apparatus.
• The films of each formulation are hydrated on one surface and up on contact
with the mucosal membrane, the film is entirely dipped in the buffer solution.
• The time required for complete detachment of the film from the mucosal
surface is to be noted.
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30. Ex Vivo Mucoadhesive Strength
• The force required to detach the attachment of mucoadhesive film from
the mucosal surface was applied as a measure of the mucoadhesive
strength.
• A modified balance method was used for determining the ex-vivo
mucoadhesive strength.
• The porcine buccal mucosa was taken and the mucosal membrane was
separated by removing the underlying fat tissues.
• The mucosa was attached to a dry petri dish surface and it was
moistened with a few drops of simulated saliva.
• The balance was adjusted for equal oscillation by keeping sufficient
weight on the left pan.
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31. • A weight of 5 g (w1) was removed from the left pan and film was brought
in contact with pre moistened mucosa for 5 min.
• Then weights were increased lightly on the left pan until the attachment
breaks (w2).
• The difference in weight (w2-w1) was taken as mucoadhesive strength.
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32. Tensile Strength
• It is defined as the resistance of the material to a force tending to tear it
separately and is identified as the maximum stress in the stress–strain curve.
• It was determined using an Instron universal testing instrument with a 5-kg
load cell.
• Films were held between two clamps positioned at a distance of 3 cm and
were pulled by the top clamp at a rate of 100 mm/m, the force and
elongation were measured when the film broke.
• It was calculated by the replicate of 3 times.
• It is given by the following equation,
Tensile strength = Force at break (N) / Cross - sectional area of the film (m𝑚2
).
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33. Percent Elongation Break
• The elongation at break is a measurement of the maximum deformation
the film can undergo before tearing apart.
• It is calculated using the following equation.
• Elongation at break = Increase in length of break / Initial film length x 100
33

34. Disintegration time:
• Slide frame method: film on slide + drop of water in it. Note the time
when hole is observed in the film.
• Petri dish method: film in Petri plate + 2 ml of water in it. Check time till
film dissolves.
Viscosity
• The viscosity of the solution used for buccal films were determined using
Brookfield viscometer.
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35. •Shear Force (for various polymers)
The shear test measures the force required to separate two polymer-
coated glass slides joined by a thin film of natural or synthetic mucus.
 The results of this technique often correlate well with in vivo test
results.
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36. TEXTURE ANALYZER: (for bioadhesion test)
• Here the force required to remove the formulation from a model
membrane is measured, which can be a disc composed of mucin , a piece
of animal mucous.
36

37. In-vivo mucoadhesion studies
• The in vivo mucoadhesion of the buccal films were determined in healthy
human volunteers.
• The volunteers were asked to apply the film by gently pressing it in the
buccal mucosa for 30 s.
• The volunteers were advised to perform their normal activity except eating
food.
• They were asked to note down the retention time of the film as well as
various criteria related to acceptability of the film for example irritation of
mucosa, taste, dryness of mouth, comfort, salivary secretion etc.
37

38. Drug Dosage Action Polymer used
Benzydamine Patch Local Pectin, PAA
Benzocaine Bioadhesive gel Local HPMC
Carvedilol Buccal patch Systemic HPMC
Clotrimazole
liposome gel Local Carbopol
Captopril Tablet Systemic Carbopol, chitosan
Clotrimazole Diltiazem
HCL
Disk local Carbopol, HPMC
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Reported buccoadhesive drug delivery system

39. •Other In vivo methods
• Gamma Scintigraphy Technique
• Distribution and retention time of the mucoadhesive tablets can be
studied using the gamma scintigraphy technique.
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40. 40

41. EVALUATION OF BUCCAL SEMI SOLID DOSAGE FORMS
• DETERMINATION OF PH
The pH of the gel/ointment was determined using a calibrated pH METER.
The readings were taken for average of 3.
GELLING CAPACITY
The gelling capacity of the formed gel was determined using visual inspection
and the different grades were allotted as per the gel integrity, weight and rate of
formation of gel with respect to time.
41

42. •VISCOSITY STUDIES
• The rheological studies were carried out using Brookfield programmable DVIII +
model pro II type (USA).
• The viscosity of in situ gels were determined at different angular.
• Calculate the viscosity.
• Evaluation was conducted in triplicate.
•SPREADABILITY
• For the determination of spreadabilty, excess of sample was applied in between two
glass slides and was compressed to uniform thickness by placing 1000g weight for
5min.
• Weight (50g) was added to the upper glass slide.
• The time in which the upper glass slide moves over to the lower plate was taken as
measure of spreadability (S) .
• S=ML/T
42

43. • Where, M= weight tide to upper slide
L = length moved on the glass slide
T=time taken
MEASUREMENT OF GEL STRENGTH
 a sample of 50g gel was placed in a 100ml graduated cylinder and gelled in a
thermostat at 37 degree celcius.
The apparatus for measuring gel strength was allowed to penetrate in buccal gel.
The gels strength, which means the viscosity of the gels at physiological temperature,
was determined by the time (sec), the apparatus took to sink 5cm down through the
parallel gel.
The gels at physiological temperature, was determined by the time ( sec), the
apparatus took to sink 5cm down through the prepared gel.
43

44. MUCOADHESIVE FORCE
• The mucoadhesive force of all the optimized batches was determined as
follows, a section of mucosa was cut from the chicken cheek portion and
instantly fixed with mucosal slide out on to each glass vial using rubber
band.
• The vial with chicken cheek mucosa was connected to the balance in
inverted position while first vial was placed on a height adjustable pan.
• Oral gel was added on to mucosa of first vial.
• Before applying the gel, 150 microlitre of simulated saliva solution was
evenly spread on the surface of the test membrane.
• Then the height of second vial was so adjusted that the mucosal surfaces
of both vials come in intimate contact.
• Two minutes time of contact was given
44

45. • Then weight was kept rising in the pan unit vials get detached.
• Mucoadhesive force was the minimum weight required to detach two
vials.
• The cheek mucosa was changed for each measurement.
• Detachment stress (dynes/cm2)=mg/A
where, m is the weight added to the balance in gms
g is the acceleration due to gravity taken as 980 cm/s2
A is the area of tissue exposed that is 8.14cm2.
45

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