1. Presented By
RAVALI VAINALA
(Reg. No: 11FP1S0316)
DEPARTMENT OF PHARMACEUTICS
ST.PETER’S COLLEGE OF PHARMACY
Under the Esteemed Guidance of
K.RAJITHA M. Pharm, (Ph.D)
DEPARTMENT OF PHARMACEUTICS
ST.PETER’S COLLEGE OF PHARMACY
1
2. INTRODUCTION
AIM AND OBJECTIVE OF THE STUDY
REVIEW OF LITERATURE
MATERIALS AND METHODOLOGY
RESULTS AND DISCUSSION
CONCLUSION
REFERENCES
2
4. Amongst various routes of drug delivery, oral route is perhaps the
preferred to the patient and the clinician alike. However this route
presents some problems for a few drugs. The enzymes in the GI fluids,
GIT pH conditions, and the enzymes bound to the GIT membranes are a
few factors responsible for the bioavailability problems. The blood that
drains the GIT carries the drug directly to the liver leading to first pass
metabolism resulting in poor bioavailability.
The inherent problems associated with the drug in some cases can
be solved by modifying the formulation or by changing the route of
administration.
4
5. In recent years, the interest in novel routes of drug administration
occurs from their ability to enhance the bioavailability of drug. Drug
delivery via the buccal route using bioadhesive dosage forms offers such
a novel route of drug administration. Extensive first pass metabolism
and drug degradation in the harsh GI environment can be circumvented
by administering the drug via the buccal route.
Buccal delivery involves administration of desired drug through the
buccal mucosal membrane lining of oral cavity. It is richly vascularized
and more acceptable for the administration and removal of the dosage
form.
5
6. Drug absorption through buccal mucosa is mainly by passive
diffusion into the lipoidal membrane. After absorption the drug is
transported through facial vein which then drains into the general
circulation via jugular vein by passing the liver and thereby sparing
the drug from first-pass metabolism.
DRUG DELIVERY VIA BUCCAL ROUTE:
Buccal delivery refers to drug release which can occur when a
dosage form is placed in the outer vestibule between the buccal
mucosa and gingiva. Various advantages and other aspects of this
route are elucidated of the following.
6
8. Drug administration via buccal mucosa offers several distinct
advantages,
Ease of administration.
Permits localization of the drug in the oral cavity for a prolonged
period of time.
Offers excellent route for systemic delivery of drugs with high first
pass metabolism, thereby offering a greater bioavailability.
A significant reduction in dose can be achieved, thereby reducing
dose dependent side effects.
Drugs which are unstable in acidic environment of the stomach or
are destroyed by the enzymatic or alkaline environment of the
intestine.
The presence of saliva ensures relatively large amount of water for
drug dissolution unlike the case of rectal and transdermal routes.
8
9. It can be made unidirectional to ensure only buccal absorption.
The buccal mucosa is highly perfused with blood vessels and offers
greater permeability than the skin.
Therapeutic serum concentrations of the drug can be achieved more
rapidly.
Better patient compliance than vaginal, rectal and nasal route of
administration.
Buccal mucosa is less prone to damage or irritation than nasal
mucosa and shows short recovery times after stress or damage.
Termination of therapy is easy.
Can be administered to unconscious patients.
Increased patient compliance.
9
10. Drugs which irritate the oral mucosa have a bitter or unpleasant
taste or odour cannot be administered by this route.
Drugs, which are unstable at buccal pH, cannot be administered by
this route.
Only drugs with small dose requirements can be administered.
Drugs may get swallowed with saliva and loses the advantages of
buccal route.
Surface area available for absorption is less.
The buccal mucosa is relatively less permeable than the small
intestine, rectum, etc.
10
11. Should adhere to the buccal mucosa quickly and have optimum mechanical
strength.
Drug should release in a controlled manner.
Facilitates the rate and extent of drug absorption.
Should have patient compliance.
Should not obstruct normal functions such as talking, eating and drinking.
Should achieve the unidirectional release of drug towards the mucosa.
Should not aid in development of secondary infections such as dental
caries.
Possess a wide margin of safety both locally and systemically. Should have
good resistance to the flushing action of saliva.
11
13. To develop the best possible formulation in accordance with the
respective standards & preparation procedures in the form of a
tablet intended for buccal administration for the symptomatic
treatment of allergic conditions.
To increase the bio-availability of the Active Pharmaceutical
Ingredient (API) by the aid of suitable approaches & techniques in
the end product.
13
14. 1. Bilayered buccal tablets having CPM as an API, in association with the
respective grade and type of polymers in a combination were prepared by
direct compression method.
2. Carbopol-934 was selected as a primary polymer along with HPMC
K4M, HPMC K15M, sodium alginate and guar gum as secondary
polymers for the preparation of bilayered buccal tablets.
3. Ethyl cellulose was used as impermeable backing layer to provide the
unidirectional drug flow.
4. Preformulation study was done by FTIR and DSC spectroscopic method
for drug polymer interaction.
5. The prepared bilayered buccal tablets would be evaluated for various
evaluation parameters like hardness, thickness, weight variation,
friability, drug content uniformity, swelling index, in vitro drug release
study etc.
14
16. Shinde et al designed mucoadhesive buccal tablets of Niacin using
sodium carboxymethyl cellulose, Carbopol 940P and HPMC K4M as
bioadhesive polymers to impart mucoadhesion. The prepared tablets were
evaluated for different parameters such as weight uniformity, content
uniformity, thickness, hardness, surface pH, swelling index, in vitro drug
release and in vitro drug permeation. From the obtained results it was
concluded that mucoadhesive buccal tablets of Niacin can be a good way to
swelling and bioadhesion properties and good improve the bioavailability of
Niacin.
Bhanja et al formulated and evaluated mucoadhesive buccal tablets of
Timolol maleate by direct compression method. The formulations were
developed with varying concentrations of polymers like Carbopol 934,
polyethylene oxide and sodium carboxymethyl cellulose. It was found that
Timolol maleate mucoadhesive buccal tablets gave a reasonable
mucoadhesion and the drug was gradually released from all formulations over
a period of 7 h sustained drug release with desired therapeutic concentration.
16
17. Gupta, Gaud, Ganga developed the extended release buccoadhesive buccal
tablets of Nisoldipine using progressive hydration technology. This technology
involves Carbopol 972P, HPMC K15M and polycarbophil in different amounts. The
formulations are designed on 32 factorial designs to check effect of Carbopol and
HPMC K15M on mucoadhesion strength and drug release and desired drug release
was obtained in the sixth hour and good mucoadhesion strength was also obtained.
Hao Lou, Min Liu, Wen Qu and Zheyi hu have performed to mask the
bitterness of CPM via encapsulating drug into Eudragit EPO microparticles, and
then incorporate these microparticles into orally disintegrating films (ODF) and
orally disintegrating tablets (ODT) for pediatric use. Spray drying of water-in-oil
emulsion was utilized to encapsulate CPM into Eudragit EPO microparticles The
optimized microparticles were incorporated into ODF and ODT with satisfactory
weight and drug content uniformity, and acceptable physical strength. Both dosage
forms disintegrated immediately (less than 40 sec) in simulated saliva solutions. The
outcome of taste-masking test indicated that microparticles alleviated drug
bitterness significantly; bitterness was not discernible with microparticles
incorporated in ODT, whereas only slight bitterness was detected from
microparticles incorporated into ODF. Both ODF and ODT are shown to be suitable
vehicles for taste masked CPM microparticles for pediatric uses.
17
18. Masheer Ahmed khan et al., have formulated sustain release tablets of
CPM by using HPMC K4M and HPMC K15M as polymers to sustain the
release up to 12hrs. The optimum formulations were selected and the results
obtained with the experimental values were compared with the predicted values.
In conclusion, the results suggest that the developed sustained-release matrix
tablets could provide quite regulated release of chlorpheniramine maleate up to
nearly 12 hrs.
Shishu, Ashima Bhatti, Tejbir Singh have formulated Rapidly
disintegrating tablets in saliva containing bitter taste masked granules of CPM
by Compression method. The taste masked granules were prepared using amino
alkyl methacrylate copolymers (Eudragit E-100) by the extrusion method. In
vitro release profile obtained at pH 6.8 indicate that perceivable amount of drug
will not be released in saliva while high percent release (more than 80% in 30
min) would be obtained at acidic pH 1.2 of the stomach. These taste masked
granules were directly compressed into tablets using sodium starch glycolate as
a super-disintegrant. The prepared tablets containing the taste masked granules
having sufficient strength of 3.5 kg/cm were evaluated for taste by both
Spectrophotometric method and through panel testing. Panel testing data
collected from 20 healthy volunteers indicate successful formulation of oral fast
disintegrating tablets which had good taste and disintegrated in the oral cavity
within 30s. 18
20. Chemical Structure:
Chemical Name: [3-(4-chlorophenyl)-3-(pyridin-2-yl) propyl] dimethylamine
Molecular formula : C16H19ClN2
Molecular mass : 274.788
Melting point : 130-135ᵒC
Category : Anti-histamine
Solubility : Freely soluble in water and methanol,Very soluble in acetic acid
Soluble in ethanol and dissolves in dilute hydrochloric acid.
20
21. Sl.No Materials Sources
1 Chlorpheneramine maleate Nehal Traders, HYD.
2 Carbopol 934 S. D. Fine Chemicals Pvt Limited.
3 Sodium alginate Crystal colloid.
4 Guar gum Crystal colloid.
5 HPMC K4M S. D. Fine Chemicals Pvt Limited.
6 HPMC K15M S. D. Fine Chemicals Pvt Limited.
7 PVP-K-30 S. D. Fine Chemicals Pvt Limited.
8 Polyethylene glycol-6000 S. D. Fine Chemicals Pvt Limited.
9 Ethyl cellulose S. D. Fine Chemicals Pvt Limited.
10 Sodium saccharine S. D. Fine Chemicals Pvt Limited.
11 Magnesium stearate S. D. Fine Chemicals Pvt Limited.
12 Talc S. D. Fine Chemicals Pvt Limited.
21
23. Preformulation study : Preformulation testing is the first step in the rational development
of dosage forms of a drug substance. It can be defined as an investigation of physical
and chemical properties of a drug substance alone and when combined with excipients.
The overall objective of preformulation testing is to generate information useful to the
formulator in developing stable, efficacious and safe dosage form. Hence Preformulation
studies were carried out on the obtained samples of drug for identification and
compatibility studies.
Compatibility Studies: FTIR and DSC studies were conducted.
Estimation of Chlorpheneramine maleate( in water):
100mg of CPM was dissolved in sufficient distilled water to produce 100 ml solution in
a volumetric flask.
5 ml of the stock solution was further diluted to 50 ml with distilled water into a 50
ml volumetric flask and diluted up to the mark with distilled water.
Aliquots of 1, 2, 3, 4 and 5ml of stock solution were pipette out into 10ml volumetric flasks
and made upto the mark to give 10,20,30,40 and 50 mcg/ml CPM respectively. Absorbance of
each solution was measured at 265 nm.
23
24. Evaluation study for pre-compressional parameters: The powder blend
was evaluated for Bulk density, Tapped density, Hausner’s ratio, Carr’s
index and Angle of repose.
Method of Preparation of bilayered buccal tablets: Direct compression.
Evaluation of postcompressional parameters: After compression the
prepared tablets were evaluated for Uniformity of weight, Thickness,
Hardness, Friability, Swelling Index, Uniformity of drug content, Surface
pH study and In vitro drug release study.
24
25. Direct compression method was employed to prepare buccal
tablets of CPM using, Carbopol 934, Sodium alginate, Guar gum,
HPMC K4M and HPMC K15M as polymers. All the ingredients
including drug, polymer and excipients were weighed accurately
according to the batch formula. The drug and all the ingredients
except lubricants were taken on a butter paper with the help of a
stainless steel spatula and the ingredients were mixed in the order of
ascending weights and blended for 10 min in an inflated
polyethylene pouch. After uniform mixing of ingredients, lubricant
was added and again mixed for 2 min. The prepared blend of each
formulation was pre-compressed by using different punches (6mm)
according to their weights on a single stroke tablet punching
machine (Rimek Press Minipress II MT, Ahmadabad) to form a
tablet. Then 50 mg of ethyl cellulose powder was added and final
compression was done to get bilayered buccal tablet.
25
29. 1.1 Identification of drug:
The IR spectrum of pure drug was found to be similar to the reference
standard IR spectrum of CPM.
1.2 Melting point determination:
The melting point of CPM was found to be 133ºC, which complied
with USP standard, thus indicating purity of obtained drug sample.
1.3 Solubility studies of CPM:
SOLVENT CPM
Water Freely soluble
Methanol Freely soluble
Acetic acid Very Soluble
Ethanol and Chloroform Soluble
0.1N HCl Soluble
6.8 pH buffer Soluble
29
30. Sl.No Ingredients
Physical Description
Initial 55°C
(2 weeks)
40±2°C
/70±5 %
RH(4 weeks)
1 API (CPM) White
colour
No change No change
2 API+ Sodium Alginate +
Carbopol
Off white No change No change
3 API+ Guar gum + Carbopol Off white No change No change
4 API+ HPMCK4M +
Carbopol
Off white No change No change
5 API+ HPMCK15M +
Carbopol
Off white No change No change
30
31. The IR spectrum of CPM with Sodium alginate, Guar gum, HPMC K4M
and HPMC K15M suggested that the characteristics peak of CPM was
undisturbed and also the characteristic peak of each polymer was
unaffected. Hence the IR study reveals that CPM was in the free form and
no drug-polymer and polymer-polymer interactions took place during
formulation development.
31
32. FTIR spectra of CPM:
FTIR spectra of CPM with Sodium alginate:
32
33. FTIR Spectra of CPM with Guar gum:
FTIR Spectra of CPM with HPMC K4M:
33
34. FTIR Spectra of CPM with HPMC K15M:
DSC Spectra of CPM with Sodium alginate, Guar gum, HPMC K4M
and HPMC K15M:
The DSC studies reveal that the drug CPM exhibited a sharp melting
endotherm at 133oc. No significant thermal shifts were observed for CPM, when
it was assessed in combination with the other excipients intended for use in tablet
production, it appears as though drug is compatible with all the excipients and
there was no major interactions observed between the excipients or between drug
and the excipients.
34
38. Bulk density and Tapped density:
The bulk density and tapped density of powder blend of CPM with
Carbopol, Sodium alginate, Guar gum, HPMC K4M and HPMC K15M
was found to be between 0.39 ± 0.09 to 0.48 ± 0.34 g/cm3 and 0.47 ±
0.43 to 0.59 ± 0.27. This indicates good packing capacity of powder
blend.
Carr’s Index:
Carr’s index was found to be between 13.46 to 22.
Hausner’s ratio :
Hausner’s ratio was found 1.15 to 1.30. This indicates good flowability.
The angle of repose:
The angle of repose of all the formulations were observed within the
range of 27.08 ± 0.54 to 33.2 ± 0.84 i.e. powders were of good flow
properties.
38
40. All the prepared bilayered buccal tablets of CPM were evaluated for
thickness, hardness, friability, weight variation, swelling index, drug
content and surface pH.
Hardness:
The hardness of prepared mucoadhesive buccal tablets were from 4.13 ±
0.41 kg/cm2 to 5.7 ± 0.06 kg/cm2. The lower values of standard deviation
indicate that the hardness of all the formulations were almost uniform and
possess good mechanical strength with sufficient hardness. As the
concentration of Carbopol was decreased, the hardness of the tablet was
increased.
Thickness:
The mean thickness (n=3) of the tablets was from 2.56 ± 0.63 to 3.27 ±
0.75 mm. The standard deviation values indicated that all the
formulations were within the range and show uniform thickness.
40
41. Weight variation test:
The values of all the formulated tablets ranged from 148.6±1.15 to
151.3±1.52mg. Thus all the formulations passed the test for weight
variation according to USP specifications.
Friability test:
The values ranged from 0.20±0.98to 0.87±0.32%. All the values are below
1% indicating that the tablets of all formulations are having good
compactness and strength.
Swelling studies:
The swelling studies of prepared buccal tablets were performed in
phosphate buffer at the pH of 6.8. The swelling behaviour of a buccal tablet
is an important property for uniform and prolonged release of drug. The
swelling behaviour depends upon nature of polymer, concentration of
polymer and pH of the medium. The swelling of all the tablets were
increased as the time proceeds because the polymer gradually absorbs
water due to hydrophilicity of the polymer.
41
42. The swelling index of tablets was found between 30.15% to 84.03%.
The highest swelling of 39.44% to 84.03% for formulations which
contains Sodium alginate and 38.06% to 82.71% for formulations which
contains HPMC K4M because HPMC K4M and sodium alginate are
more water soluble and rapidly get hydrated. The swelling index was
affected by the concentration of Carbopol, as the concentration of the
Carbopol decreases the viscosity and swelling index of tablets increases.
Drug content uniformity:
Drug content was in the range of 95.71% ± 2.74 to 101.48% ± 2.20
indicating good content uniformity in the all formulations. The reading
complies as per I P. that indicates drug was uniformly distributed
throughout the tablet.
Surface pH:
The surface pH was in the range of 6.53 ± 0.23 to 7.04 ± 0.06 which
was nearer to salivary pH (6.5-7.5) suggesting that the prepared buccal
tablets can be used without the risk of mucosal irritation and discomfort.
42
48. Finally the in vitro study was subjected to Zero order, first order,
Higuchi, Korsmeyer Peppas and Hixson Crowell. Release kinetics of
CPM for all the formulations seems to follow First order, because the
values of regression coefficient obtained for first order are higher as
compared to Zero order and Higuchi plot. From Korsmeyer-Peppas
equation the n- values were found to be 0.5 < n < 1 for all the buccal
tablet formulations. Therefore it shows that the release mechanism was
Non- Fickian diffusion.
48
50. Parameters Initial at
40°C/75%
After 1
month at
40°C/75%
After 2
months at
40°C/75%
After 3
months at
40°C/75%
Drug content 98.75 98.26 97.14 99.45
Surface pH 6.95 6.97 6.74 6.72
% of Drug
release
87.63 88.46 88.95 89.36
50
51. The Formulation and evaluation of bilayered buccal tablets of CPM
reveals following conclusion:
The mucoadhesive buccal tablets of CPM could be prepared using
Carbopol-934 as primary polymer and in combination of secondary
polymers like sodium alginate, Guar gum, HPMC K4M and HPMC
K15M by direct compression method.
The prepared bilayered buccal tablets subjected to FTIR and DSC study
suggested that there was no drug-polymer and polymer-polymer
interaction.
All the prepared tablets were in acceptable range of weight variation,
thickness, hardness, friability, swelling index and Surface pH as per
Indian pharmacopoeial specification. As the concentration of Carbopol
decreases, the hardness of tablet was increased.
51
52. The buccal tablets showed good swelling up to 6 hrs in phosphate
buffer at the pH of 6.8 maintaining the integrity of formulation
which is required for uniform and prolonged release of drug. As the
concentration of Carbopol decreases, the swelling index of tablets
increased.
The in vitro release of CPM with Carbopol and Sodium alginate in
the ratio of (10:40) (F4) shows better drug release (87.63%) than
other polymers and it is considered as optimized.
Hence, the bilayered buccal tablets of CPM can be prepared with
enhanced bioavailability and provide the prolonged therapeutic
effect for 6 hrs. The study conducted so far reveals a promising
result suggesting scope for pharmacodynamic and pharmacokinetic
evaluation.
52
54. 1. Jain NK. Controlled and novel drug delivery. 1st ed. New Delhi: CBS Publishers &
Distributors; 1997: 52-81.
2. Patel VM, Prajapati BG, Patel MM. Formulation, evaluation and comparison of bilayered and
multilayered mucoadhesive buccal devices of propranolol hydrochloride. AAPS Pharm Sci
Tech. 2007; 8(1): 1-8.
3. Miller NS, Chittchang M, Johnston TP. The use of mucoadhesive polymers in buccal drug
delivery. Adv Drug Deliv Rev. 2005; 57: 1666- 1691.
4. Vyas SP, Khar RK. Controlled drug delivery-concepts and advances. 1st ed. New Delhi:
Vallabh Prakashan; 2002.
5. Shojaei HA. Buccal mucosa as a route for systemic drug delivery: A Review. J Pharm Sci.
1998; 1(1): 15-30.
6. David Haris, Robinson JR. Buccal drug delivery via the mucous membranes of the oralcavity.
J Pharm Sci. 1992; 81(1): 1-9.
7. Tor-Tora Gorahowski. Principles of anatomy and physiology. 7th ed. Edited by Gerad J.Tor-
Collins College Publishers; 1992: 770-774.
54
55. 8. Ross & Wilson. Anatomy & physiology in health and illness. 9th ed. Edited by Anne
Waugh and Allison Goraw: Churchill Livingstone Edinburgh Publishers; 2001: 289-
293.
9. Chatterjee CC. Human physiology. 10th ed. Calcutta: Medical Allied Agency; 1985:427-
434.
10. Pramod KTM, Shivakumar HG and Desai KG. Oral transmucosal drug
deliverysystems.Indian Drugs. 2004; 41(2): 63-67.
11. Chen YS, Squier CA. The ultra structure of the oral epithelium. In: J. Meyer, CA.
Squier, SJ. Gerson (eds.), The structure and function of oral mucosa, Pergamon Press,
Oxford. 1984: 7- 30.
12. Swarbrick James. Bioadhesive drug delivery systems. 1st ed. New York: Marcel
Dekker Inc; 1999: 541-562.
13. Hayward AF. Membrane-coating granules. Int Rev Cyt. 1979; 59: 97-127.
14. N.K. Jain “Controlled and Novel Drug Delivery”, Ist Edition, CBS Publishers and
Distributors, India, 2004, 52-74. 55
56. 15. Swarbrick James, Boylan C. James, “Encyclopedia of Pharmaceutical Technology”, IInd
Edition, Vol. 2, Marcel Dekker, Inc., New York, 1990, 189-210.
16. Yie W. Chein , “Novel Drug Delivery Systems”, IInd Edition , Marcel Dekker, Inc., New
york, Vol. 50, 1992,8-9,197-228,456-457.
17. Swarbrick James, Boylan C. James, “Encyclopedia of Pharmaceutical Technology”, IInd
Edition, Vol. 10, Marcel Dekker, Inc., New York, 1990, 133.
18. Michael J. Rathbone, “Oral Mucosal Drug Delivery” Drug and Pharmaceutical sciences. IInd
Edition ,Marcel Dekker Inc., New York.1992.
19. Joseph R R and Vincent H L Lee, “Controlled Drug Delivery” IInd Edition, Vol. 29, Marcel
Dekker, Inc., New York, 1987, 42-43.
20. Edith Mathiowitz, Donald E C and Claus – Michael L, “Bioadhesive Drug Delivery Systems
–Fundamentals, Novel Approaches and Development”, IInd Edition, Vol. 98,Marcel Dekker,
Inc., New York, 1999, 541-562.
21. Swarbrick James, Boylan C. James, “Encyclopedia of Pharmaceutical Technology”, IInd
Edition, Vol. 10, Marcel Dekker, Inc., New York, 1990, 133.
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