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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
M. PHARM SYNOPSIS
YEAR OF ADMISSION 17/9/2013
TITLE OF THE SYNOPSIS
“FORMULATION AND EVALUATION OF
BUCCAL TABLETS OF VERAPAMIL HYDROCHLORIDE”
BY
AJAY CHAUHAN
M. PHARM, PART- I
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDANCE OF
Dr. PRASHANTH V.V., M. Pharm., PhD.
Professor and HOD
DEPARTMENT OF PHARMACEUTICS
INSTITUTION
GAUTHAM COLLEGE OF PHARMACY
SULTAN PALYA, R. T. NAGAR Post, BANGALORE-560 032
1
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1.
NAME OF THE CANDIDATE AND
Mr. AJAY CHAUHAN
ADDRESS
DEPARTMENT OF PHARMACEUTICS
GAUTHAM COLLEGE OF PHARMACY
SULTAN PALYA, R.T. NAGAR Post,
BANGALORE – 560 032
2.
NAME OF THE INSTITUTION
GAUTHAM COLLEGE OF PHARMACY,
SULTAN PALYA, R.T NAGAR Post,
BANGALORE – 560 032
3.
COURSE OF STUDY AND SUBJECT
MASTER OF PHARMACY IN
PHARMACEUTICS
4.
DATE OF ADMISSION TO COURSE
5.
TITLE OF THE TOPIC
17/9/2013
“FORMULATION AND EVALUATION OF
BUCCAL TABLETS OF VERAPAMIL
HYDROCHLORIDE”
2
6.
BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
Amongst the various routes of drug delivery, the oral route is most preferred to the
patient and the clinician alike. However, oral administration of drugs has disadvantages such as
hepatic first pass metabolism and enzymatic degradation within the gastro intestinal (GIT), that
prohibit oral administration of certain classes of drugs especially peptides and proteins. Trans
mucosal routes of drug delivery (mucosal linings of nasal, rectal, Vaginal, ocular and oral
cavity) offers distinct advantages over oral administration for systemic drug delivery1.
Buccal delivery of drugs provides an attractive alternative to the oral route of drug
administration, particularly in overcoming drawbacks associated with the oral mode of dosing2.
Other than the common advantages of novel drug delivery systems, buccal mucosa has several
specific advantages like, faster and richer blood flow than other parts of oral region. The
thickness of the buccal mucosa is 500 - 800 μm and is rough textured. Moreover, the
permeability of the buccal mucosa is 4 - 400 times greater than that of the skin. The mucus
network of buccal mucosa carries a negative charge, which may play role in mucoadhesion.
Buccal drug delivery offers direct access to the systemic circulation through the external
jugular vein, which bypass the drugs from the hepatic first-pass metabolism, leading to higher
bioavailability3.
Cardiovascular disease is responsible for one third of the global deaths and is
increasing contributor to the global disease burden. According to WHO globally, an estimated
17.5 million people died from cardiovascular disease in only 2005, representing 30% of global
deaths. In United States itself there are 73.6 million people who are diagnosed for hypertension
and in Indian subcontinent, it accounts to more than 25% of deaths. High blood pressure is an
independent risk factor for cardiovascular disease.4
Hypertension or high blood pressure is a cardiac chronic medical condition in which
the systemic arterial blood pressure is elevated. Means is that the heart is having to work
harder than it should to pump the blood around the body. Blood pressure involves two
measurements, systolic and diastolic. Normal blood pressure is at or below 120/80 mmHg5.
High blood pressure is anything above 140/90 mmHg. Hypertension is the opposite
of hypotension. Hypertension is classified as either primary (essential) hypertension or
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secondary hypertension; about 90–95% of cases are categorized as "primary hypertension,"
which means high blood pressure with no obvious medical cause6.The remaining 5-10% of
cases (Secondary hypertension) are caused by other conditions that affect the kidneys, arteries,
heart or endocrine system6.
The antihypertensive are a class of drugs that are used to treat hypertension (high
blood pressure). Evidence suggests that reduction of the blood pressure by 5 mmHg can
decrease the risk of stroke by 34%, of heart disease by 21%, and reduce the likelihood
of dementia, heart failure, and mortality from cardiovascular disease7. There are many classes
of antihypertensive, which lower blood pressure by different means; among the most important
and most widely used are the thiazide diuretics, the ACE inhibitors, the calcium channel
blockers, the beta blockers, and the angiotensin II receptor antagonists. This type of medication
to use initially for hypertension has been the subject of several large studies and resulting
national guidelines. The fundamental goal of treatment should be the prevention of the
important endpoints of hypertension, such as heart attack, stroke and heart failure. Patient age,
associated clinical conditions and end-organ damage also play a part in determining dosage and
type of medication administered8.
Verapamil is a calcium channel blocker (Class 4) and has the most prominent cardiac
electrophysiological action. It blocks L type calcium channels and delays their recovery. The
basic action of verapamil is to depress calcium mediated depolarization. This is to suppress
automaticity or reentry dependent on slow response. Verapamil has negative inotropic action
due to interference with Ca+ + mediated excitation – contraction coupling in myocardium9.
Verapamil inhibits voltage-dependent calcium channels. Specifically, its effect on Ltype calcium channels in the heart causes a reduction in ionotropy and chronotropy, thus
reducing heart rate and blood pressure. Verapamil's mechanism of effect in cluster headache is
thought to be linked to its calcium-channel blocker effect, but which channel subtypes are
involved is presently not known. Approximately 70% of an administered dose is excreted as
metabolites in the urine and 16% or more in the faeces within 5 days. About 3% to 4% is
excreted in the urine as unchanged drug. It has a biological half life of 2.8 – 7.4 hrs10.
The oral absorption of the drug from oral dosage forms is about 90% but it is
subjected to a very extensive first-pass metabolism in the liver and its bioavailability is only
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about 20%. Since this drug has a short elimination half-life of 2-4 hours and is eliminated
rapidly, repeated daily administration are required to maintain effective plasma levels. It has
been suggested that drugs with biological half-life in the range of 2-8 hours are good candidates
for sustained release formulations. Verapamil Hydrochloride slow release tablets in doses of
120 to 240 mg and controlled-onset extended release tablets in doses of 180 and 240 mg are
available11.
Verapamil hydrochloride is water soluble drug and has site specific absorption from GIT and
on other hand, the drug is unstable in the alkaline pH of the intestine, but it is widely absorbed
from the buccal region12. Based on the above reasons there is a clear need to localize the
developed formulation at the target area of the mucosa by preparing a buccal tablets.
Previously, studies have been carried out to formulate various mucoadhesive
buccal drug delivery devices, including tablets13-16, films17-19, patches20-22, disks23, ointments24
and gels25. Among these formulations, buccal tablets are preferred owing to their accurate
dosing, ease of preparation and stability.
This is a main concern in the delivery of this category of drugs. Therefore, in this
project we propose to overcome these lacunas by the way of formulating them into buccal
tablets.
6.2 REVIEW OF LITERATURE
Perioli et al (2004), prepared mucoadhesive tablets using different mixtures of cellulose and
polyacrylic derivatives to obtain new formulations containing metronidazole for periodontal
disease treatment. All tablets were characterized by swelling studies, ex vivo and in vivo
mucoadhesive time, ex vivo mucoadhesion force, in vitro and in vivo release. The best
mucoadhesive performance and the best in vitro drug release profile were achieved by using
hydroxyethyl cellulose (HEC) and carbomer 940 in 2:2 ratios. The chosen tablet, containing 20
mg of metronidazole, performed 12 hrs drug sustained release in healthy human volunteers
with buccal concentrations always higher than its MIC. Statistical analysis of in vitro release
data showed that the formulation followed non-Fickian release26.
Takahashi et al (2007), developed bioadhesive tablets of bovine lactoferrin (B-LF) for the
treatment of chronic inflammation in the oral cavity, which has antibacterial properties and
5
immune
regulatory
functions.
B-LF
tablets
containing
pectin,
tamarind
gum
or
carboxymethylcellulose (CMC) were prepared by direct compression. Tablets consisting of BLF, pectin and xylitol passed through 60- or 100-mesh sieves were also prepared. The tablets
containing CMC had insufficient bioadhesive force. Although the tablets containing tamarind
gum showed the longest residence time in the oral cavity, an unpleasant taste gradually
developed. The tablets containing pectin showed the highest value of bioadhesive force and the
taste was acceptable. The characteristics of the B-LF tablets were improved by adding an
appropriate amount of xylitol and using the ingredients sieved by a 100-mesh sieve. The
therapeutic effect was evaluated by using rats with an ulcer on the oral mucosa. In the present
study, swelling on the periphery of the ulcer was observed after administration of the B-LF
tablets, and then the ulcer has reduced overall27.
Borgaonkar et al (2011), Formulated mucoadhesive buccal tablets of Loratadine with an
objective of enhancing the bioavailability by minimizing first pass metabolism. The buccal
tablet were prepared by using HPMC K4M as primary polymer alone and in combination with
secondary polymers like chitosan and sodium alginate in varying concentrations by direct
compression method28.
Ankarao et al (2010), developed mucoadhesive buccal tablets of carvedilol in the form of
bilayered tablets. The tablets were prepared using HPMC K4M, sodium CMC and
carbopol
934 (CP) to impart mucoadhesion, and ethyl cellulose (EC) was used an impermeable backing
layer. Buccal tablets were evaluated for different parameters such as weight uniformity, content
uniformity, thickness, hardness, surface pH, swelling index, ex vivo mucoadhesive strength, in
vitro drug release, and in vitro drug permeation. The mechanism of drug release was found to
be non-Fickian diffusion for all the formulations. Thus, this study has concluded that
mucoadhesive buccal tablets of carvedilol may be a better choice to overcome the extensive
hepatic first-pass metabolism and to improve the bioavailability of carvedilol29.
Velmurugan et al (2010), developed buccoadhesive tablets of piroxicam by using HPMC K4M
and carbopol 934 as mucoadhesive polymers. Ten formulations were developed with varying
concentrations of polymers. H1 to H5 formulations were composed of HPMC K4M in ratios of
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1:1 to 1:5 whereas in C1 to C5 formulations Carbopol 934 were used in ratios of 1:0.25 to
1:1.5. The formulations were tested for in-vitro drug release, bioadhesive strength, moisture
absorption, residence time and drug permeation through porcine buccal mucosa. Optimized
formulation H3 showed maximum release of the drug (97.67±0.41) with the peppas model
release profile and permeated 26.52±0.19 of the drug through porcine buccal membrane. H3
formulation showed 12.5gm of mucoadhesive strength, the FTIR results showed no evidence of
interaction between the drug and polymers. The results indicated that suitable bioadhesive
buccal tablets with desired permeability could be prepared. Stability of piroxicam buccal tablets
was determined in natural human saliva; it was found that both piroxicam and buccal tablets
were stable in human saliva30.
Ashwini et al (2008), developed and evaluated sustained release mucoadhesive tablets of
itraconazole. A solid dispersion of itraconazole with eudragit E100 was prepared by spray
drying. This was formulated in matrix of hydrophilic mucoadhesive polymers carbopol 934P
(CP) and methocel K4M (HPMC). Amounts of CP and HPMC were taken as formulation
variables for optimizing response variables i.e. mucoadhesion and dissolution parameters. The
optimized mucoadhesive formulation was orally administered to albino rabbits, and blood
samples collected were used to determine pharmacokinetic parameters. The solid dispersion
markedly enhanced the dissolution rate of itraconazole. The bioadhesive strength of
formulation was found to vary linearly with increasing amount of both polymers31.
Manivannan et al., (2008) prepared mucoadhesive buccal tablets of diltiazem hydrochloride
using Carbopol-934, Sodiumcarboxy methylcellulose (SCMC), Hydroxypropyl methyl
cellulose (HPMC), sodium alginate and guar-gum as mucoadhesive polymers. Eight
formulations were developed with varying concentrations of polymers. The carbopol-934 is
used as a primary polymer because of its excellent mucoadhesive property and secondary
polymers like HPMC, SCMC, sodium alginate and guar-gum were used. The effect of
secondary polymer loading on drug release was studied. The formulations were tested for invitro drug release and in-vitro swelling studies. Formulation FA2 showed maximum release of
76.98% in 8hours. Formulation FC2 showed maximum swelling index of 3.7 after 8hours.
Formulation FA2 follows zero order drug release. FTIR studies show no evidence on
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interaction between drug and polymers. The results indicate that suitable mucoadhesive buccal
tablets with desired properties could be prepared32.
Rajkumar et al (2010), designed a mucoadhesive bi-layered tablet containing glibenclamide.
Carbopol-940, polyvinylpyrrolidone (PVP), and sodium carboxy methyl cellulose (sodium
CMC) were used as polymers. Tablets were obtained through direct compression. The core
layer constituents were glibenclamide (5 mg), carbopol, SCMC and PVP in 3 different ratios.
The mixture CP: SCMC (2:3) showed good water absorption. The CP: PVP (1:4) formulation
showed the best drug release pattern and bioadhesion property. The in vitro release data showed
zero order release kinetics based on Higuchi diffusion which was the possible drug release
mechanism33.
Saikat et al (2010), formulated buccal tablets of losartan potassium with an objective to
increase the bioavailability of the drug. Carbopol 934P was used as a primary mucoadhesive
polymer and either sodium CMC, HPMC K4M or sodium alginate as secondary polymer, in
different ratios. The results of weight variation, thickness, content uniformity, surface pH and
bioadhesive strength of all batches were satisfactory and complied with theoretically expected
values. In vitro release studies demonstrated a highest percentage of drug release for the
formulations with sodium alginate as a secondary polymer. However formulation of this group
showed fast fragmentation and higher matrix erosion. Formulations containing SCMC and
HPMC K4M, respectively, as secondary polymers showed an adequate release and better
mucoadhesion. In vitro drug release showed that the formulations followed zero order
kinetics34.
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6.3 OBJECTIVES OF THE STUDY
From literature it has been noted that, the physicochemical and pharmacokinetic profiles of
Verapamil Hydrochloride make it a suitable candidate for the preparation of a buccal adhesive
drug delivery system. The main objectives of the present work is

To formulate and characterize the buccal tablets of Verapamil Hydrochloride
with different polymer composition for buccal drug delivery

To ensure satisfactory drug release

To avoid the first-pass metabolism and thereby to enhance improved
bioavailability.
7.
MATERIALS AND METHODS
Drug
: Verapamil Hydrochloride
Polymer
: Chitosan, HPMC, PVA, Carbopol, PVP, NaCMC, Ethyl
Cellulose etc Method
: Preparation of buccal tablet by
direct compression
Method
7.1 EVALUATIONS
Pre formulation studies includes
 Complete characterization of the drug and polymers, and its analytical method
development
 Screening of excipients for suitability
Formulation studies includes
 Preparation of buccal tablets35
 Weight variation test36
 Thickness uniformity test36
9
 Measurement of bioadhesion strength37
 In vitro mucoadhesion time38
 Swelling studies39,40
 Surface pH Study41
 In vitro drug release of buccal tablets35
 Ex vivo permeation of buccal tablets42
 Determination of the mechanism of drug release from the buccal tablet43,44
 Stability of buccal tablets
 Drug –polymer compatibility study & surface morphology study using FTIR45, 46
7.2 METHOD OF COLLECTION OF DATA
 Literature review including pub med/med line and internet search.
 Gautham College of Pharmacy Library.
 Scientific journals and Articles:o International Journal of Pharmaceutical Sciences
o International Journal of Pharmaceutics
o Topical Pharmaceutical Journals
o Advanced DD Reviews
 Laboratory based studies.
 Internet Browsing.
7.3
Does the study require any investigations or invention to be conducted on
patients or other human or animals? If so, please mention briefly.
Buccal mucosal membrane of pig from the slaughter house.
7.4 Has ethical clearance been obtained from your institution in case of
7.3?
NO
10
8.
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of buccal tablets of piroxicam. Int. J. Pharm. Tech. Res. 2010;2(3):1958-1968.
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33. Rajkumar MA, Kumar KI, Nagaraju T, Laxmi BS, Srikanth G, Sandeep P. Design and
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9.
Signature of Candidate
10.
Remarks of the guide
The above information is true to the best of my knowledge and the work will be done under
my guidance.
11. 11.1 Name and Designation of Guide
Dr. Prasanth V.V, M. Pharm., Ph. D.
Professor & Head
Department of Pharmaceutics
Gautham college of Pharmacy
Sultan palya, R.T. Nagar Post,
Bangalore – 560 032
11.2 Signature
11.3 Co-Guide (IF ANY)
11.4 Signature
11.5 Head of the Department
Dr. Prasanth V.V., M. Pharm., Ph. D.
Professor & Head
Department of Pharmaceutics
Gautham college of Pharmacy
Sultan palya, R.T Nagar Post,
Bangalore – 560 032
11.6 Signature
12. 12.1 Remarks of the Chairman and Principal
The above mentioned information is correct and I recommend the same for approval.
12.2 Signature
Dr. ARCHANA SWAMY P., M. Pharm., Ph.D.
Principal
Gautham college of pharmacy
Sultan playa, R.T. Nagar Post,
Bangalore-560 032
15