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Formulation and Evaluation of Matrix Tablets for Colon Specific
Delivery of Mebendazole
M.Pharm Dissertation Protocol Submitted to the
Rajiv Gandhi University of Health Sciences,
Karnataka, Bangalore.
By
Mr. Mahantesh Kavatekar B.Pharm
Under the guidance of
Dr. Chandrashekar C. patil
M.Pharm., Ph.D.
Professor
Department of Pharmaceutical Technology
B.L.D.E.A’s College of Pharmacy, Bijapur-586103
2012-2013
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
2.
Name of the Candidate and
Address
(In block letters)
MR. MAHANTESH KAVATEKAR
Name of the Institution
B.L.D.E.A’s College of Pharmacy, BLDE
University campus ,Bijapur-586 103
3.
Course of study and subject
M.Pharm in Pharmaceutical Technology
4.
Date of admission to Course
10/12/2011
5.
Title of the Topic
Formulation and Evaluation of Matrix Tablets for
Colon Specific Delivery of Mebendazole
6.
7.
Brief resume of the intended work :
6.1 Need for the study
Enclosure-I
6.2 Review of literature
Enclosure-II
6.3 Objectives of the study
Enclosure-III
Material and Methods :
7.1 Source of data
: Enclosure-IV
7.2 Method of collection of data (including sampling procedure, if any)
: Enclosure-IV
7.3 Does the study require any investigations or interventions to be conducted on
patients or other humans or animals? If so, please describe briefly.
: Enclosure-V
7.4
Has ethical clearance been obtained from your institution in case of 7.3
: YES
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8.
List of References (about 4-6)
9.
Signature of candidate
10.
Remarks of the guide
11.
Name & Designation of
(in block letters)
11.1
Guide
11.2
Signature
: Enclosure-VI
: Enclosure-VII
Dr. CHANDRASHEKAR .C. PATIL Professor
Department of Pharmaceutical Technology
B.L.D.E.A’s College of Pharmacy,
BIJAPUR-586 103
--11.3
Co-Guide (if any)
11.4
Signature
11.5
Head of Department
11.6
Signature
12.1
Remarks of the principal
12.2
Signature
---
12.
Dr. RAGHAVENDRA. V. KULKARNI
Professor & Head
Department of Pharmaceutical Technology,
B.L.D.E.A’s College of Pharmacy,
BIJAPUR-586 103
: This study can be carried out in our
laboratory
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ENCLOSURE-I
6) Brief resume of the intended work
6.1. Need for the study
Oral controlled-release formulations for the small intestine and colon have received
considerable attention in the past 25 years for a variety of reasons including pharmaceutical
superiority and clinical benefits derived from the drug - release pattern that are not achieved
with traditional immediate (or) sustained - release products1.Targeted drug delivery into the
colon is highly desirable for local treatment of a variety of bowel diseases such as ulcerative
colitis, Crohn’s disease, amebiosis, colonic cancer, local treatment of colonic pathologies,
and systemic delivery of protein and peptide drugs.2
The colon specific drug delivery system (CDDS) should be capable of protecting the
drug en route to the colon i.e. drug release and absorption should not occur in the stomach
as well as the small intestine, and neither the bioactive agent should be degraded in either of
the dissolution sites but only released and absorbed once the system reaches the colon.3
The colon is believed to be a suitable absorption site for peptides and protein drugs for the
following reasons; (i) less diversity, and intensity of digestive enzymes, (ii) comparative
proteolytic activity of colon mucosa is much less than that observed in the small intestine,
thus CDDS protects peptide drugs from hydrolysis, and enzymatic degradation in duodenum
and jejunum, and eventually releases the drug into ileum or colon which leads to greater
systemic bioavailability.4 And finally, because the colon has a long residence time which is
up to 5 days and is highly responsive to absorption enhancers.5 Oral route is the most
convenient and preferred route but other routes for CDDS may be used. Rectal
administration offers the shortest route for targeting drugs to the colon. However, reaching
the proximal part of colon via rectal administration is difficult. Rectal administration can also
be uncomfortable for patients and compliance may be less than optimal.6
Mebendazole is a highly effective broad spectrum antihelmintic indicated for the
treatment of nematode infestations, including roundworm, whipworm, threadworm, and
4
hookworm. When administered orally, only around 10% of the mebendazole is absorbed
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with peak plasma concentrations after 1 or 2 hours. It has a short plasma half-life of 2.5 to
5.5 hours8, but this drug is less absorbed in the stomach and has the extensive hepatic
metabolism. Therefore, it requires to be formulated in the improved form to get the improved
bioavailability of drug and to reduce the frequency of dosing.
Hence, the present work is aimed at the formulation of matrix tablets for colon
specific delivery of mebendazole.
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ENCLOSURE-II
6.2. Review of literature
1. Mura et al., have developed enteric-coated calcium pectinate microspheres (MS)
aimed for colon drug delivery by using theophylline as a model drug. The
influence of pectin type (amidated or non-amidated) and MS preparation
conditions (CaCl2 concentration and crosslinking time) was investigated upon the
drug entrapment efficiency and its release behaviour. Drug stability and drug–
polymer interactions were studied by Differential Scanning Calorimetry,
thermogravimetry, X-ray diffractometry and FTIR spectroscopy. Enteric coating
with Eudragit S100 enabled maintenance of MS integrity until its expected arrival
to colon. The coating was also useful to improve the stability of MS during
storage, avoiding morphologic changes observed for uncoated MS stored under
ambient conditions. Entrapment efficiency increased by reducing cross-linking
time, and (only in the case of non-amidated pectin) by increasing CaCl2
concentration. On the other hand, release tests performed simulating the gastrointestinal pH variation evidenced an inverse relationship between CaCl2
concentration and drug release rate, whereas no influence of both pectin type
and cross-linking time was found. Unexpectedly, addition of pectinolytic enzymes
to the colonic medium did not give rise to selective enzymatic degradation of MS.
Notwithstanding this unforeseen result, coated MS prepared at 2.5% w/v CaCl2
concentration were able to adequately modulate drug release through a mixed
approach of pH and transit time control, avoiding drug release in the gastric
ambient, and reaching the colonic targeting where 100% release was achieved
within less than 24 h9.
2. Hiorth et al., have reported that the biopolymers such as pectin, alginate, and
chitosan have a great potential in colon drug delivery. The aim of their study was
to produce pellets with calcium and chitosan in the core and then by an interfacial
complexation reaction coat the cores with pectin or alginate in combination with
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calcium or chitosan. Pellets with calcium in the core acted as a reference. The
drug release was investigated in environments mimicking the stomach and the
small intestine. The morphology of the coatings indicated a more wrinkled and
irregular structure for coatings composed of pectin or alginate in combination with
chitosan compared to the coat consisting of alginate in combination with calcium.
The results from the drug release experiments showed that all the investigated
coatings, especially with alginate, slowed down the drug release compared to the
uncoated cores. The release from the chitosan-containing pellets was higher than
the reference. The swelling studies revealed a high degree of swelling of the core
consisting of chitosan. This probably explains the higher drug release from the
coated chitosan pellets10.
3. Das et al., have developed Zinc–pectin–chitosan composite microparticles as
colon-specific carrier. Resveratrol was used as model drug due to its potential
activity on colon diseases. Formulations were produced by varying different
formulation parameters (cross-linking pH, chitosan concentration, cross-linking
time, molecular weight of chitosan, and drug concentration). Single-step
formulation technique was compared with multi-step technique. Effect of these
parameters was investigated on shape, size, weight, weight loss (WL), moisture
content (MC), encapsulation efficiency (EE), drug loading (L), and drug release
pattern of the microparticles. The formulation conditions were optimized from the
drug release study. In vivo pharmacokinetics of the zinc-pectinate particles was
compared with the zinc–pectin–chitosan composite particles in rats. Formulations
were spherical with 920.48–1107.56 m size, 21.19–24.27mg weight of 50
particles, 89.83–94.34% WL, 8.31–13.25% MC, 96.95–98.85% EE, and 17.82–
48.31% L. Formulation parameters showed significant influence on drug release
pattern from the formulations. Formulation prepared at pH 1.5, 1% chitosan, 120
min cross-linking time, and pectin:drug at 3:1 ratio demonstrated colon-specific
drug release. Microparticles were stable at 40C and room temperature.
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Pharmacokinetic study indicated in vivo colon-specific drug release from the
zinc–pectin–chitosan composite particles only11.
4. Bhawna et al., have studied colon targeted system for metronidazole using guar
gum and xanthan gum. Matrix formulations containing various proportions of guar
gum and xanthan gum were prepared by wet granulation technique using 10%
starch paste. Later on, multilayer tablets were prepared by using 50 mg and 100
mg of guar gum as release controlling layer on either side of (M5) guar gum
matrix tablets of metronidazole. All the formulations were evaluated for in-process
quality control tests. The in-vitro drug release study was undertaken at 37±0.5°C
in 0.1N HCl for 2 h; followed by pH 7.4 phosphate buffer (3h) finally in, simulated
colonic fluid pH 6.8 phosphate buffer containing 4%w/v rat ceacal content for 15
h. Results indicated that guar gum was alone failed to control drug release. M5
(GG: XG, 0:100) formulation seems to quiet promising for colonic drug delivery
and only 12.3% drug is released in first 5h wherease, other matrix tablets
released 12-33% of metronidazole in physiological environment of stomach and
small intestine. When studies were continued in colonic fluids, matrix tablets
released almost 100% drug. whereas, metronidazole multilayer formulations did
not release drug in stomach and small intestine, but delivered drug to the colon
resulting in slow absorption of the drug and making drug available for local action
in the colon12.
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ENCLOSURE-III
6.3. Objectives of the study
The present work is planned with the following objectives.
1. To prepare matrix tablets by wet granulation technique using polymers like pectin,
guar gum, xanthan gum, Eudragit etc.
2. To examine the granules for angle of repose, compressibility index, bulk density etc.
3. To evaluate the tablets for hardness, weight variation, uniformity in drug content,
drug-polymer interactions, nature of drug in the formulations and surface
morphology.
4. To study the in vitro drug release from the prepared tablets in simulated colonic fluid
using dissolution tester.
5. To carry out the Roentgenographic studies.
6. To carry out the stability studies on the prepared formulations.
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ENCLOSURE-IV
7) MATERIALS AND METHODS
7.1. Source of data
The data will be collected by performing various laboratory experiments, referring
journals, text books and other literature.
7.2. Method of collection of data
The whole data is planned to collect from laboratory experiments which includes the
following,
1) The colon targeted matrix tablets will be prepared by wet granulation method using
polymers like pectin, guar gum, xanthan gum, Eudragit etc.
2) The granules will be evaluated for angle of repose, compressibility index and bulk
density.
3)
The formulations will be characterized by Differential scanning calorimetry (DSC),
Infrared Spectroscopy (FTIR), x-ray Diffraction Studies (XRD), Scanning Electron
Microscopy (SEM) and data will be collected.
4) The effects of formulation variables on the drug release will be studied by conducting
dissolution experiments in simulated colonic fluid and data will be collected.
5) The stability studies of the formulations will be carried out as per ICH guidelines and
data will be collected.
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ENCLOSURE-V
7.3. This study is aimed to carry out the following animal studies.
1) Drug release in simulated colonic fluid: The caecum will be excised from the rat
digestive system and the contents of the caecum will be used to perform drug release study
(No of rats required: 10, Sex: Either, Weight: 250-300 gm).
2) Roentgenographic study: The prepared tablet will be subjected for roentgenography
to know the colon targeting of the tablets (No of rabbits required = 03).
7.4. Animal ethical clearance has been obtained to carry out the above said animal
Experiments? Applied for IAEC permission and meeting expected to be held in the
month of August 2012
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ENCLOSURE-VI
8) List of References
1. Philip A.K., Dabas S., Pathak K. 2005 “Optimised prodrug approach: A means for
achieving enhanced anti-inflammatory potential in experimentally induced colitis”. J
Drug Targ., 17: 235-241.
2. Oluwatoyin A.O., John T.F. 2005 “In vitro evaluation of khaya and albizia gums as
compression coating for drug targeting to the colon”. J Pharm Pharmacol., 57: 63168.
3. Akala E.O., Elekwachi O., Chase V., Johnson H., Marjorie L., Scott K. 2003 “Organic
redox initiated polymerization process for the fabrication of hydrogel for colon specific
drug delivery”. Drug Ind Pharm., 29: 375-386.
4. Chourasia M.K., Jain S.K. 2003 “Pharmaceutical approaches to colon targeted drug
delivery systems”. 6: 33-66.
5. Basit A., Bloor J. 2003 “Prespectives on colonic drug delivery, Business briefing”.
Pharmtech., 185-190.
6. Watts P., Illum L. 1997 “Colonic drug delivery”. Drug Dev Ind pharm., 23: 893-913.
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Rieto J G., Justel A., Del E Tal J L., Barrio J P., Alvarez A I. 1991,” Comparative
study on gastric absorption of albendazole and mebendazole in rats”, Comp.
Biochem. Physiol.100c, No. 3:397-400
8
http://en.wikipedia.org/wiki/Mebendazole
9
Maestrelli F., Cirri M., Corti G., Mennini N., Mura P. 2008 “Development of entericcoated calcium pectnate microspheres intended for colonic drug delivery”. Eur J
Pharm and biopharm., 69: 508-518.
10 Hiorth M., Skoien T., Sande S.A. 2010 “Immersion coating of pellet cores consisting
of chitosan and calcium intended for colon drug delivery”. Eur J Pharm and
biopharm., 75: 245-253.
12
11 Das S., Chaudhury A., Yun Ng K. 2011 “Preparation and evaluation of zinc-pectinchitosan composite particles for drug delivery to the colon: Role of chitosan in
modifying in vitro and in vivo drug release”. Int J Pharm., 406: 11-20.
12 Bhawna G., Singh S.K., Mishra D. 2011 “Formulation and evaluation of colon
targeted oral drug delivery systems for metroindazole in treatment of amoebiasis”. Int
J Drug Dev., 3: 503-512.
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ENCLOSURE-VII
10) Remarks of the Guide
The present work is aimed to formulate the matrix tablets for colon specific delivery of
mebendazole. Mebendazole is a highly effective broad spectrum antihelmintic indicated
for the treatment of nematode infestations, including roundworm, whipworm,
threadworm, and hookworm. When administered orally only 10% of the mebendazole is
absorbed with peak plasma concentrations after 2 or 5 hours. It has a short plasma half-life
of 2.5 to 5.5 hours, but this drug is less absorbed in the stomach and small intestine before
reaching the colon sites. Therefore, it is preferable to deliver the drug site-specifically to the
colon.
The proposed study can be carried out in the laboratory.
Dr. C. C. Patil
Professor
(Research Guide)
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