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RAJIV GANDHI UNIVERSITYOF HEALTH
SCIENCES, KARNATAKA, BANGALORE.
M. PHARM SYNOPSIS
YEAR OF ADMISSION-JUNE 2011
TITLE OF THE SYNOPSIS
“DEVELOPMENT AND EVALUATION OF COLON TARGETED
TABLET OF ANTIDIARRHOEAL DRUG COMBINATION”
BY
Mr. Pravin P. Patil
M.Pharm, Part-I
Department of Pharmaceutics
UNDER THE GUIDANCE OF
Prof. Jagdish K. Saboji. M.Pharm.
Professor & Head,
Dept. of Pharmaceutics.
KLES’s COLLEGE OF PHARMACY,
Akkol Road, NIPANI,
KARNATAKA.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
NAME OF THE
CANDIDATE
AND ADDRESS
Mr. Pravin Patil
S/o.- Prakash Patil
A/P. - NIPANI
DIST. - BELGAUM
PIN CODE - 591237
STATE - KARNATAKA
2.
NAME OF THE
INSTITUTION
KLES’s COLLEGE OF PHARMACY
Akkol road, NIPANI
DIST:- BELGAUM
KARNATAKA.
3.
COURSE OF STUDY AND
SUBJECT
Master Of Pharmacy In Pharmaceutics
4.
DATE OF ADMISSION
JUNE- 2011
5.TITLE OF THE TOPIC
“DEVELOPMENT AND EVALUATION OF COLON TARGETED TABLET
OF ANTIDIARRHOEAL DRUG COMBINATION”
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6.0
BRIEF REVIEW OF THE INTENDED WORK
6.1 - Need for the study
Diarrhoea is defined as having loose or watery stools at least three times per day,
or more frequently than normal for an individual. Although most episodes of childhood
diarrhoea are mild, acute cases can lead to significant fluid loss and dehydration, which may
result in severe consequences – even death – if fluids are not replaced at the first sign of
diarrhoea.(1)
Infectious diarrhea is one of the greatest causes of morbidity and mortality
worldwide. Bacterial gastroenteritis is very common in developing countries like India. The
usual manifestations are vomiting, diarrhea and abdominal discomfort. (2)
Chronic diarrhoea may be defined as the abnormal passage of three or more
loose or liquid stools per day for more than four weeks and/or a daily stool weight greater than
200 g/day. (3)
Mortality from diarrhea has fallen substantially over the last four
decades.However, it still accounts for 1.9 million deaths per year, and approximately 18% of
all deaths of children under five in developing countries. Thus, infectious diarrhea remains an
important global public health problem. (4)
To treat these microorganisms,local colon targeted drug delivery was utilised.
Enterohaemorrhagic E. coli usually cause attachment and effacing lesions in the intestine. (5)
The attaching and effacing lesion is a two-step process. The first is the ability
of the E. coli to express the adhesin intimin on the bacterial surface. The second step is to
inject intimin receptor into the host cell through a microtubular structure known as a type 3
secretion system. The intimin receptor in the host becomes orientated in the host cell
membrane, permitting the E. coli to adhere. (6)
Shigella infects the cells of the lining of the large intestine (colon). The
bacteria invade and damage these cells, producing breaks (ulcers) in the mucous membrane
lining the intestine. (7)
Colon-specific drug delivery has gained increased importance in the delivery
of drugs for the treatment of local diseases associated with the colon. (8)
The conventional oral dosage forms normally dissolve in the stomach fluid or
intestinal fluid and are absorbed from these regions of the G.I.tract, which depend upon the
physicochemical properties of the drug. Localized delivery of the drugs in the colon region is
possible only when the drug is protected from the hostile environment of upper GIT. (9)
3
Ofloxacin is a fluoroquinolone anti-microbial agent with broad spectrum activity
against gram positive and gram negative aerobic bacteria Main advantage to use this
combination is in clinical settings,it involve to treat mixed aerobic-anaerobic bacteria involved
in colonic infection. Colon targeted drug delivery has benifits to drug release at the site of
colonic infection.Hence it has great advantages for its local effect and minimal the side effects.
Amongst the various enteric bacterial pathogens, diarrheagenic strains of E-coli are
considerably responsible for causing bacterial diarrhea. (10)
Metronidazole is from nitroimidazole class mainly to treat anaerobic bacteria(11).
The antibiotic susceptibility showed that the E. Coli were highly resistant to
ampicillin, tetracycline and gentamycin , and moderately resistant to chloramphenicol and
cephalothin , but highly sensitive to ofloxacin (12).
Bacteria such as Shigella are the most common causes for inflammatory diarrhea.
Because the recently emerged S. dysenteriae strain was resist to ampicillin, cotrimoxazole,
nalidixic acid, norfloxacin, and ciprofloxacin, which were commonly used for shigellosis
cases, ofloxacin is currently recommended for treatment. (13)
Protozoans are responsible only for a minority of cases of acute traveler’s diarrhea,
but are very often responsible for chronic disease. Parasitic infections are often diagnosed late,
as tests for parasites are often not obtained until patients have failed symptomatic therapy.
Metronidazole is the traditional treatment of giardiasis.(14)
Hence, from the study we concluded that Metronidazole and Ofloxacin are the
drug choice for treating mixed aerobic-anaerobic induced diarrhoea.Drug combination of
Metronidazole and Ofloxacin use for their slow absorption of drug and rapid availability for
local action and it could play a crucible role in providing effective and safety theropy for
diarrhoea. Thus in present study, there is need to go for colon target drug delivery system in
combination of metronidazole-ofloxacin for diarrhoeal disease.
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6.2 - Review of Literature

Joseph R. Robinson et al (2005),Controlled Drug Delivery.In the case where systems
are used to target a drug, the site of action is targetted.The assumption is that by
increasing drug concentration at absorption site, the amount of drug reaching the site of
action will increase corrospondingly. This is exemplified by colon drug delivery.If we
formulate plain tablet instead of colon specific tablet,some drug metabolised before
reaches to colon hence require larger dose of drug results into various side effects. (15)

M. A. EL-Massik et al (2007), Development of metronidazole colon-specific delivery
systems. The potential of matrix, multilayer and compression coated tablets of
metronidazole to reach the colon intact has been investigated in vitro, using pectin as a
carrier. Matrix tablets containing various proportions of pectin were prepared by wet
granulation and direct compression techniques. Multilayer tablets were formulated
using pectin as release controlling layers, on either side of metronidazole matrix
tablets.From this,we formulate either matrix or multilayer or compression tablet for
colon specific delivery. (16)

Ravi Kumar et al (2009),studied Polysaccharides Based Colon Specific Drug delivery.
The various approaches that can be attempted to target the release of drug to
colon.These includes prodrug formation, coating with pH sensitive polymers, coating
with biodegradable polymers, embedding in biodegradable matrices, hydrogel, timed
release systems, osmotic and bioadhesive systems. By this ,we can seen that by using
different grades of polymers,colon specific drug delivery can be acheived. (17)

O. J. Akinjogunla et al (2009),Diarrheagenic Escherichia coli : Prevalence among in
and ambulatory patients and susceptibility to antimicrobial chemotherapeutic agents.
The results of antibiotic susceptibility showed that the E. Coli were highly resistant to
antibiotics such as ampicillin, tetracyclin and gentamycin, and moderately resistant to
chloramphenicol and cephalothin, but highly sensitive to ciprofloxacin and ofloxacin.
This showed that ciprofloxacin and ofloxacin to be drugs of choice for the treatment of
diarrheagenic E. coli. Hence,we used Ofloxacin for Diarrhoea caused by E. Coli. (18)

Shanta Dutta et al (2003), Shigella Dysenteriae Serotype 1,Kolkata, India.They studied
by taking different antibiotics and reported that Emergence of multidrug-resistant
Shigella strains is of concern to clinicians in treating shigellosis cases. Because the
recently emerged S. dysenteriae 1 strain was resistant to ampicillin, cotrimoxazole,
nalidixic acid, norfloxacin, and ciprofloxacin, which were commonly used for
shigellosis cases, ofloxacin is currently recommended for treatment.(19)
5

Dworczynski A. et al, Antimicrobial Resistance in Organisms Causing Diarrheal
Disease.The alteration of the microflora of the bowel allows this anaerobic organism to
proliferate and produce its two enterotoxins, which are responsible for the diarrheal
disease. Vancomycin and metronidazole are the therapeutic drugs of choice for C.
difficile diarrhea. However, resistance to vancomycin was seen , and the choice of
antibiotic drugs may have to be modified in the future. (20)(21)

Canete R. et al (2006), Treatment of Infectious Diarrhea .They stated that Protozoans
are responsible only for a minority of cases of acute traveler’s diarrhea, but are very
often responsible for chronic disease. Parasitic infections are often diagnosed late, as
tests for parasites are often not obtained until patients have failed symptomatic therapy.
Metronidazole is the traditional treatment of giardiasis. Another drugs such as
nitroimidazole, tinidazole, is least as effective.giardiasis is one of the bacterial infection
causes diarrhoea and Metronidazole is the drug for treating such type of infectious
diarrhoea. (22)
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6.3 - Objective of the Study
Following are the objectives of the present study
a. To carry out Preformulation study.
b. To develop and formulate colon targeted tablet of Antidiarrhoeal drug.
c. To evaluate the formulated dosage form by official in vitro studies.
d. To study the effect of formulation and process variables.
e. To perform formulation optimization by various quality control parameters.
f. To perform compatibility studies.
g. To carry out stability studies as per ICH guidelines for the optimized
formulation.
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7.0
MATERIALS AND METHODS
Materials
Drug
: Metronidazole,Ofloxacin etc.
Polymers
: Guar gum,Xanthan gum,Eudragit,Methyl cellulose pthalate,Hydroxy
Propyl methyl cellulose,Microcrystalline cellulose,Chitosan etc.(These
polymers will be used alone or in combination in different proportions
so as to vary the thickness of coating)
Additives
: Magnesium stearate, Talc etc.
Method :

Development of Colon target matrix or multilayer tablet by any suitable Developed method.

Various proportions of polymer or polymers will be used to vary the coating thickness
and to achieve site specificity to colon.
7.1 - Source of Data
a) Journals such as,
1) Indian Drug.
2) Indian Journal of Pharmaceutical Sciences.
3) Indian Journal of Pharmaceutical Education and research.
4) European Journal of Pharmaceutical Sciences.
5) International Journal of Pharmaceuticals.
6) Drug Development & Industrial Pharmacy.
7) Journal of Controlled Release.
b) Review articles
c) World Wide Web.
d) J-gate@Helinet.
e) Science Direct, Pub med.
f) Library: KLES’s College of Pharmacy.
g) E-library: KLES’s College of Pharmacy.
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7.2 - Method of collection of data
.
1) Preparation of Colon Targeted Tablet of Antidiarrhoeal Drug by matrix or multilayer
or any suitable /developed method.
2) Evaluation of the various properties of Tablet.

Bulk density and tapped density.

Angle of repose.

Tablet thickness.

Weight uniformity.

Hardness test.

Friability test.

Drug content uniformity.

Disintigration testing.

Dissolution testing.
3) Carry out stability studies as per ICH guidelines.
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.
“NO”
(The study do not requires animal to evaluate Antidiarrhoeal activity.)
7.4 - Has ethical clearance been obtained from your institution in case of 7.3?
“ NOT APPLICABLE ”
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8.0
REFERENCES
1) “Global, regional and national causes of child mortality in 2008”: A systematic
analysis, in The Lancet, 2010; 375 : (9730), 1969-1987.
2) Nataro JP, Kaper JB. “Diarrhoeagenic Escherichia coli”. Clin Microbiol Rev
1998;11:142-201.
3) P D Thomas, A Forbes, J Green, P Howdle, R Long, R Playford, M Sheridan, R
Stevens. “Guidelines for the investigation of chronic diarrhea”.2.
4) Bryce J, Boschi-Pinto C, Shibuya K. “estimates of the causes of death in children”.
WHO. 2005;365:1147–52.
5) WHO/UNICEF Joint Statement: “Clinical management of acute diarrhoea”, UNICEF
New York and WHO Geneva, 2004.
6) Frankel G, Phillips AD, Rosenshine I, Dougan G, Kaper JB, Knutton S .
“Enteropathogenic and enterohaemorhagic Escherichia coli”: more subversive
elements. Mol Microbiol. 1998; 30:911–921.
7) “Shigellosis”;Clinical Update: A supplement to Issue .1991;44:1.
8) “Metronidazole colon-specific delivery systems”.Asian Journal of Pharmaceutical
Sciences. 2007; 2 (1): 18-28.
9) Pharmatech,International Journal of PharmTech Research.2009;1(0974-4304):334-346
.
10) Terashi K, Oka M, Soda H, Fukuda M, Kawabata S, Nakatomi K, Shiozawa K,
Nakamura T, Tsukamoto K, Noguchi Y, Suenaga M, Tei C, Kohno S: “Interactions of
ofloxacin and erythromycin with the multidrug resistance protein (MRP) in MRPoverexpressing human leukemia cells”. Antimicrob Agents Chemother.
2000 ;44(6):1697-700.
11) Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S,
Winnenburg R, Schroeder M, Preissner R. “A comprehensive database on
Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions”.
Nucleic Acids Res; 2010 :38237-43.
12) N.O. Eghafona, and O. H. Ekoi “ Prevalence among in and ambulatory patients and
susceptibility to antimicrobial chemotherapeutic agents”.Journal of Bacteriology
Research. 2009;1(3):34-38.
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13) Guerrant RL, Van Gilder T, Steiner TS. “Practice guidelines for the management of
infectious diarrhea”, Infectious Diseases Society of America. Clin Infect Dis.
2001;32:331–51.
14) Canete R, Escobedo AA, Gonzalez ME. “A randomized, controlled, open-label trial
of a single day of mebendazole versus a single dose of tinidazole in the treatment of
giardiasis in children” Curr Med Res Opin. 2006;22:2131–2136.
15) Robinson Joseph R.,Lee Vincent H.L. “Controlled Drug Delivery”. Fundamental and
application.Dekker series,revised and expanded.2005; 2 (5): 42.
16) M. A. Nasra, M. A. EL-Massik, V. F. Naggar. “Development of metronidazole colonspecific delivery systems”. Asian Journal of Pharmaceutical Sciences.
2007; 2 (1): 18-28.
17) Ravi Kumar, M. B. Patil, Sachin R. Patil, Mahesh S. Paschapur. “Polysaccharides
Based Colon Specific Drug delivery”. International Journal of PharmTech Research.
2009; 1 (2):334-346.
18) O.J.Akinjogunla, N.O.Eghafona and O.H.Ekoi.“Diarrheagenic Escherichia coli
(DEC)”.Journal of Bacteriology Research 2009;1(3):034-038.
19) Shanta Dutta, Dharitri Dutta, Phalguni Dutta,Shigeru Matsushita, Sujit Kumar
Bhattacharya, and Shin-ichi Yoshida. “Shigella Dysenteriae”Serotype 1,
Kolkata,India.Emerging Infectious Diseases.2003; 9 (11):1471-1474.
20) Dworczynski A, Sokol B, Meisel-Mikolajczyk F. “Antibiotic resistance of
Clostridium difficile isolates Cytobios”. 1991; 65:149-153.
21) Canete R, Escobedo AA, Gonzalez ME. “A randomized, controlled, open-label
trial of a single day of mebendazole versus a single dose of tinidazole in the treatment
of giardiasis in children”. Curr Med Res Opin, 2006;22:2131–6.
22) Rossignol JF, Ayoub A, Ayers MS. “Treatment of diarrhea caused by Giardia
intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind,
placebo-controlled study of nitazoxanide”. J Infect Dis. 2001; 184:381–4.
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9.
SIGNATURE OF THE
CANDIDATE
10.
REMARKS OF THE GUIDE
11.
NAME AND DESIGNATION
OF
11.1 Guide
Recommended
Prof.Jagdish K.Saboji, M. Pharm.
Professor of Pharmaceutics
11.2 Signature
11.3 Co-Guide ( If any)
______________________________
11.4 Signature
11.5 Head of the Department
Prof. J K. Saboji, M.Pharm
Professor & Head
Department of Pharmaceutics
11.6 Signature
12.
12.1 Remarks of the Chairman
Principal
Forwarded to the University for approval
12.2 Signature
Principal
Prof. J K.SABOJI
KLES’s College of Pharmacy
Akkol Road,
NIPANI-591237.
12