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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” 2 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. 4 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) 6 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. 7 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. 8 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 ” 9 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. 10 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. 11 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