COLON SPECIFIC DRUG DELIVERY SYSTEMS Professor S. Satyanarayana M.Pharm., Ph.D., DAS. HOD & Faculty Chairman College of Pharmaceutical Sciences Andhra University www.pharmacy2011foru.blogspot.co Visakhapatnam- AP. m Prof. S.Satyanarayana HOD & Faculty Chairman www.pharmacy2011foru.blogspot.co m Prof.L.Venugopala Reddy, www.pharmacy2011foru.blogspot.co Vice- Chancellor, Andhra University m Prof. S. Satyanarayana With Research team www.pharmacy2011foru.blogspot.co m REQUIRED IN INFLAMMATORY BOWEL DISEASES LIKE Irritable bowl syndrome Crohn’s disease Ulcerative colitis leads to colon cancer if not treated and amoebiasis Incidence in India > 66000/year Cancer of large intestine 15% of cancer cases Western countries- Still high Main treatment- surgery (partial Colectomy) Followed by Chemotherapy www.pharmacy2011foru.blogspot.co m CONVENTIONAL ORAL DOSAGE FORMS DISADVANTAGE Drugs do not reach the site in adequate concentrations Hence the need for site specific drug delivery systems COLON SPECIFIC DRUG DELIVERY SYSTEMS ADVANTAGES Reduce the incidence of adverse effects Delivery of drug in its intact form as close as possible to the target site Ability to cutdown the conventional dose Longer residence time Low peptidase activity High response to absorption enhancers Systemic absorption of drugs like Nitrendipine, metoprolol, theophylline, isosorbide mononitrate. Can be used for systemic delivery of protein and peptide drugs www.pharmacy2011foru.blogspot.co m Colonic Drug Delivery can be accomplished by Rectal Suppositories- only effective in rectum Enemas – Sigmoid and descending colon Oral – Preferred Prodrugs. Coating with pH dependent polymers Design of timed release products Use of carriers that are exclusively degraded by colonic bacteria www.pharmacy2011foru.blogspot.co m Factors to be considered in design of oral dosage forms for colon specific drug delivery Anatomy and physiology of colon. Ileocaecal junction to anus Colon Rectum Anal canal Colon (1.5 m long) -Caecum-(9 cm diameter) Ascending colon Hepatic flexure Transverse colon Splenic Flexure Descending colon Sigmoid colon (2.cm diameter ) Functions Suitable environment for growth of micro organisms storage reservoir of faecal matter Eliminations of contents at appropriate time Absorption of potassium and water from the lumen www.pharmacy2011foru.blogspot.co m GI TRACT www.pharmacy2011foru.blogspot.co m COLON www.pharmacy2011foru.blogspot.co m pH in the colon www.pharmacy2011foru.blogspot.co m Gastro intestinal Transit Organ Transit time (hr) Stomach < 1(Fasting) > 3(Fed) Small intestine 3-4 Large intestine 20-30 www.pharmacy2011foru.blogspot.co m Colonic Microflora www.pharmacy2011foru.blogspot.co m Chemical reactions Carried out by colonic bacteria Hydrolysis of glycosides, sulphate esters, amides, esters, sulphamates and nitrates Reduction of C═C, azo bonds, nitro groups, aldehydes, ketones, alcohols and N.oxides. Decarboxylation Dealkylation Dehalogenation Desamination Heterocyclic ringfission Acetylation Esterification www.pharmacy2011foru.blogspot.co m Absorption enhancers Nonsteroidal Anti-inflammatory Agents Indomethacin, Salicylates Calcium ion chelating agents Ethylenediaminetetraacetic acid Surfactants Polyoxyethylene lauryl ether Saponins Bile salts Taurocholate, glycocholate Fatty Acids Sodium caprate, Sodium laurate, Sodium oleate Mixed micelles Monoolein-taurocholate, Oleic acid-taurocholate, Oleic acid- glycocholate Other agents Acylcarnitine, phenothiazines, emanine, Dicarboxylic acid. www.pharmacy2011foru.blogspot.co m Drug candidates for colon drug delivery 5-ASA Metronidazole Tinidazole Pinaverium bromide Calcitonin Interferon Intrleukins Erythropoietin GH Insulin Theophyllin Glibenclamide www.pharmacy2011foru.blogspot.co m Approaches to colon drug delivery Coating with pH dependent polymers Timed realease dosage forms Delivery systems based on metabolic activity of colonic bacteria Coating with biodegradable azo polymers Prodrugs Hydrogels Polysaccharides as carriers oPectin oChondroitin sulphate oInulin oGuargum www.pharmacy2011foru.blogspot.co m Evaluation Of Colon specific Drug Delivery System In Vitro methods: USP/Disssolutions rate test apparatus Drug release in. 1N Hcl for 2 hrs Drug release in 7.4 Sorensen’s phopphate buffer for 3 hrs Incubation in buffer in the presence of enzymes/caecal contens of rat/GP/Rabbit 4% rat caecal content with induction for 7 days provides optimal conditions. www.pharmacy2011foru.blogspot.co m Percentage of indomethacin released from guar gum matrix tablets in pH 6.8 PBS in the absence and presence of rat caecal contents in different concentrations Cumulative mean percent drug released ± SEM (n=3) Time With caecal content (hours) Without caecal content matter (control) 2 % W/V 4 % W/V 3 9.17 ± 1.52 34.99±1.23 37.46±2.03 6 13.76±1.70 38.36±1.57 43.25±3.15 9 17.76±1.46 40.79±1.41 60.22±4.98 12 20.50±1.25 45.63±1.34 70.85±4.20 15 23.38±0.73 53.66±0.37 78.45±2.96 21 29.21±0.64 67.11±1.03 91.62±3.80 www.pharmacy2011foru.blogspot.co m Percentage of indomethacin released from guar gum matrix tablets in pH 6.8 PBS in the absence and presence of rat caecal contents in different concentrations obtained after 3 days of enzyme induction Cumulative mean percent drug released ± SEM (n=3) Time (hours) With caecal content Without caecal content matter (control) 2 % W/V 4 % W/V 3 9.17 ± 1.52 26.63±4.01 32.34±0.57 6 13.76±1.70 32.37±3.37 38.11±0.97 9 17.76±1.46 37.52±2.98 41.44±0.87 12 20.50±1.25 43.36±1.99 49.50±2.78 15 23.38±0.73 50.47±0.97 67.74±2.78 21 29.21±0.64 60.19±1.44 78.54±3.08 www.pharmacy2011foru.blogspot.co m Percentage of indomethacin released from guar gum matrix tablets in pH 6.8 PBS in the absence and presence of rat caecal contents in different concentrations obtained after 7 days of enzyme induction Cumulative mean percent drug released ± SEM (n=3) Time (hours) With caecal content Without caecal content matter (control) 2 % W/V 4 % W/V 3 9.17 ± 1.52 34.99±1.23 37.46±2.03 6 13.76±1.70 38.36±1.57 43.25±3.15 9 17.76±1.46 40.79±1.41 60.22±4.98 12 20.50±1.25 45.63±1.34 70.85±4.20 15 23.38±0.73 53.66±0.37 78.45±2.96 21 29.21±0.64 67.11±1.03 91.62±3.80 www.pharmacy2011foru.blogspot.co m In vivo Animal Models: GP,Rat and Pig TECHNIQUES : String technique Endoscope technique Radiotelemetry Roentgenography Gamma Scintigraphy Radio Isotopoes(Tc 99m) www.pharmacy2011foru.blogspot.co m Gamma Camera www.pharmacy2011foru.blogspot.co m Determination of GI transit times Gamma scintigraphs taken at various time intervals after oral administration of a gum matrix tablet in a subject guar www.pharmacy2011foru.blogspot.co m www.pharmacy2011foru.blogspot.co Continued… m www.pharmacy2011foru.blogspot.co m Invivo disintegration and site specific drug delivery www.pharmacy2011foru.blogspot.co m www.pharmacy2011foru.blogspot.co m Corelation with pharmacokinetic study Mean plasma concentration of tinidazle following oral administration of immediate release tablet ( dose 150mg) or guar gum – based colon- targeted www.pharmacy2011foru.blogspot.co tablet (TC2, dose 150mg) in human volunteers ( n=6) m Conclusion Systems that release the drug in colon or more reliable to achieve site specificity Natural polymers (Dextron,Peptin.Guargum) are more favourable with respect to safety www.pharmacy2011foru.blogspot.co m Acknowledgements Dr. K.Eswar Kumar, Dr. Y.S.R Krishnaiah, Dr. Y.V Ram Prasad, Dr. Indiramuzib. Sri. O.P Gouda, Sri. A. Srinivasa Rao. Sri. P veeresh Babu, Sri. T .Satyanarayana, Dr. V. Satyanarayana, Dr. Veerraju, Dr. Narasimha Rao, Dr. Sasi Prabha, Dr. Naidu www.pharmacy2011foru.blogspot.co m Thank you www.pharmacy2011foru.blogspot.co m
"Colonic specific drug delivery"