Colon drug delivery system

Colon DDS
advantages
approaches
evaluation

1. Colon drug delivery system Foram Machhar Roll no. 05 M pharm Sem-1 Department of Pharmaceutics

2. The goal of targeted drug delivery is to deliver the drug to the specific organ. Colon targeted drug delivery is used to deliver the substances that are degraded by the digestive enzymes in the stomach such as proteins and peptides.

3. When is Colon DDS used..? In local colonic disease. In systemic delivery of protein and peptides (because they are unstable in stomach and intestine but stable in colon). For the drugs that are only absorbed on colon. Potential site for treatment of disease sensitive circadian rhythm

4. ADVANTAGES Used for the effective treatment of inflammatory bowel diseases like ulcerative colitis , crohn’s disease, etc. Decreases the side effects in the treatment of colon diseases . Prevents gastric irritation resulting due to the administration of NSAIDs. Minimizes first pass metabolism . Provides suitable environment for proteins and peptides that are sensitive to gastric fluid and digestive enzymes. Increased patient compliance. Decreased frequency of administration. Hence decreased cost of drugs. High retention time thus increasing the bioavailability of poorly absorbable drugs

5. Limitations and Challenges Dissolution in luminal fluid. Stability of drugs. Binding of drugs to dietary residues, intestinal secretions, mucus or fecal matter. Metabolic degradation by colonic microflora . Wide range of pH values

6. Lower surface area and relative “tightness” of the tight junctions in the colon restrict drug transport. Longer residence time Requires protection against variety of the gastric enzymes. Cytochrome P450 3A class of drug metabolizing enzymes have lower activity in colon

7. Factors affecting colon targeted drug delivery Gastric emptying. pH of colon. Colonic micro flora and enzymes.

8. Gastric emptying Drug delivery to the colon upon oral administration depends mainly on gastric emptying ; bowel transit time. Upon reaching the colon the transit time of dosage form depends on the size of the particles. Smaller Particles- more transit time Diarrhoea patients- shorter transit time. constipation patients- longer transit times. Fasted state 10 min. to 2 hrs Fed state Higher than 2 hrs Small intestinal transit 3-4 hours Colonic transit 20-35 hours

9. pH of colon Part of GIT pH Stomach Fasted state 1.5-2 Fed state 2-6 Small intestine Proximal part Distal part 6.6- 7.5 6.5 7.5 Colon Ascending colon Transverse colon Descending colon 6.4 6.6 7.0

10. Diseased condition Disease like IBD, diarrhoea, constipation may change the outcome of colonic DDS.

11. Colonic microflora and enzymes The GIT contains a variety of microorganisms that produces many enzymes need for metabolism . Growth of this microflora is controlled by the GIT contents and peristaltic movements . The enzymes released by different microorganisms E. coli, Clostridia, Lactobacilli, Eubacteria , Streptococci are responsible for the various metabolic reactions that take place in the GIT.

12. Pharmaceutical factors Drug candidates Due to high retention time of colon, colon causes an increase in the absorption of poorly absorbed agents like peptides, etc. drugs used for treatment of inflammatory bowel diseases, etc. are suitable for colon targeted drug delivery system .

13. Criteria for selection Criteria Pharmacological class Non-peptide drugs Peptide drugs Drugs used for local effects in colon against GIT diseases Anti-inflammatory drugs Oxyprenolol, Metoprolol, Nifedipine Amylin, Antisense oligonucleotide Drugs poorly absorbed from upper GIT Antihypertensive and antianginal drugs Ibuprofen, Isosorbides, Theophylline Cyclosporine, Desmopressin Drugs for colon cancer Antineoplastic drugs Pseudoephedrine Epoetin, Glucagon Drugs that degrade in stomach and small intestine Peptides and proteins Bromophenaramine, 5-Flourouracil, Doxorubicin Gonadoreline, Insulin, Interferons Drugs that undergo extensive first pass metabolism Nitroglycerin and corticosteroids Bleomycin, Nicotine Protirelin,sermorelin, Saloatonin Drugs for targeting Antiarthritic and antiasthamatic drugs Prednisolone, hydrocortisone, 5-Amino-salicylic acid Somatropin,Urotoilitin

14. Approaches 1. Primary approaches for colon targeted drug delivery a . pH sensitive polymer coated drug delivery system b . Delayed release drug delivery system c . Microbially triggered drug delivery i . Prodrug approach ii. Polysaccharide based system

15. 2. New approaches for colon targeted drug delivery a . Pressure controlled drug delivery system (PCDDDS ) b . CODE c . Osmotic controlled drug delivery system (OROSCT) d . Pulsatile i . Pulsincap system ii . Port system e . Azo hydrogels f . Multiparticulate system based drug delivery

16. 1. pH sensitive Is based on the solubility of different polymers at different pH ranges. The pH varies in different parts of the gastrointestinal tract. The polymers are insoluble at lower pH values and get solubilized as the pH increases. As the polymers are insoluble at lower pH values the polymer can protect a formulation in stomach and to some extent in small intestine. In this way by altering the polymers used the release of drug from the formulation can be controlled.

17. 2. Delayed or time controlled release drug delivery system Time controlled drug delivery system includes sustained or delayed release systems. In this system the delayed release or colon targeted drug delivery is attained by prolonging the lag time. The transit time varies in different parts of gastrointestinal tract. This transit time is responsible for the delayed release of drug. The main drawbacks of this delivery system are that the transit time varies from one person to other and amount of food intake. It also varies with the peristalsis or contraction in the gastrointestinal tract.

18. Drug core HPMC layer EC layer Aqueous medium Water diffuses through EC layer causes HPMC swelling Extensive swelling beaks EC membrane & disintegrate gel layer to release drug explosively TIME CONTROLLED EXPLOSIVE SYSTEM

19. 3. Microbial triggered drug delivery system and Prodrug approach The various microflora of the colon are Bacteroides , Bifidobacteria , Eubacteria, Clostridia , Enterococci, Enterobacteria and Ruminococcus , etc. This microflora of gut depends on fermentation of undigested materials in the small intestine for their energy requirements . The microflora performs fermentation by producing a large number ofenzymes like glucoronidase , xylosidase , arabinosidase , galactosidase , nitroreductase , and deaminase and urea dehydroxylase . These biodegradable enzymes are capable of degrading the polymers used for targeting the drug delivery to colon. Different polymers are used for preventing the release of drug in the stomach and small intestine. When the coated formulations reach the intestine the biodegradable polymers gets degraded by the enzymes produced by the microbial flora and the drug gets released in the targeted region.

20. Prodrug is the main approach of microbial triggered drug delivery system in which the drug release from the formulation is triggered by the microflora present in the gut. Prodrug is the inactive form of an active parent drug that undergoes enzymatic transformation to release the active drug. The prodrugs are prepared by linking the active drug with hydrophobic moieties like amino acids, glucoronic acids, glucose, galactose, cellulose, etc. These prodrug molecules get hydrolysed in the presence of the enzymes released by the microflora .

21. 4. Time dependent delivery Difficult to predict in advance. Lag time of five hours is considered sufficient provided that the intestinal transit time is constant at three to four hours. Pulsincap is earliest system based on this principle

22. Pulsincap eg . Modified pulse in cap drug delivery system of Diclofenac sodium

23. Technique employed Polymer used Drug used Bacteria dependent/Polysaccharide based Chitosan Diclofenac Sodium Pectin Chondroitin salphate Guar gum Indomethacin Indomethacin Doxamithacin Amylose Alginate 5 – ASA 5 – ASA 5. Bacterial based approach

24. Microbial flora Enzymes produced Chiefly applied for: Majority of them Azoreductase Release of 5- ASA from variety of prodrugs Lactobacilli Glycosidase, Glucuronidase Glycosides & glucuronides Bacteroides Glycosidase, Glucuronidase Glycosides & glucuronides

25. 6. Pressure-controlled drug delivery systems Muscular contraction of the gut wall generate pressure Variable pressure generation Colon has higher luminal pressure System can be developed which withstand the pressure in intestine and ruptures in response to raised pressure in colon. Ethyl cellulose capsules have been used for this purpose.

26. 7. Osmotic controlled drug delivery system Example: ALZA pump

27. 8. Novel colon targeted drug delivery system (CODESTM) Combination approach of pH dependent and microbially triggered CDDS

28. 9. Multiparticulate system Pellets Granular matrix Beads Microspheres Nano particles

29. Evaluation In vitro dissolution study In vitro enzymatic degradation test Relative colonic tissue exposure Relative systemic exposure to drugs - Scintigraphy Magnetic moment imaging study Drug delivery index High frequency capsule

30. Reference Colon Targeted Drug Delivery Systems: A Review on Primary and Novel Approaches by Anil K. Philip and Betty Philip, Oman Med J. 2010 Apr; 25(2): 79–87. Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches by Seth Amidon , Jack E. Brown, and Vivek S. Dave AAPS PharmSciTech . 2015 Aug; 16(4): 731–741 . COLON TARGETED DRUG DELIVERY – A REVIEW ON PRIMARY AND NOVEL APPROACHES Journal of Global Trends in Pharmaceutical Sciences Volume 4, Issue 3, pp -1174-1183, July-September 2013 Controlled-Release Drug Delivery Systems for Prolonged Gastric Residence : An Overview, Drug Development and Industrial Pharmacy, 22(6), 531-539 (1996)

31. THANK YOU