colon targeted delivery system

COLON TARGETED DELIVERY SYSTEM : 

COLON TARGETED DELIVERY SYSTEM Submitted by M.Nazeer Ahamed Dept Of Pharmaceutics

colon targeted drug delivery : 

colon targeted drug delivery

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5) A number of others serious diseases of the colon, e.g. colorectal cancer, might also be capable of being treated more effectively if drugs were targeted to the colon. 6) Formulations for colonic delivery are also suitable for delivery of drugs which are polar and/or susceptible to chemical and enzymatic degradation in the upper GI tract, highly affected by hepatic metabolism, in particular, therapeutic proteins and peptides.

Colon anatomy : 

Colon anatomy Structure of human intestine Structure of colon

The entire colon is about 5 feet (150 cm) long, and is divided in to five major segments : 

The entire colon is about 5 feet (150 cm) long, and is divided in to five major segments

Function of colon : 

Function of colon

Measures of different parts of colon : 

Measures of different parts of colon

Advantages of Colon Targeted Drug Delivery System : 

Advantages of Colon Targeted Drug Delivery System

Disadvantages of Colon Drug Delivery : 

Disadvantages of Colon Drug Delivery

Colonic microflora : 

Colonic microflora 1) Over 400 distinct bacterial species have been found, 20- 30% of which are of the genus bacteroids 2)The upper region of the GIT has a very small number of bacteria and predominantly consists of gram positive facultative bacteria. 3)The rate of microbial growth is greatest in the proximal areas because of high concentration of energy source. 4)The metabolic activity of microflora can be modified by various factors such as age, GI disease, and intake of drug and fermentation of dietary residues.

pH in the colon : 

pH in the colon a)On entry in to the colon, the pH dropped to 6.4 ± 0.5. b) The pH in the mid colon was found to be 6.6 ± 1 and c)in the left colon, 7.0 ± 1

Gastrointestinal transit: : 

Gastrointestinal transit: The arrival of an oral dosage form at the colon is determined by the rate of gastric emptying is affected by various factor The presence of food increase gastric residence time in excess of 12 hrs (approx 3-4 hrs) The total transist of food and dosage form is known from stomach to ileocaecal junction is approx 3-6 hrs in fasted and 6-10hrs in fed state clonic transist isindependent of size and density of dosage form but accelerated under the condition of stress and slightly affected by the food

Drug absorption in the colon : 

Drug absorption in the colon a)Transcellular absorption involves the passage of drugs through cells and this is the route most lipophilic drugs takes b)paracellular absorption involves the transport of drug through the tight junction between cells and is the route most hydrophilic drug takes c)The slower rate if transit in colon lets the drug stay in contact mucosa for a longer period than in small intestine which compensates much lower surface area. d)The colon contents become more viscous with progressive absorption of water as one travels further through the colon. This causes a reduced dissolution rate, slow diffusion of drug through the mucosa.

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Effects on colonic absorption of drug 1) Inflammatory Bowel Diseases (Crohn's disease and ulcerative colitis) Diarrhea, fever, anemia, obstruction of lymphatic drainage and hyperplasia of lymphoid tissue, which arc observed in this condition may affect the drug, release and absorption. The inflammatory response extends from mucosa to serosa through intestinal wall. Impairment of lymphatic drainage causes malabsorption of fats and highly lipophilic drugs. Thickning of mucosa and submucosa may reduce surface area and obstruct diffusion. 2) Diarrhea Hypermotility and frequent passage of hypertonic liquid feces significantly affect drug absorption and release.

Absorption enhancer in colonic drug delivery : 

Absorption enhancer in colonic drug delivery By distributing of intercellular occulding junctional complex by modifying the epithelial permeability By distributing the integrity of the lipid of colonic enterocytes Colonic absorption of protein and peptide eg; 5-flourouracil absorption is enchanced by oleic acid Colonic absorption enchancer; NSAID ; Eg, indomethacin, salicylates Surfactants; Eg, polyoxyethylene laurylether

Approaches of Colon Targeted Drug Delivery System : 

Approaches of Colon Targeted Drug Delivery System 1) Primary Approaches for CDDS Newly Developed Approaches for CDDS

Time-controlled (or time-dependent) system : 

Time-controlled (or time-dependent) system 1)time-dependent drug delivery systems are designed to deliver drugs after a lag of five to six hours. 2)Time-controlled formulations for colonic delivery are also delayed-release formulations in which the delay in delivery of the drug is time-based. 3) the site of drug release is decided by the transit time of a formulation in the GI tract,

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4) formulations are designed such that the delivery (i.e. colon) is not affected by the individual differences in the gastric emptying time, 5) pH of the stomach and small intestine or presence of anaerobic bacteriain the colon. 6) an average, an orally administered dosage form takes about 3hrs to travel through the length of the small intestine to the beginning of the colon. Compared to gastric emptying rate, the small intestinal transit time is relatively consistent

The formulationis comprised of three parts: : 

The formulationis comprised of three parts: (i) a central core containing the drug and swelling excipients (ii) an inner semi-permeable polymer membrane containing a plasticizer which allows water influx but prevents the outward diffusion of drug (iii) an outer enteric-coating which dissolves at or above pH 5.5. The outer enteric coat keeps the tablet intact until it reaches the small intestine.

Osmotically controlled system (ORDS- CT) : 

Osmotically controlled system (ORDS- CT) 1)single osmotic unit or may incorporate as many as 5-6 push-pull units, each 4 mm in diameter, encapsulated within a hard gelatin capsule, 2) Each bilayer push pull unit contains an osmotic push layer and a drug layer, both surrounded by a semipermeable membrane. An orifice is drilled through the membrane next to the drug layer. 3) For treating ulcerative colitis, each push pull unit is designed with a 3-4 h post gastric delay to prevent drug delivery in the small intestine

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4) Drug release begins when the unit reaches the colon. 5) OROS-CT units can maintain a constant release rate for up to 24 hours in the colon or can deliver drug over a period as short as four hours.

Novel Colon Targeted Delivery System (CODESTM) : 

Novel Colon Targeted Delivery System (CODESTM) avoid the inherent problems associated with pH or time dependent systems It has been developed by utilizing a unique mechanism involving lactulose, which acts as a trigger for site specific drug release in the colon The system consists of a traditional tablet core containing lactulose, which is over coated with and acid soluble material, Eudragit E, and then subsequently overcoated with an enteric material, Eudragit L.

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4) The premise of the technology is that the enteric coating protects the tablet while it is located in the stomach and then dissolves quickly following gastric emptying. 5)The acid soluble material coating then protects the preparation as it passes through the alkaline pH of the small intestine 6) Once the tablet arrives in the colon, the bacteria enzymetically degrade the polysaccharide (lactulose) into organic acid. This lowers the pH surrounding the system sufficient to effect the dissolution of the acid soluble coating and subsequent drug release

Polysaccharide Based Delivery Systems : 

Polysaccharide Based Delivery Systems 1)naturally occurring polysaccharides is attracting a lot of attention for drug targeting the colon 2) polymers of monosaccharides are found in abundance, 3)They can be easily modified chemically, biochemically, and are highly stable, safe, nontoxic, hydrophilic and gel forming and in addition, are biodegradable. These include naturally occurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotin sulphate), algai (alginates) or microbial (dextran) origin

Polysaccharide Based Delivery Systems : 

Polysaccharide Based Delivery Systems 1)The polysaccrides can be broken down by the colonic microflora to simple saccharides 2)they fall into the category of “generally regarded as safe” (GRAS)

Microbially Triggered Drug Delivery to Colon : 

Microbially Triggered Drug Delivery to Colon 1)The microflora of the colon is in the range of 1011 -1012 CFU/mLconsisting mainly of anaerobic bacteria, e.g. bacteroides, bifidobacteria, eubacteria, clostridia, enterococci, enterobacteria and ruminococcus etc 2)This vast microflora fulfills its energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e.g. di- and tri-saccharides polysaccharides etc

Microbially Triggered Drug Delivery to Colon : 

Microbially Triggered Drug Delivery to Colon 3)For this fermentation, the microflora produces a vast number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase, deaminase, and urea dehydroxylase 4)presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-specific drug delivery seems to be a more site-specific approach 5)These polymers shield the drug from the environments of stomach and small intestine, and are able to deliver the drug to the colon.

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6) On reaching the colon, they undergo assimilation by micro-organism, or degradation by enzyme or break down of the polymer back bone leading to a subsequent reduction in their molecular weight and thereby loss of mechanical strength 7) They are then unable to hold the drug entity any longer

Methods for pulsatile drug delivery system : 

Methods for pulsatile drug delivery system Capsular system Def ; Single unit systems are mostly developed in capsule form. The lag time is continued by a plug, which gets pushed away by swelling or erosion, and the drug is released as a pulse from the insoluble capsule body.

Plugmaterial is generally made up of following: : 

Plugmaterial is generally made up of following: a) Swellable materials coated with but permeable polymer (polymethacrylates). b) Erodible compressed polymer (HPMC, polyvinyl alcohol). c) Congealed melted polymer (glyceryl monooleate). d) Enzymatically controlled erodible polymer (pectin).

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In this system a water insoluble body containing the drug formulation, system is closed with a swellable hydrogel. Plugged (insoluble but permeable and swellable) at open end. Gastrointestinal fluid or dissolution medium the plug swells pushing itself outof the capsule after lag-time. Position and dimensions of plugand control lag-time. For rapid release of water insoluble drug effervescent or disintegrating agents are added.

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Advantages of pulsatile drug delivery system Extended daytime or nighttime activity Reduced side effects Reduced dosage frequency Reduction in dose size Improved patient compliance Lower daily cost to patient due to fewer dosage units are required by the patient in therapy. Drug adapts to suit circadian rhythms of body functions or diseases. Drug targeting to specific site like colon. Protection of mucosa from irritating drugs. Drug loss is prevented by extensive first pass metabolism

Examples of colon targeted formulations based on conventional techniques. : 

Examples of colon targeted formulations based on conventional techniques.

Applications : 

Applications colon target drug Colon disease