COLON TARGETED DRUG DELIVERY

PRACHI JOSHIM. S. (Pharm.)

PHARMACEUTICS 2 nd SEM

Introduction Anatomy of colon Criteria of drug selection Approaches of colon targeting EVALUATION INNOVATIVE DEVICES Conclusion Reference

CONTENTs

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Targeted drug delivery into the colon is highly desirable for

local treatment of a variety of bowel diseases such as ulcerative colitis, Crohn’s disease, amoebiasis, colonic cancer, local treatment of colonic pathologies, and systemic delivery of protein and peptide drugs, NSAIDs, steroids.

The colon is believed to be a suitable absorption site for peptides and protein drugs for the following reasons; (i) less diversity, and intensity of digestive enzymes, (ii) less proteolytic activity of colon mucosa than that of small intestine.

INTRODUCTION

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Table 1. Colon targeting diseases, drugs and sites

Target sites Disease conditions Drug and active agents

Topical action Inflammatory Bowel Diseases, Irritable bowel disease and Crohn’s disease. Chronic pancreatitis

Hydrocortisone, Budenoside, Prednisolone, Sulfaselazine, Olsalazine, Mesalazine, Balsalazide

Local action Pancreatactomy and cystic fibrosis, Colorectal cancer

Digestive enzyme supplements 5-Flourouracil

Systemic action To prevent gastric irritation To prevent first pass metabolism of orally ingested drugs Oral delivery of peptides Oral delivery of vaccines

NSAIDS Steroids Insulin

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ANATOMY OF COLONThe GI tract is divided into the stomach and the small and large

intestine. The large intestine extending from the ileocecal junction to the anus, is divided into three main parts. These are the colon, the rectum and the anal canal.For the purpose of colonic drug delivery, there are two important physiological factors to be considered these are pH and GI transit time.The mid and left colon have pH values of approximately 6.6 and 7.0. Interspecies variability in pH is a major concern when developing and testing colon-specific delivery systems

Figure 1. Anatomy of large intestine 5

Table 2. pH in the GI tract

Location pH

Oral cavity 6.2-7.4

Oesophagus 5.0-6.0

Stomach Fasted condition: 1.5-2.0Fed condition: 3.0-5.0

Small intestine Jejunum: 5.0-6.5Ileum: 6.0-7.5

Large intestine Right colon: 6.4Mid colon and left colon:

6.0-7.6

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Drugs used for local effects in colon against

GIT diseases. Drugs poorly absorbed from upper GIT. Drugs for colon cancer. Drugs that degrade in stomach and small

intestine. Drugs that undergo extensive first pass

metabolism. Drugs for targeting.

Criteria of drug selection

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Approaches of colon

targeting

PRIMARY APPROACHES

NEW APPROACHES

pH Sensitive Polymer Coated Drug Delivery to the Colon

Delayed Release Drug Delivery to Colon

Microbially Triggered Drug Delivery to Colon

Pressure Controlled Drug-Delivery Systems

Novel Colon Targeted Delivery System (CODESTM)

Osmotic Controlled Drug Delivery (ORDS-CT)

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The pH in the transverse colon is 6.6 and 7.0 in the

descending colon. Use of pH dependent polymers is based on these differences in pH levels.

The polymers described as pH dependent in colon specific drug delivery are insoluble at low pH levels but become increasingly soluble as pH rises.

These processes distribute the drug throughout the large intestine and improve the potential of colon targeted delivery systems.

pH Sensitive Polymer Coated Drug Delivery to the Colon

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Enteric polymers Optimum pH for dissolution

Polyvinyl acetate phthalate (PVAP)

5.0

Cellulose acetate trimelitate (CAT)

5.5

Hydroxypropyl methyl cellulose phthalate

(HPMCP)

>5.5

Methacrylic acid copolymer, Type C (Eudragit L100-55)

>6.0

Cellulose acetate phthalate (CAP)

(Aquateric)

6.0

Shellac 7.0

Table 3. pH of commonly used enteric polymers.

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Time controlled release system (TCRS) such as sustained or

delayed release dosage forms are also very promising drug release systems.

The dosage forms may also be applicable as colon targeting dosage forms by prolonging the lag time of about 5 to 6 h.

Enteric coated time-release press coated (ETP) tablets, are composed of three components, a drug containing core tablet, the press coated swellable hydrophobic polymer layer, and an enteric coating layer.

Delayed Release Drug Delivery to Colon

Figure 2. Design of ETP 11

The microflora of the colon is in the range of 1011 -1012 CFU/ mL,

consisting mainly of anaerobic bacteria, e.g. bacteroides, bifidobacteria, eubacteria, clostridia, enterococci, enterobacteria and ruminococcus etc.

Microflora produces a vast number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase, deaminase, and urea dehydroxylase.

Presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-specific drug delivery.

These polymers shield the drug from the environments of stomach and small intestine, and are able to deliver the drug to the colon.

Microbially Triggered Drug Delivery to Colon

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A Prodrug is a pharmacologically inactive derivative of a parent

molecule that require some form of transformation in vivo to release the active drug at the target site.

This approach involves covalent linkage between the drug and its carrier.

Biotransformation is carried out by a variety of enzymes, mainly of bacterial origin, present in the colon. The enzymes that are mainly targeted for colon drug delivery include azoreducatase-galactosidase, β- xylosidase, nitroreductase, glycosidase deaminase, etc.

PRODRUG

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Of the multitude of bacterial enzymes that are produced in colon, 2 main classes are:-

The azo linkage exhibits a wide range of thermal, chemical, photochemical and pharmaceutical properties.

The azo compounds are extensively metabolized by the intestinal bacteria.

Sulphasalazine, which was used for the treatment of rheumatoid arthritis. This compound has an azo bond between 5-ASA and sulphapyridine.

Include naturally occurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotin sulphate), algal (alginates) or microbial (dextran) origin.

The polysaccrides can be broken down by the colonic microflora to simple saccharides. Therefore, they fall into the category of “generally regarded as safe” (GRAS).

AZOREDUCTASES POLYSACCHARIDASES

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Mechanism of prodrug

Figure 3. Linkage of drug with azo and glycoside to form prodrug15

Like prodrug, a number of naturally occuring polysaccharides are stable

in the upper intestine but susceptible to hydrolytic degradation in the colon.

Most polysaccharides can be chemically modified to optimize specific properties, such as the ability to form impermeable films. Some of them are:-

COATING AND MATRICES

POLYSACCHARIDE APPLICATIONSPectin & its salt form Matrices, enteric coated matrix

tablet

Chitosan & its derivative Coated capsule, microsphere

Cross linked dextran Hydrogels

Table 4. Polysaccharide based materials used to deliver drug to colon.

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Due to peristalsis, higher pressures are encountered in the colon

than in the small intestine. Takaya et al. developed pressure controlled colon-delivery capsules

prepared using ethylcellulose, which is insoluble in water. In such systems, drug release occurs following the disintegration of

a water insoluble polymer capsule because of pressure in the lumen of the colon.

The thickness of the ethylcellulose membrane is the most important factor for the disintegration of the formulation.

Pressure Controlled Drug-Delivery Systems

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CODESTM is a combined approach of pH dependent and

microbially triggered CDDS. CODESTM is an unique CDDS technology that was designed to

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.

Novel Colon Targeted Delivery System

(CODESTM)

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Lactulose

Organic acid

Microflora

In colon

In small intestine

In stomach Enteric coating

Acid soluble polymer (only slightly permeable)

Figure 4. Schematic design of CODESTM 19

The OROS-CT (Alza corporation) can be used to target the drug

locally to the colon for the treatment of disease or to achieve systemic absorption.

The OROS-CT system can be a 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.

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. Drug release begins when the unit reaches the colon.

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.

Osmotic Controlled Drug Delivery (ORDS-CT)

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Figure 5. Osmotically controlled system (OROS-CT)21

For evaluation, not any standardized evaluation technique

is available for evaluation of CDDS because an ideal in vitro model should posses the in-vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes, enzyme activity, and other components of food.

These conditions are influenced by the diet, physical stress, and these factors make it difficult to design a standard in-vitro model.

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EVALUATION

In-vitro dissolution test. In-vitro enzymatic test. In-vivo evaluation. Drug Delivery Index (DDI) and Clinical Evaluation of Colon-

Specific Drug Delivery Systems

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Different methods of evaluating colon drug delivery:-

PulsincapTM technology: R.R. Scherer International Corporation

(Michigan) Orbexa® Technology: Aptalis Pharmaceutical Technologies DIFFUCAPS® Technology DIFFUTAB® Technology SODAS® Technology PRODAS® Technology CONTIN® Technology: Purdue Pharma Codas® (chronotherapeutic oral drug absorption system): Elan

Corporation, USA24

Innovative Devices

Egalet®Technology: Egalet Ltd, Denmark IPDAS® (Intestinal protective drug absorption system):

Elan Drug Technologies GEOCLOCK® Technology: SkyePharma Geomatrix® Technology: SkyePharma Pulsys TM : Middle Brook Pharmaceuticals Minitabs®

ACCU-T CR Tri Layer Tablets Banner’s Versetrol Technology The CeformTM technology Timerx® Technology

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CONT.

The development of an oral, universally applicable, colonic

drug delivery system represents a considerable challenge to the pharmaceutical scientist.

Consideration must not only be given to ways in which drug release in the colon can be achieved, but also to the behaviour and environmental conditions experienced by the dosage form prior to reaching the colon.

A major problem in comparing different delivery systems is the fact that degradation studies are performed under different conditions.

CONCLUSION

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Philip AK, Philip B. Colon Targeted Drug Delivery Systems: A

Review on Primary and Novel Approaches. Oman Medical Journal 2010; 25(2): 1-3,6-7.

Kinget R, Kalala W, Vervoort L and Mooter GVD. Journal of Drug Targeting 1998; 6(2): 130-131.

Vinaykumar KV, Sivakumar T, Tamizhmani T, Sundar TR, Sarath IC. Colon targeting drug delivery system: A review on recent approaches. Int J Pharm Biomed Sci 2011; 2(1): 14.

Ashford M and Fell JT. Targeting Drugs to the Colon: Delivery Systems for Oral Administration. Journal of Drug Targeting, 1994; 2: 241,254.

REFERENCE

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THANK

YOU28