COLON DRUG DELIVERY & APPROACHES

SWAPNIL N. JAIN(Assistant Professor, JES’s COP, Nandurbar)

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Contents

Introduction Rational for the development of CDDS Drugs suitable for colon targeting Approaches for The colon targeting Evaluation parameters Conclusion References

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Fig. Anatomy of GI Tract:

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The role of digestive system is to break down complex molecules, derived from ingested food, into simple ones for absorption into the blood or the lymph.

This process occurs in five main phases, within defined regions of the gastrointestinal system-

• ingestion (mouth);• fragmentation (mouth and stomach);• digestion (stomach and small intestine);• absorption (small and large intestine);• elimination of waste products (large intestine).

Anatomy of colonIt is the lowermost part of gastrointestinaltract.

It is divided into four parts

Ascending colon Transverse colon Descending colon Sigmoid colon

The human large intestine is about 1.5m (5ft) in length.

Introduction

Fig 1. Anatomy of colon

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Fig. Structure of colon wall

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Location pH

Oral cavity 6.2-7.4

Oesophagus 5.0-6.0

Stomach 1.5-2.0 (Fasted condition)

3.0-5.0 (Fed Condition)

Small

intestine

5.0-6.5 (Jejunum)

6.0-7.5 (Ileum)

Large

intestine

6.4 (Ascending colon)

6.6-6.8 (Transverse colon)

6.8-7.6 (Descending colon)

Table pH values in the GI tract

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Table: Transit time of various parts of GIT

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Functions of colon

1)Creation of a suitable environment for the growth of colonic microorganisms.

2) Storage reservoir of fecal contents.

3) Expulsion of the contents of the colon at a suitable time and

4) Absorption of water and Na+ from the lumen, concentrating the fecal content, and secretion of K+ and HCO3

-.

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Objectives

(a) To reduce dosing frequency.

(b) To delay delivery to the colon to achieve high local concentrations in the treatment of diseases of the distal gut.

(c) To delay delivery to a time appropriate to treat acute phases of disease (chronotherapy).

(d) To deliver to a region that is metabolically less hostile, e.g., to facilitate absorption of acid and enzymatically labile materials, especially peptides.

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Factors affecting drug absorption from the colon:

1)Physical characteristics of drug (pKa, degree of ionization, etc.)2)Colonic residence time as dictated by gastrointestinal tract motility3)Degradation by bacterial enzymes and byproducts4)Selective and non-selective binding to mucus5)Use of chemical absorption enhancers, enzyme inhibitors, or bioadhesives

Rational for the development of colon targeted drug delivery systems

Drugs are available directly at the target site Less enzymatic activity Lesser amount of dose is required Bypass initial first pass metabolism Local and systemic treatment Proteins and peptides delivery Reduced gastric irritation (e.g. NSAIDS)

Limitations Establishment of an appropriate dissolution testing system Bioavailability of drug may be low Rate limiting step for poor soluble drugs

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Drugs suitable for colon targeting

1. In the treatment of Inflammatory Bowel Disease (IBD) e.g., Sulphasalazine, Osalazine, Mesalazine

2. In the treatment of colonic cancer e.g., 5- fluorouracil, Doxorubicin, Methotrexate

3. Proteins and peptides drug delivery e.g., Calcitonin, Insulin, Erythropoietin

4. To treat infectious diseases like Ameobiasis e.g., Metronidazole, Albendazole

5. To treat Rheumatoid arthritis, Nocturnal asthma, Angina, Crohn’s disease, Ulcerative colitis, etc.

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Strategies

1.Variable pH conditions throughout the GIT

2.Colonic microflora produce a variety of enzymes that are not present in the stomach or the small intestine

3.The relatively constant transit time in the small intestine of approximately 3–4 h

4.Another strategy relies on the strong peristaltic waves in the colon that lead to a temporarily increased luminal pressure.

Approaches For The Colon targeting

1.Primary approaches for colon targeting

I. pH sensitive polymer coatingII. Time controlled systemIII. Microbially triggered drug delivery

Polysaccharide based approach Prodrug approach

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2. Novel approaches for colon targeting

I. Pressure controlled drug delivery system II. Osmotic controlled drug delivery to colonIII. Pulsincap system IV. Port system

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l. pH sensitive polymer coating

Region pHAscending colon 6.4Transverse colon 6.6Descending colon 7.0

at colon pH

pH sensitive polymer

Drug core

Drug release

Important parameters - Selection of the appropriate polymers- Solubility at different pH environments

Primary approaches for colon targeting

17Fig 2. Drug release

Table. Polymers18

ll. Time controlled system

In these systems the release of the drug is decided by the transit time.

This system is useful for synchronous delivery of a drug either at preselected time or at a preselected site.

Fig3. Time controlled system

The formulation is comprised of 3 parts:-

1) a central core containing drug and swelling excipients. 2) an inner semi-permeable polymer membrane.

3) an outer enteric-coating which dissolves at or above pH 5.5

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lll. Microbially triggered drug delivery

The colonic bacteria are predominately anaerobic in nature and secrete enzymes that are capable of metabolizing substrates that escape the digestion in the upper GI tract.

On reaching the colon, their is degradation of the polymer backbone by enzyme resulting in drug release.

Table: Enzymes in colon20

The hydrogels contain acidic co-monomers and enzymatically degradable azo-aromatic cross-links.

In the acidic pH of stomach, the gels have a low degree of swelling.

In colon, the gels reach a degree of swelling making the cross-links accessible to enzymes.

Azo hydrogels

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Polysaccharide based approach

The polysaccharides are assessed to remain intact in physiological environment of stomach and small intestine.

As they reach colon they are acted upon bacterial polysaccharidases and results in degradation of the matrices.

e.g., Amylose, Pectin, Chitosan, Dextran, Guar gum, etc.

These are broken down by the colonic microflora to simple saccharides, so these fall into the category of “generally regarded as safe” (GRAS).

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Prodrug approach

A prodrug is a pharmacologically inactive derivative of a parent molecule that requires some form of transformation in vivo to release the active drug at the target site.

Generally, a prodrug is successful as a colon drug carrier if it is hydrophilic and bulky to minimize absorption from the upper GIT, and is converted into more lipophilic in colon for absorption.

Limitation- It is not a very versatile approach as its formulation depends upon the functional group available on the drug moiety for chemical linkage.

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l. Pressure controlled drug delivery system

As a result of peristalsis, higher pressures are encountered in the colon, and which forms the basis for this system.

Drug release occurs due to the disintegration of a water-insoluble polymer capsule because of pressure in the lumen of the colon.

The thickness of the polymer membrane is the critical factor for the disintegration of the formulation.

Novel approaches for colon targeting

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ll. Osmotic controlled drug delivery to colonIt can be single osmotic unit or may incorporate as many as 5-6 units, each 4mm in diameter.

It can maintain a constant release rate for up to 24 h in the colon.

25Fig 4. OROS- CT

lll. Pulsincap system

It consists of non disintegrating half capsule body filled with drug content sealed at the opened end with the hydrogel plug, which is covered by water soluble cap.

Polymers used for hydrogel plug are HPMC, PVA etc.

Fig. Pulsincap system26

27Fig. Mechanism of drug release

lV. Port system

28Fig. Drug release

Evaluation1. In vitro

a) Dissolution testing b) Enzymatic degradation testing

2. In vivo

a) Drug delivery index

= Relative colonic tissue exposure to drug Relative amount of drug in blood

b) Animal studies c) γ-Scintigraphy – to investigate GI performance of a formulation

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Marketed Formulations

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Drug Trade name

Company name

Therapeutic use

Mesalamine Mesacol Sun Pharma Ulcerative colitisOsalazine Dipentum UCB Pharma Ulcerative colitis

Sulphasalazine Sazo Wallace Ulcerative colitis

Balsalazide Intazide Intas Ulcerative colitis

Diphenoxylate HCl+ Atropine sulphate

Lomotil RPG Life Mild ulcerative colitis

Mebeverine Colospa Solvay Irritable bowelsyndromeHydrocortisone acetate

Entofoam Cipla Ulcerative colitis

Conclusion

This system is of prime importance in the treatment of diseases and disorders related to colonic region.This drug delivery requires establishment of appropriate evaluation parameters.The discontinuity in physiological parameters along the GI tract governs few mechanisms to be incorporated to produce colon specific drug release.There is a need to identify appropriate approach, which will be safe, effective, less expensive with minimum fluctuation in drug release.

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References1) Chourasia M. K., Jain S. K., (2003), Pharmaceutical Approaches to Colon Targeted Drug Delivery System, In: Journal of Pharmaceutical Sciences, 33-66.

2) Krishnaiah Y. S. R., Styanarayana S., (2000), Colon specific drug delivery systems. In: Jain N. K., ed. Advances in Controlled and Novel Drug Delivery. New Delhi, India: CBS Publishers and Distributors, 89-119.

3) Kothawade P. D., Gangurde H. H., Surawase R.K., Wagh M.A., Tamizharasi S.,Conventional and Novel Approaches for Colon Specific Drug Delivery: A Review. In : e- Journal of Science and Technology, 33-56.

4) Patel A., Bhatt N., (2011), Colon Targeted Drug Delivery System: A Review System, In: Journal of Pharmaceutical Sciences and Bioscientific Research, 37- 49.

5) Singh B.N., Kim K.H., In: Swarbrick J, Boylan JC., ed. (2002), Encyclopedia of Pharmaceutical Technology, New York, Marcel Dekker, Inc, 886-909.

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6) Kumar K. V., Sivakumar T., Mani T., (2011), Colon Targeting Drug Delivery System: A review on recent approaches, In: International Journal of Biomedical Sciences, 11-19.

7) Mehta T. J., Patel A.D., (2011), Need of Colon Specific Drug Delivery System: Review on Primary and Novel Approaches, In: International Journal of Pharmaceutical Research and Development, 134-153.

8) Patel N., Patel J., (2008), Novel Pharmaceutical Approaches For Colon-Specific Drug Delivery: An Overview. In: Journal of Pharmacy Research, 2-10.

9) Prasanth V.V., Jayaprakash. R., Colon Specific Drug Delivery Systems: A Review on Various Pharmaceutical Approaches. In: Journal of Applied Pharmaceutical Science, 163-169.

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THANK YOU

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