INTRODUCTION:

The dosage form that delivers the drug in colon rather than upper part of GIT is called as colonic drug delivery system and this delivery system has a number of advantages. The colon is attracting interest as a site where poorly absorbed drug molecule may have an improved bioavailability. This region of the colon is recognized as having a somewhat less hostile environment with less diversity and intensity of activity than the stomach and small intestine.

Oral delivery of drugs to the colon is valuable in the treatment of diseases of colon (ulcerative colitis, Chron's disease, carcinomas and infections) whereby high local concentration can be achieved while minimizing side effects that occur because of release of drugs in the upper GIT or unnecessary systemic absorption. The colon is rich in lymphoid tissue, uptake of antigens into the mast cells of the colonic mucosa produces rapid local production of antibodies and this helps in efficient vaccine delivery. The colon has a longer retention time and appears highly responsive to agents that enhance the absorption of poorly absorbed drug.

The simplest method for targeting of drugs to the colon is to obtain slower release rates or longer release periods by the application of thicker layers of conventional enteric coatings or extremely slow releasing matrices.

Colon targeted drug delivery system is of special importance in systemic delivery of protein and peptide drugs also important when delay in drug absorption require from therapeutic point of view in the treatment of nocturnal asthma, angina etc.¹

In general terms, colonic targeting must be based on :

1) Physiological realities and requirements (i.e. the function of large and small intestine).

2) Colonic absorbability of alternative, topical efficacy of the drug interest.

3) Suitable excipients to release a drug targeted fashion in the colon. and

4) The therapeutic usefulness of such system.²

The objectives of colonic drug delivery systems are:

A. To reduce dosing frequency.

B. To delay the delivery to colon to achieve high local concentration in the treatment of diseases of the distal gut.

C. To delay delivery to a time appropriate to treat acute phases of diseases (chronotherapy).

D. To deliver to a region that is less hostile metabolically eg. To facilitate absorption of acid enzymatically labile materials, especially peptides^.

The transverse colon is folded in front of the ascending and descending arms. The splenic flexure will generally prevent exposure to the transverse colon following rectal administration. From the middle of the ascending colon consolidation of luminal contents occurs into a mass that gradually becomes more homogeneous and viscous.

Table 1: Various pharmaceutical approaches to colon targeted drug delivery systems.

1	Approach	Basic feature
1.1	Covalent linkage of a drug with a carriet	The drug is conjugated via via an azo bond
1.2	Cyclodextrin conjugates	The drug is conjugated via with cyclodextrin
1.3	Glycosider conjugates	The drug is conjugated via with glycoside
1.4	Glucuronate conjugates	The drug is conjugated via with glucuronate
1.5	Dextran conjugates	The drug is conjugated via with dextran
1.6	Polypeptide conjugates	The drug is conjugated via poly (aspartic acid)
1.7	Polymeric prodrugs	The drug is conjugated via with polymer
2	Approaches to deliver the intact molecule to the colon
2.1	Coating with polymers
2.1.1	Coating with pH-sensitive polymers	Formulation coated with enteric polymers releases drug when pH moves towards alkaline range
2.1.2	Coating with biodegradable polymers	Drug is released following degradation of the polymer due to the action of colonic bacteria
2.2	Embedding in matrices	The embedded drug in polysaccharide matrices is released by swelling and by the biodegradable action of polysaccharidases.
2.2.1	Embedding in biodegradable matrices and hycrogels	Degradation of the pH sensitive polymer in the GIT releases the embeded drug.
2.2.2	Embedding in pH-sensitive matrices
2.3	Timed released systems	Once the multicoated formulation passes the stomach, the drug is released after a lag time 3.5 h that is equivalent to small intestinal transit time
2.4	Redox-sensitive polymers	Drug formulated with azo polymer and disulfide polymers that selectively respond to the redox potential of the colon proves colonic delivery.
2.5	Bioadhesive systems	Drug coated with a bioadhesive polymer that selectively provides adhesion to the colonic mucosa may release drug in the colon.
2.6	Coating with microparticles	Drug is linked with microparticles
2.7	Osmotic controlled drug delivery	Drug is released through semipermeable membrane due to osmotic pressure.

By the time the luminal contents have reached the descending colon, the mass is too solid to allow drug dispersion from a delayed-release formulation.

Current studies indicate that the distal transverse colon functions as a conduit, driving material into the descending and sigmoid colon for storage. Studies conducted in patients to measure the relative residence times of materials at steady state show that the contents are divided two-thirds into the ascending or right colon and one-third in the descending colon. This difference is exaggerated in left-sided colitis to 9:1, which may explain why management is difficult in active diseases.³

Recent trends used for colonic drug delivery systems are:

v Single unit dosage form :

E.g. Tablets, Capsules

v Multiple unit dosage form :

E.g. Micro granules, Micro spheroids, Beads, Pellets, Microcapsules.

Covalent linkage of the drug with a carrier:

It involves the formation of a covalent linkage between drug and carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine.

The function of colon: The impact on drug delivery

This approach chiefly involves the formation of prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug. Formation of prodrugs has improved delivery properties over the parent drug molecule. The problem of stability of certain drugs from the adverse environment of the upper GIT can be eliminated by prodrug formation, which is converted into parent drug molecule once it reaches into the colon. Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.^4-6

Colon targeted drug delivery system:

In recent times, colon targeted drug delivery systems have gained importance for the systemic delivery of protein and peptide drugs. This is because the peptide and protein drugs get destroyed or inactivated in acidic environment of the stomach or by pancreatic enzymes in the small intestine. ⁷ Drug targeting to colon is also useful when a delay in drug absorption is desired from therapeutic point of view, such as treatment of diseases that have peak symptoms in the early morning like nocturnal asthma, angina or arthritis.^8-9 Among the different approaches to achieve colon specific drug delivery, the use of polymers, specifically biodegraded by colonic bacterial enzymes holds promise.^10-11

The important bacteria present in the colon such as Bacteroides, Bifidobacterium, Eubacterium, Peptococcus, Lactobacillus, Clostridium secrete a wide range of reductive and hydrolytic enzymes such as β-glucuronidase, β-xylosidase, β-galactosidase, α-arabinosidase, nitroreductase, azoreductase, deaminase and urea hydroxylase. These enzymes are responsible for degradation of di-, tri- and polysaccharides.^12-13

Hence a coat of a considerable thickness is required to protect the drug core in simulated in vivo conditions. In vitro studies revealed that the tablets coated with inulin and shellac have limited the drug release in stomach and small intestinal environment and released maximum amount of drug in the colonic environment.¹⁴

approaches to deliver the intact molecule to the colon

Coating with polymers:

The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon.

Coating with pH-sensitive polymers:

The pH-dependent systems exploit the generally accepted view that pH of the human GIT increases progressively from the stomach (pH 1-2 which increases to 4 during digestion), small intestine (pH 6-7) at the site of digestion and it increases to 7-8 in the distal ileum. The coating of pH-sensitive polymers to the tablets, capsules or pellets provide delayed release and protect the active drug from gastric fluid. The polymers used for colon targeting, however, should be able to withstand the lower pH values of the stomach and of the proximal part of the small intestine and also be able to disintegrate at the neutral of slightly alkaline pH of the terminal ileum and preferably at the ileocecal junction. These processes distribute the drug throughout the large intestine and improve the potential of colon targeted delivery systems. While this release pattern can be studied in vitro , there is no real substitute for confirming reliable performance in vivo in man. The technique of gamma scintigraphy has become the most popular method to investigate the gastrointestinal performance of pharmaceutical dosage forms. The majority of enteric and colon targeted delivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. ¹⁵

Coating with biodegradable polymers

The bioenvironment inside the human GIT is of complex microflora especially the colon that is rich in microorganisms that are involved in the process of reduction of dietary component or other materials. Drugs that are coated with the polymers, which are showing degradability due to the influence of colonic microorganisms, can be exploited in designing drugs for colon targeting. These bacterial degradable polymers especially azo polymers have been explored in order to release an orally administered drug in the colon. When the dosage form passes through GIT, it remains intact in the stomach and small intestine where very little microbially degradable activity is present that is quiet insufficient for cleavage of polymer coating.

Table 3: ²¹Formulas of coating solution and standard operating conditions

Coating layer	Acid-soluble layer	Hydrophilic layer	Enteric layer
Composition of	Eudragit ^®E 5.0	TC-5^® 1.5	HPMCÒ-AS 5.0
coating solution (w/w%)	Ethanol 95.0	ACET 4.0 Ethanol 23.0 Water 71.5	Talc 2.5 Ethanol 55.8 Water 36.7
Operating conditions:
Blower temperature (0^C)	45	65	60
Exhaust temperature (0^C)	30	35	40
Spray pressure (kg/cm)	2	2	2
Air flow rate (L/ cm²)	30	30	30
Spray rate (g/min)	2.5	1.8	2.5
Rotating speed of coating pan (rpm)	40	40	40

Table 4: Drugs That Reduce Bowel Inflammation

Drug	Selected Side Effects	Comments
Aminosalicylates
· Sulfasalazine	Common: Nausea, headache, dizziness, fatigue, fever, rash, reversible male infertility Uncommon: Inflammation of the liver (hepatitis), pancreas (pancreatitis), or lung (pneumonitis); hemolytic anemia	Abdominal pain, dizziness, and fatigue are related to dose; hepatitis and pancreatitis are unrelated to dose
· Balsalazide · Mesalamine · Olsalazine	Common: Fever, rash Uncommon: Pancreatitis, inflammation of the pericardium (pericarditis), pneumonitis For olsalazine Some Trade Names DIPENTUM : Watery diarrhea	Most side effects seen with sulfasalazine Some Trade Names AZULFIDINE may occur with any of the other aminosalicylates but much less frequently
Corticosteroids
Prednisone	Diabetes mellitus, high blood pressure, cataracts, osteoporosis, thinning of skin, mental problems, acute psychosis, mood swings, infections, acne, excessive body hair (hirsutism), menstrual irregularities, gastritis, peptic ulcer disease	Diabetes and high blood pressure are more likely to occur in people who have other risk factors
Budesonide	Diabetes mellitus, high blood pressure, cataracts, osteoporosis (decreased bone density)	Same side effects as prednisone Some Trade Names DELTASONE METICORTEN but to a lesser degree
Immunomodulators
· Azathioprine · Mercaptopurine	Anorexia, nausea, vomiting, infection, cancer, allergic reactions, pancreatitis, low white blood cell count, bone marrow suppression, liver dysfunction	Side effects that are usually dose dependent include bone marrow suppression and liver dysfunction Interval blood monitoring is required
Cyclosporine	High blood pressure, nausea, vomiting, diarrhea, kidney failure, tremors, infections, seizures, neuropathy, development of lymphomas (cancers of the lymphatic system)	Side effects become more likely with long-term use
Methotrexate	Nausea, vomiting, abdominal distress, headache, rash, soreness of the mouth, fatigue, scarring of the liver (cirrhosis), low white blood cell count, infections Causes abortions and birth defects during pregnancy	Liver toxicity is likely dose dependent Not prescribed for pregnant women
Infliximab	Infusion reactions, infections, cancer, abdominal pain, liver dysfunction, low white blood cell count	Infusion reactions are potential immediate side effects that occur during the infusion such as fever, chills, hives, decreased blood pressure, or difficulty breathing Patients should be screened for tuberculosis before initiating treatment
Adalimumab	Pain or itching at the injection site, headache, infections, cancer, and hypersensitivity reactions	Side effect are similar to infliximab Some Trade Names REMICADE except does not cause infusion reactions Hypersensitivy reactions include rash, urticaria, pruritis, and hives

Release of the drugs from azo polymer coated formulation is supposed to take place after reduction and thus degradation of the azo bonds by the azo reductase enzymes released by the azo bacters present in the colonic microflora. The concept of this strategy is based on the metabolic activity of azo reductase produced by azo bacters of colon, the bacterial degradation of polymeric coating may be effected by several other factors e.g. dietary fermentation precursors, type of food consumed and coadministration of chemotherapeutic agents. Administration of antibiotics may result in the partial or complete destruction of colonic microflora, which adversely affect the release of bioactive agents. ^16-18

Azo polymers degraded specifically by the action of intestinal flora, the dosage form coated with this polymer would be effective for colon targeting of orally administered drugs. The release rate of drugs from double-coating pellets depend on the molecular weight and the composition of the polyurethane used as the overcoat as well as the hydrophilicity of the incorporated drugs.¹⁹In order to formulate inulin as a biodegradable coating material, it was incorporated as a suspension in Eudragit® RS films, since inulin itself has no film forming properties. Eudragit® RS, copolymer of acrylic acid esters with a low content of quaternary ammonium groups was chosen as film-former because it gives water-insoluble, pH-independent, low permeable films which are inert to endogenous digestive secretions and enzymes. ²⁰

Dietary Regimens: ²²

Defined-formula liquid diets, in which each nutritional component is precisely measured, may improve the condition of an intestinal obstruction or fistula at least for a short time. Nutritional therapy also may help children grow more than they might otherwise, especially when given at nighttime by tube feeding. These diets may be tried before or in addition to surgery.

Broad-spectrum Antibiotics:

Antibiotics that are effective against many types of bacteria are often prescribed. The antibiotic metronidazole Some Trade Names FLAGYL is the most common choice for the treatment of abscesses and fistulas around the anus. Metronidazole may also help relieve the noninfectious symptoms of Crohn's disease, such as diarrhea and abdominal cramps. However, when used for a long time, metronidazole can damage nerves, resulting in a pins-and-needles feeling in the arms and legs. This side effect usually disappears when the drug is stopped, but relapses of Crohn's disease after discontinuing metronidazole are common. Some other antibiotics, such as ciprofloxacin.

Some trade names Ciloxan, Cipro or Levofloxacin, quixin, levaquin may be used in place of or in combination with metronidazole. Some trade names Flagyl, Rifaximin, a non absorbable antibiotic, is also sometimes used in treating active Crohn's disease. ²³

REFERENCES:

1) M. K. Chourasia and S. K. Jain, “ Pharmaceutical approaches to colon targeted drug delivery systems ”, journal of Pharmaceutical Science, 6(1), (2003), 33-66.

2) Hans Schreier, “ Drug targeting technology ”, (Physical, Chemical, Biological methods), Marcel Dekker,Inc, New York • Basel,( 2001), chapter 2, 1-19.

3) Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts, “ Modified Release Drug Delivery Technology ”, Marcel Dekker, Inc, New York • Basel, (2003), 217-222.

4) Raffi, R., Franklin, W. and Cerniglia, C.E, “Azoreductase activity of anaerobic bacteria isolated from human intestinal microflora”. Appl Environ Mivrobiol, 56 (1990), 2146-2151.

5) Raffi, R., Franklin, W., Heflich R.H. and Cerniglia, C.E, “ Reduction of nitroaromatic compounds” by anaerobic bacteria isolated from the human intestinal tract. Appl Environ Mivrobiol 57 (1991), 962-968.

6) Walker, R. and Ryan, A.J, “Some molecular parameters influencing rate of reduction of azo compounds” by intestinal microflora. Xenobiotica, 1 (1971), 483-486.

7) Yang L, James SC, Joseph A. “ Colon-specific drug delivery: New approaches and in vitro/ in vivo evaluation”. International Journal of Pharmacy 235 (2002)1-15.

8) Schacht E, Gevaert A, El Refaie K, Koen M, Verstraete W, Adriaensens P, et al. “Polymers for colon specific drug delivery”. Journal of Control Release 39 (1996), 327-8.

9) Wilding R, Davis SS, Pozzi F, Furlani P, Gazzaniga A. “Enteric coated timed release systems for colonic targeting”. International Journal of Pharmacy 111,(1994) 99-102.

10) Krishnaiah YS, Satyanarayana V, Dinesh Kumar B, Karthikeyan RS. In vitro drug release studies on guar gum-based colon targeted oral drug delivery systems of 5-fluorouracil. Eur J Pharm Sci 16, (2002), 185-92.

11) Sinha VR, Rachna K. “ Polysaccharides in colon-specific drug delivery”. International Journal of Pharmacy 224, (2001), 19-38.

12) Sinha VR, Rachna K. Coating polymers for colon specific drug delivery: A comparative in vitro evaluation. Acta Pharma 53, (2003), 41-7.

13) Cavalcanti, OA, Van den Mooter G, Caramico-Soares I, Kinget R. “Polysaccharides as excipients for colon-specific coatings, permeability and swelling properties of casted films”. Drug Develop Ind Pharm 28, (2002) , 157-64.

14) V Ravi, TM Pramod Kumar, Siddaramaiah, “Novel colon targeted drug delivery system using natural polymers”, Indian journal of pharmaceutical sciences, 70(1), (2008), 111-113.

15) Wilding, I.R, Hardy, J.G. Sparrow, R.A., Davis, S.S, Daly, P.B. and English, J.R., In vivo evaluation of enteric coated naproxan tablets using gamma scintigraphy. Pharm Res, 9 (1992),1436-1441.

16) Kimura, Y., Makita, Y., Kumagi, T., Yamane, T., Kiato, H., Sasatani, H. and Kim, S.I., “Degradation of azo-containg polyurethane by the action of intestinal flora: its metabolism and application as a drug delivery system”. Polymer, 33,(1992), 5294-5299.

17) Ueda, T., Yamaoka, M., Miyamoto, M. and Kimura, Y., “Bacterial reduction of azo compounds as a model reaction for the degradation of azo-containing polyurethane by the action of intestinal flora”. Bull Chem Soc Jpn, 69 ,(1996) ,1139-1142.

18) Yamaoka, T., Makita, Y., Sasatani, H., Kim, S.I. and Kimura, Y., Linear type azo-containing polyurethane as drug-coating material for colon-specific delivery: its properties, degradation behaviour, and utilization for drug formulation. J Control Rel, 66, (2000) , 187-97.

19) Chavan, M.S., Sant, V.P. and Nagarsenker, M.S., Azo-containing urethane analogues for colonic drug delivery: synthesis, characterization and in-vitro evaluation. J Pharm Pharmacol, 53, (2001), 895-900.

20) Vervoort, L. and Kinget, R., In vitro degradation by colonic bacteria of inulin HP incorporated in Eudragit RS films. Int J Pharm, 129,(1996), 185-190, 199

21) Takashi Ishibashi, Kengo Ikegami, Hiroaki Kubo, Masao Kobayashi, Masakazu Mizobe, Hiroyuki Yoshino, “Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted delivery capsule (CTDC)”, Journal of Controlled Release 59 (1999) 361–376.

22) www.google.com

23) www.merc.com/ crohn’s diseases.

Received on 07.09.2009 Modified on 09.11.2009

Research J. Pharm. and Tech. 3(1): Jan.-Mar. 2010; Page 45-49