The site specificity of the drugs to the target receptor sites has the potential to reduce the side effects and improve the pharmacological response. However, for successful colon specific drug delivery, many physiological barriers must be overcome; the major one is being absorption or degradation of the active drug in the upper part of the GIT. The disease state also can also potentially alter the delivery and absorption characteristics of drugs from the colon. The colon drug delivery system should protect the drug from the absorption and degradation in the stomach and small intestine, the drug should be absorbed only at the colonic site⁷. The colon is rich in lymphoid tissue, uptake of antigens into the mast cells of colonic mucosa produces rapid local production of antibodies and this helps in efficient vaccine delivery⁸.The colon is believed to be a suitable absorption site for peptides and protein drugs and is considered as an advantageous site where the bioavailability of poorly soluble drugs can be enhanced this is due to the following reasons;

· This region is recognized as having a somewhat less hostile environment with less diversity and intensity of activity than the stomach and small intestine.

· Comparative proteolytic activity of colon mucosa is much less than that observed in the small intestine, thus CDDS protects the peptide drugs from hydrolysis, and enzyme degradation in duodenum and jejunum, and eventually releases the drug into ileum or colon which leads to greater bioavailability. And finally, because the colon has a long residence time which is up to 5 days and is highly responsive to absorption enhancers⁹.

Oral route is the most convenient route of administration for CDDS, other routes are also useful. Rectal administration offers the shortest route for targeting drugs to the colon. However, reaching the proximal part of colon via rectal administration is difficult. Rectal administration is uncomfortable to patients and compliance may be less than optimal¹⁰.

Rationale for the development of Oral Colon Targeted Drug Delivery:

· Treatment of local pathologies.

· Chronotherapy (asthma, hypertension, cardiac arrhythmias, arthritis or inflammation).

· Greater responsiveness to the absorption enhancers.

· Less enzymatic activity.

· Site for delivery of delicate drugs (Proteins and Peptides).

· Oral delivery of vaccines as it is rich in lymphoid tissue.

Advantages:¹¹

Colon-specific drug delivery system offers the following therapeutic advantages:

a. The colon is a site where both local or systemic drug delivery could be achieved, topical treatment of inflammatory bowel disease, e.g. ulcerative colitis or Crohn’s disease, Intestinal bowel syndrome (IBD). Such inflammatory conditions are usually treated with glucocorticoids.

b. Minimizing extensive first pass metabolism of steroids.

c. Preventing the gastric irritation produced by oral administration of NSAIDS.

d. Improved therapy of diseases susceptible to diurnal rhythm.

e. Delayed release of drugs to treat angina, asthma and rheumatoid arthritis.

f. Potential for oral delivery of proteins, peptides and other GI liable drugs.

g. By producing the ‘friendlier’ for peptides and proteins when compared to upper GI tract.

The therapy of various disease conditions can be improved by colon specific drug delivery systems employing various mechanisms of release, which is shown in the Table 1:

Delayed systemic absorption of drugs via colonic delivery is advisable for chronotherapy of diseases such as asthma, hypertension, cardiac arrhythmias, rheumatoid arthritis or inflammation, which are affected by circadian rhythms. These diseases are characterized by night time or early morning symptoms. These types of approaches are beneficial for nocturnal release of drug, which in turn may provide considerable relief to the patients while they are resting⁴.

The mode of drug release from colon-targeted biopolymer systems can include one or more of the following mechanisms:

1. Diffusion

2. Polymer erosion

3. Microbial degradation

4. Enzymatic degradation (mammalian and/or bacterial)

In addition, drug solubility and formulation of polymer mixes play important roles in determining the extent of drug delivery and release in the colon.

Two broad categories of biopolymers have been employed for formulating colonic systems:

(1) Biodegradable and

(2) Nonbiodegradable polymers.

Limitations¹⁴

To achieve successful colon targeting it should overcome the following limitations (Jack et al., 2006).

· The location at the distal portion of the alimentary canal, the colon is difficult to access.

· Successful delivery requires the drug to be in solution before it arrives in the colon, but the fluid content in the colon is lower and more viscous than in upper GIT, which is the limiting factor for poorly soluble drugs.

· Lower surface area and relative tightness of the tight junctions in the colon can restrict drug transport across the mucosa in to the systemic circulation.

General considerations for designing of colon specific formulations:

To achieve a desired therapeutic action of dosage form, it is necessary to design a suitable formulation with suitable qualities. In general, delayed release dosage forms are designed to provide a burst release¹⁴ or a sustained/ prolonged release once they reach colon.

Various factors include are

· Pathology and pattern of diseases, especially the affected parts of lower GIT or, Physiology and physiological composition of the healthy colon if the formulation is not intended for localized treatment.

· Physicochemical properties and biopharmaceutical properties of the drug such as solubility , stability and permeability at the intended site of delivery, and

· The desired release profile of the active ingredient.

Formulation of drugs for colon specific delivery requires careful consideration of dissolution of and / or release rate in the colon fluids. Due to the presence of less fluid content in large intestine than in small intestine the dissolution and release rate from the formulations decreases¹⁵. The poor dissolution and release rate may in turn lead to lower systemic availability of drugs. These issues could be more problematic when the drug candidate is poorly water soluble and / or require higher doses for therapy. Consequently, such drugs need to be delivered in pre solubilized form, or formulation should be targeted for proximal colon, which has more fluid than in the distal colon. Aside from drug solubility, the stability of the drug in the colonic environment is a further factor that warrants attention. The drug could bind in a nonspecific manner to dietary residues, intestinal secretions, mucus or general fecal matter, thereby reducing the concentration of free drug. Moreover, the resident micro-flora could also affect colonic performance via degradation of the drug¹⁶.

Pharmaceutical approaches to colon specific drug delivery system:

The most advanced Pharmaceutical approaches that can be exploited for the development of colon targeted drug delivery systems are given below:

· Time Dependent systems

· Pulsatile Systems

· CODES Technology

· Pressure dependent release systems

· Osmotic controlled drug delivery (ORDS-CT)

· Multiparticulates

· Microspheres

Time-dependent systems:

Time dependent systems are very promising type of drug release systems. The dosage forms also applicable to colon targeting dosage forms by prolonging the lag time of about 5 to 6 hours. However the disadvantages of this system are:

a. Gastric emptying time varies markedly between subjects or in a manner dependent on type and amount of food intake.

b. Gastrointestinal movement, especially peristalsis or contraction in the stomach would result in change in gastrointestinal transit of the drug.

c. Accelerated transit through different regions of the colon has been observed in patients with the IBD, the carcinoid syndrome and diarrhea, and the ulcerative colitis¹⁷.

Therefore, time dependent systems are not ideal to deliver drugs to the colon specifically for the treatment of colon related diseases. Colon targeting could be achieved by incorporating a lag time into formulation equivalent to the mouth to colon transit time. The basic principle involved in the system is the release of drug from dosage form should be after a predetermined lag time to deliver the drug at the right site of action at right time and in the right amount¹⁷.Enteric coated time-release press coated (ETP) tablets, are composed of three components, a drug containing core tablet (rapid release function), the press coated swellable hydrophobic polymer layer (Hydroxy Propyl cellulose layer (HPC), time release function) and an enteric coating layer (acid resistance function).The tablet does not release the drug in the stomach due to the acid resistance of the outer enteric coating layer. After gastric emptying, the enteric coating layer rapidly dissolves and the intestinal fluid begins to slowly erode the press coated polymer (HPC) layer. When the erosion front reaches the core tablet, rapid drug release occurs since the erosion process takes a long time as there is no drug release period (lag phase) after gastric emptying. The duration of lag phase is controlled either by the weight or composition of the polymer (HPC) layer. (Fig.1).

A nominal lag time of five hours is usually considered sufficient to achieve colon targeting. In this method the solid dosage form coated with different sets of polymers (listed in Table 2) and the thickness of the outer layer determines the time required disperse in aqueous environment

Table 2: List of polymers used is:

Enteric Polymers	Optimum pH for dissolution
Polyvinyl acetate phthalate (PVAP)	5.0
Cellulose acetate trimelitate (CAT)	5.5
Hydroxypropyl methylcellulose phthalate (HPMCP)	> 5.5
Hydroxypropylmethylcellulose acetate succinate (HPMCAS)	> 6.0
Methacrylic acid copolymer dispersion (Eudragit L30D-55)	> 5
Methacrylic acid copolymer, Tyep A	> 6.0
Cellulose acetate phthalate (CAP) (Aquateric)	6.0
Methacrylic acid copolymer, Type B	> 7.0
Eudragit FS30D	> 7.0
Shellac (MarCoat 125 and125N)	7.0

Hydroxy Propyl Methyl Cellulose (HPMC) compression coated tablets of 5-fluorouracil werestudied for colon drug delivery that based on time-dependent approach. In this, the core tablet was prepared by wet granulation method and then coated with 50% of HPMC/lactose coat powder bycompression-coating method. Drug release characteristics were evaluated in distilled water by using aChinese pharmacopoeia rotatable basket method¹⁸.

Pulsatile System¹⁹

Pulsatile release systems are formulated to undergo a lag-time of predetermined span of time of no release, followed by a rapid and complete release of loaded drugs. The approach is based on the principle of delaying the time of drug release until the system transits from mouth to colon. A lag-time of 5 hours is usually considered sufficient since small intestine transit is about 3-4 hours, which is relatively constant and hardly affected by the nature of formulation administered.

Advantages of Pulsatile Drug Delivery System

1. Extended daytime or night time activity

2. Reduced side effects

3. Reduced dosage frequency

4. Reduction in dose size

5. Improved patient compliance

6. Lower daily cost to patient due to fewer dosage units are required by the patient in therapy.

7. Drug adapts to suit circadian rhythms of body functions or diseases.

8. Drug targeting to specific site like colon.

9. Protection of mucosa from irritating drugs.

10. Drug loss is prevented by extensive first pass metabolism.

Conditions requiring pulsatile release include a number of hormones like renin, aldosterone and cartisole which shows daily fluctuation in their blood levels. These changes are generally known as circadian rhythm which is responsible for changes in many functions of the body like activity of liver enzyme, blood pressure, and intraocular pressure etc P^H, gastric acid secretions in stomach, gastric emptying and gastric intestinal blood transfusion. Various diseases are also dependent on the circadian rhythm for example acute myocardial insufficiency occurs most commonly around 4.00 P.M.

Fig 2: Enteric coated pulsin cap

CODES™ technology:

The design of CODES™ exploited the advantages of certain polysaccharides that are only degraded by bacteria available in the colon. This is coupled with a pH-sensitive polymer coating. Since the degradation of polysaccharides occurred only in the colon, this system exhibited the capability to achieve colon delivery consistently and reliably. In this technology the core tablet coated with three layers of polymer coatings. The first coating (next to the core tablet) is an acid-soluble polymer (e.g. Eudragit E®) and outer coating is enteric with a HPMC barrier layer in between to prevent any possible interactions between the oppositely charged polymers. The core tablet is comprised of the active, one or more polysaccharides and other desirable Excipient. The polysaccharides, degradable by enterobacteria to generate organic acid, include mannitol, maltose, stachyose, lactulose, fructooligosaccharide etc. During its transit through the bacteria will enzymatically degrade the polysaccharide into organic acid. This lowers the pH surrounding the system sufficient to affect the dissolution of the acid-soluble coating and subsequent drug release²⁴.

Fig 3: Schematics of the conceptual design of CODES™

Pressure controlled drug delivery system:

It is due to peristalsis, higher pressures are encountered in the colon than in the small intestine. Pressure controlled colon-delivery capsules were developed using ethyl cellulose, which are insoluble in water.¹⁵ In such systems, drug release occurs followed by disintegration of a water-insoluble polymer capsule because of pressure in the lumen of the colon. The thickness of the ethyl cellulose membrane is an important factor for the disintegration of the formulatio^{24, 25}.The system which also depends on capsule size and density. Because of reabsorption of water from the colon, the viscosity of luminal content is greater in the colon than in the small intestine. It is therefore been concluded that drug dissolution in the colon could present a problem in relation to colon-specific oral drug delivery systems. In pressure controlled ethyl cellulose single unit capsules the drug is in a liquid form²⁶. Lag time of three to five hours in relation to drug absorption were noted when pressure-controlled capsules were administered to humans.

Osmotic controlled drug delivery (ORDS-CT):

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 that is otherwise unattainable to elicit the action^27. The OROS-CT system can be a single osmotic unitormay incorporate as many as 5-6 push-pull units, each 4 mm in diameter, encapsulated within a hard gelatine capsule, (Fig. 4)^29.Each bilayer push pull unit contains an osmotic push layer and a drug layer; both layers are surrounded by a semipermeable membrane. An orifice is made through the membrane next to the drug layer. Immediately the OROS-CT is swallowed, the gelatine capsule containing the push-pull units dissolves. Because of its drug-impermeable enteric coating, each push-pull unit is prevented from absorbing water in the acidic aqueous environment of the stomach and hence no drug is delivered. As the unit enters the small intestine, the coating dissolves in this higher pH environment (pH >7), water enters the unit, making the osmotic push compartment to swell, and simultaneously creates a flowable gel in the drug compartment. Swelling of the osmotic push compartment forces drug gel out of the orifice, at a rate precisely controlled by the rate of water transport through the semipermeable membrane. To treat ulcerative colitis, each push pull unit is designed with a 3-4 h post gastric delay to arrest drug delivery in the small intestine. Drug is released only when the unit reaches the colon. OROS-CT system can maintain a constant release rate up to 24 hours in the colon or can deliver drug over a period as short as four hours. Recently, new phase transited systems have come; promising to be a good tool for targeting drugs to the colon^29,
30. Various in vitro / in vivo evaluation techniques have been developed and proposed to test the activity and stability of CDDS.

Figure 4: Cross-Section of the OROS- CT colon targeted drug delivery system

These days the basic CDDS approaches are applied to formulate novel drug delivery systems

Such as Multiparticulate systems, Microspheres, Liposomes, Microencapsulated particles etc.

Multiparticulates:

Multiparticulates such as pellets, non-peariles etc. are used as drug carriers in pH-sensitive, time dependent and microbial control systems for colon targeting. Multiparticulate systems have several advantages in comparison to the conventional single unit dosage forms for controlled release technology, such as more predictable gastric emptying and fewer localized adverse effect than those of single unit tablets or capsules³⁰.

A multiparticulate dosage form was prepared to deliver active substances to colonic region, which combines pH dependent and controlled release properties of the drug. This system constitutes drug loaded cellulose acetate butyrate (CAB) microspheres loaded by an enteric polymer (Eudragit S). Here the enteric coating layer prevents the drug release below pH 7. After all that CAB microspheres effectively controlling the release of budesonide, is dependent on the polymer concentration in the preparation³¹. Azo polymer coated pellets were used for colon-specific drug delivery to increase the absorption of insulin and (Asu1, 7) Eel calcitonin³².

A multiparticulate chitosan dispersed system (CDS) was prepared for colon drug delivery made of a drug reservoir and the drug release-regulating layer, incorporated with water insoluble polymer and chitosan powder. The drug reservoir was prepared by multiparticulates of drug like Non peariles in this study where the multiparticulate CDS was adopted, not only for colon specific drug delivery but also for sustained drug delivery³³.

A Multiparticulate system combining both pH sensitive property and specific biodegradability was prepared for colon targeted delivery of metronidazole. The Multiparticulate system was prepared by coating cross-linked chitosan microspheres using Eudragit L-100 and S-100 as pH sensitive polymers. The in vitro drug release studies clearly shows that no release of drug at acidic pH and higher drug release were found in presence of rat caecal contents indicating susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents³⁴.

High-Amylose corn starch and Pectin blend micro particles of diclofencac sodium for colon-targeted delivery were prepared by spray drying technique. The blending of high amylose corn-starch with pectin improved the encapsulation efficiency and decreased the drug dissolution in the gastric environment from pectin based micro particles. The drug gets released in colonic region by the action of pectinase from micro particles³⁵.

It was investigated that the effect of sodium glycocholate as absorption Promoter on orally administrated insulin absorption, utilizing a colon-targeted delivery system³⁶. A novel insulin colon-targeted delivery system (Insulin- CODES) contains insulin, lactulose as a trigger for colon-specific release, citric acid as a solubilizer of insulin, meglumine as a pH adjusting agent and sodium glycocholate as an absorption promoter.

Microspheres:

Cross-linked guar gum microspheres containing methotrexate were prepared and characterized for local release of drug in the colon for the treatment of colorectal cancer. In this method, glutaraldehyde was used as a cross-linking agent and guar gum microspheres were prepared byEmulsification method. From the results of in vitro and in vivo studies themethotrexate loaded crosslinked guar gum microspheres delivered most of the drug loaded (79%) to the colon, where as plain drug suspensions could deliver only 23% of their total dose to the target tissue³⁷.

Colon specific microspheres of 5-fluorouracil were prepared and evaluated for the treatment of colon cancer. In this method core microspheres of alginate were prepared by modified emulsification method in liquid paraffin by cross-linking with calcium chloride. The core microspheres were coated with Eudragit S-100 by solvent evaporation technique to prevent drug release in the stomach and small intestine. The results showed that this method had great potential in delivery of 5- fluorouracil to the colonic region³⁸.

Besides the above discussed systems, the others include Prodrug approach, P^HDependent systems and Microbial triggered systems.

Evaluation:

No any standardized in-vitro evaluation technique is available for CDDS as an ideal in vitro model should possess the in-vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes, enzyme activity, and other components of food which all of these are influenced by diet, physical stress, and make it difficult to design a standard in-vitro model. In vitro models used for CDDS are:

a) In vitro dissolution test:

Dissolution of controlled-release formulations used for colon-specific drug delivery are unusually not complex, while the methods described in the USP cannot fully mimic invivo conditions such as those relating to pH, bacterial environment and mixing forces²³.In invitro studies the ability of the coat/carrier to remain intact in the physiological environment of the stomach and small intestine is usually assessed by drug release studies in 0.1N HCl for two hours (to mimic gastric emptying time) and in pH 7.4 phosphate buffer for three hours (to mimic small intestinal transit time) using USP dissolution apparatus.

b) In vitro enzymatic tests:

In case of micro flora activated system dosage form, the release rate of drug is tested in vitro by incubating the buffer medium in the presence of either enzymes (e.g. pectinase, dextranase) or rat/guinea pig /rabbit caecal contents. The amount of drug released at different time intervals during the incubation is estimated to find out the degradation of the carrier under study³⁹.

c) In vivo evaluation:

i) Animal studies:

A number of animals such as dogs, guinea pigs, rats, and pigs are used to evaluate the delivery of drug to colon as they resemble the anatomic and physiological conditions as well as the microflora of human GIT. While choosing a model for testing a CDDS, relative model for the colonic diseases should be considered as well. Guinea pigs are generally used for experimental IBD model. The distribution of enzymes azoreductase and glucouronidase activity in the GIT of rat and rabbit is fairly comparable to that of humans⁴⁰. For rapid evaluation of CDDS, a novel model has been proposed. In this model, human fetal bowel is transplanted into a subcutaneous tullel on the back of thymic nude mice, which bascularizes within four weeks, matures, and then capable of developing mucosal immune system from the host.

ii) γ-Scintigraphy:

γ- Scintigraphy is a modern method of imaging which can able to visualize the in vivo performance of drug delivery system under normal physiological conditions in a non-invasive manner. It was two decades ago first employed to investigate the in vivo functionality of tablets and capsules. The principles and applications of γ-Scintigraphy are available in the literature⁴¹. γ-Scintigraphy aids in elucidating the information regarding the location as a function of time, the time and location of both initial and complete system disintegration, the extent of dispersion, the colon arrival time, stomach residence and small intestinal transit times.

CONCLUSION:

In particular the colonic region of GIT has gained importance as a site of drug delivery and absorption. In terms of both local and systemic treatment CDDS offers considerable advantage to patients. This particular colon specific drug delivery is more likely to be achieved with natural materials that are degraded by colonic bacterial enzymes. Challenges still remain even after the sophistication of colon specific drug delivery systems exist to develop and validate a dissolution method that incorporates physiological features of colon.

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Received on 06.05.2011

Accepted on 09.06.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(4): July-Aug. 2011, 122-129

Target Sites	Disease conditions	Drugs and active agents
Topical Action	Inflammatory Bowel disease, Irritable bowel Syndrome, Chronic Pancreatitis, and Crohn’s disease.	Hydrocortisone, Budenoside,Prednisolone,Sulfasalazine, Olsalazine, Mesalazine and Balsalazide.
Local Action	Pancreoctomy and Crystal fibrosis, Colorectal cancer	Digestive enzymes supplements, 5-Flourouracil.
Systemic Action	To prevent gastric irritation To prevent first pass metabolism for orally ingested drugs Orally delivered peptides Orally delivered vaccines	NSAIDS Steroids Insulin Typhoid