INTRODUCTION:

Targeted drug delivery describes the release of drug towards the specific part of the body like tissue and other organs, or at particular absorption site, thereby increasing therapeutic efficacy. An appropriately designed sustained or controlled release drug delivery system can be major advance towards solving the problem associated with the existing drug delivery system^{1, 2}.The design of dosage forms has several objectives, one of which is to Endeavour to achieve drug release at sites that will ensure maximum therapeutic benefits³.

Colon as a site offers distinct advantages on account of a near neutral pH, a much longer transit time, reduced digestive enzymatic activity and a much greater responsiveness to absorption enhancers⁴. Colonic drug delivery is also useful for systemic absorption of drugs, especially protein and peptide drugs, because of the less hostile environment prevailing in the compared with the stomach and small intestine^{5, 6}. Colonic drug delivery may be achieved by either oral or rectal administration. Rectal dosage forms like enemas and suppositories are not always much effective due to high variability in the distribution of drug administered by this route⁷.

Delivery through oral route has always been considered the favored and the most convenient way for drug administration having the highest degree of patient compliance. In particular, high patient acceptance and a high degree of flexibility in dosage form design as well as on dosing^{8, 9}.

The conventional dosage forms are delivering inadequate amount of drug to due to the absorption or degradation in the hostile upper Gastro Intestinal tract (GIT)^10,11. Conventional orally administered controlled release products normally lack special property which would facilitate them for targeting of drug to a specific site in the GIT. Targeted drug delivery to the colon has attracted much interest recently for local treatment of a variety of colonic diseases¹².

In the case of controlled drug delivery systems to the, lot of benefits would be acquired in terms of improve in safety and reduction in toxicity when treating local or systemic chronic diseases. First, for treatment of localized colonic diseases, the optimal drug delivery system, such as Colon Targeted drug delivery system (CTDDS), should selectively deliver drug to the, but not to upper GI tract. For this reason, the drug concentration must be significantly low in the upper GI tract, while considerably higher in the, resulting in alleviated GI side effects¹³.

There is a considerable interest in the specific drug delivery in order to treat diseases of the large intestine, such as colitis, colon cancer, irritable bowel syndrome, Crohn’s and infectious diseases^{14, 15}.

Drug targeting too can be used 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 nocturnal asthma, angina or arthritis^{16, 17}.

Various systems have been developed for targeting drug delivery include coating with pH dependent systems, covalent linkage of a drug with a carrier i.e. prodrugs system, design of timed release dosage forms and the use of carriers that are degraded exclusively by colonic bacteria^18-23.

Advantages of Colon Targeted Drug Delivery System (CTDDS) over Conventional Drug Delivery

In targeting larger amount of drug can be utilized and are available at targeted site, due to this lesser amount of drug is required. Some of the drugs like dexamethasone and methyl prednisolone by oral and intravenous routes produce systemic effects as adenosuppression, immunosuppression, cushinoid symptoms, and bone resorption that can be solved by targeting thus shows effective therapy. It prevents the needless systemic absorption and increases the absorption of poorly absorbed drug, and prolong drug action thus improved bioavailability^24,25.

Why targeted to the Colon …?

Ø Delay the drug absorption.

Ø Targeted drug delivery to the colon would ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.

Ø Targeted drug delivery to the colon is considered to be beneficial in the treatment of various colonic diseases.

Ø For oral administration of peptide and protein drugs.

Ø Colon targeting formulation could also be used to prolong the drug delivery.

Ø 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 GIT.

Ø To prevent asthma, arthritis attacks in early morning²⁶.

General considerations for design of colonic formulations:

The design of the colonic formulation is to provide a burst release or to sustained/controlled release when formulation reach in the. Several important factors like pathology and pattern of the disease or physiology and physiological composition of the healthy decide the formulation approach. Other factors like drug dissolution and release rate of drug in are also considered for the formulations. The pH gradient of the GIT is most important physiological factor considered in the design of delayed release colonic formulation. Generally, due to presence of less fluid in the than small intestine, the dissolution and release rate from colonic formulations is slow and this may in turn lead to lower systemic availability of the drugs²⁷.

Criteria for selection of drug for CTDDS:

Drug Candidate:

Drugs which show poor absorption from the stomach or intestine including peptide are most suitable for CTDDS. The drugs used in the treatment of IBD, ulcerative colitis, diarrhea and cancer are ideal candidates for local delivery.

Drug Carrier:

The selection of carrier for particular drug candidate depends on the physiochemical nature of the drug as well as the disease for which the system is to be used. The selection of carrier depends on factors such as chemical nature, stability and partition coefficient of the drug and the type of absorption enhancer chosen. In addition, the choice of drug carrier depends on the functional groups of the drug molecule²⁸.

Types or modified release formulations:

These are of two types

Ø Single unit dosage form:-

Ex.- Tablets, Capsules.

Ø Multiple unit dosage form:-

Ex.- Micro granules, Micro spheroids, Beads, Pellets, Microcapsules²⁹.

Approaches used for site specific drug delivery to colon:

A. Primary Approaches for CTDDS:-

1. pH -Dependent Polymer Coating Drug Delivery to Colon.

pH- dependent coated methods are gaining importance as these systems delivers the drug at specific time as per the pathophysiological need of the diseases³⁰.

The pH-dependent systems make use of 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. These enteric polymer coatings are insensitive to the acidic conditions of the stomach but ionize and dissolve at the more neutral pH of 5–6 found in the upper small intestine. This concept has adapted for targeting^{31, 32}.

In this system, drugs are formulated into solid dosage forms such as tablet and are coated with pH sensitive polymers as in enteric coating. Widely used polymers are methacrylic resins like Eudragit which are available in water soluble and water insoluble forms. Eudragit L and Eudragit S are copolymers of methacrylic acid and methyl methacrylate. Eudragit L is water insoluble at pH 6 or above and is used as an enteric coating polymer. Eudragit S is water soluble at pH 7 or above and is used to deliver drugs to the end of the small bowel and large intestine^{33, 34}.

The polymers described as pH dependent in specific drug delivery are insoluble at low pH levels but become increasingly soluble as pH rises. Although a pH dependent polymer can protect a formulation in the stomach, and proximal small intestine, it may start to dissolve in the lower small intestine, and the site-specificity of formulations can be poor. The decline in pH from the end of the small intestine to the can also result in problems, lengthy lag times at the ileo-cecal junction or rapid transit through the ascending which can also result in poor site-specificity of enteric-coated single-unit formulations^{35, 36}.The various polymers which are used as a pH-dependent are shown in Table no. I.

Table I: Polymers used as pH-dependent are follows.

Polymer	Threshold pH	Polymer	Threshold Ph
Eudragit L100	6.0	Cellulose acetate trimellate	4.8
Eudragit S100	7.0	Polyvinyl acetate phthalate (PVAP)	5.0
Eudragit L 30D	5.6	Cellulose acetate trimelitate (CAT)	5.5
Eudragit FS 30D	6.8	Shellac	7.0
HPMC phthalate 50	5.2	HPMC phthalate 55	5.4

2. Delayed (Time Controlled Release System) Release Drug Delivery.

The pulsatile effect i.e., the release of drug as a “pulse” after a lag time has to be designed in such a way that a complete and rapid drug should follow the lag time³⁷.

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 amount. Colon targeting could be achieved by incorporating a lag time into formulation equivalent to the mouth to colon transit time. 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 and the thickness of the outer layer determines the time required disperse in aqueous environment³⁸.

1. Microbially Triggered Drug Delivery to Colon.

Amongst all the approaches used for colon targeting, a microbially controlled delivery system is the most appealing as it relies on the unique enzymatic ability of the colonic micro flora and enables a more specific targeting, independent of pH variations along the GI tract³⁹.

These systems are based on the exploitation of the specific enzymatic activity of the microflora (Enterobacteria) present in the colon. The colonic bacteria are predominately anaerobic in nature and secrete enzymes that are capable of metabolizing substrates such as carbohydrates and proteins that escape the digestion in the upper GIT⁴⁰.

The presence of colonic micro flora has formed a basis for development of colon targeted drug delivery system. Interest has focused primarily on azo reduction and hydrolysis of glycoside bond. The colonic micro flora varies substantially between and within individuals, reflecting diet, age and disease. Such variation is to be taken into account in the developing of colon specific formulations depending on the presence of colonic micro flora. There is significant proteolytic activity in the colon, although this is 20-60 times less in the small bowel. Even when proteolytic activity is relatively low, a drug may remain much longer in the colon then in small intestine, with the result that it is exposed longer to proteolytic activity. Because of presence of biodegradable enzymes like glucironidase, xylosidase, arabinosidase, galactosidase, nitroreductase, xylosidase, azareductase, deaminase and urea dehydroxilase in the colon ,the use of biodegradable polymers for targeted drug delivery seems to be a more site specific approach. These polymers protect the drug from environments of stomach and small intestine and are able to deliver the drug to the colon. On reaching the colon, polymer may undergo degradation by enzyme or break down and releases the drug to ^{41, 42}.

2. Prodrug Approach for Drug Delivery to Colon.

Prodrugs can be defined as pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules, enzymatically or nonenzymatically, to exert a therapeutic effect. Ideally, the prodrug should be converted to the original drug as soon as the goal is achieved⁴³.

Once in the colon, the drugs are acted upon by enzymes produced by colonic resident bacteria to release the active moiety. Sulphasalazine (SAS) which is used in the treatment of ulcerative colitis, Crohn’s disease, and rheumatoid arthritis, is a well known -specific prodrug. It consists of 5-aminosalicylic acid (5-ASA) linked via an azo bond to sulphapyridine (SP). When orally administered, approximately 12% is absorbed in the small intestine, but the main part reaches the colon intact, where bacterial azoreductase cleaves the azo bond, thereby releasing 5-ASA and SP⁴⁴.

3. Polysaccharide Based Approach for Drug Delivery to Colon.

The important bacteria presents in the such as Bacteroids, Bifidobacterium, Eubacterium, Peptococcus, Lactobacillus, Clostridium secrets a wide range of reductive and hydrolytic enzymes such as β-glucoronidase, β-xylosidase, β-galactosidase, α-arabinosidase, Nitroreductase, Azoreductase, Deaminase and urea hydroxylase. These enzymes are responsible for degradation of di-, tri- and polysaccharides.

Natural polysaccharides such as pectin and xylan are not digested in the human stomach or small intestine, but are degraded in the colon by resident bacteria. Bacterial enzymes are capable of degrading a wide variety of polysaccharides present in the diet. These dietary polysaccharides thus have the potential as non-toxic carriers for colon specific drug delivery⁴⁵.

They can be easily modified chemically and biochemically and are highly stable, safe, nontoxic, hydrophilic and gel forming and in addition biodegradable. Several polysaccharides such as sodium alginate, chitosan, guar gum, xanthan gum, pectin, gellan gum have been employed either alone or in combination with their native or modified forms to control the drug release from different types of delivery system⁴⁶.The Polysaccharides polymers which are mostly used as for targeting the colon are shown in Table no. II.

Table II: List of Polysaccharides polymers.

Class	Examples	Class	Examples
Disaccharides	Lactose	Polysaccharides	Alginates
	Maltose		Amylose
	Cellobiose		Galactomnam (guar gum, locust bean gum)
Oligosaccharides	Cyclo dextrins		Arabinoxylan
	Lectulose		Inulin
	Raffinose		Chitosan
	Stachyose		Pectins and pectates

B. Newly developed approaches for CTDDS:

1. Pressure Controlled Drug Delivery System.

GI pressure has also been utilized to trigger drug release in the distal gut. This pressure, which is generated via muscular contractions of the gut wall for grinding and propulsion of intestinal contents, varies in intensity and duration throughout the GIT, with the colon considered to have a higher lumenal pressure due to the processes that occur during stool formation⁴⁷.

In the large intestine, the contents are moved from one part to the next, as from the ascending to the transverse colon by forcible peristaltic movements commonly termed as mass peristalsis. These strong peristaltic waves in the colon are of short duration, occurring only three to four times a day. However, they temporarily increase the luminal pressure within the colon, which forms the basis for design of pressure-controlled systems⁴⁸.

As a result of peristalsis, higher pressures are encountered in the colon than in the small intestine. Takaya et al. have developed pressure controlled colon-delivery capsules prepared by using ethyl cellulose, which is insoluble in water. In such systems drug release occurs following disintegration of a water-insoluble polymer capsule as a result of pressure in the lumen of the colon. The thickness of the ethyl cellulose membrane is the most important factor for disintegration of the formulation. The system also appeared to depend on capsule size and density. Because of re absorption of water from the colon, the viscosity of luminal content is higher in the colon than in the small intestine. It has therefore been concluded that drug dissolution in the colon could present a problem in relation to colon targeting oral drug delivery systems. In pressure-controlled ethyl cellulose single-unit capsules the drug is in a liquid. Lag times of three to five hours in relation to drug absorption were noted when pressure-controlled capsules were administered to human⁴⁹.

2. CODESTM (A Novel Colon Targeted Delivery System).

CODESTM is a unique CTDDS technology that was designed to avoid the inherent problems associated with pH or time dependent systems. It is a combined approach of pH dependent and microbially triggered CTDDS. It has been developed by utilizing a unique mechanism involving lactulose, which acts as a trigger for site-targeting drug release. The system consists of traditional tablet core containing lactulose⁵⁰.

It was developed by utilizing a unique mechanism involving lactulose as a core tablet, acting as a trigger for site specific drug release in the colon. The system consists of a traditional tablet core containing lactulose, which is coated with acid soluble material Eudragit E, and then subsequently over coated with an enteric material, Eudragit L. The final conclusion of this technology is that the enteric coating protects the tablet while it is located in the stomach and then dissolves quickly following gastric emptying. The acid soluble material coating then protects the preparation as it passes through the alkaline pH of the small intestine. Once the tablet arrives in the colon, the bacteria will enzymatically degrade the polysaccharide (lactulose) into organic acid. This lowers the pH surrounding the system sufficient to affect the dissolution of the acid soluble coating and thus cause subsequent drug release⁵¹.

3. Osmotic controlled drug delivery (OROS – CT).

The OROS-CT system can be single osmotic unit or may incorporate as many as 5-6 push-pull units, each 4mm in diameter, encapsulated within a hard gelatin capsule. Each push-pull unit is bilayered laminated structure containing an osmotic push layer and a drug layer, both surrounded by a semipermeable membrane⁵².

The osmotic device for colon targeting is a tablet formulation in which water penetrates through the pores of a semipermeable outer film, created by a pore-forming agent, and slowly dissolves the delaying agents in the drug compartment (high molecular weight PEG and low-viscosity HPMC).As soon as the viscosity of the drug compartment is low enough, it can be pushed out through the pores by the pressure of the osmotic compartment, which consists of an osmopolymer and an osmotic agent.

Figure I: Cross section of the OROS-CT.

Upon arrival on the small intestine the coating dissolves at pH≤7. As a result water enters the unit causing the osmotic push compartment to swell forcing the drug out of the orifice into colon. For treating ulcerative colitis, each push pull unit is designed with a 3-4hrs. 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 hrs in the colon. The cross section of the OROS-CT are shown in Figure no. I.

Pulsincap System.

Pulsincap was developed by R. R. Scherer International Corporation, Michigan, US, and is one such system that comprises of a water-insoluble capsule enclosing the drug reservoir. Figure no. II shows the Pulsincap® system. A swellable hydrogel plug was used to seal the drug contents into the capsule body. When this capsule came in contact with the dissolution fluid, it swelled; and after a lag time, the plug pushed itself outside the capsule and rapidly released the drug. Polymers used for designing of the hydrogel plug were various viscosity grades of hydroxyl propyl methyl cellulose, polymethyl methacrylates, poly vinyl acetate and poly ethylene oxide. The length of the plug and its point of insertion into the capsule controlled the lag time. Pulsincap was studied in human volunteers and was reported to be well tolerated. As the swelling hydrogel polymer plug replaced the erodible tablet, the dependence of the dimensional accuracy between the plug and the capsule for the pulling mechanism of the plug from the capsule was also overcome. Ross.et.al. used low substituted hydroxyl propyl cellulose for the expulsion system for the release of propanolol over a time period of 2-10 hrs. This could be controlled using compressed erodible tablets made of lactose and HPMC.

Figure II: - Design of Pulsincap® system

4. PORT System.

The Port system was developed by Therapeutic System Research Laboratory Arm Arbor, Michigan, USA, and consists of a capsule coated with a semipermeable membrane. Inside the capsule was an insoluble plug consisting of osmotically active agent and the drug formulation. System shows good in-vivo and in-vitro correlation in humans and used to deliver methylphenidate to school age children for the treatment of attention deficit hyper activity disorder (ADHD).

5. Time Clock System.

The Time clock system is a delivery device based on solid dosage form that is coated by an aqueous dispersion. This coating is a hydrophobic surfactant layer to which a water soluble polymer is added to improve adhesion to the core. Once in contact with dissolution fluid, the dispersion rehydrates and redisperses. The lag time could be controlled by varying the thickness of the film. After the lag time, i.e.; the time required for rehydration, the core immediately releases the drug. This system has shown reproducible results in-vitro and in-vivo. The effect of low calorie and high calorie meal on the lag time was studied using gamma scintigraphy. The mean lag time of drug release was 333 and 345 min respectively. Figure III shows the Design of Time clock system.

Figure III: Design of Time clock system

4. Chronotropic System.

These systems are based upon a drug reservoir surrounded with a soluble barrier layer that dissolves with time and the drug releases at once after this lag time. Chronotropic system consists of a core containing reservoir coated by a hydrophilic polymer HPMC .An additional enteric-coated film is given outside this layer to overcome intra subject variability in gastric emptying rates. The lag time and the onset of action are controlled by the thickness and the viscosity grade of HPMC. Figure IV shows the Design of Chronotropic system for colonic delivery of drug.

Figure IV: Design of Chronotropic system.

6. COLAL – PRED System.

COLAL-PRED is a proprietary gastrointestinal product developed by Alizyme for the treatment of ulcerative colitis (US). It has arisen from combining Alizyme’s properitary colonic drug delivery system, COLAL, with an approved generic steroid (Prednisolone sodium metasulfobenzoate). It is an effective anti inflammatory treatment for UC without the typical side effects of steroids. There are currently no competitor products, either on the market or in development, with the same profile of product. A ‘Safe steroid’ product with the profile of COLAL-PRED would represent a significant advance in the management of UC. COLAL-PRED has a coating that is broken down only in the colon, by locally occurring bacteria. This leads to topical delivery of prednisolone to the colon without significant systemic exposure so minimizing steroid related side effects⁵³.

7. Enterion Capsule Technology:-

The Enterion capsule has recently been developed by Phacton Research, Nottingham, UK, for targeted delivery of a wide range of different drug formulations into any region of the gut. It is a 32-mm long, round-ended capsule and contains a drug reservoir with a volume capacity of approximately 1 ml. The capsule can be loaded with either a liquid formulation (e.g. Solution, Suspension) or a particulate formulation (e.g., powder, pellets, in sit affects etc.) through an opening 9 mm in diameter, which is then sealed by inserting a push-on Cap fitted with a silicone O-ring. The floor of the drug reservoir is the piston face, which is held back against a compressed spring by a high tensile strength polymer filament⁵⁴.

8. Ticking Capsule:-

It is a chronotherapeutic devices employ some electrical means of controlling pulsatile drug release coupled with electronic timing. Ticking capsules is divided into three compartments; Porous Si-based drug delivery module; Electronic control module (e.g. mucontroller) and Battery. Many human illnesses and their Symptoms show a regular (rhythmic) pattern: Hypertension (early morning); arthritics pain (mid afternoon); heart attack (early morning + late afternoon and asthma attack (night). It is recognizing intake into the body is limed to match the severity of the Symptom⁵⁴.

9. Target Technology.

Target Technology (West Pharmaceutical services) is designed for site-targeting delivery of drugs in the GIT and, in particular, targeted release into the colonic region. A key area of application is the delivery of therapeutic agents for local treatment of lower GI diseases. The technology is based on the application of pH- Sensitive coatings onto injection-moulded starch capsules. An extensive body of clinical data has been generated showing reliable in vivo performance of the capsules. In γ-Scintigraphy studies, around 90% of target Capsules (n=84) delivered their contents to the target site of the terminal ileum and colon. Target based products are in active clinical development for the treatment of conditions including inflammatory bowel diseases^{54, 55}.

CONCLUSION:

The colonic region of the GIT has become an increasingly important site for drug delivery and absorption. CTDDS offers considerable therapeutic benefits to patients in terms of both local and systemic treatment. Different approaches are designed to develop colonic drug delivery system. For colon targeted drug delivery several Primary approaches like pH dependent systems, Prodrugs, time dependent systems and microbially degraded polymers and Novel approaches are used to targeting the colon. Novel approaches developed for CTDDS are more specific as compared to Primary approaches. There is a constant need for new delivery systems that can provide increased therapeutic benefits to the patients. Colon targeted drug delivery systems are one such system that, by delivering drug at the right time, right place and in right amounts, holds good promises of benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension, etc. Colon specificity is more likely to be achieved with systems that utilize natural materials that are degraded by colonic bacterial enzymes.

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Received on 03.07.2012 Modified on 14.07.2012

Research J. Pharm. and Tech. 5(9): September 2012; Page 1154-1160