INTRODUCTION:

The oral route of drug administration is the most convenient and important method of administering drugs for systemic effect and nearly 50% of the drug delivery systems available in the market are oral drug delivery system. Oral dosage forms also allow for a greater degree of flexibility in their manufacturing, design, improved patient adherence, relatively safe administration, and they do not require sterile preparation. During the last decade there has been interest in developing site-specific formulations for targeting drug to the colon.

Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon like crohn’s disease, ulcerative colitis, irritable bowel syndrome and constipation and also for the systemic delivery of proteins, therapeutic peptides, antiasthmatic drugs, antihypertensive drugs and antidiabetic agents.

Drug targeting is a useful tool for achieving selective and efficient delivery of active moiety at the anticipated site of action with minimized unwanted side effects. Colon-specific drug delivery system (CDDS) has been attaining tremendous curiosity among scientific community.

The delivery of these drugs specifically to the colon without being absorbed first in the upper gastrointestinal (GI) tract allows for a higher concentration of the drug to reach the colon with minimal systemic absorption. The colonic contents have a longer retention time (up to 5 days), and the colonic mucosa is known to facilitate the absorption of several drugs, making this organ an ideal site for drug delivery.

The success of (CDDS) depends on the drug’s physico-chemical properties, the type of delivery system, all other factors which may influence the GI transit time, as well as the degree of interaction between the drug and the GI tract. It is essential for oral CDDS to protect the drug from being released in the stomach and small intestine. Thus, the approaches used in developing a CDDS are aimed at delaying the drug release until the system reaches the colon, with some strategies demonstrating better success than others.

THE NEED FOR COLON TARGETTED DRUG: DELIVERY SYSTEM:

1. The direct treatment at the disease site means lower dosing and fewer side effects.

2. 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.

3. Colon-specific drug delivery system is considered to be beneficial in the treatment of colon diseases e.g. colorectal cancer, might also be capable of being treated more effectively if drugs were targeted to the colon.

4. Site-specific or targeted drug delivery system would allow oral administration of peptide and protein drugs, colon-specific formulation could also be used to prolong the drug delivery.

5. Formulations for colonic delivery are also suitable for delivery of drugs which polar and/or susceptible to chemical and enzymatic degradation in the upper GI tract, highly affected by hepatic metabolism, in particular, therapeutic proteins and peptides.

6. 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 GI tract, highly affected by hepatic metabolism, in particular, therapeutic proteins and peptides.

FACTORS TO BE CONSIDERED IN THE DESIGN OF COLON-SPECIFIC DRUG DELIVERY SYSTEM:

To develop and design of Colon Specific Drug Delivery System, it is important to analyse the various influencing factors so that a proper design of the system can be obtained. Some of the factors are as under:

a. Anatomy and Physiology of Colon:

The large intestine extends from the distal end of the ileum to the anus. Human large intestine is about 1.5m long. The colon is upper five feet of the large intestine and mainly situated in the abdomen. The cecum forms the first part of the colon and leads to the right colon or the ascending colon (just under the liver) followed by the transverse colon, the descending colon, sigmoid colon, rectum and the anal canal (Figure 1). The physiology of the proximal and distal colon differs in several respects that have an effect on drug absorption at each site. The physical properties of the luminal content of the colon also change, from liquid in the cecum to semisolid in the distal colon. The colon is cylindrical tube which is lined by moist, soft pink lining called mucosa and it is 2 – 3 inches in diameter. The colon and rectum have an anatomic blood supply. Lymph nodes are also present with blood vessels. Activity in the colon can be divided into segmenting and propulsive movements. Segmenting movements, caused by circular muscle and causing the appearance of the sac-like haustra, predominate and result in mixing of the luminal contents. Significant propulsive activity, associated with defecation and effected by longitudinal muscle is less common and occurs at an average of three or four times daily.

Figure 1: The Colon anatomy

b. pH in the Colon:

The pH of the gastrointestinal tract is subject to both inter and intra subject variations. Diet, diseased state and food intake influence the pH of the gastrointestinal fluid. The change in pH along the gastrointestinal tract has been used as a means for targeted colon drug delivery. There is a pH gradient in the gastrointestinal tract with value ranging from 1.2 in the stomach through 6.6 in the proximal small intestine to a peak of about 7.5 in the distal small intestine (Table 1). The pH difference between the stomach and small intestine has historically been exploited to deliver the drug to the small intestine by way of pH sensitive enteric coatings. There is a fall in pH on the entry into the colon due to the presence of short chain fatty acids arising from bacterial fermentation of polysaccharides.

Table 1: The Summary of anatomical, physiological and pH therein are as under:

Region of Gastrointestinal Tract		Length (cm)	pH	Internal diameter (cm)
Stomach		------	1.5-3 (fasted) 2-5 (fed)	-----
Small intestine	Duodenum	20-30	6.1(fasted) 5.4(fed)	3-4
	Jejunum	150-200	5.4
	Ileum	200-350	7-8
Large intestine	Cecum	6-7	5.5–7 7-8	6
	Ascending colon	20
	Transverse colon	45
	Descending colon	30
	Sigmoid colon	40
	Rectum	12
	Anal canal	3

c. Colonic micro flora and their enzymes:

The slow movement of material through the colon allows a large microbial population to grow there. Over 400 distinct bacterial species have been found 20-30% of which are of the genus Bacteroides. Most of these isolated bacteria are anaerobic in nature. The upper region of the GIT has very small number of bacteria and predominantly consists of Gram-positive facultative bacteria. The concentration of bacteria in the human colon is 1011- 1012 CFU/ml. The most important anaerobic bacteria are Bacteroides, Bifidobacterium, Eubacterium, Peptostreptococcus, peptococcus, Ruminococcus and clostridiums]. The rate of microbial growth is greatest in the proximal areas because of high concentration of energy source. The principal source of nutrition for the colonic microorganisms is carbohydrates arriving in intestinal chime. The carbohydrates are degraded by the action of polysaccharidase and glycosidase enzymes and the ultimate products of fermentation are short chain fatty acids, carbohydrate fermentation predominates and results in a relatively low pH. In the distal regions, there is little carbohydrate fermentation, resulting in a higher pH.

Intestinal enzymes are used to trigger drug release in various parts of the GIT. Usually, these enzymes are derived from gut micro flora residing in high number in the colon. These enzymes are used to degrade coatings/matrices as well as to break bonds between an inert carrier and an active agent (i.e., release of a drug from a prodrug.

Table 2: Summary of the most important metabolic reaction carried out by intestinal bacteria are given in Table below:

Enzymes	Microorganism	Metabolic reaction catalyzed
Nitroreductase	E. coli, Bacteroides	Reduce aromatic and heterocyclic nitro compounds
Azoreductase	Clostridia, Lactobacilli, E. coli	Reductive cleavage of azo compounds
Esterase and amidases	E. coli, P. vulgaris, B. subtilis, B. mycoides	Cleavage of esters or amidases of carboxylic acids
Glycosidase	Clostridia, Eubacterium	Cleavage of β-glycosidase of alcohols and phenols
Glucuronidase	E. coli, A. aerogenes	Cleavage of β-glucuronidases of alcohols and phenols

METHODS USEDFOR DRUG TARGETTINGTO THE COLON:

1. Prodrug approaches:

Prodrug is a pharmacologically inactive derivative of a parent molecule that requires enzymatic transformation in the biological environment to release the active drug at the target site. This approach involves covalent linkage between the drug and its carrier which upon oral administration reaches colon without being absorbed from upper part of GIT in such a manner that the moiety remains intact in the stomach and small intestine, and after reached in the colon, enzymatic cleavage regenerate the drug. In the colon drug release is triggered by high activity of certain enzymes in comparison to stomach and small intestine.

a. Azo bond conjugate:

These azo compounds are extensively metabolized by the intestinal bacteria, both by intracellular enzymatic component and extracellular reduction. The use of these azo compounds for colon-targeting has been in the form of hydrogels as a coating material for coating the drug cores and as prodrug. In the latter approach the drug is attached via an azo bond to a carrier. This azo bond is stable in the upper GIT and is cleaved in the colon by the azo-reductases produced by the microflora. Sulphasalazine, used for the treatment of IBD has an azo bond between 5-ASA and sulphapyridine (SP). In the colon, the azoreductases cleave the azo bond releasing the drug, 5-ASA and the carrier SP (Figure -2).

Figure 2: Hydrolysis of Sulphasalazine (i) into 5-aminosalicylic acid (ii) and sulfapyridine (iii)

b. Glycoside conjugation:

Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new colon targeted drug delivery system. Certain drugs can be conjugated to different sugar moieties to form glycosides. The drug part forms the aglycone and is linked to the sugar part, which forms the glycone part of the glycoside. Because they are bulky and hydrophilic, these glycosides do not penetrate the biological membranes upon ingestion. They breakdown upon action of glycosidase, releasing the drug part from the sugar. The presence of glycosidase activity in the small intestine could pose a problem in delivery of these conjugates to the large bowel, because some hydrolysis of the conjugate can be expected in the small intestine. However, the small intestinal transit time, and considering the time required for the hydrolysis of glycosidic bond, these conjugates can be expected to be good colon specific drug carriers. The major glycosidase enzymes produced by the intestinal microflora are β -D-galactosidase, α -L-arabinofuranosidase, β -D-xylopyranosidase, and β –Dglucosidase. These glycosidase enzymes are located at the brush border and hence are accessible to substrate easily.

c. Glucoronide conjugates:

Bacteria of the lower GIT secrete b-glucuronidase and can deglucuronidate a variety of drugs in the intestine. Thus, the deglucuronidation process results in the release of the active drug again and enables its reabsorption. Example: Opiates, when taken for the relief of pain, cause severe constipation by inhibiting GIT motility and secretions. Narcotic antagonists, when given as antidotes for GIT side effects, immediately relieve constipation but precipitate acute withdrawal. This is because these narcotic antagonists are not selective and they not only affect the GIT activity, but also the central nervous system (CNS). A novel approach would be to target these antagonists to the lower bowel so that they are not absorbed systemically. With this purpose, naloxone and nalmefene glucuronide prodrugs were prepared to target these drugs to the colon. When given orally to morphine dependent rats these prodrugs showed increased GIT motility and secretion in the large bowel results in a diarrhea and the resultant diarrhea flushed out the drug/prodrug from the colon thereby preventing the systemic absorption of the antagonist, which in-turn caused absence of withdrawal symptoms. Budesonide-b-glucuronide prodrug also found to be superior to budesonide itself for the treatment of colitis in the rat.

d. Cyclodextrin conjugate:

Cyclodextrins are cyclic oligosaccharides consisted of six to eight glucose units through -1,4 glucosidic bonds and have been utilized to improve certain properties of drugs such as solubility, stability and bioavailability. They are known to be barely capable of being hydrolyzed and only slightly absorbed in passage through the stomach and small intestine however, Colonic bacteria are capable of degrading cyclodextrins for carbon source by stimulating cyclodextranase activity. They are fermented by the colonic microflora to form small saccharides that are then absorbed. This susceptibility to degradation specifically by colonic micro flora together with their property to form inclusion complexes with various drugs makes them particularly useful in carrying drug moieties to the colon. The a- and b-cyclodextrins are practically resistant to gastric acid, salivary, and pancreatic amylases. A clinical study has shown clear evidence that b-cyclodextrin is poorly digested in the small intestine but is almost completely degraded by the colonic microflora.

e. Dextran conjugate:

Dextrans are polysaccharides of bacterial origin where the monosaccharides are joined to each other by glycoside linkages. The enzyme responsible for the hydrolysis of these linkages is dextranase. The dextranase activity is almost absent in the upper GIT, whereas high dextranase activity is shown by anaerobic gram-negative bacteria, especially the Bacteroides, which are present in a concentration as high as 1011 per gram in colon. This led to the use of dextran as carriers for drug molecules to the colon. In the colon, dextran’s glycosidic bonds are hydrolyzed by dextranases to give shorter prodrug oligomers, which are further split by the colonic esterases to release the drug free in the lumen of the colon. Dextran prodrug approach can be used for colon-specific delivery of drugs containing a carboxylic acid function (−COOH). NASIDS ware directly coupled to dextran by using carboxylic groups of drugs. Example is Naproxen-dextran conjugate. Glucocorticoids do not possess −COOH group so these are linked to dextran using spacer molecule. e.g. glucocorticoid-dextran conjugates.

f. Amino acid conjugation:

Due to the hydrophilic nature of polar groups like -NH2 and -COOH, that is present in the proteins and their basic units (i.e. the amino acids), they reduce the membrane permeability of amino acids and proteins. Increase in hydrophilicity and chain length of carrier amino acid; decrease the permeability of amino acids and proteins. So the amino acid conjugate show more enzymatic specificity for hydrolysis by colonic enzyme.

g. Polymeric prodrugs:

Newer approaches are aimed at use of polymers as drug carriers for drug delivery to the colon. Both synthetic as well as naturally occurring polymers are used for this purpose. Sub synthetic polymers have used to form polymeric prodrug with azo linkage between the polymer and drug moiety.

2. pH dependent approach:

This approach utilizes the existence of pH gradient in the git that increases progressively from the stomach (pH 1.5-3.5) and small intestine (5.5-6.8) to the colon (6.4-7.0). By combining the knowledge of the polymers and their solubility at different pH environments, delivery systems can be designed to deliver drugs at the target site. The most commonly used pH dependent polymers are derivatives of acrylic acid and cellulose.

a. Coating of the drug core with pH sensitive 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. The drug core includes tablets, capsules, pellets, granules, microparticles or nanoparticles. 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. 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. The problem with this approach is that the intestinal pH may not be stable because it is affected by diet, disease and presence of fatty acids, carbon dioxide, and other fermentation products. Moreover, there is considerable difference in inter- and intraindividual gastrointestinal tract pH, and this causes a major problem in reproducible drug delivery to the large intestine. Eudragit-L dissolves at a pH level above 5.6 and is used for enteric coating, whereas Eudragit S is used for the colon delivery it dissolves at pH greater than 7.0 (attributable to the presence of higher amounts of esterified groups in relation to carboxylic groups), which results in premature drug release from the system. Problem of premature drug release can be overcome by the use of Eudragit FS.

Table 3: The Threshold for various depending Polymers

Polymer	Threshold pH
Eudragit L 100	6.0
Eudragit S 100	7.0
Eudragit® L-30D	5.6
Eudragit® FS 30D	6.8
Hydroxy propyl methyl cellulose phthalate 50	5.2
Hydroxy propyl methyl cellulose phthalate 55	5.4
Cellulose acetate trimellate	4.8

Compression-coating (tablet-in-a-tablet), also known as Bdry coating is a tablet coating technique where the core tablet (containing the drug) is coated with a coating excipient (powder) on a tablet press. This technique has gained interest in the formulation development in recent years due to the dry nature of dosage form development, i.e., avoiding the process complexities and stability challenges associated with spray coatings (wet, hot). Several researchers have explored this technique for the development of colon-specificoral solid dosage formulations. The in-vitro evaluation of the formulation showed that increasing the thickness of the coating resulted in a progressive decrease in the drug release at acidic pH. Additionally, the in-vivo studies showed that this formulation did not break down until it reached the large bowel. Recently, Kadiyam et al. developed an almond-gum, matrix-based colonic drug delivery system of tramadol HCl, compression-coated with Eudragit S100. The study results showed that compression-coated tablets successfully delayed the release of tramadol HCl over 24 h. The in-vivo X-ray imaging studies in rats revealed that the compression coated tablets efficiently delivered the drug to the colon without being disintegrated in the upper GIT.

b. Embedding in pH-sensitive matrices:

The drug molecules are embedded in the polymer matrix. Extrusion spheronization technique can be used to prepare uniform-size sturdy pellets for colon targeted drug delivery when it is not possible to obtain mechanically strong granules by other methods. Excipients had a significant impact on the physical characteristics of the pellets. Eudragit S100 as a pH sensitive matrix base in the pellets increased the pellet size and influenced pellet roundness. Citric acid promoted the pelletization process resulting in a narrower area distribution.

3. HYDROGELS:

Hydrogels also can be used for site specific delivery of peptide and protein drugs through colon. The release of water-soluble drugs, entrapped in a hydrogels, occur only after water penetrates the polymeric networks to swell and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. The Hydrogels are composing of acidic commoners and enzymatically degradable azo aromatic cross-links. In the acidic pH, gels shows less swelling that protect the drug against degradation in stomach. As the pH of environment increases i.e. become basic, swelling increases. This result is easy access of enzymes like azoreductase, which ultimately release of drug. The release rate of drugs from hydrogels was primarily determined by the swelling extent which further enhanced by addition of enzyme in the buffer solutions whereas swelling of polymeric networks was depended on composition of copolymer and pH of the surrounding medium. The controlled release of active anti-microbial agents- amoxicillin, metronidazole, oxytetracycline and tetracycline-HCl from the polymeric matrix have been well reported. Diffusion mechanism of the drugs from the polymeric matrix can be calculated from the equation;

Where, Mt/M∞ is the fractional release of drug in time t, ‘k’ is the constant characteristic of the drug polymer system, and ‘n’ is the diffusion exponent ‘D’ is the diffusion coefficient and ‘λ’ is the thickness of the sample.

In the present study the effect of pH on the release pattern of tetracycline have been studied by varying the pH of the release medium. The amount of drug release in pH7.4 buffer was higher than the release medium of pH2.2 buffer and distilled water. The swelling of hydrogels [psy-clpoly (AAm)], increased when the pH of the medium changed from acidic to basic. At lower pH values the -CONH2 groups does not ionized and keep the polymeric networks at its collapsed state. At high pH values, it is partially ionize d, and the charged – COO groups repel each other, leading to the higher swelling of the polymer and resultant to more drug release. The release of drug was observed to be faster in pH 7.4. From the percent cumulative release studies of tetracycline it was observed that first 50% of the total release occurred in 90min., 120min. and 135min. in releasing medium of Ph 7.4 buffer, pH 2.2 buffer and distilled water respectively. The diffusion exponent ‘n’ have 0.74, 0.60 and 0.56 values and gel characteristic constant ‘k’ have 1.272×10-2, 2.754×10-2 and 3.639×10-2 values in distilled water, pH 2.2 buffer and pH 7.4 buffer respectively for the tetracycline release from the hydrogels and these values were obtained from the slope and intercept of the plot between ln Mt/M∞ versus ln t. It means Non-Fickian or Anomalous diffusion occurs for the tetracycline release from the hydrogels It is also observed that in each release medium the Initial diffusion coefficient was observed to more than late time diffusion coefficient.

I. TIME RELEASED SYSTEMS:

It is based on the concept of preventing the release of drug 3–5 hrs after entering into small intestine. In this approach, drug release from the system after a predetermined lag time according to transit time from mouth to colon. The lag time depends upon the gastric motility and size of the dosage form. One of the earliest approaches is the Pulsincap device.

a. Pulsincap:

(Figure 3): The first formulation introduced based on this principle was Pulsincap developed by R. R. Scherer International Corporation, Michigan, US. 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. The whole unit is coated with an enteric polymer to avoid the problem of variable gastric emptying. When the capsule enters the small intestine the enteric coating dissolves and the hydrogel plug starts to swell. The length of the plug and its point of insertion into the capsule controlled the lag time. For water-insoluble drugs, a rapid release can be ensured by inclusion of effervescent agents or disintegrants. The plug material consists of insoluble but permeable and swellable polymers (eg, polymethacrylates), erodible compressed polymers (eg, hydroxy propyl methyl cellulose, polyvinyl alcohol, polyethylene oxide), congealed melted polymers (eg, saturated polyglycolated glycerides, glyceryl monooleate), and enzymatically controlled erodible polymer (eg, pectin).

Figure -3 Design of Pulsincap System

b. Colon-Targeted Delivery Capsule based on pH sensitivity and time-release principles:

The system contains an organic acid that is filled in a hard gelatin capsule as a pH-adjusting agent together with the drug substance. This capsule is then coated with a three-layered film consisting of an acid-soluble layer, a hydrophilic layer, and an enteric layer. After ingestion of the capsule, these layers prevent drug release until the environmental pH inside the capsule decreases by dissolution of the organic acid, upon which the enclosed drug is quickly released. Therefore, the onset time of drug release is controlled by the thickness of the acid-soluble layer.

c. Chronotropic system:

The Chronotropic system consists of a drug-containing core coated by hydrophilic swellable hydroxy propyl methyl cellulose (HPMC), which is responsible for a lag phase in the onset of release. In addition, through the application of an outer gastric-resistant enteric film, the variability in gastric emptying time can be overcome, and a colon-specific release can be obtained, relying on the relative reproducibility of small intestinal transit time. The lag time is controlled by the thickness and the viscosity grades of HPMC. The system is suitable for both tablets and capsules.

d. PORT system:

The Port system was developed by Therapeutic System Research Laboratory Arm Arbor, Michigan, USA, and consists of a gelatin capsule coated with a semipermeable membrane. Inside the capsule an insoluble plug (lipidic) consisting of osmotically active agent and the drug formulation. When in contact with the aqueous medium, water diffuses across the semi permeable membrane, resulting in increased inner pressure that ejects the plug after a lag time. The lag time is controlled by coating thickness. The system showed good correlation in lag times of in-vitro and in-vivo experiments in humans. The system proposed to deliver methylphenidate for the treatment of attention deficit hyperactivity disorder (ADHD) in school-age children.

II. BIOADHESIVE SYSTEMS:

Oral administration of some drugs requires high local concentration in the large intestine for optimum therapeutic effects. Bioadhesion is a process by which a dosage form remains in contact with particular organ for an augmented period of time. This longer residence time of drug would have high local concentration or improved absorption characteristics in case of poorly absorbable drugs. This strategy can be applied for the formulation of colonic drug delivery systems. Various polymers including polycarbophils, polyurethanes and polyethylene oxide-polypropylene oxide copolymers have been investigated as materials for Bioadhesive systems. Bioadhesion has been proposed as a means of improving the performance and extending the mean residence time of colonic drug delivery systems. These BAMs were found to have higher retention time in the colon, and helped increase absorption of the drug in the colon. The in vitro drug release studies showed that only 10–12.5% of the metronidazole was released on conditions representing the stomach and less than 25% was released in a simulated small intestine. However, over 90% of the drug was rapidly released in cecal content. Additional in vivo studies showed that the drug was only released when the BAM reached the colon and was equally pharmacologically effective compared to marketed formulations.

III.OSMOTICE PRESSURE CONTROLLED SYSTEMS:

The unit reaches intact to the colon where drug release takes place due to osmotic pressure generated by the entry of the solvent. It is also known as OROS. There are two OROS systems for colon drug delivery:

a. Osmet pump.:

It consists of an enteric coated semi-permeable shell which encloses an osmotic layer along with a central impermeable and collapsible reservoir filled with drug. The interior of this compartment is connected with the external environment through a delivery orifice at one end. After dissolution of the gastric-resistant film, water is allowed to penetrate through the semi-permeable membrane, thus raising the pressure inside the device. Which cause inner reservoir to shrinks and drug formulation to pump out.

b. Oros CT.:

Immediately after ingestion, the hard gelatin capsule shell dissolves. The push and pull unit is prevented from absorbing water in the acidic medium of stomach by enteric coating. The osmotic pumping action results when the coating dissolves in the drug is delivered out of the orifice at a rate controlled by the rate of water transport across the membrane. (Figure -4)

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

IV. PRESSURE CONTROLLED SYSTEMS:

The digestive processes within the GI tract involve contractile activity of the stomach and peristaltic movements for propulsion of intestinal contents. 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 systems. The luminal pressure resulting from peristaltic motion is higher in the colon compared to pressure in the small intestine, which is attributed to the difference in the viscosity of luminal contents. In the stomach and small intestine, contents are fluidic because of abundant water in digestive juices, but in the colon, the viscosity of the content is significantly increased due to reabsorption of water from the lumen and formation of feces. Takaya et al. (1995) have developed pressure controlled colon delivery capsules prepared using an ethyl cellulose, which is insoluble in water. In such systems drug release occurs following disintegration of 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 preferred thickness of the capsule wall is about 35-60 μm. The system also appeared to depend on capsule size and density. 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 human.

V. MULTIPARTICULATE SYSTEMS:

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

Multiparticulate systems have a smaller particle size compared to single-unit systems, and studies have shown that they can reach the colon more quickly since they pass through the GI tract more easily and were retained in the ascending colon for a relatively long period of time and hence increased bioavailability. Microspheres are one example of a multiparticulate system that can be loaded with a drug for colonic delivery. Microspheres that are prepared using biodegradable components can be taken up by macrophages. Moreover, Multiparticulate systems tend to be more uniformly dispersed in the GI tract and also ensure more uniform drug absorption

A multiparticulate dosage was prepared to deliver active molecules to colonic region, which combines pH dependent and controlled drug release properties. This system was constituted by 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 that CAB microspheres efficiently. controlled the release of budesonide, which is depended on the polymer concentration in the preparation.

The researchers explored the combined properties of CA-CMC, Colon-Targeted Oral Drug Delivery Systems i.e., pH sensitivity, degradation by colonic microflora, and preferential colonic mucoadhesivity in designing colon specific delivery of 5-flurouracil, an anticancer drug. The in vitro drug release results showed that the CA-CMC beads were able to significantly extend the release of the drug beyond 24 h. Additionally, the CA-CMC beads were demonstrated to have a significantly high mucoadhesiveness at colonic pH and degrade in the presence of colonic microflora.

DESIGNS OF MULTIPARTICULATE DRUG:

The purpose of designing multiparticulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulations and yet devoid of the danger of alteration in drug release profile and formulation behavior due to unit to unit variation, change in gastro luminal pH and enzyme population.

a. pH and time dependent systems:

One of the simplest approaches for designing pH dependent multiparticulate colon specific delivery system is to formulate enteric coated granules (Figure 10). Most commonly used pH-dependent coating polymers for oral delivery are methacrylic acid copolymers, Eudragit L100 and Eudragit S100, which dissolve at pH 6.0 and 7.0 respectively. The combination of these two polymers in various ratios makes it possible to manipulate drug release within 6.0-7.0 pH range. Incorporation of organic acid in both the enteric coated granules as well as the tablet matrix retarded the in vitro release and in vivo absorption of the drug because of the prolongation in disintegration time of the core system due to the presence of the acid. In another approach, 5-fluorouracil granular matrices were designed for release of the drug in the descending colon in a controlled fashion for the treatment of colorectal carcinoma. The Glyceryl plmitostearate matrices (retardant material) coated by Eudragit S100 and were then covered by a layer of chitosan HCl and loaded inside HPMC capsules coated with 30 D. Upon hydration, the capsule shell dissolves and the chitosan layer forms a gel (internal pH of 4.5), which generates an acidic environment around the Eudragit film so that it does not dissolve in the ascending colon. In the ascending colon, the chitosan HCl gel is degraded by the colonic micro flora, thereby exposing the Eudragit film to the colonic environment. But since the ascending colon is weakly acidic where pH is less than 7.0, the film coat still remains intact. However, on arrival in the descending colon where pH is greater than 7, the Eudragit film coat dissolves and the drug is released in a controlled fashion from the matrices. It is accepted that a colonic delivery system which is based only on GI transit time or pH of the GI tract would not be reliable because of the inherent variability of pH and emptying times from the GI tract.

Figure 5: Structure of multiple unit colons

b. Microspheres:

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

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 and by cross-linking with calcium chloride. The core microspheres were coated with Eudragit S-100 by the 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 colon region.

Advantages of Microspheres:

1. Provide selective passive targeting to tum our tissues.

2. Flexibility to couple with site-specific ligands to achieve active targeting

3. Increased stability via encapsulation

4. Reduction in toxicity of the encapsulated agent

5. Improved pharmacokinetic effects.

c. Nanoparticulate systems:

Nanoparticle size colloidal carriers composed of natural or synthetic polymers have also been investigated for colon targeting. Orally administered nanoparticles serve as carriers for different types of drugs and have been shown to enhance their solubility, permeability and bioavailability. Nanoparticles have also been investigated for the delivery of protein and peptide drugs. For colonic pathologies, it was shown that nanoparticles tend to accumulate at the site of inflammation in IBD. This is because in case of colitis, a strong cellular immune response occurs in the inflamed regions due to increased presence of neutrophils, Natural Killer cells, macrophages and so on. It has been reported that microspheres and nanoparticles could be efficiently taken up by these macrophages. This results in accumulation of the particulate carrier system resulting in prolonged residence time in the desired area. However, an important area of concern is to prevent loss of Nanoparticle in the early transit through GI tract in order to optimize therapeutic efficacy. Moreover, particle uptake by Payer’s patches and/or enzymatic degradation may cause the release of entrapped drug leading to systemic drug absorption and side effects. In order to overcome this problem, drug loaded nanoparticles were entrapped into pH sensitive microspheres, which serve to deliver the incorporated nanoparticle to their site of action, thereby preventing an early drug leakage. The use of nanoparticles for bioadhesion purposes has also been investigated. Nanoparticles have a large specific surface, which is indicative of high interactive potential with biological surfaces. Since the interaction is of nonspecific nature, bioadhesion can be induced by binding nanoparticles with different molecules. For covalent attachment, the nanoparticle surface has to show free functional groups, such as carboxylic or amine residues.

EVALUATION:

The drug release in the colonic region from different CDDS is evaluated by different methods of in vitro and in vivo release studies, which show the success rate of different designs of colon drug delivery systems. Depending upon the method of preparation different evaluation methods are proposed. A successful colon specific drug delivery system is one of that remains intact in the physiological environment of stomach and small intestine, but releases the drug in the colon.

In-vitro Evaluation:

Different in vitro methods are used to evaluate the colonic drug delivery systems.

1. In in-vitro studies the ability of the coats/carriers to remain intact in the physiological environment of the stomach and small intestine is assessed by drug release studies in 0.1N HCl for two hours (mean gastric emptying time) and in pH 7.4 phosphate buffer for three hours (mean small intestine transit time) using USP dissolution apparatus. In case of micro flora activated system dosage form, the release rate of drug is tested in vitro by incubating in a 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 study.

However, the Dissolution of controlled-release formulations used for colon-specific drug delivery are usually complex, and the dissolution methods described in the USP cannot wholly mimic in vivo conditions such as those relating to pH, bacterial environment and mixing forces.

2. Another test is that the Incubate carrier drug system in fermenter containing suitable medium for bacteria (Streptococcus facciumor B. ovatus) amount of drug released at different time intervals determined.

In-vivo Evaluation:

Like other controlled release delivery systems, the successful development of the CDDS is ultimately determined by its ability to achieve release in colonic region thus exerts the intended therapeutic effect. When the system design is concerned and prototype formulation with acceptable in-vitro characteristics is obtained, in vivo studies are usually conducted to evaluate the site specificity of drug release and to obtain relevant pharmacokinetic information of the delivery system.

Although animal models have obvious advantages in assessing colon specific drug delivery systems, human subjects are increasingly utilized for evaluation of this type of delivery systems. The preferable animals to evaluate CDDS are rats, guinea pigs and dogs. γ-scintgraphic studies were conducted in human volunteers with technetium-99m-DTPA as tracers in sodium chloride core tablets compression coated with guar gum showed that the gum coat protect the drug (tracer) from being released in the stomach and small intestine. On entering the ascending colon, the tablets commenced to release the tracer indicating the breakdown of gum coat by the enzymatic action of colonic bacteria. Technetium-99m-DTPA was used as a tracer for γ- scintigraphy evaluation of colon specific guar gum directly compressed matrix tablets in human volunteers. The scintgraphic evaluation conducted for capsule type colon specific drug delivery system in human healthy volunteers.

In a study by Krishnaiah et al., (2001), showed the effect of metronidazole and tinidazole (antimicrobial agents) on the release of albendazole from guar gum based colon specific matrix tablets. The active antimicrobial agents (7 days) treatment of rat caecal content decreased the release of albendazole due to decreased levels of anaerobic bacteria present in rat.

High frequency capsule:

Smooth plastic capsule containing small latex balloon, drug and radiotracer taken orally. Triggering system is high frequency generator. Release of drug and radiotracer triggered by an impulse, the release is monitored in different parts of GIT by radiological localization. It checks the absorption properties of drug in colon.

Gammascintigraphy:

By means of gammascintigraphic imaging, information can be obtained regarding time of arrival of a colon-specific drug delivery system in the colon, times of transit through the stomach and small intestine, and disintegration. Information about the spreading or dispersion of a formulation and the site at which release from it takes place can also be obtained. Gammascintigraphic studies can also provide information about regional permeability in the colon. Information about gastrointestinal transit and the release behaviour of dosage forms can be obtained by combining pharmacokinetic studies and gammascintigraphic studies (pharmacoscintigraphy).

CONCLUSION:

From past two decades, considerable amount of research work has been carried out in the area of colon targeting. The colonic region of the GIT has become an increasingly important site for drug delivery and absorption. CDDS offers considerable therapeutic benefits to patients in terms of both local and systemic treatment. The advantages of targeting drugs specifically to the diseased colon are reduced incidence of systemic side effects, lower dose of drug, supply of the drug only when it is required and maintenance of the drug in its intact form as close as possible to the target site. The preferred CDDS is that should release maximum drug load in colon region. Among different approaches the pH dependent system is less suitable than others due to the large inter and intra subject variation in the gastro intestinal pH, but gives better results with combination of time-dependent system, microbially activated system and others. Considering the sophistication of colon-specific drug delivery systems, and the uncertainty of current dissolution methods in establishing possible in-vitro/in-vivo correlation, challenges remain for pharmaceutical scientists to develop and validate a dissolution method that incorporates the physiological features of the colon, and yet can be used routinely in an industry setting for the evaluation of CDDS. To ensure a balance between efficiency, target-specificity, cost, and patient compliance, it appears that a combination of conventional and newer approaches is the key to the development of colon-specific drug delivery systems. In addition to the combined approaches, the exploration of nanotechnology seems to be an area of future research for colon targeting of drug.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies, Chennai for able guidance and knowledge imparted to us.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 18.02.2020 Modified on 24.04.2020

Research J. Pharm. and Tech. 2020; 13(12):6248-6258.

DOI: 10.5958/0974-360X.2020.01089.6