INTRODUCTION:

The most convenient and important method of administering drugs for systemic effect is the oral route of drug administration. Due to patient acceptance and ease of administration nearly 50% of the drug delivery systems available in the market are oral drug delivery system and these systems have more advantages.^(1,2).

Colon drug delivery has also gained increased importance, for potential site for the systemic delivery of therapeutic proteins and peptides which are being delivered by injections. Once the drug reaches in to the colon when taken orally, these delivery systems allow drugs to release the drug from the delivery system.^(3,4) Finally and is highly responsive to absorption enhancers, because the colon has a long residence time which is up to 5 days.⁽⁵⁾ Even tough the most convenient and preferred routeis oral route but other routes for cdds may be used. The shortest route for targeting drugs to the colon is through rectal administration. However, via rectal administration it is difficult reaching the proximal part of colon. It is uncomfortable for patients and compliance may be less than optimal through rectal administration⁽⁶⁾. Formation of prodrug, coating with ph-sensitive polymers, coating with biodegradable polymers, designing formulations using polysaccharides, timed released systems, pressure-controlled drug delivery systems, osmotic pressure controlled systems these are the various systems through which colon drug delivery is possible^(7,8). The colonic contents are considerably viscous and their mixing is not efficient because of the high water absorption capacity of the colon, thus availability of most drugs to the absorptive membrane is low. Over 400 distinct species of bacteria as resident flora the human colon has, a possible population of up to 1010 bacteria per gram of colonic contents. Among the reactions carried out by gut flora are azo reduction and enzymatic cleavage i.e. Glycosides ⁽⁹⁾_. For targeting drug to the colon there has been interest in developing site-specific formulations during last decade. There is and increased importance for colon delivery of drugs 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 but also for the systemic delivery of proteins, therapeutic peptides, antiasthmatic drugs, antihypertensive drugs and antidiabetic agents ^(10,11)_.

ADVANTAGES:

a. For the delivery of agents colon is an ideal site.

b. Local treatment has the advantage of requiring smaller drug quantities.

c. Reduces dosage frequency. Hence, lower cost of expensive drugs.

d. Possibly leading to a reduced incidence of side effects and drug interactions.

e. The colon is a site where poorly absorbed drug molecules may have an improved bioavailability.^(12-14)

DISADVANTAGES:

a. Longer residence time of 3-5 days results in elevated plasma levels of the drugs and therefore higher bioavailability in general, but especially for drugs that are substrates for this class of enzyme.

b. Single unit colon targeted drug delivery system has the disadvantage of un intentional disintegration of the formulation due to manufacturing deficiency or unusual gastric physiology.

c. Development of colon specific drug is difficult due to many biological barriers.

d. Cytochrome (P450) class of drug metabolizing enzymes has lower affinity in the colonic mucosa. ^(15,16,17)

LIMITATIONS:

a. Due to its location at the distal portion of the alimentary canal, the colon is particularly difficult to access.

b. The reliability and delivery efficiency is complicated due to the wide range of pH values and different enzymes present throughout the GI tract, through which the dosage form has to travel before reaching the target site.

c. Successful delivery also requires the drug to be in solution form before it arrives in the colon or, alternatively, it should dissolve in the luminal fluids of the colon, but this can be a limiting factor for poorly soluble drugs as the fluid content in the colon is lower and more viscous than in the upper part of GI tract.

d. The drug could potentialy bind in a nonspecific manner to dietary residues, intestinal secretions, mucus or faecal matter.

e. The resident microflora could also affect colonic performance via metabolic degradation of the drug. ^(18,19)

ANATOMY:

In the gastrointestinal tract colon is the lower part and runs from ileocecal junction to the anus. Proximal part (ascending colon), transverse colon, descending colon, sigmoid colon, rectum and anus are included in it. In contrast with small intestine surface area of colon is low but effective absorption take place due to presence of villi, microvilli and long residence time. The colon is cylindrical tube which is lined by moist, soft pink lining called mucosa and it is 2 – 3 inches in diameter⁽²⁰⁾_. It is divided into 3 main parts. They are colon, rectum, and anal canal. Perinatal folds are called as mesentery which is supported by ascending and descending colon. The right colon consists of the cecum, ascending colon and hepatic flexure. The left colon consists of descending colon, splenic flexure and sigmoid. The rectum is the last anatomic segment before the anus.^(21,22)

FACTORS AFFECTING:

1.pH:

To both inter and intra subject variations the pH of the GI tract is subjected. Diet, diseased state, and food intake influences the pH of the gastrointestinal fluid. For targeted colon drug delivery the changes in the pH along the gastrointestinal tract have been used. Radio telemetry shows the highest pH (7.5±0.5) in the terminal ileum. The pH drops to 6.4±0.6 on entry into the colon. The pH in the mid colon is 6.6±0.8 and in the left colon 7.0±0.7.^(23,24,25)

2. Colonic Microflora:

With bacteria and other microflora at both ends, the human alimentary canal is highly populated, oral cavity and the colon/rectum. Azo reductase produced by the colonic microflora plays an important role in development of a number of delivery systems, particularly in catalyzing the release of 5-amino salicylic acid, from a variety of prodrugs. Other enzymes are glycosidase and glucuronidases produced by lactobacilli, bacteroids and bifidobacteria. The activity of enzyme is associated with the concentration of bacteria in particular region.^(26,27)

3. Drug Absorption:

By either paracellular or transcellular route drugs are absorbed passively. The passage of drugs through cells is involved in trancellular process and this is the route most lipophilic drugs takes and the transport of drug through the tight junction between cells involves paracellular process and is the route most hydrophilic drug takes. Due to the fact that epithelial cell junctions are very tight the poor paracellular absorption of many drugs in the colon slow rate. If transit in colon lets the drug stay in contact with the mucosa for a longer period than in small intestine which compensates the much lower surface area.^(28,29)

4.Transit Time:

Using a radiopaque marker technique, the transit times in a group of 73 healthy adults has been estimated. The mean mouth-to-anus transit time was 53.3hr. The surface area of the colon for absorption is smaller than that of the small intestine, and this is compensated by the slow transit time⁽³⁰⁾. Colonic transit time is influenced by various factors like gender and size of the dosage form and physiological conditions such as stress, presence of food and diseased state. Small particles and solutions pass slowly through the proximal colon and in human being, Men shows shorter colonic transit time than women.^(31,32)

Table no:1 Dieases conditions and its active agents (33)

Target sites	Diseases conditions	Drugs and Active agents
topical site	inflammatory chrons disease, bowels disease	hydrocortisone, prednisolone, sulfasalazine, mesalazine
local site	chronic pancreatis, pancreactomy colorectal cancer	digestive enzyme supplement, 5-Fluro uracil
systemic site	to prevent gastric irritation oral delivery of peptides	NSAIDs, Insulin

APPROACHES:

1.Prodrug:

Prodrug is defined as an inert drug that becomes active only after it is transformed or metabolized by the body.⁽³⁴⁾

a) Azo bond:

Sulfasalazine is mainly used for the treatment of inflammatory bowl diseases. It is 5- Amino Salicylic Acid (5-ASA) prodrug. Due to reduction by the anaerobic environment into 5- ASA and sulphapyridine 85% of oral dose of sulfasalazine reaches to the colon unabsorbed. The formation of other prodrug like Olsalazine, Balsalazine, 4-amino benzoyl-β- alanine takes place due to various studies that are conducted on sulphapyridine. Intestinal microflora produces glycosidase, one of prominent group of enzyme.^(35,36)

b) Cylodextrins:

In the immediate release and delayed release-formulations the hydrophilic and ionisable Cyclodextrins can serve as potent drug carriers, while hydrophobic Cyclodextrins can retard the release rate of water. To deliver a drug to a targeted site is the most desirable attribute for the drug carrier. A versatile means of constructing a new class of colon targeting prodrugs soluble drugs are conjugates of a drug with Cyclodextrins. Ibuprofen prodrugs of α-, β-and γ-Cyclodextrins were investigated.⁽³⁷⁾

c) Glucuronide conjugate:

Glucuronide and sulphate conjugation is the major mechanisms for the inactivation and preparation for clearance of a variety of drugs. A variety of drugs in the intestine are glucouronidate due to the bacteria of the lower gastrointestinal tract secrete glucuronidase. Since the glucuronidation process results in the release of active drug and enables its reabsorption, glucuronide prodrugs would be expected to be superior for colon targeted drug delivery.⁽³⁸⁾

2.Hydrogels:

Gels shows less swelling that protect the drug against degradation in stomach in the acidic pH. 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_.⁽³⁹⁾

3. pH dependent approach:

The increase of progressively from the stomach (pH 1.5-3.5) and small intestine (5.5-6.8) to the colon (6.4-7.0) due to existence of pH gradient in the git is utilized by this approach. Delivery systems can be designed to deliver drugs at the target site by combining the knowledge of the polymers and their solubility at different pH environments. The most commonly used pH dependent polymers are derivatives of acrylic acid and cellulose.⁽⁴⁰⁾

4.Pulsating delivery:

In pulsating drug delivery, the drug is released rapidly after a well-defined lag time. The lag time prior to rupture is mainly controlled by the permeation, mechanical properties of the polymer coating and the swelling behavior of the swelling layer. Methods for pulsatile drug delivery systems are capsular system, osmotic system, solubilisation or erosion of membrane and rupture of membrane.^(41,42)

5. Bioadhesion:

It is a process by which a dosage form remains in contact with particular organ for an augmented period of time. High local concentration or improved absorption characteristics in case of poorly absorbable drugs have this longer residence time of drug. For the formulation of colonic drug delivery systems this strategy can be applied. Various polymers including polycarbophils, polyurethanes and polyethylene oxide polypropyline oxide copolymers have been investigated as materials for bioadhesive systems.⁽⁴³⁾

6. Pressure controlled:

For propulsion of intestinal contents the digestive processes within the GI tract involve contractile activity of the stomach and peristaltic movements. Forcible peristaltic movements commonly termed as mass peristalsis, occurs in the large intestine, the contents are moved from one part to the next, as from the ascending to the transverse colon. In the colon these strong peristaltic waves are of short duration, as they occur only three to four times a day. For design of pressure-controlled system they temporarily increase the luminal pressure within the colon. In the colon compared to pressure in the small intestine, the luminal pressure resulting from peristaltic motion is higher in the colon, which is attributed to the difference in the viscosity of luminal contents.⁽⁴⁴⁾

7. 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.⁽⁴⁵⁾ The OROS-CT system can be a single osmotic unit or may incorporate as many as 5-6 push-pull units, each 4 mm in diameter, encapsulated within a hard gelatin capsule⁽⁴⁶⁾ Immediately after ingestion, the hard gelatin capsule shell dissolves. In the acidic medium of stomach by enteric coating the push and pull unit is prevented from absorbing water. 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 ⁽⁴⁷⁾

Figure. 1 Cross-Section of the OROS-CT colon targeted drug delivery system^(48-51)

8. CODESTM:

It is a unique CTDDS technology that was designed to avoid the inherent problems associated with pH or time dependent systems. For pH dependent and microbially triggered CTDDS it is a combined approach. 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 lactulose⁽⁵²⁾. The enteric coating protects the tablet while it is located in the stomach and then dissolves quickly following gastric emptying is the premise of the technology. The acid soluble material coating then protects the preparation as it passes through the alkaline pH of the small intestine⁽⁵³⁾. The bacteria enzymetically degrade the polysaccharide (lactulose) into organic acid once the tablet arrives in the colon. This lowers the pH surrounding the system sufficient to affect the dissolution of the acid soluble coating and subsequent drug release.

Figure 2: Schematics of the conceptual design of CODES™⁽⁵⁴⁾

EVALUATION:

1.In vitro test:

For colon-specific drug delivery are usually dissolution of controlled-release formulations used iscomplex, and the dissolution methods described in the USP like pH, bacterial environment and mixing forces cannot fully mimic in vivo conditions.⁽⁵⁵⁾Ability of coats or carriers to remain intact in stomach and small intestine is generally assessed by conducting drug release studies in 0.1NHCl for 2hrs.To prevent drug release in the stomach and small intestine the conventional method involving dissolution in various buffers is useful for assessing the ability of an enteric coating tablet. Dissolution tests relating to colon specific drug delivery systems may be carried out by using the conventional basket method.^(56,57,58). pH 1.2 to simulate gastric fluid, pH 6.8 to simulate the jejunal region of the small intestine, and pH 7.2 to simulate the ileum segment was the media selected for study. Gradient dissolution study was carried in three buffer for Enteric coated capsules for CDDS. The capsules were tested for two hours at pH 1.2, then one hour at pH 6.8, and finally at pH 7.4⁽⁵⁹⁾.

2. In vivo test:

Gamma scintigraphy: For in-vivo behavior of different colon targeted systems this technique is used. It is a non invasive imaging technique. Small amount of gamma-emitting radionuclides are incorporated in the dosage forms, which describes the GIT transit patterns and the time and place of disintegration is also depicted⁽⁶⁰⁾

The anatomic and physiological conditions as well as the microflora of human GIT resembles, a number of animals such as dogs, guinea pigs, rats, and pigs are used to evaluate the delivery of drug to colon. Relative model for the colonic diseases should also be considered while choosing a model for testing a CDDS.Guinea pigs are commonly used for experimental IBD model. In the GIT of rat and rabbit the distribution of azo reductase and glucouronidase activity is fairly comparable to that in the human.⁽⁶¹⁾ Human fetal bowel is transported into a subcutaneous tulle on the back of the thyme nude mice, which vascularizes within 4weeks,matures and capable of developing of mucosal immune system from the host.^(62,63,64).

CONCLUSION:

Drug delivery to the diseased colon are advantageous in reducing systemic side effects, lower dose of drug, supply of the drug only when it is required and maintainance of the drug in its non-altered form as close as possible to the target site. Various approaches are being researched in attempts to understand and achieve the desired goal of targeting the delivery to a specific organ, the colon. All the available approaches have their own limitations and advantages. With the systems that utilize natural materials that are degraded by colonic bacterial enzymes from where colon specificity is more likely to be achieved.

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Received on 28.05.2020 Modified on 17.12.2020

Asian J. Res. Pharm. Sci. 2020; 10(4):293-298.

DOI: 10.5958/2231-5659.2020.00051.X