INTRODUCTION

The oral root is considered the easiest root of administration for the patient. For oral administration, the amount of data is usually dissolved in juice or in the intestine, and absorption from the gastrointestinal tract site depends on the physicochemical properties of the drug. This is not good in situations where it is necessary to deliver the drug locally in the intestine or to keep the drug away from the heavy part of the GI tract¹.

Colon specific drug delivery is ideal for local treatment of various intestinal diseases (e.g. ulcerative colitis, Crohn’s disease), amebiasis, colon cancer, localisation of localized lesions, systemic delivery of protein and peptide drugs.

Colon specific drug delivery systems (CDDS) must be able to prevent the drug from reaching the colon (i.e. release and absorption of the drugs should not occur in the stomach and intestine and bioactive drugs should not be broken down) and ensure that only the drug reaches the colon enter the stomach bowel². The colon is considered a favourable site for the absorption of peptide and protein drugs for the following reasons: (i) Differentiation & Utilization of digestive enzymes is low. ii) The proteolytic activity of the colonic mucosa is lower than that found in the small intestine, so CDDS can prevent the hydrolysis and enzymatic degradation of the peptide in the duodenum and jejunum & finally in the ileum or small intestine. For this reason, increased systemic bioavailability. (iii) The residence time of colon is long (up to 5 days) and is very sensitive to absorption. The concentration of drug reaching the intestine will depend on the formulation, length of retrograde diffusion, and retention time. (ii)The proteolytic activity of the colonic mucosa is lower than that that found in the small intestine, so CDDS can prevent the hydrolysis and enzymatic degradation of the of the peptide in the duodenum and jejunum and finally in the ileum or small intestine. For this reason, increase Systematic bioavailability. (iii) The residence time of colon (up to 5 days) and is very sensitive to absorption. The concentration of drug reaching the intestine will depends on the formulation, length of retrograde diffusion, and retention time. It has been found that foam and suppositories are often retained in the rectum, sigmoid enema solution has a very good effect. Because the intestine has a strong absorptive capacity, the contents of the stomach are very solid and their composition is not good, so the medicine generally has a limited tissue use. The residence flora of the human colon has more than 400 different bacteria species and may contain up to bacteria per gram of colonic content. Reactions carried out by the intestine include azo reduction and enzymatic cleavage of glycosides. This metabolic process can be responsible for the many drugs and can also be used for the large intestine of peptide-based macro molecules (e.g. insulin) via oral administration. The option of delivering the drug into the intestine may reduce the dose needed and thus reduce side effects. This technique has the advantages of better treatment, lower dose and fewer side effects with higher doses.³.^.

Anatomy of colon:

The gastrointestinal tract includes the mouth to the anus. The intestines include the small intestine and large intestine. GIT is about 5 m long. The difference between the upper GI tract is divided into upper gastrointestinal tract and internal gastrointestinal tract. The upper part of the digestive system includes the oesophagus, stomach and duodenum.

The average length of the small intestine is approximately 6.9 to 7.1meters. It contains the duodenum, jejunum and ileum. The main function of the small intestine is to absorb nutrients and minerals from food. The duration in the intestine is 3 to 5 hours. Large intestine is approximately 1.5 m long. It includes the cecum, colon and rectum. The main function of the large intestine is to remove water and minerals from food and convey waste materials to the anus.

The colon consists of four parts: ascending colon, descending colon, transverse colon, sigmoid colon. It removes water and salts from waste products and removes them from the body. Part of the colon is in the abdominal cavity or the retroperitoneum in the lower part of the abdominal cavity. The ascending colon, descending colon and rectum are in the retroperitoneum while the transverse colon in the intraperitoneal. Intestine pH varies between 5.5 and 7.⁴

pH of colon:

The pH of the digestive system varies from person to person. Diet, diseases and other factors can affect the pH of the colon. pH changes in various part of the gastrointestinal tract from the basis for the development of drugs that target the intestines. Different Polymers are coated so that the drug targets the intestine. Different polymers are coated so that the drug can be focused on the surface.^5,6.

Table 1: pH in different parts of colon

Part of GT	pH
Stomach	Fasted state- 1.5 to 2 Fed state- 2 to 6
Small intestine	6.6 to 7.5
Colon Ascending colon Transverse colon Descending colon	6.4 6.6 7

Approaches used for site specific drug delivery to Colon:

[A]- Primary approaches for Colon targeted Drug Delivery System:

a - pH sensitive polymer coated drug delivery to colon

b - Delayed (Time controlled release system) release drug delivery to colon

c - Microbially triggered drug delivery to colon

i. Prodrug approach for drug delivery to colon

ii. Azo-polymeric approach for drug delivery to colon

iii. Polysaccharide based approach for drug delivery to colon

[B]- Newly developed approaches for Colon targeted Drug Delivery System:

a. Pressure controlled drug delivery system (PCDCS)

b. CODES™ (A Novel colon targeted delivery system)

c. Osmotic controlled drug delivery to colon (OROS-CT)

a - pH sensitive polymer coated drug delivery to colon:

During fasting, stomach pH is between 1 and 2 but increases after eating. The pH of the proximal small intestine is approximately 6.5, and the pH of the small intestine is approximately 7.5. From the ileum to the colon, pH drops significantly. The cecum is approximately 6.4. However, pH values as low as 5.7 have been measured in the colon of healthy workers. The pH of the large intestine is 6.6, and the pH of the large intestine is 7.0. The use of pH- dependent polymers is based on different pH levels. Polymers defined as pH-dependent in the intestinal tract are insoluble at low pH but become more soluble as pH increases. Although the pH- dependent polymer can protect the structure of the stomach and small intestine, it may still begin to dissolve in the lower part of the small intestine, and the specific area of the formulation will not be good. The drop in pH from the end of the small intestine to the colon can also cause problems. Longer lag times at the ileocecal junction or rapid transit through the colon may disrupt the site-specific properties of enteric-coated single-unit formulations.^5,7.

Fig. 1 Drug release in the colon from pH-sensitive polymer-based system⁸

Table No.2 Polymers and its PH⁹

Polymers	Threshold pH
Eudragit L 100	6.0
Eudragit S 100	7.0
Eudragit L-30D	5.6
Eudragit FS 30D	6.8
Eudragit L 100-55	5.5
Polyvinyl acetate phthalate	5.0
Hydroxy propyl methyl cellulose phthalate	4.5-4.8
Hydroxy propyl methyl cellulose phthalate 50	5.2
HPMC55	5.4
Cellulose acetate taramellite	4.8

b - Delayed (Time controlled release system) release drug delivery to colon:

Time-controlled release systems or delayed releases, are also useful. However, because the time it takes for the drug to change may vary between people on an empty stomach. The time it takes for a dose to reach the large intestine cannot be accurately predicted in this way, resulting in weakened colon function. Time dependant systems are not ideal for delivering drugs to the intestine, especially for the treatment of intestinal diseases. Proper integration of PH sensitivity and time release functions into a dosage form can improve site specific drug delivery to the gastrointestinal tract. The release time function should work better in the small intestine than in the stomach¹⁰

Enteric-coated time release press coated (ETP) tablets:

ETP tablets consist of three parts, including the main tablet (immediate-release), the press- packed swellable hydrophobic polymer layer (hydroxypropyl cellulose layer, extended- release function), and the enteric layer (acid resistant function). It does not enter the stomach due to the acid resistance of the enteric layer. After the stomach is emptied, the enteric coating rapidly dissolves and the gastric fluid gradually begins to form the pressed polymer (HPC) coting time. Duration of drug release after empty stomach (delayed phases). The duration of the work phase is controlled by the weight or composition of the polymer process (HPC).¹¹

c) Microbially triggered drug delivery to colon:

The colon microbial community varies between 1011 – 1012 CFU/mL and consists of anaerobic bacteria such as. Bacteroidetes, Bifidobacteria, Eubacteria, Clostridium, Enterococcus, Enterobacteriaceae and Ruminococcin etc. Tis large microbiota meets its energy needs by fermenting various types of undigested substrates in the small intestine¹² .During this fermentation process, the microbial community produces many enzymes such as glucuronidase, xylosidase, arabinoside, galactosidase, nitro reductase, azareducatase, deaminase and urea dehydroxylase. Since biodegradable enzymes are found only in the intestine, the intestine-specific delivery of drugs using biodegradable polymers appears to be the most specific site compared to other methods. These polymers protect the drug from the gastrointestinal environment and facilitate transport of the drug into the intestine. when they reach the colon, they are assimilated by bacteria or broken down by enzymes or break down the polymer skeleton, causing their molecular weight to decrease and thus loss of strength. Then they no longer have the body of the medicine¹³.

i) Prodrug approach for drug delivery to colon:

Prodrug are pharmacologically inactive derivatives of the desired parent drug molecule spontaneous or enzymatic conversion in the body to release the active drug. Prodrugs for intrauterine delivery are designed to have low absorption and hydrolysis in the upper gastrointestinal tract and undergo enzymatic hydrolysis in the small intestine, thereby releasing the active drug moiety from the drug carrier¹⁴. The metabolism of azo compounds by intestinal bacteria is one of the most studied metabolic processes. Many other compounds are subject to hydrolysis, especially the composition of the drug into amino acids, glucuronic acid, glucose, galactose, cellulose, etc. It is prepared in the intestine where it binds to hydrophobic parts such as. The limitation of the prodrug method are: is that there is no general guideline because the structure depends on the functional group of the drug moiety available for drug binding. Additionally, prodrugs are new drug products that require extensive testing before being used as carriers¹⁵.

(ii) Azo-polymeric prodrugs:

The new technique aims to use polymers as drug carriers to deliver drug to the intestine. Both synthetic and natural polymers are used for this purpose. Non-synthetic polymers are used to form polymeric compounds with azo bonds between the polymer and chemical moieties. These have been evaluated for use in cancer cells, and various azopolymers have also been evaluated as coating materials for drug cores. They were shown to be equally sensitive to the breakdown of azaduase in the large intestine. It has been found that coating peptide capsules with polymers cross- linked with azoaromatic groups prevents the drugs from being digested in the stomach and intestines. In the intestine, the azo bound decreases and the drug is released. Various azo polymer prodrugs have been described^4,16.

(iii) Polysaccharide based delivery systems:

The use of resulting polysaccharides has made a major impact in the field of antibiotics because monosaccharide polymers are abundant, versatile, inexpensive, and have many structures with many properties. They are easily replaceable and biochemically biodegradable as well as stable, safe, non-toxic, hydrophilic and gel- forming. These include natural polysaccharides derived from plants (guar gum, inulin), animal (chitosan, chondroitin sulphate), algae(alginate) or microbial (glucan) sources. These substances are broken down into simple sugars by the intestinal microbiota. They therefore fall the “generally recognized as safe” (GRAS)category¹⁷.

[B] Newly developed approaches for colon specific drug delivery system:

a) Pressure-controlled drug-delivery systems:

Due to Peristalsis, the pressure in the intestines is high in the intestines. Takatani et al. (1995) Developed an Inflammatory agent prepared using water insoluble ethyl cellulose. In such a process, during the drug is released as a result of the Water- insoluble polymer capsule breaking due to the pressure in the intestinal lumen. The thickness of the ethyl cellulose film is the most important factor. In the disintegration of the formulation. This system also seems to defend on Size and speed. The viscosity of the luminal content in the colon is higher than that in the intestine therefore water is reabsorbed from the intestine. Therefore, it was decided that alcohol use in the intestine would cause problems for the bacteria in the mouth. the drug is in liquid form in controlled ethyl cellulose single- unit capsules. when heart control pills are given to people, there is a delay of 3 to 5 Hours in the absorption of the drug¹⁸.

b) Novel colon targeted delivery system (CODES^TM):

CODES^TM is a CDDS device specifically designed to avoid problems with pH or time dependence. CODES^TM is a combined method for pH- dependent and microbially triggered CDDS. It is created using a special process Involving lactulose, which affects the release of drugs at certain places in the intestine. The system consists of a uniform tablet containing lactulose, coated with the acid- soluble substance Eudragit E followed by the enteric substances Eudragit L. The principle of this device is that enter coating protects the tablet in the stomach and then dissolves rapidly. After the stomach is emptied. The layer of acid- soluble material then protects the formulation as it passes though the alkaline pH of the small intestine. Once the tablet enters the intestine, bacteria enzymatically digest the polysaccharide (lactulose) into organic acids. This lowers the pH around the body enough to affect the separation of the acid-soluble layer and the upon release¹⁹.

(c) Osmotic controlled drug delivery (ORDS-CT):

OROS-CT (Alza corp.) can be used to target drugs locally to the colon to treat disease or improve absorption. The OROS-CT system can be a single infiltration unit or have up to 5-6 push- pull units, each with a dimeter of 4 mm, in a hard gelatine capsule. Each two-layer push- pull unit has a permeable push layer and a chemical layer, both surrounded by semi-permeable membranes. Drill a hole in the membrane next to the chemical layer. The gelatine capsule containing the push-pull casing will dissolve rapidly after ingestion of OROS-CT. Thanks to its drug- impermeable enteric layer, every car is pulled into the house without adsorbing the water in the acidic watery environment of the stomach and therefore does not distribute drugs. Once the device enters the small intestine, in a higher pH environment (pH>7) the coating dissolve and water enters the device, causing the osmotic pressure chamber to swell and gel flow to occur in the solution chamber²⁰.Expansion of the osmotic pressure chamber allows the gel solution to flow out of the mouth at a rate controlled by the amount of water transport systems in the treatment of ulcerative colitis are designed with a 3–4-hour retro gastric delay to prevent drug passage into the intestines. Once the device reaches the intestine, the drug begins to be released. The OROS-CT device provides sustained release in the colon for up to 24 hours. Analysis of specific disease of the intestine. Various in vitro/in vivo evaluation strategies have been developed and proposed to evaluate the efficacy and safety of cancer drugs^21.

CONCLUSION:

The colonic region of the intestines has become an increasingly important site for drug transport and absorption. CDDS provides many medical benefits to patients in terms of local and systemic treatment. For drug delivery to the intestines, the CDDS recommends four main methods: prodrugs, pH and time-dependent systems, and micro triggered drug systems. The first three methods are not good for CDDS. The new design of CDDS is more specific. Techniques that use natural products that can be broken down bacterial enzymes in the colon are more likely to promote colon healing.

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Received on 21.03.2024 Modified on 20.04.2024

Asian J. Research Chem. 2024; 17(3):179-183.

DOI: 10.52711/0974-4150.2024.00033