Targeting the Colon: Innovative Drug Delivery Systems for Local and Systemic Therapy

Although the oral route of drug administration is the most popular and practical for patients, there are a number of drawbacks (1). Any drug delivery system's principal objective is to deliver a therapeutic dose of medication to a specific location in the body so that the required drug concentration can be quickly reached and then sustained for the desired amount of time. With restricted access to non-target areas, targeted drug delivery entails the selective and efficient localization of the drug at the target site at a therapeutic concentration (2). Drugs with instability, low solubility, short biological half-life, high volume of distribution, poor absorption, limited specificity, and narrow therapeutic index are more suited for targeted drug administration (3). By avoiding medication inactivation or degradation while in transit to the target region, targeted drug delivery may offer the highest possible therapeutic activity. Additionally, by lowering the dosage of powerful medications, it can lessen toxicity and limit negative effects brought on by improper disposal. Both in vitro and in vivo, a targeted drug delivery system should be physicochemically stable, biocompatible, biodegradable, and nontoxic (4). Because of the many related pharmaceutical advantages and opportunities that have been found in recent years, colonic drug administration is seeing a resurgence. Improved treatment of local disorders, access to local therapeutic targets, less systemic drug exposure and related toxicity, and even increased drug bioavailability are all made possible by targeting medications to the colon. In the past, colonic medicine delivery has mostly addressed local illnesses including colorectal cancer and inflammatory bowel disease (IBD). By maximizing drug concentration at the target region and minimizing systemic exposure, colonic drug administration can enhance the treatment of local illnesses [2–4]. New local targets, including the lymphatic system, enteric immune system, and microbiome, have been identified as a result of increased characterization of the colonic and rectal environments. The incidence of colonic disorders has risen globally in recent decades, necessitating efficient local treatment in order to develop safer and more effective medication regimens. Colorectal cancer (CRC) is the third most prevalent cancer diagnosed globally and the leading cause of cancer-related fatalities in Europe, accounting for over 200,000 deaths per year. In historically low-incidence regions like Asia, the prevalence of inflammatory bowel disease (IBD) is also rising at a startling rate (5). Effectively treating colonic illnesses has therefore emerged as a significant global public health concern. Since conventional non-targeted therapy may have unfavorable side effects and low efficacy due to the systemic absorption of the drug before reaching the target site, colon-targeted drug delivery devices have been intensively pursued for the local treatment of colonic disorders. Apart from topical administration, colon-targeted drug delivery systems can also be used to increase the bioavailability of medications that are susceptible to enzymatic and/or acidic destabilization in the upper gastrointestinal (GI) tract. This is especially true for macromolecules like proteins and peptides, as the colon has lower protease activity (6).

1. Drug Candidates for Colon Targeting (7)

• It should not be well absorbed from the small intestine and stomach.
• It should readily biotransform in the large intestine and be compatible with carrier molecules.
• It ought to remain stable at the GIT's alkaline pH.
• Both systemic and local effects are expected.
• Drugs are used to treat a variety of intestinal conditions, including diarrhea, inflammatory bowel disease, ulcerative colitis, amoebiasis, and colon cancer.
• Drug criteria for colon targeted

Table No.1 Diseases, approaches and evaluation parameters for colon specific drug delivery:

2. Advantages of Colon-Specific Drug Delivery Over Conventional Drug Delivery Systems (8)

5. When treating local colonic diseases, such as constipation, spastic colon, Irritable Bowel Syndrome, Crohn's disease, ulcerative colitis, and colon cancer, colon targeted drug delivery is beneficial because it directly treats the affected area, maximizing therapeutic activity and avoiding drug degradation or inactivation during transit.
5. Because colonic drug delivery requires a lower dosage of medication, it has less systemic and local side effects and reduces the toxicity of powerful medications due to less improper disposal.
5. Drug distribution through the colon aids in the threshold entry of peptides, proteins, and medications. The development of a colon-targeted delivery system can avoid them from being enzymatically broken down or poorly absorbed in the upper gastrointestinal tract because of the stomach's acidic environment. Because brush border membrane peptidase has very little activity and pancreatic enzymes have much less activity, the colon is preferred over the small intestine for the delivery of proteins and peptides (such as insulin, calcitonin, vasopressin, growth hormones, and oral vaccines).
5. Therapeutic proteins and peptides in particular, as well as poorly absorbed medications, may be made relevantly bioavailable in the colon. Because of their polarity and/or vulnerability to enzymatic or chemical destruction, including significant hepatic metabolism, therapeutic proteins and peptides exhibit limited absorption from the upper GIT. The colon is a desirable location for medication molecules with limited absorption to have higher bioavailability.
5. Colonic medication administration works well for treating major colon disorders including colorectal cancer.
5. Colon-specific drug delivery systems lessen the gastric irritation that many medications, like NSAIDs, cause. They also explain how some medications work, like sulfasalazine, which is converted in the colon to the active moiety 5-amino salicylic acid and inhibits the growth of colon polyps, which are the initial stage of colon cancer, most likely locally.
5. The retention period of colon-targeted drug delivery is longer, and it seems to be especially sensitive to substances that improve the absorption of medications that are not well absorbed.
5. Targeting the colon lessens dosage level fluctuations.
5. Drug administration tailored to the colon increases the effectiveness of treatment.
5. From a therapeutic perspective, it is preferable to delay absorption from such a delivery system when treating conditions like nocturnal asthma, angina, and arthritis, which have their worst symptoms in the morning.

3. Approaches for Colon Drug Targeting

4.1 Prodrug approaches

i. Azo bond conjugate

This method uses an azo bond to conjugate the medication. The microflora produces azoreductases in the colon that break down the azo bond, which is stable in the upper GIT. The gut bacteria extensively metabolize these azo chemicals by extracellular reduction and intracellular enzymatic components. Sulphapyridine is the component of sulphasalazine (5-ASA), a medication used to treat IBD.This has antibacterial properties, while 5-ASA has anti-inflammatory properties. Both drugs are linked by an azo bond. The medication and its carrier sulphapyridine are released when the azoreductases in the colon break the azo link (9).

Fig No. 1 Azo bond conjugates of p-amino Salicylic acid and sulfapyridine

ii. Glycoside Conjugated prodrug

The enzyme Several human microflora generate the glycosidases D-galactosidase, Larabinofuranosidase, D-xylopyranosidase, and D-glucosidase. These glycosidase enzymes can be found along the colon's brush boundary. Glycosides and aglycon are components of natural drugs; when they enter the colon after oral administration, glycosidases react with them to release pharmacologically active aglycon. Due to their hydrophilic nature and low absorption from the gastrointestinal tract, glycosides are used as drug delivery vehicles in the colon. The lucosides, galactosides, and cellobiosides of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone are the drugs that this method targets. glucoside of daxamethasone-21. Two prodrugs—dexamethasone-21-glucoside and prednisolone-21-glucoside—as well as the unmodified steroids dexamethasone and prednisolon were used in the study (10).

iii. Glucuronid Conjugation Prodrug

The primary metabolic process of drugs is glucuronide conjugation. -Glucuronidaes, which are secreted from the large intestine, deglucuronide different drugs. When a medicine is delivered orally, it is coupled with glucuronidgonjugation; once it reaches the colon, the conjugation is selectively broken down by glucuronidaes, releasing the active drug molecule. This process is known as metabolisum. The glucuronid conjugation of the narcotic analogs nalaxone and nalmefene has been used in colon targeting studies, suggesting that this conjugation is helpful in treating constipation brought on by opiates (11).

iv. Dextran conjugated prodrug

The intestinal flora uses dextran, a carbohydrate, as an energy source. Various prodrugs of dextran are made with NSADS using an ester connection between the drug molecule's -COO group and dextran hydrogel, which is used in colon site-specific drug delivery. Following oral delivery, the enzyme Dextanase, which is found in the human colon, breaks the ester bond of this conjugation and releases the free drug (12).

4.2 Polymeric approach to deliver intact drug molecule to colon

i. Coating with pH sensitive polymer

Eudragit is one of the options for coating the tablet core when we want to create a dosage form that will release the medicine in the colon selectively. These co-polymers, which are essentially poly(meth)acrylate base polymers, are made from acrylic and methacrylic acid esters, and their physicochemical characteristics are dictated by their functional groups (R). Eudragite polymers come in a variety of physical forms, including granules, powders, organic solutions, and aqueous dispersions. Coating the tablet core with the pH-dependent polymer eugragit S100 allows for the local treatment of bowel disorders like Crohn's disease, ulcerative colitis, or intestinal cancer. However, this type of formulation causes premature drug release in the distal part of the small intestine; this issue is resolved by coating with a solution that contains a mixture of eudaragit L100 and eudragit S100 (13).

ii. Based on pH sensitive hydrogel

Depending on the pH of the surrounding environment, pH-sensitive polymers contain pendant acidic groups like carboxylic acid and sulfonic acid or basic groups like ammonium salt groups that can either give or take protons. At high pH, poly (acrylic acid) becomes ionized. Hydrogels composed of poly (ethylene glycol) (PEG) grafted onto poly (methacrylic acid) (PMA) exhibit special pH-sensitive characteristics. Low pH causes the hydrogels to shrink as a result of complexation between the acidic protons of the carboxyl groups and the ether oxygen of PEG. The crosslinking density controls the outcome as the carboxyl groups of PMA ionize at high pH. The ensuing decomplexation causes the hydrogels to expand (14).

iii. Bioadhesive polymer

In the new concept of bioadhesion, the colon drug delivery system adheres to the mucus membrane of the colon, where the polymer swells and adheres. Adhesion involves the formation of a chemical or physical bond between the polymer and the mucus membrane surface. By improving drug resident time, localized drug delivery improves both topical and systemic treatment of colonic inflammatory disease. polymers such polyethylene oxide, polyurethane, and polycarbophils. Extrusion-spheronization was used to create prednisolone pellets with various carbomers, such as Carbopol 971P, Carbopol 974P, and Polycarbophil AA1, with or without organic acids. These pellets were then coated with a novel enteric double-coating system, which dissolves at pH 7 and releases the medication (15).

iv. Redox sensitive polymer coating

Benzyl viologen and flavin mononucleotides are the redox mediators that act as an electron shunt between the intracellular enzyme and the extracellular substrate, causing a change in redox potential that results in bond cleavage and drug release from the polymer. This is a novel polymer that breaks down non-enzymatically by enzymes secreting redox mediators. Colonic microflora causes changes in the redox potential, which is around -67±90 mv in the proximal small intestine, -196±97 mv in the distal small intestine, and -145±72 mv in the colon. The colon is the target of this idea. Reduced flavins, an electron mediator that functions as an electron shuttle from the NADPH-dependent flavoprotein to the azo compound, are produced by enzymatically generating reduced flavins under anaerobic conditions. The initial substrate, which is believed to be involved in cellular electron transport, requires the presence of NADPH as its electron source. The reduction of the azo bond to the hydro-azo intermediate requires a low electron density within the azo region, which is why substituting an electron withdrawing group will enhance this reaction, according to molecular modeling of low molecular weight azo compounds (16).

4.3 Newly Developed Approaches For CDDS

i. Time dependent colon drug delivery

Pulsatile release systems are designed to have a quick and full release of the loaded substance or drugs after a predefined period of no release. The strategy is predicated on the idea of postponing the release of the medicine until the system has moved from the mouth to the colon. Since small intestine transit takes roughly 3–4 hours and is mostly unaffected by the type of formulation used, a lag time of 5 hours is typically regarded as adequate. Patient compliance, lower dosage and frequency, avoiding adverse effects, avoiding peak and valley fluctuations, and a practically constant drug level at the target site are just a few of the many benefits this system offers over traditional oral drug delivery systems (17).

Figure 3: Time-Dependent Colonspecific Suppository-Base-Matrix (TDCS-SBM) Tablet.

ii. Pressure-Controlled Drug-Delivery Systems

The colon experiences greater pressures than the small intestine due to peristalsis. Using ethyl cellulose, which is insoluble in water, Takaya et al. have produced pressure-controlled colon release capsules. In such frameworks, pressure in the colon lumen causes medication release after a water-insoluble polymer capsule disintegrates. The primary cause of the formulation's breakdown is the thickness of the ethylcellulose layer. Additionally, the mechanism appeared to depend on the thickness and size of the capsules. The consistency of luminal material is higher in the colon than in the small intestine due to the reabsorption of water from the colon. In this way, it has been argued that colon-specific oral delivery systems may face challenges due to drug disintegration in the colon. The medication is a liquid in pressure-controlled ethyl cellulose single-unit capsules. When pressure-controlled capsules were administered to people, lag durations of three to five hours based on medication absorption were observed (18).

Figure 4: Cross-Section of the OROS-CT Colon-Targeted Drug Delivery System