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).