Colonic Drug Delivery Challenges and Oppor tunities - An Overview
Jack Aurora , Naresh Talwar , Vinayak Pathak Director, Pharmaceutical Research and Development, Manager, Formulation Development and
Research Scientist, Pharmascience
Lower surface area and relative ‘tightness’ of the tight junctions in the colon can also restrict drug transport across the mucosa and into the systemic circulation. The literature also suggests that the cytochrome P450 3A class of drug-metabolising enzymes has lower activity in the colonic mucosa. A longer residence time of three to five 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.
Mechanisms of Technologies Available
In light of the above-mentioned potential difficulties, different approaches have been studied for the purpose of achieving colonic targeting and are summarised below. Targeted drug delivery is reliant on the identification and exploitation of a characteristic that is specific to a target organ. In the context of colonic targeting, the exploitable GI tract characteristics are pH, transit time, pressure and bacterial flora.
Prodrug Approach
A prodrug is a pharmacologically inactive derivative of a parent molecule that requires some form of transformation in vivo to release the active drug at the target site. This approach involves covalent linkage between the drug and its carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine. The type of linkage that is formed between the drug and carrier would decide the triggering mechanism for the release of the drug in the colon.
This biotransformation is carried out by a variety of enzymes, mainly of bacterial origin, present in the colon. The enzymes that are mainly targeted for colon drug delivery include azoreductase, β-galactosidase, β-xylosidase, nitroreductase, glycosidase deaminase, etc. Generally, a prodrug is successful as a colon drug carrier if it is hydrophilic and bulky, to minimise absorption from the upper GI tract and, once in the colon, it is converted into a more lipophilic drug molecule that is then available for absorption. Certain drugs can be conjugated to different sugar moieties to form glycosides. Because they are bulky and hydrophilic, these do not penetrate the biological membranes upon ingestion. They break down upon action of glycosidase, releasing the drug part form the sugar. Glycosidase activity of the GI tract is derived from anaerobic microflora in the large bowel or exfoliated cells of the small intestine.12,13 Friend and Chang prepared dexamethasone-2-β-glucoside and prednisolone-2-β-glucoside for delivery of these steroids to the colon.14 When free steroids were administered orally, they were almost absorbed in the small intestine and less than 1% of the oral dose reached the colon. Nakamura et al. studied the conjugation of drug molecule to the polar amino acids and prepared prodrugs for colon drug delivery.15 Proteins and their basic units, i.e. the amino acids, have polar groups like -NH2 and - COOH. These polar groups are hydrophilic and reduce the membrane permeability of amino acids and proteins. Various non-essential amino acids such as glycine, tyrosine, methionine, and glutamic acid were conjugated to salicylic acid. The conjugate showed minimal absorption and degradation in the upper GI tract and showed more enzymatic specificity for hydrolysis by colonic enzymes.16 Glucuronide and sulphate conjugation is the major mechanism for the inactivation and preparation for clearance of many drugs. Bacteria of the lower GI tract, however, secrete β-glucuronidase and can deglucuronidate a variety of drugs in the intestine.17 The azo linkage exhibits a wide range of thermal, chemical, photochemical and pharmaceutical properties. The azo compounds are extensively metabolised by the intestinal bacteria, both by intracellular enzymatic components and extracellular reduction.18 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 prodrugs.19 Sulphasalazine, which was used for the treatment of rheumatoid arthritis, was later known to have potential in the treatment of inflammatory bowel disease (IBD). This compound has an azo bond between 5-ASA and sulphapyridine.20 Numerous drugs have been described that form complexes with β-cyclodextrins, enhancing the drug stability and/or absorption performance.21,22 The β-cyclodextrins are practically resistant to gastric acid and salivary and pancreatic amylases. A clinical study has shown clear evidence that β- cyclodextrins are poorly digested in the small intestine but are almost completely degraded by the colonic microflora.23,24
The challenge of this approach is the need to identify the appropriate chemical usage for the covalent linkage, which can result in safe and effective release of the drug with minimum fluctuation in terms of site specificity.
pH-dependent Approach
This approach is based on the pH-dependent release of the drug from the system. In this case the pH differential between the upper and terminal parts of GI tract is exploited to effectively deliver drugs to the colon. One should not forget that the pH in the intestine and colon depends on many factors such as diet, food intake, intestinal motility and disease states. This makes it more challenging for the specialists working in this field to design a delivery system that would be robust enough to withstand the variability in the gastric pH as it moves from the stomach to the small intestine. By combining knowledge of polymers and their solubility at different pH environments, delivery systems have been designed to deliver the drug at the target site.25,26 Commonly used co-polymers of methacrylic acid and methyl methacrylate have been extensively investigated for colonic drug delivery systems. In vitro evaluation of Eudragit® S and Eudragit® FS was performed and it was found that the latter would be more appropriate for drug delivery to the ileocolonic region.27 Several factors, such as combinations of different polymers, pH of the media, coating level of the tablets and presence of plasticisers, influence the dissolution rate of Eudragit®.28
Inter- and intra-subject variability, electrolyte concentration and transit time are some of the key variables impacting success through this route. In spite of these limitations, pH-based systems are commercially available for mesalazine (5 ASA) (Asacol® and Salofalk®) and budesonide (Budenofalk® and Entrocort®) for the treatment of ulcerative colitis and Crohn’s disease, respectively.
