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Prodrugs and drug-delivery systems controlled by time, pH, and osmosis, are being used to prevent drug degradation in the stomach and large intestine and ensure drug release in the colon.
Oral formulations, which are still the most widely used dosage forms, can be designed to release the drug at specific sites of the gastrointestinal (GI) tract. Today, the colon is becoming a more attractive target, not only for treating diseases of the colon such as Crohn’s disease, ulcerative colitis, and colorectal cancer, but also for GI therapies in general. For example, colon targeting can be used to systemically deliver proteins and peptides that are susceptible to enzymatic degradation in the stomach or small intestine. This approach has been found to provide safe and effective therapy with proven bioavailability enhancement as well as a lower incidence of drug toxicity and unwanted side effects.
Colon-specific drug delivery exploits the differences in anatomical and physiological features of the upper and lower segments of the gut. Research has shown that the colon is more responsive to absorption enhancers, protease inhibitors, and bioadhesive and biodegrable polymers compared with other regions of the gut (1). The challenge, however, comes in ensuring that the drugs are intact when they eventually reach the colon, which is often a problem with traditional oral dosage forms. A number of different approaches are being used to target drug release in the colon. This article will summarize key trends, including the use of prodrugs, pH- and time-dependent systems, as well as newer approaches based on osmotic-controlled drug delivery.
Prodrugs. The prodrug strategy exploits the presence of the colonic microflora, which is in the order of 1011–1012 colony-forming unit (CFU) per mL in the colon, compared with 103–104 CFU/mL in the stomach and small intestine (2). To form the pharmacologically inactive prodrug, the parent drug is attached to a chemical group, and enzymatic degradation by the bacteria in the colon then frees the active drug molecule. Linkages such as azo, amide, glucuronide, and glycosidic bonds are often used in prodrug formation for colon-specific drug delivery. Ruiz et al. reported on the development of a double prodrug system for colon targeting of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitors (3). The prodrug was first activated by azoreductases followed by cyclization to release the active drug. According to the researchers, the prodrug demonstrated good stability in human intestinal extracts and was only activated under specific conditions of the colon, hence achieving targeted drug release.
pH- and time-dependent drug-delivery systems. In this approach, drug release is triggered by a change in pH as the dosage form passes through the gut. It is generally accepted that the pH of the GI tract progressively increases from the stomach (pH 1–2 in fasted state and pH 4 during digestion) to the small intestine (pH 6–8). The important thing is for the formulation to remain intact until it reaches the colon. Such formulations typically incorporate polymer coatings that are insoluble in an acidic environment but become soluble as the pH increases. Commonly used pH-sensitive polymers include Eudragit L and S, polyvinyl acetate phthalate, hydroxyl propyl methyl cellulose phthalate, and cellulose acetate, to name a few.
Time-dependent systems take a different approach by delaying drug release after a specific period of time. Taking into account gastric emptying and intestinal transit times, swellable systems that incorporate different combinations of hydrophilic and hydrophobic polymers as the coating material are used to adjust the time lag. Recent approaches often combine both pH- and time-dependent systems to achieve more targeted drug delivery to the colon. Ofokansi and Kenechukwu, for example, prepared ibuprofen tablets using Eudragit EL 100 and chitosan to form interpolyelectrolyte complexes (4). The formulation showed pH-dependent swelling properties and prolonged drug release in vitro (4). The electrostatic interaction between the carbonyl (-CO-) group of Eudragit RL 100 and the amino (-NH3+) group of chitosan was thought to prevent drug release in the stomach and small intestine, facilitating colon-targeted drug delivery.
Osmotic-controlled drug delivery. Osmotic systems are commonly used for controlled-release purposes but the concept can be applied in colon drug delivery as well. The system consists of the drug, an osmotic agent, and a semi-permeable membrane with an orifice for drug release. An additional enteric coating is applied on top of the membrane to prevent drug release in the stomach and upper GI tract. As the dosage form enters the small intestine, the increase in pH causes the enteric coating to dissolve, exposing the semi-permeable membrane. Water enters the drug core and the expanding volume forces the drug out the osmotic system through the orifice.
A number of research groups are working on the development of innovative osmotic tablets for the treatment of inflammatory bowel disease. Chaudhary et al., for example, developed microporous bilayer osmotic tablets of dicyclomine hydrochloride and diclofenac potassium for colon targeting (5). The bilayer coating consisted of a microporous semipermeable membrane and an enteric polymer. The tablets showed acid resistance and time release in in-vitro dissolution studies, demonstrating the potential for colon-specific drug delivery to treat irritable bowel syndrome.
Nath et al. incorporated Sterculia gum, which is a polysaccharide, into osmotic tablets for colon-specific drug delivery of azathioprine (6). Sterculia gum is digested by the colonic enterobacteria and swelling of the polysaccharide forces the drug out of the tablet core. To ensure that drug release does not occur in the upper GI regions, a double-layer coating of chitosan/Eudragit RLPO (ammonio-methacrylate copolymer) and enteric polymers is used to impart acid- and intestinal-resistant properties to the tablet.
In short, the colon offers an alternative drug-delivery approach for acid-labile drugs such as proteins and peptides, drugs that degrade in the stomach and small intestine or undergo extensive first pass metabolism, as well as for topical treatment of inflammatory diseases of the colon. While progress is being made in achieving more specific targeting of drugs to the colon, the complexity of these drug-delivery systems will require validated dissolution methods and establishing in-vitro/in-vivo correlation.
1. V. Sinha et al., Crit Rev Ther Drug Carrier Syst. 24 (1) 63–92 (2007).
2. V.R. Sinha and R. Kumria, Pharm Res. 18 (5) 557–564 (2001).
3. J.F. Ruiz et al., Bioorg Med Chem Lett. 21 (22) 6636–6640 (2011).
4. K.C. Ofokansi and F.C. Kenechukwu, ISRN Pharm. online, DOI: 10.1155/2013/838403, Aug. 6, 2013.
5. A. Chaudhary et al., Eur J Pharm Biopharm. 78 (1) 134–140 (2011).
6. Nath et al., PDA J Pharm Sci Technol. 67 (2) 172–184 (2013).
Article DetailsPharmacetical Technology
Vol. 39, No. 7
Citation: When referring to this article, please cite it as A. Siew, "Mission Possible: Targeting Drugs to the Colon," Pharmaceutical Technology 39 (7) 28–29 (2015).