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
Time-dependent Approach
Usually, time-dependent drug delivery systems are designed to deliver drugs after a lag of five to six hours. This approach is based upon the theory that the lag time equates to the time taken for the dosage form to reach the colon. The lag time is dependent on size of dosage form and gastric motility associated with the pathological condition of the individual. The residence times can vary from a few seconds to a number of hours.29 On the other hand the small intestine transit time is reported to be more consistent at three to four hours.30 Since the system is unable to sense and adapt to an individual’s condition, the approach clearly limits the utility.
An example of such a dosage form would be an impermeable capsule body containing the drug, fitted with a hydrogel plug that is used to deliver the drug after a predetermined time. This dosage form, for example Pulsincap®, releases the drug once the hydrogel plug hydrates and swells in aqueous media and is ejected from the device, thereby allowing the release of the drug from the capsule.33 Another example describes use of a hydrophobic material and surfactant in the tablet coating. The release of drug from the Time Clock® depends mainly on the thickness of the hydrophobic layer and is not dependent on the pH of the GI environment.34 The rationale behind all time-release delivery systems is valid provided that small intestine transit times remain constant. Changes in GI tract motility can significantly affect time-release drug delivery systems targeting the release of drugs to the colon.35
Bacteria-dependent Approach
The use of GI microflora as a mechanism of drug release in the colonic region has been of great interest to researchers in recent times. The majority of bacteria are present in the distal gut although they are distributed throughout the GI tract. Endogenous and exogenous substrates, such as carbohydrates and proteins, escape digestion in the upper GI tract but are metabolised by the enzymes secreted by colonic bacteria.36 Sulphasalazine, a prodrug consisting of the active ingredient mesalazine, was the first bacteria-sensitive delivery system designed to deliver the drug to the colon.37 Use of polysaccharides offers an alternative substrate for the bacterial enzymes present in the colon. Most of the polymers are used in pharmaceutical compositions and are considered generally regarded as safe (GRAS) excipients. Pectin alone and in combination with other polymers has been studied for colon-specific drug delivery. Pectin, when used alone, was needed in large quantities to control the release of the drug through the core. A coating composition of a mixture of pectin, chitosan and hydroxypropyl methylcellulose was proven to be very efficient as the tablets coated with this composition passed intact through the stomach and small intestine and broke in the colon.36,37
Pressure/Osmotically-dependent Approach
GI pressure is another mechanism that is utilised to initiate the release of the drug in the distal part of the gut. The muscular contractions of the gut wall generate this pressure, which is responsible for grinding and propulsion of the intestinal contents. The pressure generated varies in intensity and duration throughout the GI tract, with the colon considered to have a higher luminal pressure due to the processes that occur during stool formation. Systems have therefore been developed to resist the pressures of the upper GI tract but rupture in response to the raised pressure of the colon. Capsule shells fabricated from a water-insoluble polymer such as ethyl cellulose have been used for this purpose.38 The performance of these systems may be affected by the administered food as it may disintegrate the capsule in stomach.
