Targeting the proximal colon

The proximal colon is relatively inaccessible. Even large volume enemas will only just reach the transverse colon82. Any substance administered orally has to pass through the hostile environment of the stomach and through the small intestine where it is likely to be digested and absorbed. Protecting the drug from these factors and releasing it at the base of the ascending colon to optimise colonic exposure has been the subject of much research.

Several approaches have been expored to achieve site specific delivery to the colon. These most commonly include:

i) utilizing the pH change which occurs on transit from the small to the large intestine83

ii) providing release of a drug after a pre-determined time84-86

iii) colon-targeting lectins87

iv) utilizing degradation mechanisms of bacteria specific to the colon88 89

Eudragit and other enteric coatings are widely used to produce acid resistant formulations, and with appropriate control of dissolution time may be reasonably effective in achieving release of drug in the ascending colon. For colonic delivery, Eudragits L and S, which are anionic copolymers of methacrylic acid and methyl methacrylate, have been widely used. These polymers are insoluble at low pH but form salts and dissolve above pH 6 and 7, respectively. Eudragit L100-55, a copolymer of methacrylic acid and ethyl acrylate, is water soluble which avoids the need for organic solvents in the coating process90.

The first study which employed Eudragit S for colon-targeting used sulphapyridine as a marker for drug release84. Hard gelatin capsules containing the drug, and barium sulphate to aid radiological visualisation, were coated with the polymer and administered to 6 subjects who each swallowed 6 capsules. Twelve hours after administration, 4 capsules had broken in the distal ileum, 23 in the colon and 9 remained intact. The same approach was used with 5-aminosalicylic acid (5-ASA) but the thickness of the polymer coating was reduced from 120 to 80 pm91. This formed the basis of the commercial formulation of 5-ASA tablet. There has been at least one report of patients taking 5-ASA and reporting the transit of intact tablets in their stools. This is probably a result of the high pH at which the Eudragit S-based coatings dissolve.

The study of Eudragit S coated tablets (10 mm diameter) in 7 volunteer subjects using gamma scintigraphy yielded some interesting results92. In some subjects, stasis at the ileocaecal junction was noted. Other subjects had rapid transit through the colon, leading the authors to speculate whether the variability in transit meant that a pH-based coating was an unreliable means of delivery to the colon.

Recently the potential for pH-sensitive dextran hydrogels to be used as colon-specific delivery systems has been investigated in vitro93 94.

The constancy of transit of dosage forms through the small intestine has been well established. It has been speculated that if a unit could be timed to release drug around four hours after leaving the stomach, the unit should be at the base of the ascending colon at the time of drug release. Approaches to achieve targeted colonic delivery based on hydrogel technology, exemplified by the Pulsincap™ delivery system (Figure 7.8), appear to largely succeed. The Pulsincap comprises an impermeable capsule body containing the drug formulation, sealed at the neck edge with a hydrogel polymer plug95. On ingestion, the capsule becomes exposed to gastric fluids and the water soluble gelatin cap dissolves, allowing the hydrogel plug to hydrate. At a pre-determined and controlled time point after ingestion, the swollen plug is ejected from the capsule body thereby enabling the drug formulation to be released. The time of plug ejection is controlled by the length of the hydrogel plug and its position relative to the neck of the capsule body.

Time

Gastroresistant

Hydrogel

Gastroresistant

Hydrogel

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