Physiological Pharmaceutics

160 Physiological Pharmaceuticscompared to 5mm particles, which became significant following laxative administration.Selective retention of small particles is known as colonic sieving and may be important indrug delivery, although the upper cut-off size limit for retention of particles has yet to beestablished. The sieving behaviour in disorders such as ulcerative colitis, where the degreeof haustration is reduced, may influence the upper size limit for retention.If units become too large, they can have prolonged transit due to periods of stasis atthe ileo-caecal junction, hepatic and splenic flexures. Care should be taken when using largerigid units to study drug absorption from the colon, since an unphysiologically long colonictransit time would suggest an erroneously long time for drug absorption. The absorptiontimes would then be significantly reduced when the drug was administered in a morenormally sized dosage form.The sieving effect causes dispersible dosage forms such as pellets to become widelydistributed in the colon, whilst large single units or fragments of tablets travel rapidlythrough the colon ahead of the smaller pellets (Figure 7.7). This phenomenon is related tothe observation that batches of markers of increasing sizes given with successive mealsbecome interdispersed within the large intestine 80 which could be explained by the largerparticles moving fastest. In the descending colon, the particles come together beforedefaecation. This data suggests that optimisation of drug delivery to the proximal colon maybe achieved with a multiparticulate preparation which remains intact for approximately thefirst 5 hours after administration to the fasted patient. This would allow time for gastricemptying and transit through the small intestine. The drug preparation should then disperseallowing release of the material over the following 10 to 12 hours in the ascending andtransverse colon. Extending the release profile over a longer period would not be an addedadvantage due to the variability of excretion patterns and the slower diffusion throughconsolidating faecal material.Figure 7.7 Distribution of pellets within the colon following pulse release at the ileocaecaljunction