Small intestinal transit time of dosage forms

During fasting, both monolithic and multiparticulate dosage forms will be swept rapidly through the small bowel by the migrating myoelectric complex. The action is propulsive and not mixing in nature, thus a capsule containing pellets given on an empty stomach may leave the stomach and pass down the small intestine as a bolus with minimal dispersal27. The increased dispersal of pelleted formulations within the small intestine when the formulations are taken with a meal occurs because the pellets become dispersed in the food mass within the stomach28 29. As their particle size is small, pellets will continue to be emptied from the stomach as part of the chyme, thus prolonging their delivery to the small intestine (Figure 6.7). Monolithic tablets, on the other hand, depending upon their size, will empty erratically from the stomach after food and as the single unit traverses the small bowel. Hence, the presentation of the drug to the small intestinal mucosa will depend solely upon its dissolution characteristics in each area. The degree of spread of a formulation within the small intestine is particularly important for drugs with poor solubility or for drugs which are slowly transported across the epithelium. Microparticulate dosage forms show longer and more reproducible median transit times compared with single unit tablets30, giving rise to more predictable and uniform blood levels and reducing the risk of enlodgement and mucosal damage.

A review of data suggests that the small intestinal transit is around 4 hours for solutions, pellets and single unit formulations (Figure 6.8)31. Small intestinal transit of a

Figure 6.8 Small intestinal transit times of various dosage forms

dosage forms is not affected by their physical state, size or the presence or absence of food, but high calorific loads may slow it slightly although the majority of the effect is on gastric emptying (Figure 6.9)32. Small intestinal transit time is remarkably resistant to pharmaceutical intervention and in man physical properties such as shape, density or putative bioadhesive properties are without significant effect on transit. In a study of the spread of controlled-release isosorbide-5-dinitrate within the gastrointestinal tract33 (Figure 6.10), a deconvolution technique was used to calculate the drug absorption profile, and revealed that isosorbide-5-nitrate was well absorbed from the preparation whilst the pellets resided in the stomach and small intestine. However, absorption was reduced when the preparation entered the colon, hence the absorption window based on an average mouth-caecum transit time (6-8 hours) represents the maximum acceptable time for drug release from this oral controlled-release preparation. These studies suggest that if matrix tablets are

Figure 6.9 Delivery of multiparticulates from the stomach to the small intestine in fasted volunteers (□) after a heavy breakfast (■)

Figure 6.10 Gastrointestinal transit and absorption of isosorbide-5-dinitrate from controlled release pellets using combined gamma scintigraphy and blood sampling

(ROI=region of interest)

Figure 6.10 Gastrointestinal transit and absorption of isosorbide-5-dinitrate from controlled release pellets using combined gamma scintigraphy and blood sampling

(ROI=region of interest)

designed to release their contents over 12 h then colonic absorption of the drug is necessary and the drug must not be degraded by colonic bacteria.

Large amounts of unabsorbable carbohydrate or a large amount of fluid accelerates transit through the small bowel, and could therefore reduce the degree of absorption from a controlled-release formulation taken with the meal34. This principle has been used as the basis for a sustained release tablet containing riboflavin and myristyl tripalmitate35. Increasing the viscosity of the luminal contents by ingesting viscous polysaccharides such as guar gum or pectin will also prolong small bowel transit time, and may therefore increase the degree of absorption from slowly released or slowly absorbed drugs36. For example, the absorption of riboflavin is enhanced after being mixed with a viscous sodium alginate solution37.

The prolonged mouth-to-caecum transit may explain why the recovery of hydrochlorthiazide in the urine is greater when a controlled-release formulation of the drug is given with food than when given to fasted subjects38. Controlled-release lithium preparations are thought to cause diarrhoea by an action on ion transport in the ileum but this does not occur when they are taken with food39. This may also be due to enhanced absorption of the drug in the upper part of the small intestine, which occurs with a more prolonged transit in this region produced by the food, thus reducing the amount of lithium reaching the ileum to induce diarrhoea.

Scintigraphy often demonstrates accumulation or bunching of material at the ileocaecal junction. Non-disintegrating matrices may remain at this location for some time15 40. The stagnation at the ileocaecal junction may also cause problems for controlled-release dosage forms which are designed to release drug over a period of 9 to 12 hours, since the concentration of drug could build up within this localized area. This will have no effect on the absorption of most drugs, providing that the rate at which the drug is released from the dosage form is slower than the rate of uptake across the ileal epithelium, and the drug is not degraded by ileal bacteria.

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