Regulating Gastric Emptying

The duodenum regulates the supply of material from the stomach to the small intestine. Fat, high salinity and highly acid solutions cause the duodenal wall pressure to increase and slow down the exit of the gastric contents. Because the gastroduodenal system regulates the exit of the slurried contents from the stomach, the transit time from duodenum to the caecum is relatively constant. The diameter of the pyloric opening varies according to the nature of the gastric contents. When taken with water in a fasted individual, the time of tablet emptying will be highly variable. Tablets will be emptied at various times after ingestion according to posture, volume of fluid taken and the calorific value of food taken before or with the dosing. If they disintegrate and dissolve, pulses of material will appear regularly in the small intestine at a rate determined by the meal, with the rise to intestinal pH (Fig. 2.8).

Pellets and disintegrated dosage forms empty from the stomach as either a series of pulses when fasted or distributed in the meal when fed [7]. The emptying of pellets is much more predictable in the fasted state as illustrated in Fig. 2.9. Tablets that remain intact will empty at very variable times when fasted but eating a light meal reduces the variability in emptying as illustrated.

Large tablets will stay in the stomach for prolonged periods of time especially in the more elderly subject where the laxity in stomach becomes predominant.

Gastric Motility
Fig. 2.8 pH and motility in the upper gastrointestinal tract

Fig. 2.9 Emptying of tablet components with a meal. Dissolving drug will follow the liquid emptying curve, disintegrated API the disperse phase. Any large fragments or intact tablets will exit with the housekeeper sequence

Fig. 2.9 Emptying of tablet components with a meal. Dissolving drug will follow the liquid emptying curve, disintegrated API the disperse phase. Any large fragments or intact tablets will exit with the housekeeper sequence

When food is taken, this discrimination is more extreme as the effective diameter of the pylorus decreases and large tablets are retropulsed back into the body of the stomach at the end of a gastric contraction. Smaller particulates are emptied in the mass of the food and the presentation of the dose in a dispersed system is a function of calorific load and mass of the gastric contents [8]. If food is eaten throughout the day after a heavy breakfast and subsequent meals, then in some individuals a conventional enteric-coated ibuprofen will remain intact up to the end of the day having neither disintegrated nor emptied [9].

Drug, ejected with chyme from stomach will be absorbed in the first highly permeable part of the intestine; however, transit through this region occurs rapidly. Thus, whilst high drug absorption can be demonstrated under in vitro conditions, it is most probable that duodenal absorption occurs when the dose remains in the body of the stomach. When recumbent, the fundus or first part of the stomach is positioned lower in the abdomen than the pyloro-duodenal sphincter. As a consequence, drug released in the upper stomach may not appear in the systemic circulation until a postural movement allows flow through to the distal stomach and out into the intestine.

Once the intake of food stops and blood sugar and free fatty acids decrease, the "housekeeper sequence" (migrating myoelectric complex) is initiated which serves to remove debris. This powerful peristaltic wave causes powerful contractions against an open pylorus. In scintigraphy studies, in young people who have fasted, this is evident about 2 h postdosing (i.e. around 10 a.m.). As tablets travel down the gut, the movement slows and periods of stasis are common just before the tablet leaves the ileum and enters the large intestine. Eating food later on will cause a gastrocolic reflex (see Sect. 2.6.2), enabling the contents to move from small intestine to large bowel.

This mechanism, colloquially known as the housekeeper sequence or more properly as the migrating motor complex (MMC) can be recorded externally with

Men Hair Length Guide
Fig. 2.10 The migrating myoelectric complex or housekeeper sequence

electrodes on the abdomen (Fig. 2.10). This was first described in the literature following the first experiments described by Code and Martlett and by Bull and colleagues [10, 11]. The mixing activity gives way to strong propulsive waves, which migrate through the small intestine. The strong contractile activity during phase III of the MMC is an important factor limiting the retention of dosage forms, but the cycle may be interrupted and reset by the intake of food.

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