Physiological Pharmaceutics

124 Physiological PharmaceuticsFigure 6.7 Effect of light () and heavy breakfast () on the gastric emptying and colonarrival of a co-administered multiparticulate formulationonly contains a small fraction of the total dose administered so local concentrations of thedrug would be small thus reducing mucosal damage.Castor oil is believed to decrease the activity of the circular smooth muscle which isthought to produce an increase in intestinal transit. The mechanism by which castor oilproduces its effect on the gut could involve inhibition of Na + , K + -ATPase, activation ofadenylate cyclase, stimulation of prostaglandins and nitric oxide biosynthesis. Castor oilalso changes the intestinal permeability and causes histological abnormalities.Small intestinal transit time of dosage formsDuring fasting, both monolithic and multiparticulate dosage forms will be swept rapidlythrough the small bowel by the migrating myoelectric complex. The action is propulsive andnot mixing in nature, thus a capsule containing pellets given on an empty stomach may leavethe stomach and pass down the small intestine as a bolus with minimal dispersal 27 . Theincreased dispersal of pelleted formulations within the small intestine when the formulationsare taken with a meal occurs because the pellets become dispersed in the food mass withinthe stomach 28 29 . As their particle size is small, pellets will continue to be emptied from thestomach as part of the chyme, thus prolonging their delivery to the small intestine (Figure6.7). Monolithic tablets, on the other hand, depending upon their size, will empty erraticallyfrom the stomach after food and as the single unit traverses the small bowel. Hence, thepresentation of the drug to the small intestinal mucosa will depend solely upon itsdissolution characteristics in each area. The degree of spread of a formulation within thesmall intestine is particularly important for drugs with poor solubility or for drugs whichare slowly transported across the epithelium. Microparticulate dosage forms show longerand more reproducible median transit times compared with single unit tablets 30 , giving riseto more predictable and uniform blood levels and reducing the risk of enlodgement andmucosal damage.A review of data suggests that the small intestinal transit is around 4 hours forsolutions, pellets and single unit formulations (Figure 6.8) 31 . Small intestinal transit of a