GASTRORETENTIVE DOSAGE FORMS

This article begins with a review of gastric emptying, small intestine transit, and colonic transit of drug delivery systems with special at tention paid to the different physiological processes involved in stom ach emptying and to the cut-off size of nondigestible solids for passa ge through the gastroduodenal junction during the digestive phase. The n, the proposed means for prolonging the gastric residence time (GRT) of drug delivery systems are reviewed and analyzed with special emphas is on floating (F) dosage forms. The following means are discussed: th e use of passage-delaying agents, large single-unit dosage forms, bioa dhesive drug delivery systems, ''heavy'' pellets, and buoyant forms. I n the section devoted to bioadhesive forms, the influence of the turno ver time of the intestinal mucus gel layer on the performance of mucoa dhesive preparations is pointed out to explain the poor results obtain ed in humans with such peroral products. The use of a specifically des igned apparatus for measuring the total force acting vertically on an object immersed in a liquid is presented as a methodology for selectin g optimized buoyant formations in vitro. Scintigraphic studies are des cribed in nonfasting human volunteers either in upright or in supine p osture, who concurrently were given one optimized F and one nonfloatin g (NF) hydrophilic matrix capsules of the same size, for three differe nt sizes (small, medium, and large). In upright subjects, the F forms stayed continuously above the gastric contents irrespective of their s ize, whereas the NF ones sank rapidly after administration and never r ose back to the surface thereafter. Consequently, the F forms show pro longed and more reproducible GRTs compared to the NF ones. The signifi cance and extent of this prolongation are the most marked for the smal l size units (p < 0.001) but gradually lessen as the dosage form size increases (p < 0.05 for the medium size units), to become insignifican t for the large size units (p > 0.05). Moreover, there is no significa nt difference between the mean GRTs of the small, medium, and large F units (p > 0.05). This indirectly confirms that the intragastric buoya ncy of the F forms is the main process determining their prolonged GRT and protecting them from random gastric emptying related to antral pe ristaltism. Thus, their GRT depends mainly on the occurrence of the en d point of digestion. To the contrary, the lasting retention of the NF forms in the stomach is only size dependent. It appeared systematical ly with the large size units but not with all of the medium size units and never with the small size units (mean GRT small < medium < large, p < 0.05). In supine subjects (lying on their back), both the F and t he NF forms are better retained as their size increases. There is no s ignificant difference between the GRTs of both types of forms of the s ame size (F vs. NF, p > 0.05) because the F forms remain buoyant anywh ere between the lesser and greater curvatures of die stomach. This pos ition does not protect them from random emptying when they move distal ly toward the pylorus. Thus, in supine subjects, the GRTs of die F for ms vary according to their size (mean GRT small < medium < large units , p < 0.05). Moreover, the GRTs of all the F forms are significantly r educed and more scattered in supine subjects when compared to those in upright ones (p < 0.05). The GRTs of the NF forms are, size for size, not noticeably modified by the change of body posture (upright vs. su pine, p > 0.05) and they still increase with the size of the form (mea n GRT small < medium < large units, p < 0.05). Drawbacks related to th e approach of GRT enhancement based on a size effect are discussed. Th e gastric retention performances of F forms within a frequent feeding regimen are reported. All the F forms were systematically emptied much later in the frequently fed subjects than in subjects having received a single meal (p < 0.001). The scintigraphic images prove that the F forms are able to remain buoyant when submitted to repeated meal inges tion. This brings evidence, for the first time, of the applicability o f F forms in patients having normal diet and feeding habits of everyda y life. All these scintigraphic results also have been analyzed to add ress the relationship between the diametral size of the tested forms a nd gastric emptying during the digestive phase. The cut-off size may s ometimes be much higher than 7 mm but important intersubject variation s exist, which may be related to differences in the diameter of the py loric opening. In an attempt to clarify the conflicting views on the g astric retention capabilities of F forms, several publications are cri ticized in light of the above-mentioned in vivo results. Finally, it i s demonstrated that the formulation of bilayer hydrophilic matrix caps ules allowing the separate regulation of the floating properties and o f the drug release kinetics is feasible. No separation of the layers c ould be detected either in vitro or in vivo when bilayer capsules were administered to subjects after a single meal or with a succession of meals. Several tables containing examples of composition of either hom ogeneous or bilayer floating hydrophilic matrix capsules are presented .