Author : Mette Uhre Anby
Publisher :
ISBN 13 :
Total Pages : 508 pages
Book Rating : 4.:/5 (11 download)
Book Synopsis Understanding the Determinants of Drug Absorption Following Oral Administration of Lipid-based Drug Delivery Systems by : Mette Uhre Anby
Download or read book Understanding the Determinants of Drug Absorption Following Oral Administration of Lipid-based Drug Delivery Systems written by Mette Uhre Anby and published by . This book was released on 2012 with total page 508 pages. Available in PDF, EPUB and Kindle. Book excerpt: The current project has explored the determinants of drug absorption following oral administration of lipid-based drug delivery systems (LBDDS) and the role of intestinal digestive processes on formulation performance. Particular focus has been directed to the role of formulation excipients and drug loading on the generation and maintenance of drug supersaturation during LBDDS processing and the subsequent impact on drug bioavailability. The data show that initiation of digestion by pancreatic enzymes functions as an effective supersaturation trigger and that addition of polymeric precipitation inhibitors (PPI) may be utilised to stabilise supersaturation for longer periods and therefore to enhance absorption. Formulation performance was highly correlated with the maximum degree of supersaturation that the formulation generated on dispersion and digestion. In vitro, increasing drug dose initially increased drug thermodynamic activity in the aqueous colloidal phases formed by formulation digestion. Above a critical drug loading, however, supersaturation 'pressure' increased to a point above which nucleation and crystal growth dominated, resulting in drug precipitation. The utilisation of lower drug loads, higher surfactant levels, reduced cosolvent and the addition of PPI all enhanced formulation performance in vitro (i.e. supported ongoing solubilisation), however, subsequent studies showed that only in some cases was the addition of PPI able to support enhanced absorption in vivo. Consistent with the potential for increases in thermodynamic activity with increase in drug dose, non-linear increases in bioavailability were evident after administration of a series of LBDDS containing increasing quantities of drug to beagle dogs. In further alignment with the in vitro data, non-linear increases in bioavailability were also only evident up to a critical point, beyond which further increases in drug dose resulted in a reduction in bioavailability. The initial in vivo studies were therefore highly consistent with the in vitro supersaturation data. Replication of the in vivo study in a younger cohort of animals, however, was not able to reproduce the same trends and linear increases in exposure with dose were apparent in this animal cohort. Further studies failed to show a significant difference in hepatic function across the two cohorts, and instead suggested that age-related changes in GI solubilisation, potentially through increased bile salt secretion in the older cohort, may have led to better stabilisation of supersaturation and therefore increases in danazol absorption. Increases in the quantity of drug absorbed at higher doses in the older cohort may have also magnified differences in exposure due to greater saturation of first pass metabolism. The latter data led to a more detailed evaluation of the role of drug dose on the bioavailability of danazol from LBDDS. These studies were conducted in rats to allow more direct exploration of the role of first pass metabolism, and gastric and intestinal processing on danazol bioavailability. Surprisingly, danazol exposure in the rat following oral administration of danazol formulated in similar LBDDS as those used in the dog studies was low ( 12%), and incorporation of PPI had limited effect. In contrast, co-administration of an inhibitor of CYP450 enzymes resulted in a large increase in bioavailability suggesting that the major limitation to oral bioavailability was first pass metabolism. The applicability of previous in vitro models of lipid digestion to events in the rat was also examined, and a number of modifications to the model suggested. The data obtained indicate that in the rat, lipid digestion may be less efficient than it is in the dog (or human), and therefore that digestion-mediated reductions in solubilisation capacity are less important, that danazol absorption from LBDDS formulations is high ( 50%) and that the principle limitation to danazol bioavailability in the rat is first pass metabolism. In summary, this thesis contributes to a better understanding of the mechanisms by which LBDDS promote drug solubilisation and absorption and specifically to the influence of drug dose, animal model and the inclusion of polymeric precipitation inhibitors (PPI) on supersaturation generation and stabilisation.
