In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs

Although several routes of administration can be considered for new drug entities, the most popular remains the oral route. To predict the in vivo performance of a drug after oral administration from in vivo data, it is essential that the limiting factor to absorption can be modelled in vitro. In the case of BCS class II drugs dissolution is rate-limiting to absorption, so the use of biorelevant dissolution tests can be used to predict differences in bioavailability among different formulations and dosing conditions. To achieve an a priori correlation, the composition, volume and hydrodynamics of the contents in the gastrointestinal lumen following administration of the dosage form must be accurately simulated. Four media have been chosen/developed to model composition of the gastric and intestinal contents before and after meal intake. These are SGF, milk, FASSIF and FeSSIF, which model fasted and fed state conditions in the stomach and small intestine respectively. Using these media, excellent correlations have been obtained with the following poorly soluble drugs: danazol, ketoconazole, atovaquone and troglitazone. In all cases, fed vs. fasted state effects can be predicted from dissolution data and, where several formulations were available for testing, dissolution tests could also be used to determine which would have the best in vivo performance. Copyright (C) 2000 Elsevier Science B.V

Gastric juice as a dissolution medium: Surface tension and pH

Aspirated gastric juice from eight patients was measured for surface tension, bile salt concentration and pH. Surface tension ranged between 35 and 45 mM/m, while pH was usually in the range 1-2 and bile salt concentrations were usually between 0 and 1 mM. No correlations were found between the three parameters. These findings suggest that the low surface tension of gastric juice cannot be attributed solely to refluxed bile salts. Once the source of the reduced surface tension is identified dissolution test media should be adjusted to represent these conditions

Longitudinal versus radial effects of hydroxypropylmethylcellulose on gastrointestinal glucose absorption in dogs

Many water soluble fibers have been shown to favorably affect the postprandial glucose profile in humans. Hydroxypropylmethylcellulose (HPMC), a fiber which has been shown to increase glucose tolerance in dogs and noninsulin dependent diabetics, was chosen to study the luminal interactions which mediate this effect. The ability of HPMC to influence upper gastrointestinal (GI) viscosity, transit, and water flux of 5% and 20% glucose solutions was studied in five female dogs fistulated at the proximal duodenum and/or midjejunum. HPMC elevated intraluminal viscosity, with a linear relationship existing between input and luminal viscosity. The ability to modify intraluminal viscosity was greater for isoosmotic (5%) glucose solutions than for hyperosmotic (20%) glucose solutions. HPMC also modified the transit profile of isoosmotic (5%) glucose solutions at midgut by both increasing the lag times before the onset of chyme recovery from 5.5 ± 3.1 min to 9-55 min (depending on the viscosity of the administered solution) and decreasing the first-order transit rate constants from 0.115 ± 0.07 min-1 to 0.014-0.035 min-1. By contrast, the transit profile of hyperosmotic (20%) glucose solutions was not significantly affected. Net cumulative water flux across the gut wall was not significantly affected in either case by the presence of HPMC. These results, in combination with the amount of glucose recovered from midgut fistula, suggest that following the administration of glucose solutions, HPMC effects on blood glucose levels are mediated by mechanisms which relate to the increased intraluminal viscosity but vary according to the input glucose load. For isoosmotic glucose loads, both the decreased upper GI transit rate and hindered radial movement play a role. Although HPMC modifies glucose absorption from hyperosmotic solutions, this study shows that luminal effects occurring before midgut are modest

Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update

Purpose. The aim of this study was to update the compositions of biorelevant media to represent the composition and physical chemical characteristics of the gastrointestinal fluids as closely as possible while providing physical stability during dissolution runs and short-term storage. Methods. Media were designed to reflect postprandial conditions in the stomach and proximal small intestine in the "early", "middle", and "late" phases of digestion. From these "snapshot" media, general media for simulating postprandial conditions were devised. Additionally, media reflecting preprandial conditions in the stomach and small intestine were revisited. Results. A set of four media is presented. A recently published medium to represent the fasted stomach, FaSSGF, needed no further revision. To simulate the postprandial stomach, a new medium, FeSSGF, is presented. Media representing the upper small intestine in the fed and fasted states were fine-tuned according to physicochemical and biochemical characteristics in vivo. All four media proved to be stable under ambient storage conditions for at least 72 h as well as under usual dissolution test conditions. Conclusions. The updated dissolution media can be used to predict formulation performance and food effects in vivo. These media are more physiologically relevant and show better physical stability than their corresponding predecessors. © 2008 Springer Science+Business Media, LLC

Unusual solubility behaviour of cyclosporin A in aqueous media

Abstract— The solubility of cyclosporin A was determined in water and in Sorensen buffers at pH 1.2 and 6.6 at temperatures ranging from 5 to 37°C. No differences in solubility behaviour were observed among the three aqueous media. Solubility was found to be inversely proportional to the temperature in each medium, indicating that the heat of solution was exothermic in each case. 1991 Royal Pharmaceutical Society of Great Britai

Effect of elevated viscosity in the upper gastrointestinal tract on drug absorption in dogs

The objectives of these studies were, first, to determine the effect of elevated luminal viscosity on the gastrointestinal absorption of four model drags and, second, to identify the key processes influencing drag absorption under elevated viscosity conditions. Studies were conducted in vitro and in healthy female mongrel dogs under fasting conditions. In the canine model, both the rate and extent of paracetamol and hydrochlorothiazide absorption were significantly decreased by the coadministration of 15 g guar gum dissolved in 500 ml normal saline. In the case of cimetidine, the rate but not extent of absorption was decreased. Owing to the high variability in the data, no statistically based conclusion could be drawn about the effects of coadministered guar gum on the oral absorption of the poorly soluble mefenamic acid. Based on the in vitro data, it appears that substantial reductions in the dissolution rate of paracetamol, hydrochlorothiazide and cimetidine account for the effects observed in vivo. It is concluded that the effect of an elevation in the intraluminal viscosity on drug absorption is greatest for highly soluble drags, and results from a combination of a decrease in dissolution rate and gastric emptying rate

Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data

Purpose. To assess the usefulness of biorelevant dissolution tests in predicting food and formulation effects on the absorption of four poorly soluble, lipophilic drugs. Methods. Dissolution was studied with USP Apparatus II in water, milk, SIF(sp), FaSSIF, and FeSSIF. The in vitro dissolution data were compared on a rank order basis with existing in vivo data for the tested products under fasted and fed state conditions. Results. All drugs/formulations showed more complete dissolution in bile salt/lecithin containing media and in milk than in water and SIF(sp) (USP 23). Comparisons of the in vitro dissolution data in biorelevant media with in vivo data showed that in all cases it was possible to forecast food effects and differences in absorption between products of the same drug with the physiologically relevant media (FaSSIF, FeSSIF and milk). Differences between products (both in vitro or in vivo) were less pronounced than differences due to media composition (in vitro) or dosing conditions (in vivo). Conclusions. Although biorelevant dissolution tests still have issues which will require further refinement, they offer a promising in vitro tool for forecasting the in vivo performance of poorly soluble drugs