42 research outputs found
Dissolution profile evaluation of solid pharmaceutical forms containing chloramphenicol marketed in Brazil
Development of dissolution test method for a telmisartan/amlodipine besylate combination using synchronous derivative spectrofluorimetry
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
Predicting the Changes in Oral Absorption of Weak Base Drugs Under Elevated Gastric pH Using an In Vitro-In Silico-In Vivo Approach: Case Examples - Dipyridamole, Prasugrel, and Nelfinavir
The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH-dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasugrel, and nelfinavir were simulated and compared with pharmacokinetic data reported in humans with or without use of proton pump inhibitors or histamine H2 receptor antagonists. The in vitro dissolution and precipitation data for the weakly basic drugs in biorelevant media were obtained using paddle apparatus. An in silico prediction model based on the STELLA software was designed and simulations were conducted to predict the oral pharmacokinetic profiles of the 3 drugs under both usual (low) and elevated gastric pH conditions. The changes in oral absorption of dipyridamole and prasugrel in subjects with elevated gastric pH compared with those with low stomach pH were predicted well using the in vitro–in silico–in vivo approach. The proposed approach could become a powerful tool in the formulation development of poorly soluble weak base drugs
Estimate of Volume/Flow Ratio of Gastrointestinal (GI) Fluids in Humans Using Pharmacokinetic Data
Based on the mixing tank and tube models for drug absorption, the apparent absorption rate constant is shown to be related to the fraction of dose absorbed as a function of the volume/flow ratio of GI fluids. This analysis applies to drugs that are absorbed according to first-order kinetics, without limitation by dissolution rate, lumenal decomposition, or first-pass metabolism. Analysis of pharmacokinetic data of drugs that fit these criteria and are absorbed to varying extents enabled the estimation of the volume/flow ratio of GI fluids in humans; it was found to be 1.6 ± 0.3 (SE) hr using a mixing tank model and 0.32 ± 0.05 hr using a tube model. These findings are discussed with respect to volume and flow parameters used in the design of various types of drug absorption studies. © 1990, Plenum Publishing Corporation. All rights reserved
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 testing as a prognostic tool for oral drug absorption: Immediate release dosage forms
Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test
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
Estimating drug solubility in the gastrointestinal tract
Solubilities measured in water are not always indicative of solubilities in the gastrointestinal tract. The use of aqueous solubility to predict oral drug absorption can therefore lead to very pronounced underestimates of the oral bioavailability, particularly for drugs which are poorly soluble and lipophilic. Mechanisms responsible for enhancing the luminal solubility of such drugs are discussed. Various methods for estimating intra-lumenal solubilities are presented, with emphasis on the two most widely implemented methods: determining solubility in fluids aspirated from the human gastrointestinal tract, and determining solubility in so-called biorelevant media, composed to simulate these fluids. The ability of the biorelevant media to predict solubility in human aspirates and to predict plasma profiles is illustrated with case examples. © 2007