Christos Reppas
National and Kapodistrian University of Athens
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Pharmaceutical Research | 1998
Jennifer B. Dressman; Gordon L. Amidon; Christos Reppas; Vinod P. Shah
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.
Pharmaceutical Research | 1998
Eric Galia; Eleftheria Nicolaides; D. Hörter; Raimar Löbenberg; Christos Reppas; Jennifer B. Dressman
AbstractPurpose. In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Methods. Dissolution behavior of two class I drugs, i,e, acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Results. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. Conclusions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.
European Journal of Pharmaceutical Sciences | 2000
Jennifer B. Dressman; Christos Reppas
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.
Journal of Pharmacy and Pharmacology | 2004
Maria Vertzoni; Nikoletta Fotaki; Eleftheria Nicolaides; Christos Reppas; Edmund S. Kostewicz; Erika Stippler; Christian Leuner; Jennifer B. Dressman
The objective of this study was to test various aspects of dissolution media simulating the intralumenal composition of the small intestine, including the suitability of the osmolality‐adjusting agents and of the buffers, the substitution of crude sodium taurocholate (from ox bile) for pure sodium taurocholate and the substitution of partially hydrolysed soybean phosphatidylcholine for egg phosphatidylcholine. It was concluded that biorelevant media should contain sodium as the major cation species to better reflect the physiology. However, the use of non‐physiologically relevant buffers is inevitable, especially for simulation of the fed state in the small intestine. The buffers used may affect the solubility product of weakly basic compounds with pKa(s) higher than about 5, the solubility of extremely highly lipophilic compounds due to salting in/out properties of the anion of the buffer and the stability of the dissolving compound. It is prudent in relevant situations to run an additional dissolution test in a modified fed state simulated intestinal fluid (FeSSIF) (or fasted state simulated intestinal fluid (FaSSIF), where applicable) containing alternative buffer species. Although a mixture of bile salts is physiologically more relevant than pure sodium taurocholate, this issue seems to be of practical importance in only a few cases. Adequate simulations in these cases will probably require the use of a number of pure substances and could substantially increase the cost of the test. Finally, unless the drug is extremely lipophilic (ca. logP > 5), egg phosphatidylcholine can be substituted by partially hydrolysed soybean phosphatidylcholine.
Pharmaceutical Research | 2001
Eleftheria Nicolaides; Moira Symillides; Jennifer B. Dressman; Christos Reppas
AbstractPurpose. To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved. Methods. Previously published dissolution data from seven products of four lipophilic drugs were compared using the first order model, the RRSBW distribution, and a model based on the Noyes-Whitney theory. Simulated plasma profiles were then obtained using a model-dependent approach. Simulated and observed plasma profiles were compared with the difference factor, f1. Results. No model consistently provided the best fit to the in vitrodata, which varied significantly with medium composition. Prediction of the plasma profile was possible (9.6 ≤ f1≤ 34.2) in seven out of eleven cases. Conclusions. Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.
Pharmaceutical Research | 1999
Eleftheria Nicolaides; Eric Galia; Constantin Efthymiopoulos; Jennifer B. Dressman; Christos Reppas
AbstractPurpose. 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, SIFsp, 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 SIFsp (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 promisingin vitro tool for forecasting the in vivo performance of poorly soluble drugs.
European Journal of Pharmaceutical Sciences | 2014
Erik Sjögren; Bertil Abrahamsson; Patrick Augustijns; Dieter Becker; Michael B. Bolger; Marcus E. Brewster; Joachim Brouwers; Talia Flanagan; Matthew D. Harwood; Christian Heinen; René Holm; Hans-Paul Juretschke; Marlies Kubbinga; Anders Lindahl; Viera Lukacova; Uwe Münster; Sibylle Neuhoff; Mai Anh Nguyen; Achiel Van Peer; Christos Reppas; Amin Rostami Hodjegan; Christer Tannergren; Werner Weitschies; Clive G. Wilson; Patricia Zane; Hans Lennernäs; Peter Langguth
This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in todays knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.
European Journal of Pharmaceutics and Biopharmaceutics | 2009
Yasushi Shono; Ekarat Jantratid; Niels Janssen; Filippos Kesisoglou; Yun Mao; Maria Vertzoni; Christos Reppas; Jennifer B. Dressman
Since the rate-determining step to the intestinal absorption of poorly soluble drugs is the dissolution in the gastrointestinal (GI) tract, postprandial changes in GI physiology, in addition to any specific interactions between drug and food, are expected to affect the pharmacokinetics and bioavailability of such drugs. In this study, in vitro dissolution testing using biorelevant media coupled with in silico physiologically based pharmacokinetic (PBPK) modeling was applied to the prediction of food effects on the absorption of a poorly soluble drug, celecoxib, from 200mg capsules. A PBPK model was developed based on STELLA software using dissolution kinetics, solubility, standard GI parameters and post-absorptive disposition parameters. Solubility, dissolution profiles and initial dissolution rate from celecoxib 200mg capsules were measured in biorelevant and compendial media. Standard GI parameters (gastric emptying rate and fluid volume) were varied according to the dosing conditions. Disposition parameters were estimated by fitting compartmental models to the oral PK data, since intravenous data are not available for celecoxib. Predictions of food effects and average plasma profiles were evaluated using the AUC and C(max) and the difference factor (f(1)). An approximately 7-fold difference in the maximum percentage dissolved was observed in in vitro dissolution tests designed to represent the fed and fasted states. By contrast, the food effect estimated by simulating the plasma profiles with the PBPK model predicted only a slight delay in the peak plasma level ( approximately 1h), and modest increases in the C(max) and AUC of approximately 1.9-fold and 1.3-fold in the fed state, respectively. The PBPK approach, combining in silico simulation coupled with biorelevant dissolution test results, thus corresponds much better to the food effect observed for celecoxib in vivo. Additionally, point estimates of AUC and C(max) as well as f(1) calculations demonstrated clear advantages of using results in biorelevant rather than compendial media in the PBPK model.
Journal of Pharmacy and Pharmacology | 1991
George Ismailos; Christos Reppas; Jennifer B. Dressman; P. Macheras
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.
European Journal of Pharmaceutics and Biopharmaceutics | 2010
Yasushi Shono; Ekarat Jantratid; Filippos Kesisoglou; Christos Reppas; Jennifer B. Dressman
This study coupled results from biorelevant dissolution tests with in silico simulation technology to forecast in vivo oral absorption of micronized and nanosized aprepitant formulations in the pre- and post-prandial states. In vitro dissolution tests of the nanosized aprepitant formulation and micronized drug were performed in biorelevant and compendial media. An in silico physiologically based pharmacokinetic (PBPK) model was developed based on STELLA software using dissolution kinetics, standard gastrointestinal (GI) parameters and post-absorptive disposition parameters. GI parameters (gastric emptying rate and GI fluid volume) were varied according to the dosing conditions. Disposition parameters were estimated by fitting compartmental models to the in vivo oral PK data. Predictions of in vivo performance in each prandial state were evaluated using the AUC and C(max) generated from the simulated PK profiles. To predict oral absorption from the extremely fast dissolving nanosized aprepitant formulation, several variations on a previously published model were evaluated. Although models that assumed that the formulation behaved as an oral solution or that adjusted the dissolution kinetics according to the different numbers of particles per gram between micronized and nanosized aprepitant generated profiles similar to the observed in vivo data in the fed state, simulated profiles for the fasted state showed much faster absorption than that observed in the in vivo data. This appeared to result from the assumption of no absorption restrictions in those models. To better predict in vivo performance in both fasted and fed states, a model that adds permeability restrictions to absorption was applied. This model not only simulated the in vivo profiles for aprepitant well in both prandial states, but also predicted the dependency of the pharmacokinetics on the dose and the particle size of aprepitant. In conclusion, a model based on STELLA software combined with dissolution results in biorelevant media successfully forecasts the in vivo performance of both nanosized and micronized formulations of aprepitant in the fed and fasted states. Although dissolution is the primary limitation to the rate of absorption for micronized aprepitant, some permeability restrictions are revealed for the nanosized formulation. The results also indicate that biorelevant dissolution media have strong advantages over compendial media in forecasting the in vivo behavior of aprepitant.