Christos Reppas

National and Kapodistrian University of Athens, Athínai, Attica, Greece

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Publications (86)276.86 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.
    Pharmaceutical Research 03/2014; · 4.74 Impact Factor
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    ABSTRACT: 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 pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 03/2014; · 2.61 Impact Factor
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    ABSTRACT: OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organisation, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery and. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using API, formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and) and modified-release formulations, as well as allowing optimisation of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo is expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2013; · 2.61 Impact Factor
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    ABSTRACT: In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TMCaco and FeSSIF-TMCaco, respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TMCaco and FeSSIF-TMCaco, and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TMCaco, following the rank order aq-TMCaco > FaSSIF-TMCaco > FeSSIF-TMCaco. The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TMCaco, permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TMCaco whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 10/2013; · 3.15 Impact Factor
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    ABSTRACT: The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (∼70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65-72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in-vitro digestion did not adversely impact fenofibrate bioavailability in-vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 10/2013; · 3.15 Impact Factor
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    ABSTRACT: Studies on the characterization of ascending colonic fluids are scarce, limited to physicochemical characterization of their composition, and little is known for the morphology of the produced colloidal phases. In an attempt to gain insights for their structure at the ultrastructural level, samples from the lumen of ascending colon were collected from patients with ulcerative colitis in remission. After ultracentrifugation, the supernatants of two samples (one with high and one with low cholesterol level) were visualized by means of cryogenic transmission electron microscopy. In the supernatants with high cholesterol content, micellar-like structures, bilayer fragments, open vesicles, and uni-, bi- and trilamellar vesicles were abundant. In addition, crystals of cholesterol were frequently observed. In contrast, in the sample with low cholesterol content, oily solids, plates of cholesterol monohydrate and elongated structures were present. Few unilamellar vesicles were occasionally visualized. The current study gives direct evidence, for the first time, of the existence of 'remnants' of lipolytic products in the fasted ascending colon. The impact of these structures to colonic absorption of drugs is an open question.
    The Journal of pharmacy and pharmacology. 10/2013; 65(10):1482-7.
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    ABSTRACT: Evaluate the impact of luminal micellar phase on passive permeability of five lipophilic (1.9 ≤ clogP ≤ 9.0) small molecules using biorelevant media and evaluate the impact of luminal coarse lipid particles on danazol permeability after oral administration of a triglyceride solution to fed adults using PAMPA. Permeability of carbamazepine, furosemide, danazol, and Compound A was evaluated using Prisma™ HT, FaSSIF-V2, and FeSSIF-V2 in the donor compartment. Compound B could not be tested using Prisma™ HT, due to negligible solubility. Individual intestinal aspirates collected after administration of danazol solution in the olive oil portion of a meal and corresponding micellar phases were subjected to PAMPA. Commercially available Acceptor Sink Buffer was used in all cases. Unlike with furosemide (under constant pH) and Compound B, permeability of carbamazepine, danazol, and Compound A steadily decreased in the presence of increasing micelle concentration of media. Danazol permeability from aspirates was reduced compared to that from micellar phases; fluxes were similar. Using PAMPA, the impact of luminal micellar phase on passive permeability of lipophilic molecules varies with the molecule. After administration of a triglyceride solution of danazol, high danazol concentrations in coarse lipid particles balance in terms of drug flux the reduced permeability.
    Pharmaceutical Research 07/2013; · 4.74 Impact Factor
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    ABSTRACT: Human biorelevant media have been shown to be a useful tool in pharmaceutical development and to provide input for in silico prediction of pharmacokinetic profiles after oral dosing. Dogs, in particular Beagles, are often used as animal models for preclinical studies. Key differences in the composition of human and canine gastric and intestinal fluids are described in literature and underscore the need to develop a discrete set of biorelevant media, adapted to the conditions of the proximal canine gastrointestinal (GI) tract, to improve forecast and interpretation of preclinical results using in vitro dissolution studies. Canine biorelevant media can also be used in the development of oral dosage forms for companion animals, which is a rapidly growing market. The compositions of Fasted State Simulated Gastric Fluid canine (FaSSGFc) and Fasted State Simulated Intestinal Fluid canine (FaSSIFc) are adapted to the physiological composition of the corresponding gastrointestinal fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid, and free fatty acid content (in terms of concentration and reported subtypes). It was demonstrated that canine Fasted State Simulated Intestinal Fluid (FaSSIFc) is superior in predicting the solubility of model compounds in Canine Intestinal Fluid (CIF) compared to the human biorelevant media (FaSSIF and FaSSIF-V2). Two different versions of FaSSGFc, composed at pH 1.5 and pH 6.5, offer the possibility to design in vitro studies which correspond to the in vivo study design, depending on whether pentagastrin is used to decrease the gastric pH in the dogs or not. Canine biorelevant media can therefore be recommended to achieve more accurate forecasting and interpretation of pharmacokinetic studies of oral drug products in dogs.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 02/2013; · 3.15 Impact Factor
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    ABSTRACT: PURPOSE: To develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on ketoconazole and dipyridamole luminal data. Evaluate usefulness of methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data. METHODS: A three-compartment in vitro setup was used. Depending on the dosage form administered in in vivo studies, a solution or a suspension was placed in the gastric compartment. A medium simulating the luminal environment (FaSSIF-V2plus) was initially placed in the duodenal compartment. Concentrated FaSSIF-V2plus was placed in the reservoir compartment. RESULTS: In vitro ketoconazole and dipyridamole concentrations and precipitated fractions adequately reflected luminal data. Unlike luminal precipitates, in vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data confirmed previously published human pharmacokinetic data suggesting that absorption rates are not affected by luminal precipitation. In vitro SB705498 data predicted that significant luminal precipitation occurs after a 100 mg or 400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data. CONCLUSIONS: An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.
    Pharmaceutical Research 08/2012; · 4.74 Impact Factor
  • Christos Reppas, Maria Vertzoni
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    ABSTRACT: This review focuses on the evolution and current status of biorelevant media and hydrodynamics, and discusses the usefulness of biorelevant performance testing in the evaluation of specific dosage form related lumenal processes. During the last 15 years our knowledge of the gastrointestinal environment (including the lower gut) has improved dramatically and biorelevant media composition and, to a lesser extent, biorelevant hydrodynamics, have been refined. Biorelevant dissolution/release testing is useful for the evaluation of formulation and food effects on plasma levels after administration of immediate release dosage forms containing low solubility compounds and after administration of extended release products. Lumenal disintegration times of immediate release dosage forms and the bile acid sequestering activity of resins in the lumen can also be successfully forecasted with biorelevant in vitro testing. Biorelevant in-vitro performance testing is an important tool for evaluating intralumenal dosage form performance. Since the formulation of new active pharmaceutical ingredients for oral delivery is more challenging than ever before, efforts to improve the predictability of biorelevant tests are expected to continue.
    The Journal of pharmacy and pharmacology. 07/2012; 64(7):919-30.
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    ABSTRACT: For predicting food effects and simulating plasma profiles of poorly soluble drugs, physiologically based pharmacokinetic models have become a widely accepted tool in academia and the pharmaceutical industry. Up till now, however, simulations appearing in the open literature have mainly focused on BCS class II compounds, and many of these simulations tend to have more of a "retrospective" than a prognostic, predictive character. In this work, investigations on the absorption of a weakly basic BCS class IV drug, "Compound A", were performed. The objective was to predict the plasma profiles of an immediate release (IR) formulation of Compound A in the fasted and fed state. For this purpose, in vitro biorelevant dissolution tests and transfer model experiments were conducted. Dissolution and precipitation kinetics were then combined with in vivo post-absorptive disposition parameters using STELLA® software. As Compound A not only exhibits poor solubility but also poor permeability, a previously developed STELLA® model was revised to accommodate the less than optimal permeability characteristics as well as precipitation of the drug in the fasted state small intestine. Permeability restrictions were introduced into the model using an absorption rate constant calculated from the Caco-2 permeability value of Compound A, the effective intestinal surface area and appropriate intestinal fluid volumes. The results show that biorelevant dissolution tests are a helpful tool to predict food effects of Compound A qualitatively. However, the plasma profiles of Compound A could only be predicted quantitatively when the results of biorelevant dissolution test were coupled with the newly developed PBPK model.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 05/2012; 82(1):127-38. · 3.15 Impact Factor
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    ABSTRACT: The first aim of this study was to characterize the luminal contents and their micellar phase after the administration of a heterogeneous liquid meal to healthy adults. The second aim was to evaluate the impact of micellar lipids and coarse lipid particles on danazol flux through intestinal monolayers. A third aim was to compare the micellar composition in the upper small intestine with the composition of fed state simulating intestinal fluid (FeSSIF-V2), a medium that has been proposed for investigating dissolution of poorly soluble drugs in the fed state. Danazol (150 mg), predissolved in the olive oil portion of the meal, was administered via the gastric port of a two-lumen tube to the antrum of eight adults. Aspirates from the ligament of Treitz [collected up to 4 h postdosing (~15 mL every 30 min)] were characterized physicochemically. Comparison of these characteristics with FeSSIF-V2 indicates that FeSSIF-V2 is an appropriate medium for evaluating drug solubilization in the luminal micellar phase in the fed state. Individual aspirates and their corresponding micellar phases were also diluted with aqueous transport medium and subjected to Caco-2 cell permeation experiments. Permeability coefficients for danazol in the diluted aspirates were smaller than those for the diluted micellar phases, which in turn were similar to those for aqueous transport medium. The high danazol concentrations overcompensated the reduced permeability coefficient values in the diluted aspirates in terms of total drug flux. We conclude that drug dissolved in the coarse lipid particles formed after administration of a triglyceride solution can directly contribute to the flux of lipophilic drugs across the intestinal mucosa.
    Molecular Pharmaceutics 04/2012; 9(5):1189-98. · 4.57 Impact Factor
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    ABSTRACT: In this study, we evaluated the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM). DB, DM, and doxazosin hydrochloride (DH) were prepared and characterized. In vitro data were collected in various media, including human aspirates. Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid containing physiological components (FaSSGF-V2) but not by data in HCl(pH 1.8). Unlike data in FaSSGF-V2, dissolution of DB and DM tablets in HCl(pH 1.6) is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described modeling procedures, the cumulative doxazosin profile in plasma was simulated and the 0-2h profile was used for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet administrations to 24 adults, were constructed from corresponding actual plasma profiles. Compared with in vitro DM data in pure aqueous buffers, DM data in biorelevant media led to better prediction of early exposure. Based on intersubject variability in early exposure after DM administration and simulated profiles, the administered phase, DB or DM, does not have a significant impact on early exposure. Partial AUCs were used for evaluating early exposure after DB and DM administration in 4 dogs. Early exposure was significantly higher after administration of DM to dogs. Dogs are not appropriate for evaluating differences in early exposure after DB and DM administrations.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 02/2012; 80(2):402-9. · 3.15 Impact Factor
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    ABSTRACT: The current work aims to study at the ultrastructural level the morphological development of colloidal intermediate phases of human intestinal fluids (HIFs) produced during lipid digestion. HIFs were aspirated near the ligament of Treitz early (30 min), Aspirate(early), and 1 h, Aspirate(1h)(ave,comp), after the administration of a heterogeneous liquid meal into the antrum. The composition of the sample aspirated 1 h after meal administration was similar to the average lumenal composition 1 h after meal administration (Aspirate(1h)(ave,comp)). The colloidal structures of individual aspirates and supernatants of aspirates after ultracentrifugation (micellar phase) were characterized by means of atomic force microscopy (AFM) and cryogenic transmission electron microscopy (Cryo-TEM). AFM revealed domain-like structures in Aspirate(early) and both vesicles and large aggregates Aspirate(1h)(ave,comp). Rough surfaces and domains varying in size were frequently present in the micellar phase of both Aspirate(early) and Aspirate(1h)(ave,comp). Cryo-TEM revealed an abundance of spherical micelles and occasionally presented worm-like micelles coexisting with faceted and less defined vesicles in Aspirate(early) and Aspirate(1h)(ave,comp). In Aspirate(1h)(ave,comp) oil droplets were visualized with bilayers closely located to their surface suggesting lipolytic product phases accumulated on the surface of the oil droplet. In the micellar phase of Aspirate(early), Cryo-TEM revealed the presence of spherical micelles, small vesicles, membrane fragments, oil droplets and plate-like structures. In the micellar phase of Aspirate(1h)(ave,comp) the only difference was the absence of oil droplets. Visualization studies previously performed with biorelevant media revealed structural features with many similarities as presented in the current investigation. The impression of the complexity and diversion of these phases has been reinforced with the excessive variation of structural features visualized ex vivo in the current study offering insights at the ultrastuctural level of intermediate phases which impact drug solubilization.
    Molecular Pharmaceutics 12/2011; 9(2):237-47. · 4.57 Impact Factor
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    ABSTRACT: To compare the degradation kinetics of metronidazole and olsalazine by the bacteria of ascending colon and the bacteria of feces of healthy adults. Contents of the ascending colon of seven healthy adults were collected under conditions simulating the bioavailability/bioequivalence studies in the fasted and in the fed states on a crossover basis. Material from the contents of the ascending colon was prepared by ultracentrifuging and diluting the precipitate with a volume of normal saline equivalent to that of the supernatant. Fecal material was prepared from feces of three healthy adults collected at two occasions that were separated by at least 6 months. Ex vivo drug degradation kinetics were evaluated under anaerobic conditions. Mean half-lives of metronidazole degradation in material from the contents of the ascending colon collected in the fasted state and in fecal material were 16.1 and 2.4 min, respectively (p<0.001). The corresponding numbers for olsalazine were 57.8 and 9.2 min, respectively (p<0.001). Both compounds were stable in material from the contents of ascending colon collected in the fed state. Compared with data in fecal material, degradation of metronidazole and olsalazine in material from the contents of the ascending colon is significantly slower and it becomes non-significant during the arrival of fresh food remnants in the region.
    International journal of pharmaceutics 07/2011; 413(1-2):81-6. · 2.96 Impact Factor
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    ABSTRACT: In 2003, the FIP Dissolution Working group published a position paper on dissolution/drug release testing for special/novel dosage forms that represented the scientific opinions of many experts in the field at that time (1). The position paper has supported activities, programs, and decisions in the scientific, technical, and regulatory community. Due to the rapid evolution of new practices and techniques for in vitro testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of in vitro release testing practices for different pharmaceutical dosage forms. This article represents the current updates to the previously published paper. This revision has been aligned to coincide with the USP taxonomy including route of administration, intended site of drug release, and dosage form. The revised paper includes information from current literature, expert discussions, and presentations from recent workshops (2,3). The authors acknowledge and expect further updates to be made as additional progress is made in the relevant areas. Thus, comments and additional contributions are welcome and may be considered for the next revision of the position paper.
    AAPS PharmSciTech 06/2011; 12(2):782-94. · 1.58 Impact Factor
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    ABSTRACT: To evaluate precipitation in and supersaturation of intestinal contents after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to 12 healthy adults. On two separate days each subject was administered in stomach 240 ml aqueous solutions of two dipyridamole doses (30/90 mg) and two ketoconazole doses (100/300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (≤7 ml) aspirated at specific times post-dosing. Drug concentration after incubation (37°C/48 h) and equilibrium solubility were measured. Precipitate crystallinity was evaluated by x-ray powder diffraction. Precipitated fraction was minimal (dipyridamole, ≤7%) or limited (ketoconazole, ≤16%). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH > 3.6 were supersaturated with dipyridamole up to 10 and 30 min and with ketoconazole up to 30 and 50 min post-administration. Intestinal contents with pH > 5 and concentration of micellar components <5 mM were supersaturated with ketoconazole or dipyridamole, but precipitated fraction was significant only for ketoconazole. After incubation, crystalline precipitates were found in almost all samples. Slow precipitation of base and/or precipitation of other phases account for this observation. Intralumenal precipitation of weakly alkaline, lipophilic, high permeability drugs may not be substantial. Estimating intestinal supersaturation in regard to free base is inadequate as other phases may precipitate.
    Pharmaceutical Research 06/2011; 28(12):3145-58. · 4.74 Impact Factor
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    ABSTRACT: The ability of in vitro biorelevant dissolution tests to predict the in vivo performance of nanosized fenofibrate (Lipidil 145 ONE®) and microsized fenofibrate (Lipidil - Ter®) was evaluated in this study. In vitro dissolution was carried out using USP apparatus 2 (paddle method) with updated biorelevant media to simulate the pre- and postprandial states. Membrane filters with different pore sizes were evaluated for their ability to hold back undissolved, nanosized drug particles. It was shown that filters with pore sizes of 0.1 μm and 0.02 μm were able to separate molecularly dissolved drug from colloidal and undissolved particles. In vitro results obtained with a suitable filter were used to generate simulated plasma profiles in combination with two different models using STELLA® software: (a) under the assumption of no permeability restrictions to absorption and (b) under the assumption of a permeability restriction. The simulated plasma profiles were compared to in vivo data for the nanosized and the microsized formulation in the fasted and fed states. The first model approach resulted in good correlation for the microsized fenofibrate formulation, but the plasma profile of the formulation containing nanosized fenofibrate was overpredicted in the fasted state. The second model successfully correlated with in vivo data for both formulations, regardless of prandial state. Comparison of simulations with the two models indicates that in the fasted state, absorption of fenofibrate from the nanosized formulation is at least partly permeability-limited, while for the microsized formulation the dissolution of fenofibrate appears to be rate-determining.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 11/2010; 77(2):257-64. · 3.15 Impact Factor
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    ABSTRACT: To develop media simulating human colonic fluids (HCFs), to evaluate their use in predicting intracolonic solubility of ketoconazole, danazol and felodipine and to compare solubilities in HCFs with previously determined solubilities in gastric (HGFs) and small intestinal (HIFs) fluids. Fasted state simulated colonic fluid (FaSSCoF) and fed state simulated colonic fluid (FeSSCoF) were designed to reflect fluids previously collected from the ascending colon in healthy adults. Solubilities of the three model compounds were determined in HCFs, simulated HCFs, and plain buffers. For ketoconazole, solubilities in FaSSCoF and FeSSCoF were closer than those in the corresponding plain buffers to the solubility in HCFs. For danazol and felodipine, solubilities in FaSSCoF and FeSSCoF predicted solubilities in HCFs. In the fasted state, solubilities of danazol and felodipine in HCFs were higher than or similar to in HGFs or HIFs, while the ketoconazole solubility was lower. In the fed state, solubilities of all three model compounds in HCFs were lower than in HGFs or HIFs. FaSSCoF and FeSSCoF more closely predict solubility of poorly soluble compounds in HCFs than plain buffers. In most cases, solubility in HCFs differs from those in HGFs and HIFs.
    Pharmaceutical Research 10/2010; 27(10):2187-96. · 4.74 Impact Factor
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    ABSTRACT: 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.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 09/2010; 76(1):95-104. · 3.15 Impact Factor

Publication Stats

2k Citations
174 Downloads
276.86 Total Impact Points

Institutions

  • 1998–2014
    • National and Kapodistrian University of Athens
      • • Faculty of Pharmacy
      • • Department of Pharmaceutical Technology
      • • Division of Pharmacology
      Athínai, Attica, Greece
  • 2013
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 1998–2013
    • Goethe-Universität Frankfurt am Main
      • Institut für Pharmazeutische Technologie
      Frankfurt, Hesse, Germany
  • 2011
    • University of Copenhagen
      • Department of Pharmaceutics and Analytical Chemistry
      Copenhagen, Capital Region, Denmark
  • 1991–2007
    • University of Michigan
      • College of Pharmacy
      Ann Arbor, MI, United States
  • 1990–2006
    • Athens State University
      Athens, Alabama, United States