Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential (original) (raw)
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Keywords: fenofibrate in vitro models in vitroein vivo correlation (IVIVC) oral absorption bioavailability clinical pharmacokinetics dissolution partition biphasic poorly water soluble drugs BCS a b s t r a c t This study is to evaluate 3 fenofibrate (FEN) formulations including Fournier® 200 mg capsule, Lipidil® 145 mg tablet, and a clinical HME 160 mg tablet by an in vitro biphasic method. Key experimental parameters were evaluated including the selection of biorelevant media, the United States Pharmacopeia IV flow rate, and the United States Pharmacopeia paddle speed. Varying the hydrodynamic condition resulted in a significant impact on FEN concentration time profiles in both aqueous and octanol phases for these formulations. In vivo pharmacokinetic profiles of the HME tablet, the Lipidil tablet, and Fournier capsule under the fasting and low-fat fed states are reported. Their corresponding absorption-time profiles were obtained through deconvolution by the Wagner-Nelson method. When fed state simulated intestinal fluid version 2 was used, the partitioned FEN amountetime profiles in octanol from the 3 formulations under an appropriate hydrodynamic condition exhibited a good agreement with their in vivo absorbed amountetime profiles, permitting a quantitative in vitroein vivo correlation. When fasted state simulated intestinal fluid version 2 was used, partitioned FEN amounts into octanol from these formulations are significantly lower than those from in vivo data. Although no food effect was observed for both HME and Lipidil tablets, the positive food effect of the Fournier capsules significantly overestimated by the biphasic test.
Journal of Pharmaceutical Sciences, 2021
The aim of this work was to develop a new in vitro lipolysis-permeation model to predict the in vivo absorption of fenofibrate in self-nanoemulsifying drug delivery systems (SNEDDSs). More specifically, the in vitro intestinal lipolysis model was combined with the mucus-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model. Biosimilar mucus (BM) was added to the surface of the PVPA barriers to closer simulate the intestinal mucosa. SNEDDSs for which pharmacokinetic data after oral dosing to rats was available in the literature were prepared, and the ability of the SNEDDSs to maintain fenofibrate solubilized during in vitro lipolysis was determined, followed by the assessment of drug permeation across the mucus-PVPA barriers. The amount of drug solubilized over time during in vitro lipolysis did not correlate with the AUC (area under the curve) of the plasma drug concentration curve. However, the AUC of the drug permeated after in vitro lipolysis displayed a good correlation with the in vivo AUC (R 2 > 0.9). Thus, it was concluded that the in vitro lipolysis-mucus-PVPA permeation model, simulating the physiological digestion and absorption processes, was able to predict in vivo absorption data, exhibiting great potential for further prediction of in vivo performance of SNEDDSs.
The goal of this study was to investigate the in vitro-in vivo correlation (IVIVC) for fenofibrate immediate release (IR) tablet formulations based on MeltDose 1 -technique. The in vitro determined drug solubility and permeability data were related to the C max values observed from two in vivo human studies. Solubility and permeation studies of fenofibrate were conducted in medium simulating the fasted state conditions in the upper jejunum, containing the surfactant compositions of the six formulations at different concentrations. The behavior of all surfactant compositions was characterized by surface tension, dynamic light scattering, and cryo-TEM. The obtained solubility and permeation data were combined and compared with the C max values for the fenofibrate formulations, assuming a 50 mL in vivo dissolution volume. A good IVIVC was observed for five fenofibrate formulations (R 2 ¼ 0.94). The in vitro studies revealed that the formulation compositions containing sodium lauryl sulfate (SLS) interfered with the vesicular drug solubilizing system of the biorelevant medium and antagonized its solubilization capacity. The opposing interaction of surfactants with the emulsifying physiological constituents in intestinal juice should be taken into consideration in order to prevent unsatisfactory in vivo performance of orally administered formulations with low soluble active pharmaceutical ingredients. ß
Frontiers in Pharmacology
Background: The choice of lipid excipients and their origin are crucial determinant factors in the design of self-nanoemulsifying drug delivery system (SNEDDS). Aim: To investigate the aspects of alternative excipients which can influence the development of efficient SNEDDS and determine the fate of fenofibrate in aqueous media. Methods: SNEDDS of two groups (a and b) were developed using Cremercoor MCT/Capmul MCM and Kollisolv MCT/Imwitor 742 blended oils and water soluble surfactants (to improve lipid polarity) for the model anti-cholesterol drug fenofibrate. Visual assessment was employed and droplet size measurement was taken into initial consideration for optimized SNEDDS. Further SNEDDS optimizations were done on the basis of maximum drug loading by equilibrium solubility studies and maximum solubilized drug upon aqueous dispersion by dynamic dispersion studies. In vitro lipolysis was examined under simulated Fed and Fasted conditions. Intestinal permeability study of the optimal SNEDDS formulation was compared with the raw fenofibrate dispersion using non-everted "intestinal sac technique." Results: Initial characterization and solubility studies showed that mixed glycerides of Kollisolv MCT/Imwitor 742 (group b) containing formulations generated highly efficient SNEDDS as they are stable and produced lower nanodroplets with higher drug loading (group b) as compared to mixed glycerides of Cremercoor MCT/Capmul MCM (group a). In vitro dispersion and digestion studies confirmed that SNEDDS of group b (polar mixed glycerides) can retain high amount of drug (99% drug in solution for more than 24 h time) in dispersion media and have high recovery after digestion. The results from the permeability assessment confirmed that fenofibrate had 4.3-fold increase with F3b SNEDDS compared with the control.
European Journal of Pharmaceutics and Biopharmaceutics, 2014
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.
AAPS PharmSciTech, 2012
Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV selfemulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH 7.5 for 30 min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations.
Lat Am J …, 2009
The present work deals with the comparison of in vitro dissolution profiles of fenofibrate liquisolid tablet formulations with those of marketed fenofibrate tablets, and the application of statistical methods to evaluate each method for its usefulness. The methods used to study dissolution profile comparison include Model independent method (Similarity factor, f 2 ); Model dependent methods (Zero order, First order, Hixson-Crowell, Matrix, Peppas, Higuchi models) and statistical methods based on ANOVA. Model independent method was found to be easier and simple to interpret. The f 2 value relates closeness of dissolution profiles. Dissolution profile followed Peppas model as "best fit" model. The application and evaluation of model dependent methods are more complicated. These methods give acceptable model approach which is indication of true relationship between percent drug release and time variables, including statistical assumptions. Statistical approach is very simple and is more discriminative of dissolution profiles. The liquisolid formulation of fenofibrate serves to be an effective way to enhance dissolution rate of fenofibrate.
Journal of Controlled Release, 2019
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Journal of Drug Delivery Science and Technology, 2018
Fenofibrate has recently been used as drug model in several studies with the objective of optimizing the development of some drug delivery systems to overcome the problem of poor aqueous solubility of the newly discovered API. The adequacy of the drug delivery systems to improve the oral bioavailability of encapsulated drug is generally evaluated by a pharmacokinetic study. The use of mouse as animal model for pharmacokinetic studies has become more important in the last decade because of many similarities with the human model in terms of the mechanisms of absorption, metabolism and elimination. Nevertheless, the mouse is often hampered by the very small volumes of blood that could be obtained during sampling. The aim of this work was to overcome the problem of lower volumes of plasma withdrawn by developing an appropriate protocol for sample preparation and a suitable HPLC method for drug quantification in mouse plasma. Linear calibration curve was obtained over the concentration range from 0,16µg/mL to 32µg/mL (r²=0,9999) with LLOQ of 0,16µg/mL The RSD in both intra-run and inter-run precision study was less than 11% and the extraction recoveries were above 91.9%. The reproducible method was successfully applied to the pharmacokinetic study of fénofibrate in mouse.