Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bio in equivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for “very rapidly dissolving” or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are “rapidly dissolving.”. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1639–1653, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64911/1/21954_ftp.pd

Human Gastrointestinal Juices Intended for Use in In Vitro Digestion Models

The aim of this study was to characterise the individual human gastric and duodenal juices to be used in in vitro model digestion and to examine the storage stability of the enzymes. Gastroduodenal juices were aspirated, and individual variations in enzymatic activities as well as total volumes, pH, bile acids, protein and bilirubin concentrations were recorded. Individual pepsin activity in the gastric juice varied by a factor of 10, while individual total proteolytic activity in the duodenal juice varied by a factor of 5. The duodenal amylase activity varied from 0 to 52.6 U/ml, and the bile acid concentration varied from 0.9 to 4.5 mM. Pooled gastric and duodenal juices from 18 volunteers were characterised according to pepsin activity (26.7 U/ml), total proteolytic activity (14.8 U/ml), lipase activity (951.0 U/ml), amylase activity (26.8 U/ml) and bile acids (4.5 mM). Stability of the main enzymes in two frozen batches of either gastric or duodenal juice was studied for 6 months. Pepsin activity decreased rapidly and adjusting the pH of gastric juice to 4 did not protect the pepsin from degradation. Lipase activity remained stable for 4 months, however decreased rapidly thereafter even after the addition of protease inhibitors. Glycerol only marginally stabilised the survival of the enzymatic activities. These results of compositional variations in the individual gastrointestinal juices and the effect of storage conditions on enzyme activities are useful for the design of in vitro models enabling human digestive juices to simulate physiological digestion

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

Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans

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 Cmax 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. © 2010 Elsevier B.V

Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form

In vitro biorelevant dissolution tests enabling the prediction of in vivo performance of an oral modified-release (MR) dosage form were developed in this study. In vitro dissolution of MR diclofenac sodium pellets containing 100 mg active ingredient was evaluated under simulated pre- and postprandial conditions using USP Apparatus 3 (reciprocating cylinder, Bio-Dis) and 4 (flow-through cell) and results compared with compendial methods using USP Apparatus 1 (basket) and 2 (paddle). In vivo, the effects of food on the absorption of diclofenac sodium from the pellet dosage form were investigated by administering the product to 16 healthy volunteers pre- and postprandially in a crossover-design study. The in vitro results were compared with the in vivo data by means of Level A in vitro-in vivo correlation (IVIVC) and Weibull distribution analysis. The compendial dissolution tests were not able to predict food effects. The biorelevant dissolution tests predicted correctly that the release (and hence absorption) of diclofenac sodium would be slower in the fed state than in the fasted state. No significant differences in extent of absorption due to changes in extent of release were predicted or observed. The results demonstrate good correlations between in vitro drug release and in vivo drug absorption in both pre- and postprandial states using the biorelevant dissolution test methods. © 2009 Elsevier B.V. All rights reserved

Biorelevant in vitro dissolution testing of products containing micronized or nanosized fenofibrate with a view to predicting plasma profiles

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. © 2010 Elsevier Inc. All rights reserved

Predicting the oral absorption of a poorly soluble, poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model

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. © 2012 Elsevier B.V. All rights reserved