Mechanistic investigation of the negative food effect of modified release zolpidem.

AIMS: When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. METHODS: Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgut model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction. RESULTS: It was possible to simulate the mean plasma profiles using a "middle-out" approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations. CONCLUSIONS: The present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.

In vitro biorelevant models for evaluating modified release mesalamine products to forecast the effect of formulation and meal intake on drug release.

AIMS: Postprandial administration of solid oral dosage forms greatly changes the dissolution environment compared to fasted state administration. The aims of this study were to investigate and forecast the effect of co-administration of a meal on drug release for delayed and/or extended release mesalamine formulations as well as design of in vitro tests to distinguish among formulations in a biorelevant way. METHODS: Five different mesalamine formulations (Asacol® 400 mg, Mezavant® 1200 mg, Pentasa® 500 mg and Salofalk® in the 250 mg and 500 mg strengths) were investigated with biorelevant dissolution methods using the USP apparatus III and USP apparatus IV (open loop mode) under both fasted and fed state conditions, as well as with the dissolution methods described in pharmacopeia for delayed and extended release mesalamine products. RESULTS: Using the biorelevant experimental conditions proposed in this study, changes in release in the proximal gut due to meal intake are forecast to be minimal for Asacol®, Mezavant®, Pentasa® and Salofalk® 500 mg, while for Salofalk® 250 mg release was predicted to occur much earlier under fed state conditions. The USP apparatus III generally tended to result in faster dissolution rates and forecast more pronounced food effects for Salofalk® 250 mg than the USP apparatus IV. The biorelevant dissolution gradients were also able to reflect the in vivo behavior of the formulations. CONCLUSIONS: In vitro biorelevant models can be useful in the comparison of the release behavior from different delayed and extended release mesalamine formulations as well as forecasting effects of concomitant meal intake on drug release.

Two-Stage Single-Compartment Models to Evaluate Dissolution in the Lower Intestine.

The purpose was to propose two-stage single-compartment models for evaluating dissolution characteristics in distal ileum and ascending colon, under conditions simulating the bioavailability and bioequivalence studies in fasted and fed state by using the mini-paddle and the compendial flow-through apparatus (closed-loop mode). Immediate release products of two highly dosed active pharmaceutical ingredients (APIs), sulfasalazine and L-870,810, and one mesalamine colon targeting product were used for evaluating their usefulness. Change of medium composition simulating the conditions in distal ileum (SIFileum ) to a medium simulating the conditions in ascending colon in fasted state and in fed state was achieved by adding an appropriate solution in SIFileum . Data with immediate release products suggest that dissolution in lower intestine is substantially different than in upper intestine and is affected by regional pH differences > type/intensity of fluid convection > differences in concentration of other luminal components. Asacol® (400 mg/tab) was more sensitive to type/intensity of fluid convection. In all the cases, data were in line with available human data. Two-stage single-compartment models may be useful for the evaluation of dissolution in lower intestine. The impact of type/intensity of fluid convection and viscosity of media on luminal performance of other APIs and drug products requires further exploration.

Characterization of Contents of Distal Ileum and Cecum to Which Drugs/Drug Products are Exposed During Bioavailability/Bioequivalence Studies in Healthy Adults.

PURPOSE: Characterize the contents of distal ileum and cecum in healthy adults under conditions simulating the bioavailability/bioequivelance studies of drug products in fasted and fed state. METHODS: Twelve males participated in a two-phase crossover study. Phase I: subjects remained fasted overnight plus 4.5 h in the morning prior to colonoscopy. Phase II: subjects remained fasted overnight, consumed breakfast in the morning, and abstain from food until colonoscopy, 4.5 h after breakfast. Upon sampling, volume, pH and buffer capacity were measured; after ultracentrifugation, supernatant was physicochemically characterized and non-liquid particles diameter was measured. RESULTS: In distal ileum, pH is ~8.1 and size of non-liquid particles is ~200 µm, regardless of dosing conditions; in fed state, liquid fraction was lower whereas osmolality and carbohydrate content were higher. In cecum, the environment was similar with previously characterized environment in the ascending colon; in fasted state, size of non-liquid particles is smaller than in distal ileum (~70 µm). Fluid composition in distal ileum is different from cecum, especially in fasted state. CONCLUSION: Differences in luminal environment between distal ileum and cecum may impact the performance of orally administered products which deliver drug during residence in lower intestine. Dosing conditions affect cecal environment more than in distal ileum.

In-vitro simulation of luminal conditions for evaluation of performance of oral drug products: Choosing the appropriate test media.

BACKGROUND: Biorelevant media for evaluation of dosage form performance in the gastrointestinal lumen were first introduced in the late 1990s. Since then, a variety of additional media have been proposed, making it now possible to simulate most regions in the gastrointestinal tract in both prandial states. However, recent work suggests that the complexity and degree of biorelevance required to predict in-vivo release varies with the drug, dosage form and dosing conditions. OBJECTIVE: The aim of this commentary was to establish which levels of biorelevant media are appropriate to various combinations of active pharmaceutical ingredient(s), dosage form and dosing conditions. With regard to their application, a decision tree for the selection of the appropriate biorelevant medium/media is proposed and illustrative case scenarios are provided. Additionally, media to represent the distal small intestine in both prandial states are presented. CONCLUSION: The newly proposed levels of biorelevance and accompanying decision tree may serve as a useful tool during formulation development in order to ensure high quality, predictive performance results without unnecessary complexity of media. In future work, further specific case examples will be evolved, which will additionally address the need to take gastrointestinal passage times and type and intensity of agitation into consideration.

In vitro and ex vivo investigation of the impact of luminal lipid phases on passive permeability of lipophilic small molecules using PAMPA.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Luminal lipid phases after administration of a triglyceride solution of danazol in the fed state and their contribution to the flux of danazol across Caco-2 cell monolayers.

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.

Stability of oleuropein in the human proximal gut.

OBJECTIVES: We aimed to assess the intralumenal stability of oleuropein in human gastric and small intestinal contents. We additionally aimed to assess the stability characteristics of oleuropein in media simulating the intralumenal conditions. METHODS: The intralumenal stability of oleuropein was assessed in aspirates from the stomach and the upper small intestine of healthy volunteers collected under both fasted and fed state conditions and in media simulating the intralumenal environment. KEY FINDINGS: Oleuropein degraded in aspirates collected in the fasted state. When the initial concentration was about 50 microg/ml (close to expected intragastric concentration after single dose of commercially available products of oleuropein) the mean zero-order half-life of oleuropein in aspirates collected from the fasted small intestine was estimated to be 3.14 +/- 0.08 h at 37 degrees C (i.e. after oral administration in the fasted state, a substantial fraction of oleuropein degrades before reaching the intestinal mucosa). In contrast, oleuropein was stable in aspirates collected from the fed stomach; in small intestinal contents aspirated in the fed state the estimated zero-order degradation half-life was at least 12 h. CONCLUSIONS: These data suggest that oleuropein should not have substantial intralumenal stability problems when administered in the fed state. Data collected in media simulating the intragastric and intraintestinal environment suggest that pH affects the stability of oleuropein only at low pH values (of about 2). At higher pHs degradation characteristics are at least partly affected by the presence of other scavengers of reactive oxygen species in the medium.