Biowaiver monographs for immediate-release solid oral dosage forms: Voriconazole.

According to the ICH M9 Guideline, the triazole antifungal voriconazole is a Biopharmaceutics Classification System (BCS) class II drug, being highly soluble at the highest dose strength but not at the highest single dose. Although the ICH M9 allows for consideration of BCS-based biowaivers in such cases, voriconazole does not meet the additional requirement of dose proportional pharmacokinetics (PK) over the therapeutic dose range. By contrast, if the classification were based on the FDA solubility criteria that were in place prior to ICH M9 (based on the highest dose strength), voriconazole would belong to BCS class I and thus qualify for the BCS-based biowaiver.

Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant.

Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

Purpose: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles.

Methods: Meloxicam and ezetimibe were used as model drugs.

Self-micellizing solid dispersion of tacrolimus: Physicochemical and pharmacokinetic characterization.

The present study was undertaken to develop a self-micellizing solid dispersion (SMSD) of tacrolimus (TAC) to improve the biopharmaceutical properties of TAC. An SMSD formulation of TAC (SMSD/TAC) and amorphous solid dispersion formulation of TAC (ASD/TAC) were prepared with Soluplus , an amphiphilic copolymer, and hydroxypropyl cellulose, respectively. Physicochemical properties were characterized in terms of morphology, crystallinity, storage stability, interaction of TAC with Soluplus , and micelle-forming potency; pharmacokinetic behavior was also evaluated in rats.

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations.

Optimization of the in vivo performance of dosage forms in humans is essential in developing not only conventional formulations but also drug delivery system (DDS) formulations. Although animal experiments are still useful for these formulations, in silico approaches have become increasingly important for DDS formulations with regard to species-specific differences in physiology that can affect the in vivo performance of dosage forms between animals and humans. Furthermore, it is also important to couple in vitro characterizations with in silico models to predict in vivo performance in humans precisely.

[Control and Prediction of Drug Absorption at Mucosal Tissues].

The mucosal drug delivery system (mDDS) is one of the promising approaches to control the pharmacokinetic behavior of drugs. In this approach, surface properties of drug nanoparticles are key determinants to provide particles with mucoadhesive and mucopenetrating properties for prolonged retention at mucosal tissue and rapid mucosal absorption, respectively. In this paper, we would like to discuss the preparation of mDDS formulations by flash nanoprecipitation using a four-inlet multi-inlet vortex mixer, in vitro and ex vivo evaluation of mucopenetrating and mucoadhesive properties of polymeric nanoparticles as well as the application of mDDS to the pharmacokinetic control of cyclosporine A after oral administration to rats.

Food effects on gastrointestinal physiology and drug absorption.

Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in the stomach and small intestine, GI transit of water and dosage forms, and microbiota.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Levocetirizine Dihydrochloride.

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information.

Biowaiver Monograph for Immediate-Release Dosage Forms: Levamisole Hydrochloride.

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III.

Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the Performance of Oral Solid Dosage Forms in Humans in the Fed State.

The aim of this study was to develop a simulation model to predict the performance of solid oral dosage forms in humans in the fed state. We focused on investigating the effect of dynamic changes in gastrointestinal (GI) fluid characteristics in the fed state on the performance of solid dosage forms. We used six solid dosage forms containing weak base drugs as model formulations, two with positive food effects in humans, two with negative food effects, and two which are not affected by food ingestion.

Quantitative assessment of disintegration rate is important for predicting the oral absorption of solid dosage forms containing poorly soluble weak base drugs.

This study aimed to develop a novel in silico modeling and simulation that considers the disintegration rate in the stomach to predict the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs. Oxatomide and manidipine hydrochloride were used as model drugs. First, the in vitro disintegration rate and dissolution rate were determined in biorelevant media that simulate the gastrointestinal fluids in fasted humans using a USP apparatus II paddle dissolution tester.

Importance of Gastric Secretion and the Rapid Gastric Emptying of Ingested Water along the Lesser Curvature ("Magenstraße") in Predicting the In Vivo Performance of Liquid Oral Dosage Forms in the Fed State Using a Modeling and Simulation.

The objective of the present study was to develop an in silico model of the stomach for predicting oral drug absorption in fed humans. We focused on a model capable of simulating dynamic fluid volume changes and included a simulated Magenstraße "stomach road," a route along the lesser curvature that often carries fluids rapidly to assess the gastric emptying of drugs. Two types of model liquid drug formulations, liquid-filled soft gelatin capsules (enzalutamide, cyclosporine, and nifedipine) and oral solutions (levofloxacin and fenfluramine), were used.

Gummi Formulations Comprising Amenamevir Solid Dispersions with Polyvinyl Alcohol.

The aim of the present study was to determine whether solid dispersions (SDs) are applicable to gummi formulations. Amenamevir was selected as a model of a poorly water-soluble drug, and polyvinyl alcohols (PVAs) with various degrees of hydrolysis (PVA 66, PVA 80, PVA 88, and PVA 66/88) were used as SD carriers. Design of experiments (DOE) was used to develop a gummi formulation that was suitable for an amenamevir SD using SD with PVA 66.

Towards Virtual Bioequivalence Studies for Oral Dosage Forms Containing Poorly Water-Soluble Drugs: A Physiologically Based Biopharmaceutics Modeling (PBBM) Approach.

The objective of the present study was to develop a physiologically based biopharmaceutics (PBBM) approach to predict the bioequivalence of dosage forms containing poorly soluble drugs. Aripiprazole and enzalutamide were used as model drugs. Variations in the gastrointestinal (GI) physiological parameters of fasted humans were taken into consideration in in vitro biorelevant dissolution testing and in an in silico PBBM simulations.

Exploring clinically relevant dissolution specifications for oral solid dosage forms of weak acid drugs using an in silico modeling and simulation approach.

The aim of this study was to explore clinically relevant dissolution specifications for weak acid drugs using an in silico drug absorption model. Loxoprofen sodium and ibuprofen were used as model drugs in this study. An in silico drug absorption model was developed using Stella Professional software and the prediction model accurately represented the plasma concentration profiles of the model drugs following oral administration.

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect).

Scintigraphic evaluation of the in vivo performance of dry-coated delayed-release tablets in humans.

We characterized the gastrointestinal (GI) transit and drug release characteristics of dry-coated delayed-release tablets under both prandial states in humans using a gamma scintigraphy approach. We also estimated the onset time of drug release from the dry-coated tablets after dissolution of the outer layer in a clinical study, and compared findings with those of in vitro release testing. The dry-coated tablets used in this study were composed of a core containing radiolabeled resin (111-Indium) and a gel forming outer layer made of polyethylene oxide and polyethylene glycol.

A physiologically-based drug absorption modeling for orally disintegrating tablets.

The aim of this research was to simulate oral pharmacokinetic (PK) profiles of atorvastatin from orally disintegrating tablets (ODTs) dosed without water ingestion in fasted humans. The in vitro dissolution profiles of three different formulations of ODTs were evaluated with fasted state biorelevant media using a paddle dissolution apparatus, and the results were coupled with an in silico model to simulate the in vivo oral PK profiles of ODTs following administration to humans. Since the dissolution rates of the ODTs in the intestinal medium (FaSSIF-V2) were highly affected by pre-exposure of the tablets to the stomach medium (FaSSGF), the simulation model took account of the relationship between the gastric emptying time and the dissolution performance of the tablets in the small intestine.

Characterization of the buccal and gastric transit of orally disintegrating tablets in humans using gamma scintigraphy.

The present study characterized the buccal cavity-emptying and gastric-emptying kinetics of orally disintegrating tablets (ODTs) in fasted humans using gamma scintigraphy. Indium-diethylenetriaminepentaacetic acid and technetium-99 m-labeled ion exchange resin were used as a model soluble drug and insoluble pellet-type drug, respectively, and housed in ODTs. These ODTs were then administered to human subjects with or without ingestion of water, after which scintigraphic images were collected in order to characterize the buccal and gastric transit of the radioactivity.

Effects of Diurnal Variation and Food on Gastrointestinal Transit of In-Labeled Hydrogel Matrix Extended-Release Tablets and Tc-Labeled Pellets in Humans.

The aim of this research was to characterize the effect of food ingestion and circadian rhythm on the gastrointestinal transit of 2 dosage forms: a hydrogel matrix extended-release (ER) tablet and pellets with the diameter of 9 mm and 150-200 μm, respectively, in humans. Radiolabeled (In) hydrogel matrix ER tablet and capsule containing radiolabeled (Tc) pellets were administered with 240 mL of water under the following dosing conditions: fasted state at 8 AM or 8 PM and fed state at 8 AM or 8 PM. A high-fat and high-calorie meal was ingested in the fed state studies.