How the Magenstrasse Is Formed After Meals: Protein Aggregation Hypothesis.

Magenstrasse (stomach road) is reported to potentially influence the absorption of orally administered drugs by facilitating a gastric emptying of ingested water under postprandial condition. We hypothesized the Magenstrasse is a consequence of the formation of protein aggregates due to the decrease in gastric pH associated with stimulated gastric acid secretion. The formation mechanism of the Magenstrasse was examined in vitro using a gastric chamber system which reproduces postprandial conditions in the stomach.

Assessment of in Vivo Performance of Lipid-Based Formulations: Correlation between in Vitro Drug Release Profiles and in Vivo Absorption Rate Profiles.

The purpose of this study was to assess the in vivo absorption enhancement effects of lipid-based formulations (LBFs) through in vitro release studies. The type IIIA-MC (medium-chain) and type IIIA-LC (long-chain) formulations containing a Biopharmaceutics Classification System (BCS) Class II drug (dipyridamole or ketoconazole) were used as model LBFs. The type IIIA-MC formulation, but not the type IIIA-LC formulation, showed a higher initial absorption rate than the control suspension for both model drugs in rats.

Characterization of oral drug absorption from jelly formulations: Effects of membrane permeability and intestinal fluid volume.

This study aims to clarify the process of oral drug absorption from jelly formulations. Agar and pectin-based jellies containing drugs with different membrane permeability (high: antipyrine [ANT], medium: metoprolol [MET], low: atenolol [ATE]) were prepared and tested for in vitro drug release and in vivo drug absorption in rats. All drugs showed similar release profiles in vitro from both jelly formulations, except for the faster release from pectin jelly at neutral pH.

Development of Drug Discovery Platforms Using Artificial Intelligence and Cheminformatics.

Recently, remarkable progress has been achieved in artificial intelligence (AI), including machine learning. Various AI models have been proposed for drug discovery, including the design of small molecules, activity prediction, and three-dimensional (3D) structure prediction of proteins. AI consists of diverse elements, including information retrieval and machine learning, and can be used in a wide range of drug discovery scenarios.

Effect of particle size on gastric emptying of enteric-coated granules in fasted beagle dogs: Relationship with interdigestive migrating motor complex.

This study investigates the particle size threshold at which the interdigestive migrating motor complex (IMMC) becomes active in gastric emptying for fasted beagle dogs. Enteric-coated granules containing cetirizine dihydrochloride (CET) were prepared in three particle sizes, 200, 660, and 1,200 µm (D). To mark IMMC timing and water movement from the stomach, enteric-coated aspirin tablets and acetaminophen solution were used.

In vitro demonstration of antedrug mechanism of a pharmacokinetic booster to improve CYP3A4 substrates by CYP3A4-mediated metabolism inhibition.

We previously reported novel benzyl-ether derivatives with an imidazole ring and a hydroxyl group (A-01) or carboxyl group (B-01) and esters (2 esters of A-01, and 7 esters of B-01) as pharmacokinetics (PK) boosters. This study demonstrates how these ester compounds embody the concept of a safe pharmacokinetic booster, with potent and transient inhibition of CYP3A4-mediated drug metabolism. As a model CYP3A4 substrate and CYP3A4 enzyme, midazolam (MDZ) and rat liver microsomes were used.

Near-infrared imaging of in vivo performance of orally administered solid forms to rats: Feasibility study with indocyanine green.

This study demonstrates the applicability of near-infrared (NIR) imaging to evaluating in vivo oral formulation performance. As a NIR probe and model drug, indocyanine green (ICG) and acetaminophen (ACE) were selected, respectively. The fluorescence intensity of ICG greatly increased upon dissolution, with the dissolved ICG passing through the gastrointestinal tract over time.

Development of an In Vitro Methodology to Assess the Bioequivalence of Orally Disintegrating Tablets Taken without Water.

To assess the probability of bioequivalence (BE) between orally disintegrating tablets (ODTs) taken without water and conventional tablets (CTs) taken with water, an in vitro biorelevant methodology was developed using the BE Checker, which reproduces fluid shifts in the gastrointestinal tract and drug permeation. In addition to the fluid shift from the stomach to the small intestine, the process of ODT disintegration in a small amount of fluid in the oral cavity and the difference in gastric emptying caused by differences in water intake were incorporated into the evaluation protocol. Assuming a longer time to maximum plasma concentration after oral administration of ODTs taken without water than for CTs taken with water due to a delay in gastric emptying, the fluid shift in the donor chamber of the BE Checker without water was set longer than that taken with water.

Contribution analysis of metabolic tissues on systemic exposure of an active metabolite after oral administration of verapamil using a stable isotope-labeled compound.

The present study illustrates the advantage of an isotope-IV study for the contribution analysis of metabolic tissues on systemic exposure of metabolites. A model parent drug, verapamil (VER), and its metabolite, norverapamil (Nor-VER), were used. This isotope-IV study used rats with and without the pre-treatment of the CYP inhibitor 1-aminobenzotriazole (ABT), was performed by the oral administration of VER (1 mg/kg) combined with the intravenous administration of stable isotope-labeled VER (VER-d6, 0.

Control of Dissolution and Supersaturation/Precipitation of Poorly Water-Soluble Drugs from Cocrystals Based on Solubility Products: A Case Study with a Ketoconazole Cocrystal.

This study demonstrates in vitro and in vivo control of cocrystal dissolution with drug supersaturation/precipitation based on the solubility product of a cocrystal. As a cocrystal model, KTZ-4ABA (ketoconazole, KTZ, a poorly water-soluble drug cocrystal, with 4-aminobenzoic acid, 4ABA, a coformer) was used. The presence of 4ABA in the dissolution media dramatically reduced the dissolution rate of KTZ-4ABA and regulated the supersaturation/precipitation of KTZ, supported by the solubility product of KTZ-4ABA.

The effects of degree and duration of supersaturation on in vivo absorption profiles for highly permeable drugs, dipyridamole and ketoconazole.

The prediction of oral absorption from a supersaturating drug delivery system (SDDS) remains a significant challenge. Here we evaluated the effects of the degree and duration of supersaturation on in vivoabsorption for dipyridamole and ketoconazole. Various dose concentrations of supersaturated suspensions were prepared by a pH shift method, and in vitro dissolution and in vivo absorption profiles were determined.

[Development of New Sublingual Formulation for Transmucosal Delivery of Peptides].

Since oral bioavailability of peptides is extremely low, self-injectable and intranasal formulations have been developed; however, these treatments have problems such as storage and discomfort. The sublingual route is considered suitable for peptide absorption because there is less peptidase and it is not subject to hepatic first-pass effects. In this study, we attempted to develop a new jelly formulation for sublingual delivery of peptides.

Development of Magnetocardiograph without Magnetically Shielded Room Using High-Detectivity TMR Sensors.

A magnetocardiograph that enables the clear observation of heart magnetic field mappings without magnetically shielded rooms at room temperatures has been successfully manufactured. Compared to widespread electrocardiographs, magnetocardiographs commonly have a higher spatial resolution, which is expected to lead to early diagnoses of ischemic heart disease and high diagnostic accuracy of ventricular arrhythmia, which involves the risk of sudden death. However, as the conventional superconducting quantum interference device (SQUID) magnetocardiographs require large magnetically shielded rooms and huge running costs to cool the SQUID sensors, magnetocardiography is still unfamiliar technology.

Effects of Ingested Water Volume on Oral Absorption of Fenofibrate, a BCS Class II Drug, from Micronized and Amorphous Solid Dispersion Formulations in Rats.

In this study, we investigated the effects of ingested water volume on the oral absorption of fenofibrate (FEN) with several formulations to confirm the applicability of rats for oral formulation screening. Oral absorption of suspended crystalline FEN was significantly improved by increasing ingested water volume (from 0.5 to 2 mL).

Discovery of benzyloxyphenyl- and phenethylphenyl-imidazole derivatives as a new class of ante-drug type boosters.

Although cytochrome P450 3A4 (CYP3A4) inhibitors are used as boosters to increase drug absorption, the inhibition of CYP3A4 activity may affect the metabolism of other co-administered drugs. Therefore, we screened for and developed a new class of boosters to improve the oral availability of drugs. We identified benzyloxyphenyl imidazole and phenethylphenyl imidazole derivatives as new types of CYP3A4 inhibitors.

Liposomal Formulation for Oral Delivery of Cyclosporine A: Usefulness as a Semisolid-Dispersion System.

Purpose: This study aims to understand the process and mechanism of oral drug absorption from liposomes and to verify the usefulness of liposomal formulation for poorly soluble drugs.

Methods: Cyclosporine A (CsA) was used as a model drug and entrapped into Dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) liposomes. Molecular state of CsA in the liposomes was analyzed using powder X-ray diffraction (PXRD) and polarized light microscopy (PLM).

In Vitro-In Vivo Correlation in Cocrystal Dissolution: Consideration of Drug Release Profiles Based on Coformer Dissolution and Absorption Behavior.

This study assessed the in vitro-in vivo correlation in cocrystal dissolution based on the coformer behavior. 4-Aminobenzoic acid (4ABA) was used as a coformer. Cocrystals of poorly water-soluble drugs with 4ABA, ketoconazole cocrystal (KTZ-4ABA), posaconazole cocrystal (PSZ-4ABA), and itraconazole cocrystal (ITZ-4ABA) were used.

Bioequivalence of Oral Drug Products in the Healthy and Special Populations: Assessment and Prediction Using a Newly Developed In Vitro System "BE Checker".

In order to assess and predict the bioequivalence (BE) of oral drug products, a new in vitro system "BE checker" was developed, which reproduced the environmental changes in the gastrointestinal (GI) tract by changing the pH, composition, and volume of the medium in a single chamber. The dissolution and membrane permeation profiles of drugs from marketed products were observed in the BE checker under various conditions reflecting the inter-patient variations of the GI physiology. As variable factors, initial gastric pH, gastric emptying time, and GI agitation strength were varied in vitro.

Maximizing the Oral Bioavailability of Poorly Water-Soluble Drugs Using Novel Oil-Like Materials in Lipid-Based Formulations.

Lipid-based formulations, such as self-microemulsifying drug-delivery systems (SMEDDSs), are promising tools for the oral delivery of poorly water-soluble drugs. However, failure to maintain adequate aqueous solubility after coming into contact with gastrointestinal fluids is a major drawback. In this study, we examined the use of a novel cinnamic acid-derived oil-like material (CAOM) that binds drugs with a high affinity through π-π stacking and hydrophobic interactions, as an oil core in a SMEDDS for the oral delivery of fenofibrate in rats.

In vitro-in vivo correlation in the effect of cyclodextrin on oral absorption of poorly soluble drugs.

In this study the concentration effect of 2-Hydroxypropyl-beta-cyclodextrin (HP-βCyD) on oral drug absorption of the BCS class II drugs Danazol (DNZ) and Albendazole (ABZ) was evaluated. In vitro permeation of solutions and suspension systems was compared with their in vivo intestinal absorption in rats and their in vitro-in vivo correlation assessed. In solutions excess amounts of HP-βCyD decreased both in vitro permeation and in vivo absorption due to the decrease in free drug concentration, as expected.

In Vitro Sensitivity Analysis of the Gastrointestinal Dissolution Profile of Weakly Basic Drugs in the Stomach-to-Intestine Fluid Changing System: Explanation for Variable Plasma Exposure after Oral Administration.

An in vitro methodology for simulating the change in the pH and composition of gastrointestinal fluid associated with the transition of orally administered drugs from the stomach to the small intestine was developed (the stomach-to-intestine fluid changing system (the SIFC system)). This system was applied to in vitro sensitivity analysis on the dissolution of weakly basic drugs, and the obtained results were discussed in relation to the intrasubject variability in the plasma exposure in human bioequivalence (BE) study. Three types of protocols were employed (steep pH change: pH 1.

An enteric polymer mitigates the effects of gastric pH on oral absorption of poorly soluble weak acid drugs from supersaturable formulations: A case study with dantrolene.

This study demonstrated that an enteric polymer can mitigate the effects of gastric pH on the oral absorption of a poorly water-soluble weak acid drug, dantrolene (DNT). An amorphous solid dispersion (ASD) of DNT with hydroxypropyl methylcellulose (HPMC) acetate succinate (ASD-HPMCAS) was prepared as the enteric released ASD (ER-SF). ASD with HPMC (ASD-HPMC) and DNT sodium salt were also used as immediate-release supersaturable formulations (IR-SFs) with and without water-soluble polymer, respectively.

Species differences in the drug-drug interaction between atorvastatin and cyclosporine: In vivo study using a stable isotope-IV method in rats and dogs.

In this study, drug-drug interaction (DDI) between atorvastatin (ATV) and cyclosporine (CsA) was kinetically analyzed using a stable isotope-IV method in rats and dogs. Obtained results were compared with the clinical data quoted from literatures to clarify the species difference in DDI both qualitatively and quantitatively. ATV only or ATV with CsA was orally administered to rats or dogs, and at 90 minutes after administration, a small amount of deuterium labeled ATV (ATV-d5) was intravenously injected.

In Vivo Fluid Volume in Rat Gastrointestinal Tract: Kinetic Analysis on the Luminal Concentration of Nonabsorbable FITC-Dextran After Oral Administration.

Previously, 1 mL of purified water (hyposmotic) or saline (isosmotic) which dissolved 200 μM of FITC-dextran (FD-4), a nonabsorbable marker, was orally administered to rats, and luminal concentration-time profile of FD-4 was directly measured. In this study, at first, luminal FD-4 concentration was measured after oral administration of 0.5 mL of FD-4 purified water solution (200 μM).