Understanding the Impact of Lipids on the Solubilizing Capacity of Human Intestinal Fluids.

Lipids in human intestinal fluids (HIF) form various structures, resulting in phase separation in the form of a lipid fraction and a micellar aqueous fraction. Currently used fed state simulated intestinal fluids (SIF) lack phase separation, highlighting the need for a deeper understanding of the effect of these fractions on intestinal drug solubilization in HIF to improve simulation accuracy. In this study, duodenal fluids aspirated from 21 healthy volunteers in fasted, early fed, and late fed states were used to generate 7 HIF pools for each prandial state.

Development and validation of LC-MS/MS methods for the pharmacokinetic assessment of the PROTACs bavdeglutamide (ARV-110) and vepdegestrant (ARV-471).

Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. To foster the translation of PROTACs into the clinics it is of high importance to establish sensitive bioanalytical methods that enable the assessment of absorption, bioavailability, and disposition of PROTACs after oral dosing.

Topically Confined Enhancement of Cutaneous Microcirculation by Cold Plasma.

Introduction: We aim to explore potentials and modalities of cold atmospheric pressure plasma (CAP) for the subsequent development of therapies targeting an increased perfusion of the lower leg skin tissue. In this study, we addressed the question whether the microcirculation enhancement is restricted to the tissue in direct contact with plasma or if adjacent tissue might also benefit.

Methods: A dielectric barrier discharge (DBD)-generated CAP device exhibiting an electrode area of 27.

Effect on healing rates of wounds treated with direct cold atmospheric plasma: a case series.

Objective: The response of different critical acute and hard-to-heal wounds to an innovative wound care modality-direct application of cold atmospheric plasma (CAP)-was investigated in this clinical case series.

Method: Over an observation period of two years, acute wounds with at least one risk factor for chronification, as well as hard-to-heal wounds were treated for 180 seconds three times per week with CAP. CAP treatment was additional to standard wound care.

Novel Physics-Based Ensemble Modeling Approach That Utilizes 3D Molecular Conformation and Packing to Access Aqueous Thermodynamic Solubility: A Case Study of Orally Available Bromodomain and Extraterminal Domain Inhibitor Lead Optimization Series.

Drug design with patient centricity for ease of administration and pill burden requires robust understanding of the impact of chemical modifications on relevant physicochemical properties early in lead optimization. To this end, we have developed a physics-based ensemble approach to predict aqueous thermodynamic crystalline solubility, with a 2D chemical structure as the input. Predictions for the bromodomain and extraterminal domain (BET) inhibitor series show very close match (0.

Direct Visualization of Drug-Polymer Phase Separation in Ritonavir-Copovidone Amorphous Solid Dispersions Using Synchrotron X-ray Fluorescence Imaging of Thin Films.

Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at the molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed, however, that the drug release profile deteriorates significantly beyond a certain DL.

JRgui: A Python Program of Joback and Reid Method.

Using the modern object-oriented programing language Python (e.g., and modules) and a chemoinformatics open-source library (RDKit), the classic Joback and Reid group contribution method was revisited and written into a graphical user interface program, JRgui.

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding.

Effect of direct cold atmospheric plasma (diCAP) on microcirculation of intact skin in a controlled mechanical environment.

Objective: The microcirculatory response of intact human skin to exposure with diCAP for different durations with a focus on the effect of implied mechanical pressure during plasma treatment was investigated.

Methods: Local relative hemoglobin, blood flow velocity, tissue oxygen saturation, and blood flow were monitored noninvasively for up to 1 hour in 1-2 mm depth by optical techniques, as well as temperature, pH values, and moisture before and after skin stimulation. The experimental protocol (N = 10) was set up to differentiate between pressure- and plasma-induced effects.

The solubility-permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation.

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described.

Co-crystals of caffeine and hydroxy-2-naphthoic acids: unusual formation of the carboxylic acid dimer in the presence of a heterosynthon.

A group of caffeine-containing co-crystals of hydroxy-2-naphthoic acids were synthesized and analyzed via single-crystal X-ray diffraction and IR analysis. The imidazole-carboxylic acid synthon was observed in co-crystals involving 1-hydroxy-2-naphthoic and 3-hydroxy-2-naphthoic acid. In the case of 6-hydroxy-2-naphthoic acid, the co-crystal exhibits a hydrogen-bonded carboxylic acid dimer in the presence of a hydroxyl-caffeine heterosynthon.

Efficient co-crystal screening using solution-mediated phase transformation.

We have extended the established physical stability treatment for hydrates/solvates to co-crystals with solid co-crystal formers. Based on the proposed treatment, a suspension/slurry screening technique is developed and tested in sixteen pharmaceutical co-crystal systems with success. The theoretical treatment and the practical screening technique should benefit the researchers in the field of co-crystallization in improving the screening efficiency.

A "hidden" co-crystal of caffeine and adipic acid.

Co-crystal formation between caffeine and adipic acid has been explored over the years without success; utilizing the newly developed co-crystal screening method, we have finally discovered this "hidden" caffeine and adipic acid co-crystal.