Deep Learning Prediction of Drug-Induced Liver Toxicity by Manifold Embedding of Quantum Information of Drug Molecules.

Purpose: Drug-induced liver injury, or DILI, affects numerous patients and also presents significant challenges in drug development. It has been attempted to predict DILI of a chemical by in silico approaches, including data-driven machine learning models. Herein, we report a recent DILI deep-learning effort that utilized our molecular representation concept by manifold embedding electronic attributes on a molecular surface.

What matters for drug delivery to tumor by nanoparticles: Gaining insights from PBPK/PD simulation of drug nanocrystals.

Background And Purpose: In our previous studies, drug nanocrystals were directly prepared by solution crystallization, possessing uniform particle size and morphology suitable for intravenous (IV) injection. These nanocrystals accumulated in a small percentage of their injected dose in tumor-bearing mice but showed similar anti-tumor effectiveness and much-reduced side effects compared with current commercial solubilized and encapsulated delivery systems.

Experimental Approach: In this study, we aimed to delineate possible controlling factors for the pharmacokinetics (PK) and biodistribution behaviors of paclitaxel (PTX) nanocrystals tested in mice by applying physiologically based pharmacokinetics (PBPK) modeling, coupled with pharmacodynamics (PD) simulation, to the data.

Bohemian Rhapsody of Future Drug Delivery Systems: Rational Changes Necessary for the Next Revolution.

Controlled drug delivery technology has matured for more than 70 years, starting from a twice-a-day oral formulation to 6 month long-acting injectable formulations. Further technological advances require superior formulations to treat various diseases more efficiently. Developing future formulations with practical innovations for treating existing and new diseases necessitates our continued efforts to overcome at least three main hurdles.

Unsupervised manifold embedding to encode molecular quantum information for supervised learning of chemical data.

Molecular representation is critical in chemical machine learning. It governs the complexity of model development and the fulfillment of training data to avoid either over- or under-fitting. As electronic structures and associated attributes are the root cause for molecular interactions and their manifested properties, we have sought to examine the local electron information on a molecular manifold to understand and predict molecular interactions.

In vivo deposition of poorly soluble drugs.

Administered drug molecules, whether dissolved or solubilized, have the potential to precipitate and accumulate as solid forms in tissues and cells within the body. This phase transition can significantly impact the pharmacokinetics of treatment. It is thus crucial to gain an understanding of how drug solubility/permeability, drug formulations and routes of administration affect in vivo behaviors of drug deposition.

A Peptoid-like Approach Led to Lactam-Lactam Dimer Formation in 2-Hydroxy--alkyl--phenyl-nicotinamides and Their Polymorphism and Solvatomorphism.

Four 2-hydroxy--alkyl--phenyl-nicotinamides (-) were synthesized, and their crystal structures were analyzed to investigate the effect of substitution on their crystal packing of -phenyl-2-hydroxynicotinanilides. In these compounds, substituents were introduced on the amide N, leading to a peptoid-like structure. One solvent-free form and two hydrates were harvested for compound , and one anhydrous form and one hydrate were obtained for compound .

Multiphysics-Informed Pharmacokinetic Modeling of Systemic Exposure of Intramuscularly Injected LNPs.

Lipid nanoparticle (LNP) constructs have been widely developed for gene therapy delivery. Understanding local absorption and presystemic clearance kinetics of LNPs, however, remains limited. This subsequently restrains the prediction and assessment of the systemic exposure of locally injected LNPs.

A Perspective on Model-Informed IVIVC for Development of Subcutaneous Injectables.

Subcutaneously administered drugs are growing in popularity for both large and small molecule drugs. However, development of these systems - particularly generics - is slowed due to a lack of formal guidance regarding preclinical testing and in vitro - in vivo correlations (IVIVC). Many of these methods, while appropriate for oral drugs, may not be optimized for the complex injection site physiologies, and release rate and absorption mechanisms of subcutaneous drugs.

Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

Introduction: Subcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood.

Objective: To bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products.

Multiphysics modeling and simulation of local transport and absorption kinetics of intramuscularly injected lipid nanoparticles.

Recent clinical applications of mRNA vaccines highlight the critical role of drug delivery, especially when using lipid nanoparticles (LNPs) as the carrier for genetic payloads. However, kinetic and transport mechanisms for locally injected LNPs, such as lymphatic or cellular uptake and drug release, remain poorly understood. Herein, we developed a bottom-up multiphysics computational model to simulate the injection and absorption processes of LNPs in muscular tissues.

Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals.

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPβCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization.

Biological and intracellular fates of drug nanocrystals through different delivery routes: Recent development enabled by bioimaging and PK modeling.

Nanocrystals have contributed to exciting improvements in the delivery of poorly water-soluble drugs. The biological and intracellular fates of nanocrystals are currently under debate. Due to the remarkable commercial success in enhancing oral bioavailability, nanocrystals have originally been regarded as a simple formulation approach to enhance dissolution.

Kinetic Retraction at the Onset of Concomitant Crystallization and Implication on Polymorphic Formation.

The four-quadrant regimes of attainable polymorph crystallization (FQR-APC) plot was recently developed through numerical simulations of crystallization kinetics of a dipolymorphic system. Retraction in the polymorphic composition of the most stable form in crystallized samples was unveiled a characteristic indication of concomitant polymorphism. Comparisons were made with a recently developed concept, the Ostwald ratio (OR), in light of characterization of polymorphic formation.

Understanding Formulation and Temperature Effects on Dermal Transport Kinetics by IVPT and Multiphysics Simulation.

Purpose: It is often unclear how complex topical product formulation factors influence the transport kinetics through skin tissue layers, because of multiple confounding attributes. Environmental factors such as temperature effect are also poorly understood. In vitro permeation testing (IVPT) is frequently used to evaluate drug absorption across skin, but the flux results from these studies are from a combination of mechanistic processes.

A new solvate of clonixin and a comparison of the two clonixin solvates.

A new solvate of clonixin (CLX), a dimethylacetamide (DMA) solvate, has been obtained by crystal growth in DMA. The new form was characterized by NMR, single-crystal X-ray diffraction, and PXRD. The crystal structure is stabilized by a strong hydrogen bond between the carboxylic acid OH of CLX and the DMA carbonyl, the strength of which is on par with those of the four solvent-free forms of CLX and the DMF solvate.

Paclitaxel Drug Delivery Systems: Focus on Nanocrystals' Surface Modifications.

Paclitaxel (PTX) is a chemotherapeutic agent that belongs to the taxane family and which was approved to treat various kinds of cancers including breast cancer, ovarian cancer, advanced non-small-cell lung cancer, and acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Several delivery systems for PTX have been developed to enhance its solubility and pharmacological properties involving liposomes, nanoparticles, microparticles, micelles, cosolvent methods, and the complexation with cyclodextrins and other materials that are summarized in this article. Specifically, this review discusses deeply the developed paclitaxel nanocrystal formulations.

Biodistribution and Non-linear Gene Expression of mRNA LNPs Affected by Delivery Route and Particle Size.

Purpose: Lipid nanoparticles (LNPs) are widely utilized as means to deliver mRNA molecules. However, metric connections between biodistribution and pharmacokinetics (PK) of the nanoparticle carrier and transgene expression dynamics remain largely unknown.

Methods: LNPs containing mRNAs encoding the firefly luciferase gene were prepared with varying sizes.

Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics.

Subcutaneously injected formulations have been developed for many biological products including monoclonal antibodies (mAbs). A knowledge gap nonetheless remains regarding the absorption and catabolism mechanisms and kinetics of a large molecule at the administration site. A multiscale pharmacokinetic (PK) model was thus developed by coupling multiphysics simulations of subcutaneous (SC) absorption kinetics with whole-body pharmacokinetic (PK) modeling, bridged by consideration of the presystemic clearance by the initial lymph.

Preferential Oxycodone Loss of Physically Manipulated Abuse Deterrent Oxycodone HCl Extended Release Tablets Prepared for Nasal Insufflation Studies.

A method to reproducibly mill abuse deterrent oxycodone hydrochloride (HCl) extended release (ER) tablets was developed for a nasal insufflation pharmacokinetic (PK) study. Several comminution methods were explored before determining that a conical mill resulted in controlled milling of tablets to a size range equal to or below 1000 μm. However, milling resulted in significant loss of oxycodone from abuse deterrent oxycodone HCl ER tablets compared to minimal oxycodone loss from oxycodone HCl immediate release (IR) tablets.

Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Sensitivity Analysis.

Purpose: A multiphysics simulation model was recently developed to capture major physical and mechanical processes of local drug transport and absorption kinetics of subcutaneously injected monoclonal antibody (mAb) solutions. To further explore the impact of individual drug attributes and tissue characteristics on the tissue biomechanical response and drug mass transport upon injection, sensitivity analysis was conducted and reported.

Method: Various configurations of injection conditions, drug-associated attributes, and tissue properties were simulated with the developed multiphysics model.

Intracellular uptake of nanocrystals: Probing with aggregation-induced emission of fluorescence and kinetic modeling.

Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals.