Isoliquiritigenin Nanosuspension Enhances Cytostatic Effects in A549 Lung Cancer Cells.

Isoliquiritigenin, a flavonoid extracted from licorice root, has been shown to be active against most cancer cells; however, its antitumor activity is limited by its poor water solubility. The aim of this study was to develop a stable isoliquiritigenin nanosuspension for enhanced solubility and to evaluate its in vitro cytostatic activity in A549 cells. The nanosuspension of isoliquiritigenin was prepared through wet media milling with HPC SSL (hydroxypropyl cellulose-SSL) and PVP K30 (polyinylpyrrolidone-K30) as stabilizers, and the samples were then characterized according to particle size, zeta-potential, SEM (scanning electron microscopy), TEM (transmission electron microscopy), DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction), FTIR (Fourier transform infrared spectroscopy), XPS (X-ray photoelectron spectroscopy), and in vitro release. The isoliquiritigenin nanosuspension prepared with HPC SSL and PVP K30 had particle sizes of 238.1 ± 4.9 nm and 354.1 ± 9.1 nm, respectively. Both nanosuspensions showed a surface charge of approximately - 20 mV and a lamelliform or ellipse shape. The dissolution of isoliquiritigenin from the 2 nanosuspensions was markedly higher than that of free isoliquiritigenin. In vitro studies on A549 cells indicated that the cytotoxicity and cellular uptake significantly improved after treatment with both nanosuspensions in comparison to the isoliquiritigenin solution. Furthermore, cell apoptosis analysis showed a 7.5 - 10-fold increase in the apoptosis rate induced by both nanosuspensions compared with pure drug. However, the cytotoxicity of pure drug and nanosuspension on normal cells (HELF) was lower, which indicated both isoliquiritigenin nanosuspensions have low toxicity to normal cells. Therefore, the isoliquiritigenin nanosuspension prepared with HPC SSL and PVP K30 as stabilizers may be a promising approach to improve the solubility and cytostatic activity of isoliquiritigenin.

Molecular Mechanisms Involved in Supersaturation of Emodin Ternary Solid Dispersions Based on Bonding Agents.

The use of solid dispersions (SDs) is an established method for improving the dissolution rate of poorly water-soluble drugs. However, there have been few studies on the molecular mechanisms contributing to SD supersaturation. Emodin ternary SDs (TSDs) were prepared by hot melt extrusion (HME) using Kollidon® VA64 as the polymer carrier and nicotinamide as the bonding agent. Molecular docking and solubility tests were used to assist screening of polymer carriers, and in vitro dissolution and dissociation constant data were used to optimize the formulation. A variety of analytical methods and molecular dynamics simulations were used to investigate the mechanism of SD supersaturation at the molecular level. The results showed that molecular migration, intermolecular interactions, drug crystal transformation and dissociation constant were particularly important factors in SD supersaturation. This study proposes a new strategy to improve solubility of poorly water-soluble drugs and explore the molecular mechanisms of TSD supersaturation, which could provide a basis for the rational selection of excipients for pharmaceutical preparations.

Nanocrystals with different stabilizers overcome the mucus and epithelial barriers for oral delivery of multicomponent Bufadienolides.

Using nanocrystals (NCs) technology may be a promising drug delivery strategy for oral administration of multicomponent anticancer drugs. However, the intestinal epithelium and the mucus layer on the intestine extremely limited drug transport and absorption by orally. In this study, we selected multicomponent inartificial compound Bufadienolides (BU) with broad spectrum antitumor activity as the model drug to prepare BU NCs with different stabilizers by wet grinding, and explored the efficiency of penetrating through the mucus layer and transporting intestinal epithelial cells in vitro and ex vivo. Results revealed that BU NCs can dramatically improve dissolution behavior synergistically and the efficiency of mucus permeation. Besides, we found that BU NCs with different stabilizers enhanced cellular uptake, which was mainly attributed to increasing or changing the endocytosis pathway and plasma membrane/Endoplasmic reticulum (ER) pathway involved in the transmembrane transport of NCs. Furthermore, BU NCs could definitely improve intestinal absorption efficiency and change the absorption site of BU ex vivo. This multi-angle exploration will provide reference for the development of BU oral delivery formulations.

Prediction of the physical stability of amorphous solid dispersions: relationship of aging and phase separation with the thermodynamic and kinetic models along with characterization techniques.

Introduction: Solid dispersion has been considered to be one of the most promising methods for improving the solubility and bioavailability of insoluble drugs. However, the physical stability of solid dispersions (SDs), including its aging and recrystallization, or phase separation, has always been one of the most challenging problems in the process of formulation development and storage.Areas covered: The high energy state of SDs is one of the primary reasons for the poor physical stability. The factors affecting the physical stability of SDs have been described from the perspective of thermodynamics and kinetics, and the corresponding theoretical model is put forward. We briefly summarize several commonly used techniques to characterize the thermodynamic and kinetic properties of SDs. Specific measures to improve the physical stability of SDs have been proposed from the perspective of prescription screening, process parameters, and storage conditions.Expert opinion: The separation of the drug from the polymer, the formation, and migration of drug crystals will cause the SDs to shift toward the direction of energy reduction, which is the intrinsic cause of instability. Furthermore, computational simulation can be used for efficient and rapid screening suitable for the excipients to improve the physical stability of SDs.

Mechanism and Improved Dissolution of Glycyrrhetinic Acid Solid Dispersion by Alkalizers.

The purpose of this study was to increase the dissolution of glycyrrhetinic acid (GA) by preparing ternary solid dispersion (TSD) systems containing alkalizers, and to explore the modulating mechanism of alkalizers in solid dispersion systems. GA TSDs were prepared by hot melt extrusion (HME) with Kollidon® VA64 as the carrier and L-arginine/meglumine as the alkalizers. The in vitro release of the TSD was investigated with a dissolution test, and the dissociation constant (pKa) was used to describe the ionization degree of the drug in different pH buffers. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FTIR), Raman spectra, X-ray photoelectron spectroscopy (XPS), and a molecular model were used for solid-state characterizations and to study the dissolution mechanism of the TSDs. It was evident that the dissolution of GA significantly increased as a result of the TSD compared to the pure drug and binary solid dispersion. SEM, DSC, and XPRD data showed that GA transformed into an amorphous form in TSD. As illustrated by FTIR, Raman, XPS, and molecular docking, high binding energy ion-pair complexes formed between GA and the alkalizers during the process of HME. These can destroy the H-bond between GA molecules. Further, intermolecular H-bonds formed between the alkalizers and Kollidon® VA64, which can increase the wettability of the drug. Our results will significantly improve the solubility and dissolution of GA. In addition, the lower pKa value of TSD indicates that higher ionization is beneficial to the dissolution of the drug. This study should facilitate further developments of TSDs containing alkalizers to improve the dissolution of weakly acidic drugs and gain a richer understanding of the mechanism of dissolution.