Pair Potential between Poloxamer 407 Micelles in 14 wt % Aqueous Solution Clarifying the Sol-Gel-Sol Transition by Temperature Rise.

Poloxamer 407 (P407) is used as a safety-guaranteed, invaluable pharmaceutical nanocarrier. The aqueous solution of P407 exhibits sol-to-gel and gel-to-sol transitions, specifically during a temperature rise. Here, we develop a method to determine the pair potential between colloidal particles based primarily on experimental small-angle scattering data.

NMR-based analysis of impact of siRNA mixing conditions on internal structure of siRNA-loaded LNP.

This study aimed to assess the applicability of solution-state H NMR for molecular-level characterization of siRNA-loaded lipid nanoparticles (LNP). Dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA, MC3) was used as an ionizable lipid, and siRNA-loaded LNPs were prepared by pre-mixing and post-mixing methods. The pre-mixing method involved mixing an acidic solution containing siRNA with an ethanolic lipid solution using a microfluidic mixer.

Effect of Acetaminophen on Poloxamer 407 Micelles and Hydrogels: The Relationship between Structural and Physical Properties.

Poloxamer hydrogel possesses thermosensitive sol-gel transition characteristics and is widely used as a drug-controlled-release carrier for topical or injectable formulations. In this study, the effect of loading of a drug, acetaminophen (ACE), on the physical and structural properties of poloxamer 407 (P407) micelles and hydrogels was investigated. Differential scanning calorimetry measurements revealed that ACE reduced the critical micelle temperature and enthalpy of micellization of P407 solutions.

Impact of colloidal drug-rich droplet size and amorphous solubility on drug membrane permeability: A comprehensive analysis.

This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in AS-HF grade of hypromellose acetate succinate (HPMC-AS) solution was significantly reduced compared to that in non-polymer solution due to AS-HF partitioning into the CND-rich phase. In contrast, AS-LF grade of HPMC-AS has minimal effect on the amorphous solubility.

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid-Liquid Phase Separation.

Drug-rich droplets formed through liquid-liquid phase separation (LLPS) have the potential to enhance the oral absorption of drugs. This can be attributed to the diffusion of these droplets into the unstirred water layer (UWL) of the gastrointestinal tract and their reservoir effects on maintaining drug supersaturation. However, a quantitative understanding of the effect of drug-rich droplets on intestinal drug absorption is still lacking.

The Effect of Cholesterol Content on the Adjuvant Activity of Nucleic-Acid-Free Lipid Nanoparticles.

RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response.

Controlled Sublimation Rate of Guest Drug from Polymorphic Forms of a Cyclodextrin-Based Polypseudorotaxane Complex and Its Correlation with Molecular Dynamics as Probed by Solid-State NMR.

Encapsulation of active pharmaceutical ingredients (APIs) in confined spaces has been extensively explored as it dramatically alters the molecular dynamics and physical properties of the API. Herein, we explored the effect of encapsulation on the molecular dynamics and physical stability of a guest drug, salicylic acid (SA), confined in the intermolecular spaces of γ-cyclodextrin (γ-CD) and poly(ethylene glycol) (PEG)-based polypseudorotaxane (PPRX) structure. The sublimation tendency of SA encapsulated in three polymorphic forms of the γ-CD/PEG-based PPRX complex, monoclinic columnar (MC), hexagonal columnar (HC), and tetragonal columnar (TC), was investigated.

Mechanistic Analysis of Temperature-Dependent Curcumin Release from Poly(lactic-co-glycolic acid)/Poly(lactic acid) Polymer Nanoparticles.

In this study, we investigated the mechanism of curcumin (CUR) release from poly(lactic--glycolic acid) (PLGA) and poly(lactic acid) (PLA) nanoparticles (NPs) by evaluating the temperature-dependent CUR release. NPs were prepared by the nanoprecipitation method using various PLGA/PLA polymers with different lactic:glycolic ratios (L:G ratios) and molecular weights. Increasing the polymer molecular weight resulted in a decrease in the particle size of NPs.

Unveiling the flavone-solubilizing effects of α-glucosyl rutin and hesperidin: probing structural differences through NMR and SAXS analyses.

Flavonoids often exhibit broad bioactivity but low solubility and bioavailability, limiting their practical applications. The transglycosylated materials α-glucosyl rutin (Rutin-G) and α-glucosyl hesperidin (Hsp-G) are known to enhance the dissolution of hydrophobic compounds, such as flavonoids and other polyphenols. In this study, the effects of these materials on flavone solubilization were investigated by probing their interactions with flavone in aqueous solutions.

Molecular-Level Structural Analysis of siRNA-Loaded Lipid Nanoparticles by H NMR Relaxometry: Impact of Lipid Composition on Their Structural Properties.

H NMR relaxometry was applied for molecular-level structural analysis of siRNA-loaded lipid nanoparticles (LNPs) to clarify the impact of the neutral lipids, 1,2-distearoyl--glycero-3-phosphocholine (DSPC) and cholesterol, on the physicochemical properties of LNP. Incorporating DSPC and cholesterol in ionizable lipid-based LNP decreased the molecular mobility of ionizable lipids. DSPC reduced the overall molecular mobility of ionizable lipids, while cholesterol specifically decreased the mobility of the hydrophobic tails of ionizable lipids, suggesting that cholesterol filled the gap between the hydrophobic tails of ionizable lipids.

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption.

Coamorphous formulation is a useful approach for enhancing the solubility of poorly water-soluble drugs via intermolecular interactions. In this study, a hydrogen-bonding-based coamorphous system was developed to improve drug solubility, but it barely changed the apparent permeability () of the drug. This study aimed to design a novel coamorphous salt using ionic interactions to improve drug permeability and absorption.

Preparation of a ternary amorphous solid dispersion using hot-melt extrusion for obtaining a stable colloidal dispersion of amorphous probucol nanoparticles.

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low T (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant.

Supersaturation maintenance of carvedilol and chlorthalidone by cyclodextrin derivatives: Pronounced crystallization inhibition ability of methylated cyclodextrin.

Cyclodextrin (CD) is used to solubilize poorly water-soluble drugs by inclusion complex formation. In this study, we investigated the effect of CD derivatives on stabilizing the supersaturation by inhibiting the crystallization of two poorly water-soluble drugs, carvedilol (CVD) and chlorthalidone (CLT). The phase solubility test showed that β-CD and γ-CD derivatives enhanced the solubility of CVD to a greater extent, whereas the solubility of CLT was enhanced more by β-CD derivatives.

Quantitative Analysis of Drug Supersaturation Region by Temperature-Variable Nuclear Magnetic Resonance Measurements, Part 1: Effects of Polymer and Drug Chiralities.

We examined the effects of the polymer-additive and drug chiralities on the ketoprofen (KTP) supersaturation region using temperature-variable nuclear magnetic resonance (NMR). Quantitative NMR analysis revealed that the racemic KTP and corresponding -enantiomer (rac- and s-KTP) exhibited similar amorphous solubilities in a buffer, while the crystalline solubility of s-KTP was higher than that of rac-KTP. Therefore, rac-KTP exhibited a larger supersaturation region than s-KTP.

Quantitative Analysis of Drug Supersaturation Region by Temperature-Variable Nuclear Magnetic Resonance Measurements, Part 2: Effects of Solubilizer.

This study utilized temperature-variable nuclear magnetic resonance (NMR) spectroscopy to investigate the effects of a solubilizing agent on the ketoprofen (KTP) supersaturation region. Quantitative NMR analysis showed that the solubilizing agent cetyltrimethylammonium bromide (CTAB) increased both the crystalline and amorphous solubilities of KTP, shifting the KTP supersaturation region to a higher KTP concentration range. The amorphous solubility of KTP was found to be independent of the enantiomeric composition of KTP, even in the presence of CTAB.

Understanding the rod-to-tube transformation of self-assembled ascorbyl dipalmitate lipid nanoparticles stabilized with PEGylated lipids.

We previously established a nanoparticle-based drug delivery system (DDS) for high-dose ascorbic acid therapy by self-assembly of a lipid-modified ascorbic acid derivative, L-ascorbyl 2,6-dipalmitate (ASC-DP). The particles' morphology should be modified for effective DDSs. Here, we modulated the morphology of self-assembled ASC-DP nanoparticles using two different PEGylated lipids, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and cholesterol-polyethylene glycol (Chol-PEG), with various PEG molecular weights.

Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells.

Myofibroblast-like activated hepatic stellate cells (aHSCs), which produce collagen, a major cause of liver fibrosis, are specific target cells for antifibrotic treatment. Recently, several reports have indicated that extracellular vesicles (EVs) play important roles in cell-to-cell communication through their tropism for specific cells or organs. Therefore, the present study aimed to identify aHSC-directed EVs by focusing on cell-to-cell interactions in the liver under pathological conditions.

Drug-Loaded Nanocarriers Composed of Cholesteryl Oleate Crystal Cores and Multiple-Nanosheet Shells of γ-Cyclodextrin Inclusion Complex Crystals.

In this study, we prepared drug-loaded nanocarriers made of cholesteryl oleate (ChO) and γ-cyclodextrin (γ-CD). A nanosuspension (nanosuspension-I, NS-I) containing nanoparticles with a mean size of approximately 170 nm was obtained through the solvent-diffusion method using ethanol. A second nanosuspension (nanosuspension-II, NS-II), which was prepared by freeze-drying and redispersion of NS-I, exhibited an increased particle size of approximately 210 nm.

Unusual Correlation between the Apparent Amorphous Solubility of a Drug and Solubilizer Concentration Revealed by NMR Analysis.

Herein, we investigated the effect of the solubilizers, cetyltrimethylammonium bromide (CTAB) and amino methacrylate copolymer (Eudragit E PO, EUD-E), on the apparent amorphous solubility of ketoprofen (KTP) and free KTP concentrations in an aqueous phase when a KTP-rich phase was generated by liquid-liquid phase separation. Quantitative analysis by solution nuclear magnetic resonance (NMR) revealed that the apparent amorphous solubility of KTP increased with increasing EUD-E concentrations by the solubilization of KTP into the EUD-E micelles; this was reminiscent of the improvement in the apparent crystalline solubility of KTP observed when EUD-E was added. In contrast, the apparent amorphous solubility of KTP decreased with increasing CTAB concentrations, although the solubilizing ability of CTAB was stronger than that of EUD-E when the KTP-rich phase was absent.

Multistep Crystallization of Pharmaceutical Amorphous Nanoparticles via a Cognate Pathway of Oriented Attachment: Direct Evidence of Nonclassical Crystallization for Organic Molecules.

Crystallization of organic molecules is important in a wide range of scientific disciplines. However, in contrast to maturely studied crystallization of inorganic materials, the crystallization mechanisms of organic molecules involving nucleation and crystal growth are still poorly understood. Here, we used time-resolved cryogenic transmission electron microscopy to directly map the morphological evolution of amorphous cyclosporin A (CyA) nanoparticles during CyA crystallization.

Computational approach to elucidate the formation and stabilization mechanism of amorphous formulation using molecular dynamics simulation and fragment molecular orbital calculation.

α-Glycosyl rutin (Rutin-G) consists of a flavonol skeleton and sugar groups and is a promising additive for amorphous formulations. In our previous study, experimental approaches suggested an interaction between the model drug carbamazepine (CBZ) and flavonol skeleton of Rutin-G that stabilizes amorphous formulations. In the present study, the formation and stabilization mechanisms of CBZ/Rutin-G amorphous formulation were investigated using a computational approach.

Transition from Amorphous Cyclosporin A Nanoparticles to Size-Reduced Stable Nanocrystals in a Poloxamer 407 Solution.

Amorphous drug nanoparticles usually exhibit low storage stability. A comprehensive understanding of the molecular states and physicochemical properties of the product is indispensable for designing stable formulations. In the present study, an amorphous cyclosporin A (CyA) nanosuspension with a mean particle size of approximately 370 nm was prepared by wet bead milling with poloxamer 407 (P407).

Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations.

We previously reported that the polymers used in amorphous solid dispersion (ASD) formulations, such as polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate (PVP-VA), and hypromellose (HPMC), distribute into the drug-rich phase of ibuprofen (IBP) formed by liquid-liquid phase separation, resulting in a reduction in the maximum drug supersaturation in the aqueous phase. Herein, the mechanism underlying the partitioning of the polymer into the drug-rich phase was investigated from a thermodynamic perspective. The dissolved IBP concentration in the aqueous phase and the amount of polymer distributed into the IBP-rich phase were quantitatively analyzed in IBP-supersaturated solutions containing different polymers using variable-temperature solution-state nuclear magnetic resonance (NMR) spectroscopy.