Quercetin (QCT), a natural flavonoid, is of research interest owing to its pharmacological properties. However, its pharmacokinetic limitations could hinder its widespread therapeutic use. Nanocarriers, especially solid lipid nanoparticles (SLNs), might overcome this constraint. This study aimed to investigate QCT-loaded SLNs prepared via a new approach using a volatile oil. The phase-inversion temperature method was used to incorporate rosemary oil (RMO) into SLNs prepared using solid lipids possessing different chemical structures. Among the solid lipids used in the formulations, trilaurin (TLR) exhibited the smallest particle size and good stability after a temperature cycling test. SLNs prepared with a ratio of RMO to TLR of 1:3 could load QCT with an entrapment efficiency of >60% and drug loading of ~2% w/w. The smallest particle size was achieved using the polyoxyethylene-hydrogenated castor oil RH40, and the particle size depended on the concentration. The drug-release profile of QCT_TLR exhibited prolonged biphasic release for >24 h. QCT_TLR was a safe formulation, as indicated by a cell viability percentage of >75% at <2% v/v. In a computer simulation, the system with RMO enabled smaller sized SLNs than those without RMO. This new discovery shows great promise for producing SLNs via the phase-inversion temperature method with incorporation of volatile oil, particularly for delivering compounds with limited water solubility.

2,5-Diketopiperazine derivatives, consisting of benzylidene and alkylidene substituents at 3 and 6 positions, have been considered as a core structure for their antiviral activities. Herein, the novel N-substituted 2,5-Diketopiperazine derivatives were successfully prepared and their antiviral activities against influenza virus were evaluated by monitoring viral propagation in embryonated chicken eggs. It was found that (3Z,6Z)-3-benzylidene-6-(2-methyl propylidene)-4-substituted-2,5-Diketopiperazines (13b–d), (3Z,6E)-3-benzylidene-6-(2-methylpropyli dene)-1-(1-ethyl pyrrolidine)-2,5-Diketopiperazine (14c), and Lansai-C exhibited negative results in influenza virus propagation at a concentration of 25 µg/mL. Additionally, molecular docking study revealed that 13b–d and 14c bound in 430-cavity of neuraminidase from H5N2 avian influenza virus and the synthesized derivatives also strongly interacted with the key amino acid residues, including Arg371, Pro326, Ile427, and Thr439.

This research investigates the gel formation behaviour and drug-controlling performance of doxycycline-loaded ibuprofen-based in-situ forming gels (DH-loaded IBU-based ISGs) for potential applications in periodontal treatment. The investigation begins by exploring the physical properties and gel formation behaviour of the ISGs, with a particular focus on determining their sustained release capabilities. To gain a deeper understanding of the molecular interactions and dynamics within the ISGs, molecular dynamic (MD) simulations are employed. The effects of adding IBU and DH on reducing surface tension and water tolerance properties, thus affecting molecular properties. The phase transformation phenomenon is observed around the interface, where droplets of ISGs move out to the water phase, leading to the precipitation of IBU around the interface. The optimization of drug release profiles ensures sustained local drug release over seven days, with a burst release observed on the first day. Interestingly, different organic solvents show varying abilities to control DH release, with dimethyl sulfoxide (DMSO) demonstrating superior control compared to N-Methyl-2-pyrrolidone (NMP). MD simulations using AMBER20 software provide valuable insights into the movement of individual molecules, as evidenced by root-mean-square deviation (RMSD) values. The addition of IBU to the system results in the retardation of IBU molecule movement, particularly evident in the DMSO series, with the diffusion constant value of DH reducing from 1.2452 to 0.3372 and in the NMP series from 0.3703 to 0.2245 after adding IBU. The RMSD values indicate a reduction in molecule fluctuation of DH, especially in the DMSO system, where it decreases from over 140 to 40 Å. Moreover, their radius of gyration is influenced by IBU, with the DMSO system showing lower values, suggesting an increase in molecular compactness. Notably, the DH-IBU configuration exhibits stable pairing through H-bonding, with a higher amount of H-bonding observed in the DMSO system, which is correlated with the drug retardation efficacy. These significant findings pave the way for the development of phase transformation mechanistic studies and offer new avenues for future design and optimization formulation in the ISG drug delivery systems field.

As an alternative to the traditional polymeric-based system, it is now possible to use an in situ forming system that is based on small molecules. Borneol was used as matrix formation in this study. While triacetin was incorporated into the formulation for prolonging the drug release. The objective of this study is to understand the initial period of the solvent exchange mechanism at the molecular level, which would provide a basis for explaining the matrix formation and drug release phenomena. The evaluation of basic physical properties, matrix formation, in vitro drug release, and molecular dynamics (MD) simulation of borneol-based in situ forming matrixes (ISM) was conducted in this study. The proportion of triacetin was found to determine the increase in density and viscosity. The density value was found to be related to viscosity which could be used for the purpose of prediction. Slow self-assembly of ISM upon the addition of triacetin was associated with higher viscosity and lower surface tension. This phenomenon enabled the regulation of solvent exchange and led to sustaining the drug release. In MD simulation using AMBER Tools, the free movement of the drug and the rapid approach to equilibrium of both solvent and water molecule in a solvent exchange mechanism in borneol-free ISM was observed, supporting that sustained release would not occur. Water infiltration was slowed down and NMP movement was restricted by the addition of borneol and triacetin. In addition, the increased proportion of triacetin promoted the diminished down of all substances’ movement because of the viscosity. The diffusion constant of relevant molecules decreased with the addition of borneol and/or triacetin. Although the addition of triacetin tended to slow down the solvent exchange and molecular movement from computation modelling results, it may not guarantee to imply the best drug release control. The Low triacetin-incorporated (5%) borneol-based ISM showed the highest ability to sustain the drug release due to its self-assembly and has proper solvent exchange. MD simulation addressed the details of the mechanism at the beginning of the process. Therefore, both MD and classical methods contribute to a clearer understanding of solvent exchange from the molecular to macroscopic level and from the first nanosecond of the formulation contact with water to the 10-day of drug release. These would be beneficial for subsequent research and development efforts in small molecule-based in situ forming systems.

Solvent-exchange-induced in situ forming gel (ISG) refers to a drug delivery system that transforms from a solution state into a gel or solid matrix upon administration into the body and exposure to physiological aqueous fluid. This study investigates the molecular behavior and phase inversion process of cellulose acetate butyrate (CAB)-based in situ forming gel (ISG) formulations containing moxifloxacin (Mx) or benzydamine HCl (Bz) as model drugs dissolved in N-methyl pyrrolidone (NMP) using molecular dynamics (MD) simulations and density functional theory (DFT) calculations. The simulations reveal a solvent exchange mechanism, where the diffusion of water molecules replaces NMP, driving the formation of the CAB matrix. Bz exhibited faster diffusion and a more uniform distribution compared to Mx, which aggregated into clusters due to its larger molecular size. The analysis of the root mean square deviation (RMSD) and radius of gyration confirmed the faster diffusion of Bz, which adopted a more extended conformation, while Mx remained compact. The phase transformation was driven by the disruption of CAB-NMP hydrogen bonds, while CAB–water interactions remained limited, suggesting that CAB does not dissolve in water, facilitating matrix formation. The molecular configuration revealed that drug–CAB interactions were primarily governed by hydrophobic forces and van der Waals interactions rather than hydrogen bonding, controlling the release mechanism of both compounds. DFT calculations and electrostatic potential (ESP) maps illustrated that the acetyl group of CAB played a key role in drug–polymer interactions and that differences in CAB substitution degrees influenced the stability of drug-CAB complexes. Formation energy calculations indicated that Mx-CAB complexes were more stable than Bz-CAB complexes, resulting in a more prolonged release of Mx compared to Bz. Overall, this study provides valuable insights into the molecular behavior of CAB-based Mx-, Bz-ISG formulations.

In this study, a hyaluronic acid (HA)-coated glabridin nanoemulsion was developed for enhanced macrophage uptake using the phase inversion temperature (PIT) method. The optimized cationic nanoemulsion consisted of a 10% w/w 60:40 peppermint oil:virgin coconut oil ratio, 10% w/w Cremophor RH40, 1% w/w cetyltrimethylammonium bromide, and 1% w/w ethanol. It exhibited a small droplet size, narrow size distribution, and positive zeta potential. Molecular dynamics simulations supported the experimental results, showing that systems containing a cosurfactant formed smaller droplets than those without a cosurfactant, particularly when ethanol was used as the cosurfactant. A concentration of 0.15% w/w HA solution at a 1:10 nanoemulsion–HA ratio yielded favorable characteristics, including a small droplet size (69.98 ± 0.48 nm), narrow size distribution (0.30 ± 0.00), and negative zeta potential (−23.00 ± 2.08 mV). Transmission electron microscopy image confirmed the presence of HA coating at 0.15% w/w. The incorporation of glabridin stabilized the droplet size (67.63 ± 0.33 nm) and polydispersity index (0.36 ± 0.01) but slightly decreased the absolute zeta potential (−10.83 ± 1.91 mV), whereas the entrapment efficiency was 91.65% ± 1.52% w/w. The nanoemulsion exhibited good physicochemical stability after storage at 40 °C for 6 months. HA coating enhanced the cellular uptake of the nanoemulsion into macrophage cells. The HA-coated glabridin nanoemulsion significantly inhibited the production of reactive oxygen species and nitric oxide and it also demonstrated low cytotoxicity. These findings indicated the potential of the PIT method to produce HA-coated glabridin nanoemulsion as a receptor-mediated delivery system for treating inflammation.