BACKGROUND: The presence of barnyardgrass poses a threat to global food security by reducing rice yields. Currently, herbicides are primarily applied for weed management. However, the effectiveness of herbicide deposition and uptake on barnyardgrass is limited as a consequence of the high wax content on leaves, low water solubility and extreme lipophilicity of herbicides. Therefore, it is imperative to develop novel formulations for efficient delivery of herbicides to improve herbicidal activity and reduce dosage.
RESULTS: We successfully prepared nanosuspension(s) (NS) of quinclorac through the wet media milling technique. This NS demonstrates excellent physical stability and maintains nanoscale during dose transfer. The deposition concentration and uptake concentration of NS on barnyardgrass were 3.84-4.47- and 2.11-2.58-fold greater than those traditional formulations, respectively. Moreover, the NS exhibited enhanced herbicidal activity against barnyardgrass at half the dosage required by conventional formulations without compromising rice safety.
CONCLUSIONS: These findings suggest that NS can effectively facilitate the delivery of hydrophobic and poorly water-soluble herbicide active ingredients, thereby enhancing their deposition, uptake and bioactivity. This study expands the potential application of NS in pesticide delivery, which can provide valuable support for optimizing pesticide utilization, improving economic efficiency and mitigating environmental risks. © 2024 Society of Chemical Industry.

Cinnamomum zeylanicum is a traditional medicinal plant known for its anti-inflammatory, antidiabetic, antimicrobial, anticancer, and antioxidant properties. Its therapeutic efficacy using nanosuspensions is still unclear for treating infectious diseases. This study was designed to evaluate the bioactivities, biochemical characterization, and bioavailability of freshly prepared nanosuspensions of C. zeylanicum. Structural and biochemical characterization of C. zeylanicum and its biological activities, such as antioxidants, antimicrobials, antiglycation, α-amylase inhibition, and cytotoxicity was performed using Fourier-transform infrared (FTIR) spectroscopy and High-Performance Liquid Chromatography (HPLC). C. zeylanicum extract and nanosuspensions showed TPCs values of 341.88 and 39.51 mg GAE/100 g while showing TFCs as 429.19 and 239.26 mg CE/100g, respectively. DPPH inhibition potential of C. zeylanicum extract and nanosuspension was 27.3% and 10.6%, respectively. Biofilm inhibition activity revealed that bark extract and nanosuspension showed excessive growth restraint against Escherichia coli, reaching 67.11% and 66.09%, respectively. The α-amylase inhibition assay of extract and nanosuspension was 39.3% and 6.3%, while the antiglycation activity of nanosuspension and extract was 42.14% and 53.76%, respectively. Extracts and nanosuspensions showed maximum hemolysis at 54.78% and 19.89%, respectively. Results indicated that nanosuspensions possessed antidiabetic, antimicrobial, anticancer, and antioxidant properties. Further study, however, is needed to assess the clinical studies for the therapeutic use of nanosuspensions.

Kaempferol (KAE) is a naturally occurring flavonoid compound with antitumor activity. However, the low aqueous solubility, poor chemical stability, and suboptimal bioavailability greatly restrict its clinical application in cancer therapy. To address the aforementioned limitations and augment the antitumor efficacy of KAE, we developed a kaempferol nanosuspensions (KAE-NSps) utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a stabilizing agent, screened the optimal preparation process, and conducted a comprehensive investigation of their fundamental properties as well as the antitumor effects in the study. The findings indicated that the particle size was 186.6 ± 2.6 nm of the TPGS-KAE-NSps optimized, the shape of which was fusiform under the transmission electron microscope. The 2% (w/v) glucose was used as the cryoprotectant for TPGS-KAE-NSps, whose drug loading content was 70.31 ± 2.11%, and the solubility was prominently improved compared to KAE. The stability and biocompatibility of TPGS-KAE-NSps were favorable and had a certain sustained release effect. Moreover, TPGS-KAE-NSps clearly seen to be taken in the cytoplasm exhibited a stronger cytotoxicity and suppression of cell migration, along with increased intracellular ROS production and higher apoptosis rates compared to KAE in vitro cell experiments. In addition, TPGS-KAE-NSps had a longer duration of action in mice, significantly improved bioavailability, and showed a stronger inhibition of tumor growth (the tumor inhibition rate of high dose intravenous injection group was 68.9 ± 1.46%) than KAE with no obvious toxicity in 4T1 tumor-bearing mice. Overall, TPGS-KAE-NSps prepared notably improved the defect and the antitumor effects of KAE, making it a promising nanodrug delivery system for KAE with potential applications as a clinical antitumor drug.

The drug nanosuspensions is a universal formulation approach for improved drug delivery of hydrophobic drugs and one the most promising approaches for increasing the biopharmaceutical performance of poorly water-soluble drug substances, especially for nature products. This review aimed to summarize the nanosuspensions preparation approaches and the main technological difficulties encountered in nanosuspensions development, such as guidelines for stabilizers screening, in vivo fate of the intravenously administrated nanosuspensions, and how to realize the intravenously target delivery was reviewed. Furthermore, challenges of nanosuspensions for the nature products delivery also was discussed and commented. Therefore, it hoped to provide reference and assistance for the nanosuspensions production, stabilizers usage, and predictability of in vivo fate and controllability of targeting delivery of the nature products nanosuspensions.

Celecoxib (CXB) has a good analgesic effect on postoperative acute pain, but clinically its compliance is compromised because of frequent administration. Therefore, the development of injectable celecoxib nanosuspensions (CXB-NS) for long-acting analgesic effects is highly desirable. However, how the particle size affects the in vivo behaviors of CXB-NS remains unclear. Herein, CXB-NS with different sizes were prepared by the wet-milling method. Following intramuscular (i.m.) injection in rats (50 mg/kg), all CXB-NS achieved sustained systemic exposure and long-acting analgesic effects. More importantly, CXB-NS showed size-dependent pharmacokinetic profiles and analgesic effects, and the smallest CXB-NS (about 0.5 μm) had the highest Cmax, T1/2, and AUC0-240h and the strongest analgesic effects on incision pain. Therefore, small sizes are preferred for long action by i.m. injection, and the CXB-NS developed in this study were alternative formulations for the treatment of postoperative acute pain.

The study aimed to explore the size effect on the in vitro-in vivo correlation (IVIVC) in the oral absorption of andrographolide nanosuspensions (Ag-NS). Ag-NS with controllable particle sizes were prepared by ultrasonic dispersion method, and the formulation and process parameters were optimized through single factor experiments using mean particle size, polydispersity index, and stability as evaluation indicators. The morphology of Ag-NS was observed by scanning electron microscopy (SEM), and the crystalline state of the nanosuspensions was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The dissolution tests were carried out with the paddle method in two different mediums simulating the pH conditions in intestinal fluid pH 6.8 and gastric fluid (pH 1.2), respectively. The pharmacokinetic behaviors were investigated in rats after oral administration, and a deconvolution approach was introduced to determine the correlation between in vitro dissolution and in vivo absorption (IVIVC). The formulation with the use of lecithin and PEG-800 as stabilizers showed its potential in the size-controllable preparation of Ag-NS. Via altering the ultrasonication amplitude and time, three Ag-NS suspensions with particle sizes of particle size, i.e., Ag-NS 250 (244.3 ± 0.4 nm), Ag-NS 450 (464.3 ± 32.2 nm), Ag-NS 1000 (1015 ± 36.1 nm) were prepared. Their morphological and crystal characteristics did not change during the size reduction process, but both of their in vitro dissolution and in vivo absorption were improved. Relatively better IVIVC performance was observed with the in vitro dissolution data at pH 6.8 (r > 0.9). With the reduction of particle size, the in vivo absorption fraction was more closed to the level of the in vitro dissolution. In conclusion, the decrease in particle size would improve the dissolution and absorption of Ag-NS, and also affect their IVIVC performance. The study would facilitate the design and quality control of Ag-NS in terms of particle size and dissolution specifications.

This study was designed to explore the potential of gypenosides as a novel natural stabilizer for the production of nanosuspensions. The gypenosides-stabilized quercetin nanosuspensions(QUE-NS) were prepared using the high-speed shearing and high-pressure homogenization method with quercetin as a model drug, followed by their in vitro evaluation.Based on the measured mean particle size and polydispersity index(PDI) of QUE-NS,the single factor experiment was conducted to optimize the preparation process parameters.The freeze-drying method was used to transform QUE-NS into freeze-dried powders, whose storage stability and saturation solubility were then studied.Moreover, the effects of pH and ionic strength on the physical stability of the nanosuspension system were examined.According to the results, the optimized process parameters were listed as follows: shear rate 13 000 r·min~(-1),shear time 2 min, homogenization pressure 100 MPa, and homogenization frequency 12 times.The mean particle size of QUE-NS prepared under the optimum process conditions was(461.9±2.4) nm, and the PDI was 0.059±0.016.During the two months of storage at room temperature, the freeze-dried QUE-NS powders remained stable.The saturation solubility of freeze-dried QUE-NS powders was proved higher than those of quercetin and the physical mixture.The results of stability testing demonstrated that QUE-NS stabilized with gypenosides exhibited good stability within the pH range of 6 to 8,while coalescence was prone to occur in the presence of salt.Overall, gypenosides is expected to become a new natural stabilizer for the preparation of nanosuspensions.

Local administration of therapeutic agents provides a favorable approach to enhance drug accumulation at pathological sites. In this study, a novel honokiol nanosuspensions loaded thermosensitive injectable hydrogels (HK-NS-Gel) was designed as the local delivery system for the combination therapy with systemic paclitaxel (PTX). The formed HK-NS-Gel showed superior gelation time and temperature. In vitro release and in vivo drug retention assay showed that HK-NS-Gel can slowly and steadily release the HK during 12 days. Meanwhile, enhanced PTX accumulation in the tumor was observed after intratumoral injection of HK-NS-Gel. In vitro cytotoxicity and cell apoptosis tests against 4T1 cells proved the synergistic effects of free PTX combined with HK-NS-Gel. In vivo antitumor study was conducted on 4T1 bearing mice, indicating that co-administration HK-NS-Gel and PTX could effectively enhance tumor growth suppression, and the tumor inhibitory rate was as high as 72.51%. In conclusion, intravenous delivery of PTX combined with intratumoral delivery of HK-NS-Gel was a promising combination for breast cancer therapy with enhanced therapeutic response and safety.

Nanosuspensions can effectively increase saturation solubility and improve the bioavailability of poorly water-soluble drugs attributed to high loading and surface-to-volume ratio. Wet media milling has been regarded as a scalable method to prepare nanosuspensions because of its simple operation and easy scale-up. In recent years, besides particle aggregation and Ostwald ripening, polymorphic transformation induced by processing has become a critical factor leading to the instability of nanosuspensions. Therefore, this review aims to discuss the influence factors comprehensively and put forward the corresponding improvement strategies of polymorphic transformation during the formation of nanosuspensions. In addition, this review also demonstrates the implication of molecular simulation in polymorphic transformation. The competition between shear-induced amorphization and thermally activated crystallization is the global mechanism of polymorphic transformation during media milling. The factors affecting the polymorphic transformation and corresponding improvement strategies are summarized from formulation and process parameters perspectives during the formation of nanosuspensions. The development of analytical techniques has promoted the qualitative and quantitative characterization of polymorphic transformation, and some techniques can in situ monitor dynamic transformation. The microhydrodynamic model can be referenced to study the stress intensities by analyzing formulation and process parameters during wet media milling. Molecular simulation can be used to explore the possible polymorphic transformation based on the crystal structure and energy. This review is helpful to improve the stability of nanosuspensions by regulating polymorphic transformation, providing quality assurance for nanosuspension-based products.HighlightsPolymorphic transformation depends on the intensity and temperature of milling.Stress intensities of milling can be elucidated and improved by microhydrodynamics.Higher stress intensities of milling perhaps be accompanied by higher temperatures.Molecular simulation used in polymorphs is based on crystal structure and energy.Molecular dynamics simulations can demonstrate the stability of amorphous forms.

The objective of this study was to develop novel herpetrione (HPE) nanosuspensions stabilized by glycyrrhizin (HPE NSs/GL) for enhancing bioavailability and hepatoprotective effect of HPE. HPE NSs/GL were prepared by wet media milling method and then systemically evaluated by particle size analysis, scanning electronic microscopy (SEM), X-ray powder diffraction (XRPD), dissolution test, pharmacokinetics, and hepatoprotective effect. HPE-NSs stabilized by poloxamer 407 (HPE NSs/P407) were also prepared and used as a reference for comparison. HPE NSs/GL and HPE-NSs/P407 with similar particle sizes around 450 nm and PDI less than 0.2 were successfully prepared and both of them appeared to be spherical under SEM. The XRPD results demonstrated that HPE in both HPE NSs/GL and HPE NSs/P407 was presented in the amorphous state and the addition of GL or P407 and the milling process didn\'t alter the physical state of HPE. The dissolution and pharmacokinetic studies demonstrated that HPE NSs/GL exhibited significant enhancement in drug dissolution (72.44% within 24 h) and AUC0-t (24.91 ± 3.3 mg/L·h) as compared to HPE coarse suspensions (HPE CS, 34.19% & 13.07 ± 1.02 mg/L·h), but was similar with those of HPE NSs/P407 (80.06% & 26.75 ± 4.06 mg/L•h). Moreover, HPE NSs/GL exhibited significantly better hepatoprotective effect as compared to HPE CS and HPE NSs/P407 as indicated by the lowering of the elevated serum ALT and AST levels and the improvement of the hepatic morphology and architecture, which might be attributed to the improved bioavailability of HPE, and synergistic hepatoprotective effect of GL via alleviating inflammation evidenced by the significant decreased hepatic levels of inflammatory cytokines IL-1β, IL-6 and TNF-α. It could be concluded that GL might be an effective stabilizer for preparing HPE NSs, and HPE NSs/GL is a potential formulation strategy for improving oral bioavailability and hepatoprotective effect of HPE.