Inclusion Complexes of Daidzein with Cyclodextrin-Based Metal-Organic Framework-1 Enhance Its Solubility and Antioxidant Capacity.

Daidzein, an aglycone-type isoflavone, is useful in the prevention of atherosclerotic cardiovascular diseases. However, the solubility of daidzein remains relatively low even with pharmaceutical interventions (e.g., γ-cyclodextrin inclusion complex). In the present study, daidzein-cyclodextrin-metal organic framework solid dispersion complexes were prepared by the solvent evaporation method. The physicochemical properties of the complex and its effect on the solubility of daidzein were evaluated. The enhancement effect of a cyclodextrin-metal organic framework on the antioxidant properties of daidzein was verified using a diphenyl-picrylhydrazyl radical scavenging test. Powder X-ray diffraction results showed that the characteristic diffraction peaks of daidzein and cyclodextrin-metal organic framework disappeared and new peaks (2θ = 7.1°, 16.5°) were observed. FT-IR measurements showed that the peak derived from the carbonyl group of daidzein shifted to the lower wavenumber. NOESY 1H-1H NMR showed cross peaks at the proton on the resorcinol side of daidzein and the proton (H-5, H-6) in a cyclodextrin-metal organic framework. Dissolution rate of daidzein at 5 min in distilled water was 0.06% for daidzein alone while the daidzein inclusion complex was about 100%. When fasted state simulated intestinal fluid was used, the dissolution rate of the daidzein complex was about 71% compared with that of daidzein alone (~ 3.0%) at 5 min. The daidzein inclusion complex improved the antioxidant capacity to ~ 1.3 times (17.8 µg/mL) compared to the IC50 of daidzein alone (22.9 µg/mL). Preparations of cyclodextrin-metal organic framework inclusion complexes will be a platform in developing pharmaceutical formulations to enhance the bioavailability and activity of drugs.

Characterization, Preparation, and Promotion of Plant Growth of 1,3-Diphenylurea/ß-Cyclodextrin Derivatives Inclusion Complexes.

The study aimed to prepare inclusion complexes of 1,3-diphenylurea (DPU) with ß-cyclodextrin (ßCD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ßCD) using a three-dimensional ground mixture (3DGM). Their physicochemical properties, intermolecular interactions, solubilities, and plant growth-promoting activities were investigated on broccoli sprouts. Phase-solubility diagrams indicated the stability constant (Ks) and complexation efficiency (CE) of ßCD/DPU were found to be K1/1 = 250 M-1, CE = 2.48× 10-3. The Ks and CEs of HP-ßCD/DPU were found to be K1/1 = 427 M-1, CE = 3.93 × 10-3 and K2/1 = 196 M-1, CE = 1.93 × 10-3 respectively. The powder X-ray diffraction results of 3DGM (ßCD/DPU = 2/1, HP-ßCD/DPU = 2/1) showed that the diffraction peaks originating from the DPU and ßCD disappeared, indicating a halo pattern. Differential scanning calorimetry results showed an endothermic peak at 244 °C derived from the melting point of DPU, but the endothermic peak disappeared in the 3DGM (ßCD/DPU = 2/1, HP-ßCD/DPU = 2/1). Near-infrared absorption spectra showed peak shifts in 3DGM (ßCD/DPU and HP-ßCD/DPU) at the -CH and -NH groups of DPU and the -OH groups of ßCDs and free water. In the dissolution test (after 5 min), the concentration of intact DPU was 0.083 µg/mL. However, the dissolution concentrations of DPU in the 3DGM (ßCD/DPU = 1/1), 3DGM (ßCD/DPU = 2/1), 3DGM (HP-ßCD/DPU = 1/1), and 3DGM (HP-ßCD/DPU = 2/1) were 3.27, 3.64, 5.70, and 7.03 µg/mL, respectively, indicating higher solubility than that of the intact DPU. Further, 1H-1H NOESY NMR spectroscopic measurements showed cross-peaks between H-A (7.32 ppm) and H-B (7.12 ppm) of DPU and H-6 (3.79 ppm) in the ßCD cavity of the 3DGM (ßCD/DPU = 2/1). A cross-peak was also observed among DPU H-A (7.32 ppm), H-B (7.11 ppm), and H-6 (3.78 ppm) in the ßCD cavity. The results of the broccoli sprout cultivation experiment showed that 3DGM (ßCD/DPU = 1/1), 3DGM (ßCD/DPU = 2/1), 3DGM (HP-ßCD/DPU = 1/1), and 3DGM (HP-ßCD/DPU = 2/1) increased the stem thickness compared with that of the control group (DPU). These results indicated that the ßCD/DPU and HP-ßCD/DPU inclusion complexes were formed by the three-dimensional mixing and milling method, which enhanced the solubility and plant growth-promoting effects.

Development of Self-Administered Formulation to Improve the Bioavailability of Leuprorelin Acetate.

In recent years, the development of self-injectable formulations has attracted much attention, and the development of formulations to control pharmacokinetics, as well as drug release and migration in the skin, has become an active research area. In the present study, the development of a lipid-based depot formulation containing leuprorelin acetate (LA) as an easily metabolizable drug in the skin was prepared with a novel non-lamellar liquid-crystal-forming lipid of mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE). Small-angle X-ray scattering, cryo-transmission electron microscopy, and nuclear magnetic resonance observations showed that the MGE-containing formulations had a face-centered cubic packed micellar structure. In addition, the bioavailability (BA) of LA after subcutaneous injection was significantly improved with the MGE-containing formulation compared with the administration of LA solution. Notably, higher Cmax and faster Tmax were obtained with the MGE-containing formulation, and the BA increased with increasing MGE content in the formulation, suggesting that LA migration into the systemic circulation and its stability might be enhanced by MGE. These results may support the development of self-administered formulations of peptide drugs as well as nucleic acids, which are easily metabolized in the skin.

Comparison of various commercially available cinnamon barks using NMR metabolomics and the quantification of coumarin by quantitative NMR methods.

Cinnamon bark is an important spice worldwide. In this study, the chemical diversity of various commercially available cinnamon barks that differed in their production areas and utility applications (culinary spice or medicines) were investigated by the use of 1H NMR metabolomics. Our results indicated that principle component analysis (PCA) and hierarchical cluster analysis (HCA) of the 1H NMR spectra of the cinnamon bark methanolic extracts including the deduction of their species by nucleotide sequence analysis enabled differentiation of the cinnamon barks according to their species, production areas and utility applications. The constituents of Vietnam cinnamon were found to differ significantly from the other samples investigated based on PCA score plots and HCA constellation dendrograms. Coumarin was found to be a key compound for the discrimination of Vietnamese cinnamon by multivariate analysis of the 1H NMR spectral data and direct comparison of the 1H NMR spectra. In addition, coumarin was quantified using quantitative NMR methods. As a result, coumarin was contained in Vietnamese cinnamon at a higher level compared to other cinnamons. This study indicated that 1H NMR metabolomics could deduce spices, utility, and producing area of commercially available cinnamon barks. Furthermore, combining quantitative 1H NMR methods with 1H NMR metabolomics enable quantification of coumarin in cinnamon bark on a single measurement.