Amphiphilic disodium glycyrrhizin as a co-former for ketoconazole co-amorphous systems: Biopharmaceutical properties and underlying molecular mechanisms.

Co-amorphous systems (CAMs) have been extensively investigated to improve the dissolution of hydrophobic drugs. However, drug precipitation during the storage or dissolution of CAMs has still been a major challenge. Here, disodium glycyrrhizin (Na2GA) was first used as a co-former in CAMs based on its multiple hydroxyl groups and amphiphilic structure. Ketoconazole (KTZ), a BCS class II drug, was selected as a model drug. KTZ-Na2GA CAMs at mass ratios of 1:1, 1:2.5, 1:5 and 1:10 were prepared by the spray drying method and further characterised by PXRD and DSC. The 1:2.5, 1:5 and 1:10 groups exhibited significantly enhanced Cmax (all approximately 26.67-fold) and stable maintenance of supersaturation compared to the crystalline KTZ and the corresponding physical mixtures in non-sink dissolution tests, while the 1:1 group exhibited an unstable medium Cmax (all approximately 14.67-fold). The permeability tests revealed that the permeation rate of KTZ in KTZ-Na2GA CAMs under the concentration of Na2GA in solution above the critical micelle concentration (CMC) showed a significant downwards trend compared to that below CMC. The underlying molecular mechanisms were involved in molecular miscibility, hydrogen bond interactions, solubilisation and crystallisation inhibition by Na2GA. Pharmacokinetic studies demonstrated that the AUC0-∞ of KTZ in 1:1, 1:2.5, 1:5 and 1:10 groups were significantly higher than those of the crystalline KTZ group with 2.13-, 2.30-, 2.16- and 1.86-fold, respectively (p < 0.01). In conclusion, Na2GA has proven to be a promising co-former in CAMs to enhance hydrophobic drug dissolution and bioavailability. Its effect on intestinal permeation rate of drugs also deserves attention.

Significantly activated persulfate by novel carbon quantum dots-modified N-BiOCl for complete degradation of bisphenol-A under visible light irradiation.

The practical application of bismuth-based photocatalysts in the field of micropollutant photodegradation is limited due to their weak light absorption and rapid charge recombination. Herein, we have developed a novel carbon quantum dots-modified N-BiOCl (CDs-N-BiOCl) photocatalyst to activate persulfate (PS) for the complete elimination of endocrine-disruptor bisphenol A (BPA) under visible light irradiation. The photoelectric properties characterization shows that N atoms could replace Cl atoms or adsorb on Bi atoms to form local N 1s states in the BiOCl lattice, accompanied by the introduction of doping energy levels that shorten the electron migration distance. Meanwhile, the decorated CDs could effectively accept the photoinduced electrons from N-BiOCl conduction band to facilitate the charge separation. Thus, the 7%CDs-N-BiOCl (7CNB) nanocomposite synergistically activated PS realized rapid and effective degradation of BPA within 20 min (degradation efficiency and mineralization reached 100 % and 66.4 % respectively). Moreover, the 7CNB/PS system displayed favorable adaptability, durability, and interference resistance. Furthermore, the biotoxicity experiments demonstrated that the photodegradation intermediates promoted the growth of Escherichia coli which indicates its eco-friendliness for practical application. Finally, the electron transfer mechanism and the formation of reactive oxygen species in the photodegradation process were interpreted. In short, this work will present a promising strategy for bismuth-based photocatalysts to be used for the efficient treatment of real water bodies under visible light irradiation.

Use of surfactant-based amorphous solid dispersions for BDDCS class II drugs to enhance oral bioavailability: A case report of resveratrol.

This paper aimed to improve in vitro dissolution/solubility as well as inhibit intestinal metabolism and thus enhance oral bioavailability for a BDDCS class II drug by constructing surfactant-based amorphous solid dispersions using resveratrol (RES) as a model drug. After preliminary screening of polymers and surfactants, and subsequent prescription optimization, two optimized spray-drying RES-polymer-surfactant ASDs were obtained and exhibited a significant increase in solubility of RES by 2.69-3.45-fold compared to crystalline RES, and by 1.13-1.56-fold compared to corresponding RES-polymer ASDs, maintaining a higher concentration in the dissolution process. A metabolism study using everted sacs showed that two optimized ASDs reduced the concentration ratio of RES-G to RES to 51.66%-52.05% of crystalline RES on the serosal side of the rat everted intestinal sac at 2 h. Consequently, these two RES-polymer-surfactant ASDs achieved significantly higher exposure of RES in the plasma with significant enhancements in Cmax (2.33-2.35-fold higher than crystalline RES, and 1.72-2.04-fold higher than corresponding RES-polymer ASDs), and in AUC 0-∞ (3.51-3.56-fold higher than crystalline RES, and 1.38-1.41-fold higher than corresponding RES-polymer ASDs). These advantages of the RES-polymer-surfactant ASDs in oral absorption of RES were attributed to solubilization by ASDs and metabolic inhibition by UGT inhibitors. The introduction of surfactants including EL and Lab to ASDs plays an important role in inhibiting glucuronidation and further improving solubility. This study demonstrated that such surfactant-based amorphous solid dispersions may serve as a new approach to increase the oral absorption of BDDCS class II drugs.

Co-amorphous systems using epigallocatechin-3-gallate as a co-former: Stability, in vitro dissolution, in vivo bioavailability and underlying molecular mechanisms.

Co-amorphous strategy has been extensively investigated to improve the dissolution of hydrophobic drugs. Here, epigallocatechin-3-gallate (EGCG) was exploited as a co-former in co-amorphous systems based on its unique structure including phenyl rings, phenolic hydroxyl groups and the galloyl moiety. Two model BCS class II drugs, simvastatin (SIM) and nifedipine (NIF), were selected to be co-amorphized with EGCG. All drug-EGCG systems at three molar ratios became amorphous by the means of spray drying and showed high physically stable either under dry condition and 75 % RH at 40 °C or under dry conditions at 25 °C. The optimal feed molar ratios of both EGCG based co-amorphous systems fabricated were determined to be three, under which the significant increases were obtained in the maximum apparent concentrations of 4.90-fold for SIM at 1 h and 106.03-fold for NIF at 0.25 h compared to crystalline drugs by non-sink dissolution studies. The underlying molecular mechanisms of two co-amorphous systems formation were involved in molecular miscibility, hydrogen bonds and π-π stacking interactions unraveled by means of DSC, FTIR and molecular dynamics simulations. More to the point, oral pharmacokinetic studies in rats demonstrated that co-amorphous SIM-EGCG and NIF-EGCG systems at 1:3 have a significant increase in Cmax of 1.81- and 5.69-fold, and AUC 0-24h of 1.62- and 4.57-fold compared with those of corresponding crystalline drugs, respectively. In conclusion, EGCG is proved to be a promising co-former in co-amorphous systems.

Mechanism insight into efficient peroxydisulfate activation by novel nano zero-valent iron anchored yCo3O4 (nZVI/yCo3O4) composites.

Novel nano zero-valent iron anchored bio-matrix supported Co3O4 (nZVI/yCo3O4) composites were fabricated for tetracycline (TC) efficient degradation by activating peroxydisulfate (PS). The systematical characterizations verified that the nZVI/yCo3O4 composites with magnetism have higher surface area than yCo3O4 and pure Co3O4, contributing to more accessible active sites. Various catalytic parameters (nZVI mass ratio, leached ions, initial pH, catalyst dosage, PS concentration and coexisting anions) were thoroughly investigated. In nZVI/yCo3O4/PS system, 97.6 %, 93.4 % and 77.3 % TC were degraded within 15 min at pH 3.0, 6.0 and 9.0, respectively. Based on four successive degradation runs, the excellent mineralization rate and reusability of nZVI/yCo3O4 composites were mainly benefited from the suppressed metals leaching. The PS activated mechanisms were proposed as non-radicals (1O2) dominated pattern at acidic conditions and radicals (SO4-) predominant pattern at alkaline environment, which may be highly related to the electron donating capacity of nZVI at different pH and the M(n + 1)+/Mn+ redox cycling between Fe or Co metal. The plausible degradation routes of TC were presented based on the detected intermediates. Overall, the synthesized heterogeneous nZVI/yCo3O4 composites can efficiently active PS at a wide pH range, and further broaden the application of Co-based catalysts in PS activation.

Protective roles of Pyracantha fortuneana extract on acute renal toxicity induced by cadmium chloride in rats.

PURPOSE: To investigate the protective roles of pyracantha fortune fruit extract (PFE) on acute renal toxicity induced by cadmium chloride (CdCl2) in rats. METHODS: Rats were pretreated with PFE and consecutively injected with CdCl2 (6.5 mg/kg) for 5 days. RESULTS: The concentration of Cd, kidney weight, malondialdehyde (MDA), and nitric oxide (NO) production were remarkably increased in CdCl2 group as well as the levels of plasma uric acid, urea, and creatinine (P < 0.001). However, the body weight and glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione peroxidase (GR) levels were markedly reduced by CdCl2 treatment (P < 0.001). Histological manifestations of renal tissue showed severely adverse changes. Moreover, CdCl2 treatment significantly decreased the B-cell lymphoma-2 (Bcl-2) expression while increased the Bcl-2-Associated X Protein (Bax), tumor necrosis factor-α (TNF-α) expression (P < 0.001). Additionally, the expression of Nrf2/Keap 1 related proteins Keap-1 gained a significant increase (P < 0.001), whereas the Nrf2, HO-1, γ-GCS, GSH-Px and NQO1 expression decreased by CdCl2 treatment (P < 0.05). These rats were pretreated with PFE to improve the changes caused by CdCl2 treatment. CONCLUSION: PFE could protect the kidney against acute renal toxicity induced by CdCl2.

Protective roles of Pyracantha fortuneana extract on acute renal toxicity induced by cadmium chloride in rats

Abstract Purpose: To investigate the protective roles of pyracantha fortune fruit extract (PFE) on acute renal toxicity induced by cadmium chloride (CdCl2) in rats. Methods: Rats were pretreated with PFE and consecutively injected with CdCl2 (6.5 mg/kg) for 5 days. Results: The concentration of Cd, kidney weight, malondialdehyde (MDA), and nitric oxide (NO) production were remarkably increased in CdCl2 group as well as the levels of plasma uric acid, urea, and creatinine (P < 0.001). However, the body weight and glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione peroxidase (GR) levels were markedly reduced by CdCl2 treatment (P < 0.001). Histological manifestations of renal tissue showed severely adverse changes. Moreover, CdCl2 treatment significantly decreased the B-cell lymphoma-2 (Bcl-2) expression while increased the Bcl-2-Associated X Protein (Bax), tumor necrosis factor-α (TNF-α) expression (P < 0.001). Additionally, the expression of Nrf2/Keap 1 related proteins Keap-1 gained a significant increase (P < 0.001), whereas the Nrf2, HO-1, γ-GCS, GSH-Px and NQO1 expression decreased by CdCl2 treatment (P < 0.05). These rats were pretreated with PFE to improve the changes caused by CdCl2 treatment. Conclusion: PFE could protect the kidney against acute renal toxicity induced by CdCl2.