This study aimed to screen an effective flavonoid with promising whitening and antioxidant capacities, and design flavonoid-loaded niosomes to improve its solubility, stability, and penetration. In vitro anti-tyrosinase and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiments were conducted to investigate the whitening and antioxidant capacities of several flavonoids, including quercetin, morin, festin, myricetin, rutin, and breviscapine. The conductivity, viscosity, and particle size of Span60-RH40-based formulation of nonionic surfactant vesicles (niosomes) with different mass ratios were studied to determine the most appropriate formulation. Drug-loaded niosomes were characterized for size, zeta potential, morphology, and entrapment efficiency. The photostability, solubility, release behavior, ex vivo drug penetration, and skin retention were also studied. The results showed that quercetin has considerable whitening and antioxidant capacities and Span60-RH40 at a mass ratio of 9:11 forms spherical or oval niosomes of 97.6 ± 3.1 nm with a zeta potential range of 31.1 ± 0.9 mV, and drug entrapment efficiency as high as 87.3 ± 1.6%. Niosomes remarkably improved the solubility and photostability of quercetin. Furthermore, compared to quercetin solution, quercetin-niosomes had the advantages of sustained release and improved transdermal penetration, with skin retention 2.95 times higher than quercetin solution.

The aim of this study was to develop a formulation to improve the oral absorption of baicalin (BA) by combining a phospholipid complex (PC) and self-emulsifying microemulsion drug delivery system (SMEDDS), termed BA-PC-SMEDDS. BA-PC was prepared by a solvent evaporation method and evaluated by complexation percentage (CP). The physicochemical properties of BA-PC were determined. The synergistic effect of PC and SMEDDS on permeation of BA was studied in vitro with Caco-2 cells and in situ with a single pass intestinal perfusion model. The improved bioavailability of BA in BA-PC-SMEDDS was confirmed in an in vivo rat model. The CP of BA-PC reached 100% when the molar ratio of drug to phospholipid (PP) was ≥1:1. The solubility of BA-PC increased in both water and octanol, and the log P o/w of BA-PC was increased significantly. BA-PC-SMEDDS could be dispersed more evenly in water, compared to BA and BA-PC. Both the Caco-2 cell uptake and single-pass intestinal perfusion models illustrated that transport of BA in BA-PC was lower than that of free BA, while improved significantly in BA-PC-SMEDDS. The relative bioavailability of BA-PC(1:2)-SMEDDS was 220.37%. The combination system of PC and SMEDDS had a synergistic effect on improving the oral absorption of BA.

Objective: A non-lipolysis nanoemulsion (NNE) was designed to reduce the first-pass metabolism of raloxifene (RAL) by intestinal UDP-glucuronosyltransferases (UGTs) for increasing the oral absorption of RAL, coupled with in vitro and in vivo studies. Methods: In vitro stability of NNE was evaluated by lipolysis and the UGT metabolism system. The oral bioavailability of NNE was studied in rats and pigs. Finally, the absorption mechanisms of NNE were investigated by in situ single-pass intestinal perfusion (SPIP) in rats, Madin-Darby canine kidney (MDCK) cells model, and lymphatic blocking model. Results: The pre-NNE consisted of isopropyl palmitate, linoleic acid, Cremophor RH40, and ethanol in a weight ratio of 3.33:1.67:3:2. Compared to lipolysis nanoemulsion of RAL (RAL-LNE), the RAL-NNE was more stable in in vitro gastrointestinal buffers, lipolysis, and UGT metabolism system (p < 0.05). The oral bioavailability was significantly improved by the NNE (203.30%) and the LNE (205.89%) relative to the suspension group in rats. However, 541.28% relative bioavailability was achieved in pigs after oral NNE intake compared to the suspension and had two-fold greater bioavailability than the LNE (p < 0.05). The RAL-NNE was mainly absorbed in the jejunum and had high permeability at the intestine of rats. The results of both SPIP and MDCK cell models demonstrated that the RAL-NNE was absorbed via endocytosis mediated by caveolin and clathrin. The other absorption route, the lymphatic transport (cycloheximide as blocking agent), was significantly improved by the NNE compared with the LNE (p < 0.05). Conclusion: A NNE was successfully developed to reduce the first-pass metabolism of RAL in the intestine and enhance its lymphatic transport, thereby improving the oral bioavailability. Altogether, NNE is a promising carrier for the oral delivery of drugs with significant first-pass metabolism.

The objective of this study was to compare the in vitro Fick's first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption. The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC). In the cell model, the solubility of GRI, PHE, IND, and KET increased 6-8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15-21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (F r). The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.

The anaphylactoid reactions induced by andrographis injection have repeatedly been reported. The aim of our study was to evaluate the immuno-sensitizing potential of extracts from Andrographis paniculata Nees and to screen for the constituent that is responsible for inducing the anaphylactoid reaction. In the direct popliteal lymph node assay (D-PLNA), female BALB/c mice were randomly divided into several groups with ten mice per group according to the experiment design, the right hind footpads of mice received a single subcutaneous injection of Andrographis paniculata (50 μl), and the left hind footpads received the same volume of vehicle. Seven days later, the mice were sacrificed by cervical dislocation, and the popliteal lymph nodes from both the left and right sides were removed. The weight (WI) and cellularity indices (CI) of the popliteal lymph nodes (PLNs) were then calculated, and the pathological changes of the PLNs were measured. In addition, P815 mast cells were collected for the in vitro cell degranulation experiment. The level of histamine, the percentage of cell degranulation and the ratio of ammonia glycosidase released were measured to further evaluate the potential allergenicity. Alcohol extract (AEE), ethyl acetate extract (EAE) and n-butanol extract (NBE) significantly increased the weight (WI > 2) and cell number (CI > 5) of PLNs (P < 0.05, P < 0.01). Additionally, all the three monomers of andrographis, namely NAD, AND, and DDA, significantly increased the weight (WI > 2) and cell number (CI > 5) of the PLNs (P < 0.05, P < 0.01). In the cell model, all of the different extract fractions (AEE, EAE and NBE) and the three monomers of andrographis markedly elevated the level of histamine, the percentage of cell degranulation and the ratio of ammonia glycosidase released. The diterpene lactone compounds of Andrographis paniculata Nees (total lactones of andrographolide) may have a potential sensitizing capacity in andrographis injection.