Shixiao Jin

Development and in vivo/in vitro evaluation of novel herpetrione nanosuspension

Herpetrione (HPE), is a new compound extracted from Herpetospermum caudigerum, which is proved to be a novel and potent antiviral agent. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To improve the dissolution and absorption of the drug, formulation of HPE as nanosuspension has been performed in this study. HPE nanosuspension were produced by high pressure homogenization and transformed into dry powder by lyophilization. The nanosuspension was then investigated using photon correlation spectroscopy (PCS), zeta potential measurement, SEM and PXRD. To verify the theoretical hypothesis on the benefit of decreased particle size and increased surface area, in vitro dissolution characterization and in vivo pharmacokinetics were investigated. The inhibitory effect on HBsAg, HBeAg, and HBV-DNA of HPE nanosuspension in 2.2.15 cells was studied. Results showed that a narrow size distributed nanosuspension with a mean particle size of 286±1.3 nm, a polydispersity index of 0.18±0.06 and a zeta potential of -26.9±2.4 mV was obtained. The result of PXRD showed that HPE was amorphous state in both coarse powder and nanosuspension. In the in vitro dissolution test, HPE nanosuspension showed an increased dissolution velocity markedly. In the in vivo evaluation, compared to coarse HPE, nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. The inhibitory effect of HBsAg, HBeAg, and HBV-DNA of 2.2.15 cells treated by HPE nanosuspension were stronger than those of the HPE. The in vitro activity experiments provided evidence for an enhanced efficacy of the HPE nanosuspension formulation compared to HPE coarse suspension. These results revealed that particle size reduction could enhance HPE dissolution rate and absorption in gastrointestinal tract, and nanosuspension might be a good choice for oral delivery of poor bioavailability drug like HPE.

Improvement of oral bioavailability of glycyrrhizin by sodium deoxycholate/phospholipid-mixed nanomicelles

Glycyrrhizin (GL), extracted from the Glycyrrhiza glabra L., is active triterpenoid saponin components. However, due to its impermeability across the gastrointestinal mucosa, oral bioavailability of the drug was relatively low. To improve its oral bioavailability, formulation of GL as sodium deoxycholate/phospholipid-mixed nanomicelles (SDC/PL-MMs) has been performed in this study. GL-SDC/PL-MMs were produced by a film dispersion method and then investigated using photon correlation spectroscopy (PCS), zeta potential measurement, as well as its physical stability after storage for 10, 20, 30, 60, 90 and 120 days. To verify the theoretical hypothesis, pharmacokinetics and pharmacodynamic studies based on carbon tetrachloride (CCl4)-induced acute liver injury was investigated. Results showed that a narrow size distributed nanomicelles with a mean particle size of 82.99 ± 7.5 nm and a zeta potential of −32.23 ± 1.05 mV was obtained. In the pharmacokinetics, GL-SDC/PL-MMs show a significant superiority in AUC0–t, Cmax and other pharmacokinetic parameters compared with the control group. In the pharmacodynamic studies, compared with the bifendate control group, GL-SDC/PL-MMs showed an equivalent effect in reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST) and improving the pathological changes of liver tissue. These results revealed that SDC/PL-MMs could enhance GL absorption in gastrointestinal tract and pharmacodynamic effect in the treatment of acute liver injury caused by CCl4, and SDC/PL-MMs might be a good choice for oral delivery of poor bioavailability drug like GL.

Comparison of anti-bacterial activity of three types of di-O-caffeoylquinic acids in Lonicera japonica flowers based on microcalorimetry

The anti-bacterial activities of three types of di-O-caffeoylquinic acids (diCQAs) in Lonicera japonica flowers, a traditional Chinese medicine (TCM), on Bacillus shigae growth were investigated and compared by microcalorimetry. The three types of diCQAs were 3, 4-di-O-caffeoylquinic acid (3, 4-diCQA), 3, 5-di-O-caffeoylquinic acid (3, 5-diCQA), and 4, 5-di-O-caffeoylquinic acid (4, 5-diCQA). Some qualitative and quantitative information of the effects of the three diCQAs on metabolic power-time curves, growth rate constant k, maximum heat-output power Pm, and the generation time tG, total heat output Qt, and growth inhibitory ratio I of B. shigae were calculated. In accordance with a thermo-kinetic model, the corresponding quantitative relationships of k, Pm, Qt, I and c were established. Also, the half-inhibitory concentrations of the drugs (IC50) were obtained by quantitative analysis. Based on the quantity-activity relationships and the IC50 values, the sequence of inhibitory activity was 3, 5-diCQA > 4, 5-diCQA > 3, 4-diCQA. The results illustrate the possibility that the caffeoyl ester group at C-5 is the principal group that has a higher affinity for the bacterial cell, and that the intramolecular distance of the two caffeoyl ester groups also has an important influence on the anti-bacterial activities of the diCQAs.

Schisandra lignans-loaded enteric nanoparticles: preparation, characterization, and in vitro-in vivo evaluation.

Schisandrae lignans (SL) have been well proven to possess hepatoprotective effect against the hepatic dysfunction induced by various chemical hepatotoxins. Deoxyschisandrin (DA) and schisantherin A (SA) are both considered as the major active components in SL. The objective of the study was to prepare and evaluate Schisandra lignans (composed of DA and SA)-loaded enteric nanoparticles produced by a novel toxic solvent-free modified spontaneous emulsification solvent diffusion (SESD) method. An organic Schisandra lignans/Eudragit® S100 solution was injected into an aqueous poloxamer 188 solution under a agitation. The nanoparticles were characterized with respect to particle size distribution, morphology, encapsulation efficiency (EE) and physical stability of the drug, wettability, in vitro release and in vivo bioavailability. Nanoparticles with a smooth surface and dense structure were obtained with high EE (EEDA >90%; EESA >85%). The drug was in a noncrystalline state in the matrix and physically stable for 120 days at room temperature. In vitro drug release study, the drug dissolution rate from the nanoparticles was significantly enhanced compared to the physical mixture and to the pure drug; the release profile of the nanoparticles was stable after 120 days. The appropriate size of nanoparticles (~93 nm), the solubilization of the surfactant, the noncrystalline state of the drug in the matrix and the fast dissolution rate contributed to a significantly enhanced oral bioavailability from the nanoparticles when compared to pure drug suspension.

Enhanced intestinal absorption activity and hepatoprotective effect of herpetrione via preparation of nanosuspensions using pH-dependent dissolving-precipitating/homogenization process.

The main purpose of this study was to enhance the intestinal absorption activity and hepatoprotective effect of herpetrione by drug nanosuspensions.

Changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha-naphthylisothiocyanate-induced experimental hepatic injury after Yinchenhao Decoction (茵陈蒿汤) treatment

ObjectiveTo study the changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha-naphthylisothiocyanate (ANIT)-induced experimental hepatic injury after oral administration of Yinchenhao Decoction (茵陈蒿汤, YCHD) using an ultra pressure liquid chromatography (UPLC) method.MethodsRats were divided into a normal group and a model group, after modeled by 4% ANIT (75 mg/kg) for 48 h, they were orally administrated with YCHD extract at the dose of 0.324 g/kg, and then blood was collected from their orbital sinus after different intervals. Changes in liver function were monitored by the levels of liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] and bilirubins [total bilirubin (TBIL), direct bilirubin (DBIL)], the concentration of 6,7-dimethoxycoumarin in plasma were measured by UPLC, and the pharmaceutical parameters were calculated with DAS2.1.1 software.ResultsThe concentration-time curve of both normal and modeled rats after oral administration of YCHD was obtained. Their time to maximum plasma concentration (tmax) were both 0.25 h, the maximum concentration (Cmax) were 4.533 μg/mL and 6.885 μg/mL, and their area under concentration-time curve (AUC)0→24h were 16.272 and 32.981, respectively. There was a 51.88% and 100.46% increase in Cmax and AUC0-t (P<0.05), but there showed a 45.52% and 92.93% reduction in clearance of drug and volum of distribution (P<0.05), respectively.ConclusionsHepatic injury could significantly influence the pharmacokinetics of 6,7-dimethoxycoumarin after oral administration of YCHD, the absorption and distribution process was accelerated in liver injured rats, but the metabolism and elimination process was slowed. And this may lead to a significant accumulation of 6,7-dimethoxycoumarin in the body.

Lignans-rich extract from Herpetospermum caudigerum alleviate physical fatigue in mice

ObjectiveTo ascertain anti-fatigue constituents and mechanisms of Herpetospermum caudigerum.MethodsThe 80% ethanol extracts of Herpetospermum caudigerum were partitioned with chloroform, ethyl acetate and n-butanol, respectively. Male Kunming mice were divided into 13 groups with 16 mice in each group: a control group fed with water, 9 groups treated with 3 fractions of Herpetospermum caudigerum (chloroform fraction, ethyl acetate fraction and n-butanol fraction) at dose of 80, 160 and 320 mg/kg for the low-dose group, medium-dose group and high-dose group, 3 herpetrione (HPE) treated groups fed with HPE at dose of 15, 30, and 60 mg/kg for the low-dose group, medium-dose group and high-dose group. All animals were treated once per day for 30 days. Anti-fatigue activity was assessed through the forced swimming test and serum biochemical parameters including blood lactic acid (BLA), blood urea nitrogen (BUN), malondialdehyde (MDA), hepatic glycogen (HG), lactic dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GPx) determined following the recommended procedures provided by the commercial kits.ResultsCompared with the control group, the lignans extract (ethyl acetate fraction) of Herpetospermum caudigerum and HPE could signifificantly prolonged the exhaustive swimming time (P<0.05 or P<0.01), and also increased the HG levels (P<0.05 or P<0.01) and the activities of antioxidant enzymes (SOD, GPx and LDH, P<0.05 or P<0.01); BLA and MDA levels were decreased considerably in lignans extract and HPE treated groups (P<0.05 or P<0.01). HPE also could significantly decrease the BUN contents compared with the control group (P<0.05). The chloroform and n-butanol fraction showed no effect on swimming time and biochemical parameters.ConclusionsThe lignans extract had antifatigue activities and HPE may be partly responsible for the anti-fatigue effects of Herpetospermum caudigerum. The possible mechanisms of anti-fatigue activity were related to the decrease of BUN and BLA, the increase of the HG storage and protecting corpuscular membrane by preventing lipid oxidation via modifying several enzyme activities.