The aim of this study is to investigate the effect of nicotinamide (NIC) on the solubility/dissolution of a poorly soluble drug ibuprofen (IBU), and to explore the mechanism of the formed soluble complex by complexation model, fluorescence quenching and Raman spectroscope. The results showed that NIC could significantly improve the solubility of IBU, and exhibited an A_p type complexation profile. The calculated complexation constants of K_1:1 and K_1:2 were 0.24 and 4.00, respectively. In the solution, the fluorescent intensity of IBU gradually decreased with the increase of NIC, exhibiting the typical fluorescence-quenching phenomenon. The Raman spectrum showed stretching vibrations, bending vibrations, and rocking vibrations ascribed to benzene ring of IBU and pyridine ring of NIC disappeared or significantly shifted, suggested that the soluble complex was formed by dipole-dipole interaction force between the benzene group on IBU and pyridine group on NIC, resulting in the aqueous solubility enhancement of IBU. In comparison to IBU alone, the physical mixture of IBU and NIC showed significantly higher dissolution rate (1.6-fold) and extent.

Cyclodextrin can increase the solubility of poorly soluble drugs, but also decrease the permeability of poorly soluble drugs in inclusion complexes simultaneously, which partially or completely counteracts the contribution of improvement in solubility to the oral absorption of poorly soluble drugs. If a competing agent is added to the system to compete binding sites of cyclodextrins with drugs, drug permeability can be improved by increasing the concentration of free drugs in the inclusion complex system. In this paper, a rapid in vitro screening method for competing agents of cyclodextrin inclusion complex is proposed based on the principle that good drug permeability is in accord with good cell uptake. The equilibrium constants between drugs and hydroxypropyl-beta-cyclodextrin (HPCD) were determined by phase equilibrium solubility method. Cinnarizine (CN) with a high equilibrium constant was selected as a competing agent, coumarin 6 (C6) and 9-octadecyl berberine (BD) with smaller equilibrium constants were selected as model drugs. Both changes of solubility and uptake by Caco-2 and A549 cells of C6 and BD were investigated different concentrations of CN to the HPCD solution of C6 and BD. The results showed that the uptake of C6 and BD increased in a CN concentration-dependent manner, and the solubility of C6 and BD in HPCD solution decreased with the prolongation of equilibrium time. It might be due to increased free drug concentrations that resulted from the competition of CN for drug binding sites with HPCD. In our study, in vitro cell uptake method was firstly used to validate the ability of CN as a competing agent to increase drug permeability (cell uptake). This method can be used for preliminarily screening of competing agents for drug-cyclodextrin inclusion complexes.

The objective of this paper was to establish a level A in vitro-in vivo correlation (IVIVC) for goserelin acetate extended release microspheres for injection. Three kinds of goserelin acetate microspheres with different release rates were prepared and the critical physicochemical properties, such as drug loading, particle size, glass transition temperature and morphology were characterized. In vitro dissolution test of the prepared goserelin acetate microspheres was performed using sample-and-separate method at 45℃ in 5% (v/v) methanol. The morphology of the microspheres and the molecular weight of poly (lactic-co-glycolic acid) (PLGA) of the prepared goserelin acetate microspheres were investigated to research the release mechanism of microspheres. The plasma concentration of goserelin was detected after intramuscular injection of goserelin acetate microspheres to SD rats, and correlated with the in vitro release profiles after processing by percent AUC method. The pharmacokinetic experimental protocol of goserelin acetate microspheres for injection in SD rats was approved by the Animal Ethics Committee of Shandong Luye Pharmaceutical Co., Ltd. The results indicated that the developed sample and separate method was able to detect differences in the release characteristics of the prepared goserelin acetate microspheres, and the in vitro-in vivo correlation of goserelin acetate microspheres was excellent (r > 0.98) and had good predictive ability in SD rats.

Artemisinin and its derivatives have been proved for their anti-tuberculosis activities, despite its low water solubility which hampered its efficacy and corresponding formulation development. In this study we designed and synthesized a novel artemisinin analog by conjugating an arginine through a succinic acid linker. This design not only enhanced the water solubility of the artemisinin, but also increased the efficacy of the molecule towards tuberculosis bacteria due to disruption by arginine. The results showed that the solubility of the synthesized derivatives A-2 and A-3 increased 19.8-27.8 folds compared to artemisinin. In vitro cytotoxicity experiment showed that compound A-3 had negligible toxicity to THP-1 cells up to 1 mg·mL^-1, the minimal inhibitory concentration (MIC) of A-2 and A-3 was 20 and 10 μg·mL^-1, respectively, which was 5 or 10 times lower than that of artemisinin. Intracellular bacteria inhibition experiment showed that compound A-3 at lower concentrations such as 100 or 200 μg·mL^-1 significantly inhibited the growth of tuberculosis bacteria (P < 0.05 or P < 0.01), which efficacy was stronger than artemisinin at the concentration of 100 μg·mL^-1. These results strongly suggested that compound A-3 was a potential anti-tuberculosis lead compound.

The aim of this study was to investigate the effect of Jujubae Fructus (JF) on the gastrointestinal toxicity and diuretic effect of Crotonis Semen Pulveratum (CT). Forty-eight mice were randomly divided into the control group, low dose of CT group (0.039 g·kg^-1·d^-1, CTL), high dose of CT group (0.078 g·kg^-1·d^-1, CTH), JF group (9.75 g·kg^-1·d^-1), low dose of CT combined with JF group (CT 0.039 g·kg^-1·d^-1 and JF 9.75 g·kg^-1·d^-1, JFCTL), high dose of CT combined with JF group (CT 0.078 g·kg^-1·d^-1 and JF 9.75 g·kg^-1·d^-1, JFCTH). On the 9^th day of oral administration, the urine output of all mice was measured. After oral administration for ten days, fresh fecal samples were collected, and the 16S rDNA sequencing method was used to study the changes of intestinal bacteria when CT used alone and combined with JF. All experimental protocols were approved by the Animal Ethics Committee of Nanjing University of Chinese Medicine. The results showed that JF slowed down the rapid diuretic effect of CT, and significantly increased serum interleukin-2 (IL-2), interleukin-6 (IL-6), gastrin (GAS), somatostatin (SS). JF also reduced small intestine injury and improved the disorder of intestinal flora caused by CT. Low dose CT combined with JF significantly decreased the relative abundance of Sphingomonas and Oscillospira. The level of Bilophila was decreased after the combined application of high dose CT and JF. The results suggest that JF exhibited a tendency to reduce the toxicity of CT in the aspects of serum immune index, intestinal movement, intestinal damage, and intestinal microflora structure. In addition, the JF could also slow down the rapid diuretic effect of CT, behaving a tendency to reduce the clinical effect of CT.

Gentiana section Cruciata (Gentianaceae) is a medicinally important section of herbs, including Chinese traditional medicine Gentianae Macrophyllae Radix and Tibetan herb Jieji. Here, we assess the taxonomic significance using mtDNA nad1/b-c and nad5/d-e sequence data. A total of 144 nad1/b-c and nad5/d-e sequences from 11 species within Gentianaceae were obtained, including 138 sequences from 10 species within Gentiana section Cruciata and 6 sequences from Halenia elliptica (outgroup). The results showed that mtDNA nad1/b-c has species-level resolution within the section of Cruciata, i.e. the variable in the position 45 "C" could be used as a stable marker locus to distinguish G. robusta from other taxa; the variable in the position 352 and 353 "GA" could distinguish G. crassicaulis and G. tibetica from other taxa within the section. Intraspecies genotype variability was detected in nad1/b-c sequences of G. officinalis and G. siphonantha, respectively. These genotypes could be used as potential DNA barcode. In addition, intraspecies genotype variability was detected in nad5/d-e sequences of G. macrophylla, G. officinalis and G. siphonantha, respectively. Based on the stable marker locus, a species-specific PCR protocol was developed using the primer PF to identifying G. robusta in the section. This study could expand the understanding of the diversity of mtDNA nad1/b-c and nad5/d-e in the genus Gentiana, and provide the essence for the species identification within Gentiana section Cruciata.

This study was designed to prepare a novel lipid bilayer coated hollow mesoporous silica nanocarrier for co-delivery of gene drugs and chemotherapeutic drugs to enhance the inhibitory activity of antitumor drugs in hepatoma cells. Hollow mesoporous silica was synthesized by modified StÖber method. Lipid-fusion principle was used to prepare lipid-hollow co-loaded doxorubicin (DOX) and miR-375 (LHMSN-DOX/miR-375). Meanwhile, the morphology, particle size, surface potential, drug loading and release were characterized in vitro. The inhibition of cell proliferation, cell migration and invasion was then evaluated. The results indicated that the core-shell structure of LHMSN-DOX/miR-375 was clear with an intact outer lipid membrane and an ordered internal HMSN mesoporous structure. The drug release amount was pH responsive while the drug was rapidly released under simulated intracellular acidic conditions relative to normal physiological environment. Compared with free DOX, LHMSN-DOX/miR-375 can deliver DOX and miR-375 to liver cancer cells and inhibit the proliferation, migration and invasion of cells more effectively.

Using the lipidomics method based on UHPLC-Q-Exactive Orbitrap/MS, the change of phospholipid metabolism in lung tissue of mice induced by lipopolysaccharide (LPS)-induced acute lung injury was analyzed to observe the regulation of abnormal lipids by Jiegeng Decoction and to explore the regulation effect of Jiegeng Decoction on LPS-induced acute lung injury. The lung tissue samples from control group, model group, dexamethasone (positive drug) group, and Jiegeng Decoction group were collected and the lipid components of the sample were extracted. All procedures over mice were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Nanjing University of Chinese Medicine, and the experiments were approved by the Animal Ethics Committee of our university. The lipidomics technique of UHPLC-Q-Exactive Orbitrap/MS was used to study change of phospholipids in lung tissue of each group. LPS induced acute lung injury in mice with metabolic abnormalities of phospholipids, the specific performance of the PC was significantly upregulated, phosphatidyl ethanolamine (PE), phosphatidyl glycerol (PG), phosphatidyl serine (PS), phosphatidylinositol (PI) and other metabolic disorders, Jiegeng Decoction have a certain role in these phospholipids. LPS-induced acute lung injury caused disturbances of phospholipid in vivo, and Jiegeng Decoction regulates metabolic phospholipids.

An ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) method was developed to evaluate the chemical consistency of triterpene acids in ethanol extracts of Poria and acetic ether extracts thereof. First, high resolution mass spectrometry data were obtained with Full scan mode, by comparing with MS data from the reference compounds and literatures, a total of 23 components were unequivocally or tentatively identified in ethanol extracts and acetic ether extracts thereof. Then, a mimic multiple reaction monitoring (mMRM) mode was established using UPLC-QTOF-MS/MS to quantify the triterpene acids in ethanol extracts and acetic ether extracts thereof. Eleven components were absolutely quantified with reference compounds, while 12 components without reference compounds were relatively quantified with peak areas, the transfer and enrichment rate of triterpene acids during liquid-liquid extraction were calculated. It was found all of the 23 triterpene acids identified in Poria ethanol extracts could be transferred into acetic ether extracts with high transfer and enrichment rate. The present study provides not only scientific evidence for further extraction of triterpene acids in Poria by acetic ether, but also an approach for comprehensive evaluation of the chemical consistency of herbal medicine extracts before and after the liquid-liquid extraction.

The solubility of nebivolol hydrochloride was determined in acidic aqueous media in the absence and presence of different concentration of NaCl, NaBr, or NaI at 37℃ in order to facilitate proper selection of dissolution media that have adequate discriminating power for enhancing the likelihood of a generic drug product to successfully pass in-vivo bioequivalence test. In the range of pH 5.0 to pH 1.0, the solubility of nebivolol hydrochloride decreased with the decrease in the pH of aqueous solution, and the solubility of nebivolol hydrochloride further decreased with the increase in the concentration of added sodium chloride. The solubility decrease of a few weakly basic drug molecules in acidic media and in higher concentration of added chloride was published previously by other researchers, and the observed decrease in the solubility in the presence of higher chloride concentration was interpreted in terms of common-ion effect. However, the results in this paper showed that the solubility of nebivolol hydrochloride also decreased when sodium chloride was replaced with sodium bromide or iodide. The approach described in this paper (i.e. substituting sodium chloride with sodium bromide or iodide) provides an effective method to verify whether common-ion effect is the true (or at least the sole) driving force behind the observed decrease in the solubility of nebivolol hydrochloride in the presence of sodium chloride. The solubility decrease reported in this paper can be interpreted in terms of salting-out effect of sodium chloride, bromide, and iodide. For hydrochloride salt of a weakly basic drug molecule like nebivolol hydrochloride, its solubility in an acidic dissolution medium can be purposely decreased to the lower end of sink condition by adding sodium chloride to make the resulting medium more discriminating. As shown in this paper, a medium at pH 1.2 with added sodium chloride is discriminating and this medium is shown to be bio-relevant to the in-vivo data collected under fasting condition (in-vivo study protocol was approved by Institutional Review Board).