"Felodipine-indomethacin" co-amorphous supersaturating drug delivery systems: "Spring-parachute" process, stability, in vivo bioavailability, and underlying molecular mechanisms.

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation ("spring-parachute" process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize "felodipine-indomethacin" CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous "spring-parachute" process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current "drug-drug" CAS supersaturable formulations.

Rapid separation and identification of 31 major saponins in Shizhu ginseng by ultra-high performance liquid chromatography-electron spray ionization-MS/MS.

BACKGROUND: Among the various ginseng strains, Shizhu ginseng is endemic to China, mainly distributed in Kuandian Manchu Autonomous County (Liaoning Province, China); however, not much is known about the compounds (especially saponins) in Shizhu ginseng. METHODS: A rapid, sensitive, and reliable ultra-high performance liquid chromatography coupled with MS/MS (UHPLC-MS/MS) method was developed to separate and identify saponins in Shizhu ginseng. RESULTS: The separation was carried out on a Waters ACQUITY UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm) with acetonitrile and 0.1% formic acid aqueous solution as the mobile phase under a gradient elution at 40°C. The detection was performed on a Micromass Quattro Micro API mass spectrometer equipped with electrospray ionization source in both positive and negative modes. Under the optimized conditions, a total of 31 saponins were identified or tentatively characterized by comparing retention time and MS data with related literatures and reference substances. CONCLUSION: The developed UHPLC-MS/MS method was suitable for identifying and characterizing the chemical constituents in Shizhu ginseng, which provided a helpful chemical basis for further research on Shizhu ginseng.

Evaluation of the protective effect of Zhi-Zi-da-Huang decoction on acute liver injury with cholestasis induced by α-naphthylisothiocyanate in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-Zi-Da-Huang decoction (ZZDHD), a classic traditional Chinese medicine (TCM) formula composed of four herbal medicines, has been widely used to treat various hepatobiliary disorders for a long time in China. However, the pharmacological effect of ZZDHD on liver injury with cholestasis is unrevealed. AIM OF THE STUDY: To investigate the hepatoprotective effect of ZZDHD against α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis in rats. MATERIALS AND METHODS: The rats were intragastrically (i.g.) given ZZDHD at doses of 1, 2 and 4 g/kg (crude drug/body weight) once a day for seven days and treated with ANIT (75 mg/kg via i.g.) to cause liver injury at 12h after the fifth administration. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (γ-GTP), total bilirubin (TBIL), direct bilirubin (DBIL) and total bile acid (TBA), as well as bile flow were measured at 48 h after ANIT treatment to evaluate the protective effect of ZZDHD. Moreover, the possible protective mechanisms were elucidated by assays of liver enzyme activities and component contents including malondialdehyde (MDA), myeloperoxidase (MPO), lipid peroxide (LPO), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). The biochemical observations were supplemented by histopathological examination. Ultra fast liquid chromatography-mass spectrometry (UFLC-MS) was used for the phytochemical analysis of ZZDHD. RESULTS: The high dose (4 g/kg) and middle dose (2g/kg) of ZZDHD exhibited significant and dose-dependent protective effect on ANIT-induced liver injury with cholestasis by reversing the changes in bile flow, the serum and hepatic enzymes, and histopathology of the liver tissue. Meanwhile, it was found that the low dose (1g/kg) of ZZDHD did not improve the biochemical indexes except serum TBIL, DBIL and TBA, which showed little protective effect. Phytochemical analysis revealed the presence of sixteen compounds in ZZDHD. CONCLUSIONS: This study indicates that ZZDHD exerted a hepatoprotective effect on ANIT-induced liver injury with cholestasis in rats, and the mechanism of this activity is possibly related to its antioxidant properties.

Deoxycholic acid-grafted PEGylated chitosan micelles for the delivery of mitomycin C.

Mitomycin C (MTC) was incorporated to a micelle system preparing from a polymer named deoxycholic acid chitosan-grafted poly(ethylene glycol) methyl ether (mPEG-CS-DA). mPEG-CS-DA was synthesized and characterized by (1)H nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. mPEG-CS-DA formed a core-shell micellar structure with a critical micelle concentration of 6.57 µg/mL. The mPEG-CS-DA micelles were spherical with a hydrodynamic diameter of about 231 nm. After poly(ethylene glycol)ylation of deoxycholic acid chitosan (CS-DA), the encapsulation efficiency and drug loading efficiency increased from 50.62% to 56.42% and from 20.51% to 24.13%, respectively. The mPEG-CS-DA micelles possessed a higher drug release rate than the CS-DA micelles. For pharmacokinetics, the area under the curve (AUC) of the mPEG-CS-DA micelles was 1.5 times higher than that of MTC injection, and these micelles can enhance the bioavailability of MTC. mPEG-CS-DA micelles reduced the distribution of MTC in almost all normal tissues and had the potential to improve the kidney toxicity caused by MTC injection.

[Comparative study on pharmacokinetics of gentiopicroside and gentianae radix extract in rats].

OBJECTIVE: To compare the pharmacokinetics of gentiopicroside and Gentianae Radix extract in rats and assess the effect of other components in Gentianae Radix on the pharmacokinetics of gentiopicroside. METHODS: The rats were oral administrated with gentiopicroside and Gentianae Radix extract, the content of geritiopicroside was chosen as index and determined by HPLC. The pharmacokinetic parameters were calculated with DAS 2.1.1 program. RESULTS: The concentration-time curve of gentiopicroside and Gentianae Radix extract was described by two compartment model. The main pharmacokinetic parameters of gentiopicroside and Gentianae Radix extract were: C(max) (16.53 +/- 0.37) g/mL and (16.61 +/- 0.49) g/mL, T(max) 0.25 h and 1.5 h, t1/2(alpha) (0.20 +/- 0.04) h and (0.69 +/- 0. 14) h, t /2 (beta) (0.64 +/- 0.08) hand (0.80 +/- 0.11) h, AUC(0-infinity) (18.20 +/- 1.97) g x h/mL and (39.20 +/- 1.18) g x h/mL, CL( 2.75 +/- 0.32) L/(h x kg) and (1.22 +/- 0.04) L (h x kg), respectively. CONCLUSION: There are significantly differences in pharmacokinetic parameters between gentiopicroside and Gentianae Radix extract in rats.

[Pharmacokinetics and tissue distribution of Schisandra chinensis extract in mice].

OBJECTIVE: To investigate the pharmacokinetics and tissue distribution of Schisandra chinensis in mice. METHODS: Schisandrin in mice plasma and tissues including heart, liver, spleen, lung and kidney was quantitatively determined by HPLC. RESULTS: The concentration-time curve of Schisandra chinensis extract was described by a single compartment model, Cmax was (2.17 +/- 0.27) mg/ mL, t(max) was (1.00 +/- 0.32) h, AUC0-->infinity, was (4.07 +/- 0.62) mg x h/mL. The sequence of distribution of schisandrin in mice body was as follows: liver > plasma > kidney > lung > heart > spleen. CONCLUSION: The distribution of extract in the body is abroad. Liver has relative high concentration of schisandrin, which is beneficial to the treatment of hepatic disease.