Table of Content

    30 June 2018, Volume 27 Issue 6
    Original articles
    Mechanism-based pharmacokinetic/pharmacodynamic modeling of the effects of sitagliptin on DPP-4 activity, insulin and glucose in diabetic rats
    Ye Yao, Xiangfei Jiu, Siyuan Wang, Wei Lu, Tianyan Zhou
    2018, 27(6):  371-382.  DOI: 10.5246/jcps.2018.06.038
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    Dipeptidyl peptidase-4 (DPP-4) inhibitors exert their antihyperglycemic effects through repressing inactivation of certain incretin hormones and thus increasing insulin secretion and controlling glucose level. In this study, the plasma concentrations of sitagliptin, a potent DPP-4 inhibitor, after a single oral dose of 300 mg/kg in streptozotocin-induced type 2 diabetic rats were determined by HPLC. A one-compartment pharmacokinetic (PK) model with first order absorption was developed to describe the PK profile of sitagliptin, and the drug concentrations at the doses given in the pharmacodynamic (PD) study were simulated accordingly. The dynamic changes in DPP-4 activity, insulin concentration and blood glucose level in diabetic rats at doses of 1, 5 and 10 mg/kg were measured, and a mechanism-based PK/PD model was established subsequently. In this model, the inhibitory effect of sitagliptin on DPP-4 activity was demonstrated using the Hill’s function with direct link, and the downstream increase in insulin secretion and inhibition of glucose production were characterized using indirect response (IDR) models. This model interpreted the mechanism of antihyperglycemic action of sitagliptin, and may be modified and applied to other species or other agents in this class.

    Novel cationic lipid with reduction-responsive cleavable hydrophobic tail for siRNA delivery
    Yi Yan, Shihe Cui, Jing Sun, Piaopiao Li, Haitao Zhang, Jiancheng Wang
    2018, 27(6):  383-396.  DOI: 10.5246/jcps.2018.06.039
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    To achieve a higher transfection efficiency and lower toxicity, a novel herringbone-like cationic lipid (2ssHLL) composed of hydrophilic aspartic acid linked with two reduction-responsive cleavable hydrophobic oleic acid tails was synthesized and assessed in this study. In our results, the cationic nanoplexes with a uniform spherical shape and a particle size of ~150 nm were successfully prepared by the electrostatic interaction between siRNAs and 2ssHLL-based liposomes. From the results evaluated in HepG2 cells, it was shown that the nanoplexes exhibited high cellular uptake of siRNA with a low cytotoxicity. Moreover, the significant down-regulation effects of 2ssHLL/siEGFR nanoplexes on target mRNA were displayed by RT-PCR analysis, which were similar to those of Lipofectamine2000. It suggested that the enhanced siRNA gene silencing efficiency was probably attributed to the detachment of hydrophobic tail chains induced by reduction-responsive cleavage. This mechanism was also confirmed by the changes of size distribution and siRNA release of nanoplexes in the reductive environment and DTT-absence condition. Overall, we believed that the redox-active herringbone-like 2ssHLL would be a potential nanocarrier towards siRNA delivery.

    Preparation and characterization of intestine PepT1-targeted calcium carbonate nanoparticles
    Yunqiang Deng, Yao Jin, Chuyu He, Yang Zou, Yuanhang Zhou, Shidi Han, Chuhang Zhou, Qi Liu, Xinru Li, Yanxia Zhou, Yan Liu
    2018, 27(6):  397-407.  DOI: 10.5246/jcps.2018.06.040
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    To improve the oral absorption of poorly water-soluble drugs by overcoming the intestinal epithelium barrier, calcium carbonate nanoparticles targeting to intestine peptide transporter 1 (PepT1) were fabricated by modification of the surface of calcium carbonate nanoparticles with Gly-Sar. Gly-Sar-conjugated TPGS was successfully synthesized and characterized, and coumarin 6-loaded Gly-Sar modified calcium carbonate nanoparticles were then prepared and characterized to have a nano-scaledsize of about 193 nm in diameter, cracked surface morphology under a scanning electron microscope, and high drug loading efficiency (60.5±5.9)%. Moreover, the Gly-Sar-modified calcium carbonate nanoparticles exhibited better drug loading stability during the process of their transcellular transport, and evidently enhanced intestinal absorption of poorly water-soluble agents. Therefore, the designed intestine PepT1-targeted calcium carbonate nanoparticles might have a promising potential for oral delivery of poorly water-soluble drugs.

    Preparation and evaluation of liposomal clarithromycin with antimicrobial effect
    Wenxi Zhang, Guanghua Peng, Maoyuan Song, Jiaxing Wang, Mengya Yin, Jiajia Li, Yajie Liu, Yuanyuan Zhang, Xinru Li
    2018, 27(6):  408-414.  DOI: 10.5246/jcps.2018.06.041
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    In this study, we developed a novel liposomal delivery system modified by Tat peptide and wheat germ agglutinin (WGA) with antimicrobial effect. Physicochemical parameters, in vitro antimicrobial, time-kill study, cellular uptake, biofilm formation inhibition and in vivo antibacterial efficacy against Methicillin-resistant Staphylococcus aureus (MRSA) were investigated. Minimum inhibitory concentrations (MICs) and colony-forming units (CFUs) in the time-kill study for Tat-WGA-modified liposomal clarithromycin (CLA-TatWGALip) were lower than those of free and other modified liposomal CLA. Flow cytometry analysis disclosed that TatWGALip delivered more coumarin 6 into bacteria. Furthermore, Tat-WGA-modified liposomal CLA efficiently inhibited the formation of MRSA biofiom. CFU of MRSA in the abscess of mice treated with CLA-TatWGALip was significantly lower than that of any others (P<0.01). Collectively, liposomal delivery system modified by Tat and WGA could be a promising anti-resistant infection strategy.

    Modeling the molecular interactions of budesonide with bovine serum albumin guides the rational preparation of nanoparticles for pulmonary delivery
    Shuai Meng, Wei Cui, Shaohui Lin, Guiling Wang, Yu Hei, Bo Deng, Shuang Ma, Zhan Zhang, Yingchun Liu, Ying Xie
    2018, 27(6):  415-428.  DOI: 10.5246/jcps.2018.06.042
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    Large Hollow nanoparticulate aggregates (LHNAs) based on albumin nanoparticles is a promising technology for developing dry powder inhaler (DPI) with good aerodynamic properties in order to provide a new drug delivery system (DDS) for the treatment of lung disease. Improved understanding of molecular interactions could lead to prepare the DDS rationally. Therefore, this investigation utilized computations and experiments to reveal the mechanisms of budesonide (BUD) interactions with bovine serum albumin (BSA) at the molecular level. The molecular dynamics (MD) simulation revealed that there were three critical stable binding sites of BUD on BSA (P1, P2, P3) mainly by hydrophobic interaction and hydrogen bond. The energydecomposition of each residue to the whole BUD-BSA complex system in P1-P3 showed that nonpolar residues in or around the binding site played an important role in the binding of BUD to BSA. The molar ratio was close to 3 in preparations in drug-loading efficiency experiment, which was confirmed to the simulation results. The details of the binding sites from computation provided a guideline for the design of the BSA nanoparticles carrying BUD, which was prepared successfully at last. Combination of the MD simulation and experiment as well as the mechanism of the molecular interaction provided a solid theoretical basis for the preparation of BSA-LHNAs for DPI in the future.

    Lignans and flavonoids from Artemisia brachyloba
    Puming Zhang, Chen Zhang, Kewu Zeng, Yong Jiang, Pengfei Tu
    2018, 27(6):  429-435.  DOI: 10.5246/jcps.2018.06.043
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    A phytochemical investigation on the aerial parts of Artemisia brachyloba led to the isolation of 13 compounds (113) for the first time, including eight lignans (18) and five flavonoids (913). The structures of the isolated compounds were elucidated by analysis of the NMR spectroscopic data and comparison with the literature.The 1H and 13C NMR data of 1 were fully assigned for the first time by the 2D NMR analysis. All the isolates were evaluated for their inhibitory effects on nitric oxide production in lipopolysaccharide-challenged BV-2 microglial cells.

    Detection of bacterial endotoxin in paclitaxel liposome
    Yusheng Pei, Tong Cai, Guolai Zhang, Chen Chen, Hua Gao
    2018, 27(6):  436-441.  DOI: 10.5246/jcps.2018.06.044
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    Based on current research, there are three technologies during the test of bacterial endotoxin of liposomes: (1) extraction of bacterial endotoxin from liposomes; (2) addition of bacterial endotoxin in the process of recovery test; and (3) elimination of the interference factors from drugs and excipients. In the present study, we pointed out that the key technologies to test bacterial endotoxin from paclitaxel liposome included following steps: extraction of bacterial endotoxins from ethanol-dissolved liposomes; preparation of positive control of recovery solution by adding 0.01 mL standard endotoxins in 1 mL liposome ethanol solution; and the use of 0.5% human albumin to eliminate the interference from detection, and accurate detection of the bacterial endotoxin of liposomes.

    Preparation and stability study of lansoprazole for injection
    Zhenyu Lu, Rong Xu, Wei Dai, Jing Lin, Chen Shen
    2018, 27(6):  442-450.  DOI: 10.5246/jcps.2018.06.045
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    In the present study, we aimed to assess the preparation method of sterile lansoprazole powder for injection, as well as its quality and stability. By cryodesiccation technology in combination with the control of its quality and stability, the optimal formulation and preparation route were screened. Through small-scale and pilot-scale production validation, the formulation and preparation route were confirmed, in which mannitol was used as skeletal matter, meglumine was used as solubilizer and pH stabilizer, and sodium hydroxide was used as pH regulator. The formulation and preparation route were reasonable, showing good quality control and stability and fitting the pharmaceutical and clinical need.