主办:上海医药工业研究院
   中国药学会
   中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA

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    Perspectives & Review
  • Perspectives & Review
    LI Xia, SUN Qingyan, ZHANG Weidong
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    Activator protein-1(AP-1) is an important transcriptional regulator composed of DNAbinding proteins involved in several cellular processes responsible for cell survival, proliferation and differentiation. Overactivation of AP-1 leads to increased expression of downstream proteins associated with tumor invasion and metastasis, which plays a key role in tumor invasion and metastasis. Therefore, targeting and inhibiting AP-1 has recently developed as an attractive therapeutic strategy for cancer prevention and therapy. This paper reviews our current understanding of the structure and function of AP-1, and discusses the anti-tumor effects and action mechanisms of several natural active compounds reported in recent years by regulating AP-1 associated signaling pathways.
  • Perspectives & Review
    QIU Mingxing, BAI Jiaojiao, ZHOU Xiaoju
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    Immunoliposomes are liposomes modified with antibodies or their fragments, which have molecular recognition ability to target cells. Compared with free drugs, non-specific antibody modified liposomes and monoclonal antibodies, immunoliposomes have better selectivity and stronger cytotoxic activity. In animal experiments, immunoliposomes can specifically distribute drugs at the lesion sites, thereby enhancing the efficacy of the drug and reducing adverse reactions. Moreover, PEGylation also enhances the circulation time of immunoliposomes in the body. This paper reviews the different types of antibodies used for modification, and how they are conjugated to immunoliposomes. The applications of immunoliposomes in antineoplastic drugs, gene therapy, in vivo imaging technique and treatment of infectious, autoimmune and neurodegenerative diseases are summarized.
  • Perspectives & Review
    KONG Songtao, LAN Ying, ZHAO Lijun, REN Jianbing, WANG Kun
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    Fluidized bed coating technology with the advantages of high efficiency, good heat and mass transfer performance has a wide range of application value in various industries. Based on the complex gas-solid two-phase flow, the coating process can be carried out smoothly. Accurate understanding of gas-solid flow behavior and its flow characteristics, and mastering fluidized bed coating process and its amplification law have been the focus of scholars at home and abroad. Firstly, this paper introduces the basic process of fluidized bed coating. Then, the effects of particle characteristics on the gas-solid flow characteristics and final coating performance are reviewed and briefly analyzed from three aspects of rotation, collision and shape of the particles in the fluidized bed. Finally, the direction of further research is pointed out. It may be an effective way to solve the traditional scale-up problem of coating technology by studying the scale-up technology of fluidized bed coating from the mesoscopic particle group scale.
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  • Paper
    HUANG Zongqing, HUA Haoju, LU Weigen, WU Yong
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    This study described a novel approach for the large scale production of recombinant pig adrenocorticotropic hormone (pACTH) in Escherichia coli. The pACTH was fused at the N-terminus to the N-terminal autoprotease Npro mutant EDDIE from classical swine fever virus, and was expressed in the E. coli cytoplasm in inclusion bodies at levels about 36.2% of the wet cell weight. The renatured inclusion bodies were able to induce EDDIE autoproteolysis to obtain pACTH. By optimizing the refolding conditions, the self-cleavage rate of EDDIE-pACTH protein was increased from 25% to 60%. The refolding solution was subjected to one-step acid precipitation to remove the heteroprotein, and purified by reverse phase chromatography to obtain pACTH having a purity of 99.56%.
  • Paper
    LI Yajun, LI Ji'an, ZHANG Jianbin, GUO Ruiling, LIN Huimin
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    The crude pingyangmycin(1) chelating copper was purified by column-based chromatography with the prepacked column of monodisperse polymer microspheres, and the HPLC purity of 1 chelating copper reached above 98%. The crude 1 chelating copper was purified sequencely by reversed column-based chromatography with the prepacked column of XR 3SP microspheres and POlyRP 30-300 microspheres. The purify and yield for the first step reached over 50% and 85%, while those for the second step were up to 98% and 88%. The total yield reached above 75%. The process was simple, reliable and suitable for industrial production.
  • Paper
    XU Yaqiang, HE Zhiyong, WANG Jun, LI Na
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    This study was to establish a process for production of acarbose at low maltose that could save production cost significantly by reducing the amount of maltose and adding a certain amount of NaCl to maintain the appropriate osmotic pressure. After the shake flask test, the feed concentration of maltose and the addition way of NaCl were determined. The concentration of maltose in the feed medium was reduced by 20%, and a certain amount of NaCl was added on the third and fifth days of fermentation. Based on this, the pilot scale study showed that under optimized process conditions, the fermentation level of acarbose could be ensured to reach the original level, and the production material cost was reduced by about 10%.
  • Paper
    ZHAI Lihai, ZHOU Youchun, GUO Lihong, XIA Xianglai, ZHANG Guimin
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    The impurity, [(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[[1,3]dioxolo)- [4,5-b:4',5'-d]pyran-3a-yl]methyl][(3aS,5aS,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)- [4,5-b:4',5'-d]pyran-3a-yl]methyl]sulfamate(4), was found in the synthesis of topiramate(1). Its structure was confirmed by NMR and MS. In this paper, it was proved that 4 was resulted from the reaction of residual 2,3:4,5-bis- O-(1-methylethylidene)-β-D-fructopyranoside(3) in the oily 2,3:4,5-bis-O-(1-methyethylidene)-β-D-fructopyranose chlorosulfonate(2) with 1. Therefore, the synthetic process of 2 was improved. Compound 3 reacted with sulfuryl chloride in DCM/toluene to give the oily 2, which was purified with isopropyl ether to obtain the solid form of 2 for the first time. The content of 3 in solid 2 was reduced to 0.05%. Then the solid 2 reacted with NH3 to give 1 in a purity of 99.93% and a total yield of 87%(based on 3), which did not need the further purification. This process was easy to remove the impurities, and the intermediate 2 obtained was solid, which was convenient for storage and sampling.
  • Paper
    LIU Dong, WEI Ruixia, FENG Zhong, LI Tiejian, ZHANG Guimin
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    In this report, preparative high-performance liquid chromatography was used to purify crude ularitide containing more polypeptide mixtures with similar structures. One-step purification process was optimized by singlefactor experiments and response surface method. The results showed Daiso-SP-ODS(30 nm, 10 μm) packing was used for the purification in the conditions of 70 mmol/L ammonium dihydrogen phosphate solution, pH 4.0 and column temperature of 30 ℃ to obtain the one-step purified sample in a purity of 98.65% and a yield of 70%. After the two-step purification of trans-salting, the purity of the product was increased from 98% in the literature to 99.91%, and the total yield was increased from 29% to 56%. This two-step purification process could provide a reference for the establishment of a method for polypeptide separation and purification.
  • Paper
    PENG Chunrui, WANG Yinhu, LIU Hong, LI Lingling, JIANG Feng
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    4-(Methylsulphonyl)phenylacetic acid(3) reacted with methyl 6-methylnicotinate(2) in the presence of tert-butyl magnesium chloride to give 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone(1), a key intermediate of etoricoxib, with a purity of 99.5% and a yield of 81%(based on 3). Grignard reagent and 2 were charged in parts alternatively to reduce the content of 1-(6-methylpyridin-3-yl)-2-[4-[(6-methylpyridin-3-yl)carbonylmethylsulfonyl] phenyl]ethanone(4) to 2.2% in this process. In the work-up, the content of 4 could be reduced to 0.2% by purification with acetone/water. In addition, neutralization with ammonia instead of sodium carbonate could avoid the waste solid. The improved process was suitable for industrial production.
  • Paper
    CHEN Mengting, TIAN Wenjun, GUO Yekun, ZHONG Jingfen
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    Two related substances of benfotiamine, named 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-[2- [[hydroxy(phosphonooxy)phosphoryl]oxy]ethyl]-4-methyl-1,3-thiazol-3-ium chloride(5) and diphosphoric acid mono- [4-[(4-amino-2-methylpyrimidin-5-ylmethyl)-formyl-amino]-3-benzoylsulfanyl-pent-3-enyl]ester(6), were synthesized in this report. 3-[(4-Amino-2-methyl-5-pyrimidinyl)-methyl]-5-(2-hydroxyethyl)-4-methylthiazolium chloride hydrochloride(2) reacted with polyphosphoric acid to obtain the crude product 5, which was purified with a D301 anion exchange resin column, and the eluent was concentrated under reduced pressure. Isopropanol was added to precipitate 5 with a purity of 96.55%. Compound 5 reacted with benzoyl chloride in the presence of alkali at low temperature to give 6, which was followed by freeze-drying, with a purity of 97.57%. The product structures were confirmed by MS, 1H NMR and 13C NMR.
  • Paper
    HU Yang, JIANG Faqin, ZHANG Yong, ZHANG Dongdong, FU Lei
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    Based on the binding conformation of Staphylococcus aureus transpeptidase Sortase A and the substrate LPXTG as a template, twelve 2-phenyl-benzofuran-3-amide derivatives with L-shape conformation were designed and synthesized. The structures were confirmed by NMR and high-resolution mass spectrometry, and among them, ten target compounds had not been reported in the literature. Nine compounds showed excellent in vitro inhibitory activities on Sortase A[IC50=(22.2 - 62.3) μmol/L]. The structure-activity relationship analysis revealed that the inhibitory activity was better when -CONHCH2CH(CH3)2 at the 3-position of benzofuran, while the inhibitory activity was lost when -COOH at the same position, when the 2-position benzyl group had an electron withdrawing group such as cyano, the inhibitory activity was improved, compared with the electron donor group, such as -OH, the substituents at other positions of benzofuran had no significant effect on the inhibitory activity.
  • Paper
    HUANG Yan, CHEN Zhenyang, ZENG Huanxiang, CHENG Gang, PAN Weisan
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    Chlorphenamine maleate (CPM) was used as a model drug to prepare drug-resinates using ion exchange resin (Amberlite IRP-69) as a carrier. Then, the microcapsules loaded with drug-resinates with acrylic resin (Eudragit RS100) as a surface coating material were prepared by the surface coating technology via ion exchange reactions. The process parameters of the surface coating technology were investigated to prepare the microcapsules loading drug-resinates with good sustained-release properties. The results of a single factor test showed that the higher drug-loading of the drug-resinates was, the slower drug released from the microcapsules. The similar phenomena occurred in the investigations of Eudragit RS100 concentration, the amount of reaction medium (95% ethanol) and reaction temperature. These results indicated that the surface coating technology was simple and reproducible, and the obtained microcapsules of drug-resinates with good sustained-release properties could be further processed as a pharmaceutical preparation.
  • Paper
    HUANG Yinghao, ZHANG Jie, SUI Jiying, HUANG Guihua
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    On basis of our previous research of the enteric-coated pellets loaded with aspirin or esomeprazole magnesium, the co-loaded enteric-coated pellets were prepared in this paper. Firstly, the aspirin pellet cores were fabricated by extrusion-spheronization method, then the cores were sequentially coated with the isolation layer Ⅰ, esomeprazole magnesium layer, isolation layer Ⅱ and enteric layer by bottom spray-type fluid-bed coating process to obtain the final product, the aspirin and esomeprazole magnesium co-loaded enteric-coated pellets. The results of in vitro test showed that the cumulative releases of two drugs from the pellets were below 5% in 0.1 mol/L hydrochloric acid within two hours, while in pH 6.8 phosphate buffer, the cumulative releases of aspirin and esomeprazole magnesium were (5.9±1.1)% and (78.5±1.4)% for 15 min, (77.4±3.3)% and (83.5±1.9)% for 60 min, respectively. The pharmacokinetic test of the co-loaded enteric-coated pellets was carried out with rats as the models. The tmax, AUC0→∞, cmax and MRT0→∞ in rats after gavage administration were (1.50±0.00) and (3.50±0.50)h, (15.73±2.50) and (1 158.39±73.73)mg·L-1·h, (2.89±0.09) and (75.13±2.14)mg/L, (8.30±1.30) and (11.679±0.60)h respectively. There results showed that esomeprazole magnesium could burst release in pH 6.8 medium, while aspirin could release after a certain time lag, which was conducive to play a synergistic effect and reduced the gastrointestinal irritation of aspirin in long-term application.
  • Paper
    DENG Zulei, HONG Qiuju, CUI Tian, LIU Dahu
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    A method for evaluating dissolution similarity of solid preparations was established based on the similarity system theory. A re-improved extent similarity (Q'') was calculated as an index to evaluate the similarity of dissolution curves between the genetic and reference preparations, and the judgment criterion for similarity was recommended that the value of Q'' should be no less than 85. This method was used to calculate Q'' values based on the literature data and compared with the reported similarity factor (?2) method. The results showed that the evaluation results of both methods were consistent, indicating the feasibility of this method for similarity evaluation. Moreover, this method could avoid some of the shortcomings of the similarity factor method.
  • Paper
    CHENG Yiqing, HU Qing, MAO Xiuhong, JI Shen
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    An ion chromatography method for determination of chloride and two cations(sodium and ammonium)in Gualoupi injection was established in this study. Thermo ICS-5000 Ion Spectrometer with inhibitory electrical conductivity detector was adopted. For chloride, IonPac AS11-HC column(4 mm×250 mm, 13 μm)was chosen, and eluted by 20 mmol/L potassium hydroxide solution. While IonPac CS12A column(4 mm×250 mm, 8.5 μm)was used for cations with a mobile phase of 20 mmol/L methanesulfonic acid solution. All ions could be separated and revealed good linear relationships. Their linear correlations over the investigated concentration were in the range of 0.996 2 - 0.999 9, and the average recoveries ranged from 98.2% to 99.9%, respectively. The method is rapid, simple, specific, sensitive and suitable for determination and quality control of the anion and cations in Gualoupi injection.
  • Paper
    DONG Shubo , XU Liang, YANG Hanyue, YE Deju, WANG Jiantao
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    In this study, a GC-MS/MS method was established for the simultaneous determination of benzaldehyde, benzyl alcohol, 2-cyanobenzyl bromide and tri-n-butylamine in alogliptin benzoate. The method was performed on a DB-624 capillary column(6% cyanide propylbenzene-94% dimethylsiloxane copolymer, 0.32 mm×30 m, 1.8 μm) and the analytes were detected with MS/MS in multiple reaction monitoring mode. The results showed that there was a good linearity(r≥0.999 2). The limits of detection all were 2 ng/ml and their average recoveries were 90% - 100%. The test solution, reference solution and system suitability solution were stable for at least 12 h at 25 ℃. 2-Cyanobenzyl bromobenzyl, benzaldehyde, benzyl alcohol and tri-n-butylamine were not detected in three batches of alogliptin benzoate. With high sensitivity, good resolution and accuracy, the method could be reliably and effectively used in the determination of the above four kinds of trace impurities in alogliptin benzoate as well as provided a guarantee for the quality control of alogliptin benzoate.
  • Paper
    GE Yang, LIU Yi, WU Yanfan, WANG Xuejun, ZONG Xinhua
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  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    WANG Xuecheng, WU Zhenfeng, ZANG Zhenzhong, LI Yuanhui, YANG Ming
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  • Pharmaceutical Management & Information
    DAI Hu, DING Mansheng, ZHU Jianwei
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  • Pharmaceutical Management & Information
    YE Menghan, ZHUANG Qian, CHU Shuzhen
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