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
    PANG Yanting , SUN Qingyan, ZHANG Weidong,
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    Reactive oxygen species(ROS) are byproducts of cellular redox metabolism. Excessive ROS can lead to oxidative damage of DNA, proteins and lipids, thereby exacerbating the genetic instability of cancer cells and promoting tumor initiation and progression. Peroxiredoxin 1(PRDX1), a key member of the peroxidase family, plays a pivotal role in maintaining intracellular ROS balance, effectively protecting cells from ROS-induced damage. Simultaneously, PRDX1 acts as a molecular chaperone in various malignancies, exhibiting dual roles in either promoting or inhibiting tumor growth. In recent years, numerous PRDX1-targeting candidate drugs have demonstrated significant antitumor effects both in vitro and in vivo, confirming PRDX1 as a potential target for cancer therapy. This review summarizes recent advances in understanding the mechanisms of PRDX1 as a tumor treatment target, as well as the development of antitumor natural products targeting PRDX1.
  • Perspectives & Review
    QIN Yu , ZHANG Bojin , CHEN Linlin
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    Diseases caused by bacterial infections pose a significant threat to human health. In recent years, the overuse of antibiotics has led to the emergence of drug-resistant microorganisms and the development of new bacterial strains. These factors have further exacerbated the threat of bacteria to human health and environmental safety. Consequently, the development of novel antibacterial materials to prevent the emergence of “superbugs” has become a key research focus. Metal-organic framework materials(MOFs) have emerged as star materials in the antibacterial field, owing to their exceptional crystallinity, high porosity, large specific surface area, and facile tunability through modification. However, traditional MOFs also exhibit some shortcomings, such as poor hydrophilicity, long antibacterial cycles, and lack of targeting. To overcome these drawbacks, post-synthetic modification of conventional MOFs has emerged as an important strategy. Based on this, this article summarizes several design approaches for novel MOF-based antimicrobial materials, including modification of MOFs metal nodes, functionalization of organic ligands, surface and pore structure modification, and the formation of composites with other materials. The aim is to provide a reference for the future synthesis of advanced antimicrobial MOFs.
  • Paper
  • Paper
    WANG Bing , LI Zhen , XIA Lintao , CHI Yongjian , LI Zhong
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    The synthesis process of the antihyperglycemic drug linagliptin(1) was optimized, and the key process parameters for each step were determined, along with the impurities generated. Starting from 8-bromo-7-(but- 2-yn-1-yl)-3-methylxanthine(3), crude 1 was obtained through a two-step substitution reaction and deprotection. The pure target 1 was afforded by recrystallization from ethanol with an overall yield of 74.6% (based on 3) and HPLC purity of 99.85% , while individual impurity below 0.05% . By replacing the deprotection reagent with trimethylsilyl trifluoromethanesulfonate(TMSOTf), the process was stabilized and simplified, significantly reducing the formation of the dimer impurity of 1(namely related substance B). This optimized process was suitable for industrial production. Furthermore, nine related substances were synthesized, among which the synthetic routes of related substances A, C, D, E, F, G, H, and I were reported at the first time. This study is expected to provide a valuable reference for the quality control of 1.
  • Paper
    JIN Shixin, CAI Hongming, LIU Yubin, CAI Zhengyan, LIN Kuaile
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    Dimetridazole(1) is a nitroimidazole antibacterial agent and an antiprotozoal veterinary drug. The traditional batch methylation for the synthesis of 1 has issues such as low yield, abundant disubstituted impurities, and high safety risks. In this study, 1 was prepared through a continuous flow reactor, which effectively reduced potential risks in the methylation reaction and increased the yield from 53% (reported in the literature) to 73% . Meanwhile, four related substances of 1 were discovered and synthesized, namely 1,2-dimethyl-4-nitro-1H-imidazole(3), 1,2,3-trimethyl-5- nitroimidazolium monomethyl sulfate(4), and a mixture of N-methyl-N-(2-methylamino-2-nitrovinyl)acetamide(5) and N-methyl-N-(2-methylamino-1-nitrovinyl)acetamide(6), which provided some references for the quality control of 1. In addition, it was found that when ammonia was used in the work-up of the methylation reaction, the quaternary ammonium salt 4 could be demethylated into the target product, offering a new approach to turning waste into valuable product.
  • Paper
    CHEN Ziqi, HUANG Lei, FU Cuiping, LUO Kun, WANG Guan,
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    In this study, a novel synthetic process of finerenone(1), an anti-diabetic nephropathy drug, was developed. Using 2-hydroxyethyl methyl sulfone(20) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one(21) as starting materials, the target product 1 was synthesized through sequential steps including alcoholysis, Knoevenagel condensation, Hantzsch cyclization, etherification, chiral resolution, β-elimination, and ammonolysis, with an overall yield of 19.9% (based on 20), purity of 99.80% , and ee value of 99.82% . The novel process features mild reaction conditions and well-controlled quality, yielding intermediate 2-(methylsulfonyl)ethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxylate with high optical purity following resolution, making it suitable for industrial production.
  • Paper
    HUANG Hao , WANG Yapeng, FENG Junwu , LU Jianguang , FENG Jun
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    Recombinant human granulocyte colony-stimulating factor(1) is clinically used to treat neutropenia caused by chemotherapy or radiotherapy in cancer patients. When expressed in Escherichia coli, 1 predominantly accumulates as inactive inclusion bodies. So, the low yield of inclusion body denaturation and refolding limits the overall process yield. In this study, soluble expression of 1 was achieved by employing a fusion expression strategy with the small ubiquitin-related modifier protein, with an expression level of 2.19 g/L. Further steps including extraction, enzymatic cleavage, clarification, anion exchange chromatography, cation exchange chromatography, and ammonium sulfate precipitation yielded 1 with a purity of 99.3% and a recovery rate of 44.2% . The structure and function of the self-produced 1 were confirmed through HPLC retention time comparison, mass spectrometry, peptide mapping, disulfide bond localization, and in vitro biological activity assays. Finally, a 50 L scale-up test demonstrated the feasibility of industrial-scale manufacturing for this process. This study provides a robust foundation for the industrialization and subsequent structural optimization of 1.
  • Paper
    WU Yuzhou , XU Jun, HUA Haoju, LU Jianguang , FENG Jun
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    Teduglutide(1) exerts its physiological effects by binding to glucagon-like peptide-2(GLP-2) receptors on the intestinal and digestive tract walls. Clinically, it is used to treat short bowel syndrome. In light of the current situation where only an expensive original product with limited accessibility is available on the domestic market, this study aims to develop a more efficient production method. To achieve this, small ubiquitin-related modifier protein was fused with 1 for intracellular soluble expression in Escherichia coli. The results showed that the target peptide reached a productivity of over 800 mg per liter of fermentation broth, with a purification yield of approximately 46% and a purity exceeding 99% . The LC-MS/MS analysis confirmed that relative molecular weight and amino acid sequence of the peptide were consistent with the theoretical predictions. This research offers a simple, low-cost, high-yield approach for 1 production, laying a foundation for future large-scale manufacturing.
  • Paper
    FAN Wenrong, MIAO Jiaying, XI Quan
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    Oligonucleotide drugs have been utilized in the prevention and treatment of various diseases. To enhance their stability and facilitate transmembrane delivery, lipid nanoparticles(LNPs) are commonly employed as carriers. However, the poor stability of miRNA-LNPs results in stringent storage requirements, limiting their broad application. Therefore, this study investigated the effects of formulation and process parameters on miRNA-LNPs physical stability, using particle size and encapsulation efficiency as key indicators. The results indicated that various phospholipids contributed to the physical stability of LNPs, among which PEGylated phospholipids effectively preventing LNPs aggregation. The phase transition of water directly destroyed the LNPs structure, and the combination of cryoprotectant sucrose and PEGylated phospholipids could effectively resist the damage caused by water phase transition to the LNPs structure. By elucidating the mechanisms by which structural materials and water phase transitions affect miRNALNPs physical stability, this study introduced cryoprotectants as a novel strategy to improve the physical stability of oligonucleotide drug-loaded LNPs. These findings provide valuable insights for optimizing LNP-based formulations, thereby strengthening the clinical applicability of small nucleic acid therapeutics.
  • Paper
    WANG Shurui# , QUAN Xin# , SHEN Dan, ZHU Xingyi
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    To enhance the solubility and dissolution rate of epalrestat(EP), a cocrystal of EP and benzamide(BAM), as well as its inclusion complex with hydroxypropyl-β-cyclodextrin(HP-β-CD), were prepared using a mechanical ball milling method. The preparation conditions for both the EP-BAM cocrystal and its inclusion complex were optimized. Structural characterization was performed using powder X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. The solubility performance was evaluated through saturation solubility experiments and in vitro dissolution tests were also carried out. The results showed that the solubility of the EP-BAM cocrystal increased by 1.08- fold compared to EP, while that of the EP-BAM/HP-β-CD inclusion complex increased by 11.53-fold. The results of in vitro dissolution tests showed that both the cocrystal and the inclusion complex exhibited superior dissolution rates and amounts compared with the physical mixture. The EP-BAM cocrystal and the EP-BAM/HP-β-CD inclusion complex significantly improve the solubility and dissolution rate of EP, providing an effective strategy to enhance its bioavailability.
  • Paper
    SHEN Xiuwei, LI Yinghui, WU Shujuan, CHEN Fan
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    An ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method was established for the determination of dictamnine(1) and fraxinellone(2) in rat plasma. A UPLC HSS T3 chromatographic column(2.1 mm×50 mm, 1.8 μm) was used, and the analysis was carried out in the gradient elution mode with acetonitrile as mobile phase A and water(containing 0.1% of formic acid) as mobile phase B. Positive ion mode detection and multiple reaction monitoring mode were used for quantitative analysis, with midazolam as the internal standard. The results showed good linearity for 1 and 2 in the range of 2 - 2 000 ng/mL. The extraction recovery rates of 1 and 2 were above 79.5% , the precisions were less than 15% , and the accuracies were 87.3% - 109.8% . In pharmacokinetic studies in rats, after gavage administration(2 mg/kg) or sublingual administration(0.1 mg/kg), the cmax of 1 were (1 382.4±129.6) and (382.6±118.9)ng/mL, with t1/2 of (1.5±0.2) and (2.3±0.5)h, respectively; the cmax of 2 were (57.5±2.2) and (742.6± 109.7)ng/mL, with t1/2 of (2.7±1.0) and (2.1±0.5)h, respectively. The bioavailability values of 1 and 2 were 68.1 % and 7.6% , respectively. This established method provides a reference for its clinical use.
  • Paper
    XIN Yuqian , GONG Liping , XUE Weili, HANG Baojian , SHI Feng , SUN Yong
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    A HPLC method was established for the simultaneous determination of sodium chondroitin sulfate(2), vitamin B1(3), and vitamin B6(4) in compound cerebroprotein hydrolysate tablets(1), and the content uniformity was also investigated. Chromatographic separation was performed on a Hypersil BDS C18 column(4.6 mm×250 mm, 5 μm) using gradient elution with 0.02 mol/L sodium heptanesulfonate solution as mobile phase A and acetonitrile as mobile phase B. The column temperature was set at 35 ℃ , with an injection volume of 20 μL. The detection wavelengths were set at 200, 246, and 291 nm for compounds 2, 3, and 4, respectively. The methodological research results showed that the established method exhibited strong specificity, good linearity, repeatability, and accuracy. The sample determination results showed that the content and content uniformity of the three components in 1 from different manufacturers were significantly different, indicating the necessity for enhancing its quality control measures.
  • Paper
    GAO Liqiong, SHEN Guofang, LIN Linqin, WANG Xiuxiu
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    A centrifugal assisted liquid-liquid extraction combine with gas chromatography method was established for the determination of 17 related substances in sodium valproate(1) sustained-release tablets. The HP-FFAP column (0.32 mm×30 m×0.25 μm) and the hydrogen flame ionization detector were used with programmed temperature. The flow rate was 3.0 mL/min, the inlet temperature was 220 ℃ , and the detector temperature was 300 ℃ . The results showed that the established method could effectively separate 17 process impurities and degradation impurities, with a detection limit of about 0.25 μg/mL(0.005 % ). The impurities 2-methylvaleric acid and 2-methyl-2-ethylvaleric acid were detected in 1 sustained-release tablets by this method. This method solves the problem of difficult detection caused by material swelling and inability to dissociate in 1 sustained-release tablets and enables accurate determination of the related substances, providing a reference for the quality control and standard improvement.
  • Paper
    YANG Min, HUANG Chengchao, ZENG Tao, LI Ye, LIN Huangjing
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    Cytotoxicity tests were conducted to evaluate the biosafety of medical polyurethane(PU) products. In this study, cytotoxicity tests of PU products mainly composed of bis(4-isocyanatocyclohexyl)methane(HMDI) and poly(tetramethylene ether)glycol(PTMEG) were conducted. The cytotoxicity of the PU products, raw materials and additives in the formulations were tested respectively according to the MTT method. The results showed that PU had no acute systemic toxicity, but the cell viability of PU was less than 50%, which indicated a cytotoxic potential. This laboratory prepared a small-batch of PU samples using the same formulation as commercial products, which passed acute systemic toxicity tests but exhibited only 8% cell viability. After acetone cleaning, the cell viability increased to 60% . The cell viabilities of the formulations containing HMDI and the additives such as chain extenders, antioxidants, light stabilizers and catalysts were more than 70% in the cytotoxicity test, indicating no cytotoxicity. However, the cell viability of PTMEGcontaining formulations was less than 70% , with viability decreasing as concentration increased, indicating that PTMEG might be the primary cause of PU cytotoxicity. It is recommended to adjust the proportion of PTMEG or replace it with polyols exhibiting superior biosafety performance in PU products, and optimize the cleaning process during production to ensure the biosafety of PU.
  • Paper
    ZENG Nianli, WANG Xiaolan, GUO Yanyan, PU Xiaocong
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    In order to meet the regulatory requirements for halide identification of pharmaceutical rubber stoppers(mainly chlorinated and brominated rubber stoppers) in packaging material changes and generic drug research and development, a rapid and accurate method based on pretreatment of ignition residue and ion chromatography detection was established. After ignition and ashing, residual ions in samples were extracted with water. The Dionex IonPac™ AS19 column was used, with 20 mmol/L potassium hydroxide solution as eluent, at a flow rate of 1 mL/min, column temperature of 30 ℃ , and injection volume of 25 μL. The results showed that it was linear for chloride and bromine ions in the range of 2 - 100 μg/mL, with satisfactory recovery and strong method specificity. The method was applied to determine 16 batches of halogenated butyl rubber stoppers from different manufacturers, and the determination results were completely consistent with the formulations claimed by the manufacturers. This simple, rapid, and accurate method enables effective identification and quantitative detection of halides in pharmaceutical stoppers, providing reliable technical support for packaging material changes of marketed drugs, generic drug packaging screening, and quality control of rubber stoppers.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    ZHU Qilei, CHEN-ZHUANG Tianyi , CAO Meng,
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  • Pharmaceutical Management & Information
    JIA Ruibo, XU Guilian, LU Dan, GONG Shanshan, LI Xiangang
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  • Pharmaceutical Management & Information
    SHU Beiyan , WANG Qinghua , LIU Lei , GENG Jia , SUN Lifang , ZHOU Jie , GENG Wenjun
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  • Pharmaceutical Management & Information
    XIA Tiantian, WANG Hui , ZHOU Zeyu
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