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

Current Issue

  • Select all
    |
    Perspective & Review
  • Perspective & Review
    DONG Junjun, LIN Kuaile, CAI Zhengyan
    Abstract ( )   Knowledge map   Save
    Targeted protein degradation technology eliminates pathogenic target proteins via two endogenous degradation pathways, namely the ubiquitin-proteasome system and the lysosomal system, and has rapidly emerged as a promising drug discovery in recent years. The lysosomal degradation pathway exhibits unique developmental advantages owing to its capability to degrade a broad spectrum of substrates including intracellular proteins, extracellular proteins and protein aggregates. This paper systematically reviews the latest research advances of lysosome-based targeted protein degradation technologies. It comprehensively elaborates on the mechanisms, core advantages and existing challenges of novel lysosomal degraders corresponding to the endosome - lysosome and autophagy -lysosome pathways, including lysosome-targeting chimeras, autophagy-targeting chimeras, autophagosome-tethering compounds, and chaperone-mediated autophagy targeting chimeras. Furthermore, the future application prospects of these technologies in innovative drug research and development are highlighted.
  • Perspective & Review
    TANG Hongxia , LIANG Jiawei
    Abstract ( )   Knowledge map   Save
    Vaborbactam(1) is a novel boron-containing β-lactamase inhibitor. Used in combination with meropenem, it can treat complicated urinary tract infections. This combination therapy exhibits a favorable safety proffle and robust clinical efffcacy alongside substantial market demand, making research into its industrial synthetic routes highly signiffcant. This review summarizes the currently reported synthetic routes of 1. One category of routes ffrstly utilized chiral enzymatic resolution to obtain the enantiomer tert-butyl (R)-3-hydroxy-4-pentenoate, followed by a Matteson reaction to construct the chiral boronate intermediate. Adopting continuous flow technology for the Matteson reaction can improve efffciency and safety. Another category of routes utilizes Ellman chiral imines for asymmetric borane addition to highly selectively generate the chiral boronate intermediate, which then undergoes deprotection and cyclization to yield the target 1. These routes feature readily available starting materials, mild conditions, as well as safety and environmental friendliness. A NiH-catalyzed hydroamidation route can prepare the chiral boronate intermediate from alkenyl boronic esters in a single step without the need for chiral auxiliaries or precious metal catalysts, but it is not suitable for industrial production. This paper compares and analyzes the advantages and limitations of various synthetic routes, and proposes that the synthesis of compound 1 should be optimized toward fewer reaction steps, higher yields, milder reaction conditions and greener manufacturing processes.
  • Paper
  • Paper
    GUO Jiabin, CHEN Chengfu, ZHANG Naihua, WANG Wei, ZHANG Guimin,
    Abstract ( )   Knowledge map   Save
    Acipimox(1) is mainly used for the treatment of hyperlipidemia. In this study, 2,5-dimethylpyrazine(3) was used as the starting material, and a continuous flow reaction scheme in series was adopted instead of the batch reaction to obtain 1. By taking advantage of the high heat and mass transfer efficiency of the continuous flow microreactor, the selectivity of the reaction was improved. By taking advantage of the small liquid holding capacity of the continuous flow microreactor, the safety of the reaction was enhanced, and the continuous flow total synthesis of 1 was ultimately achieved. The total yield was 86.94 %(based on 3), and the purity was 99.24 % . This technology not only significantly enhances production efficiency and safety, but also features a small equipment footprint, low renovation costs, and a green and pollution-free production process, resulting in high economic and social benefits.
  • Paper
    ZHU Anguo, ZHANG Naihua, WU Caijiao, ZHANG Zhongkui, ZHANG Guimin
    Abstract ( )   Knowledge map   Save
    An improved synthetic process for the key intermediate of prucalopride succinate, 1-(3-methoxypropyl)- piperidin-4-amine(1), was reported in this study. Commercially available 4-hydroxypiperidine(2) was reacted with acetonitrile in the presence of calcium bisulfate to afford 4-N-acetylpiperidinamine(3) through a Ritter reaction. Then, compound 3 was alkylated with 1-bromo-3-methoxypropane to give 4-N-acetyl-1-(3-methoxypropyl)piperidinamine(4). Finally, the acetyl group of 4 underwent deacetylation catalyzed by boron trifluoride diethyl etherate, to afford the target compound 1 in an overall yield of 78.7% (based on 2) and a purity of 99.86% . The improved process offers advantages of simple operation and mild conditions, and has been validated at kilogram-scale.
  • Paper
    SUN Shimin, ZHAO Lili, LIU Zhong, ZHANG Guimin, ZHU Zhongsong,
    Abstract ( )   Knowledge map   Save
    Tumor necrosis factor receptor 2(TNFR2) is highly selectively expressed on tumor cells and regulatory T cells, and represents an important target for tumor immunotherapy. Current TNFR2-targeted drugs encounter developmental bottlenecks such as off-target cross-reactivity and species-specific differences. In this study, a recombinant human TNFR2 monoclonal antibody termed anti-hTNFR2 mAb was generated, and its in vitro and in vivo activities were systematically evaluated. First, through murine immunization, hybridoma screening, complementarity determining region grafting-mediated humanization, and affinity maturation, an anti-hTNFR2 mAb was obtained. After expression and purification, its efficacy was investigated through in vitro activity assays and in vivo studies using mouse solid tumor models. The results showed that the anti-hTNFR2 mAb exhibited high binding affinity(KD=1.18×10﹣10 mol/L) and blocking activity (IC50=0.037 4 nmol/L), both surpassing those of the positive control antibody 1-H10. Antibody-dependent cell-mediated cytotoxicity of anti-hTNFR2 mAb was quantified via fluorescence-activated cell sorting, yielding an EC50 of 0.078 2 nmol/L, which was superior to that of 1-H10(0.140 2 nmol/L). Collectively, the antibody exhibited significant anti-tumor effects in mice. At a dose of 10 mg/kg, the tumor growth inhibition rate reached 99.1% , outperforming that of 1-H10 (93.9% ).
  • Paper
    LIU Yuxuan, LIU Zhong
    Abstract ( )   Knowledge map   Save
    This study constructed an antibody-drug conjugate(ADC) targeting nectin cell adhesion molecule 4 (nectin-4) and evaluated the functional activity of the obtained conjugate. First, murine antibodies were humanized to obtain five humanized antibodies. Through assessments of competitive binding affinity, cell binding capacity, and tumor cell endocytosis efficiency, a humanized antibody, CH7-2-3, was selected. It was then conjugated with monomethyl auristatin E (MMAE) to construct the ADC, CH7-2-3-MMAE. The results of in vitro and in vivo activity assays showed that CH7-2- 3-MMAE exhibited EC50 values of 11.64 and 15.42 nmol/L against human breast cancer cells(MCF-7 cells) and human pancreatic cancer cells(BxPC-3 cells), respectively. After a single intravenous injection in mice, the tumor growth inhibition rate reached 141.3% on D17. These data indicated that CH7-2-3-MMAE had promising development potential and provided a reference for its subsequent preclinical and clinical development.
  • Paper
    JIANG Yanping#, CHEN Hongyue#, TANG Yifei, WU Wenzhe
    Abstract ( )   Knowledge map   Save
    Amphotericin B(1) is the gold standard drug for treating invasive pulmonary fungal infections. However, its intravenous administration causes severe systemic toxicity, and inhalation administration is an effective strategy to reduce systemic toxicity. Nevertheless, there is a lack of systematic research on the structural stability and aerodynamic properties of 1 liposomes after nebulization, restricting the development of their inhaled formulation. In this study, inhalable 1 liposomes were prepared by the film dispersion-high-pressure homogenization method. The entrapped efficiency was evaluated by ultrafiltration centrifugation and hollow-fiber ultrafiltration centrifugation, respectively. The effects of the nebulization process on the liposomes were comprehensively characterized by dynamic light scattering, transmission electron microscopy, and ultraviolet spectroscopy. The results showed that the vibrating mesh nebulizer exhibited superior performance, with a nebulization delivery efficiency of (58.98±1.67)% , a delivery rate of (348.43±34.63)μg/min, a fine particle fraction of (57.83±1.40)% , and a mass median aerodynamic diameter of (4.42±0.04) μm. This study demonstrates that the 1 liposomal formulation possesses the fundamental performance characteristics required for an inhalable antifungal formulation, providing a reference for optimizing inhalation liposomal formulations and the selection of compatible nebulization equipment.
  • Paper
    GUO Huiqing, GU Yanli, YANG Xiaoguang, BAI Huizhong, ZHU Aijun, Temuer, WANG Zhaoyang
    Abstract ( )   Knowledge map   Save
    In order to develop an oral negative computerized tomography(CT) contrast agent to improve the detection rate of small gastrointestinal lesions and overcome the poor imaging performance of existing contrast agents, an oral O/W nanoemulsion using white oil as the oil phase was prepared by high-pressure homogenization. Then, its physicochemical properties, stability, and imaging effects were systematically evaluated. First, the emulsifier was screened via pseudo-ternary phase diagrams, while formulation composition and preparation process were optimized by single-factor experiments and central composite design-response surface methodology. Subsequently, the nanoemulsion prepared by the optimized process was characterized for particle size, ζ potential, morphology, viscosity, and stability, and its in vitro imaging capability was further evaluated via CT values and using an ex vivo porcine intestinal model. The results showed that the nanoemulsion exhibited uniform particle size and good physical stability. It remained stable under acidic, alkaline, high-temperature, and centrifugal conditions, but was susceptible to intense light and high humidity, thus requiring lightproof and moisture-proof storage. The prepared white oil nanoemulsion achieved a CT value of ﹣ 91.1 HU. In the ex vivo porcine intestinal model, the nanoemulsion yielded a markedly higher contrast-to-noise ratio than water, enabling clearer visualization of the intestinal wall. As a novel oral negative CT contrast agent, this white oil nanoemulsion features a simple preparation process, stable properties under conventional conditions, and excellent in vitro imaging performance, providing a promising alternative for CT diagnosis of small gastrointestinal lesions.
  • Paper
    YANG Yinglan, YI Shengjie, ZENG Xuefeng, LI Huixin, SUN Yichun,
    Abstract ( )   Knowledge map   Save
    FT-IR, principal component analysis, cluster analysis, and orthogonal partial least squaresdiscriminant analysis were used, combined with ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-QTOF-MS), were adopted to characterize the overall component differences in Uncaria rhynchophylla before and after a bidirectional solid fermentation with Ganoderma lucidum for 15 days. The content changes of the two main components, rhynchophylline and isorhynchophylline, were compared by HPLC. After fermentation of Uncaria rhynchophylla with Ganoderma lucidum, the contents of rhynchophylline and isorhynchophylline increased by 4.46- and 8.90-fold, respectively. FT-IR analysis showed that the intensity of the characteristic absorption peak of polysaccharides near 1 053 cm–1 decreased after fermentation, and a broadened absorption band of humic acids was formed in the range of 1 660 - 1 575 cm–1, suggesting that the structural polysaccharides in Uncaria rhynchophylla were degraded during fermentation, accompanied by the generation of humic products. Chemometric analysis revealed that samples before and after fermentation could be completely separated(Q2=0.871), confirming that the chemical composition of Uncaria rhynchophylla differed significantly before and after fermentation. Based on the retention time, quasi-molecular ion peaks and tandem mass spectrometry information of the compounds, combined with reference standards and literature reports, a total of 64 chemical constituents were identified. In summary, fermentation with Ganoderma lucidum can significantly increase the contents of the main alkaloids in Uncaria rhynchophylla and modify its chemical composition, providing a scientific basis for the targeted processing and activity enhancement of Uncaria rhynchophylla.
  • Paper
    CAO Xiu, ZHANG Lei, LI Huiting, MA Yini, SHI Tianlu
    Abstract ( )   Knowledge map   Save
    An ultra-high performance liquid chromatography coupled with Q-Exactive Orbitrap high-resolution mass spectrometry (UPLC-Q-Exactive Orbitrap HRMS) method was established for the determination of xanthatin concentration in rat plasma. The rat plasma was firstly admistrated with a mixture of chloroform and ethyl acetate(2 ∶ 1) for protein precipitation. The UPLC-Q-Exactive Orbitrap HRMS method used a Shim-pack GIST C18 column(2.1 mm× 50 mm, 2 μm)to separate the plasma sample. The mobile phase consisted of water containing 0.1% of formic acid and 0.1% of ammonium formate and methanol in gradient elution mode, at a flow rate of 0.3 mL/min. The column temperature was 40 ℃ and the injection volume was 10 μL. The analysis was conducted using an electrospray ionization source in positive ion mode with full-scan and selected ion monitoring. The calibration curve showed good linearity over the concentration range of 1 - 1 000 ng/mL, and the LOQ was 1 ng/mL. After intravenous administration of 15.0 mg/kg xanthatin via the rat tail vein, the drug plasma concentration was measured at different time points. The pharmacokinetic parameters were calculated by Phoenix WinNonlin 8.1. The results showed that the t1/2 was (69.89±15.19)min, the Vd was (31.05±16.32)L, and the AUC0 → ∞ was (4.40±2.30)mg·min·mL–1. This method is sensitive, rapid, simple, and suitable for the determination of xanthatin in rat plasma and for pharmacokinetic studies.
  • Paper
    ZHANG Xue, ZHANG Ye
    Abstract ( )   Knowledge map   Save
    This study established an in vitro dissolution test method for clotrimazole(1) vaginal tablets based on the open-loop mode of a flow-through cell method. The dissolution conditions were optimized and the method was applied to the dissolution determination of 1 vaginal tablets from different sources. The optimized dissolution conditions were as follows: a 22.6 mm tablet cell, a combination of 1.5 and 0.7 μm glass fiber filters, citrate-dipotassium hydrogen phosphate buffer (pH 4.0) containing 0.15% SDS as the dissolution medium, a flow rate of 8 mL/min, a temperature of 37℃ , and approximately 3.0 g of glass beads. Under these conditions, the cumulative dissolution of 1 vaginal tablets exceeded 85% within 8 h. This method was used to evaluate the similarity of dissolution profiles between the locally manufactured and the reference products, and the results showed that their dissolution curves were comparable. The dissolution test method established in this study exhibited good reproducibility, could effectively distinguish products manufactured by different processes, and featured a high degree of standardization and automation, thus providing a reliable means for the quality control of 1 vaginal tablets.
  • Paper
    QI Mingyan, ZHOU Pan, SUN Chunyan, WANG Ruwei
    Abstract ( )   Knowledge map   Save
    A UPLC-MS/MS method was established for the simultaneous determination of two genotoxic impurities, 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylil acid(2) and 4-(4-amino-3-fluorophenoxy)-N-(2-fluoro- 4-hydroxyphenyl)picolinamide(3), in regorafenib(1) bulk drug. The analysis was performed on a Poroshell 120 EC-C18 column(3.0 mm×100 mm, 1.9 μm) with gradient elution using 0.5% formic acid aqueous solution and acetonitrile at a flow rate of 0.60 mL/min, a column temperature of 30 ℃ . A mass spectrometric detector equipped with an electrospray ionization source operating in positive ion mode was adopted, and the analytes 2 and 3 were quantified using multiple reaction monitoring. The results showed that impurities 2 and 3 exhibited good linearity over the mass concentration ranges of 0.92 - 110.70 and 0.93 - 112.19 ng/mL, respectively. The LODs were 0.18 and 0.19 ng/mL for 2 and 3, and the average spiked recoveries at levels of 10% , 50% , 100% and 200% were all within acceptable ranges. This method was simple, rapid and accurate, and could be applied to the quality control of genotoxic impurities in regorafenib(1) bulk drug.
  • Paper
    WANG Ke , SUN Long , CHEN Qiuya , XIAO Zhichao, WANG Ruwei
    Abstract ( )   Knowledge map   Save
    A turbidimetric method was developed for evaluating the creaming stability of lipid emulsion injections. After the etomidate medium and long chain fat emulsion injection was stored for 5, 15, and 30 d, the mean percentage differences in turbidity between the upper and lower layers of the samples were (8.9±0.1)% , (21.2±0.4)% , and (49.5±0.4)% , respectively(n=3). After storage for 30 d, the turbidity of the upper and lower layers showed trends consistent with those of drug content and particle size distribution. The method was further applied to analyze propofol medium and long chain fat emulsion injection and clevidipine injectable emulsion samples from different manufacturers after storage for 5 d. The results showed that stratiffcation of emulsion injection after storage is a common phenomenon. Compared with the static observation method, centrifugation, and testing by stability analyzer, the turbidimetric method established in this study features shorter test duration and easily accessible instruments. It can characterize the stratification changes of samples under routine storage conditions, and can serve as a reference for the research on stratiffcation stability during development, manufacturing and clinical application of medium and long chain fat emulsions.
  • Paper
    LU Ying, # , SONG Minghui # , HU Yaying , ZHANG Yanfeng , ZHANG Ping
    Abstract ( )   Knowledge map   Save
    This study collected settled bacteria from areas of different cleanliness levels in the cleanroom used for pharmaceutical microbial limit testing, along with surface microorganisms from equipment and personnel. After isolation and purification, matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF MS) and targeted nucleic acid sequencing(16S rRNA gene sequencing for bacteria and internal transcribed spacer sequencing for fungi) were comprehensively applied for strain identification. This approach successfully established an environmental microbial library containing strain information and viable cultures. A total of 212 microbial strains were identiffed, covering 39 genera and 74 species, among which Staphylococcus(41.51% ) and Micrococcus(13.21% ) were the dominant bacteria, while Penicillium(5.66% ) and Aspergillus(3.77% ) were the dominant fungi. This study further established a hierarchical identification strategy comprising initial screening by MALDI-TOF MS followed by verification through nucleic acid sequencing, effectively balancing detection efffciency and identiffcation accuracy. The establishment of this database can provide support for real-time monitoring of microbial communities in the cleanroom, precise prevention and control of contamination risks, and assessment of disinfection effects, thereby ensuring the reliability of microbial testing results for drugs.
  • Clean Environment Monitoring and Contamination Control Strategy for · Sterile Pharmaceuticals
  • Clean Environment Monitoring and Contamination Control Strategy for · Sterile Pharmaceuticals
    LI Yang , GAO Dejin , TAO Bo , XU Hang , XIE Langui , JIN Ying
    Abstract ( )   Knowledge map   Save
  • Clean Environment Monitoring and Contamination Control Strategy for · Sterile Pharmaceuticals
    WANG Jie , XIN Yun , WEI Jiaming , ZHANG Chuang
    Abstract ( )   Knowledge map   Save
  • Clean Environment Monitoring and Contamination Control Strategy for · Sterile Pharmaceuticals
    ZHAO Yanjun, AI Lun, XIE Langui, TIAN Lin, WU Hui, ZHAO Xia
    Abstract ( )   Knowledge map   Save
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    HU Xiaojuan , ZHAN Jinbao , QIAN Shengwen , ZHANG Weiwei , WANG Lixin
    Abstract ( )   Knowledge map   Save
  • Pharmaceutical Management & Information
    QI Yuying, LIU Juan, TANG Ling, HENG Mingli, PAN Pengyu, HUANG Fanghua, GENG Ying
    Abstract ( )   Knowledge map   Save