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
    ZHAO Lili, ZHU Yuqiang, WANG Hongtao, ZHANG Guimin , LIU Zhong
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    Biopharmaceuticals, especially therapeutic monoclonal antibodies(mAbs), are mainly produced in mammalian cell culture systems. Glycosylation is a critical quality attribute of mAbs, which has a significant impact on their biological activity, pharmacokinetics, half-life, and immunogenicity. Therefore, in order to better control the quality of glycosylation modification, the glycosylation process of mAbs must be regulated and monitored throughout the culture process of mammalian cells. This review focuses on the engineering of mammalian cells, optimization of cell culture processes and culture media, glycosylation regulators, mathematical models and omics technologies. And it introduces the technological progress achieved in the regulation of glycosylation modification of monoclonal antibodies during mammalian cell culture.
  • Perspectives & Review
    TENG Jianhao, LIU Qingxin, LIU Tao, ZHAO Jian
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    Complex injectables is a hotspot in global pharmaceutical research and development, but its traditional preparation technology has many problems. Microfluidics is a technology that uses microchannels to precisely manipulate fluids with excellent controllability and reproducibility, easy process scale-up, and obvious advantages over traditional technologies. The article provides a review on the introduction of microfluidic technology and its applications to laboratory research and industrial manufacture, with a view to providing references for the further development and application of this technology.
  • Perspectives & Review
    FAN Hanqiu# , CHEN Dongli# , LIU Xiaojing, QIN Guohong
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    Ultraviolet-visible absorption spectrometry is a rapid and simple method for quantifying protein concentration post-purification. It is widely utilized in the development of protein drugs. Based on extensive research on ultraviolet absorption of proteins and amino acids, a diverse range of detection methods has been developed to address different phases of research and sample types. Various factors can interfere with the accuracy of measurements, such as the state of the protein affecting its A280 value, protein aggregation leading to an artificially high A280 reading, and protein degradation or unfolding resulting in a lower apparent A280 value. By summarizing the ultraviolet absorption measurement methods for different protein contents, a more applicable method can be found for certain products. In addition, by discussing the impact of protein state on UV absorption, some corresponding simple and easy-to-operate methods and measures for judgment could be proposed.
  • Paper
  • Paper
    ZHANG Kedan , LIU Dongliang, JIN Chen
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    This paper reported a new synthetic method of camptothecin derivative T030(1). The starting material, ortho-nitroacetophenone(3), was condensed with N,N-dimethylformamide dimethyl acetal(DMF-DMA) to obtain(E)-3-(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one(4). Compound 4 underwent substitution and reduction, followed by salt formation to obtain 3-(isopropylamino)-1-(2-nitrophenyl)propan-1-one hydrochloride(6). Compound 6 underwent sulfonylation and catalytic hydrogenation to obtain N-[3-(2-aminophenyl)-3-oxopropyl]-Nisopropylmethanesulfonamide(8). Finally, compound 8 underwent Friedlander condensation with the CDE ring to obtain the target compound 1. The total yield was 39% with the purity of 99.7% . The new synthetic method involved six steps and might reduce the production costs, which was suitable for process research.
  • Paper
    HUANG Chun, TANG Chunlei
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    The synthetic process of cabazitaxel(1) was improved in this report. Starting from 10-deacetylbaccatin Ⅲ (2), 7,10-bis(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin Ⅲ (3) was obtained through hydroxyl protection. Under the condition of N,N'-dicyclohexyl carbodiimide and 4-dimethylaminopyridine, 3 was condensed with docetaxel sidechain to obtain 7,10-bis(2,2,2-trichloroethoxycarbonyl)-13-sidechain-10-deacetylbaccatin Ⅲ (5), then 5 was deprotected under zinc powder/acetic acid conditions to obtain 13-sidechain-10-deacetylbaccatin Ⅲ (6). Compound 6 was reacted with trimethyloxonium tetrafluoroborate to obtain 7,10-dimethoxy-13-sidechain-10-deacetylbaccatin Ⅲ (7), which was then subjected to ring-opening in hydrochloric acid/methanol solution to generate the target product 1 in a total yield of 45.7% (based on 2) with HPLC purity over than 99.5% . In this process, efficient dimethylation of 7-/10-hydroxyl was achieved with mild reaction conditions. Besides, a new crystallization process improved purification efficiency with high product purity and yield. The optimized process features simple operations, high safety, and cost-effective materials, making it suitable for industrial production.
  • Paper
    GAO Long , LU Shengxin , LI Shuwei , WU Ye , ZHANG Weidong,
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    Tachyplesin Ⅰ (1) is a β-hairpin peptide containing two disulfide bonds, known for its significant antineoplastic and antibacterial activities. Herein a novel synthetic method of 1 was reported. Solid-phase peptide synthesis(SPPS) was employed to assemble the linear peptide precursor 3 of 1, with Fmoc-amino acids as raw materials and Rink Amide resin as the support. The cleaved 3 was subjected to sequential oxidative formation of the two disulfide bonds in solution by sequentially adding two different doses of iodine solution to give the crude product, which was purified by preparative HPLC to get the target product 1 with greater than 95% purity. The innovation of this method lies in the “one-pot” sequential oxidative formation of the two disulfide bonds. Compared with the reported process, this new process significantly increased the overall yield of 1 from 16% to 36% (based on 3), and greatly shortened the whole reaction time from 9.5 d to 4.5 d, which demonstrated the excellent potential for industrial production.
  • Paper
    LIANG Rui, WU Ye, LUAN Xin
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    Pine needle peptide(1) is a natural bioactive peptide with antineoplastic potential. To enhance its structural stability and bioactivity, two stapled 1 derivatives were successfully designed and synthesized based on the secondary structural characteristics of 1, utilizing computer aided design and all-hydrocarbon stapling strategy. These derivatives were characterized by HPLC and MS analyses. The results of in vitro antiproliferative assays demonstrated that both derivatives exhibited significantly enhanced inhibitory effects against melanoma cells compared with 1(IC50>32 μmol/L), with the derivative 1-3 showing the highest potency(IC50 value 6.28 μmol/L for B16F10 cells and 7.58 μmol/L for A375 cells). Structure-activity relationship analysis revealed that the derivative 1-3 displayed a 31.14% increase in α-helix content and a 81-fold improved stability in chymotrypsin solution compared with 1 while maintaining favorable biosafety. These results indicated that the stapled derivative 1-3 represented a promising lead compound for melanoma treatment, providing a novel strategy for structural optimization of 1.
  • Paper
    ZHUANG Yuanbei, YE Yongjing , YANG Yueqi , WEI Aihong , ZHANG Shengyuan,
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    Currently, the methods used for evaluating tyrosinase inhibitory activity in tyrosinase inhibitor screening are not suitable for the screening of traditional Chinese medicinal plants. Therefore, this study established a novel in vitro screening method for tyrosinase inhibitors based on HPLC. With the substrate levodopa content as the detection indicator, the chromatographic and reaction conditions of this method were optimized. The optimized chromatographic conditions were as follows: XBridge Peptide C18 column(4.6 mm×250 mm, 5 μm), 280 nm of detection wavelength, mobile phase consisting of 0.1% formic acid-acetonitrile(in a volume ratio of 95 ∶ 5) under isocratic elution, 20 μL of injection volume, 30 ℃ of column temperature, and 0.8 mL/min of flow rate. The optimized enzyme reaction system consisted of 300 μL of PBS(pH 6.8), 150 μL of test sample, 300 μL of 300 IU/mL tyrosinase solution. The system was mixed and incubated at 37 ℃ for 10 min, followed by the addition of 150 μL of 10 mmol/L levodopa sdution. After that, the above system was mixed and reacted at 37 ℃ for 10 min again, and then terminated with 4.2 mL of 0.4 mol/L hydrochloric acid. The tyrosinase inhibitory activities of the positive controls(vitamin C and kojic acid) were detected by both this method and the microplate reader method, and the results showed no significant difference in IC50. When applied to screen nine medicinal plant extracts, the HPLC method detected tyrosinase inhibitory activity in all extracts, whereas the microplate reader method only detected activity in four extracts, with higher IC50 values compared with the HPLC results. These results indicated that the screening method based on HPLC outperformed the traditional microplate reader method in terms of specificity, accuracy, and precision, providing a reliable analytical approach for screening natural tyrosinase inhibitors, particularly suitable for complex matrix samples.
  • Paper
    ZHENG Huazhang, XIE Jin, ZENG Lijuan, HUANG Tao, ZHU Wentao
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    This study aimed to optimize the functional scoring design of self-developed trazodone hydrochloride sustained-release tablets by analyzing the characteristics of the reference listed drug(RLD). Firstly, the weight differences, content uniformity, mass loss, and in vitro release profiles of the divided segments of the RLD were systematically investigated. The results showed that the release profile of the middle 1/3 segment of the RLD was dissimilar to that of the intact tablet(f2<50). Subsequently, based on these findings, this study optimized the score line parameters of the selfdeveloped preparation by adjusting the inter-score distance from 4.00 mm(RLD) to 3.68 mm. After this improvement, the content of the middle 1/3 segment of the self-developed tablets became similar to that of the edge 1/3 segment, and its release profile was similar to that of the intact tablet(f2>50). This enhanced design not only ensured the convenience of the dividing operation but also allowed patients to maintain the same dividing method as with the RLD, providing valuable practical references for the optimization of functional score lines.
  • Paper
    YAN Wenqi#, ZHANG Shengyu#, YAN Shen, LU Kangwei, WU Duo
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    The transport stability of a carrier-free dry powder for inhalation(CfDPI) produced by spray freeze drying was investigated. Ciprofloxacin hydrochloride was served as a model drug, and L-leucine was used as an excipient to prepare the precursor liquid. Two different atomizers(ultrasonic atomizer and two-fluid atomizer) and a self-designed micro-fluidic jet spray freezing tower(MfJSFT) with a freeze dryer were used to prepare two types of model microparticles, and their morphology, static geometric diameter, dynamic geometric diameter and in vitro deposition performance were compared. The simulated transport stability of the microparticles was also evaluated at various speeds(20, 40, 60 and 80 r/min) and time points(15, 30, 60, 180 and 360 min). The results showed that the model microparticles produced by the two-fluid atomizer had better in vitro deposition performance, and its simulated transport stability was also relatively high.
  • Paper
    ZHOU Jin , NIE Lanlan , CUI Mingjun , FU Kaicong , HU Xiao , HUANG Chunyue, HOU Aijun
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    A UPLC-QTOF-MS method was established to analyze the chemical constituents of Fufang Dengtaiye tablets. Based on the mass spectrometry data, reference substances, and literature reports, a total of 52 constituents were identified or speculated. The chemical material basis was composed of 12 alkaloids, 13 terpenoids, 14 flavonoids, 3 phenolic acids, and 10 other chemical constituents(e.g., stilbenes and organic acids). The phenol red-induced tracheal excretion mouse models, ammonia-induced mouse cough models, and histamine phosphate combined with acetylcholine chloride-induced guinea pigs asthma models were established to evaluate the expectorant, antitussive and anti-asthmatic effects of Fufang Dengtaiye tablets. The results showed that compared with the model group, the medium- and high-dosage(2 and 4 g/kg) group of Fufang Dengtaiye tablets could significantly increase the secretion of phenol red, prolong the cough incubation period, reduce the number of cough in two minutes of mice(P<0.05, P<0.01), and increase asthma incubation period of guinea pigs. This study elucidated the chemical constituents of Fufang Dengtaiye tablets and its expectorant, antitussive and antiasthmatic activities, which provided a experimental basis for its quality control and clinical application.
  • Paper
    LI Hongmei , ZHOU Hairuo , SU Rijia
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    In order to investigate the physical stability of the microspheres in microsphere specialized solvents during the suspension process, a method for evaluating the suspension effect of the microsphere specialized solvent was conducted based on the principle of multiple light scattering. The results showed that within 10 min of testing, the suspension effects of two microsphere specialized solvents on the same kind of microspheres could be distinguished. The Turbiscan backscattering curves of the suspension formed by the solvent with good suspension performance and microspheres did not change, indicating that no aggregation, precipitation, flocculation or emulsification occurred in the suspension. This study proposed a new research method for investigating the suspension effect(stability) of microsphere specialized solvents. Compared with the traditional methods, this method could more intuitively distinguish the suspension effect of microsphere specialized solvents, and it was simple and convenient to operate, making it of certain reference value in the development of microsphere formulations.
  • Paper
    LIU Jiajia , MAI Zidan , HAN Yuewen , LI Ying , HE Yongfu , ZHANG Fuli
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    Voclosporin is a novel calcineurin inhibitor that has been included in the third batch of the encouraged generic drug list. This study developed a separation and purification process for voclosporin based on macroporous resins, and optimized the type of macroporous resins and purification process parameters. The optimal conditions were as follows: using Resin No. 3, preparing voclosporin sample solution(0.1 g/mL) with 50% ethanol aqueous solution, maintaining an sampling flow rate of 20 mL/h, a loading volume of 30 mL, employing 50 % - 70 % ethanol as eluent, and utilizing the acetone-water mixture in a volume ratio of 3 ∶ 3 as crystallization solvent. This optimized process consistently yielded voclosporin with purity over 99.2% and purification recovery of 60% . These results demonstrated the high efficiency, stability, and reproducibility of the developed method, providing a viable and effective purification strategy for industrial production of voclosporin.
  • Paper
    YE Xiaoxia, #, ZHANG Fan#, WU Jingwen, ZHANG Ye, GAO Zhongban , LE Jian,
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    Characterization and immigration research on the leachables from the butyl rubber plugs of iohexol(1) injection was carried out by extractables research and accelerated immigration research with HPLC-UV and GC-MS technologies. By comparing the retention time in HPLC and GC chromatograms, UV spectrum and mass spectrum of the chromatographic peak with xylene(2) reference substance, the extractables 2 from butyl rubber plugs was characterized. The accelerated immigration research conformed that the unknown compound found in 1 injection was 2, which leached from the butyl rubber plugs. An HPLC method was established to detect the leaching amount of 2 in commercially available 1 injection, and the leaching degree of 2 was predicted by the accelerated immigration test. The results showed that after being placed upside down at 60 ℃ for 15 days, the leaching amount of 2 in 1 injection(specification: 20 mL) could reach 56 μg, which provided a reference for the study of the leachables of 1 injection.
  • Paper
    LI Chengzhi, LIU Xiaoshuai, MA Heng, ZHANG Xiaohan, ZHANG Jing
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    A polymerase chain reaction(PCR) method was established for four pathogenic bacteria(Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Salmonella) on non-sterile medical devices. Selecting common bacterial strains in the microbial limit laboratory as control bacteria for each other, the identification of four pathogenic bacteria was completed in one experiment by designing specific sequence primers for different strains. The applicability of this method was determined by evaluating its specificity and minimum detection limit, and compared it with time-offlight mass spectrometry and traditional identification methods. This method can determine the presence of four pathogenic bacteria in a sample based on whether the target gene has been amplified and the melting temperature value of the amplified product, which provide a rapid detection method for pathogenic bacteria in production and testing.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    GUO Wei, LIANG Yi
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  • Pharmaceutical Management & Information
    LI Xinyue, CUI Jia , LI Huiqi, JIANG Rong,
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  • Pharmaceutical Management & Information
    LING Xing , FAN Bingbing , GUO Wen,
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