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
    LIANG Chaochao, XIAN Ruiqing, SHI Feng, WANG Weijian, GONG Liping
    Abstract ( )   Knowledge map   Save
    Host cell proteins(HCPs) are critical impurities that are difficult to remove completely during biopharmaceutical production. Their residual presence may compromise product safety, efficacy, and stability, while potentially inducing immune responses. Characterized by low abundance, HCPs demand exceptionally high detection sensitivity. Therefore, the precise quantification and rigorous control of HCPs are of paramount importance in biopharmaceutical quality assurance. This paper systematically reviews the current global regulatory status of HCPs, and analyzes the principles, application status, advantages and disadvantages of existing quality control technologies(including traditional detection methods and emerging technologies), providing a more comprehensive framework for HCPs control. Furthermore, it systematically addresses the major challenges encountered in HCPs detection, aiming to establish a theoretical foundation for future research and development of related technologies, as well as for drug regulation.
  • Perspectives & Review
    DU Xi , , LAN Fang, ZHAO Xiaoxiao , DONG Yanli , LI Zhimin,
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    Heparin is widely used clinically as an anticoagulant drug, with its main source being porcine intestinal mucosa. Due to the impacts of the heparin sodium incident and the African swine fever incident, a supply shortage of porcinederived heparin was once caused. Therefore, the FDA encourages manufacturers to increase the supply of heparin from other sources to mitigate the risk associated with relying on a single source. This paper focuses on bovine-derived heparin, analyzing differences from porcine-derived heparin in relative molecular weight, anticoagulant activity, and chemical structure(including monosaccharides, disaccharides, and tetrasaccharides). And the research progress on the preparation of low molecular weight heparin(LMWH) from bovine-derived heparin is also reviewed. Unfractionated bovine heparin can be directly applied to clinical practice, but due to its lower anticoagulant activity, it requires approximately twice the dose of porcine heparin to achieve the same effect. There are signiffcant differences in structure and anticoagulant activity between bovine LMWH and porcine LMWH. Thus, if bovine LMWH is to be developed as a drug, it may need to be registered in accordance with the standards for new drugs.
  • Paper
  • Paper
    LONG Xianwei, LI Chunni, LI Xiaocui, CHEN Shuo, LU Qun
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    Using 2-chlorotrityl chloride resin as the carrier, five natural amino acids(L-valine, L-tyrosine, L-glutamine, L-alanine, and L-alanine), one special amino acid(D-allo-threonine), and one chiral fatty side chain(5- hydroxytetradecanoic acid) as raw materials, the linear peptide was synthesized by Fmoc solid-phase synthesis with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate/1-hydroxybenzotriazole as the condensation system. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/4-dimethylaminopyridine was used as the cyclization system, followed by deprotection with triffuoroacetic acid and rapid column chromatographic puriffcation to obtain the anti-tuberculosis drug, cordycommunin(1). The structure of 1 was conffrmed by 1 H NMR, 13 C NMR and high resolution mass spectrometry(HRMS). After separation and puriffcation, (R)-1[yield of 28.5 % (calculated based on L-valine) with the purity of 98.2%] and (S)-1[yield of 23.7%(calculated based on L-valine) with the purity of 97.5%] were obtained. This method is simple and suitable for the synthesis of this series of cyclic peptides, providing a certain reference for the further research and application of highly anti-tuberculosis active cyclic peptides.
  • Paper
    WANG Haibo , JIN Hui , JIN Shiyuan , XIAO Yang , KUANG Hongfu
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    An improved synthetic process of tofacitinib citrate(1) was reported. 4-Chloro-7H-pyrrolo[2,3-d]- pyrimidine(2) was protected with p-toluenesulfonyl, followed by substitution with (3R,4R)-N,4-dimethyl-1-benzyl3-piperidinamine dihydrochloride, then deprotection, hydrogenation and salification to give N-methyl-N-[(3R,4R)-4- methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride(7). Subsequently, the condensation of 7 with cyanoacetic acid N-hydroxysuccinimide(9, obtained by esteriffcation of cyanacetic acid), followed by the saltiffcation with citraric acid to obtain tofacitinib citrate 1, with an overall yield of 47.7% (based on 2). The ffnal product 1 showed a purity of over 99.9% , without signiffcation impurities. The improved process shortened heterogeneous reaction times, moderated deprotection conditions, and improved quality of the key intermediates 7 and 9. These modiffcations resulted in an elevated overall yield and delivered high-purity product, which is suitable for industrial-scale production.
  • Paper
    LU Xinyu, , ZHOU Yang, , XIA Zhaoping, , WANG Guan,
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    The synthetic process of asciminib hydrochloride, a drug for treating chronic myeloid leukemia, was optimized. Methyl 5-bromo-6-chloronicotinate(2) was used as the starting material and condensed with (R)-pyrrolidin3-ol(3) to generate methyl (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl) nicotinate(4). Compound 4 was subjected to Suzuki coupling reaction with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester to produce methyl 6-[(R)-3-hydroxypyrrolidin-1-yl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl] nicotinate(6). Compound 6 was coupled with 4-(chlorodifluoromethoxy) aniline to produce (R)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-N- [4-(chlorodiffuoromethoxy)phenyl]-6-(3-hydroxypyrrolidin-1-yl) nicotinamide(8). Then compound 8 was deprotected to obtain free base of asciminib(1), while 1 was ffnally saliffed to obtain asciminib hydrochloride. Overall yield was 39.27% (based on 2) with purity of 99.89% and ee value of 99.88% . The optimized synthesis process of asciminib hydrochloride has mild conditions, controllable quality, and simple operation, which is suitable for industrial production.
  • Paper
    CHEN Hui # , ZHANG Fen# , WANG Jianan, WANG Qingfang, CHU Wanglong
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    The study systematically compared the performance differences between domestic and imported culture media in the cultivation of mesenchymal stem cells(MSCs). Three distinct culture systems were employed to culture MSCs, and key indicators including cell morphology, cell surface markers, differentiation potential, immunomodulatory capacity, karyotype analysis, cellular senescence, and soft agar colony formation were comprehensively evaluated to assess the safety, efffcacy, and cell yield of MSCs in different culture systems. The results demonstrated that MSCs cultured in all three systems exhibited the typical spindle-shaped morphology, with cell surface markers conforming to international stem cell standards, and possessed osteogenic, adipogenic, and chondrogenic differentiation potential. The karyotype was normal, and soft agar colony formation assays conffrmed the absence of tumorigenic risk. The results indicated that there was no signiffcant difference between domestic and imported culture media. However, the domestic culture medium demonstrated certain advantages in some aspects: it had stronger cell proliferation ability and higher passage stability. In terms of immunomodulatory function, the domestic medium exhibited stronger inhibitory effects on T lymphocyte suppression and TNF-α. Cellular senescence assays showed a lower senescence rate in the domestic culture system. Additionally, when the domestic medium was used as a cryopreservation solution component, cells demonstrated faster recovery of viability postthawing. This study provides scientiffc evidence to advance the domestic production of culture media in China, thereby enhancing the country’s independent innovation capabilities and international competitiveness in the field of stem cell research and application.
  • Paper
    YANG Chuanji , ZHU Chunmei , YU Caixia , ZHANG Fuli , WU Haoxiang
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    Dexmethylphenidate hydrochloride resin complexes(dMPH-DRC) and their sustained-release microcapsules(dMPH-CM) were prepared using ion exchange resin and immersion coating technology. The preparation processes of dMPH-DRC and dMPH-CM were optimized by single factor tests. The results showed that Amberlite ® IRP69 (drug-to-resin mass ratio of 1 ∶ 1.5) exhibited the good drug loading performance. The prepared dMPH-DRC could achieve a drug loading capacity of (37.1±0.4) % and a drug utilization rate of (87.1±0.2) % . X-ray powder diffraction, polarizing light microscopy and differential scanning calorimetry analyses revealed that the drug-resin interaction was not merely physical adsorption. The sustained-release effect of dMPH-CM was primarily inffuenced by the coating material type and concentration, drug loading of the drug resin complex and preparation temperature. The optimized sustained-release microcapsules had a drug content of (36.75±0.34) % , an average particle size of (105±5)μm, a continuous and dense coating membrane, and a sustained-release duration of 12 hours. This simple preparation method provides a new approach for developing dexmethylphenidate sustained-release formulations.
  • Paper
    HU Yang , ZONG Zheng , CHEN Luning , LI Wenlan, , YANG Bo, DING Zhenduo
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    The stability of Semen Cuscutae-Fructus Lycii(SC-FL) couplet medicines in artiffcial gastric juice and artiffcial intestinal ffuid was investigated and its metabolism process in vitro was analyzed. A BEH C18 column(2.1 mm× 50 mm, 1.7 μm) was used with acetonitrile-0.1% formic acid water as mobile phase in a gradient elution mode. SC-FL couplet medicines were co-incubated with in vitro artiffcial gastric juice, artiffcial intestinal ffuid and liver homogenate, followed by qualitative analysis via UPLC-Q-TOF-MS. The results showed that the stability of SC-FL couplet medicines was good in artiffcial gastric juice but poor in artiffcial intestinal ffuid. A total of 124 compounds were characterized and identiffed in the three types of samples, including 90 prototypical components, 23 metabolites, and 11 components that were both prototypical components and metabolites. The main components of SC-FL couplet medicines underwent phase Ⅰ metabolic reactions, such as hydrolysis, reductive hydrogenation, and dehydroxylation, as well as phase Ⅱ metabolic reactions, such as methylation, sulfation, and glucuronidation. The possible metabolic pathways were also speculated. This experiment can lay a foundation for further revealing the pharmacodynamic material basis and in vivo action process of SCFL couplet medicines in the treatment of premature ovarian insufffciency.
  • Paper
    LUO Jiang , JIANG Yanping , WANG Jian , LI Huiyi , WU Wenzhe
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    In order to formulate the pharmacopoeia standard of ambroxol hydrochloride inhalation solution, the key indicators of this product, including related substances, delivery characteristics, pH value, and osmolarity, were studied by referring to standards of four domestic enterprises. The methods for quality standard were optimized and veriffed according to the test results. The general methods and limits for accurately determining relevant substances, delivery characteristics, pH value, and osmolarity were ultimately established. This method was used to test and verify products from various manufacturers, and all results showed compliance. The newly established standards shall not be lower than the requirements of Pharmacopoeia of the People’s Republic of China for inhalation solutions and ambroxol hydrochloride injection, and can be used for quality control of ambroxol hydrochloride inhalation solutions from various manufacturers.
  • Paper
    ZHANG Runli , , WANG Ganggang , REN Fengjiao, , WANG Sijin , MA Shihong
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    Pharmaceutical water samples from various sources were collected, and 18 strains of microorganisms were isolated and purified from the samples. These 18 strains were identified by 16S rDNA sequencing, and their growth curves were analyzed. The results showed that most of the strains from pharmaceutical water system(except Cellulosimicrobium) grew well in R2A medium with a short lag phase, and a specialized microbial bank was successfully constructed. For the 18 strains in this specialized microbial bank, the minimum detection concentration range of the ampliffed ATP bioluminescence-based rapid detection technology was 10 - 1.0×104 cfu/mL, while for common Gram-negative bacteria in water systems, the range was 10 - 1.0×103 cfu/mL. After pre-culture based on the characteristics of the strains, most test strains showed “positive” or “overload” results under the corresponding pre-culture system and time conditions.
  • Paper
    WU Jianfu# , KE Hui # , PAN Xinghua , LUO Zhiyong , LIU Muyun
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    This study developed proficiency testing samples for microbiological safety assessments of mesenchymal stem cells(MSCs), focusing on bacterial endotoxin detection, sterility testing, and mycoplasma detection, and evaluated the effectiveness of inter-laboratory comparisons. Non-interfering raw materials were screened and processed, followed by homogeneity and stability validation. These samples were distributed to nine testing laboratories nationwide. Stability experiments revealed that under 2 - 8 ℃ storage, bacterial endotoxin- and mycoplasma-positive samples maintained detectable validity for 7 d, while sterility-positive samples remained stable for 21 d. At 35 ℃ , sterility samples retained a 21-day detection window, and mycoplasma samples stored at –20 ℃ showed stability for 21 days. Inter-laboratory comparison results indicated variability in qualification rates across testing items: bacterial endotoxin and mycoplasma detection achieved 100% compliance, whereas sterility testing showed deviations with a 94.4% qualiffcation rate. In summary, the constructed validation samples effectively supported laboratory competency evaluation in microbiological safety testing, and provide a standardized technical framework for quality control in stem cell applications.
  • Paper
    LING Ming, JIANG Yanjie, QIU Yinger, YING Ke, FU Zhengyang
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    The study aims to develop a rapid detection method for environmental microorganisms in pharmaceutical production by gene membrane chip technology to improve the efficiency of drug production quality supervision. Seven typical microorganisms of pharmaceutical production environment, including Bacillus cereus, Micrococcus luteus, Staphylococcus epidermidis, Staphylococcus warneri, Staphylococcus aureus, Escherichia coli and Bacillus subtilis were selected. Speciffc primers and probes were designed for each microorganism, and synchronous nucleic acid detection and result analysis were achieved by combining gene membrane chip with multiplex PCR technology. The method exhibits excellent specificity and stability, with a detection sensitivity of 1.0×105 copies/mL, and is suitable for routine monitoring of common microorganisms in the pharmaceutical production environment. The established sevenin-one inspection technology has advantages of simple operation, low cost and high automation, which can not only provide real-time monitoring for quality safety of drug production process, but also offer efffcient technical support for government regulatory departments.
  • Paper
    WANG Xiaolong , SHI Min , LIAN Rongwei , DONG Zhikui , WANG Ruwei
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    To identify the structure and trace the source of an unknown impurity with a content slightly greater than 0.05% in low-density polyethylene packaged drugs. Using levosalbuterol hydrochloride nebuliser solution as the model drug, the unknown target impurity was separated and puriffed via preparative HPLC, and its structure was conffrmed by high-resolution mass spectrometry, nuclear magnetic resonance, infrared spectroscopy. The results showed that the unknown impurity was phenylmethanol, which was originated from glue components in the product label rather than a degradation product of the drug itself. It could be classiffed as a general impurity with no new high-toxicity structure. This study provides a reference for the identiffcation of unknown impurities in low-density polyethylene packaged drugs and quality control of similar products.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    MA Junwei, LIU Yonghui, REN Lianjie
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  • Pharmaceutical Management & Information
    ZHANG Baomei, LUO Junyong, WEI Tingting, TIAN Jie
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  • Pharmaceutical Management & Information
    YUAN Xiao, LIANG Yi
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  • Pharmaceutical Management & Information
    ZHANG Haonan, GENG Gexia, LI Liping, WANG Yaoyao, LI Xiaopeng
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  • Pharmaceutical Management & Information
    ZHAO Benjie
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