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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2024 Volume 55 Issue 1   Published: 10 January 2024
  
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    Perspectives & Review
  • Perspectives & Review
    ZHOU Wei, LIN Kuaile, ZHOU Weicheng
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    The U.S. FDA approved 53 new drugs in 2023, including 31 chemical small molecules, 21 biological products and 1 botanical drug. According to the prescription information for professionals and the related literature as well as patent information, this review describes the descriptions, indications, mechanism of action, dosage forms and strengths, adverse reactions, and one synthetic route of the chemical small molecules, and brief information about biological and botanical products.
  • Perspectives & Review
    LI Conghu, FENG Mengmeng, YANG Niuniu, WANG Lu, CHENG Xu
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    Hypoxia, a critical environmental characteristic of advanced solid tumors, not only stimulates the proliferation and metastasis of cancer cells, but also becomes one of the main obstacles in the process of tumor treatment. Consequently, manipulating hypoxia within tumor microenvironment is deemed an effective approach to enhance the success rate of cancer therapy. With the progressions in nanotechnology and material science, nanobiomaterial-assisted oxygen therapy has garnered increasing interest in the field of cancer treatment. This review mainly summarizes three strategies based on nanobiomaterials to alleviate tumor hypoxia according to the oxygen supplementation methods at the tumor sites, namely, the remodeling of the tumor microenvironment(endogenous oxygen supplementation), targeted delivery of nanoscaled oxygen carriers(exogenous oxygen transport), and in situ oxygen catalytic regeneration. It is hoped that this review can provide new ideas for researchers in the study of tumor hypoxia relief.
  • Perspectives & Review
    XIE Liqi, BI Baoshuai, HUANG Yi
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    Particulate matter can indicate potential quality problems and immunogenic risks of injections, so as to be a necessary indicator for injection evaluation in the quality management. Microffow digital imaging(MDI) is a new technology for detecting particulate matter. Compared with the light obscuration method, which is the “gold standard” for particulate matter analysis, MDI can not only provide the detailed information on the size and quantity of particles, but also obtain the type and shape characteristics through high-resolution images. In addition, MDI requires a small sample volume and is especially suitable for the quality analysis of protein drug injections. From prospects of the formation causes of particulate matter and the technical requirements of drug regulatory agencies and pharmacopoeias in various countries for the quality control of particulate matter in injections, this paper reviews the application progress of MDI technology in formulation development and process research of protein drugs, in order to ensure the safety and efffcacy of protein drug formulations.
  • Paper
  • Paper
    CHEN Xiangwei, SU Zhuanzhuan, HUANG Wenzhan, GAN Chunli
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    Travoprost(13) was obtained with benzoyl Corey lactone(1) as the starting material in a ten-step synthetic route, which consisted of selective oxidation in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy(TEMPO)/ sodium hypochlorite, Wittig-Hornor reaction, chiral reduction, debenzoylation, triethylchlorosilane protection of hydroxyl, lactone reduction, Wittig reaction, ester formation, hydroxyl protection and deprotection, with the total yield of 15.3%. The structure of the ffnal product was conffrmed by 1 H NMR, 13 C NMR and MS. In this paper, the separation and puriffcation processes of various intermediates were simpliffed by pulping with ethanol/n-hexane, recrystallization by methyl tert-butyl ether and separation by silica gel column chromatography. By the way, the synthetic route had the advantages of availability of raw materials, and mild and controllable reaction conditions, which could provide some references for the industrial production of travoprost generic drugs.
  • Paper
    HAN Ying’ang , TENG Dawei , LONG Zhongzhu, CAI Chang , CAI Shuihong
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    Starting with ethyl nicotinate(4) and 3-chlorobenzyl cyanide(5) as raw materials, through the Claisen condensation, acid hydrolysis and decarboxylation, 2-(3-chlorophenyl)-1-(pyridin-3-yl)-1-ethanone(6) was obtained. Compound 3-(3-chlorophenethyl)pyridine(7) was generated by Huang Minglong reduction with hydrazine hydrate. After sodium tungstate catalysis and subsequent oxidation with hydrogen peroxide, followed by the ReissertHenze pyridine cyanation reaction, 3-(3-chlorophenethyl)-2-cyanopyridine(8) was obtained. After hydrolysis and ring closure, 8-chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cyclohept-5-one(3) was obtained. Then compound 3 reacted with 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone(12) by McMurry coupling reaction and salted with fumaric acid, resulting in rupatadine fumarate(1). The overall yield was 28.0%(based on 4), with a purity of 99.7%. This synthetic route avoids the use of Grignard reagents. Additionally, the cyclization employs a “one-pot” method, providing convenient operation and suitability for industrial production.
  • Paper
    ZHU Jun , SUN Zhen , ZHANG Yaohua , YU Jie , ZHAO Jianhong
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    An improved synthetic process of the intermediate of tofacitinib, 4-chloro-7H-pyrrolo[2,3-d]- pyrimidine(1), was described in this paper. Started from malononitrile, the desired product 1 was synthesized via α-alkylation with bromoacetaldehyde diethyl acetal(2), cyclization with thiourea, deprotection, cyclization, acidiffcation, removal of the thiol group, as well as Sandmeyer chlorination, with an overall yield of 49%(based on 2) and a purity of 99.10%. The improved process had three apparent advantages compared with previously reported procedures, including: ① direct precipitation of the potassium 4,6-diamino-5-(2,2-diethoxyethyl)pyrimidine-2-thiolate(4), from the reaction solvent ethanol as a salt with a high yield of 85%, overcoming the technical difffculties in purifying the thiol compound; ② preparation of the 4-amino-7H-pyrrolo[2,3-d]pyrimidine-2-thiol(5) via a one-pot sequential three-step reaction of deprotection, cyclization, and acidiffcation in the presence of hydrochloric acid, simplifying the process; ③ elimination toxic reagents such as phosphorus oxychloride, 2-methyl-3,3-dichloroacrylonitrile, and 2-chloroacetaldehyde, which ensured process safety and improved environmental friendliness, especially the elimination of phosphorus oxychloride. All the raw materials and reagents used in the improved syntheses are inexpensive and readily available, and the operation is simple with mild conditions and high yield, which is suitable for industrial production.
  • Paper
    ZHAO Lili , , ZHANG Xiaoli , , ZHAO Wenpeng , ZHU Zhongsong, , LIU Zhong
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    Agonistic CD40 antibodies hold great potentials in the treatment of malignant tumors, yet their efffcacy and safety remain to be fully established. This research identiffed and humanized two high-binding and highafffnity agonistic anti-CD40 monoclonal antibodies(31A2-2 and 42D11-8) via hybridoma technique, and evaluated their pharmacodynamics through the NPG mouse xenograft model. The results revealed that the modiffed antibodies maintained high binding afffnity after measurement, and demonstrated robust activation capacity in dendritic cell activation assays, thereby stimulated dendritic cells to release IL-12. Both antibodies exhibited signiffcant antitumor activities in NPG mice, with tumor growth inhibition rates reaching 86.83% and 87.95% respectively. This study provided data support for the development of agonistic CD40 drugs.
  • Paper
    ZHU Lin, ZHANG Weijie, ZHANG Yuxing, WU Fei, JIN Tuo
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    Polyvinyl alcohol(PVA)-based phase-transition microneedles can be utilized to load drugs through pores formed by swelling, and are highly promising for biomolecular drug delivery. However, due to the drug distribution at the root and center of drug-loaded microneedles prepared by the conventional premixing method, the diffusion distance during drug release is large and penetration through the hydrogel network matrix is difffcult, which limit the bioavailability of the drug. Therefore, the diffusion method was used for protein drug-loading and the mass ratio of PVA solution to excipient(sodium carboxymethylcellulose and dextran) solution was optimized to improve the drug loading, drug release rate, and epidermal permeability. The results showed that when the mass ratio of PVA solution to excipient solution was 3∶1 and the solid content was 17.8%, the microneedles had high swelling properties and strong mechanical properties, and could effectively deliver the drug to the dermis. Using insulin aspart as a model drug, compared with the traditional premixing method(the transdermal delivery rate was less than 25%), the transdermal delivery rate of drugloaded microneedles prepared by the diffusion method could reach 31.0% - 34.6%, and the in vitro release rate was up to 93%. The drug-loaded microneedles prepared by the diffusion method can improve the release rate and bioavailability of hydrophilic macromolecules, providing a new strategy for the development of transdermal drug delivery systems.
  • Paper
    CHEN Hao, LI Yingtao, CAI Yanqu, ZHANG Shangshi, LI Yuanxin
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    Wintergreen oil inclusion complexes with α-, β-, or γ-cyclodextrin(CD) were respectively prepared by the saturated aqueous solution method, then their corresponding creams were also prepared. The in vitro transdermal permeation and release behaviors of aforementioned inclusion complex-based creams were investigated by the modiffed Franz diffusion cell method. The results showed that among the three inclusion complexes of wintergreen oil, the γ-CD inclusion complexes had the highest inclusion rate and yield, which were (88.53±0.72)% and (98.21±0.80)% respectively. And the cream loaded with the γ-CD inclusion complexes also had the highest in vitro transdermal permeation and release rates among the three creams; its in vitro release data were fftted to zero order kinetic model. Compared with the commercially available compound methyl salicylate cream, three creams loaded with different inclusion complexes had lower in vitro transdermal permeation and release rates, but had no obvious skin irritation. It was concluded that the cream loaded with the γ-CD inclusion complexes had good appearance and stability, no skin irritation, and showed a certain therapeutic effect on chronic eczema model rats.
  • Paper
    HUANG Chunyue , YANG Zixuan , SUN Yichun , LI Huixin , HU Xiao
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    The monosaccharide HPLC ffngerprint method of Epimedium polysaccharides using acid hydrolysis by pre-column derivatization was established. The Epimedium polysaccharides were hydrolyzed into monosaccharides by 2.0 mol/L hydrochloric acid and derivatized by 1-phenyl-3-methyl-5-pyrazolone(PMP). Then, the monosaccharide components were detected by HPLC. The YMC-Pack ODS-A column(4.6 mm×250 mm, 5 μm) was used with a mixture of phosphate buffer and acetonitrile as the mobile phase, in a ffow rate of 0.8 mL/min and at a detection wavelength of 254 nm. The common fingerprints of forty batches of Epimedii Folium were established with ten common peaks by Similarity Evaluation System for Chromatographic Fingerprint of TCM(Version 2012). Eight peaks in which were identiffed as D-mannose, D-glucuronic acid, rhamnose, galacturonic acid, D-glucose, galactose, xylose and arabinose by reference substances. Similarity analysis and orthogonal partial least squares analysis were applied to investigate the differences between Epimedium and seven batches of E. wushanense T.S.Ying. The similarities were less than 0.9, and four monosaccharides showing significant differences were distinguished. The established method is simple and repeatable, which can provide references for the quality evaluation of Epimedium.
  • Paper
    JIN Wei , , ZHANG Shaomin, , LE Jian, , YANG Yongjian,
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    A supercritical ffuid chromatography(SFC) method was established for the separation and determination of erlotinib hydrochloride(1) and its four related substances. A Torus 2-PIC column(3.0 mm×100 mm, 1.7 μm) was used with the mobile phase containing a mixture of supercritical CO2 and methanol by gradient elution. The injection volume was 1 μL, the column temperature was 50 ℃, and the ffow rate was 1.0 mL/min. The results showed that each compound peaked and was completely separated within 7 minutes. And it was linear for four related substances and 1 in the ranges of 0.5 – 40, 2 – 60, 0.4 – 40, 0.5 – 40, 5 - 100 μg/mL, respectively. The LODs of 1 and impurities A, B, C, D were 0.2, 0.2, 0.5, 0.1, 0.2 μg/mL, respectively, and the LOQs were 0.5, 0.5, 2.0, 0.4, 0.5 μg/mL, respectively. The recoveries(n=3) of four related substances were between 96.0% and 104.2%, with RSDs all less than 3.0%. The established method is rapid, effective, highly sensitive, environmentally friendly, which can be effectively used for quality control of 1 bulk drug and tablets.
  • Paper
    LIU Yanfeng , WANG Weiwei , CHEN Xiaojie , FENG Zhong, , ZHANG Guimin,
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    The dissolution of cetylpyridinium chloride(1) buccal tablets was determined by ffow-through cell method, and the concentration of the dissolution medium, the construction method and amount of glass beads, and the flow rate of the flow-through cell were optimized. Meanwhile, the dissolution curves of the self-made and reference samples were tested using the established method. The results showed that the concentration of the dissolution medium and the amount of glass beads had little effect on the release behavior, while different glass bead construction methods and ffow rates of the ffow-through cell had a signiffcant effect on the release behavior. This method has certain feasibility and discriminatory ability, which can be used to evaluate the in vitro dissolution behavior of 1 buccal tablets.
  • Paper
    SUN Zhen, XU Mingming, YAN Cuixia, ZHENG Luxia, SHAO Hong
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    An HPLC method was established to determine the related substances in calcium dibutyryladenosine cyclophosphate(1) bulk drug, which were sodium 2′-O-monobutyryladenosine cyclophosphate(3), sodium N6 - monobutyryladenosine cyclophosphate(4) and adenosine cyclophosphate(5). The ODS Hypersil column(4.6 mm×200 mm, 5 μm) was used, with 0.1 mol/L potassium dihydrogen phosphate solution-methanol(600∶400) as the mobile phase. The detection wavelength was 273 nm, the column temperature was 30 ℃ and the ffow rate was 1.0 mL/min. A main component self-compare with correction factor method was established to determine three known impurities, and the correction factors of impurities 3, 4, and 5 to the principal component were determined to be 1.7, 0.9, and 1.4, respectively. The results showed that it was linear for sodium dibutyryladenosine cyclophosphate(2), 3, 4, 5 in the ranges of 0.1 - 20, 4 - 20, 1 - 20, 0.1 - 2 μg/mL, respectively. The average recoveries(n=2) of 3, 4 and 5 were 101.0%, 98.5%, and 99.7%, respectively, and the precision RSDs(n=6) were 0.1%, 0.2%, and 0.1%, respectively. The repeatability RSDs(n=6) were 1.5%, 1.6%, and 2.5%, respectively. The detection limits for 3, 4, 5, and 1 were 0.2, 0.1, 0.1, and 0.2 ng, respectively. This method has good speciffcity, accuracy, and sensitivity, which can provide a reference for quality research of 1.
  • Paper
    LI Yaping, , LIU Xu , LIN Liya , ZHANG Fuli , HE Yongfu
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    An HPLC method was established to determine the related substances in N-tert-butoxycarbonyl-5,7- dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(1), a key starting material for lifftegrast. A Thermo AcclaimTM Mixed-Mode WAX-1 column(4.6 mm×250 mm, 5 μm) was used, and the analysis was carried out in the gradient elution mode with 30 mmol/L potassium dihydrogen phosphate solution-acetonitrile(95∶5) as mobile phase A, and acetonitriletetrahydrofuran(80∶20) as mobile phase B. The flow rate was 0.9 mL/min, the column temperature was 30 ℃, the detection wavelength was 205 nm, and the injection amount was 50 μL. The results showed that the separation between the main component and various impurities was good, and it was linear for the main component and various impurities in the corresponding concentration ranges. The average recoveries(n=9) were 96.4% - 105.6%, with the RSDs less than 5.1%. This method is easy to operate, accurate, and reliable, which is suitable for the determination of related substances in 1.
  • Paper
    DENG Xuezhen, CHEN Lele, TAN Yumeng, QIAN Kun, YANG Jie
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    A cocrystal of hydrochlorothiazide(1) and flucytosine(2) was prepared to improve the solubility of 1 and the hygroscopicity of 2. The 1-2 cocrystal was characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. The solubility and hygroscopicity of the 1-2 cocrystal were also examined. Compared with 1, the equilibrium solubility and intrinsic dissolution rate of 1 in the 1-2 cocrystal in hydrochloric acid(pH 1.2), phosphate buffer(pH 6.8), and pure water(pH 7.0) were increased. Meanwhile, the weight of 1-2 cocrystal did not increase under the conditions of 25 ℃ and relative humidity of 95%. These results indicated that the solubility of 1 was increased and the hygroscopicity of 2 was weakened by forming a cocrystal of 1 and 2, which provided a reference for the research on improving the solubility of poorly water-soluble drugs.
  • Paper
    TONG Yanjun, CHEN Tong, FU Shuguang, HE Qian, MA Chao, LI Jialin
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    In order to explore the impact of sterilizing ffltration in the produce process of semi-ffnished products on the quality attributes of trivalent rotavirus vaccines, and to evaluate the feasibility of implementing sterilizing ffltration in this produce process, sterilizing ffltration experiments of 22 batches of semi-ffnished product were conducted in two stages. The test fflter membrane had a pore size of 0.22 μm and was made from polyvinylidene ffuoride(PVDF). The effect of sterilizing ffltration on virus titer, appearance, pH value, osmotic pressure, and clarity of the test products was investigated, and a bacterial interception test on the proposed selected filter membrane material was performed. The results indicated that the PVDF sterilizing fflter with a pore size of 0.22 μm for the sterilizing ffltration of the semi-ffnished trivalent rotavirus vaccines did not signiffcantly affect the virus titer, appearance, pH value, and osmotic pressure of the test products(P>0.05), but notably enhanced the clarity of the test products(P<0.05). This research provides valuable data and insights for applying sterile ffltration to the formulation process of the semi-ffnished trivalent rotavirus vaccines.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    ZHAO Chen, , QI Xiaole , , FAN Ruixin
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  • Pharmaceutical Management & Information
    YU Yinghui , TAN Yang , CHEN Guiliang
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  • Pharmaceutical Management & Information
    LI Jinlian , YANG Yifan , XIE Jinping , WANG Yun , SHAO Rong
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  • Pharmaceutical Management & Information
    SUN Zhixuan, GONG Lingchen, NA Xin, WANG Junxia, CHU Shuzhen
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  • Pharmaceutical Management & Information
    ZHU Jia , DING Yuqi , SHEN Hong , LIU Zhu , MAO Yangdui
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