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
    BIAN Yanlin, ZHOU Yuexian, LIN Tong, ZHU Jianwei
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Triple-negative breast cancer(TNBC) is defined as a subset of breast cancers lacking expression of human epidermal growth factor receptor 2(HER2), estrogen receptor (ER) and progesterone receptor(PR). Patients with TNBC have been close to 20% of total patient population with breast cancer. As a mortal subtype of breast cancer, TNBC is associated with higher incidence of visceral metastases, higher risk of early recurrence and worse prognosis. Few suitable treatment option is available while chemotherapy is the mainstay of treatment for the patients with TNBC due to less understanding of the mechanism and associated molecular targets. Recent years there are increasing number of research focusing on targeted therapy and immunotherapy through subtyping TNBC. Individualized precision treatment will become the future trend of TNBC. This report firstly summarizes signal transduction pathways, targeted therapy and potential new therapeutic targets dependent upon molecular profile of TNBC. Then it presents recent information associated with different immunotherapies for TNBC including development of immune checkpoint inhibitors, adoptive cell therapy, therapeutic tumor vaccines and combo treatment of different therapeutic reagents. Besides, several emerging treatment strategies are introduced such as utilizing oncolytic viruses, antibody-drug conjugates, bispecific antibodies and so on. The information package is expected to serve as a reference to pharmaceutical development and clinical precision treatment of TNBC.
  • Perspectives & Review
    HAN Xiaolu, WANG Zengming, GAO Jing, ZHANG Hui, ZHENG Aiping
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    Owing to the increasing pressure of pediatric treatment and the special psychophysiological characteristics of pediatric patients, it is urgent to develop preparations and new technology platforms with strict dosages and drug combinations for pediatric patients. At present, the pharmaceutical industry is receiving the impact of various new technologies. And 3D printing technology has shown unique advantages in drug discovery, development and manufacturing. Its digital and personalized manufacturing mode has promoted the development of pediatric preparations in the current medical environment. This paper shows the technical difficulties, products status and related policies of pediatric preparations, as well as the development of 3D printing technology in pharmaceutical field, especially pediatric preparations. It is expected that 3D printing technology can improve the distress faced by pediatric preparations.
  • Perspectives & Review
    PENG Wei, XU Yang, WANG Wenrui
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    Layered double hydroxide(LDH) is a new type of two-dimensional inorganic nanomaterial, which has unique advantages and good application prospects as a gene drug carrier. On the basis of the related reports at home and abroad in recent years, the preparation methods, characterization, intracellular transport pathway, targeting performance, biosafety and applications in the fields of biological imaging and tumor treatment of LDH-gene nanocomposites are reviewed.
  • Paper
  • Paper
    JIN Yongjun, HAN Zheng, QIAN Liangwei, HUANG Wenfeng, ZHANG Jian
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    (2S,3aS,7aS)-Octahydroindole-2-carboxylic acid benzyl p-toluenesulfonate(4) was obtained by catalytic hydrogenation and condensation-salification from (S)-indololine-2-carboxylic acid(2). Meanwhile, N-[(S) - 1-ethoxycarbonylbutyl]-(S)-alanine(6) was synthesized by one-step method with L-n-valine(5). Compound 4 reacted with compound 6 by condensation, hydrogenation and salt forming to give perindopril tert-butylamine salt(1). In the hydrogenation of 2, rhodium carbon was used as catalyst, and the reaction pressure was decreased from 5 MPa to 2.0 - 3.0 MPa, the reaction time was reduced from 40 h to 4 - 8 h, and the yield was 81%. In the last step, appropriate amount of water was added into hydrogenation solvent and the one-pot method of hydrogenation and salt formation was adopted, which could inhibit the formation of the impurity, ethyl (S)-2-[(3S,5aS,9aS,10aS)-3-methyl-1,4- dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl]pentanoate(7), and the purity of 1 was 99.61%.
  • Paper
    YU Liguo, JIN Xiaofeng, WANG Bin, ZHU Yijun
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    The synthetic process of clozapine(1) was improved based on green chemistry in pharmaceutical industry. 2,5-Dichloronitrobenzene(3) coupled with o-aminobenzoic acid(2) to give potassium 2-(4-chloro-2- nitrophenyl)aminobenzoate(4). In the reaction, N-methyl pyrrolidone(NMP) instead of N,N-dimethylformamide(DMF) was used as solvent to avoid the formation of dimethylamine-substituted impurity (4-chloro-N,N-dimethyl-2- nitroaniline, 7). Sodium dithionite/sodium hydroxide was used to replace hydrazine hydrate/FeCl3 to give 2-[(2-amino- 4-chlorobenzyl)amino]benzoic acid(5) by reduction of 4, and the above two steps were merged into one-pot operation. 8-Chloro-5,10-dihydro-11H-dibenzodiazepine[b,e][1,4]diazotre-11-one(6) was obtained by dehydration condensation from compound 5 in 10% sulfuric acid instead of polyphosphoric acid/xylene, with the yield of 90%. Compound 6 reacted with N-methyl piperazine in the presence of titanium tetrachloride(TiCl4) to obtain 1 in a purity of 99.93% and a total yield of 41%(based on 3). This improved process was easy to operate and the process mass intensity(PMI) was reduced by half, which was more suitable for industrial production.
  • Paper
    ZHANG Qilong, ZHUGE Wenyun, GAO Lingfeng, ZHENG Gengxiu, XU Kun
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    An improved synthetic process of (R)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2- one(1), the key intermediate of vilanterol, was reported in this paper. The product was obtained from salicylaldehyde(2) through Friedel-Crafts reaction with bromoacetyl bromide, selective reduction with sodium borohydride, Delépine reaction, protection of amino, chiral reduction, and cyclization. In the Friedel-Crafts reaction, the complexation between the product and aluminum trichloride was reduced by adjusting pH to 2 in the work-up, so the yield of this step was increased from 61% to 78%. The mixed solution of 1,2-dichloroethane and acetic acid was used in selective reduction to decrease the activation rate of sodium borohydrate, which could decrease the content of impurity 1-(4-hydroxy-3- hydroxymethylphenyl)-2-bromoethanol(9) to 1.22%. In the Delépine reaction, ethanol was used as a single solvent for the "one-pot" synthesis. And the total yield of this improved process was increased from 19% to 43%, with a purity of 99.55% and ee value of 99.23% for the target compound.
  • Paper
    HUO Lingyan, ZHANG Sasa, JIA Haijun, SHI Jianghua, ZHANG Guimin
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    A new synthesis of (S)-4,5-dimethoxy-1-cyanobenzocyclobutane(1), the key chiral intermediate of ivabradine hydrochloride, was developed in this report. 3,4-Dimethoxyphenylacetic acid was used as starting material to synthesize 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one(5) by iodination, amidation and cyclization. Compound 5 reacted with N,N-diethylanilineborane in the presence of (S)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c]- [1,3,2]oxazaborole as catalyst to obtain (R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol(6). Compound 6 reacted with trimethylsilyl cyanide to give 1 with inversion of configuration, in a purity of 99.85% and ee value of 99.32%. In this paper, compound 6 was obtained by asymmetric synthesis which had not been reported in literature. This process had mild reaction conditions, by which the final product was obtained with high ee value and the total yield of 75%(based on 2).
  • Paper
    ZHANG Naihua, ZHANG Wenwen, BAO Guanglong, GUO Xinliang, ZHANG Guimin
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    In order to control the quality of parecoxib sodium, a cyclooxygenase-2 inhibitor, five related substances, namely N-[[4-(3-methyl-5-phenylisoxazol-4-yl)phenyl]sulfonyl]propionamide(related substance A), 4,4'-[sulfonylbis(4,1-phenylene)]bis(5-methyl-3-phenylisoxazole)(related substance B), 3,3'-(5-methylisoxazol-3,4- diyl)dibenzenesulfonamide(related substance C), N,N'-[(5-methylisoxazol-3,4-diyl)bis(3,1-phenylenesulfonyl)]- dipropionamide(related substance D) and N-[[4-(5-methyl-4-phenylisoxazol-3-yl)phenyl]sulfonyl]propionamide (related substance E) were synthesized in this paper. Among them, neither related substances C and D nor the preparation method of related substance A has been found in literature. The structures of above related substances were confirmed by MS, 1H NMR and 13C NMR, which could be used as the references for quality control of parecoxib sodium.
  • Paper
    LI Liping, ZHANG Xiaojie, SI Langyun, MIAO Qingzhu, ZHANG Liping
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    Six related substances of codeine phosphate, namely 7,8-didehydro-4,5α-epoxy-3,6α-dimethoxy-17- methylmorphinan(related substance A), 7,7',8,8'-tetradehydro-4,5α:4',5'α-diepoxy-3,3'-dimethoxy-17,17'-dimethyl-2,2'- bimorphinanyl-6α,6'α-diol(related substance C), 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α,10- diol(related substance E), 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α,14-diol(related substance F), 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methyl-6α-hydroxymorphinan-17-oxide(related substance H) and 7,8-didehydro-4,5α-epoxy-3-methoxymorphinan-6α-ol(related substance I), were synthesized and confirmed by NMR and MS in this report. Among them, the synthesis methods of related substances C and E have not been found in literature. These compounds would be used as the references for the quality control of codeine phosphate.
  • Paper
    LI Xiaowan, WU Yong, HUANG Zongqing, ZHAO Wenjie, FENG Jun
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    A method for acquisition plecanatide by recombinant expression was established in this paper. Through high-density fermentation and high-pressure homogenization of the recombinant Escherichia coli gp55-SUMOSP304 strain constructed by our laboratory, the gp55-SUMO-SP304 inclusion bodies were obtained. The fusion tag of gp55-SUMO-SP304 inclusion body protein could be removed by acid digestion and restriction enzyme digestion, and plecanatide and its isomers were obtained by ultrafiltration and reverse-phase concentration. The results showed that 33.4 g of inclusion body protein per liter could be obtained in fermentation broth of gp55-SUMO-SP304 strains, and 148.47 mg of plecanatide could be produced after removing the fusion tag.
  • Paper
    ZHANG Yeye, LU Guangzhao, ZOU Hao
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    The photo-responsive chitosan oligosaccharide(COS) was structurally modified with NMDBester that contained photo-trigger to obtain a new photo-responsive amphiphilic block copolymer, COS-NMDB, with different grafting ratios of 40.3%, 49.8%, 58.1% and 64.5%. Then, the nile red(NR)-loaded photo-responsive micelles based on COS-NMDB with different grafting ratios were prepared, respectively. The influences of organic solvent and grafting ratio of COS-NMDB on the properties of the micelles were investigated to select the optimal parameters. At the same time, photo-responsive release properties of the micelles were studied preliminarily. The results showed that N,N-dimethylformamide(DMF) was the suitable solvent and the optimal grafting ratio was selected as 49.8%(COSNMDB7.5) for preparing micelles. The particle size, polydispersity index and ζ potential of the optimal micelles based on COS-NMDB7.5 were (55.0±2.3)nm, 0.199±0.024 and (29.0±1.3)mV, respectively. And the optimal micelles also showed higher stability. Compared with COS-NB reported in literature, COS-NMDB with long dodecyl chain showed better drug loading performance. After UV irradiation, the COS-NMDB micelles were disassembled and the spherical particles were collapsed. NR could be released in a light controlled manner, which was induced by gradual photo-cleaving. It was concluded that the photo-responsive COS-NMDB could be used as a light-sensitive drug carrier for further research.
  • Paper
    ZHANG Guozhen, HUANG Lanzhen, GUO Hu, LI Cunjun
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    Based on the memory effect of layered double hydroxides(LDH), the two- and three-dimensional LDH nanocomposites loaded with methotrexate(MTX) were prepared by calcination and reconstruction method with the corresponding two- and three-dimensional layered oxides(LDO). Their structures and drug-loading properties, in vitro drug release profiles and inhibition effects on the growth of HepG2 cells were preliminarily investigated. The results showed that the purity of the MTX-3D-LDH nanocomposites was higher than that of the MTX-2D-LDH nanocomposites, and the MTX-2D-LDH nanocomposites still contained a small amount of unreconstituted 2D-LDO. The release amount of MTX from MTX-3D-LDH nanocomposites continuously increased within 6 h and an equilibrium situation had been reached at 7 h. While the MTX-2D-LDH nanocomposites still adsorbed MTX along with LDO reconstruction during the release of MTX. The concentration of MTX released from MTX-2D-LDH nanocomposites reached peak value at 3 h and equilibrated at 7 h. No obvious cytotoxic effects of the blank 2D-LDH and 3D-LDH were observed during the cytotoxicity test. When the mass concentration of MTX was 12.8 μg/ml, both drug-loaded LDH nanocomposites had stronger effects on inhibiting cell growth than the bulk drug. Moreover, MTX-3D-LDH nanocomposites had better inhibitory effect on the growth of HepG2 cells.
  • Paper
    WANG Jiangyu, CHEN Lan, CHEN Donghao
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    In this paper, gelatin and hydroxypropyl methylcellulose(HPMC) capsule shells were selected as research subjects, then they were respectively stored under low, middle and high relative humidity conditions for 15 d to obtain the test capsule shells with different moisture contents for evaluating the difference in physical properties. Furtherly, dry powder inhaler(DPI) of chlorpheniramine maleate based on Breezhaler? device were prepared by immediately filling the mixture of drug and lactose carrier(Respitose SV003 or ML001) into the above gelatin and HPMC capsule shells with different moisture contents. Their in vitro deposition profiles were investigated by fast screening impactor(FSI). The results showed that both the residual amount in capsules and deposition in preseparator of drug from DPI prepared by capsule shells with high or low moisture contents were higher due to the combination of the capillary force and electrostatic force, thus resulting in the decline of fine particle dose(FPD). Under the high moisture content condition, the dispersion performance of HPMC capsule shells was superior to that of gelatin capsule shells. However, almost no differences were observed in dispersion performance for the same formulation when gelatin and HPMC capsule shells contained moderate moisture content. The formulation with ML001 performed better in dispersion, due to the more content of the fine lactose powder and the greater surface roughness of ML001.
  • Paper
    Zhao Jingdan, Liu Hao
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    The high performance liquid chromatography(HPLC)-evaporative light scattering detection(ELSD) method and HPLC-fluorescence detection(FLD) with post-column derivatization method were established to detect the related substances in kanamycin sulfate injection. A Welch LP-C18 column was used for HPLC-ELSD method with the mobile phase of 0.2 mol/L trifluoroacetic acid solution∶methanol(98∶2). A Zorbax Eclipse Plus C18 column was used for HPLC-FLD method, and a linear gradient elution program was employed with the mobile phase composed of different ratios of sodium heptanesulfonate solution to methanol. The derivatization temperature was 35 ℃, the fluorescence excitation wavelength was 340 nm, and the emission wavelength was 455 nm. The results showed that for HPLC-ELSD method, the separation effects of the kanamycin process impurities, main degradation impurities and other excipients in injections were good. The detection limit of the method was 0.6 μg/ml, and the RSD of repeated determination results of the largest unknown impurity with content of 0.3% was less than 6%. The detection limit of the HPLC-FLD method was 0.03 μg/ml, and the RSD of repeated determination results of the largest unknown impurity with content of 0.4% was less than 1%. Two methods have their own characteristics for the quality evaluation of kanamycin sulfate injection. The optimized HPLC-ELSD method has fast analysis speed and low inspection cost, and it is suitable for the rapid quality analysis and evaluation. The sensitivity of HPLC-FLD method and the resolution between degradation products are better than those of HPLC-ELSD method, so that it is suitable for the accurate quantification of trace impurities.
  • Paper
    ZHAO Xianliang, XU Junbo, ZHANG Na, XU Zuozhi, ZHANG Qin
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    The detection method of related substances was established for nifedipine sustained-release tablets(Ⅱ). According to the comparative analysis on the quality control methods of nifedipine sustained- and controlled-release tablets in the United States pharmacopoeia, British pharmacopoeia, China import registration standard JX20160382 and national standard YBH03572010, the HPLC method for determination of related substances of nifedipine sustained-release tablets(Ⅱ) was optimized by adjusting the chromatographic conditions such as mobile phase, detection wavelength and injection volume. This method was verified by comprehensive methodology, and all verification indicators could meet the requirements. The standard limits for related substances of nifedipine sustained-release tablets(Ⅱ) were specified as follows: impurityⅠ was no more than 0.3%, impurityⅡ was no more than 0.3%, any other single impurity was no more than 0.2%, and total impurities were no more than 0.8%. The established method is accurate and reliable, and the limit requirements are more stringent, which provides a reference for the quality control of nifedipine sustainedrelease tablets(Ⅱ).
  • Paper
    ZHAI Ziran, ZHANG Xiaowen, LI Xiaorui, LI Jianqi, ZHOU Ainan
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    The headspace gas chromatography-hydrogen flame ionization detection(GC-FID) method was established to determine 1-chloropropane and 2-chloropropane, which were the genotoxic impurities in the starting material for synthesis of bedaquiline fumarate. The DB-624 capillary column and hydrogen flame ionization detector were used, both the detector temperature and the injection port temperature were 250 ℃. The carrier gas was high purity nitrogen. Split injection and headspace injection were used with the split ratio of 10∶1. The equilibrium temperature and time were set at 115 ℃ and 30 min. The temperatures for loop and transfer line were 125 and 135 ℃, respectively. The results showed that it was linear for both 1-chloropropane and 2-chloropropane in the range of 0.450 - 3.000 mg/ml, and the limits of detection for both compounds were 225 ng/ml. The average recoveries of 1-chloropropane and 2-chloropropane were 96.77% and 100.11% with RSDs of 3.40% and 4.90%, respectively. This method is accurate, sensitive and reliable, which can be used for the determination of residual 1-chloropropane and 2-chloropropane in the starting material for synthesis of bedaquiline fumarate.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    TANG Han, WANG Minjiao, WANG Wen, LIU Pengcheng
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  • Pharmaceutical Management & Information
    WANG Sijin, YU Meng, WANG Ganggang, MA Shihong
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  • Pharmaceutical Management & Information
    GUO Wen, ZHANG Tianyi, SU Hong, DING Weihong, ZHOU Bin
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