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
    ZHENG Qiwen, CHEN Guiliang,WANG Jian
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    Inhaled drugs are drug-device combination products, which require the cooperation of preparations, devices and patients to achieve desired treatment outcome. Common inhalation devices have problems such as difficult operation skill requirements, low drug availability, and long nebulization time due to their nebulization mechanisms. In terms of these issues, several novel techniques and inhalers are put forward in recent years, such as vibration mesh, soft mist, thermal evaporation atomization, and electrohydrodynamic atomization. Fundamental theory of traditional inhalers and these novel techniques are reviewed in this paper, aiming to provide some inspirations for future inhaler development.
  • Perspectives & Review
    FAN Ning, YIN Dongfeng
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    Central nervous system disease is one of the major diseases that significantly affect human health and quality of life. Most drugs cannot cross the blood-brain barrier(BBB), so that their concentrations are too low to completely produce therapeutic effects. Liposomes with special surface modifications can be used as brain-targeted drug carriers to effectively deliver drugs to the brain. This review summarizes the biological properties, BBB crossing mechanisms, and the application of nose-to-brain delivery of brain-targeted liposomes to provide new ideas for drug brain targeting strategies.
  • Perspectives & Review
    WANG Xuecheng, WU Zhenfeng, XU Shijun, WU Zhicheng, YANG Ming
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    Drying is one of the most important processes in the manufacture of traditional Chinese medicines, including drying of herbs, extracts and preparations. It is an important research direction of drying of traditional Chinese medicines to explore the drying technology and process that is fast, efficient and can guarantee the quality and clinical efficacy of traditional Chinese medicines. The advantages of low-frequency and high-power ultrasound in enhancing the drying heat and mass transfer process are gradually highlighted, and this technique has a broad application prospect in the field of high quality drying of traditional Chinese medicines. In this paper, the influences of key technological parameters of ultrasonic drying on the drying process and the research status and development trend of typical equipment are analyzed. Meanwhile, the application status and problems of ultrasonic drying in the field of traditional Chinese medicines are discussed and the countermeasures are put forward. It is hoped to provide some references for promoting the theoretical development and industrial application of ultrasound-assisted drying technology.
  • Perspectives & Review
    LI Mingjian, ZHAO Zhiyuan, ZHENG Luyao, SUN Lijing, WANG Chengxiao
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    Ionic liquids(ILs) or deep eutectic solvents(DES) are regarded as a kind of green and designable solvents, which emerge as the hot topic in pharmacy because of their excellent solubility, high stability, and simple preparation process. This review illustrates the recent applications of ILs and DES in transdermal drug delivery systems(TDDS). The penetration-enhancing activities of ILs and DES are classified and summarized, their structureactivity relationships for skin permeation are elabrated, and the promising potential of ILs in transdermal immunization and transdermal delivery of nanoparticles is prospected, which could provide a new perspective for further development and application.
  • Perspectives & Review
    GE Fan, SUN Jian, HUANG Lu
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    In this study, five small-molecule cyclin-dependent kinase 4/6(CDK4/6) inhibitors, marketed at home and abroad, are analyzed and researched in detail, so does their patent information. To provide practical patent information and references for Chinese pharmaceutical companies to establish and develop projects of CDK4/6 inhibitors for innovative or generic drugs, as well as new patent mining, patent protection and layout, this study mainly focuses on the patents of product, crystalline form, salt form, process, formulation, drug combination, new use and development derivatives.
  • Paper
  • Paper
    ZHU Ranran, TIAN Tianen, WANG Jianyao, DONG Zhikui
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    In order to control the quality of minodronic acid, this study determined the dimer, [2,5-dihydroxy- 3,6-bis(imidazole[1,2-a]pyridin-3-ylmethyl)-2,5-dioxo-1,4,2,5-dioxodiphosphine-3,6-diacyl]bis(phosphonic acid), a relative substance of minodronic acid based on the production process of minodronic acid. It was obtained by the new strategy by reaction of 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid with phosphorus trichloride in methanesulfonic acid(5.5 times amount of substance). The yield was more than 50%, and the purity was not less than 99.0%. The structure of the dimer was confirmed by 1 H NMR, 13C NMR, 31P NMR and high resolution mass spectrometry(HRMS), which could be used as a standard for the quality study of minodronic acid.
  • Paper
    BAO Guanglong, ZHANG Naihua, ZHANG Li, ZHU Anguo, ZHANG Guimin
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    A novel synthetic process of ethyl (2R,4R)-4-methylpiperidine-2-carboxylate(1), the key intermediate of thrombin inhibitor argatroban, was reported in this paper. 4-Methylcyclohexan-1-one(2) was reacted with hydroxylamine hydrochloride to obtain 4-methylcyclohexan-1-one oxime(3). Compound 3 transformed into 5-methylazepan-2-one(4) through Beckmann rearrangement under p-toluenesulfonamide(p-TSA)/ZnCl2 condition. Compound 4 was treated with cupric bromide to prepare 3-bromo-5-methylazepan-2-one(5). Ethyl 4-methylpiperidine- 2-carboxylate(6) was available from 5 via Favorski rearrangement on exposure to sodium ethoxide. Fractionation of 6 under reduced pressure to separate ethyl trans-4-methylpiperidine-2-carboxylate(7). Finally, the target compound 1 was obtained from 7 through resolution by L-(+)-tartaric acid with a purity of 99.58%, a chiral purity of 99.13% and an overall yield of about 9%(based on 2). The new route was easy to operate, safe in production process, which was suitable for industrial production.
  • Paper
    ZHANG Zhen, WANG Guan, QIU Yongfu, LIU Xuyan, LI Jianqi
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    In order to control the quality of ivabradine hydrochloride, five related substances were prepared: 7,8-dimethoxy-3-propyl-1,3-dihydro-2H-benzo[d]azepin-2-one(related substance A), 3-allyl-7,8-dimethoxy-1,3-dihydro- 2H-benzo[d]azepin-2-one(related substance B), 3,3'-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3-dihydro-2H-benzo[d]- azepin-2-one)(related substance C), (S)-[2-[2-[[3-[[[3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl]methyl]- (methyl)amino]propyl]amino]ethyl]-4,5-dimethoxyphenyl]acetic acid(related substance D), 3-(7,8-dimethoxy-2-oxo- 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-N-[[(S)-3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-triene-7-yl]methyl]- N-methylpropan-1-amine oxide(related substance E). The structures were confirmed by MS and 1 H NMR. Among them, both related substance A and B have not found in literature.
  • Paper
    CAI Jianguang, LIN Tanghuan, ZHANG Heng, CHEN Yan'an, CHEN Liru
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    In order to perform the quality control of posaconazole, the two process impurities were synthesized, namely 4-[4-[4-[4-[[(3R,5R)-5-[2-fluoro-4-(1H-1,2,4-triazol)phenyl]-5-(1H-1,2,4-triazol-1-ylmethy1)-3-furanyl]- methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(2S,2S)-2-hydroxy-3-pentyl]-1,2,4-triazol-3-one(the related substance A)- and 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,3,4-triazol-1-ylmethy1)-3-furanyl]methoxy]phenyl]-1- piperazinyl]phenyl]-2-[(2S,2S)-2-hydroxy-3-pentyl]-1,2,4-triazol-3-one(the related substance B). The synthesis routes of the related substance A and the related substance B were first reported. The structures of the products were confirmed by 1 H NMR and HRMS, which could be used as the references for quality control of posaconazole.
  • Paper
    XU Chenxiao, ZHU Jianwei, ZHANG Baohong
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    Chimeric antigen receptor(CAR)T cell therapy has become the focus of research in the field of malignant tumor treatment. Prolactin receptor(PRLR) is one of the potential targets for breast cancer treatment, and its overexpression will affect the occurrence and development of breast cancer. In this study, a three-plasmid system[pHIVgreen fluorescent protein(GFP), psPAX2, pVSVG] was established to package lentivirus and applied to the newly constructed CAR lentiviral expression vector targeting PRLR. By further optimizing the preparation conditions of lentivirus and measuring the titer of lentivirus, CAR-T cells targeting PRLR were constructed successfully. The results showed that when the mass ratio of PRLR-CAR∶psPAX2∶pVSVG was 3∶2∶1, and mixed with transfection reagent at a mass ratio of 1∶2, the condition for the preparation of lentivirus was the optimality, and the titer could reach 1.88× 107 TU/ml after concentration. After infecting human T cells with the lentivirus and screening with a final concentration of 0.5 μg/ml puromycin for two days, CAR-T cells were obtained with the expression positive rates of CD4 and CD8 for 55% and 35%, respectively. And the expression positive rate of PRLR-CAR could be over 50%. The constructed novel CAR-T cells targeting PRLR can provide a reference for the immunotherapy of breast cancer.
  • Paper
    TANG Han, SUN Yani, MING Yuan, GE Yuebin
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    Using spherical porous aluminum magnesium silicate(Neusilin? US2) as the carrier, the solid dispersions of trimetazidine hydrochloride with different drug loadings were prepared by solvent dispersion method. Then, these products were characterized by powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy and dynamic water adsorption. The stability, flowability and compressibility of physical mixtures, different solid dispersions and their mixtures with other excipients were investigated. The results showed that the drug in the solid dispersion prepared with spherical porous aluminum magnesium silicate existed in an amorphous form, and no crystalline form was found in the solid dispersions under the accelerated conditions for 1 month and room temperature for 18 months. Compared with the bulk drug, the fluidity of the solid dispersion was significantly improved, and the compressibility after mixing with other excipients(such as microcrystalline cellulose) was also increased. After mixing the solid dispersion with a drug-carrier ratio of 3∶10 and different amounts of croscarmellose sodium(as a disintegrant), the title tablets were prepared by direct powder compression. The results showed that the dissolution behavior of the solid dispersible tablets with the 2% disintegrant was similar to that of the commercially available trimetazidine hydrochloride tablets(the similarity factor f2 was 59.94).
  • Paper
    CHEN Boqi, ZHANG Ding, WANG Shubin, FANG Yanqiu, WANG Qing
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    The effects of chemical penetration enhancers and polymeric surfactant poloxamer 101(P101) on the percutaneous penetration of cannabidiol(CBD) through the excised nude skin were investigated by the methods of premixing and skin pretreatment in this paper. The relevant penetration mechanism was further explored by means of attenuated total reflectance Fourier transform infrared spectroscopy, molecular dynamic simulation and molecular docking. The results showed that the skin pretreatment approach outperformed premixing. The best CBD percutaneous penetration effect was found in the skin pretreatment group of P101 with 1%, reaching a penetration enhancement rate of 12.97. According to the results of molecular dynamic simulation, a stronger interaction was observed between P101 and ceramide NS(lipids in the stratum corneum of the skin), where the binding energy was –8.85 kcal/mol and the cohesive energy density of the lipid bilayer system diminished from 4.15×108 kcal/mol to 3.87×108 kcal/mol, indicating that P101 promoted the skin penetration by disturbing the well-ordered structure of the lipid bilayer system in the stratum corneum and thus increasing its fluidity. This study showed an essential guiding impact for the development of transdermal drug delivery of CBD.
  • Paper
    LIU Yaping, ZUO Lingnan, KE Junxiong, DANG Yunjie, DU Qing
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    In this study, the chitosan(CS) and polyvinyl alcohol(PVA) based nanofibers were prepared by electrospinning technology in order to load shikonin nanocrystals. The formulation and process parameters were optimized by a single factor experiment with average particle size, polydispersity index, and stability index as the indicators. The diameter of the nanofibers, and the porosity, wettability, water vapor transmission rate and water absorption of the nanofiber membranes were characterized. After optimization, the diameter of the nanofibers was (76.30±18.34)nm; the porosity, contact angle water vapor transmission and water absorption of the membranes were (51.9±5.1)%, (47.35± 1.40)°, (0.25±0.01)g·(cm2 ·24 h)–1 and (180.1±41.7)%, respectively. The observation of scanning electron microscopic images showed that the diameter of the drug-loaded CS/PVA nanofibers was (82.60±22.71)nm. The drug-loaded nanofiber membranes had a utilization rate of (90.97±0.09)% with the porosity of 50.92%. The drug release within 5 h reached more than 90% in 1% Tween-80 solution. In conclusion, this CS/PVA nanofiber membranes loaded with shikonin nanocrystals had the potential applications for wound dressing.
  • Paper
    WANG Yaqing, HAO Guizhou, LI Qian, CHEN Yuqing, ZHANG Guimin
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    The nanosuspension of phillygenin(1) was prepared by wet grinding technique, then the pellets were prepared with coating liquid consisted of the above nanosuspension, hydroxypropyl methylcellulose, lactose and mannitol by the bottom-spray fluid bed method to improve the stability. The parameters of the coating process were optimized by single factor test and central composite design-response surface methodology. The obtained optimal parameters were as follows: the viscosity of coating solution was 130 mPa·s; the temperature of inlet air was 50 ℃; and the rate of feed was 12 r/min. The average particle size of the optimal nanosuspension and pellets(the redispersed suspension) stored at room temperature for three months were (265.5±5.9) and (220.6±3.8)nm, and polydispersity index were 0.253±0.071 and 0.199±0.069, indicating the stability of nano-sized crystals of 1 was improved by solidification process. The results of in vitro dissolution test showed that the dissolution profiles of nanosuspension and pellets in various pH media were significantly enhanced, compared with the micronized bulk drug.
  • Paper
    ZHANG Qian, YAN Nana, GAO Xinyi, HE Ping, LIU Wanhui
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    The tropisetron hydrochloride(TRO) ethosomes with different drug loadings were prepared by ethanol injection method. The particle size, ζ potential, morphology, entrapment efficiency and skin permeability in vitro of the products were characterized. Orthogonal design was adopted to screen the critical excipients in cataplasm. Meanwhile, the TRO ethosomes with different drug loadings were incorporated into cataplasms to solve the problems of inconvenient administration and difficult to continuous delivery. The results of in vitro transdermal permeation study showed that the percutaneous penetration rate and cumulative permeability within 24 h of the cataplasm containing ethosomes with drug loading of 0.36% were 21.66% and (92.45±6.85)μg·cm-2 , respectively. Moreover, the in vitro release and in vitro skin permeation of the TRO ethosomal cataplasm and common TRO cataplasm with the same concentration were investigated and compared. It was found that the release of TRO from the ethosomal cataplasm was slower than the common cataplasm, while the transdermal permeation of the ethosomal cataplasm was significantly higher than that of the common cataplasm(P<0.05). The tack and peel adhesion of TRO ethosomal cataplasm was investigated, and the results showed good adhesive properties.
  • Paper
    ZHAO Rongjun, CHEN Hongye, CHEN Zhuxia, SU Chaofen, LIANG Chaofeng
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    A method for determination of particle size distribution(PSD) of sprayed aerosols by laser diffractometer was established with azelastine hydrochloride nasal sprays as the models. And the influences of actuation force and spray distance on the PSD of aerosols were investigated. The results showed that actuation force had a significant impact on the PSD of aerosols. Then, the consistency of aerosol PSD between different batches of samples from two companies(A and B) was analyzed by this method. The results showed that the intra- and inter-batch variability of the aerosol PSD of nasal spray from company A was less than that of the product from company B. The aerosol PSD results of the products from companies A and B were different, which might be attributed to the differences in formulation and preparation process. Therefore, it was necessary to strengthen the investigation on detection methods of aerosol PSD and comparison study of different products in the development of nasal spray product.
  • Paper
    WANG Meiting, YANG Xin, XU Yibing, ZHANG Yizhe, WANG Xijie
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    The directed differentiation of human induced pluripotent stem cells(hiPSCs) into peripheral neurons was explored in this paper, and hiPSCs was used to evaluate drug-induced neurotoxicity. The directed differentiation of hiPSCs was induced by a combination of selected small molecule inhibitors and neurotrophins, and the hiPSC-derived peripheral neurons(hiPSC-PNs) model was established successfully. After the identification of peripheral neurons relevant markers using immunofluorescence and real time quantitative polymerase chain reaction(RT-qPCR), vincristineinduced neurotoxicity of hiPSC-PNs was evaluated by combining the high-content imaging technique. The results showed that hiPSC-PNs expressed the specific markers. In addition, vincristine significantly reduced the neurite length of hiPSCPNs and had the risk of peripheral neurotoxicity. This study provided a new differentiation method in which hiPSCs could be directed to differentiate into peripheral neurons. Moreover, the new method improved the differentiation efficiency and time course. The hiPSC-PNs model combined with a high-content imaging technique could have broad prospects in druginduced neurotoxicity evaluation.
  • Paper
    ZHANG Jun, SUN Bingting, DAI Guoliang, JU Wenzheng
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    An LC-MS/MS method was established for the simultaneous determination of roflumilast(1) and its active metabolite roflumilast N-oxide(2) in human plasma. Plasma samples were extracted with tert-butyl methyl ether and separated on a Phenomenex Gemini C18 column(2.0 mm×100 mm, 3 μm). The mobile phase was acetonitrile∶ 5 mmol/L ammonium acetate buffer containing 0.006% formic acid(62∶38). Electron spray ionization(ESI) and multiple reaction monitoring(MRM) mode were used. Stable isotope-labeled internal standards of d4-1 and d4-2 were used as internal standards for 1 and 2, respectively. The results showed that it was linear for 1 and 2 in the ranges of 0.040 7 - 15.89 and 0.205 8 - 20.58 ng/ml, respectively. The intra-day and inter-day precision and accuracy of 1 and 2 all met the relevant requirements for biological sample analysis. The established LC-MS/MS method is accurate, sensitive and convenient, which can be used for human pharmacokinetic studies of 1 and 2.
  • Paper
    XU Pan, DONG Shubo, YANG Hanyue, LI Shanjin, CHENG Qingfang
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    A gas chromatography-mass spectrometry(GC-MS) method was established for the determination of the genotoxic impurity trimethyl phosphate(3) in sitagliptin phosphate(1). The DB-624(0.25 mm×30 m×1.4 μm) capillary column was used, and the selected ion monitoring(SIM) mode was adopted. The results showed that it was linear for 3 in the range of 40.93 - 233.90 ng/ml, the limit of quantification was 40.9 ng/ml, and the limit of detection was 12.3 ng/ml. The average sample recovery(n=12) was 97.0%, with the RSD of 5.2%, and the stability was good. The sample test results showed that 3 was not detected in three batches of 1. The established method has good repeatability, strong specificity and high sensitivity, which is suitable for the detection of genotoxic impurity 3 in 1.
  • Paper
    SUN Jianhe, HOU Jipeng, SHI Xiaoyan, FENG Zhong,ZHANG Guimin
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    A UPLC-MS/MS method was established for the determination of the genotoxic impurity 2-ethylphenyl hydrazine(2) in etodolac(1). The ACQUITY HSS T3 column(2.1 mm×100 mm, 1.8 μm) was used, and the analysis was carried out in the gradient elution mode with 0.1% formic acid as mobile phase A, and acetonitrile containing 0.1% formic acid as mobile phase B. Electron spray ionization(ESI), positive ion mode acquisition and selective reaction monitoring(SRM) mode was used. The m/z 137.14→108.13 was selected as qualifier transition, and m/z 137.14→120.05 was selected as quantifier transition. The results showed that it was linear for 2 in the range of 12.25 - 122.5 pg/ml, and the LOD and LOQ were 3.68 and 12.25 pg/ml, respectively. The average recovery(n=9) was 85.46%, with the RSD of 3.56%, which could provide a reference for the determination of 2 in 1.
  • Paper
    LI Cui, MA Heng, MIAO Ceyu, LIU Xingcui, HAO Shubin
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    A detection method of initial contaminating bacteria was established for the determination of primary packaging material of medical devices, namely nonwoven packaging materials. By designing different microbial elution methods and parameters, and according to the comparison results of the method recovery, the average microbial recovery(n=10) of ultrasonic elution method was the highest that reached 52.2%. According to the results of single factor experiment and orthogonal experiment, the ultrasonic elution method to collect microorganism was determined as the optimal with the following settings: the ultrasonic time was 10 min, the ultrasonic power was 40 kHz, the amount of Tween-80 in the eluent was 2 g/L, and the eluent volume was 200 ml. The recovery of microorganism collection was increased to 67.2%, which was 15.0% higher than that before optimization, which provided a reference for the initial contamination bacteria detection of the packaging material.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    LI Qing, WU Lihua, GE Yuanyuan
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  • Pharmaceutical Management & Information
    WANG Miao, CHEN Ying, WU Weicong, LUO Zhuoya
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  • Pharmaceutical Management & Information
    ZHANG Meng, JIANG Dan, HAN Meng, LAN Yafei, GAO Ziwen, CHU Shuzhen
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