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 5   Published: 10 May 2024
  
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    Perspectives & Review
  • Perspectives & Review
    HU Yangyang, LUO Huafei
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    Microfluidic chips have been widely used in drug delivery, real-time detection, cell sorting and organ chips. Based on the application of microfluidic chips in skin-related research fields, this review mainly introduces the basic principles of microfluidic flow in microfluidic chips, the manufacturing materials and compositions of chips, and the application of microfluidic chips in the development of drug transdermal delivery systems, percutaneous detection and modeling of skin diseases. It is hoped that this review can provide references for researchers in the preparation of transdermal drug delivery systems, health monitoring and looking for in vitro skin model.
  • Perspectives & Review
    ZHANG Tiantian, WU Dongyu, CHAI Xuyu
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    The current majority therapeutic approaches for esophageal diseases are systemic administrations, which often present disadvantages such as limited efficacy and significant adverse effects. Local administration can efficiently increase the concentration of drugs at the lesion sites, making it particularly suitable for the treatment of esophagitis, esophageal cancers, and other esophageal diseases. However, esophageal administration still faces numerous difficulties, the most significant of which are the short drug retention time and the difficulty of penetrating the mucosa. In recent years, various new delivery systems have been developed for localized esophageal drug delivery to overcome the challenges posed by esophageal histology and physiology, offering new hope for patients with related diseases. Based on the introduction of the histological and physiological features of the esophagus, this review analyzes the challenges of local drug therapy, summarizes the new progress in drug administration schemes like oral preparations, esophageal stents and local injections as well as the development of in vitro and in vivo evaluation methods, which provide some references for the further development of esophageal local drug delivery systems.
  • Perspectives & Review
    ZHANG Zhongkui, WANG Shuzhen, ZHANG Naihua, LU Xiaodong, ZHANG Guimin
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    Lemborexant(1) is an orexin receptor antagonist drug used for the treatment of insomnia. The chemical structure of this drug is relatively complex, with two chiral centers and a cyclopropane structure, which creates certain difficulties for chemical synthesis. This review analyzes and summarizes the synthesis routes of 1 from the perspective of how to construct chiral cyclopropane, using 3-fluorophenylacetonitrile(5), 2-bromo-5-fluorophenylacetic acid(20), allyl 2-(3-fluorophenyl)acetate(23) or methyl 3-fluorophenyl acetate(30) as the starting materials, with corresponding mechanism analysis in the key part and a brief overview of each route.
  • Perspectives & Review
    DONG Wenbin, LI Hui, CHEN Yifei
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    In recent years, organoids and organ chips have been developed rapidly. Organoids show certain advantages such as physiological, human origin, genetic stability, high throughput and easy operation, and can be widely used in many fields including drug development, drug evaluation and regenerative medicine. The application of organoids to drug developing include the evaluation of pharmacodynamics, pharmacokinetics, effectiveness and safety, especially for non-clinical pharmacodynamic evaluation. Here, the applications of organoids and their representative models in drug evaluation are introduced, the regulatory international regulatory policy and industry developments are briefly reviewed. Finally, the applications and challenges of organoids and organ chips for non-clinical alternative or complementary models are discussed.
  • Perspectives & Review
    YAN Meng, HE Chaoxing, LI Feng, WANG Yueheng, XIANG Bai, SHAO Juan
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    Ultrasound imaging has been widely used in various fields due to its non-invasiveness, relative simplicity, and no ionizing radiation. Ultrasound contrast agents play an important role in ultrasound imaging, which are usually composed of soft or hard shell materials, with sizes ranging from nanometers to micrometers. And their functions have evolved from initial imaging diagnosis to the integrated mode of diagnosis and treatment. Some marketed ultrasound contrast agents, such as Levovist®, Optison®, Definity® and SonoVue® have been used in clinical ultrasound examinations in Europe, Asia and elsewhere. This review focuses on the research progress of microbubble ultrasound contrast agents and their clinical applications, in order to provide a reference for the development of new ultrasound contrast agents.
  • Perspectives & Review
    ZHANG Weifeng, LI Guoxiang, QI Shuye, WU Xueping, YANG Jie,
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    The route of oral administration has many advantages, but the palatability of drugs with unpleasant taste has become a key obstacle to their oral administration. The establishment of appropriate palatability evaluation method is an important procedure in the product development and evaluation of drugs with unpleasant taste. In vitro dissolution test is an effective evaluation method of palatability, with the advantages of simple operation and good repeatability, which plays an important role in the evaluation of taste-masking efficacy and palatability of drug products. Based on physiological characteristics of oral cavity and the characteristics of in vitro dissolution testing methods for palatability evaluation, this review summarizes and discusses the dissolution apparatuses, dissolution media(composition and volume), and sampling times, and introduces case studies of in vitro dissolution test for application in palatability evaluation, in order to provide ideas and references for the rational application of in vitro dissolution testing in palatability evaluation.
  • Perspectives & Review
    LIU Jia, SHEN Shuwei, YAO Han, CHEN Guoguang, CHEN Lei
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    Relative molecular weight and its distribution are important functionality-related characteristics for polymeric pharmaceutical excipients. They are closely related to many properties of polymeric excipients, such as the solubility, mechanical and rheological properties. Many methods have been developed to determine the relative molecular weight and its distribution, including end-group analysis, viscosity method, field flow fractionation and size exclusion chromatography(SEC). The former three traditional methods have certain limitations in applications due to the range and the type of relative molecular weight. SEC is a new liquid chromatographic technique based on volume exclusion separation, and it has gradually become an effective technique for determination of relative molecular weight and molecular weight distribution of polymeric pharmaceutical excipients due to its advantages of high separation efficiency, high accuracy, simple operation and easy automation. In this study, the characteristics and applications of the SEC technique to the determination of relative molecular weight and its distribution of polymeric pharmaceutical excipients are summarized.
  • Paper
  • Paper
    YANG Xilin, SU Weike, LUO Guihua, SU An,
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    N-Benzyl-p-toluenesulfonamide(1) is an inhibitor of skeletal muscle myosin Ⅱ that specifically inhibits contraction of skeletal muscle fast fibers. A continuous flow synthesis system was developed for 1 and the main reaction parameters were optimized with a Bayesian optimization algorithm. After 10 rounds of Latin hypercube sampling and 10 rounds of Bayesian optimization iterations, two sets of optimal reaction conditions were obtained. ① The reaction temperature was 3.8 ℃ , the residence time was 14.6 min, the dosage of acid binding agent(N,N-diisopropylethylamine) was 1.5 equiv. and the concentration of p-toluenesulfonyl chloride(2) was 0.26 mol/L, which corresponded to a product yield of 91.4 % (based on 2) with a purity of 99.5 % . ② The reaction temperature was 7.5 ℃ , the residence time was 18.5 min, the dosage of DIEA was 1.6 equiv. and the concentration of 2 was 0.37 mol/L, which corresponded to a product yield of 92.3 % with a purity of 99.7 % . The Bayesian optimization can greatly improve the efficiency of searching optimal conditions. The reaction time of the optimized process is greatly reduced, and the solvent is single and economical, which is valuable for industrial application.
  • Paper
    ZHAO Lizhi, TIAN Bo, CUI Qiang, DENG Rong, ZHANG Guimin
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    Three impurities of plerixafor were synthesized with the purity more than 99 % , which named 1,11-bis[4-[(1,4,8,11-tetraazacyclotetradecan-1-yl)methyl]benzyl]-1,4,8,11-tetraazacyclotetradecane hydrochloride(related substance A hydrochloride), 1,4-bis[4-[(1,4,8,11-tetraazacyclotetradecan-1-yl)methyl]benzyl]-1,4,8,11-tetraazacyclotetradecane hydrochloride(related substance B hydrochloride)and 1,8-bis[4-[(1,4,8,11-tetraazacyclotetradecan-1-yl)methyl]benzyl]- 1,4,8,11-tetraazacyclotetradecane hydrochloride(related substance C hydrochloride), and their chemical structure were confirmed by 1H NMR and ESI-MS. The synthesis routes of the related substances A hydrochloride and B hydrochloride had been reported at the first time. They can be used as the references for the quality study of plerixafor.
  • Paper
    ZHAO Lili, SUN Shimin, ZHU Zhongsong, ZHANG Guimin, LIU Zhong
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    Anti-CD73 antibody can inhibit tumor development and metastasis, but there are few studies on its targets and efficacy, and there is no antibody drug on the market at present. In this study, a murine CD73 antibody was humanized, and its efficacy in a mouse solid tumor model was further studied. The results showed that the humanized anti- CD73 20huM51 antibody had a high affinity and neutralizing activity. The anti-CD73 antibody reversed the AMP-mediated inhibition on the release of IFN-γ by CD4+ T/CD8+ T cells and promoted the secretion of IFN-γ. At a dose of 20 mg/kg, the antibody had a significant antitumor activity in mice. The tumor volume and weight inhibition rates were 26.3% and 21.6% , respectively. This study provided data support for the preclinical development of anti-CD73 drugs.
  • Paper
    ZONG Zaiwei, WANG Yucheng
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    Based on the concept of quality by design, the key risk factors affecting the quality of deferasirox dispersible tablets were screened out by cause and effect matrix combined with failure mode and effect analysis. The proportion of internal adding microcrystalline cellulose, the proportion of internal adding cross-linked polyvinylpyrrolidone(PVPP) and the concentration of adhesive (PVP K30) were optimized by a full-factorial design with Minitab 17 Software, with the dissolution rate at 15 min as the evaluation index. By implementing validated experiments, the dissolution rates of three batches of the self-made deferasirox dispersible tablets were lower than 40% in pH 1.0 or pH 4.5 media containing 0.5% Tween-20, but the dissolution rates at 15 min were more than 90% in pH 6.8 medium containing 0.5% Tween-20. And the dissolution behaviors between the self-made dispersible tablets and the reference listed drug(Exjade ®) were similar.
  • Paper
    SHI Xiaoyan, WANG Yanhua, WANG Nan, PAN Zengyu, FENG Zhong,
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    The solubility and dissolution characteristics of two crystal forms(A and D) of zolpidem tartrate (1) were investigated. Firstly, the two crystal forms were characterized by XRD and DSC. The results showed that they had different crystal structures and thermodynamic properties. Subsequently, the apparent dissolution rates and intrinsic dissolution rates of crystal forms A and D were measured in various pH media(water, 0.01 mol/L hydrochloric acid, pH 4.5 acetate buffer, and pH 6.8 PBS). The results showed that there were significant differences in the apparent dissolution rate, apparent solubility, and intrinsic dissolution rate between the two crystal forms in pH 6.8 PBS. According to the test results, both crystal forms of 1 showed the high solubility. The results of the parallel artificial membrane permeation test showed that the effective permeability coefficient of 1 was 8×10–5 - 9×10–5 cm/s, indicating they had high permeability. Although both crystal forms in this study could be classified to BCS class Ⅰ drugs, there were certain differences in solubility and dissolution rates, crystal structure, and melting point, which should be given some references for screening the crystal forms of drug substance in formulation development.
  • Paper
    TIAN Yanrong, WANG Jiawei, LI Huixin, HU Xiao, SUN Yichun,
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    The material basis and blood-entering components of the Heiguteng Zhuifeng Huoluo Capsules(HZHC) extract were investigated by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS/MS). Based on the retention times, quasi-molecular ion peaks, and secondary mass spectrometry information, combined with the reference substances and literature data, a total of 82 compounds were identified from the HZHC, including 47 alkaloids, 9 phenylpropanoids, 7 steroids, and 19 other compounds. Based on this, 9 prototype compounds absorbed into the blood were identified in the serum of rats that received HZHC via gavage, including 7 alkaloids, which were N-demethylsinomenine, dihydrosinomenine, sinomenine, stepharine, magnoflorine, isosinomenine and 6-O-demethylmenisporphine, 1 nucleoside and 1 fatty acid. This preliminary investigation elucidated the material basis and blood-absorbed components of the HZHC, which would provide a reference for subsequent experimental research.
  • Paper
    ZHANG Xinyue, ZOU Wenbo, LIU Wei, SUN Chunmeng, SHI Jifeng, NING Baoming
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    Investigating the impacts of reciprocating frequency and screen aperture on the dissolution behavior of aspirin enteric-coated tablets. Establishing a reciprocating cylinder method for determining the dissolution of aspirin enteric coated tablets, to figure out the in vitro dissolution profiles for different formulations. The dissolution behavior of reference listed drugs and 4 test formulations was evaluated by f2-bootstrap method, the similarity factor(f2) of the dissolution profiles between formulations A, B, C, D and reference listed drugs was 81.4, 33.5, 20.9 and 17.9. The dissolution profiles of formulation A and reference listed drugs were similar, however, the dissolution profiles of formulation B, C and D were different. Compared with basket apparatus, using reciprocating cylinder is a discriminative and durable method for dissolution behavior characterization of aspirin enteric-coated tablets, providing reference for the application of reciprocating cylinder method in drug quality evaluation.
  • Paper
    GAO Xinli, WANG Shuxiao, WANG Xihui, WANG Yongjie
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    Triptolide liposomes(1-Lips) were prepared by thin film dispersion method, and their physicochemical properties were characterized. The tumor inhibition and the effect of 1-Lips on phosphatidylinositol 3 kinase/protein kinase B/Cyclin D1(PI3K/Akt/Cyclin D1) signaling pathway were investigated with breast cancer-bearing mice. The results showed that 1-Lips had a phospholipid bilayer and a spherical structure with the average particle size of (113.7±2.0)nm, the ζ potential of (–1.1±0.6) mV, and the average encapsulation rate of (90.48±1.24)% . The results of anti-breast cancer effect showed that 1-Lips could significantly reduce the tumor volume, destroy the tissue structure, inhibit the tumor cell proliferation, promote apoptosis, inhibit the expressions of PI3K, p-Akt, Cyclin D1, CDK4, and increase the expression of p21 protein. This demonstrated that 1-Lips could enhance the antitumor effect of 1 and that the antitumor mechanism might be related to the inhibition of the PI3K/Akt/Cyclin D1 signaling pathway.
  • Paper
    LU Zheng, AN Haoyue, DU Zhenxia
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    Non targeted screening of extractables in three biopharmaceutical pre-filled injection pens was conducted with ultra-high performance liquid chromatography tandem quadrupole time of flight mass spectrometry (UPLC-QTOF-MS) and gas chromatography tandem quadrupole mass spectrometry(GC-MS) techniques. Based on the actual use of the injection pens, the components were extracted as a whole using four extraction agents at 70 ℃ for 4 d. By setting an analysis evaluation threshold(AET) and utilizing a database of extractables combined with manual spectral analysis, a total of 29 organic compounds were detected, including antioxidants, plasticizers, lubricants, and other components. Among them, 27 substances were detected in injection pens with ordinary halogenated butyl rubber stoppers, and 4 extractables were detected in injection pens with coated rubber stoppers. The list of extractables obtained in this study can provide data references for subsequent compatibility studies.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    SUN Wen, XIE Jinping
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  • Pharmaceutical Management & Information
    ZHANG Lei, GAO Yi’e, WANG Ling
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  • Pharmaceutical Management & Information
    XIN Yun, WANG Jie, WEI Jiaming
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  • Pharmaceutical Management & Information
    WANG Liqing, ZHANG Fan, GENG Ying, FAN Yi
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