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
    BI Siju, LIN Kuaile, LIU Lingling, ZHOU Weicheng
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 1-18. https://doi.org/10.16522/j.cnki.cjph.2023.01.001
    The U.S. Food and Drug Administration(FDA) approved 37 new drugs into the market in 2022, including 22 chemical small molecules and 15 biological products. 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 form and strength, adverse reactions, and one synthetic route of the chemical small molecules, and brief information about biological products.
  • Pharmaceutical Management & Information
    SUN Qinyi, JIANG Bin, LIU Lingling
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 154-159. https://doi.org/10.16522/j.cnki.cjph.2023.01.020
    分析集中带量采购中选企业供应保障的影响因素,为国家集采相关政策的完善提出建议。通过对国家集中带量采 购中选企业供应保障的相关案例进行分析,咨询相关专家以了解背后的影响因素,剖析潜在的和现存的影响中选药品供 应保障的因素,总结如下:受战争、疫情和环保等不可抗力因素影响,药品原材料供应不稳定;医疗机构报量不科学, 部分企业产能不足;企业报价不科学,中选后出现价格倒挂;药品上市后管理政策变更导致部分审批周期变长,部分企 业产能变更审批周期变长。国家组织药品带量采购落地执行到第 6 批,部分品种的断供现象偶有发生,需要从生产端、 流通端、使用端、监管端全流程出发,完善带量采购及其相关配套措施,确保中选药物保质、保量供应。
  • Paper
    LIU Xiao, YANG Danqi, YU Jun, QIU Pengcheng, ZHANG Fuli
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 63-66. https://doi.org/10.16522/j.cnki.cjph.2023.01.007
    The industrial synthetic process of (S)-3-hydroxytetrahydrofuran was improved. (S)-4-Chloro-1,3- butanediol(3) was obtained by reduction of the starting material, ethyl (S)-4-chloro-3-hydroxybutyrate(2), with sodium borohydride in ethanol. The reaction mixture was quenched, followed by evaporation of the solvent. Then, the system was directly heated to give the title compound by ring-closure in water. The continuous extraction was used in the work-up so that the extraction efficiency was improved. After the distillation in vacuum and purification, 1 was obtained in a yield of 76.2% with 99.8% of chemical purity and the ee value greater than 99.8%. The improved synthetic process was lowcost and safe, which was suitable for industrial production.
  • Paper
    HE Jiachen, ZENG Shun, PENG Zegen, YANG Zhenhao, HU Aixi
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 347-350. https://doi.org/10.16522/j.cnki.cjph.2023.03.007
    1-(2,3-Dichlorophenyl)-4-[4-(3-nitrophenoxy)butyl]piperazine(5a) or 1-(benzo[b]thiophenyl)- 4-[4-(3-nitrophenoxy)butyl]piperazine(5b) were prepared from 3-nitrophenol by etherification, and then N-alkylation reaction with 1-(2,3-dichlorophenyl)piperazine hydrochloride or 1-(benzo[b]thiophenyl)piperazine hydrochloride. The intermediate of aripiprazole or brexpiprazole, 1-(2,3-dichlorophenyl)-4-[4-(3-aminophenoxy)butyl]piperazine(3a) or 1-(benzo[b]thiophenyl)-4-[4-(3-aminophenoxy)butyl]piperazine(3b) were prepared by electroreduction reactions of 5a or 5b with yields of 93% and 97%, respectively.
  • Perspectives & Review
    WANG Ao, WANG Yawan, YANG Yushe
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 165-174. https://doi.org/10.16522/j.cnki.cjph.2023.02.001
    Due to many factors, such as point mutations in the ligand-binding domain of the androgen receptor(AR) and expression of splice variants, the existing treatment methods for prostate cancer have been successively ineffective. Therefore, new strategies for prostate cancer treatment are urgently needed. In recent years, significant progress has been made in targeted protein degradation technology. For example, AR degraders, which are expected to solve the problem of drug resistance in clinical prostate cancer patients, can block the androgen receptor signaling pathway by promoting AR degradation. This review focuses on the proteolysis targeting chimeras(PROTAC) technology and small molecule degraders targeting AR, and summarizes the research progress in this field from the mechanism of action and representative compounds, respectively. Compared with the inherent druggability defects of PROTAC molecules, small molecule AR degraders have more advantages and are now becoming the leading research direction for the treatment of prostate cancer.
  • Perspectives
    ZHANG Furong, SHI Yuxiao, LUO Huafei
    Chinese Journal of Pharmaceuticals. 2023, 54(05): 636-645. https://doi.org/10.16522/j.cnki.cjph.2023.05.001
    Compared with traditional topical formulations, foam agents have many advantages, including easy application, less residue, high penetration, which are suitable for local administration to the skin or mucosa. Therefore, this dosage form has good patient compliance. Establishment of simple and reproducible evaluation method is particularly important for the development of foam agents. In addition, the researches on non-propellant, nanocarrier-based and bionic foam agents further expand the advantages of foam agents, and the application of new manufacturing technique accelerates the industrialization of foam agents. In this paper, the performance evaluations for the expansion, stability, density, rheology and permeability of foam agents, the recent research progress and manufacturing technique of foam agents are reviewed to provide some references for the development of green and efficient foam agents.
  • Perspectives & Review
    LI Xiaojia, LI Song
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 320-329. https://doi.org/10.16522/j.cnki.cjph.2023.03.004
    The industrialization of drugs often involves some dangerous chemical reaction steps, which affect the feasibility of large-scale industrial preparation in terms of environment, health and safety. Microreactor is a new type of reactor, compared with the traditional tank reactor, it has a more efficient mass and heat transfer effects, and higher safety performance. This paper reviews the characteristics and advantages of microreactor, summarizes the application of microreaction technology in the large-scale preparation, such as nitration, diazotization, chlorination, oxidation, hydrogenation, cyclization, and discusses its prospects of development of industrial applications.
  • Paper
    ZHANG Wei, ZHANG Hui, XIONG Jing, XU Mingzhe, LIANG Chenggang
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 111-117. https://doi.org/10.16522/j.cnki.cjph.2023.01.013
    The equilibrium solubility, oil-water partition coefficient and permeability values of oseltamivir phosphate(2) and sofosbuvir(3) were determined. The equilibrium solubilities of 2 and 3 in buffer solutions of pH 1.2, pH 4.5 and pH 6.8 were determined by flask shaking method to judge the solubility properties of two drugs. The oil-water partition coefficients of 2 and 3 in octanol-buffer solutions with different pH values were measured. The permeabilities of 2 and 3 in pH 5.0, pH 6.5 and pH 7.4 buffer solutions were measured by parallel artificial membrane permeation assay(PAMPA). The results showed that 2 was a drug with high solubility and permeability characteristics, and the oilwater partition coefficient was greatly affected by the volume ratio of oil to water. And 3 was a drug with low solubility, high permeability and high lipid solubility characteristics. However, the solubility of methyldopa(1) could not be determined by the same method due to the problem of sample stability. In addition, this study described and analysed the possible problems and influencing factors in the research process, which provided the data to support the establishment of the WHO list of essential medicines.
  • Perspectives & Review
    TAO Yuping, ZHAO Zhenyu, LI Youxin , SUN Kaoxiang, SHI Yanan
    Chinese Journal of Pharmaceuticals. 2023, 54(04): 471-480. https://doi.org/10.16522/j.cnki.cjph.2023.04.001
    Small interfering RNA(siRNA), a representative therapeutic tool for targeted therapy and precision medicine, can silence the expression of any disease-related gene through sequence-specific RNA interference(RNAi). However, its therapeutic prospects have historically been limited by short half-lives in vivo, difficulties in delivery, and safety concerns. Non-viral vector drug delivery has efficiently achieved siRNA delivery in vivo and silenced the target gene, becoming a successful strategy to overcome above limitations. Currently, several drugs are already in clinical trials, and four new siRNA-based therapies have been approved recently by the U.S. FDA, marking the beginning of a new era of targeted therapies. This review summarizes the recent development and application of siRNA-based non-viral vector delivery strategies and predicts the future development trend of siRNA drug research.
  • Perspectives & Review
    LYU Xunlei, LIN Kuaile, ZHOU Weicheng
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 175-181. https://doi.org/10.16522/j.cnki.cjph.2023.02.002
    The classic resolution of racemates is one of the choices for production of chiral compounds in large scale. Due to the advantages of inexpensive and readily available of resolution agents, mature methods, simple operation, and ease of large-scale production, resolution still plays a role in the pharmaceutical industry. However, its main disadvantage is that half of the products are unwanted enantiomers, resulting in significant waste. Recycle process of resolution-racemization is a direct and effective way to remedy this disadvantage. In this paper, the applications of recycle process of resolution-racemization in synthesis of chiral drugs are reviewed based on the different mechanisms of racemization(carbanion/carbocation mechanism and mechanism of elimination-reduction).
  • Paper
    SONG Changjiang, WANG Yunlong, YAO Qiyu, YU Haitian, ZHANG Guimin
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 210-212. https://doi.org/10.16522/j.cnki.cjph.2023.02.007
    Using dimethyl 4-isobutoxyisophthalate(SM) as raw material to generate ammonolysis reaction for giving 4-isobutoxyisophthalamide(2), 4-isobutoxyisophthalonitrile(3) was generated by dehydration of 2, and the yield of this two-step reaction was 87.9%. After the addition of 3 and thioacetamide, it was cyclized with ethyl chloroacetoacetate to produce ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate(5), which was hydrolyzed in an alkaline solution and acidified to obtain febuxostat(1). The total yield was 54.9%(based on SM). The process simplifies the synthesis route of 1, reduces the use of cyanide and other highly toxic chemicals, and its reaction conditions are mild. It is suitable for industrial production of 1.
  • Perspectives & Review
    LIN Huangjing, TIAN Shaoqiong, MEI Lei, LI Ye, ZHANG Yilan
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 339-346. https://doi.org/10.16522/j.cnki.cjph.2023.03.006
    Suitable pharmaceutical packaging materials can provide safety, protection, functionality, convenience and other properties of drugs. The high popularity of high-tech pharmaceutical researches(innovative drugs, biological drugs, etc.), increasingly popular green environmental protection concept, and constantly developing technologies(biology, material science, electronic informatics, etc.), have put forward new demands for pharmaceutical packaging materials, thus promoting the rapid development of pharmaceutical packaging industry. On the basis of meeting the basic safety and protection requirements, pharmaceutical packaging materials also need to meet the higher requirements such as environmental protection, intelligence and convenience. In this paper, the research trend of pharmaceutical packaging materials in recent years is briefly reviewed from four perspectives, including green packaging, safe packaging, intelligent packaging and standard for packaging materials, which is expected to provide some references for the improvement and innovative research of pharmaceutical packaging materials.
  • Perspectives & Review
    GAO Shuying, LIANG Shuang, LIU Yongjun, ZHANG Na
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 295-303. https://doi.org/10.16522/j.cnki.cjph.2023.03.001
    Gene therapy provides a new treatment method for malignant tumors, genetic diseases and rare diseases. However, there are many barriers in the process of in vivo gene delivery, which limit the clinical application of gene therapy. It is urgently needed to develop suitable carriers for encapsulating, delivering and protecting gene. As a lipid bilayer membrane vesicle actively secreted by living cells(including tumor cells, platelets, antigen presenting cells), exosomes have many advantages, such as natural activity, high biocompatibility, low immunogenicity, and low toxicity, which are considered to be one of the most potential gene delivery carriers. Based on the advantages of exosomes, this paper reviews the isolation of exosomes, gene loading methods and transformation strategies of exosomes, which provides a reference for exosomes as a carrier in the field of gene therapy.
  • Paper
    ZENG Yinhai, YAN Xianguang, YANG Hanyue, DONG Shubo, CHENG Qingfang
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 351-356. https://doi.org/10.16522/j.cnki.cjph.2023.03.008
    In order to control the quality of roxadustat, six related substances of roxadustat were prepared: methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate(related substance A), N-(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine(related substance B), methyl N-(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycinate(related substance C), 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid(related substance D), methyl 4-hydroxy-1-methyl- 7-phenoxyisoquinoline-3-carboxylate(related substance E), methyl N-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3- carbonyl)glycinate(related substance F), and their structures were confirmed by mass spectrometry(MS) and nuclear magnetic resonance(NMR).
  • Paper
    WANG Dongwei, ZHANG Bo, YU Xiaohui, DONG Yunfan, XU Kai
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 268-276. https://doi.org/10.16522/j.cnki.cjph.2023.02.016
    The key parameters of vacuum decay method for the container closure integrity testing of sterile product packaging system were studied. The key parameters, namely test environment, the residual chamber volume, the sealing property of chamber, the chamber material and the process parameters, that could affect the test results were determined. Then, the tests were carried out to verify the influence of above key parameters by designing and developing research programs. The data showed that the test results could be affected by the above key parameters. It was recommended to control the test environment of 23 ℃ and the relative humidity of 45%. The selected chamber should conform to the overall dimensions of the test samples as much as possible, and the sealing ring should be replaced regularly. It was also recommended to select stainless steel material with stable performance and high sensitivity for chamber and negative samples. The negative samples should be solid or leak free based on the tested samples. The setting of process parameters should take the possible leakage risk points of samples on the basis of different packaging forms and different contents into consideration. And in the actual test, reasonable design and selection of key parameters were required to ensure scientificity of the test results.
  • Paper
    QIU Shoushuai, HUA Chenlin, XU Lingfen, ZHAO Dongmei, CHENG Qingfang
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 141-147. https://doi.org/10.16522/j.cnki.cjph.2023.01.018
    An HPLC method for the simultaneous determination of twelve related substances(2 - 13) in rosuvastatin calcium(1) was established. The Welch C18 column(4.6 mm×250 mm,5 μm) was used, and the analysis was carried out in the gradient elution mode, with a solvent mixture comprising of 1% trifluoroacetic acid in water, acetonitrile and water(1∶35∶65, volume ratio) as mobile phase A, and a solvent mixture comprising of 1% trifluoroacetic acid in water, acetonitrile and water(1∶90∶10, volume ratio) as mobile phase B. The detection wavelength was 242 nm, the flow rate was 1.0 mL/min, and the column temperature was 40 ℃. The results showed that the resolution between 1 and its related substances was greater than 1.5, and it was linear for 1 - 13 in the corresponding mass concentration ranges. The LODs of 1 - 13 were 0.028 95 - 0.060 21 μg/mL, and the LOQs were 0.096 50 - 0.200 71 μg/mL. The average recoveries(n=9) of 2 - 13 were 94.59% - 102.00%, with the RSDs of 0.79% - 4.06%. The determination results of three batches of 1 bulk drug showed that the contents of all related substances were less than 0.1% and the total impurity content was less than 1.0%, except related substance 3, whose content was less than 0.2%. The established method has good resolution, high sensitivity and specificity, which is suitable for the determination of related substances in 1.
  • Perspectives & Review
    WANG Danyang, XU Tingting, CHEN Jianjun, QIU Yunliang
    Chinese Journal of Pharmaceuticals. 2023, 54(04): 481-488. https://doi.org/10.16522/j.cnki.cjph.2023.04.002
    Gene therapy is a new approach to treating diseases by altering gene expression in vivo, provides a new treatment strategy for tumors, rare diseases, and other refractory diseases. Gene therapy modifies the pathogenic genes of an individual through gene editing technology and relies on gene delivery vectors to improve the stability and targeting in vivo of genes. This review briefly describes gene therapy methods, introduces the development of viral and non-viral vectors for gene delivery and gene editing technologies in gene therapy combined with the current gene therapy products, and summarizes the safety issues of gene therapy in clinical practice.
  • Perspectives & Review
    CHANG Hongwei, XU Long
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 200-206. https://doi.org/10.16522/j.cnki.cjph.2023.02.005
    Compared with traditional inactivated vaccines, mRNA vaccines have strong immunogenicity and can activate both humoral and cellular immunity. In addition, it has the advantages of a short development cycle, broad neutralization breadth, low cost, and a relatively simple manufacturing process that can be rapidly scaled to respond to sudden and rapidly mutating pandemic outbreaks. As a new vaccine technology, mRNA vaccines have many novel features and challenges. Taking the three coronavirus disease 2019(COVID-19) vaccines, BNT162b2 from Pfizer/ BioNTech, mRNA-1273 from Moderna, and ARCoV developed by several Chinese institutions, as examples, this paper summarizes and analyzes the development and manufacturing strategy for mRNA vaccines in terms of antigen selection, nucleoside modification, and lipid nanoparticles(LNP) formulation preparation. The current challenges and future directions are discussed to contribute to a better understanding of mRNA vaccine technology.
  • Perspectives & Review
    ZHAO Mengyao, SHI Zengfang, SONG Lili, REN Xiaoliang, CAO Ying
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 19-28. https://doi.org/10.16522/j.cnki.cjph.2023.01.002
    Phage display technology(PDT) is an efficient screening technology in vitro for specific peptides of disease targets. This technology not only can screen out disease-related biomarkers but also serve as a powerful tool for drug research and development. Nowadays, PDT applies widely in the diagnosis and treatment of diseases and drug research. This paper reviews the principle of PDT, and its application in disease diagnosis, treatment, and drug research and development. The existing shortcomings of PDT and its application prospects are discussed to provide references for further research of PDT in modern medicine.
  • Perspectives & Review
    GUO Zuojuan, LIANG Rongcai
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 312-319. https://doi.org/10.16522/j.cnki.cjph.2023.03.003
    Traditional microspheres loaded with protein/polypeptide drugs have some shortcomings, such as
    burst release, delayed release, and incomplete release of protein/peptide drugs. However, microspheres with poly(lactideco-
    glycolide)(PLGA) as carriers can achieve sustained release delivery of protein/polypeptide drugs and improve patient
    compliance. This paper analyzes the various factors that affect drug release performance of microspheres, and summarizes
    a variety of improvement strategies from the aspects of carrier materials and preparation technology, especially the
    remolding methods on the internal water phase in the emulsion-solvent evaporation method. Besides, the application of
    new technology, such as microfluidic, supercritical fluid, self-healing encapsulation, and the development of core-shell
    microspheres controlled-release drug delivery systems are also introduced to provide new ideas for the preparation of
    protein/polypeptide microspheres.
  • Paper
    ZHANG Yiming, RAN Qijun, CHENG Cheng, TANG Lei, WANG Jianta, ZHU Gaofeng
    Chinese Journal of Pharmaceuticals. 2023, 54(04): 533-539. https://doi.org/10.16522/j.cnki.cjph.2023.04.008
    In order to perform the quality control of ursodeoxycholic acid, seven related substances were synthesized. 3,7-Dioxocholanoic acid, 7α-hydroxy-3-oxocholanoic acid, 7-oxolithocholic acid, 3-hydroxy-6-oxocholanoic acid, 3,6-dioxocholanoic acid, 3-oxocholanoic acid and 3β,7α-dihydroxycholanoic acid were synthesized from chenodeoxycholic acid, hyodeoxycholic acid, or lithocholic acid via oxidation, esterification, acylation and reduction. The yields were 68%, 17%, 74%, 60%, 76%, 70% and 15%, respectively. The chemical structures of above related substances were confirmed by NMR and HRMS.
  • Paper
    YAO Yu, LIN Huaqing, ZHANG Jiaqi, LIU Hanbing, PENG Cheng
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 93-100. https://doi.org/10.16522/j.cnki.cjph.2023.01.011
    Based on the concept of Quality by Design, the quality target product profile(QTPP) and critical quality attributes(CQAs) of the self-made generic-retentive sustained-release tablets were defined with the marketed pregabalin sustained-release tablets as the reference listed drug. The amounts of a blend of polyvinyl acetate and povidone(Kollidon SR), polyoxyethylene, carbomer and crospovidone were optimized by single factor test combined with central composite design-response surface methodology with floating lag time, long floating duration and cumulative release rates at different sampling points(1, 4 and 24 h) as the dependent variables. By drawing the three-dimensional response surface plots, the optimized formulation parameters were obtained as follows: 19.25% of Kollidon SR, 15.50% of polyoxyethylene, 3.25% of carbomer, and 31.50% of crospovidone. The cumulative release rates at 1, 4 and 24 h of the optimized formulation were respectively 17.12%, 43.73% and 97.19% in the validation test, and the release behaviors between the self-made tablets and the resfecence listed drug were similar. The floating lag time was 30 s and long floating duration was over 10 h, indicating the floating characteristics of the self-made tablets met the design requirements.
  • Paper
    HE Xin, XU Ji, YAO Tiantian, HU Binbin, LUO Kaiwei, WANG Wei
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 207-209. https://doi.org/10.16522/j.cnki.cjph.2023.02.006
    Terbutaline sulfate(1) is a selective β2 adrenoreceptor agonist for the treatment of bronchial asthma. In this paper, a novel synthetic process for 1 and its crystal form B was reported. 1-[3,5-Bis(phenylmethoxy)phenyl]-2- bromoethan-1-one(3) was obtained from 3,5-dibenzyloxyacetophenone(2) with copper(Ⅱ) bromide by bromination. 1-[3,5-Bis(benzyloxy)phenyl]-2-bromoethanol(4) was synthesized directly by the reduction of 3 with potassium borohydride in methanol. The bromine atom in 4 was substituted with tert-butylamine to give 1-[3,5-bis(benzyloxy)- phenyl]-2-(tert-butylamino)ethanol(5). After purification, 5 was hydrogenated in the catalysis of Pd/C and then salification with sulfuric acid to obtain 1. The crystal form B of 1 was obtained by recrystallization in the mixture of acetone and water in a total yield of 42%. In this process, the materials are inexpensive and easily available. This process has been tested by pilot-scale experiment, which is suitable for industrial production.
  • Paper
    ZHU Ranran, WEI Zhenghua, HAN Shuo, ZHAO Xinqing, TIAN Tianen, WANG Jianyao, DONG Zhikui
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 213-215. https://doi.org/10.16522/j.cnki.cjph.2023.02.008
    In this study, the synthesis of minodronic acid by phosphorylation was improved. Started from (imidazolo[1,2-a]pyridin-3-yl)acetic acid(2), the phosphorylation was carried out only with phosphorus trichloride in methanesulfonic acid(as solvent). The product was obtained in a yield of 82.4% and a purity of 99.82%. The process did not use phosphorous acid and any organic solvent, so the heterogeneous reaction state was avoided. These reaction conditions were mild, and the production cost was reduced.
  • Paper
    LI Chunhuan, XIAN Ruiqing, XUE Weili, YOU Pengfei, ZHANG Naibin
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 243-253. https://doi.org/10.16522/j.cnki.cjph.2023.02.013
    At present, there is no uniform standard for enoxaparin sodium injection in the pharmacopoeia, and enoxaparin sodium injection belongs to the species with safety risks. Therefore, it is very important to supervise its quality. A follow-up inspection of the product for 3 consecutive years was carried out. The sampling range was wide, the sample specifications were complete, and the representativeness was strong, so the inspection results could better reflect the quality status of enoxaparin sodium injection nationwide. According to the daily supervision and sampling test, combined with the existing research results of national evaluation sampling test, the quality status of more than 200 batches of samples from 8 manufacturers was summarized in this paper, and the quality difference of enoxaparin sodium injection from different enterprises was evaluated. In addition, the quality consistency between the products of domestic enterprise and reference listed drug(RLD) was inspected for the first time; and the quality of RLD marketed in the Chinese market, the US market and the European market was also compared and analyzed for the first time, so as to provide references for the improvement of quality standards and the safety of clinical medication. Through investigations, inspections according to current legal standards, and exploratory research, combined with the comprehensive analysis of the scientificity and rationality of the current standards, it was found that enoxaparin sodium injection still had inconsistencies in quality standards, inconsistencies between prescription and production processes in individual enterprises, and other problems. Therefore, the current quality standards still have defects and need to be further unified and improved.
  • Perspectives & Review
    ZHU Yangbin, CHEN Yirui, LING Fei, ZHONG Weihui
    Chinese Journal of Pharmaceuticals. 2023, 54(04): 512-527. https://doi.org/10.16522/j.cnki.cjph.2023.04.006
    Florfenicol is a kind of veterinary chloramphenicol broad-spectrum antibacterial drug, which is widely used in countries around the world due to its strong antibacterial ability. Since the molecular structure of florfenicol contains two chiral centers, the existing synthetic methods can be divided into chiral resolution and asymmetric synthesis. Chiral resolution is relatively unexpensive and has been industrialized, while asymmetric synthesis is greener and in line with the future development trend, but it is challenging. In this paper, the synthesis methods of florfenicol and its key intermediates are reviewed. The preparation methods of D-threo-p-methylsulfonylphenylserine ethyl ester, an intermediate of florfenicol, are described in detail, and different preparation methods including fluorination process are compared.
  • Perspectives
    QIN Xu, TONG Zhenbo, REN Hongxian
    Chinese Journal of Pharmaceuticals. 2023, 54(07): 984-992. https://doi.org/10.16522/j.cnki.cjph.2023.07.001
    Inhalation therapy is the superior choice for treating respiratory diseases. Unlike traditional methods of drug administration, inhalation therapy requires the use of inhalation devices to deliver the drugs to targeted areas. Innovations in inhalation devices aim to improve the delivery efficiency, reduce the impact of respiratory flow rate on drug delivery and improve patient compliance. This paper reviews the development trends of oral inhalation devices and their progress in intelligentization. The soft mist inhaler based on innovative microfluidic nebulization technology and its nebulization mechanism and delivery characteristics are analyzed and discussed. Moreover, this paper further elaborates on the different stages of the development of intelligent inhalation devices. The impact of intelligent inhalation devices on patient compliance is also discussed, providing a reference for further research on intelligent inhalation devices.
  • Paper
    ZHENG Xuemei, WANG Tingliang, ZHANG Min, WANG Lili, ZHANG Jiquan
    Chinese Journal of Pharmaceuticals. 2023, 54(05): 734-738. https://doi.org/10.16522/j.cnki.cjph.2023.05.012
    In this study, the synthetic method of the small molecule antineoplastics alpelisib(BYL719, 1) was improved. Using 2,4-dibromopyridine as the starting material, the key intermediate 4-bromo-2-(1,1,1-trifluoro- 2-methylpropan-2-yl)pyridine(8) was obtained via 5 steps, including nucleophilic substitution, silylation protection, deprotection, methanesulfonylation and substitution. Intermediate 8 condensed with [2-[(tert-butoxycarbonyl)amino]-4- methylthiazol-5-yl]boronic acid under the Pd-catalyzed Suzuki coupling reaction to give [4-methyl-5-[2-(1,1,1-trifluoro- 2-methylpropan-2-yl)pyridin-4-yl]-tert-butyl thiazol-2-yl]carbamate. Followed by removing the Boc protection group and condensation, the target compound 1 was obtained in a 15.9% total yield.
  • Pharmaceutical Management & Information
    XU Xiaohong, LI Fei, YANG Liu, SI Yongai, GONG Qing
    Chinese Journal of Pharmaceuticals. 2023, 54(05): 791-796. https://doi.org/10.16522/j.cnki.cjph.2023.05.021
    药物晶型是影响药物疗效的重要因素,关系到药物的安全性、有效性和质量可控性。近年来,药物晶型研究已成 为国内外研究的热点。该研究结合国内外药品监管机构的指导原则、技术要求以及当前国内审评技术要求,分析药物晶 型研究的关注点、表征方法及典型案例,旨在为多晶型药物的开发和仿制药注册申报提供参考。
  • Paper
    CHENG Peipei, ZHAI Hongwei, ZHAO Yuting, LONG Lin, HU Hui
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 237-242. https://doi.org/10.16522/j.cnki.cjph.2023.02.012
    The aim of this paper was to optimize the dry granulation technology of modified Yupingfeng granules. Lactose, dextrin and silicon dioxide were respectively mixed with the modified Yupingfeng extract, followed by dry granulation. Then, an orthogonal test was employed to comprehensively evaluate the properties of the granules with the primary forming rate, moisture absorption rate, rate of dissolving and angle of repose as the indicators. Combined with actual industrial application, the optimal mass ratio of different excipients to the extract was selected as m(lactose)∶m(dextrin)∶m(silicon dioxide)∶m(the extract powder)=0.6∶0.4∶0.05∶1. On the basis of this ratio, the process parameters of dry granulation, namely the wheel speed, wheel rolling pressure and feeding speed, were optimized by the orthogonal test with the single effective particle forming rate, particle bulk density and fragility as indexes. The optimal dry granulation process parameters were as follows: wheel speed was 15 r/min, wheel rolling pressure was 20 MPa, and feeding speed was 80 r/min. The optimized dry granulation process of modified Yupingfeng granules was proved to be stable and feasible based on the pilot-scale test, which could provide a reference for industrial production.
  • Paper
    FENG Zhong, ZHU Dongqing, PANG Yujiang, ZHU Zhixiang, SONG Yupeng, ZHANG Guimin
    Chinese Journal of Pharmaceuticals. 2023, 54(05): 785-790. https://doi.org/10.16522/j.cnki.cjph.2023.05.020
    An HPLC-CAD method was established for the determination of seven related substances(2 - 8) in sugammadex sodium(1) bulk drug. The Poroshell 120 SB-C8 column(4.6 mm×150 mm, 2.7 μm) was used, and the analysis was carried out in the linear gradient elution mode with 0.5% formic acid solution as mobile phase A, and methanol as mobile phase B. The flow rate was 0.5 mL/min and the column temperature was 35 ℃. The temperature of the atomizer of the charged aerosol detector(CAD) was 35 ℃, the filtration constant was 3.6 s, and the data acquisition rate was 5 Hz. The results showed that it was linear for 3 in the range of 5 - 300 μg/mL, and it was linear for 1 bulk drug and other related substances in the range of 2 - 40 μg/mL. The LOQs and LODs of 1 - 8 were 0.985 - 1.145 μg/mL and 0.493 - 0.573 μg/mL, respectively. The average recoveries(n=9) of 2 - 8 were 95.6% - 99.4%, with the RSDs of 1.21% - 3.32%. This method is accurate, reproducible, and highly precise, which can be used to detect the related substances in 1 bulk drug, and also provides a reliable detection method for the quality control of 1.
  • Perspectives & Review
    ZHANG Jingya, WANG Yixia, GAO Wenshuo, YU Bin
    Chinese Journal of Pharmaceuticals. 2023, 54(06): 813-824. https://doi.org/10.16522/j.cnki.cjph.2023.06.001
    2-Phenylcyclopropylamine and its derivatives are important chiral pharmaceutical intermediates for antineoplastics, antidepressants and anticoagulants. The strategies for the synthesis of 2-phenylcyclopropylamine mainly include direct synthesis from cyclopropane-based derivatives and de novo construction of cyclopropane(Corey- Chaykovsky reaction, Kulinkovich-de Meijere reaction, etc.). In this paper, synthetic routes of 2-phenylcyclopropylamine derivatives are systematically summarized and outlined, the advantages and disadvantages of each route are briefly reviewed.
  • Perspectives & Review
    WANG Lu, GUO Meiyu, QI Xiaodan
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 57-62. https://doi.org/10.16522/j.cnki.cjph.2023.01.006
    At present, the clinical applications of over 70% of drug candidates are limited due to their poor solubility. Adding hydrotropes is one of the common methods to improve the solubility of poorly soluble drugs. Hydrotropes are nonflammable, easily accessible, eco-friendly, and rapidly recyclable, so the applications of hydrotropes in improving the solubility of poorly soluble drugs are more and more extensive. However, the solubilization mechanisms of many hydrotropes are still unclear, and exploration of solubilization mechanisms is one of the current research hotspots. This paper introduces the classifications of hydrotropes, and focuses on the mechanisms of hydrotropes, including the molecular self-assembly of hydrotropes, the complexation of hydrotropes with solute molecules, and water structure changes, in order to provide theoretical references for applying hydrotropes to improve the solubility of poorly soluble drugs.
  • Paper
    GANG Hongyue, SUN Kaoxiang, SUN Huimin
    Chinese Journal of Pharmaceuticals. 2023, 54(03): 374-382. https://doi.org/10.16522/j.cnki.cjph.2023.03.011
    The differences in structure and functionality-related characteristics of croscarmellose sodium(CCS) from different sources at home and abroad were investigated, and their moisture absorption behaviors were characterized. Then, the orthogonal partial least squares(OPLS) model was established to analyze the impacts of the quality of CCS on the disintegration time and dissolution of domperidone tablets. The results showed that the degree of substitution, crosslink density, particle morphology, particle size, swelling, settling volume, powder fluidity and water uptake rate of CCS from different sources were different. The particle morphology and particle size would affect the powder fluidity. The proportion of basic substituents would affect the water absorption of CCS. Swelling, settling volume, degree of acidic substitutions, degree of basic substitutions, inter-particle porosity, crosslink density, d(0.5) and moisture content of CCS from different sources had a large effect on the disintegration time and dissolution of domperidone tablets. Therefore, the analysis of structural and functionality-related characteristics of CCS from different sources will help to provide a basis on selecting the appropriate excipients for formulation design.
  • Perspectives
    LI Xiangmei, YE Yong, LUO Huafei
    Chinese Journal of Pharmaceuticals. 2023, 54(05): 646-653. https://doi.org/10.16522/j.cnki.cjph.2023.05.002
    Vagina has the advantages of rich blood supply, large surface area and avoidance of liver first-pass effect, which is beneficial for the drug to exert its pharmacological effect. Among vaginal drug delivery systems, semisolid formulations have a certain fluidity and a larger spreading area in the vagina compared with solid formulations, which increases the absorption of drugs by the vaginal mucosa. The temperature-responsive gel for vaginal use can respond to the change of temperature and transform to a semi-solid from a liquid, so it is easy to spread and resist the clearance effect of vaginal fluid. This paper reviews the quality characterization and in vitro evaluation methods of semisolid preparations for vaginal use through literature search, hoping to provide some references for the further development of semi-solid preparations.
  • Perspectives & Review
    CHEN Xi, JIANG Nan
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 182-190. https://doi.org/10.16522/j.cnki.cjph.2023.02.003
    Protein-protein interactions(PPIs) and the protein complexes formed through the interactions are essential for the cells to perform various basic functions. Most important life activities, such as DNA replication and transcription, protein synthesis and transport, cellular signal transduction and regulation of substance metabolism, are maintained through dense PPI networks. Genetic mutations, epigenetic alterations, and changes in the cellular microenvironment can interfere with PPI patterns or directly induce protein binding to form new tumor-specific interactions, leading to the genesis, progression, invasion and metastasis of tumors. In recent years, significant progress has been made in developing antineoplastics targeting PPI, some of which are in clinical trials or have been approved for marketing. There is growing evidence that drugs targeting specific PPI may have higher specificity and efficacy than those that inhibit the activity of proto-oncogene proteins and offer therapeutic opportunities to cure specific cancers. This paper systematically reviews the research progress of antineoplastics targeting PPI, and describes the challenges and countermeasures for the research of antineoplastics targeting PPI to provide a reference for their development.
  • Perspectives & Review
    HOU Zhiyuan, CHENG Xiaoxiao, WEN Qiang, ZHANG Hailong, DING Jinsong
    Chinese Journal of Pharmaceuticals. 2023, 54(02): 191-199. https://doi.org/10.16522/j.cnki.cjph.2023.02.004
    The incidence of mental disorders is high and has been increased year by year, and antipsychotics are still the main effective methods for treatment of mental disorders at present. However, traditional routes of administration(oral, injection, etc.) cannot fully meet clinical needs due to the limitations of high frequency of medication, large fluctuation in blood drug concentrations, more adverse reactions, and poor patient compliance. Transdermal drug delivery system(TDDS) is a non-invasive drug delivery method that can continuously deliver drugs, maintain stable blood drug concentrations for a long time, and discontinue the drug administration at any time. TDDS can avoid the liver first-pass effect and gastrointestinal irritation, reduce dose-related side effects of oral administration, and with better medication compliance. This paper reviews the latest research results and clinical trials of TDDS in the treatment of mental disorders, and addresses key points to consider in clinical studies of this kind of products, hoping to provide a reference for the pharmaceutical and clinical research of antipsychotics.
  • Pharmaceutical Management & Information
    CHEN Wei, GE Siyi, XU Yiming, WU Mingyang, LIANG Yi
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 148-153. https://doi.org/10.16522/j.cnki.cjph.2023.01.019
    以浙江某制药公司为实证研究对象,应用统计过程技术对该药品生产企业质量回顾中所采集的数据进行分析,并 采取风险管理技术进行管控。结果显示,充分运用统计过程技术挖掘产品质量回顾信息,有效降低了原料药生产过程中 的质量风险,增强了企业发现药品质量安全问题及潜在风险问题的能力,真正实现了质量回顾工作的价值与意义,提高 了产品的质量水平与质量管理体系运行水平。
  • Paper
    GAO Feng, DAI Jiawei, WANG Junfeng, XIA Chunnian
    Chinese Journal of Pharmaceuticals. 2023, 54(07): 1060-1064. https://doi.org/10.16522/j.cnki.cjph.2023.07.010
    Continuous flow process for the synthesis of losartan(1) was realized by microchannel reactor technology based on the synthetic routes reported in the literature. Compound 1 was obtained with an overall yield of 70.3% [based on 2-cyano-4'-methylbiphenyl(2)] via bromination, N-alkylation and tetrazolium cycloaddition reaction using 2 and 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde(3) as the starting materials. The optimized process bearing mild reaction conditions, simple operation and higher security is suitable for industrial production.
  • Perspectives & Review
    LIU Wan, YANG Shilin, JIN Yi, FENG Jianfang, TU Liangxing
    Chinese Journal of Pharmaceuticals. 2023, 54(01): 48-56. https://doi.org/10.16522/j.cnki.cjph.2023.01.005
    Drug nanoparticles are often used to improve the bioavailability of oral drug delivery. However, due to physiological barriers such as mucus layer, P-glycoprotein(P-gp) efflux, and tight junctions in the gastrointestinal tract, the improvement of bioavailability of oral drugs by nanoparticles is limited. Nanoparticles modified with functional materials have become a research hotspot for oral drug delivery strategies due to their functionality, modifiability, and diversity. This study briefly describes the factors that limit the bioavailability of drugs and focuses on the summary of functional nanomaterials that enhance drug bioavailability by improving drug physicochemical properties and overcoming biological barriers to provide references and literature support for the study of drug loading strategies for poorly soluble drugs.