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
    FU Qinghui, LIU Jie, HE Jun
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Metabolic associated fatty liver disease(MAFLD) is a liver disease characterized by hepatic steatosis, accompanied by metabolic abnormality. In recent years, the incidence of MAFLD has significantly increased due to lifestyle changes and rising obesity rates, becoming an important public health challenge globally. Despite advancements in mechanistic understanding and escalating research efforts on therapeutic agents, effective pharmacological interventions for MAFLD remain limited. Notably, the development of potential therapeutics is often hindered by critical drawbacks such as poor stability, low bioavailability, and inadequate hepatic targeting. Nanoparticle drug delivery systems offer a promising solution by enhancing drug stability, improving solubility and bioavailability, and enabling precise hepatic targeting. This review primarily introduces the pathogenesis, diagnostic criteria, current treatment status, and challenges in drug development for MAFLD, with a particular focus on the application of nanoparticle drug delivery systems to MAFLD treatment, aiming to provide references for the development of therapeutic drugs for MAFLD.
  • Perspectives & Review
    CUI Wenyu, LIU Di, ZHANG Qiao, LYU Chunyan
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    As an emerging transdermal drug delivery technology, microneedles can bypass the hepatic firstpass effect, effectively reducing the pain associated with traditional subcutaneous injections and realizing minimally invasive and painless drug administration. Polymer microneedles, characterized by their excellent mechanical properties and biocompatibility, can accurately penetrate the stratum corneum to create microchannels, significantly enhancing the efficiency of transdermal drug delivery. They have found widespread application to diabetes management, dermatological treatments, and vaccine delivery. This review emphasizes the analysis of matrix materials utilized in the preparation of various types of polymer microneedles, and discusses the application of polymer microneedles with different matrix materials to vaccine delivery, dermatological treatment and diabetes management, while also addressing the specific applications of these materials and highlighting the challenges and future development trends in this field.
  • Paper
  • Paper
    LIAO Zhiwei, BU Yonghai , HE Kangyong , ZHANG Linjie, NI Feng,
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    This study developed a new synthetic process of roxadustat(1). Starting from 5-phenoxyisobenzofuran- 1(3H)-one(2), the process involved ring-opening with thionyl chloride followed by isoquinoline ring construction using sodium ethoxide to yield ethyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate(4). Compound 4 was then brominated with N-bromosuccinimide to afford ethyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate(5). Next, compound 5 underwent Suzuki coupling with methylboronic acid under the catalysis of palladium acetate and triphenylphosphine to produce ethyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate(6). Finally, compound 6 was condensed with glycine under activation by 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) followed by purification to afford the final product 1. The total yield was about 47.4% (based on 2) with the purity of 99.8% . This route features mild reaction conditions and controllable product quality, making it suitable for industrial production.
  • Paper
    GONG Wanchun, XIE Jianshu, XIA Guangxin
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    The synthesis process of dabigatran etexilate mesylate(1) was improved. Using N-(4-cyanophenyl)- glycine(2) and 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]ethyl propionate(3) as the starting materials, 1 was synthesized through amidation, cyclization, aminolysis, reduction, amidation and salinization. The overall yield was approximately 34.5% (based on 3), with a purity of 99.73% . The key step of the improvement lay in the preparation of ethyl 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]- propionate benzenesulfonate. This step abandoned the purification by column chromatography and the use of flammable solvent system, and also avoided the use of expensive Pd/C and heavily polluting Fe powder in the catalytic hydrogenation. The improved process features low cost, simple and safe operation, making it suitable for industrial production.
  • Paper
    GUAN Qiming, ZHANG Fengxiang, ZENG Bingyang, LI Yawei, PENG Ying
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    Based on the industrial synthetic route of orlistat(1), eight related substances of 1 were synthesized, namely L-leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester(related substance A), (2S,3S,5S)- 5-[(N-formyl-L-leucyl)oxy]-2-hexyl-3-hydroxyhexadecanoic acid(related substance B), N-formyl-L-leucine [S-(E)]- 1-(2-nonenyl)dodecyl ester(related substance C), N-formyl-L-leucine (3S,4S,6S)-3-hexyl-2-oxo-6-undecyltetrahydro- 2H-pyran-4-yl ester(related substance D), N-formyl-L-leucine (3S,4R,6S)-3-hexyl-2-oxo-6-undecyltetrahydro-2H-pyran- 4-yl ester(related substance E), N-formyl-L-isoleucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester(related substance F), N-formyl-L-leucine 1-[(2S,3S)-2-hydroxy-3-[1-phenyl-(R)-ethylcarbonylamino]nonyl] dodecyl ester(related substance G), N-formyl-D-leucine (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxacyclobutyl]methyl]dodecyl ester(related substance H). Their structures were confirmed by 1 H NMR, 13C NMR and MS. The synthetic methods of related substance A, B, F and G were reported for the first time.
  • Paper
    LIU Changchun, ZHOU Xinxin, XUE Chun
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    Herein, a new three-step synthetic route for the key intermediate of the tyrosine kinase 2(TYK2) inhibitor deucravacitinib, 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline(1) was described. N'-Hydroxy-2-methoxy- 3-nitrobenzimidamide(3) was prepared via one-pot etherification/addition reaction of 2-fluoro-3-nitrobenzonitrile(2) with methanol and hydroxylamine hydrochloride in the presence of potassium hydroxide and tetrabutylammonium bromide. The esterification of compound 3 with tosyl chloride gave N'-(tosyloxy)benzimidamide(4), without further separation and purification, which was directly subjected to the condensation cyclization with methanamine hydrochloride and triethoxymethane to afford 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole(5). Compound 5 was reduced by thiourea dioxide in the presence of sodium hydroxide to obtain the target product 1 with overall yield of 76%(based on 2) and purity of 99.3%. This new synthetic route has fewer reaction steps, higher overall yield, good selectivity, safe operation, which avoids the use of toxic hydrazine (or its derivatives) to construct 1,2,4-triazoles.
  • Paper
    DUAN Yu , DONG Yuanzhen, WANG Chengcheng , LU Jianguang, HUANG Shuaiyi, FENG Jun,
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    Cagrilintide(1) is a long-acting lipidated analogue of amylin, and its compound preparation with semaglutide, known as CagriSema, has demonstrated a weight reduction effect of up to 22.7% in the latest phase Ⅲ clinical trials. However, the long amino acid sequence of 1 poses challenges for its synthesis and purification. In this paper, using Rink Amide AM resin as the carrier, Fmoc-protected amino acids as raw materials, ethyl cyanoglyoxylate-2-oxime/N,N'- diisopropylcarbodiimide as condensation reagents, and trifluoroacetic acid system as the lysis solution, the reduced crude peptide was synthesized by a solid phase peptide synthesis(SPPS) method from the C-terminus to the N-terminus of C20 diacid according to the amino acid sequence of 1. The intramolecular disulfide bonds were subsequently formed through iodine oxidation. The crude peptide was purified by RP-HPLC, affording a purified product with a purity of 98% and a total yield of 26%. Additionally, this study explored and optimized the preparation process parameters, providing valuable insights for industrial production of 1.
  • Paper
    ZANG Zongwu , BAI Xin, CUI Huixin, BIAN Jing, XU Zhiru,
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    A LC-MS/MS method was established to detect the content of melphalan(1) in dog plasma and rat tissue, with lower quantification limits of 1 ng/mL and 1 ng/g, respectively. Using parallel experiments, the pharmacokinetics and tissue distribution characteristics of the test formulation of 1 with a commercially available reference formulation in dogs and rats were compared. After a single intravenous injection of 1 hydrochloride injection in dogs, the main pharmacokinetic parameters of the test and reference formulations were as follows: cmax (1 671.19±295.19) and (1 654.22±159.20)ng/mL, respectivelys; AUC0→t was (56 602±6 864) and (55 289±8 174) min·ng–1 ·mL–1 , respectively, and t1/2 was (45±3)min for both. Rats were also given 1 hydrochloride for injection, and the results showed that 1 was more distributed in the pancreas, kidney, liver, heart, and lung, but less distributed in tissues such as muscle, bone marrow, fat, and brain. The drug concentration in the bone marrow was lower than that in the blood at all sampling points. An unpaired t-test showed no significant difference in concentration between the test and reference formulations in various tissues, indicating that the two formulations had consistent pharmacokinetic behavior in dogs and consistent tissue distribution in rats, providing a reference for subsequent clinical applications.
  • Paper
    GONG Jiajia, HUANG Chunyue , HU Xiao, DENG Jina , HUANG Jie
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    An UPLC method was established to determine the fingerprints of 21 batches of Guanjie Kebi Wan, and the similarity evaluation software(2012 version) for traditional Chinese medicine chromatographic fingerprint was used for similarity evaluation. Meanwhile, the UPLC-QTRAP-MS/MS method was established to determine 6 types of aconitum alkaloids(benzoylmesaconine, benzoylaconine, benzoylhypaconine, mesaconitine, aconitine, and hypaconitine). The results showed that the fingerprint similarity of 21 batches of Guanjie Kebi Wan was greater than 0.952, and 17 common peaks were identified. Additionally, 8 components were confirmed according to the standard comparison. It was linear for the 6 aconitum alkaloids in the corresponding mass concentration ranges, with an average recovery rate of 84.3 % to 105.5 % (RSD ≤ 1.37% ). The established method is simple, sensitive, reliable, and has good reproducibility, which can be applied to the quality control of Guanjie Kebi Wan.
  • Paper
    XU Qinke, XU Wenjun , SUN Ying, WEI Xuebing, XU Jijun, MA Xiao, GUO Zhaohui,
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    A microwave digestion-inductively coupled plasma mass spectrometry(ICP-MS) method was established to determine the contents of 37 inorganic elements(Ag, As, Ba, Be, Bi, Cd, Ce, Co, Cr, Cs, Cu, Dy, Er, Eu, Gd, Ho, Hg, In, La, Li, Lu, Mn, Nd, Ni, Pb, Pr, Rb, Sc, Sm, Sr, Tb, Th, Tl, Tm, V, Y, and Yb) in Cynomorium songaricum Rupr samples from different origins. Hierarchical clustering analysis, principal component analysis, and orthogonal partial least squares discriminant analysis were used to perform cluster analysis, correlation analysis, and difference analysis on the samples, aiming to explore the relationship between Cynomorium songaricum Rupr from different origins and their inorganic elements. The results showed differences in the contents of inorganic elements among samples from different origins. Combined with hierarchical clustering analysis, principal component analysis, and orthogonal partial least squares discriminant analysis, the samples were classified into two categories, and nine differential inorganic elements(In, Th, Y, Cd, Gd, Dy, Yb, Pr, and Sm) were identified. The established method can effectively distinguish the distribution characteristics of Cynomorium songaricum Rupr samples from different production areas, providing data support for optimizing the cultivation of Cynomorium songaricum Rupr and ensuring the quality and safety of medicinal materials.
  • Paper
    CAO Jiayu, WANG Xijing , WANG Yuan , ZHANG Wenjun , ZHANG Jiye
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    An HPLC method was established for the determination of the related substances in aprepitant(1) capsules. A ZORBAX SB-Aq C18 column(4.6 mm×250 mm, 5 μm) was used, and the analysis was carried out in the gradient elution mode with tetrabutylammonium hydrogen sulfate buffer solution-acetonitrile as mobile phase. The flow rate was 1.0 mL/min, the column temperature was 30 ℃ , the detection wavelength was 210 nm, and the injection volume was 20 μL. The results showed that the main component and each impurity peak could be well separated under this chromatographic condition. The quantification limits of 1, impurities A, C, E, and F were 0.36, 0.52, 0.48, 0.46, and 0.39 ng, respectively. And it was linear for 1, impurities A, C, E, and F in the corresponding concentration ranges(r ≥ 0.999 6). The determination results of 6 batches of 1 capsules showed that the known impurities and an unknown maximum individual impurity were all less than 0.07% , and the total impurity content was less than 0.07% . The established method has strong specificity and high accuracy, which can be used for the determination of the related substances in 1 capsules.
  • Paper
    ZHANG Naibin, SHEN Zhen, HU Wenhong, FENG Danyang, DING Bo
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    During the production process of sodium bicarbonate Ringer’s injection, carbon dioxide gas is used to adjust the pH of the injection, thus requiring control of the microbial limit of the gas. This study employed two sampling methods and three cultivation conditions to conduct microbial limit testing on three batches of compressed carbon dioxide gas. Using a pinhole compressed air microbial sampler, the filtered compressed carbon dioxide gas was sampled at a flow rate at 100 L/min with a total sampling volume of 1 000 L. Pancreatic casein soy peptone agar was used as the culture medium, which was incubated at 30 - 35 ℃ for 5 days. The test results showed that a concentration of less than 1 cfu/m3 , meeting the requirements for planktonic bacteria in class A clean environments. No microorganisms were detected under other sampling methods or cultivation conditions, indicating that the risk of microbial contamination from compressed carbon dioxide gas was low, and the filters used in production could effectively remove microorganisms from the gas.
  • Pharmaceutical Production Cleanroom Environment Monitoring Technology · and Quality Assurance
  • Pharmaceutical Production Cleanroom Environment Monitoring Technology · and Quality Assurance
    LI Yang , GAO DeJin , TAO Bo , XIE Langui , XU Hang
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    The production environment for sterile pharmaceuticals plays a crucial role in fields such as drug manufacturing, directly impacting product quality and safety. In accordance with the latest domestic and international regulations and guidelines, this article introduces the environmental monitoring performance qualification(EMPQ) process for sterile pharmaceutical production environments. It focuses on cleanroom EMPQ procedures and risk assessment methods, and demonstrates the overall transition from EMPQ to environmental monitoring(EM) through specific examples. The aim is to provide a scientific basis for continuous optimization of sterile production environment monitoring in enterprises, ensuring more stable and safer product quality.
  • Pharmaceutical Production Cleanroom Environment Monitoring Technology · and Quality Assurance
    SONG Jiahui, #, BAO Zhihong#, ZHAO Yanjun, XIE Langui, ZHAO Xia,
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    As a core device for detecting the concentration of suspended particles in clean environments, airborne particle counters play a vital role in ensuring product quality control through its measurement accuracy and operational reliability. This article systematically reviews the technological evolution of airborne particle counters and the challenges in their calibration and traceability. In terms of technological advancements, the instrument has transitioned from a white light source to a laser light source, with the detection limit improved from the micrometer level to the nanometer level. Additionally, the optimization of optical systems, upgraded signal-processing algorithms, and miniaturization designs have significantly enhanced sensitivity and detection efficiency. Innovative technologies such as dynamic monitoring and multiparameter integration have further expanded its functional applications. Regarding calibration and traceability, technological iterations have raised demands for higher precision, yet challenges persist, including the incompatibility of static singleparameter calibration with dynamic multi-dimensional monitoring, insufficient stability of standard particle aerosols, and low calibration accuracy in large particle size channels. Future efforts should focus on overcoming both technical performance and calibration accuracy challenges to meet increasingly stringent requirements for clean environment testing.
  • Pharmaceutical Production Cleanroom Environment Monitoring Technology · and Quality Assurance
    YAO Ying, XUAN Ze, WANG Xia, ZHANG Guanghua, JIANG Zhijie
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    Microbial contamination control in pharmaceutical production environments is crucial for ensuring drug quality. This study utilized 16S rRNA sequencing to comprehensively analyze the distribution characteristics of 98 microbial isolates collected from air conditioning systems(42 isolates), equipment surfaces(11 isolates), personnel workwear(25 isolates), and water systems(20 isolates). Results showed that microbial community structures varied significantly across sources. Air conditioning systems were dominated by Actinomycetes, Bacilli, and Gammaproteobacteria; Bacilli and Actinomycetes predominated in personnel workwear and equipment samples; water systems exhibited a distinct prevalence of α-, β-, and γ-Proteobacteria with no cross-distribution to other environments. Cross-environmental analysis revealed shared strains among air conditioning systems, equipment, and personnel, suggesting airflows, human contact, and equipment surfaces as potential transmission routes. It is recommended that pharmaceutical enterprises should establish environmental strain banks, integrating dynamic monitoring results and phylogenetic analyses to achieve precise microbial risk management.
  • Pharmaceutical Production Cleanroom Environment Monitoring Technology · and Quality Assurance
    LI Yang , XU Hang , MA Bing , XIE Langui , XIE Hui
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    Commercially available prefabricated tryptic soy agar(TSA) plates are the primary format for culture media used in environmental monitoring. Their quality significantly impacts the accuracy of environmental monitoring. This study evaluated the pH value, gel strength, and growth promotion capability of TSA plates from four different manufacturers in accordance with the Chinese Pharmacopoeia 2020 Edition and relevant standards. Additionally, in alignment with the latest requirements of EU GMP, the effects of environmental exposure and irradiation treatment on the media were investigated. Results showed that the pH value, gel strength, and growth promotion capability of the four TSA plates generally met the standard requirements. Under unexposed or 0.5 h exposure conditions, some plates exhibited pH values exceeding the standard limit. After 4 h of exposure, the moisture loss rates for the plates from four manufacturers were 17.99% , 16.80% , 17.73% , and 18.44% , respectively. Three brands showed recovery rates below 0.5 for Escherichia coli, Pseudomonas aeruginosa, Salmonella, and environmental isolates of Pseudomonas sediminis. While nitrogen content showed no significant changes in pre- and post-irradiation. And increasing irradiation doses led to a dose-dependent decline in pH value, gel strength, and growth promotion capability. These results demonstrated that the irradiation sterilization process significantly compromised the quality of prefabricated TSA plates. In conclusion, users should conduct comprehensive quality assessments of prefabricated TSA in consideration of specific challenges in practical applications(such as exposure handling).
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    WANG Jiaqiang, LI Shanshan, CUI Wenjing, LUO Junyong
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  • Pharmaceutical Management & Information
    QIANG Yan, WANG Xiaoyong , SONG Yan,
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  • Pharmaceutical Management & Information
    GUO Qiao, XU Bin, LI Wanghua, QIAO Jian, MING Pinggang
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