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• 2024 Volume 55 Issue 8
  Published: 10 August 2024

    

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Perspectives & Review
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  Perspectives & Review

  Progress of Site-specific Integration of Large Exogenous DNA Fragments Based on Non-viral Methods

  CUI Jia, LIU Zhenhua

  2024, 55(8): 1045-1052. https://doi.org/10.16522/j.cnki.cjph.2024.08.001

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  Site-specific integration of large DNA fragments based on non-viral methods are widely used in gene therapy and cell therapy because of their low cost, large capacity, non-immunogenicity, and the ability to avoid genotoxicity and oncogene expression. According to the mechanism, non-viral methods can be classified into three types, DNA damage repair-, recombinase- and transposase-based site-specific integration technologies. All three non-viral DNA targeting methods can be combined with the clustered regularly interspaced short palindromic repeats(CRISPR) and CRISPR associated proteins 9(Cas9) technology to quickly and easily direct exogenous DNA to the target DNA region. In this study, the research progress of the three non-viral-based DNA targeting methods and their applications are summarized to provide new ideas for the development of more efficient cell therapy systems.
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  Perspectives & Review

  Application of Bionics in the Field of Microneedles

  YANG Jing , WANG Weiqing , AN Yue , FANG Renhua , JIANG Changzhao , YE Jincui

  2024, 55(8): 1053-1060. https://doi.org/10.16522/j.cnki.cjph.2024.08.002

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  Microneedles are a novel transdermal drug delivery method with the advantage of improving drug permeation efffciency and bioavailability. However, microneedle technology faces problems such as insufffcient hardness and poor drug delivery accuracy in actual clinical applications. Bionics is a scientific approach that constructs technical systems with specific functions by utilizing the functions and behaviors of biological systems in nature, it can effectively achieve innovative integration between systems, and provide new ideas for solving above problems. At present, bionic microneedles are widely applied in the medical field, such as assisting in wound healing, surgical operations, and physiological/pathological monitoring. This paper summarizes the researches on improving microneedle performance using bionics, and discusses the clinical development prospects of bionic microneedles to provide a new perspective for the future development of microneedle technology.
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  Perspectives & Review

  Application of in situ Gel to Different Routes of Administration

  YU Ziyi , HAO Leilei , LI Peiqiang , ZHAI Guangxi , ZHANG Tao,

  2024, 55(8): 1061-1068. https://doi.org/10.16522/j.cnki.cjph.2024.08.003

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  In situ gel is a novel formulation which is administered in solution and can rapidly occur phase transformation at the site of application to become semi-solid or solid gel. In addition, it can respond to the changes in external factors such as temperature, light, pH value, hydrophily/hydrophobicity, ionic strength. In situ gel has shown unique advantages in a variety of applications, including ophthalmic, nasal, oral, transdermal, injectable and vaginal routes, due to its excellent biocompatibility, bioadhesion ability, sustained- and controlled-release properties. In this paper, the advantages and disadvantages of traditional dosage forms and in situ gel are compared according to the characteristics of various routes of administrations. The research progress of in situ gel in above routes is introduced, and some approval in situ gel products are presented.
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  Perspectives & Review

  Research Progress of Probiotics in the Treatment of Inffammatory Bowel Disease

  GENG Yingjie, QI Haolong, LI Yuan, CAI Xiaoqing

  2024, 55(8): 1069-1077. https://doi.org/10.16522/j.cnki.cjph.2024.08.004

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  Inflammatory bowel disease(IBD) is a chronic intestinal inflammatory disease with an increasing incidence rate year by year, but its etiology is still unclear. And there is a lack of well-targeted and safe therapeutic drugs. In recent years, probiotics have shown large potential as a potential treatment strategy for the prevention and treatment of IBD. This paper elaborates on the mechanism of probiotics in the treatment of IBD, summarizes common probiotic species used in the treatment of IBD, and looks forward to the application of probiotics, aiming to lay a foundation for the research on probiotics in the treatment of IBD.
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  Traceability and Synthesis of Impurities of Dexmethylphenidate Hydrochloride

  HUANG Jie, PAN Haibo, YANG Kaijin, ZHANG Yu, ZHANG Fuli, QIU Pengcheng

  2024, 55(8): 1078-1084. https://doi.org/10.16522/j.cnki.cjph.2024.08.005

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  In order to control the quality of dexmethylphenidate hydrochloride(1), possible impurities were traced and synthesized, including four impurities of 1, namely (±)-threo-2-phenyl-2-(piperidin-2-yl)acetic acid(impurity A), (±)-erythro-methyl-2-phenyl-2-(piperidin-2-yl)acetate(impurity B), (±)-threo-ethyl-2-phenyl-2-(piperidin-2-yl) acetate(impurity E), dimethyl 2,2'-(piperidine-1,2-diyl)bis(2-phenylacetate)(impurity G), and two intermediate impurities, namely (E)-4-methyl-N'-[2-oxo-1-phenyl-2-(piperidin-1-yl)ethylidene]benzenesulfonohydrazide(impurity α) and 2,2'-(hydrazine-1,2-diylidene)bis[2-phenyl-1-(piperidin-1-yl)ethan-1-one](impurity β). The structures of above six impurities were confirmed by 1H NMR, 13C NMR and MS, which could be used as reference substances for the quality control of 1, and provided references for isolation and purification of 1.
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  Improved Synthesis Process of Dipalmitoylphosphatidylcholine(DPPC)

  WU Xinyu, LIU Yubin, YAN Hong, LIN Kuaile, ZHOU Weicheng

  2024, 55(8): 1085-1088. https://doi.org/10.16522/j.cnki.cjph.2024.08.006

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  1,2-Dipalmitoyl-sn-glycero-3-phosphorylcholine(DPPC, 1) can be used not only as a pharmaceutical excipient, but also as an exogenous lung surfactant for the treatment of neonatal respiratory distress syndrome(NRDS). Glycerophosphatidylcholine(GPC, 2) reacted with palmitic acid(PA, 3) in the presence of 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide(DCC) in DCM to yield 1. But it was found that an impurity was produced, which seriously affected the puriffcation of the product. After isolation and puriffcation, the impurity was conffrmed by MS and 1 H NMR to be 1,1'-methylene-bis(4-dimethylaminopyridinium) dichloride. Through replacing reaction solvent to acetonitrile and reducing the feeding molar ratio of DMAP from 3 to 1, the yield of the target product 1 was increased from 33.20％ to 49.18％ with purity of 99.92％ .
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  Improvement of the Synthesis Process of Benfluorenol

  YANG Kang, ZHENG Qun, WU Weiting, CHEN Xuxiang, ZHAO Jianhong

  2024, 55(8): 1089-1092. https://doi.org/10.16522/j.cnki.cjph.2024.08.007

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  Using fluorene(2) as the starting material, it was chlorinated by trichloroisocyanuric acid to obtain 2,7-dichlorofluorene(3), which was acylated with chloroacetyl chloride to produce 2,7-dichlorofluorene-4-chloroethyl ketone(4). Then, α-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenylmethanol(5) was obtained via reduction, cyclization and amination by one-pot method. Finally, 5 was condensed with p-chlorobenzaldehyde to obtain benfluorenol(1), with an overall yield of 36％ and a purity of 99.4％ . The improved process used trichloroisocyanuric acid as the chlorinating agent, which improved the selectivity and safety of the reaction. The reduction, cyclization and amination were completed by onepot method, which reduced the reaction temperature, shortened the reaction cycle, improved production efficiency, and increased the yield from 60％ to 80％ . The improved process was simple to operate, low in production cost and suitable for industrial production.
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  Synthesis of the Related Substances of Vitamin K1

  LI Ru, WANG Ming, LIU Sheng

  2024, 55(8): 1093-1097. https://doi.org/10.16522/j.cnki.cjph.2024.08.008

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  Four potential related substances were synthesized, namely 2-[(7R,11R)-2,3-dihydroxy-3,7,11,15- tetramethylhexadecyl]-3-methylnaphthalene-1,4-dione(related substance A), 1α-methyl-7α-[(7R,11R,E)-3,7,11,15- tetramethylhexadec-2-en-1-yl]-1α,7α-dihydronaphtho[2,3-b]oxirene-2,7-dione(related substance B), 2-[(7R,11R,E)-3- hydroxy-3,7,11,15-tetramethylhexadec-1-en-1-yl]-3-methylnaphthalene-1,4-dione(related substance C) and 2,5-dimethyl- 2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-benzo[h]chromen-6-ol(related substance D).Their structures were confirmed by 1H NMR and MS, which provided a reference for the quality control of vitamin K1.
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  Preparation of Fludarabine Phosphate

  HAO Erjun, ZHAO Yan, JIA Ruping, SONG Yuman, CUI Yangbo, LI Tong, LU Binghui

  2024, 55(8): 1098-1099. https://doi.org/10.16522/j.cnki.cjph.2024.08.009

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  An improved synthetic process of fludarabine phosphate(1) was developed. Commercially available fludarabine was subjected to a nucleophilic substitution with triethyl phosphate. Subsequently, the target compound 1 was obtained through hydrolysis of triethyl phosphate on exposure to phosphorus oxychloride condition with an overall yield of 81％ and a purity of 99.91％ . The optimized process bearing mild reaction conditions, simple operation and stable process had been tested by process verification, and was suitable for industrial production.
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  Evaluation of Spray Characteristics of Suspension Nasal Sprays

  TONG Ying, LI Wenbo

  2024, 55(8): 1100-1106. https://doi.org/10.16522/j.cnki.cjph.2024.08.010

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  The droplet size distribution was measured by the laser particle size measurement system, while the spray pattern and plume geometry were measured by SprayVIEW laser imaging system. The spray performances of two kinds of suspension nasal sprays between the original drugs and the generic drugs were compared. Additionally, the consistency of spray performances between different batches of the samples from 4 companies(A, B, C, D) was analyzed in this study. The results showed that d(0.5) was in the range of 27 - 51 μm. The droplet size distribution results of the products from companies A and B, C and D were different. The intra- and inter-batch variabilities of the droplet size distribution of nasal sprays from companies A and D were less than those of the products from companies B and C, respectively. The spray area showed a signiffcant difference between the original drugs and the generic drugs. The plume geometry results of the products from companies A and B, C and D were similar. The cross section of the spray was nearly circular with elliptical rate of 1.13 to 1.41. The spray performance results of the products from the original drugs and the generic drugs were different. Therefore, it was necessary to strengthen the investigation on detection methods of the spray performances and comparison study of different products in the development of nasal spray products.
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  Determination of Salbutamol Sulfate in Rat Respiratory Tract by LC-MS/MS and Its Lung Tissue Distribution

  ZUO Yaru, YANG Xian, HOU Haiting, ZHAO Fanghong, MA Xiaoyang, SUN Lijie,

  2024, 55(8): 1107-1113. https://doi.org/10.16522/j.cnki.cjph.2024.08.011

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  The LC-MS/MS method was established to determine salbutamol sulfate in rat tracheobronchial and lung tissues. The results showed that the linear ranges in tracheobronchial and lung tissues were 10.41 - 10 410 and 5.205 – 5 205 ng/g, respectively. The intra- and inter-day RSDs of the samples from different tissues were less than 15％ .After inhalation administration, salbutamol sulfate showed similar dynamic changes in the tracheobronchial and lung tissues of rats, and reached maximum concentration immediately after administration, followed by rapid elimination. The inhalation of salbutamol sulfate solution was widely distributed in the tracheal and bronchus of the target site, which provided a reference basis for the clinical use.
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  Factors Affecting the Formation of Sulfamethoxazole-trimethoprim Co-crystal

  LU Jihong , FAN Shanshan , WANG Qiang , LIU Xiangkui , SHEN Yuhui

  2024, 55(8): 1114-1128. https://doi.org/10.16522/j.cnki.cjph.2024.08.012

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  Drug co-crystal had a promising application in improving the solubility and dissolution of poorly water-soluble drugs. The compound sulfamethoxazole tablets contain two active pharmaceutical ingredients: sulfamethoxazole and trimethoprim, which may form co-crystal. In this paper, the existence of the co-crystal in the tablets had been conffrmed by comparison with the standard samples. Then, three influence factors introduced in the formulation process, namely water content, pressure and temperature, on the formation of sulfamethoxazole-trimethoprim co-crystal was investigated. The results showed that water content was the key parameter for the formation of the co-crystal, whereas the co-crystal was formed only when the temperature reached above 128 ℃ . Pressure was proved to have no effect on the formation of the co-crystal. The formed co-crystal had a stable crystal structure, which improved the compression resistance of the tablets.
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  Comparison and Optimization of Dye Ingress Method for Package Integrity Assessment of Small Volume Injection Packaging System

  Shenzhen Kangtai Biological Products Co., Ltd., Shenzhen

  2024, 55(8): 1121-1128. https://doi.org/10.16522/j.cnki.cjph.2024.08.013

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  A dye ingress method was established to assess the package integrity of prefflled syringes and vials. On the basis of setting rational parameters as well as preparing negative and positive samples, the vacuum, negative pressure holding time and the processing method of the prefflled syringe packaging system were optimized, and the method was verified. The results showed that the sensitivity of this method for assessment the integrity of the prefilled syringe packaging system and the vial packaging system was 10 - 15 μm, and was better than those in the USP, EP and International Organization for Standardization under the same conditions. This method could effectively assess the integrity of the prefilled syringe packaging system and the vial packaging system, which provided a reference for establishing the test standard for the prefflled syringe packaging system and the vial packaging system by dye ingress method.
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  Determination of Amino Acid Ratios in Plecanatide by DTDPA-OPA Combined with Pre-column Derivatization HPLC

  PAN Jing, YANG Xinru, LI Tiejian, HAN Zhongli, ZHANG Guimin

  2024, 55(8): 1129-1134. https://doi.org/10.16522/j.cnki.cjph.2024.08.014

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  An pre-column derivatization HPLC method with dithiodipropionic acid(DTDPA) and o-phthalaldehyde(OPA) was established to determine the amino acid ratios in plecanatide. The results showed that the quantitative limits were 0.006 9 - 0.012 7 μmol/mL, the detection limits were 0.003 5 - 0.006 3 μmol/mL. The linearity and solution stability of all amino acids were good with minimum r of 0.999 6 and the maximum RSD(n=9) of 4.058％ . The precision was good with the maximum RSD(n=12) of 2.41％ . The mean recoveries(n=9) were 97.32％ - 101.96％ , the maximum RSD was 1.22％ . In case of detection parameters slight change, the durability was good with the maximum RSD(n=16) of 1.61％ . The established method is speciffc, accurate and efffcient, which can be used for determination of the amino acid ratios of plecanatide.
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  Considerations for the Plasmid Designing and Compliance of Recombinant Adeno-associated Virus Vector Production

  CHEN Yifei , MA Linsha , LIU Fen

  2024, 55(8): 1136-1142. https://doi.org/10.16522/j.cnki.cjph.2024.08.015

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  At present, recombinant adeno-associated virus is the most commonly used vectors for in vivo gene therapy products. For producing virus vectors, plasmids are believed to be the important starting raw material. The designing and managing of plasmids directly contribute to the biological mechanisms, pharmaceutical properties, efffcacy, and safety of products. Therefore, understanding the properties of plasmids and their gene elements is the basis for the “quality by design” of such products. The functions of different plasmids are introduced in this paper, the construction of main genetic elements are summarized, the considerations for designing of plasmids are discussed, the compliance for developing and manufacturing of plasmids are reviewed, in order to provide some references for the development and management of gene therapy products, especially for the recombinant adeno-associated virus products.
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  Case Study of mRNA Vaccine Regulation——Based on the FDA Review of COVID-19 mRNA Vaccines

  LIU Fen, CHEN Yifei, YU Jianing

  2024, 55(8): 1143-1169. https://doi.org/10.16522/j.cnki.cjph.2024.08.016

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  Characterization and Mechanism of VP3 Variant Peak in AAV Capsid Subunit Purity Analysis

  TAO Cuiping, YI Jia, REN Haoran, ZHOU Yilin, SUN Haohang

  2024, 55(8): 1148-1155. https://doi.org/10.16522/j.cnki.cjph.2024.08.017

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  This study aimed to investigate the cause of an unidentified peak that appeared ahead of the VP3 subunit peak during the purity analysis of adeno-associated virus(AAV) capsid subunits by capillary electrophoresis sodium dodecyl sulfate(CE-SDS) technique. Initially, a point mutation was introduced to the second start codon within the base sequence of the recombinant adeno-associated virus(rAAV) capsid protein’s VP3 subunit via PCR to generate a mutant rAAV. Subsequently, the relationship between this mutation and the unidentified signal peak was elucidated using CE-SDS technique. Additionally, the relative molecular weight and peptide analysis of the unknown peak was detected by LC-MS. The results indicated that if the VP3 subunit’s base sequence contain two initiation codons(ATG), the translation might start from the second initiation codon. And the expression product was a variant of the VP3 subunit(VP3'), which aligned with the unidentified signal peak observed in CE-SDS analysis. Consequently, this unidentified peak should be regarded as a AAV capsid subunit peak during the purity assessment of AAV capsid proteins.
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  Key Production Process Points and Marketed Cases Analysis of Recombinant Adeno-associated Virus Products

  SUN Chengjie, ZHUO Yang

  2024, 55(8): 1156-1162. https://doi.org/10.16522/j.cnki.cjph.2024.08.018

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  Discussion of Regulatory Inspection Key Points on Ad5 Adenovirus Vector Vaccines

  CHENG Yin

  2024, 55(8): 1163-1169. https://doi.org/10.16522/j.cnki.cjph.2024.08.019

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