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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  • Paper
    MAO Yuanhu, CHENG Fei, HE Qing, LIU Bin, TANG Lei
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1270-1273. https://doi.org/10.16522/j.cnki.cjph.2022.09.005
    In this paper, the drug finerenone for diabetic nephropathy treatment was synthesized. Firstly, the intermidate ethyl 2-cyanoacetoacetate(6) was prepared with 3,5,5-trimethyl-4,6-dioxacyclohex-2-en-1-one(16) and 3-hydroxypropionitrile, and then react with 4-cyano-2-methoxybenzyaldehyde and 4-amino-5-methylpyridin-2-ol via continuous Knoevenagel condensation and Hantzsch cyclization, respectively. Finally, finerenone was obtained via O-alkylation, hydrolysis, ammonolysis and chiral column resolution with an overall yield of 30.8%(based on 16), and 99.7% HPLC purity as well as 99.4% ee value. The improved process had the advantages of simple operation, mild condition, high yield and low cost.
  • Paper
    ZHANG Xiaojie, MIAO Qingzhu, JIA Jingyang, DU Chaoyu, HE Feng
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1419-1423. https://doi.org/10.16522/j.cnki.cjph.2022.10.006
    Five related substances of sufentanil citrate, namely N-[4-(methoxymethyl)piperidin-4-yl]-Nphenylpropionamide( related substance A), cis-4-(methoxymethyl)-4-(N-phenylpropionamido)-1-[2-(thiophen-2-yl)- ethyl]piperidine 1-oxide(related substance B), trans-4-(methoxymethyl)-4-(N-phenylpropionamido)-1-[2-(thiophen- 2-yl)ethyl]piperidine 1-oxide(related substance Ⅰ), [4-(phenylamino)-1-[2-(thiophen-2-yl)ethyl]piperidin- 4-yl]methanol(related substance C), and N-[4-(methoxymethyl)-1-[2-(thiophen-2-yl)ethyl]piperidin-4-yl]-Nphenylacetamide citrate(related substance D). Their structures were confirmed by NMR and ESI-MS. These compounds may be used as the references in the quality control of sufentanil citrate.
  • Perspectives & Review
    HAO Mengya, ZHU Peixi, SU Feng, SU Weike
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1377-1385. https://doi.org/10.16522/j.cnki.cjph.2022.10.001
    Natural products are physiologically active chemical components extracted from natural resources. The key issue to enhance the utilization efficiency of natural products is to explore rapid, efficient and environmentally friendly extraction technologies. Mechanochemical-assisted extraction technology has the advantages of high yield, short extraction time and environmental-friendly. Thus, it has broad application prospects in the field of natural product extraction. This paper mainly introduces the method procedure, process principle, application mode and future trend of mechanochemical-assisted extraction technology. Meanwhile, the limitations of current mechanochemistry in industrial extraction applications are also discussed. Furthermore, the countermeasures are put forward. It could provide new research ideas for promoting the improvement and industrial applications of mechanochemical-assisted extraction technology.
  • Perspectives & Review
    TANG Yifei, WU Wenzhe, WANG Jian
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1227-1239. https://doi.org/10.16522/j.cnki.cjph.2022.09.001
    The production mode of oral solid dosage forms is gradually changing from batch to continuous manufacturing. Using process analysis technology to analyze and control the critical quality attributes of raw materials, intermediate products and final products can realize high efficiency manufacturing, automatic monitoring, high product quality requirements and real-time release testing. Continuous manufacturing which integrates continuous production lines, process analysis technology and advanced feedback control system is more in line with the concept of pharmaceutical industry 4.0. In this paper, the development and status, the preparation process and application of process analysis technology in oral solid dosage forms are reviewed to provide references for further research.
  • 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.
  • Perspectives & Review
    CHEN Wei, FENG Mingjie, XU Bo, PAN Yi, CHEN Hua, TANG Lida
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1386-1393. https://doi.org/10.16522/j.cnki.cjph.2022.10.002
    Continuous flow chemistry is a promising new pharmaceutical technology, which has the advantages of reducing production cycle, higher automation, more environmentally friendly, energy-saving and emission reduction, and it also has the ability to perform chemical reactions that are difficult or impossible to do in batch manufacturing. It is the trend of active pharmaceutical ingredient(API) technology innovation. However, it has been slowly popularized in the pharmaceutical industry for a long time. With publication of ICH guideline Q13 on continuous manufacturing of drug substances and drug products, the key points of process development and control strategies have been put forward, and the regulatory expectation will gradually become clear. The characteristics, application scenarios and quality considerations of continuous flow chemistry are reviewed in this paper based on ICH Q13. Through literature research, the research points and control strategies of continuous flow chemistry are discussed, so as to promote the application of continuous flow chemistry in domestic pharmaceutical enterprises, improve the manufacturing level of the industry, strive to achieve carbon peaking and carbon neutrality goals.
  • Paper
    FENG Ying, CHU Guobiao, ZHAO Xin, ZHAO Zhihui, JING Zhenbo
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1279-1285. https://doi.org/10.16522/j.cnki.cjph.2022.09.007
    In this study, the osmotic pressure regulator dosage, the preservative type and dosage in sumatriptan succinate nasal spray as well as its pH value were optimized. Then, the safety of the preparation was evaluated by the bacteriostatic efficacy of benzalkonium chloride, the contents of related substances, rabbit nasal mucosa irritation and guinea pig allergic reaction. And the plasma concentration of sumatriptan in Beagle dogs was determined by LC-MS to assess pharmacokinetic behaviors of the self-made nasal spray and the reference preparation(Imitrex). The results showed that there were no significant differences in pH, osmotic pressure, related substances, and drug content per spray between the self-made sumatriptan succinate nasal spray and the reference preparation, and the product showed no irritation or allergy. After administration of the self-made and reference preparations, the cmax of sumatriptan in dogs were (319.7±149.0) and (296.0±84.5)μg/L, and the tmax were (0.75±0.3) and (0.89±0.63)h, respectively. The relative bioavailability of sumatriptan succinate nasal spray was 105.6%, indicating it was bioequivalent to the reference preparation.
  • Paper
    GAO Yadong, JIANG Wenming, LE Jian, DING Jingyuan, GUO Shengrong
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1458-1464. https://doi.org/10.16522/j.cnki.cjph.2022.10.012
    The nasal mucosal permeabilities and pharmacokinetic characteristics of one formulation of budesonide nasal spray and two formulations of mometasone furoate nasal spray for the treatment of allergic rhinitis in clinical practice were compared. In this study, the solubilities of two raw material drugs, the permeabilities of the drugs from three approved nasal sprays through goat nasal mucosa and retention amounts, and the drug concentrations in plasma and main tissues of the rats were determined. The results showed that the solubility of budesonide in ultrapure water at 25 ℃ was (18.92±0.03)μg/ml, while the solubility of mometasone furoate was lower than the lower limit of linearity (5 μg/ml). The permeation rate of budesonide from the nasal spray across goat nasal mucosa was 1.07 μg·cm–2·h–1, while the permeation rates of mometasone furoate from two formulations of the nasal spray were lower than 0.77 ng·cm–2·h–1. The retention amount of budesonide in goat nasal mucosa was 19.27 μg, which was significantly higher than those of mometasone furoate from two nasal sprays(2.27 and 2.61 μg, respectively). After administration to rats(equivalent to 5 times of human daily dose), the drug concentrations in plasma and tissue samples were all lower than 1 ng/ml. It indicated that the amounts of the drugs which had been absorbed into the systemic circulation were low and the clinical safeties of three approved nasal sprays were high.
  • Paper
    JIANG Shaobo, YANG Lei, WEI Xiaohui
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1446-1452. https://doi.org/10.16522/j.cnki.cjph.2022.10.010
    This study aimed to establish a top spray granulation for ibuprofen arginine(Ibu-Arg) granules by fluid-bed technology based on Quality by Design(QbD) concept and approach. The quality target product profile(QTPP) and critical quality attributes(CQAs) of Ibu-Arg granules were firstly identified. The relevant CQAs for top spray granulation process were screened out by risk assessment. The percent of the labeled content and particle size distribution(PSD) were selected as the key responses. Risk assessment on critical process parameters(CPPs) was performed by failure mode and effect analysis(FMEA) methodology. By the results of FMEA, spray rate and atomization pressure were screened out as the high-risk process variables to be further studied. A center composite design(CCD) was employed for process optimization. Experimental results were analyzed by response surface methodology(RSM), process parameters model was established for exploration of design space and optimized operation conditions by Design Expert 10 software. The optimized process parameters were established as follows: inlet air volume 55 – 70 m3/h, product temperature 40 – 45 ℃, atomization pressure 80 - 120 kPa and spray rate 17.5 – 18.5 g/min. By implementing validated experiments, the process was confirmed to be robust with high yield, the product CQAs such as the percent of the labeled content and PSD complied with quality requirements.
  • Perspectives & Review
    ZAN Mengqing, NIU Jianzhao, XU Mingdi, LIU Qian
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1402-1407. https://doi.org/10.16522/j.cnki.cjph.2022.10.004
    The concept of continuous manufacturing and process analysis technology is expounded, and the relevant guiding principles of continuous pharmaceutical manufacturing and the consideration of relevant control strategies are introduced. Then, the principles, characteristics and application examples of commonly used analytical tools, such as near-infrared spectroscopy, Raman spectroscopy, terahertz pulsed imaging, ultrasound technique and X-ray microscopy imaging technology, in the continuous pharmaceutical manufacturing process are summarized. Finally, the factors affecting the continuous manufacturing of pharmaceuticals and the difficulties in the application of process analysis technology are reviewed, and the development direction of continuous pharmaceutical manufacturing is prospected. It is hoped to provide a reference for the development of process analysis technology related to continuous manufacturing.
  • Perspectives & Review
    LI Manqi, WEI Liping, TAO Qiaoyu, HE Weiwei, CHANG Yan
    Chinese Journal of Pharmaceuticals. 2022, 53(12): 1671-1682. https://doi.org/10.16522/j.cnki.cjph.2022.12.001
    The efficient delivery of genes to target tissues or target cells by vectors is a critical step in gene therapy. Selecting a suitable, safe, and effective gene delivery vector is an urgent task in gene therapy. Gene therapy delivery vectors can be divided into two categories, viral vectors and nonviral vectors. In this review, the current application status and safety of viral vectors, synthetic nonviral vectors, and biological nonviral vectors are summarized, and the advantages and disadvantages of various delivery vectors are compared. Furthermore, the key points for evaluating the nonclinical safety of gene delivery vectors are summarized to provide references for the selection, application, and safety evaluation of vectors in the field of gene therapy.
  • Perspectives & Review
    CAO Meng, GE Yuanyuan, HU Yanchen, WANG Yamin, CAO Yi
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1394-1401. https://doi.org/10.16522/j.cnki.cjph.2022.10.003
    With the release of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) Q13 guideline and the approval of several oral solid dosage form drug products adopting continuous manufacturing techniques, the regulatory development in this area is receiving increasing attention. Material handling is an important part of a continuous manufacturing platform. In this paper, the material handling for continuous manufacturing of oral solid dosage forms is introduced through analyzing the technical characteristics of material input, continuous feeding and continuous mixing. Also, the concerns of supervision and inspection are studied from the aspects of process validation, robustness, facilities and equipment, process control, quality assurance and cleaning. For technical consideration, process equipment should handle materials continuously and stably, with risks controlled and losses reduced as much as possible, so it is necessary to have a deep understanding of material characteristics, scientifically design process equipment and carry out qualification and verification; while regulatory inspections may focus on continuous process-specific risks and their possible effects on product quality. Hopefully this paper could accelerate the application of continuous manufacturing in pharmaceutical industry together with the aid of cooperation of regulation agencies, industrial community as well as the whole society, making full use of process analysis technology, innovative testing methods and digital quality assurance to steadily manufacture qualified products, thus promote domestic pharmaceutical industry to a high level of modernization.
  • Paper
    CHEN Debao, SHENG Rong
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1274-1278. https://doi.org/10.16522/j.cnki.cjph.2022.09.006
    Ethyl (1R,5S,6S)-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate(2) was the key starting material of oseltamivir phosphate(1). Compound 3, the (1R,5R,6R)-diastereomer of 2, was synthesized as the standard control to evaluate the chiral purity of 2 as well as 1. With shikimic acid as starting material, compound 3 was obtained through esterification, 3-pentanone protection, 5-hydroxybenzylation, reductive ring opening of the ketals, 4-hydroxymethylsulfonylation, and alkalic hydrolysis. The structure was conformed by 1H NMR, 13C NMR and ESI-MS.
  • Perspectives & Review
    HUANG Lu, SUN Jian, WANG Mingwei, GE Fan
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1408-1418. https://doi.org/10.16522/j.cnki.cjph.2022.10.005
    Three small molecule JAK inhibitors, namely ruxolitinib phosphate, fedratinib hydrochloride, and pacritinib citrate, for the treatment of myelofibrosis have been marketed worldwide. Their research progress and the published patents on chemical compound, crystalline form, salt form, process, formulation, drug combination, new use, and product derivatives, as well as the compounds in pharmaceutical research are unscrambled and researched in this paper. It is hoped to provide patent information and reference for Chinese pharmaceutical companies conducting project establishment and development, new patent mining, patent protection, and patent layout.
  • Paper
    LI Min, HONG Bibo, CHEN Yinbo, HU Liang, LIU Xiangkui
    Chinese Journal of Pharmaceuticals. 2022, 53(07): 962-968. https://doi.org/10.16522/j.cnki.cjph.2022.07.005
    In this report, 4-nitrophenylacetic acid(5) reacted with acetic anhydride to give 1-(4-nitrophenyl)- propan-2-one(6). Condensation of 6 with ethyl cyanoacetate followed by cyclization with sulfur afforded ethyl 2-amino- 4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate(7), which was acylated with butyl chloroformate to afford ethyl 2-[(butoxycarbonyl)amino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate(8). Then 8 was substituted with 2,6-difluorobenzyl chloride and the resulting product ethyl 2-[(butoxycarbonyl)(2,6-difluorobenzyl)amino]-4-methyl- 5-(4-nitrophenyl)thiophene-3-carboxylate(9) was reacted with N-bromosuccinimide and dimethylamine to generate ethyl 2-[(butoxycarbonyl)(2,6-difluorobenzyl)amino]-4-[(dimethylamino)methyl]-5-(4-nitrophenyl)thiophene- 3-carboxylate(11). And then 2-[(butoxycarbonyl)(2,6-difluorobenzyl)amino]-4-[(dimethylamino)methyl]-5-(4- nitrophenyl)thiophene-3-carboxylic acid(12) was obtained after hydrolysis of 11 with potassium hydroxide. Next, 12 was subjected to condensation with 3-amino-6-methoxypyridazine and cyclization with sodium methoxide to result in 1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno[2,3-d]- pyrimidine-2,4(1H,3H)-dione(14). Then 14 reacted with hydrogen under catalysis of Pd/C to afford 6-(4-aminophenyl)- 1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione(15). Finally, Substitution of 15 with phenyl chloroformate and methoxamine hydrochloride reduction to prepare relugolix(1) with an overall yield of 22.9%(based on 5).
  • Paper
    ZOU Xixi, GAO Zhenye, ZHANG Weijie, WU Fei, JIN Tuo
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1439-1445. https://doi.org/10.16522/j.cnki.cjph.2022.10.009
    Coagulation factor Ⅷ(F8), one of the most common drug for treating hemophilia, has the disadvantage of a short half-life(10 - 14 h), and its injection needs to be administered several times a week. In order to obtain a long-acting sustained-release preparation of F8, a triblock polymer PLGA-PEG-PLGA with reverse thermosensitive properties synthesized by thermal ring-opening polymerization was used as a thermosensitive hydrogel matrix to prepare a novel long-acting sustained-release preparation loaded with F8. This thermosensitive hydrogels of F8 was an aqueous solution below 4 ℃ and turns into gel at around 37 ℃. In vitro activity and in vitro and in vivo release behaviors of F8-loaded hydrogel formulation were investigated. The results of in vitro release test showed that 17.4% of the drug loading, namely initial burst release, was observed on d1 and the drug release from the gels could maintain for 3 weeks. The cumulative amount of F8 at 22 d reached 92%. The results showed that the bioactivities of F8 in the solution before and after gelation was more than 97%, and the bioactivities of F8 in release media were all above 60% during the release process, indicating the stability of F8 in the thermosensitive hydrogels. The results of in vivo test showed that F8 quickly reached the peak plasma concentration[(113.21±14.50)ng/ml] within one hour after injection administration to the rats. During the whole release period, the plasma concentration could maintain above the lowest therapeutic concentration(10 ng/ml) for up to 15 days. In this study, we successfully developed a long-acting sustained-release formulation of F8, which had potential for clinical application.
  • Perspectives & Review
    ZENG Yongnian, WANG Chenyuan, ZHANG Wen, LI Wei
    Chinese Journal of Pharmaceuticals. 2022, 53(08): 1081-1090. https://doi.org/10.16522/j.cnki.cjph.2022.08.001
    Influenza has posed a severe threat to global public health security, and vaccination is an effective way to prevent and control the spread of influenza. Influenza vaccines are usually intramuscularly injected. There are many constraints imposed on this traditional vaccination method, such as the need for medical personnel, pain caused by the injection, and low patient compliance, leading to a low rate of influenza vaccination and inadequate vaccine effectiveness. Microneedle is a new transdermal drug delivery method that shows excellent superiority in delivering influenza vaccines for its advantages of delivering drugs without pain, enabling self-administration, improving patient compliance, avoiding cross-infection, and causing low cost. Besides the fact that skin has many antigen-presenting cells, especially Langerhans cells, that makes skin an ideal place to get vaccinated against influenza. Therefore, transdermal delivery of vaccines by microneedles can be an excellent alternative to traditional intramuscular injection and has a great potential application. In this review, the types of microneedles utilized to deliver influenza vaccines are summarized, the strategies used to load influenza vaccines into microneedles are analyzed, and future research perspectives are included in order to provide some references for further development and application of microneedles for transdermal delivery of influenza vaccines.
  • 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.
  • 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.
  • QIAN Zhuang, ZHANG Yaqun, LI Yanchuan, CHEN Xiaojun, LYU Jianjun
    Chinese Journal of Pharmaceuticals.
    Accepted: 2022-11-30
    在药物临床前安全性评价啮齿动物致癌试验中,肿瘤性病变是判断药物是否具有潜在致癌作用的重要依据。分析一个致癌试验中的肿瘤数据是一个非常复杂的过程,某些情况下将同一器官或组织或者不同器官/组织中形态学相似的良、恶性肿瘤的发生率合并进行统计分析是合理的,特别是一些全身性肿瘤。该文简要介绍美国国家毒理学项目中心推荐的啮齿动物致癌试验肿瘤合并的基本原则、区分良恶性肿瘤及细分肿瘤的意义以及肿瘤合并标准,以期为我国药物临床前安全性评价啮齿动物致癌试验的结果分析和基于证据权重进行药物的潜在致癌作用判断提供一定参考。
  • Paper
    GUO Chen, FENG Jun, CAI Zhengyan, DONG Yuanzhen, YANG Guiying
    Chinese Journal of Pharmaceuticals. 2022, 53(08): 1133-1140. https://doi.org/10.16522/j.cnki.cjph.2022.08.006
    In this paper, using Rink Amide MBHA resin as the carrier, Fmoc-protected amino acids as the raw materials, 1-hydroxybenzotriazole(HOBt)/N,N'-diisopropylcarbodiimide(DIC) as the condensation reagents, and trifluoroacetic acid(TFA) system as the lysis solution, the prototype setmelanotide(1) crude peptide was synthesized by a solid-phase synthesis method according to the amino acid sequence of 1, a weight loss agent. Then the oxidative type 1 was obtained by hydrogen peroxide oxidation method. After separation and purification by the RP-HPLC method, the 1 purified product with a purity of more than 98% was obtained. The total yield of this process was about 47%. The related process parameters in the preparation process of 1 were discussed and optimized. In line with the principle of improving yield and reducing cost, the process parameters of each link were clarified and kept within a controllable range, which laid the foundation for its industrialized large-scale production and also provided a technical reference for other peptide drug researches.
  • Paper
    FANG Zhikun, ZHU Yang, YAO Changliang
    Chinese Journal of Pharmaceuticals. 2022, 53(08): 1141-1147. https://doi.org/10.16522/j.cnki.cjph.2022.08.007
    To improve quality control of remdesivir, the key chiral impurities easily generated in the production process of remdesivir were designed and synthesized. The structures of these compounds included (S)-2-ethylbutyl 2-[[(S)-[[(2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl]- methoxy](phenoxy)phosphoryl]amino]propanoate, (S)-2-[(R)-(2R,3S,4R,5R)]-type and (S)-2-[(R)-(2R,3S,4R,5S)]- type optical isomers were confirmed by MS and NMR. This method was suitable for laboratory synthesis due to its mild reaction conditions, high yield and no need for chiral separation.
  • Paper
    SHAO Tianshu, GUO Lei, LI Xiao, ZHOU Changming
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1494-1498. https://doi.org/10.16522/j.cnki.cjph.2022.10.016
    An HPLC method was established to determine the content of cystine(1) and cysteine(2) in compound amino acid injection(18AA). The Waters SunFire C18 column(4.6 mm×150 mm, 3.5 μm) was used, and the analysis was carried out in the gradient elution mode, with ammonium sulfate buffer∶acetonitrile(97∶3) as mobile phase A, acetonitrile as mobile phase B. The detection wavelength was 205 nm, the column temperature was 40 ℃, and the injection volume was 25 μl. The results showed that it was linear for 1 and 2 in the 0.002 - 0.040 mg/ml and 0.001 - 0.027 mg/ml, respectively. The detection limits were 0.99 and 0.67 μg/ml, respectively. The mean recoveries(n=9) of 1 and 2 were 102.3% and 100.5%, with the RSDs of 1.6% and 1.5%. The results of the simulation test on the formulation showed that the content of 1 in the sample was lower than the labeled amount, which might be related to the addition of the antioxidant sodium bisulfite. The established method is simple, rapid and accurate, which can provide a reference for the determination of 1 and 2 in compound amino acid injection.
  • Paper
    PENG Yanjie, ZHANG Lin, PANG Zheng, ZHONG Lijun, LIU Fang
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1453-1457. https://doi.org/10.16522/j.cnki.cjph.2022.10.011
    TP25 is a highly active recombinant immunotoxin that targets human epidermal growth factor receptor 2(HER2) positive breast cancer. In this study, the lyoprotectant was selected and the lyophilization procedure of TP25 was optimized through the appearance of lyophilized products and half maximal inhibitory concentration(IC50) of reconstituted TP25 determined by tetrazolium method. The results showed that the lyophilized product in the group with 3.5 μg/ml of human albumin and 40 μg/ml of mannitol as lyoprotectant combination had a smooth and full appearance, and the activity recovery rate of the product was the highest. This study promoted the development process of TP25 industrial preparation and also provided ideas for the research of lyophilization of similar biological products.
  • ZHAO Ying, XU Kexin, HU Hao, WANG Huimei, WANG Lianyan
    Chinese Journal of Pharmaceuticals.
    Accepted: 2023-01-30
    In the treatment of bladder dysfunctional diseases and bladder tumors, as an emerging therapeutic strategy, nanotechnology provides promising applications for efficient drug delivery in vivo due to its effective size effect and targeting modifications. As an effective administration route for the treatment of bladder diseases, intravesical instillation shows superior efficacy compared with systemic administration. However, periodic urination flushes out the instilled drug, resulting in a reduced duration of action. In addition, the existence of a bladder permeability barrier limits drug penetration into the inflammatory sites and tumor tissues. Therefore, it is crucial to develop a novel nano-drug delivery system. This study reviews research related to nano-drug delivery systems for the treatment of bladder dysfunctional diseases and bladder tumors, with the aim of providing more ideas and methods for improvement of clinical treatments in the future.
  • 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
    LI Mingyan, YANG Liuliu, WANG Bing, CHEN Fang
    Chinese Journal of Pharmaceuticals. 2022, 53(08): 1091-1100. https://doi.org/10.16522/j.cnki.cjph.2022.08.002
    Electrospinning technology is a kind of electrohydrodynamic method which can continuously produce nanofibers by atomizing the polymer solution into a fluid jet in a high voltage electrostatic field. Electrospun nanofibers have gradually attracted attention in the pharmaceutical industry for the advantages of high specific surface area, high porosity, and adjustable morphology and diameter. This review addresses the equipment components, solution properties, process parameters of electrospinning, and types of drug-loaded nanofibers. Further, the applied actuality and developing prospects in the field of pharmaceuticals are also introduced to provide literature support for the further development of electrospinning.
  • Perspectives & Review
    OUYANG Junfang, ZHANG Yongjie, CHEN Xijing
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1240-1250. https://doi.org/10.16522/j.cnki.cjph.2022.09.002
    Protein and peptide drugs(PPDs) have good specificity, biocompatibility and good therapeutic effects. Due to the better patient compliance and safety of oral administration route, the oral delivery of PPDs has become one of the current research hotspots in the field of materials science and pharmaceuticals. However, the stability and absorption of oral biomacromolecules in the gastrointestinal tract are restricted. Lipid nanocarriers can effectively encapsulate lipophilic or hydrophilic PPDs through chemical modification, hydrophobic ion pairing and other methods. At the same time, the surface modification of lipid nanocarriers can overcome many physiological barriers of the oral absorption, which in turn promote the dissolution of PPDs in mixed micelles and strengthen lymphatic uptake. Therefore, it has good biocompatibility and high in vivo stability. In this paper, the encapsulation methods of lipid nanocarriers for PPDs and the corresponding mechanisms of overcoming physiological barriers are reviewed, and the important properties and latest research progress of lipid nanocarriers to improve the oral bioavailability of PPDs are introduced, the potential application and development prospects are further prospected as well.
  • Perspectives & Review
    ZENG Sumei, CAI Wenjian, ZENG Shaoqun, YAO Meicun, YUE Feng
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1251-1261. https://doi.org/10.16522/j.cnki.cjph.2022.09.003
    Wet media milling technology, with the advantages of simple operation, avoiding the use of organic solvents, and high drug loading, has been proven to be a preparation technology for bioavailability enhancement of poorly water-soluble drugs, especially for injectable nanosuspensions. This review summarizes the research progress of injectable nanosuspension prepared by wet media milling technology and introduces the active pharmaceutical ingredients, stabilizers, dispersants, and cryoprotectants. The process parameters and critical quality attributes are also analyzed to provide a basis for the research and development of injectable nanosuspensions prepared by wet media milling technology, so as to promote the transition of safe, effective, quality-controllable injectable nanosuspensions from experimental research to clinical applications at a faster speed.
  • Perspectives & Review
    LU Wangding, GE Yuanyuan, CHEN Guiliang , WANG Jian, HE Jun, LUO Huafei, ZHANG Jingchen
    Chinese Journal of Pharmaceuticals. 2022, 53(12): 1683-1688. https://doi.org/10.16522/j.cnki.cjph.2022.12.002
    Drug-device combination products are a special class of drug product with relatively high technical barriers. The research of their generic products has been a hot and difficult issue. However, the success rate of the product development is extremely low. Compared with ordinary dosage forms, human factor should be systematically considered in the development of generic drug-device products. Currently, there is no guideline for human factors engineering research in China. This study conducts a comparative analysis of factors based on the latest guidelines from FDA, such as "Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA: Draft Guidance for Industry ", and "Bridging for Drug-Device and Biologic-Device Combination Products: Draft Guidance for Industry ". Several case studies are applied for the illustration of some key considerations on development of generic drug-device combination products to provide a reference for researchers.
  • Paper
    WANG Kexin, WANG Yapeng, LU Jianguang, YANG Guiying, HUA Haoju, FENG Jun
    Chinese Journal of Pharmaceuticals. 2022, 53(08): 1148-1154. https://doi.org/10.16522/j.cnki.cjph.2022.08.008
    This paper reported the fermentation expression, separation and purification, activity assay, and enzymatic property analysis of pig-baboon chimeric urate oxidase(1). Recombinant Escherichia coli high-density fermentation technique was used to express 1 in inclusion body form, and the fermentation yield was 6.88 g/L. The inclusion bodies were extracted by alkali solution and purified by anion-exchange chromatography to obtain the target protein with a purity of 99.61%, and the total enzyme activity yield was 78.95%. According to the results of mass spectrometric identification and enzyme activity analysis, the relative molecular weight of a single subunit was correct, and the specific activity reached 6.25 u/mg, which proved that 1 was correctly expressed in E. coli and capable of degrading uric acid. This study provided a methodological reference for efficiently preparing 1 drugs.
  • Paper
    LENG Feng, LI Xiaolu, REN Fengzhi, LI Ning, YANG Zhaohui
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1504-1510. https://doi.org/10.16522/j.cnki.cjph.2022.10.018
    The effects of the crystallization temperature, the dripping rate of antisolvent adding, the initial concentration of the crystallization and the occasion of seed crystal adding on the polymorph formation of fusidic acid(1) were investigated by the orthogonal experiment. The results showed that the crystallization temperature was the key factor affecting the polymorph formation of 1, followed by the dripping rate of antisolvent. Anhydrous 1 was formed when the antisolvent dripping rate was 0.1 ml/min and crystallized at 40 ℃, while 1 hemihydrate was obtained with more than 0.2 ml/min of dripping rate and 20 – 30 ℃ of crystallization temperature. The crystallization process of 1 was recorded online in real time with process analysis technology tools, and the transformation process of 1 crystal forms was revealed. Powder X-ray diffractometry(PXRD) and infrared spectroscopy(IR) were applied for both anhydrate and hemihydrate products. The analysis results were consistent with the literature reports. The experimental results could provide technical guidance for the large-scale production of 1 hemihydrate.
  • 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
    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).
  • Pharmaceutical Management & Information
    LU Shihua, LI Shan, JIANG Mingyan, ZHAO Jie, JIANG Shoujun, ZHANG Jie
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1516-1521. https://doi.org/10.16522/j.cnki.cjph.2022.10.020
    注射剂类药品品种为高风险品种,为确保药品的质量安全,充分了解注射剂类药品生产企业在生产过程中存在缺 陷和风险的规律及特点就显得尤为重要。文章分析汇总了2020 年广西辖区内11 家注射剂类药品生产企业接受风险防控 检查产生的缺陷情况,结果显示,企业在无菌工艺模拟试验、无菌操作、洁净区环境监测、质量管理体系、偏差管理、 文件记录信息或内容以及工艺验证和确认7 个方面存在不足。建议注射剂生产企业加强风险管理意识,重点关注生产过 程中出现的薄弱环节,持续提升注射剂企业生产过程中的无菌保障水平,全面提高无菌药品的质量。
  • Pharmaceutical Management & Information
    YUAN Lijia, WANG Jian
    Chinese Journal of Pharmaceuticals. 2022, 53(12): 1810-1813. https://doi.org/10.16522/j.cnki.cjph.2022.12.019
    吸入制剂在疾病治疗中发挥着越来越重要的作用,也是我国近年来新型制剂开发研究的热点之一。该研究简要分 析了过去 5 年来我国吸入制剂开发应用与审批监管现状,剖析新形式下吸入制剂产业发展存在的关键问题,为我国吸入 制剂的开发提供参考。
  • Paper
    XU Haiyue, WU Yong, LI Lele, HUANG Zongqing, HUA Haoju, FENG Jun
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1432-1438. https://doi.org/10.16522/j.cnki.cjph.2022.10.008
    Ubiquitin-like protein-specific protease 1(Ulp1) is a crucial tool for protease in removing small ubiquitin-related modifier protein(SUMO) tags from the fusion protein. It has been widely used in the production of recombinant peptides and proteins. The easy aggregation of Ulp1 protein brings many challenges to the downstream separation and purification process. An S13-Ulp1 fusion protein was designed and recombinantly expressed to improve the solubility of Ulp1, reduce its aggregation, and decrease its isoelectric point for the convenient purification by anion exchange chromatography. After optimizing the parameters of fermentation and clarification, a preparation process of S13- Ulp1 fusion protein with high yield and simple purification was established. Finally, for S13-Ulp1, the fermentation yield reached 2.34 g/L, the total yield of downstream separation and purification was 64%, and the purity shown in SDS-PAGE analysis was about 95%. The enzymatic reaction assay showed that S13-Ulp1 fusion had the same specificity as Ulp1, which could efficiently remove the SUMO tag to obtain the targeted peptide.
  • Perspectives & Review
    LIU Xinyang, OU Shuiping, ZHAO Yun, YANG Ming, WANG Sen
    Chinese Journal of Pharmaceuticals. 2022, 53(12): 1699-1705. https://doi.org/10.16522/j.cnki.cjph.2022.12.004
    The selection of an effective taste masking technique is the key to improving the taste of drugs, and the research on drug taste masking techniques focuses on the sensitivity and accuracy of bitterness evaluation methods. This paper aims to review the in vivo and in vitro evaluation techniques of drug bitterness, and put an emphasis on advantages, disadvantages, and applicability of these techniques. It is suggested that the scope of determination should be standardized after the evaluation by traditional human taste panel method under the premise of ensuring safety, and then other methods, for example, electronic tongue method, should be used to screen other similar preparations and formulations to provide some references for bitter taste masking research.
  • Paper
    JIN Longlong, ZHANG Yajun, SUN Huimin, LU Yong, WU Xianfu
    Chinese Journal of Pharmaceuticals. 2022, 53(12): 1715-1718. https://doi.org/10.16522/j.cnki.cjph.2022.12.006
    In order to perform the quality control of mifepristone(1), its 17-stereoisomer, 11β-[4-(N,Ndimethylamino)- 1-phenyl]-17α-hydroxy-17β-(1-propinyl)-estra-4,9-dien-3-one(1'), was synthesized. The target product 1' was prepared from easily available 1 via esterification with fuming nitric acid, hydrolysis and inversion of configuration in the presence of AgNO3, with a purity of more than 95%. Meanwhile, its absolute configuration (8S,11R,13S,14S,17R) was determined by electronic circular dichroism.
  • 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.