Chinese Journal of Pharmaceuticals

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Perspectives & Review

Application of Injectable Thermosensitive Gels in Local Cancer Therapy

GUAN Li, ZHANG Zipeng, LIU Yongjun, ZHANG Na

2020, 51(09): 1091-1098. https://doi.org/10.16522/j.cnki.cjph.2020.09.001

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Injectable thermosensitive gels have gained increasing attention in recent years as novel local drug delivery system for antineoplastics, which have a number of advantages including phase transition with temperature change, precise delivery of drug, sustained- and controlled-release of drugs and excellent biocompatibility. In this review, the advantages, commonly used materials and recent applications of injectable thermosensitive gels in local cancer therapy are summarized, which can provide some references for the development and clinical application of injectable thermosensitive gels.

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Perspectives & Review

In vitro-in vivo Research Methods and Significance of Binding of Drugs with Melanin

WANG Ruonan, QIAN Yimin, RUAN Bin, SONG Shuo, LI Hua

2020, 51(09): 1099-1106. https://doi.org/10.16522/j.cnki.cjph.2020.09.002

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Melanin is a kind of polymers synthesized in melanosomes. Studies have shown that basic and lipophilic aromatic compounds can theoretically bind with melanin, causing accumulation of drugs in tissues containing melanin, changing their local pharmacokinetic and pharmacodynamic profiles to introduce potential toxicity. However, in the field of drug delivery, the melanin binding can be used to increase the targeting of drugs for ocular fundus diseases. The current research methods for drugs binding with melanin include in vitro, in vivo, and in silico modeling, but there are no research methods based on mechanistic understanding of melanin binding with drugs. Herein the in vitro and in vivo research methods of melanin binding in recent years, the applicability and scientificity are summerized in order to provide effective references for non-clinical research of ophthalmic drugs.

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Perspectives & Review

Research Progresses of Urate Oxidase Drugs

WANG Yapeng, LU Jianguang, MA Jie, ZHANG Qingbin, FENG Jun

2020, 51(09): 1107-1117. https://doi.org/10.16522/j.cnki.cjph.2020.09.003

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Urate oxidase is an important enzyme in the purine metabolism pathway, which can catalyze the production of allantoin from uric acid. The lack of urate oxidase will lead to a decline in the ability of uric acid to metabolize, so it is easy to suffer from various diseases caused by the accumulation of uric acid. The three urate oxidase drugs that have been on the market still have problems such as short half-life and strong immunogenicity. Therefore, the researchers used mutant construction, modification, and drug delivery system optimization methods to modify urate oxidase drugs, and obtained multiple candidate drugs. This paper reviewed the biological and clinical significance of urate oxidase, marketed drugs and drugs under development, which provided references for the future development of such drugs.

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Synthesis and Cytotoxicity Evaluation of Mitochondria-targeted Fluorescent Probes

HAO Zhiqiang, HU Yixin, XIE Fangzhou, FU Lei

2020, 51(09): 1118-1132. https://doi.org/10.16522/j.cnki.cjph.2020.09.004

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Twelve mitochondria-targeted fluorescent probes as new compounds that have not been reported in the literature were synthesized by coupling fluorescein ethyl ester with five respective lipophilic cations via four different types of linkers. The resulting twelve probes were evaluated for their mitochondrial localization abilities, cellular uptakes and cytotoxicities by laser scanning confocal microscopy imaging, flow cytometry and cytotoxicity assays. It was found that all synthesized probes were capable of localizing within mitochondria under conventional cell culture conditions in vitro, whereas their cellular uptakes were dependent on the nature of lipophilic cations and linkers. The overall optimal probe was the one with a triphenylphosphonium cation and aliphatic linker.

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Improved Synthetic Process of Cinacalcet Hydrochloride

LU Jun, WANG Dong, ZHOU Haiquan, FENG Lingling, HAO Zhongyan

2020, 51(09): 1133-1135. https://doi.org/10.16522/j.cnki.cjph.2020.09.005

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The synthetic process of cinacalcet hydrochloride(1) was improved in this report. 3-Trifluoromethyl phenylpropionic acid(3) was synthesized from 3-trifluoromethyl phenylacrylic acid(2) with ammonium formate instead of hydrogen as hydrogen source in the catalyst of palladium carbon. Then (R)-N-(1-naphthylethyl)-3-(3-trifluoromethyl)- phenylpropionamide(5) was synthesized by the reaction of (R)-1-(1-naphthyl)ethylamine(4) and 3 in the presence of N,N'-carbonyldiimidazole(CDI), and the yield was increased from 71％ to 93％. Compound 5 was reduced with sodium borohydride in the presence of boron trifluoride, and then followed by salt formation with hydrochloric acid to give 1 with a purity of 99.97％ and a total yield of 78％. This improved process had the advantages of simple operation, mild reaction conditions and high safety, which was more suitable for industrial production.

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Improved Synthetic Process of Masalazine

ZHANG Wenwen, WENG Zhibing, GONG Bingqian,WANG Yupeng,YE Aiying

2020, 51(09): 1136-1138. https://doi.org/10.16522/j.cnki.cjph.2020.09.006

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Masalazine in a total yield of 54％ was obtained via three steps of improved Duff formylation, oxidization in presence of CuBr2/TBHP/t-BuOK, and reduction in the SnCl2/HCl system, from p-nitrophenol as starting material. The structures of intermediates and product were characterized by IR and 1H NMR. p-TSOH used in the process of Duff formylation not only simplified the operation steps, but also improved the yield to 93％, higher than that reported in the literature(67％). The whole route was easy to operate and suitable for industrial production.

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Synthesis and Identification of the Related Substances of Parecoxib Sodium

QI Chuangyu

2020, 51(09): 1139-1143. https://doi.org/10.16522/j.cnki.cjph.2020.09.007

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In order to control the quality of parecoxib sodium, five related substances of parecoxib sodium, namely (Z)-diphenylethan-1-one oxime(related substance A), 3-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonyl chloride(related substance B), ethyl 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonate(related substance C), methyl 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonate(related substance D), and isopropyl 4-(5-methyl-3-phenylisoxazol- 4-yl)benzenesulfonate(related substance E), were synthesized and confirmed by NMR and HRMS in this report. Among them, the related substances D and E have not been reported in literature. The geometric configuration of deoxybenzoin oxime was proved as E-form by SXRD. 2D-NMR afforded the correct structure of mono-substituted sulfonyl chloride byproduct (related substance B).

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Improved Synthetic Process of Key Intermediate of Risperidone

JIN Yongjun, HUANG Wenfeng, HU Jiaxing, ZHANG Jian, YU Wenlong

2020, 51(09): 1144-1146. https://doi.org/10.16522/j.cnki.cjph.2020.09.008

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The improved synthetic process of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]- pyrimidin-4-one(1), a key intermediate of risperidone, was reported. 2-Aminopyridine(3) reacted with 2-acetyl-γ- butyrolactone(4) in POCl3 to give 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(2), followed by the hydrogenation catalyzed by Pd/C to obtain the target compound with a total yield of 72％(based on 3), and the purity was more than 99.5％. Feeding orders had a significant effect on the yield of intermediate 2. The toluene solution of 3 and 4 was added dropwise to POCl3, and the yield by the above feeding method could be increased from 52％ to 80％. In the hydrogenation reaction, 9％ hydrochloric acid aqueous solution as the solvent(about 4 eq HCl of 2) could help to inhibit the formation of dechlorination impurity. This process reported herein was suitable for industrial production.

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Improved Synthetic Process of 3'-Amino-2'-hydroxybiphenyl-3-carboxylic Acid

GAO Ji, WANG Guorui, ZANG Chao, ZHANG Guimin

2020, 51(09): 1147-1149. https://doi.org/10.16522/j.cnki.cjph.2020.09.009

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The synthetic process of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid(1), a key intermediate of eltrombopag, was improved in this report. 2-Bromo-6-nitrophenol(2) was subjected to hydroxyl protection to give 1-bromo-2-methoxy-3-nitrobenzene(3), which was further treated with 3-carboxyphenylboronic acid(4) to afford 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid(5) via Suzuki coupling reaction. Compound 5 was refluxing in the mixed solution of hydrobromic acid and acetic acid to obtain 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid(6), then followed by reduction with Raney nickel/hydrogen to give 1 with a purity of 99.82％ and a total yield of 84％(based on 2). In this process, Raney nickel/hydrogen system was used to the redution of 6 under normal pressure condition, thus avoiding high pressure operation. This synthetic route had some advantages of mild reaction condition, simple operation and high purity of the product, which were more suitable for industrial production.

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Effect of DNMT3A on the Methylation of ATF3 Gene in CHO Cells

ZHANG Mengxiao, WANG Jiaxian, ZHU Jianwei, LU Huili

2020, 51(09): 1150-1157. https://doi.org/10.16522/j.cnki.cjph.2020.09.010

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Activate transcription factor 3(ATF3) is an early stress response gene that can affect the proliferation, differentiation, transformation and apoptosis of cells. Chinese hamster ovary(CHO) cell is one of the main host cells for the production of recombinant protein, monoclonal antibody and other biological macromolecular drugs. ATF3 can promote tumor cell proliferation and anti-apoptosis, and ATF3 may have a promoting effect on the growth of CHO cells. Therefore, we conducted an in-depth study on the methylation level of ATF3 in CHO cells. The methylation level of ATF3 in CHO-K1 cells was detected by bisulfite sequencing, and it was found that the cytosine-phosphoric acid-guanine(CpG) methylation in the promoter region of ATF3 was as high as 90％. In order to study the upstream regulatory mechanism of ATF3 methylation, CHO-K1 knocked out DNA methyl transferase 3A(DNMT3A) was constructed to study the effect of DNMT3A on the level of ATF3 methylation. The results showed that after knocking out DNMT3A, the ATF3 methylation level in CHO-K1 cells was reduced to 0, which proved the regulatory effect of DNMT3A on ATF3 methylation. This paper provides a theoretical basis for the study of ATF3 gene regulation in CHO cells and the subsequent transformation of CHO cell lines.

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Process Validation and in vitro-in vivo Evaluation of Montelukast Sodium Tablets

XUN Mingjin, ZHANG Guimin, FENG Zhong, CUI Qingyan, JIANG Xiuting

2020, 51(09): 1158-1164. https://doi.org/10.16522/j.cnki.cjph.2020.09.011

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According to the concept of quality by design(QbD), the critical quality attributes(CQAs) of montelukast sodium tablets were clarified, then the risk analysis was carried out to confirm the influencing factors of formulation and process. The equipment and preparation process were evaluated and verified. The drug contents of three verification batches were all above 95％, total impurities were below 1％, and other inspection items met the quality requirements. The dissolution behaviors of self-made tablets and reference listed drug(RLD, Singulair?) in 0.5％ sodium dodecyl sulfate solution, pH 1.2 and pH 6.8 media were investigated and compared, and the results showing the similarity between self-made tablets and RLD. There were no statistically significant differences in the pharmacokinetic parameters of 36 healthy volunteers after single oral administration of self-made tablets or RLD under fasting condition or fed condition(P>0.05). Under fasting and fed conditions, the oral relative bioavailabilities of self-made tablets were (104.69±10.32)％ and (102.60±9.57)％, respectively.

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Investigation on Formulation and Preparation Process of Trihexyphenidyl Hydrochloride Liposomes for Nasal Administration

PAN Tao, XIAO Xue, FEI Peizhe, ZHOU Jianwen, HAN Cuiyan

2020, 51(09): 1165-1171. https://doi.org/10.16522/j.cnki.cjph.2020.09.012

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In this paper, the preparation methods for trihexyphenidyl hydrochloride liposomes for nasal administration were firstly screened with encapsulation efficiency, particle size and ζ potential as the indexes, then the formulation and process of the liposomes were optimized by single factor test and central composite design-response surface methodology with encapsulation efficiency as the index. The results showed that the optimal liposomes were prepared at film forming temperature of 50 ℃ and incubated at hydration temperature of 30 ℃ for 30 min by ethanol injection method with the mass ratio of lecithin to cholesterol of 6.02, the lecithin-to-drug ratio of 41.96, and organicwater phase volume ratio of 1∶1. The particle size, ζ potential, encapsulation efficiency and drug loading of the prepared liposomes were (73.23±0.98)nm, (6.29±0.60)mV, (91.49±2.77)％ and (1.69±0.08)％, respectively. The cumulative release at 12 h of trihexyphenidyl hydrochloride from the liposomes was (84.1±1.9)％ in pH 7.4 phosphate buffer. The release data fit well to a Higuchi model.

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A Novel Flow-through Cell Method Based on Dialysis Adapter for Evaluating in vitro Release of Paclitaxel Polymeric Micelles

SHANG Pingping, HAO Guizhou, ZHENG Hua, CHEN Xiaowei, ZHANG Guimin

2020, 51(09): 1172-1177. https://doi.org/10.16522/j.cnki.cjph.2020.09.013

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The poly(ethylene glycol)-poly(DL-lactide) block copolymers with different of molecular weight(Mw) values were synthesized to prepare the paclitaxel polymeric micelles. A flow-through cell method based on dialysis adapter for in vitro release testing of paclitaxel polymeric micelles was established, and the influences of type and molecular weight cut-off(MWCO) of dialysis membrane, flow rate of flow through cell, amount of glass beads placed in cell and sample concentration on in vitro release behavior of paclitaxel from the prepared micelles were investigated. Moreover, this method was adopted to testing the release of paclitaxel-loaded preparations, namely the self-made micelles and the commercial injection and liposomes. The results showed that the type and MWCO of the dialysis membrane had a certain effect on the in vitro release of the micelles; both flow rate and amount of glass beads had little effect on the release results; but the sample concentration had a significant effect on the test results. The release behaviors of different dosage forms of paclitaxel tested by this method were quite different, while there were only slight differences among the micelles with different MW polymers in the early stage of release.

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Effect of Different Sources on Properties and Functions of HPMC

GONG Yanchang, YANG Baixue, SUN Ruimeng, SUN Huimin, LI Sanming

2020, 51(09): 1178-1183. https://doi.org/10.16522/j.cnki.cjph.2020.09.014

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The particle size and size distribution, wettability, flowability and compressibility of different sources of hydroxypropyl methyl cellulose(HPMC) were measured, and thermogravimetric analysis and differential scanning calorimetry were also conducted. Further, blank matrix tablets were prepared with HPMC from different sources, and their differences in the properties of water absorption, swelling and erosion were compared by weighing method. The results showed that there were certain differences in particle size and size distribution, wettability, flowability and compressibility among the HPMC products from different sources. Correspondingly, the water absorption rate constant, expansion index and erosion rate constant of their matrix tablets were different. The properties of HPMC with same viscosity but different sources were quite different, which subsequently affected the erosion and swelling properties of the matrix tablets. Therefore, it is of great significance to investigate the impact of the differences in the properties of HPMC from different sources on the quality of pharmaceutical preparations and even the development of generic drugs.

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Development and Application of the Proficiency Test Program for Staphylococcus Aureus Detection in Pharmaceuticals

YANG Yan, FAN Yiling, LI Fang, QIN Feng, YANG Meicheng

2020, 51(09): 1184-1188. https://doi.org/10.16522/j.cnki.cjph.2020.09.015

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According to the procedures prescribed by China National Accreditation Service for Conformity Assessment(CNAS), the proficiency test samples of Staphylococcus aureus containing drug substrates was produced in this study, and they were used to carry out proficiency test in different laboratories. Univariate analysis of variance was used to test the uniformity of the prepared proficiency test samples, and the t-test was used to investigate the transport stability and storage stability of the samples. The results showed that all the samples met the requirements. In the implementation of assessment application, the data collusion was prevented by adding interference samples and sample groups. The report test results showed that, in the 63 tested laboratories, 53 laboratories were qualified and 10 were unqualified. This proficiency test has formulated an objective and reasonable evaluation plan, which provides a valuable reference for the ability verification of drug microbial detection.

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Purity Determination of Human Immunoglobulin for Intravenous Injection by Agarose Gel Electrophoresis

KE Bingbing, WANG Derong, WU Jianxiang, XIE Yuyuan, JIANG Hong, GUO Jianghong

2020, 51(09): 1189-1193. https://doi.org/10.16522/j.cnki.cjph.2020.09.016

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An agarose gel electrophoresis method was established to determine the purity of human immunoglobulin for intravenous injection. The automatic electrophoresis instrument and its matching kit were used, with the 0.35％ acid blue as staining solution. The volume of the staining solution was 800 μl, and the sample volume was 50 μl. 115 Batches of human immunoglobulin for intravenous injection samples were tested, and results were compared with those of the cellulose acetate membrane electrophoresis method. The results showed that the quantitative determination interval of agarose gel electrophoresis was that the protein concentration was 1％ to 5％. The minimum detection protein concentration was 0.5％ and the precision test RSDs were 0.17％ and 0.20％. The observation results of agarose gel electrophoresis method and cellulose acetate membrane electrophoresis method were similar, but the statistical analysis showed that the measurement results of two methods were significantly different. The reason for the difference between the two methods will be studied in the future. The agarose gel electrophoresis method is precise and durable, which can be used to determine the purity of human immunoglobulin for intravenous injection.

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Determination of Diethyl Sulfite Inpemetrexed Disodium by GC-MS

LU Honghua, SUN Jianhe, LI Na, FENG Zhong, ZHANG Guimin

2020, 51(09): 1194-1196. https://doi.org/10.16522/j.cnki.cjph.2020.09.017

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A GC-MS method was established for determination a genotoxic substance diethyl sulfite in pemetrexed disodium. Samples were separated by HP-5MS column, and determined by mass spectrometry in SIM mode. The diethyl sulfite showed good linearity at the range of 20 - 100 ng/ml. The limit of determination was 20 ng/ml. The recovery was 101.09%, with RSD of 3.59%. Due to the high specificity, this method could be used to detect diethyl sulfite in pemetrexed disodium product.

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Determination of the Related Substances in Acipimox by HPLC

SUN Jianhe, LI Qian, LIU Depeng, FENG Zhong, ZHANG Guimin

2020, 51(09): 1197-1201. https://doi.org/10.16522/j.cnki.cjph.2020.09.018

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An HPLC method was established for the determination of the related substances in acipimox(1). A Ultimate XB-C18 column was used, with the mobile phase of methanol-0.01 mol/L tetrabutylammonium hydroxide solution (20∶80, adjusted pH to 6.0 with phosphoric acid), at a flow rate of 1.0 ml/min and a detection wavelength of 220 nm. The calibration curves for 1 - 5 were linear in the ranges of 0.1 - 1.5 or 0.03 - 0.45 μg/ml. The recoveries for the impurity were 101.4％ - 102.9％, with RSDs of 0.9％ - 1.9％.The proposed method was simple, accurate and sensitive, and provided support for the optimization of the synthesis process, and also significantly improved the quality control level of 1.

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Simultaneous Determination of Four Additives in Medical Rubber Materials by HPLC

ZHAI Xiaoyu, WU Ying, ZHANG Yilan

2020, 51(09): 1202-1207. https://doi.org/10.16522/j.cnki.cjph.2020.09.019

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An HPLC method was established for the determination of 2-mercaptobenzothiazole, 2-mercaptobenzimidazole, benzothiazole, 2-methylthiobenzothiazole in medical rubber. The different factors influencing the extraction efficiency of the materials were investigated, and the extraction amount of the four additives in different simulated media was studied. The results showed that it was linear for the four additives in the range of 0.03 - 3.41 μg/ml, 0.01 - 1.01 μg/ml, 0.36 - 36.20 μg/ml and 0.03 - 3.44 μg/ml. The recoveries in the extraction of materials ranged from 119.4％ to 96.7％, and the RSD was less than 6.77％. The recoveries ranged from 81.9％ to 114.7％ in the simulated media including pH 3.0 hydrochloric acid solution, pH 6.0 purified water, pH 11.0 sodium hydroxide solution, and 15％ ethanol, with the RSD was less than 3.77％. The method is specific and sensitive, which can be applied successfully to the determination of the four additives in medical rubber products.

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Pharmaceutical Management & Information

Investigation and Handling of OOS and OOT Results

YAN Ruoxi, CAO Yi, ZHAI Tiewei, DONG Jiangping

2020, 51(09): 1208-1212. https://doi.org/10.16522/j.cnki.cjph.2020.09.020

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Pharmaceutical Management & Information

The Challenges and Mechanisms of Research Institutes Becoming MAH

REN Xiaochen, CHEN Xianhong