Chinese Journal of Pharmaceuticals

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Overviews of the New Drugs in 2016 Approved by U.S. FDA

MA Shuai, ZHOU Weicheng

2017, 48(01): 1. https://doi.org/10.16522/j.cnki.cjph.2017.01.001

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The U.S. Food and Drug Administration(FDA) approved 22 new drugs into the market in 2016, including 12 chemical small molecules and 10 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.

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Synthesis of Loxoprofen Sodium

ZENG Xianguo1, GUO Heng1, WU Haibo1, CONG Rigang2, ZHANG Fuli1,2*

2017, 48(01): 12. https://doi.org/10.16522/j.cnki.cjph.2017.01.002

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Ethyl 6-oxo-6-phenylhexanoate was prepared via chlorination and Friedel-Crafts reaction with adipic acid ethyl monoester as the starting material, then it was subjected to Dieckmann condensation and selective catalytic reduction to give 2-benzyl cyclopentanone, which was followed by Friedel-Crafts reaction and acetal reaction to afford
6-[4-[2-(1-chloroethyl)-1,3-dioxolan-2-yl]benzyl]-1,4-dioxaspiro[4.4]nonane, the latter was subjected to a 1,2-aryl rearrangement in the presence of zinc oxide to prepare 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoic acid, after an salification, loxoprofen sodium was obtained with an overall yield of 58.9％(based on adipic acid ethyl monoester) and a purity of 99.89％. This process had the advantages of simple procedures and steady yield, and was suitable for production.

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Synthesis of Levomilnacipran Hydrochloride

LI Xiaoyuan1,2, ZHAI Ning2, LIU Xiaohua3, TIAN Dafeng3, ZHANG Fuli2*, ZHANG Yue1*

2017, 48(01): 16. https://doi.org/10.16522/j.cnki.cjph.2017.01.003

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Phenyl acetonitrile reacted with (R)-epichlorohydrin in the presence of sodium amide, followed by hydrolysis and intramolecular cyclization to provide (1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, then it reacted with diethylamine in the presence of aluminium trichloride to give (1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropane-1-carboxamide, the latter was subjected to chlorination, Gabriel synthesis, ammonolysis and salification to prepare the target compound levomilnacipran hydrochloride with an overall yield of 25.5％. The process was suitable for industrial production in view of the mild condition and simple operation.

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Synthesis of Fosaprepitant Dimeglumine

REN Wenjie1, LIU Wentao1, WANG Fan1, LI Chengwen2, ZHENG Deqiang1*

2017, 48(01): 20. https://doi.org/10.16522/j.cnki.cjph.2017.01.004

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Aprepitant reacted with tetrabenzyl pyrophosphate to give dibenzyl [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholino]methyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]phosphonate, which was deprotected in methanol to give monobenzyl [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholino]methyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]phosphonate, then the latter was re-deprotected by catalytic hydrogenation to remove another benzyl group, followed by salification with meglumine to afford fosaprepitant dimeglumine, a neurokinin-1 receptor antagonist, with an overall yield of 63％(based on aprepitant).

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Synthesis of a New Anti-heart Failure Drug Entresto

WANG Mixiang

2017, 48(01): 24. https://doi.org/10.16522/j.cnki.cjph.2017.01.005

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(2R,4S)-5-([1,1'-Biphenyl]-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid reacted with ethanol and thionyl chloride in one-pot via esterification-deprotection to afford (2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride, then the latter reacted with succinic anhydride via acylation to give 4-[[(2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl]amino]-4-oxobutanoic acid (sacubitril, 4), followed by salification with sodium acetate and combination with valsartan to obtain the anti-heart failure drug, Entresto, with an overall yield of 81％.

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Synthesis of Blonanserin

HE Lei, WEI Na, YANG Yong, YU Jun, DU Zuyin

2017, 48(01): 27. https://doi.org/10.16522/j.cnki.cjph.2017.01.006

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The key intermediate 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one was prepared via substitution, hydrolysis, and cyclization, started from methyl 4-fluorobenzoate. Then it reacted with trifluoromethanesulfonic anhydride to give the active ester, followed by iodination to afford 4-(4-fluorophenyl)-2-iodo-
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine by “one-pot” method. The latter reacted with N-ethyl piperazine in the presence of copper iodide and cesium carbonate to give blonanserin with an overall yield of 46％.

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Synthesis of Arbidol Hydrochloride

WANG Jinyu1, LIU Baomei1, ZHENG Kun1, ZHUANG Qianjun1, LUO Zhaoliang2

2017, 48(01): 30. https://doi.org/10.16522/j.cnki.cjph.2017.01.007

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4-Acetoxylaniline was prepared by acetylation of 4-nitrophenol and reduction, then it reacted with ethyl acetoacetate with indium bromide as the catalyst, followed by cyclization in the presence of potassium carbonate, palladium acetate and cupric acetate to give ethyl 5-acetoxy-2-methyl-1H-indole-3-carboxylate, the latter was subjected to methylation followed by bromination, substitution with thiophenol and deprotection to afford ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methyl-1H-indole-3-carboxylate, then it was subjected to a Mannich reaction in the presence of sulfamic acid in water to give arbidol hydrochloride with an overall yield of 45.4％(based on 4-nitrophenol).

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Application of Crispr/Cas9 Technology in Targeted Gene Integration in CHO cells

WANG Jiaxian, ZHAO Menglin, DING Kai, LU Huili, ZHU Jianwei*

2017, 48(01): 33. https://doi.org/10.16522/j.cnki.cjph.2017.01.008

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Mammalian cells are the most widely used hosts for the production of industrial biopharmaceuticals. However, recombinant cell lines often exhibit low expression and instability during culture period. In order to circumvent such a situation, targeted gene integration is designed to optimize product expression. Crispr/Cas9 technology is a newly developed gene editing tool and has been widely used in animals, plants and mammalian cells. In this work, we described a universal protocol as well as some cases using Crispr/Cas9 technology to target gene into Chinese hamster ovary (CHO) cells, a commonly used cell line for industrial purpose, based on available publications and the experiment experience in our laboratory.

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Construction and Identification of Recombinant HEK293 Cells with FGFR2 Over-expression

OUYANG Man, WANG Hailong, ZHAO Ying, LI Xiaoyan, CHEN Xiaojia*

2017, 48(01): 38. https://doi.org/10.16522/j.cnki.cjph.2017.01.009

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A recombinant FGFR2 expression vector was constructed and co-transfected with lentiviral packaging vectors into 293T to get recombinant lentiviral particles. The recombinant human embryonic kidney 293(HEK293) cells over-expressing FGFR2 were obtained after infection with the lentiviral particles and screening with 20 µg/ml puromycin. Western Blot assay verified that the expression level of FGFR2 in recombinant cells was higher compared with the blank control HEK293 cells. The results of QPCR and ELISA assays showed that the transcription and secretory expression of uPA and other molecules in FGFR2 downstream pathways were up-regulated in mRNA and protein level. Clones formation detection also suggested that the recombinant cells had higher proliferation ability. The results proved that the recombinant FGFR2 cell model could be conducted in the followed function studies and FGFR2-targeted drug screening.

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Reconstitution of G Protein Coupled Receptor APJ into Nanodiscs

GUO Zheng1, SHEN Jian1,2, JIN Meichen1, FU Lei1*

2017, 48(01): 43. https://doi.org/10.16522/j.cnki.cjph.2017.01.010

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The nanodiscs loaded with G protein coupled receptor APJ, the putative receptor protein related to the angiotensin receptor AT1, were prepared with membrane scaffold protein (MSP) and phospholipid. The effects of molar ratio of APJ to MSP (1∶2, 1∶4 and 1∶8) and incubation time (2, 4 and 6 h) after adding Bio-BEADs resin
[poly(styrene-divinylbenzene) resin] at 4 ℃ on assembly efficiency and the proportion of monomers were investigated. The optimal conditions were as follows: the molar ratio of APJ to MSP was 1∶4, and the incubation time was 2 h. The average diameter and thickness of the AJP-loaded nanodiscs were approximately 10 nm and 5 nm, respectively. The AJP reconstituted into the nanodiscs remained the ability to bind its antagonist, ML221, which indicated that the nanodiscs could maintain the biological activity of AJP.

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Preparation of Micronized Acemetacin by Supercritical CO2 Anti-solvent Process

YAN Tingyuan1,2, LIN Wen1, SONG Xingfang3, YAN Tingxuan1, WANG Zhixiang1*

2017, 48(01): 55. https://doi.org/10.16522/j.cnki.cjph.2017.01.012

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The process parameters of the micronized acemetacin prepared by supercritical CO2 anti-solvent (SAS) technology were optimized with single factor experiment and orthogonal design. The optimal parameters were as follows: the optimal product was prepared with a mixture of acetone and dichloromethane (1∶1) as the solvent
under conditions of pressure of 16 MPa, temperature of 40 ℃, and drug concentration of 9 mg/ml. The particle size of the optimal product was reduced to 6.02 µm, and the product was characterized by scanning electron microscopy (SEM), infrared spectroscopy (IR), and differential scanning calorimetry (DSC). The results of these analyses showed no significant changes in physicochemical properties between the micronized acemetacin and the bulk drug. While the dissolution at 10 min of the micronized acemetacin in water was above 20％ and at 80 min was about 80％, which indicated that the dissolution performance was significantly improved compared with the bulk drug.

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Preparation and Formulation Optimization of Rosiglitazone Transdermal Patches

MOU Jian, CHEN Yan*

2017, 48(01): 60. https://doi.org/10.16522/j.cnki.cjph.2017.01.013

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The skin permeation enhancement effects of three kinds of penetration enhancers (oleic acid, 1,2-propanediol and azone) at concentration of 3％ or 5％ on rosiglitazone were investigated with excised mouse skin as the barrier. The results showed that 5％ azone had the strongest effect among the tested enhancers. The formulation of the rosiglitazone transdermal patches was optimized by orthogonal test with the adhesion performance and penetration rate (Js) as the indexes. The optimal formulation was as follows: pressure sensitive adhesive (Eudragit E100)∶plasticizer (succinic acid)∶crosslinking agent (dibutyl sebacate) was 8∶3∶1, and the amount of viscosity increaser (polyethylene glycol 400) was 20％. The adhesion performances and penetration rates of three batches of the optimal rosiglitazone
transdermal patches had no significant differences. Those Js values were 26.38, 25.73 and 25.23 µg·cm-2·h-1, respectively.

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Evaluation Method for Surface Roughness of Extrudates in Extrusion-spheronization Process

LI Xue1, HONG Yanlong1,2*, DU Ruofei1,2, XIAN Jiechen1,2, FENG Yi1,2

2017, 48(01): 63. https://doi.org/10.16522/j.cnki.cjph.2017.01.014

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The physical properties of extrudates have direct effects on the quality of the final products in the extrusion-spheronization process, which are the key factors for the research of pharmaceutical formulation and process optimization. The previous studies showed that the surface roughness of extrudates was one of the important
physical properties, which also had a significant effect on the pellet formation. The extrudates of Baiqian extract and microcrystalline cellulose with different amounts of moistening agent, distilled water, were prepared by extrusionspheronization process. Their images were made by the microscope and their surface roughness were analyzed by the particle shape and size analyzer. The equation for surface roughness based on the perimeter of ellipse with the equivalent area was established and confirmed in this paper. The results of methodological validation showed that this method had well precision, accuracy and sensitivity. Furthermore, the surface roughness values of the extrudates with different amounts of moistening agent were calculated by this method, and the correlation between the surface roughness and the formation of pellets was also investigated. The results showed that there were different effects of surface roughness of extrudes containing different raw materials on pellet formation.

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Mass Fragmentation Patterns of Sartans and Application

CAI Pengjun, LI Yue*

2017, 48(01): 68. https://doi.org/10.16522/j.cnki.cjph.2017.01.015

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Six listed sartan drugs were studied by electron impact ionization-mass spectrometry (EI-MS) and electrospray ionization-tandem mass spectrometry (ESI-MS/MS) in order to explore a rapid method for the identification of unknown impurities in angiotensin Ⅱ receptor blockers. Through the analysis of the main fragment ions and the data of high resolution mass spectrometry, fragmentation patterns and regularities were summarized and utilized in the rapid identification of unknown impurities. The structures of two unknown enantiomeric impurities in azilsartan were identified based on the above findings, impurity 1 was the ethylated product on nitrogen of oxadizole and impurity 2 was the ethyl ester of azilsartan.

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Investigation of the Property of Lappaconitine-phosphatidylcholine Complex

SUN Wenxia, ZHONG Jialiang, WANG Guangdong, HOU Jiawei, HAO Haijun*

2017, 48(01): 78. https://doi.org/10.16522/j.cnki.cjph.2017.01.016

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The complex of lappaconitine (1)-phosphatidylcholine was prepared and its property was investigated. The structure of the complex was analyzed by X-ray diffraction(XRD), differential scanning calorimetry(DSC) and nuclear magnetic resonance(NMR). Its apparent solubility was also investigated to confirm the formation of
1-phosphatidylcholine complex. The results indicated that 1 existed in an amorphous form in the phosphatidylcholine complex. It was speculated that hydrogen bonds or intermolecular forces existed between 1 and phosphatidylcholine, but no new compound formed. The complex significantly increased the apparent solubility in water and n-octanol, and enhanced its dissolution rate and cumulative release to some extent, which could contribute to higher oral bioavailability of 1.

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Rapid Screening of the Chemical Components Illegally Added in Anti-hypertensive Chinese Patent Medicine by TLC-SERS Method

WU Mianmian1, WU Meiran2, ZHANG Binbin2, CHEN Hui1, LU Feng1*

2017, 48(01): 82. https://doi.org/10.16522/j.cnki.cjph.2017.01.017

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A surface-enhanced Raman spectral library of 12 anti-hypertensive chemical components was established and twelve spectra were indentified and assigned originally by means of mean spectra and second-derivative spectra. After the investigation of the enhancement of silver colloids and optimization for the Raman conditions, a thinlayer chromatography coupled with surface-enhanced Raman spectroscopy (TLC-SERS) method combined with the characteristic wave and correlation coefficient methods was applied for the rapid detection of the chemical components illegally added in the Chinese patent medicine. As a result, comparatively stable SERS signals of anti-hypertensive components were achieved with silver colloids substrate reduced by N,N-dimethyl formamide (DMF), with RSDs less than 20％. Meanwhile, with the aid of principal component analysis, 12 chemical components were divided into four groups (prils, sartans, prolols and zosins) and the correlation coefficients among structural analogues were more than 0.80. Moreover, the second derivative method was utilized for the further identification of homologues. The chemical compounds could be seperated from the complex matrix in the Chinese patent medicine by TLC. The results showed that the TLC-SERS method was endowed with favorable predictability and promised to be a tool with rapidity, accuracy and high efficiency for the detection of the chemical components illegally added in the anti-hypertensive Chinese patent medicine on market.

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Determination of Six Compounds in Erlong Pills by HPLC with Wavelength Switching

HAO Chengyi, CHANG Sheng*

2017, 48(01): 90. https://doi.org/10.16522/j.cnki.cjph.2017.01.018

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An HPLC method was established for the determination of six main components in Erlong pills. A Dikma Platisil ODS column was used, with the mobile phase of acetonitrile∶0.1％ phosphoric acid by gradient elution. The detection wavelength was switched from 240 nm for genipin 1-gentiobioside, geniposide and calceolarioside B to 274 nm for gentiopicrin, baicalin and ammonium glycyrrhizinate. The results showed that all the six components were well separated, and the linear relationships were good in their corresponding ranges. Their average recoveries were 97.5％—104.6％, with RSDs of 1.15％—1.83％.

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Advances of Cell Membrane-camouflaged Nanoparticles Delivery System

GU Xiaotong1, LI Yang1, WANG Dong2, WANG Yonglu1*, LI Xueming1,2

2017, 48(01): 94. https://doi.org/10.16522/j.cnki.cjph.2017.01.019

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In recent years, there have been great advances in the development of drug delivery system based on nanoparticles, while they are found to be immunogenic and nanotoxic. Therefore, as a safer and more efficient vector, cell membrane has become a hot research area. Incorporating cell membranes onto nanoparticles enables the nanoparticles having better biocompatibility. Moreover, through modifying with different types of cell membranes, such as blood cells, stem cells and bacteria cells, the nanoparticles will get valuable characters, such as better targeting, lower chance to be recognized by immune system and longer systemic circulation time. In this review, the fabrication processes, characters and applications of cell membrane-camouflaged nanoparticles are introduced to promote the application of nanoparticles
to drug delivery system.

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Progress on Anti-tumor Activities of Hederagenin and Its C-28 Derivatives

MAO Yichu1, HUANG Ting2, ZENG Jia2*

2017, 48(01): 102. https://doi.org/10.16522/j.cnki.cjph.2017.01.020

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Hederagenin is a pentacyclic triterpenoid which exists in numerous plants with the form of a free state or binding to glycosides/esters, and it exhibits anti-tumor activities to different tumor cell lines. It is shown that introducing substituent groups at C-28 will significantly improve the anti-tumor activities. This paper gives a review of the anti-tumor activities of hederagenin and its C-28 derivatives, which provides the basis for further study of its chemical components and pharmacological activities.

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Research Progress of Vulcanization in the Application of Pharmaceutical Rubber Products and Compatibility Study

LI Zhiyan, ZHANG Yilan*

2017, 48(01): 106. https://doi.org/10.16522/j.cnki.cjph.2017.01.021

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The types, mechanisms and applications of vulcanization in manufacturing pharmaceutical rubber products are introduced. The selection principle of commonly used vulcanization in pharmaceutical rubber products is briefly introduced. In addition, the main contents of compatibility study are also introduced. The detection methods of
extractable substances from rubber after vulcanization, the interaction between the vulcanizing agents and drugs as well as the related toxicological research progress are summarized. Several toxicological databases are provided in this paper for reference, and some solutions are cited to the compatibility issues of home and outside.

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Graphical Synthetic Routes of Obeticholic Acid

REN Wenjie, WANG Changbin, ZHENG Deqiang*

2017, 48(01): 112. https://doi.org/10.16522/j.cnki.cjph.2017.01.022

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Graphical Synthetic Routes of Riociguat

ZHOU Haiping1, ZHANG Yunran2, ZHU Qihua3*

2017, 48(01): 116. https://doi.org/10.16522/j.cnki.cjph.2017.01.023

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