Chinese Journal of Pharmaceuticals

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Perspectives & Review

Applications of Texture Analyzer in Tablets

LI Yao1, LIU Shulai2, XIONG Subin1*

2018, 49(07): 875. https://doi.org/10.16522/j.cnki.cjph.2018.07.001

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Texture analyzer is a multifunctional instrument for measuring the mechanical properties of materials by applying the penetration, compression, shear, or tensile stress, etc. It is necessary for researchers to understand the relationship between the microstructure of tablets and the therapeutic efficacy. This paper aims to give an overview of the application of texture analyzer in determination of mechanical properties of tablets. The mechanical strength of single layer and multilayer tablets, the disintegration of fast disintegrating tablets, the kinetics of gel swelling and erosion, gel thickness and gel strength as well as the release mechanism of hydrophilic matrix tablets, and the bioadhesion, floating and influence of destructive force of gastrointestinal tract on drug release of bioadhesive tablets have been highlighted.

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Perspectives & Review

Research Progress of Thrombus Targeted Drug Delivery System

WANG Songli, WANG Ruifeng, XIE Cao, LU Weiyue*

2018, 49(07): 885. https://doi.org/10.16522/j.cnki.cjph.2018.07.002

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Thrombosis disease has been another serious threat to human health after cancer. The development of clinical thrombolytic drugs for decades still cannot avoid the substantial hemorrhagic risks and other side effects. In recent years, many achievements have been made in research of targeting thrombus vectors. Many studies have shown that the thrombus targeted drug delivery system can achieve the aim of accumulation at the thrombus and effectively reduce side effects such as hemorrhage. In this paper, three aspects of magnetic targeting, active targeting, biomimetic targeting in targeted delivery strategy of thrombus are briefly reviewed. Sufficient understanding of these mechanisms will help us to design more efficient thrombus-targeting drug delivery system to address the challenges encountered in targeted drug delivery systems for thrombosis disease. Molecular imaging technique provides a noninvasive imaging method of thrombus and plays a significant role in prevention and treatment. So, the progress of the research and the evaluation methods of target performance are briefly reviewed. There are still many problems in the currently studied thrombustargeting drug delivery system, and the biomimetic thrombus-targeting drug delivery system will have a broad application prospect.

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Perspectives & Review

Coating Technology and Materials Used in Preparation of Probiotics Microcapsules

JI Rui1,2, SHAO Lei2, WANG Jian1, CHEN Daijie2,3*

2018, 49(07): 893. https://doi.org/10.16522/j.cnki.cjph.2018.07.003

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Microencapsulation technology can improve the stability of probiotics during production and storage, which contributes to setting and slow release of probiotics in the intestinal tract. However, there are some disadvantages of unprocessed microcapsule such as loose skeleton, low hardness, further causing low probiotic survival rate. Recently, studies show that coating technology can improve the above shortcomings and significantly protect the probiotics in simulated gastrointestinal fluid. Coating process and materials are the main effect factors. Finally, the basic principle, characters and future directions of probiotic microcapsule coating technology, as well as the structure, properties and application of coating materials are discussed deeply in this paper.

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Perspectives & Review

Progress in Synthesis of Ertugliflozin

WANG Jiantao1,2, YANG Hanyue2, ZHU Simei2, DONG Shubo2, ZHU Hailiang1*

2018, 49(07): 901. https://doi.org/10.16522/j.cnki.cjph.2018.07.004

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Ertugliflozin is a sodium-glucose cotransporter 2(SGLT2) inhibitor, and clinically it is used for treatment of type 2 diabetes in adult patients. In this paper, the synthetic methods of ertugliflozin are reviewed. Based on different materials and intermediates, five synthetic routes have been reported. The synthetic route, which uses 2,3,4,6-tetra-O-benzyl-D-glucopyranose as the starting material to synthesize ertugliflozin linearly, has good stereoselectivity and is suitable for industrial production. This route includes 12 steps reactions, only 3 intermediates need to be separated, and the total yield is up to 30％.

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Perspectives & Review

Industrialization Process of Oxytocin Production

ZHU Jun1,2, HUANG Zhenhui2, ZHU Jianwei1*

2018, 49(07): 910. https://doi.org/10.16522/j.cnki.cjph.2018.07.005

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Oxytocin is one of the most common polypeptide drugs used in clinic application. Liquid phase synthesis process of oxytocin was developed in production. However, in recent years, solid phase synthesis has shown significant advantages in manufacturing of polypeptide drugs. In this paper, the liquid phase and solid phase synthesis processes of polypeptide drugs are compared, the domestic production technology, quality control and stability of oxytocin are summarized. We also analyze and discuss the advantages and disadvantages of various purification methods, and prospect the development direction of oxytocin production technology.

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Paper

Combinatorial Optimization of MEP Pathway to Improve β-Carotene Yield

LIU Leshan, LIU Haiyuan, XIE Liping, HU Youjia*

2018, 49(07): 917. https://doi.org/10.16522/j.cnki.cjph.2018.07.006

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One goal of metabolic engineering is to improve yields with robust and simply executed methods. However, unbalanced utilization of metabolic pathway flux and insufficient activity of enzymes are the major challenges of microbial biosynthesis efficiency. Numerous researches on single enzyme optimization have been reported through studies in microorganisms, our work presents a new combinatorial optimization approach which balances metabolic flux with modular genetic elements. This approach is based on Gibson Assembly (GA) and bicistronic design (BCD) standard initiation elements. We used methylerythritol 4-phosphate (MEP) pathway as an example to demonstrate this approach. Two rate-limiting enzymes coding genes dxs and idi, and five insulated modular initiation elements were employed to generate a combination library in limited steps. A β-carotene indicated screening method was adopted to obtain a recombinant strain that increased the production yield to more than 10 folds. The results demonstrated the effectiveness of this combinatorial optimization approach and the potential of pathway optimization engineering. We believed that this approach could be applicable for a range of secondary metabolic pathways.

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New Synthetic Process of Amrubicin Hydrochloride

YOU Junhui, WANG Junliang, CAO Jin, YU Jun, DU Zuyin

2018, 49(07): 927. https://doi.org/10.16522/j.cnki.cjph.2018.07.007

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A new synthetic process of amrubicin hydrochloride was reported. (7S,9S)-9-Acetyl-9-amino- 6,7,11-trihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione (6) was obtained from (R)-2-acetyl-2-trifluoroacetamido-5,8- dimethoxy-1,2,3,4-tetrahydronaphthalene (12) via Friedel-Crafts acylation with phthaloyl chloride, ketalization of the carbonyl group with neopentylglycol, photochemical cyclization with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and hydrolysis with hydrochloric acid sequentially. Then compound 6 was sujected to glycosidation with 2-deoxy-1,3,4- tri-O-acyl-β-D-erythro-pentopyranose in the presence of trimethylsilyl trifluoromethanesulfonate, deprotection of the acetyl groups and salification to prepare amrubicin hydrochloride with a total yield of 10.7％ and a purity of 99.8％. This process has some advantages such as convenient operation, simple work-up, and high purity, and the synthetic method for compound 6 from 12 has not yet been reported in literature.

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A New Synthetic Method of Dyclonine Hydrochloride

SHI Hongyuan

2018, 49(07): 933. https://doi.org/10.16522/j.cnki.cjph.2018.07.008

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A new method for the synthesis of dyclonine hydrochloride was reported. Phenol (2) reacted with 1-bromobutane to give n-butoxybenzene, which was followed by Friedel-Crafts acylation with 3-chloropropionyl chloride to afford 1-(4-butoxyphenyl)-3-chloropropan-1-one (6). Then the latter reacted with piperidine hydrochloride in the presence of triethylamine to produce the target compound with an overall yield of 62％(based on 2). The reaction conditions of this synthetic process were mild and the operation was simple. In this method, compound 6 is a new compound which has not yet been reported in literature.

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Asymmetric Synthesis of (R)-3-[Benzyl(methyl)amino]-1-phenylpropan-1-ol

QU Xingxin1, LIU Yangang1, LIU Delong1*, ZHANG Wanbin1,2

2018, 49(07): 936. https://doi.org/10.16522/j.cnki.cjph.2018.07.009

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3-[Benzyl(methyl)amino]-1-phenylpropan-1-one (4) was obtained via Mannich reaction using easily accessible acetophenone, N-methylbenzylamine and paraformaldehyde as starting materials. The planar chiral catalyst, RuPHOX-Ru (developed in our group), then catalyzed the asymmetric hydrogenation of 4 (S/C=10 000), affording the title compound (R)-3-[benzyl(methyl)amino]-1-phenylpropan-1-ol in an overall yield of 92％ and with a ee value more than 99％. The current work provides a practical synthetic route for several drugs such as tomoxetine and fluoxetine, which is more feasible for industrial production.

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New Synthetic Process of the Key Intermediate of Nebivolol

CHENG Zufu1, WANG Fujun1*, PU Tong2, CHEN Tian2, SONG Qingbao3

2018, 49(07): 940. https://doi.org/10.16522/j.cnki.cjph.2018.07.010

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2-Chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-one, the key intermediate of nebivolol, was synthesized by a new synthetic process. The target compound was prepared by “one-pot” method of condensation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid with ethyl chloroformate, followed by diazotization and chlorination. The yield was 85% and the purity was more than 99% with a chiral purity of 99.5％. The chirality of the target product was identical to the starting material's. This process has been proven by pilot-scale test.

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Active Protein Components and Potency Detection of Kinases in Lumbrokinase

XIE Yuyuan, WANG Wenxi, GUO Jianghong*

2018, 49(07): 944. https://doi.org/10.16522/j.cnki.cjph.2018.07.011

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The lumbrokinase samples from different manufactures were digested by trypsin, then were separated and analyzed by UPLC-Q-TOF-MS technology. The MS data was processed by PLGS 3.0 software to identify the protein components that related to fibrinolytic activity of lumbrokinase. In five enterprises' products, 8-9 proteins related to fibrinolytic activity were identified, 4-5 proteins among them belonged to the kinase activity components. The kinase activity of lumbrokinase was investigated by agarose-fibrin plate method with urokinase as the reference. The potency determination results showed that every 1 000 IU of lumbrokinase was equivalent to 1.509 1-2.819 1 IU urokinase. The proteins of kinase activity in lumbrokinase were identified and the kinase activity were quantitatively detected.

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Bioconversion of 20(R)-Panaxatriol by Mucor racemosus and Antitumor Activities of Its Bioconversion Products

ZHANG Qinglan1, SONG Yan2, LI Jianlin2, CHEN Guangtong2*

2018, 49(07): 950. https://doi.org/10.16522/j.cnki.cjph.2018.07.012

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The bioconversion of 20(R)-panaxatriol was conducted by Mucor racemosus AS 3.20. Six carbonylated and hydroxylated products were isolated and identified as 3,6,23-trioxo-20(R)- panaxatriol (1), 3,6-dioxo- 15β-hydroyl-20(R)-panaxatriol (2), 3,6-dioxo-15β-hydroyl-20(S)- panaxatriol (3), 3,6-dioxo-5α,15α-dihydroyl-20(R)- panaxatriol (4), 3,6-dioxo-15α-hydroyl-20(R)- panaxatriol (5), 3,6-dioxo-16β-hydroyl-20(R)-panaxatriol (6) by MS, 13C NMR and 1H NMR analyses. Among them, compounds 3 and 4 were new compounds. A preliminary pharmacological test revealed that compounds 1, 3, 4 and 5 exhibited stronger antitumor activities than 20(R)-panaxatriol.

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Pollution Investigation of Aflatoxins in Traditional Chinese Medicines from Guizhou Province in 2016

YANG Chang1,2,3, LIU Fan1,2, LI Lina1,2, LIU Chunhua1,3,4, WANG Aimin1,3,4*

2018, 49(07): 956. https://doi.org/10.16522/j.cnki.cjph.2018.07.013

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Taking 16 kinds of Chinese herbal medicine commonly used by pharmaceutical enterprises in Guizhou province as the research object to investigate the pollution of aflatoxins in traditional Chinese medicinese (TMC). 130 Batches of different kinds of TMC from the pharmaceutical enterprises in Guizhou province were collected in 2016. The contents of aflatoxin B1, B2, G1 and G2 were determined by HPLC with immune affinity column chromatography, which was recorded in the Chinese pharmacopoeia 2015 edition, in order to reveal the pollution status of aflatoxins in the traditional Chinese medicinal herbs of Guizhou and provide data for the quality control of these medicinal herbs. Among them, the aflatoxin pollution levels of tangerine peel, jujube and other fruit-type Chinese herbal medicines were generally low, while the seed species (such as biota seed, betel nut, etc.) and animal medicines (such as centipede, Bombyx batryticatus, etc.) had higher degrees of pollution, which should be paid attention to.

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Effect of Chiral O-Acylmenthol Derivatives on in vitro Permeation of Flubiprofen

LI Yang1, ZHAO Ligang2,3*, LIU Chunyan2,3

2018, 49(07): 962. https://doi.org/10.16522/j.cnki.cjph.2018.07.014

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The aim of this paper was to investigate the penetration effect of chiral O-acylmenthol derivatives, including 2-isopropyl-5-methylcyclohexyl decanoate (l-M-DEC, d-M-DEC) and 2-isopropyl-5-methylcyclohexyl dodeconoate (l-M-DOD, d-M-DOD), on permeation behavior of flubiprofen (FP) in the isopropyl myristate (IPM) system and the dug-in-adhesive (DIA) patches. The in vitro percutaneous permeability test was carried out with twochamber cells and excised rabbit skin as the barrier. The results showed that all enhancers at 3％ had significant enhancing effects on the penetration of FP in the IPM system compared with the blank control (Pl-M-DOD>d-M-DEC>l- M-DEC>d-menthol>l-menthol. FP could penetrate the rabbit skin well with O-acylmenthol derivatives as the penetration enhancers in both the IPM system and the DIA patches.

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Preparation and Release Mechanism of Silybin Meglumine Osmotic Pump Tablets

WANG Li, XUE Bing, LIU Huashi, XIN Xuewei, ZHANG Wenjun*

2018, 49(07): 968. https://doi.org/10.16522/j.cnki.cjph.2018.07.015

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The tablet cores were prepared with silybin meglumine as the main drug, then the title osmotic pump tablets were obtained by coating a layer of cellulose acetate containing polyethylene glycol (PEG) 400 as porogenic agent. The formulation factors of the tablet cores and coating layer were optimized by single factor test with the similarity between the release curves of the products in pH 6.8 phosphate buffer solution as the index. Besides, the release mechanism of the optimal tablets was preliminarily investigated. The produced silybin meglumine osmotic pump tablets exhibited a zero-order release kinetic pattern within 12 h (r>0.99). The title tablets had a better controlled-release effect, and a more complete release with the cumulative release at 12 h over 90％.

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Optimization of Enteric Coating Technology for Hydroxypropyl Methylcellulose Hollow Capsules

SUN Wuqian, WANG Dingyang, OUYANG Weihong, QIAN Guoying, LIU Liping*

2018, 49(07): 975. https://doi.org/10.16522/j.cnki.cjph.2018.07.016

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The composition of coating liquid and parameters of secondary dipping gluing for the preparation of enteric-coated hydroxypropyl methylcellulose (HPMC) hollow capsules were optimized with appearance, thickness of the coating layer, forming rate, breakage and disintegration time as the indexes by single factor and orthogonal experiments. The results showed that the most appropriate composition was polyacrylic resin Ⅲ 10％, Tween-80 6.5％ and ethanol 85％. The coating time was 5-9 s during the process of secondary dipping gluing, then the coated capsules were dried in room temperature for 30-40 min. The optimal enteric-coated HPMC hollow capsules had smooth appearance and low breakage and was stable in pH 1.0 medium within 2 h and completely disintegrated within 1 h in pH 7.2 medium. The prepared capsules met the requirements in Chinese pharmacopeia 2015 edition.

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Impurity Profile of Calcium Dibutyryladenosine Cyclophosphate by 2D-LC-Q-TOF MS

XU Mingming1, YIN Hongrui1, SHAO Hong1, LIU Guoqiang2, CHEN Gang1*

2018, 49(07): 981. https://doi.org/10.16522/j.cnki.cjph.2018.07.017

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A two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (2D-LCQ- TOF MS) method was established for profiling the impurities of calcium dibutyryladenosine cyclophosphate. A C18 column was used in the first dimensional chromatography, with the mobile phase of 0.1 mol/L potassium dihydrogen phosphate buffer∶methanol (60∶40), at the detection wavelength of 273 nm. A Poroshell 120 EC-C18 column was used in the second dimensional chromatography, with the mobile phase of water (containing 0.1％ formic acid) and acetonitrile (containing 0.1％ formic acid) for linear gradient elution. The target peak from the first dimensional LC was trapped in a 40 μl loop via switching valve, and then was separated using a MS compatible mobile phase from pump 2. The data was collected in positive ion mode. The ion source was Dual AJS ESI, and the temperature of dry gas was set at 200 ℃ and the electrospray ionization (ESI) needle voltage was set at 4 000 V. The nebulizer gas was set at 350 ℃. The molecular formulas were determined by their exact masses and isotope distributions. The structures were postulated by the protonated molecular ions and the manufacturing process of calcium dibutyryladenosine cyclophosphate. Seven impurities of calcium dibutyryladenosine cyclophosphate were characterized and the origination of the impurities was deduced. Four of them were unknown impurities to the best of our knowledge. 2D-LC-Q-TOF MS method established in this work can be used for profiling the impurities in calcium dibutyryladenosine cyclophosphate. The results obtained are referential experiences for the optimization of manufacturing process and quality control of calcium dibutyryladenosine cyclophosphate.

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HPLC and LC-MS Analysis of Therapeutic rhIL-15 and Its Oxidation and Reduction By-products

CHEN Huanhuan, LI Ninghuan, BIAN Yanlin, LU Huili, ZHU Jianwei*

2018, 49(07): 988. https://doi.org/10.16522/j.cnki.cjph.2018.07.018

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Interleukin-15 is a strong immune stimulant for T lymphocytes and NK cells, and the recombinant human interleukin-15 (rhIL-15) has been a promising clinical candidate for tumor immunotherapy as well as being an effective vaccine adjuvant. To assist the pre-clinical and clinical development of rhIL-15, its preparation has been extensively studied in recent years. However, rhIL-15 is unstable and easy to be oxidized or reduced during manufacturing processes. Therefore, the quality control system with high sensitivity and precision is needed urgently. In this study, we adopted advanced RP-HPLC and LC-MS methods to analyze the oxidation and reduction by-products of rhIL-15. The results illustrated the significant differences between rhIL-15 and its oxidative or reductive derivatives. At most 3 oxygen or 4 hydrogen atoms were successfully determined by the intact molecular weights in LC-MS, which could precisely annotate the peaks separated by RP-HPLC. The method reported here is promising to be applied in the quality control of rhIL-15 manufacturing, helping to optimize the processes, thus improving the quality of rhIL-15 products.

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Determination of Polycyclic Aromatic Hydrocarbons as Leachables in Meter Dose Inhalers by GC-MS/MS

YE Xiaoxia1, MA Juan2, JIN Fang3, YANG Yongjian1*

2018, 49(07): 994. https://doi.org/10.16522/j.cnki.cjph.2018.07.019

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A GC-MS/MS method was established for the determination of 17 polycyclic aromatic hydrocarbons (PAHs) as leachables in meter dose inhalers (MDI). The leached PAHs in commercial MDIs were inspected by the validated method, which was based on GC-MS/MS in multiple reaction monitoring (MRM) mode. Calibration curves of 17 PAHs were all linear with correlation coefficients R2 no less than 0.993 4, and their limits of detection were no more than 2.0 ng/ml. Their recoveries were 84.3％-105.8％. PAHs were all detected in all valve systems with the same formulation. With the extension of storage time, the PAHs cumulative leaching amount increased. PAHs leaching amount of 11 batches of commercially MDIs were 70.41-245.96 ng per canister. The established method was sensitive, specific, accurate, and suitable for the detection of PAHs in aerosols.

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Pharmaceutical Management & Information

Brief Discussion on Key Points for Quality Consistency Evaluation of Injections for Generic Drugs

LIU Xiaodan1, HE Jun2, ZHANG Jingchen1, CHEN Guiliang1*

2018, 49(07): 999. https://doi.org/10.16522/j.cnki.cjph.2018.07.020

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Pharmaceutical Management & Information

A Comparative Study on the Performance Evaluation of Chinese and Foreign Pharmaceutical Industry under the Framework of "Two-Invoice" Policy

DING Jinxi, ZHAO Lin, CHEN Ye, CHEN Ru, ZHANG Jing

2018, 49(07): 1006. https://doi.org/DOI：10.16522/j.cnki.cjph.2018.07.021

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Pharmaceutical Management & Information

Comparative Study and Revelation of the Chinese and American Biological Products Appraisal Institutions

LI Feng1,2, WU Xiaoming1*

2018, 49(07): 1014. https://doi.org/10.16522/j.cnki.cjph.2018.07.022

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Pharmaceutical Management & Information

Pre-approval Case Studies of Two FDA-approved CAR-T Immune Cell Products

WANG Chong1, WANG Qingqing2, HUANG Zhihong2*

2018, 49(07): 1021. https://doi.org/10.16522/j.cnki.cjph.2018.07.023

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Pharmaceutical Management & Information

Signature Analysis of Pharmaceutical Industry Spatial in Jiangsu-Zhejiang-Shanghai Area Base on Social Network

LI Shuxiang, ZHUANG Qian, CHU Shuzhen

2018, 49(07): 1027. https://doi.org/10.16522/j.cnki.cjph.2018.07.024

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Pharmaceutical Management & Information

Study on the Industrial Structure Competitiveness of Guangdong Pharmaceutical Industry Based on Shift-share Analysis

XUE Yonggang

2018, 49(07): 1033. https://doi.org/10.16522/j.cnki.cjph.2018.07.025

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