Chinese Journal of Pharmaceuticals

Select

Perspectives & Review

Practice of “Co-production” Process Innovation in the Production of Aminoglycoside Antibiotics and the Potential Application for Other Products

LI Ji'an, LIN Huimin, CHEN Daijie

2020, 51(11): 1347-1355. https://doi.org/10.16522/j.cnki.cjph.2020.11.001

Abstract ( ) Download PDF ( )

Knowledge map

Save

Antibacterial drugs, including synthetic antibacterial drugs(quinolones for example) and secondary metabolites and derivatives produced by microorganisms, are substances with inhibitory and killing effects on pathogenic bacteria and other microorganisms. Due to the poor substrate specificity of biosynthetic enzymes involved in secondary metabolites, a series of derivatives with similar structures will be produced during the fermentation of antibiotics, which is not conducive to the separation and purification of antibiotics, but it creates conditions for the technological innovation of “co-production” of antibiotics. In the project of “Green, High-efficiency Key Technology Innovation and Industrialization of Etimicin and Gentamicin Co-production”, which won the second prize of the National Science and Technology Progress Award in 2019, we first proposed the concept of antibiotics “co-production”. The technological innovation of antibiotics “co-production” is not a by-product recovery in the conventional sense. Indeed, it uses strain breeding and fermentation control technology to balance and improve the synthesis ability of the “co-produced” products. And according to the requirements of the target product, the separation and purification technology is used to carry out “active deployment” to realize the high-efficiency antibacterial preparation process that maximizes economic and environmental benefits. In this paper, the basic ideas and conditions of the process innovation of antibiotics “co-production” are analyzed, and some of the antibiotics that are suitable for “co-production” process are listed. Meanwhile, the practical results of the process innovation of aminoglycoside antibiotics “co-line triple production” are illustrated, which provides some references for the process innovation of antibiotics.

Select

Perspectives & Review

Application and Prospect of Bioplastics in Food and Medicine Packaging

YUAN Chunping, HOU Huimin

2020, 51(11): 1356-1363. https://doi.org/10.16522/j.cnki.cjph.2020.11.002

Abstract ( ) Download PDF ( )

Knowledge map

Save

Promoting the use of bioplastics is the only way to solve the environmental pollution caused by plastics. Bioplastic is a general term for bio-based plastics and biodegradable plastics. The 14C measurement is usually used to evaluate the environmental value of bioplastics by determination the biocarbon content of bio-based plastics, and/ or degradation degree of biodegradable plastics converted to carbon dioxides and water under composting conditions is also adopted for the evaluation. This paper mainly introduces the structures and properties of several commercial biodegradable bioplastics such as starch-based bioplastics, polylactic acid, polyhydroxyalkanotes, polybutylene succinate, cellulose acetate and their applications in food and pharmaceutical packaging as well as drug carriers. The future application of bioplastics in pharmaceutical packaging is also prospected.

Select

Perspectives & Review

Advances in New Drug Delivery Systems for Glaucoma Treatment

ZHANG Hui, LUAN Hansen, WANG Jian

2020, 51(11): 1364-1370. https://doi.org/10.16522/j.cnki.cjph.2020.11.003

Abstract ( ) Download PDF ( )

Knowledge map

Save

Glaucoma is an irreversible blinding eye disease. Generally, the drug treatment is mainly based on ocular hypotensive agents. However, the traditional eye drops have low bioavailability and poor patient compliance, resulting in unsatisfactory clinical treatment. In recent years, novel drug delivery systems have achieved the purpose of sustained release by prolonging the residence time of the drug in eyes, so as to improve the therapeutic effect of glaucoma medications. In this paper, novel drug delivery systems are divided into two types: non-invasive and invasive types. Noninvasive drug delivery systems include eye drops(such as nanoliposomes, in situ gel and cubosomes), contact lenses and ocular inserts. Invasive drug delivery systems include ocular implants and injectable microparticles. At the same time, advantages and disadvantages of each drug delivery system as well as new technologies applied in ocular drug delivery are introduced and the drug release mechanism is specified. It is expected that this paper can provide some references for the development of new preparations for glaucoma.

Select

Paper

New Synthetic Process of the Bcl-2 Inhibitor Venetoclax

CHENG Weiyan

2020, 51(11): 1371-1375. https://doi.org/10.16522/j.cnki.cjph.2020.11.004

Abstract ( ) Download PDF ( )

Knowledge map

Save

A new synthetic process of venetoclax(1), an inhibitor of B-cell lymphoma-2 gene(Bcl-2), was reported in this paper. Methyl 4-fluorosalicylate(4) was prepared from 2,4-difluorobenzoic acid(2) as the starting material by hydroxylation and methylation, and then 4 was coupled with piperazine to afford methyl 4-(piperazin- 1-yl)salicylate(5). Compound 5 was subjected to the reductive amination and condensation to give methyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]- piperazin-1-yl]benzoate(9), following by hydrolysis and condensation to obtain 1. This synthetic route avoided the expensive intermediate 1-(triisopropylsilyl)-5-hydroxy-7-azaindole(12) and its complicated preparation process reported in literature, and selectively introduced hydroxyl group at the 2-position of 2 to avoid poor selectivity, low yield and difficult purification caused by methyl 2,4-difluorobenzoate(13). And it reduced the preparation cost and simplified the process.

Select

Paper

New Synthetic Process of 2-(2-Amino-3-methoxyphenyl)chromone

TONG Hongjuan, LIU Bin, ZHANG Cuiya

2020, 51(11): 1376-1378. https://doi.org/10.16522/j.cnki.cjph.2020.11.005

Abstract ( ) Download PDF ( )

Knowledge map

Save

A new synthetic process of 2-(2-amino-3-methoxyphenyl)chromone(PD98059, 1) was reported in this paper. 2-Hydroxy acetophenone(2) reacted with 3-methoxy-2-nitrobenzoic acid(3) to give 2-acetylphenyl 3-methoxy-2-nitrobenzoate(4). Then the latter was subjected to Baker-Venkataraman rearrangement and intramolecular cyclization to obtain the flavonoid. The nitro group was reduced to amino group in the presence of tin/concentrated hydrochloric acid to afford the target compound 1, with a total yield of 37％(based on 2). This synthetic process was simple to operate, with low cost and easy availability of raw materials.

Select

Paper

New Synthetic Process of 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine

CHENG Jiawei, LI Mengna, LIN Yanqin, ZHENG Zhiyao, ZHAO Xueqing

2020, 51(11): 1379-1382. https://doi.org/10.16522/j.cnki.cjph.2020.11.006

Abstract ( ) Download PDF ( )

Knowledge map

Save

A new synthetic process for 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine(1), the key intermediate of lasmiditan hemisuccinate, was reported in this paper. N-(6-bromopyridin-2-yl)pivalamide(4) was obtained via the coupling reaction of 2,6-dibromopyridine(2) and pivalamide(3). Compound 4 was transformed into the corresponding pyridin-2-yl magnesium chloride by i-PrMgCl, followed by the addition of the N-methoxy- N,1-dimethylpiperidin-4-carboxamide(5) to give N-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]pivalamide(6), and 1 was obtained by the hydrolysis of 6. Since its brief work-up procedure and good total yield of 67％(based on 2), this method would be suitable for the manufacturing.

Select

Paper

Synthesis of the Related Substances of Clozapine

YU Liguo, SUN Guangxiang, ZHANG Yunran, ZHU Yijun, WANG Bing

2020, 51(11): 1383-1386. https://doi.org/10.16522/j.cnki.cjph.2020.11.007

Abstract ( ) Download PDF ( )

Knowledge map

Save

In order to control the quality of clozapine, six related substances, namely 8-chloro-5,10-dihydro-11Hdibenzo[ b,e][1,4]diazepin-11-one(related substance A), 11,11'-(piperazin-1,4-diyl)bis(8-chloro-5H-dibenzo[b,e][1,4]- diazepine)(related substance B), 8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine(related substance C), [2-[(2-amino-4-chlorophenyl)amino]phenyl](4-methylpiperazin-1-yl)methanone(related substance D), 8-chloro-11- (4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine-1-oxide(related substance E) and 11-(4-methylpiperazin-1- yl)-5H-dibenzo[b,e][1,4]diazepine(related substance F), were synthesized based on the synthetic process of clozapine. Among them, the synthetic method of related substance F has not been found in literature. The structures of the above related substances were confirmed by ESI-HRMS and 1H NMR.

Select

Paper

Key Parameters of Five Litre High-density Fermentation of Ranibizumab

LI Lele1, WU Yong, HUANG Zongqing, LU Jianguang, FENG Jun

2020, 51(11): 1387-1393. https://doi.org/10.16522/j.cnki.cjph.2020.11.008

Abstract ( ) Download PDF ( )

Knowledge map

Save

Ranibizumab has five pairs of disulfide bonds. Due to the reducing environment of the Escherichia coli(E. coli)cytoplasm, the disulfide bonds cannot be correctly paired to form the inactive inclusion bodies. Moreover, the denaturation and renaturation of inclusion bodies are tedious and inefficient. However, the periplasmic space of E. coli contains disulfide bond oxidoreductase, which can provide a suitable oxidizing environment for the correct pairing and folding of disulfide bonds. Therefore, the disulfide bond of ranibizumab, which guided by signal peptide to periplasmic space, can pair and fold correctly and have good biological activity. In this study, recombinant E. coli with periplasmic soluble expression gene was constructed. On the scale of a five litre fermentor, the key parameters were investigated during the high-density fermentation process, such as isopropyl β-D-thiogalactoside concentration, feed rate, induction temperature and dissolved oxygen. The expression of ranibizumab reached (360±4.24)mg/L, and the purified ranibizumab had good antigen binding activity. This method increased the expression of ranibizumab enormously, and realized its high-efficiency expression in the periplasmic space of E. coli, which could provide a reference for its industrialization.

Select

Paper

Preparation of G5-BGG/pDNA and Its Inhibition on SGC-7901 Cells

SONG Jie, WANG Dongli, ZHANG Zhiyi, LU Weiyue, LIU Min

2020, 51(11): 1394-1401. https://doi.org/10.16522/j.cnki.cjph.2020.11.009

Abstract ( ) Download PDF ( )

Knowledge map

Save

Non-viral vectors have the advantages of controllable quality, high carrying capacity and low immunogenicity, but the low transfection efficiency limits their application. In the present study, a new functional group 1,3-dicarbamimidoylisophthal amide(BGG) designed by computer simulation was modified to generation 5(G5) polyamidoamine dendrimer by amido bonds, and the product G5-BGG was used as the carrier for delivery of gene drugs. G5-BGG could condense plasmid DNA into positive complexes. Both qualitative and quantitative transfection experiments in vitro showed that G5-BGG could significantly improve the transfection efficiency of report genes in human gastric adenocarcinoma cells(SGC-7901). Meanwhile, the blank vector G5-BGG possessed good biocompatibility. Besides, tumor necrosis factor-related apoptosis-inducing ligand gene(pTRAIL) loaded gene complex G5-BGG/pTRAIL could induce the apoptosis of SGC-7901 cells and inhibit the growth of SGC-7901 cells. In summary, G5-BGG has the potential application in gastric cancer gene therapy.

Select

Paper

Preparation and Pharmacokinetics in Beagle Dogs of Metoprolol Succinate Pellet-based Sustained-release Coating Tablets

JIA Junwei, FENG Zhong, ZHANG Guimin, YU Shanshan, ZHANG Zhao

2020, 51(11): 1402-1409. https://doi.org/10.16522/j.cnki.cjph.2020.11.010

Abstract ( ) Download PDF ( )

Knowledge map

Save

Box-Behnken design-response surface methodology and single factor method were respectively adopted to optimize the parameters of pellet core preparation and coating process for sustained-release layer with particle size distribution, roundness and weight gain as indexes. The results showed that the optimal pellet cores had uniform particle size distribution and good roundness, and the optimal coated pellets also had uniform particle size distribution and stable weight gain. There were no significant differences in the release curves of the obtained pellets in water before and after tableting. The release curves of 3 batches of self-made pellet-based sustained-release coating tablets in various pH media were similar to those of the reference listed drug(RLD, Betaloc ZOK), indicating that the process had good reproducibility. A two-period crossover design was used to investigate the pharmacokinetic behaviors of the self-made preparation and RLD in Beagle dogs under fasting and fed conditions, the in vivo and in vitro correlation(IVIVC) and bioequivalence of the self-made preparation were further evaluated. The results showed that the self-made preparation had good IVIVC under both fasting and fed states, and the product was bioequivalent to the RLD.

Select

Paper

null

GUAN Yongmei, HU Yusen, LIU Jia, KONG Zhaodi, CHEN Lihua

2020, 51(11): 1410-1417. https://doi.org/10.16522/j.cnki.cjph.2020.11.011

Abstract ( ) Download PDF ( )

Knowledge map

Save

null

Select

Paper

Investigation on Improving Physical Stability of Tadalafil Solid Dispersions by Cosolvent

ZHANG Xiaoting, LUO Dandong1LI Qingguo, QIU Zhenwen

2020, 51(11): 1418-1423. https://doi.org/10.16522/j.cnki.cjph.2020.11.012

Abstract ( ) Download PDF ( )

Knowledge map

Save

To improve the physical stability of tadalafil solid dispersions(SDs), the effect of cosolvent on the existing state and dissolution of tadalafil in SDs was investigated. The carrier, polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer(Soluplus), and drug were dissolved in acetone or different mixed solvents consisted of acetone and three cosolvents(water, 0.1％ formic acid solution and absolute ethanol), then these systems were spray dried to obtain tadalafil SDs. The dynamic light scattering method was used to analyze the average particle size of Soluplus for evaluating the compatibility between tadalafil and Soluplus in different solvent systems. The prepared SDs were characterized by Fourier-transform infrared spectroscopy, X-ray powder diffraction and differential scanning calorimetry, and their dissolution profiles in 0.1％ sodium dodecyl sulfate solution were also investigated. Furtherly, the preliminary stabilities of different SDs stored at (40±2)℃ and (75±5)％ of relative humidity for 3 months were tested to evaluate the changes in physical properties of the SDs prepared with different mixed solvent systems. The results showed that the mixed solvents consisted of acetone and water in the ratio of 7∶3 improved the compatibility between tadalafil and Soluplus compared with pure acetone, and the corresponding SDs had a superior dissolution rate and good stability among the prepared SDs.

Select

Paper

Filling Volume Optimization and Process Control Method Design for Multi-dose Oral Solution

HUANG Lujia, BI Fan, WANG Zhenghao, CHAI Xinyi, WU Qiongzhu

2020, 51(11): 1424-1427. https://doi.org/10.16522/j.cnki.cjph.2020.11.013

Abstract ( ) Download PDF ( )

Knowledge map

Save

To meet the requirements of Chinese pharmacopoeia 2015 edition and improve the yields of multi-dose oral solution, the parameter range setting of filling volume was discussed in this paper. In process quality control(IPQC) criteria were designed by mathematical modeling and statistical analysis. The specific approaches were measurement of equipment filling accuracy, interpretation of pharmacopeial standards, mathematical model construction and calculation, IPQC criteria setting and performance qualification. The results indicated that the filling volume of current equipment was in accordance with normal distribution and the setting range of filling volume was 150.9 - 152.0 ml. The IPQC criteria were set as following: sampling 32 bottles every 30 min during production process, recording the number of bottles with filling volume less than 150 ml. If the number was greater than or equal to four, it could be considered an accuracy or precision drop of equipment. Then, measures should be taken such as increasing the setting volume or debugging equipment. Statistical methods were applied to data analysis and quality evaluation in this work, which was not only in line with cGMP, but also of universal significance for determining the key parameters of production.

Select

Paper

null

CHEN Yu, WANG Liyong, LI Wenting, XU Liping, ZHAO Guiyan

2020, 51(11): 1428-1431. https://doi.org/10.16522/j.cnki.cjph.2020.11.014

Abstract ( ) Download PDF ( )

Knowledge map

Save

null

Select

Paper

Determination of Genotoxic Impurities in Gefitinib by GC-MS

DING Bing, LU Honghua, SUN Jianhe, FENG Zhong, ZHANG Guimin

2020, 51(11): 1432-1434. https://doi.org/10.16522/j.cnki.cjph.2020.11.015

Abstract ( ) Download PDF ( )

Knowledge map

Save

null

Select

Paper

Simultaneous Determination of Three Organic Acids in Entacapone by HPLC-UV

LIU Jinyan, ZHOU Ainan, CHENG Zhiguo, GUO Dan, LI Jianqi

2020, 51(11): 1435-1438. https://doi.org/10.16522/j.cnki.cjph.2020.11.016

Abstract ( ) Download PDF ( )

Knowledge map

Save

null

Select

Paper

Separation and Purification of Components and Related Impurities in A40926 by Medium Pressure Preparative Liquid Chromatography

LIU Qingyuan, LIU Zhiyu, ZHU Bingfeng, LIU Zhijiang, ZHANG Guimin

2020, 51(11): 1439-1444. https://doi.org/10.16522/j.cnki.cjph.2020.11.017

Abstract ( ) Download PDF ( )

Knowledge map

Save

A40926 is the precursor for dalbavancin, and in this report, medium pressure preparative chromatography( MPLC) was adopted to separate and enrich each component and related impurities in A40926 mixture. By optimizing the packing and elution method, the polymer microsphere SKP-10 was selected as the packing, and ethanolwater system as the mobile phase for gradient elution. The results showed that the components A1 and B0 with a purity of >95% were obtained through preparing once, and the impurities RS1 and RS3 with a purity of >95% were obtained through preparing twice. Their structures were confirmed by HPLC-QTOF-MS, which were consistent with the structures described in literature. This method was suitable for purification of the components and related impurities in A40926 mixture, and it could provide support for the quality research of dalbavancin.

Select

Pharmaceutical Management & Information

Introduction of the First Gene Therapy Drug Approved by the United States for Treatment of Spinal Muscular Atrophy

LI Shuai, LI Gang, CHEN Guiliang

2020, 51(11): 1445-1453. https://doi.org/10.16522/j.cnki.cjph.2020.11.018

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Pharmaceutical Management & Information

Market Share Allocation Method of Purchasing with Quantity of High-value Medical Consumables

ZHENG Yangyang, DING Jinxi, LI Jiaming, WU Qiuting, LI Wei

2020, 51(11): 1454-1460. https://doi.org/10.16522/j.cnki.cjph.2020.11.019

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Pharmaceutical Management & Information

Risk Control Measures for Marketing Authorization Holder Based on Isotretinoin Case

LIU Pengcheng, WANG Wen, WANG Minjiao, CHI Huihui, REN Jingtian

2020, 51(11): 1461-1467. https://doi.org/10.16522/j.cnki.cjph.2020.11.020

Abstract ( ) Download PDF ( )

Knowledge map

Save

Select

Pharmaceutical Management & Information

Economic Operation of Chinese Pharmaceutical Industry in the First Half of 2020

GUO Wen, ZHANG Tianyi, ZHOU Bin

2020, 51(11): 1468-1474. https://doi.org/10.16522/j.cnki.cjph.2020.11.021

Abstract ( ) Download PDF ( )

Knowledge map

Save

Please choose a citation manager

Content to export

Archive