Chinese Journal of Pharmaceuticals

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Perspectives & Review

Research Progress of Prodrugs for Tumor Targeted Therapy

ZHOU Jianfen, LU Weiyue

2021, 52(05): 583-598. https://doi.org/10.16522/j.cnki.cjph.2021.05.001

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The application of conventional chemotherapy in tumor treatment is limited due to lack of specificity and toxicity to healthy cells, resulting in inefficient treatment for tumor patients. Prodrugs are drug conjugates connected by linkers to targeted molecules(such as antibodies, polypeptides, aptamers and polymers), which can improve the tumor targeting efficiency, efficacy and safety of chemotherapy drugs. This review puts emphasis on several small molecule drug conjugates that can be used for tumor targeted therapy, including antibody-drug conjugates, peptide-drug conjugates, aptamer-drug conjugates, and polymer-drug conjugates, by introducing the basic composition, basic principles of targeted drug delivery, progress in clinical or preclinical research and listed products. The problems in the clinical application of these prodrug strategies are also analyzed and discussed, which can provide some references for relevant researches.

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Perspectives & Review

Research Progress on Quality Control of Traditional Chinese Medicine Injection

HE Zihui, WANG Qing, LIU Mo, WU Tong, OUYANG Danwei

2021, 52(05): 599-610. https://doi.org/10.16522/j.cnki.cjph.2021.05.002

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Traditional Chinese medicine injection is a new formulation originally created in China. It has the advantages of fast onset and high curative effect, breaking the traditional concept that traditional Chinese medicines are only suitable for the treatment of chronic diseases. In addition, it has made up for the vacancy of traditional Chinese medicines in clinical emergency treatment, and has a good treatment effect on some difficult and critical illnesses. However, with the wide application and great variety of traditional Chinese medicine injections, adverse reactions have been reported frequently, and the safety has attracted widespread attention, which greatly limits the application and development of traditional Chinese medicine injections. In order to strengthen the quality and safety control of traditional Chinese medicine injections and reduce the incidence of adverse reactions, the quality control on safety and chemical composition, toxicity research, and material basic research work are reviewed based on the current research status of traditional Chinese medicine injections.

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Perspectives & Review

Application of Human Stem Cells-derived Neural Cultures in Drug-induced Neurotoxicity Evaluation

WANG Meiting, ZHANG Yizhe, XING Hongyan, ZHAO Qi, WANG Xijie

2021, 52(05): 611-618. https://doi.org/10.16522/j.cnki.cjph.2021.05.003

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The self-renewal ability and potential of multi-directional differentiation of human stem cells have opened up the possibility for a new model system for early drug screening and pre-clinical neurotoxicity evaluation. And human pluripotent stem cells are capable of differentiation into neurons, glial cells and brain organoids. Currently, the in vitro models based on neural cultures derived from human stem cells have been used for drug screening, efficacy and safety evaluation, elucidation of the unknown mechanisms of disease, which provides the basis for conducting clinical trials and reducing the incidence of adverse effects. In this paper, we review the current progress in the models based on neural cultures derived from human stem cells and summarize the characteristics. Finally, prospects of human stem cells-derived neural cultures in the future application to evaluation of neurotoxicity induced by antineoplastics and other medicines are discussed.

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Perspectives & Review

Recent Progress of Self-assembly-based Chitosan/phospholipid Nanoparticles for Advanced Drug Delivery

MA Qingming, JIN Yuqiong, CAO Jie, XI Lian, SUN Yong

2021, 52(05): 619-627. https://doi.org/10.16522/j.cnki.cjph.2021.05.004

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This paper reviews the recent progress of self-assembly-based chitosan/phospholipid nanoparticles for delivering a variety of drugs, interprets the critical underlying formation mechanisms and reveals the unique coreshell structure as well as the interactions between drug delivery and the structure. Moreover, the preparation methods are summarized, and the classic solvent dropping method is described in detail. Then, a comprehensive depiction of the advanced applications of the self-assembly-based nanoparticles for delivering antineoplastics, anti-inflammatory drugs, peptides, hypolipidemics, antibacterial drugs and gene therapy drugs are categorized and reviewed. Finally, in-depth conclusions and outlooks on further advancing the self-assembly-based chitosan/phospholipid nanoparticles toward a more versatile platform for developing multi-functional drug delivery systems are discussed.

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Perspectives & Review

Research Progress of Loss of Tabletability in Tableting by Dry Granulation

ZHANG Kunfeng, LI Wanting, YU Jiaqi, SHI Chenfeng, XU Bing

2021, 52(05): 628-635. https://doi.org/10.16522/j.cnki.cjph.2021.05.005

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This paper summarizes the main hypotheses explaining the phenomenon of loss of tabletability in tableting by dry granulation, including "work hardening" "granule hardening" and "granule size enlargement". For plastic materials, key mechanisms and factors that influence tabletability of dry granulated powders involve "granule hardening" "granule size enlargement" and lubricants. For brittle materials, "granule hardening" is the key mechanism. Because of extensive fracture of brittle granules during compaction, tabletability of brittle granules is relatively insensitive to "granule size enlargement" and lubricants. In order to reduce loss of tabletability in tableting by dry granulation, the solutions are summarized from the aspects of formulation properties, ribbon quality control, granule quality control and lubricants. It is hoped that these solutions could provide some references for optimization and control of the dry granulation process of pharmaceutical preparations.

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Paper

Improvement Process of Lasmiditan Succinate

SUN Xiaolei, GUO Xinliang, ZHANG Naihua, ZHANG Zhongkui, ZHANG Guimin

2021, 52(05): 636-638. https://doi.org/10.16522/j.cnki.cjph.2021.05.006

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In this study, the synthesis process of lasmiditan succinate(1) was improved. Thionyl chloride, used as both a solvent and a reagent, reacted with N-methylpiperidin-4-carboxylic acid hydrochloride(2) to give N-methylpiperidin-4- carbonyl chloride(3). Subsequently, treatment 3 with dimethylamine afforded N,N,N'- trimethylpiperidin-4-carboxamide(4), which was then reacted with 2,6-dibromopyridine to generate 2-bromo-6-(1- methylpiperidin-4-ylcarbonyl)pyridine(5) by Grignard reaction. Without purification, 5 was transformed into 2-amino-6- (1-methylpiperidin-4-ylcarbonyl)pyridine(6) in NH4Cl/NaOH system. The latter was coupled with 2,4,6-trifluorobenzoyl chloride to provide lasmiditan(7). Finally, 1 was obtained through salification with succinic acid in a purity of 99.9％ and an overall yield of 50％(based on 2).

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Improved Synthesis of Rasagiline Mesylate

LI Jie, PAN Xinmei, LAI Yongli, ZHONG Huiyun

2021, 52(05): 639-641. https://doi.org/10.16522/j.cnki.cjph.2021.05.007

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The synthetic method of rasagiline mesylate was improved. Propargyl alcohol(3) was reacted with tosyl chloride(2) in dichloromethane to get propargyl p-toluenesulfonate(4). 1-Indanone(5) was reacted with ammonium formate under the catalysis of 10％ Pd/C to give 1-indanamine(6), which was then treated with 4 to afford N-propargyl-1- indanamine(7), then through enantioseparation by L-tartaric acid to get (R)-(+)-N-propargyl-1-indanamine tartrate(8). Finally, the target product was prepared by reacting with methanesulfonic acid. The overall yield was 12％(based on 5). During preparation of 6, the reductive amination was accomplished by ammonium formate and Pd/C with one pot method, which reduced the steps and substantially increased the yield from 37％ to 70％. In the preparation of 7, 3-chloropropyne was replaced by 4 with large steric hindrance, which effectively reduced the side reaction of amino disubstitution, and increased the yield from 68％ to 78％. This improved synthetic method has several advantages, such as simple operation, inexpensive materials, mild conditions and high yield, which offers great potential for industrial application.

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Paper

A New Synthetic Route of 2'-C-Methylcytidine

ZHENG Xianxian, YAN Linjie, ZHONG Wu

2021, 52(05): 642-647. https://doi.org/10.16522/j.cnki.cjph.2021.05.008

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D-Ribose reacted with anhydrous methanol under acid conditions to obtain 1-O-methyl-D-ribose(2) through a nucleophilic addition reaction, the hydroxyl groups of 2 were protected by 4-chlorobenzyl chloride, and then the 4-chlorobenzyl of 2-position of 2 was removed selectively by anhydrous Tin(Ⅳ) chloride to obtain 1-O-methyl-3,5- di-O-(4-chlorobenzyl)-α-D-ribose(4). Compound 4 underwent 2,2,6,6-tetramethyl-1-piperidinyloxy(TEMPO) oxidation and methylation reaction to obtain the key intermediate 1-O-methyl-2-methyl-3,5-di-O-(4-chlorobenzyl)-α-D-ribose(6). Finally, the 2'-C-methylcytidine(1) was obtained through Vorbrüggen glycosylation coupling of the acylated product of 6 and N4-benzoylcytosine followed by two steps of deprotection with an overall yield of 11％(based on D-ribose) and a purity of 99.76％.

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A Novel Synthetic Method of the Key Intermediate of Elagolix

KONG Rui, YUAN Zhedong

2021, 52(05): 648-651. https://doi.org/10.16522/j.cnki.cjph.2021.05.009

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In this paper, the new synthetic route of the key intermediate of elagolix, tert-butyl (R)-[2-[5- (2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin- 1(2H)-yl]-1-phenylethyl]carbamate was reported. Innovatively, ethyl 3-aminocrotonate was used as a raw material, and after being activated by phenyl chloroformate, it was condensed with tert-butyl (R)-(2-amino-1-phenylethyl)- carbamate acetate(4), then cyclized to obtain tert-butyl (R)-[2-[4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]- 1-phenylethyl]carbamate(6). The latter was condensed with 2-fluoro-6-trifluoromethylbenzyl bromide to give tert-butyl (R)-[2-[3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]- carbamate(7), brominated with N-bromosuccinimide, and coupled with 2-fluoro-3-methoxyphenylboronic acid to obtain the key intermediate 1. The synthetic route reduces the reaction steps, eliminates the condensation reaction step that easily produces debrominated impurities, greatly reduces the cost of raw materials, and avoids the use of hazardous chemicals. The total yield of 1 increased from 48％ to 71％, which is more conducive to industrial scale-up production.

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Strain Breeding and Fermentation Process Optimization for Production of Pneumocandin B0 by Filamentous fungus

XIE Qiuping, WEI Tengyun, XIE Yaru, ZHANG Haixia, CHEN Shaoxin

2021, 52(05): 652-660. https://doi.org/10.16522/j.cnki.cjph.2021.05.010

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Pneumocandin B0(PB0) is a secondary metabolite produced by Filamentous fungus, which can be used to synthesize the antifungal drug, caspofungin. In order to increase the yield of PB0, the Filamentous fungus SIPI 2776 strain was subjected to nitrosoguanidine(NTG), 60Co gamma-ray(60Co-γ), ultraviolet(UV) and atmospheric rooom temperature plasma(ARTP) mutagenesis. The mutant strain 11-γ-12 was obtained, and the yield of PB0 shake flask was 1.48 g/L. In addition, genetic engineering technology was used to obtain an engineered strain F-ap-htyE with reduced pneumocandin C0(PC0) composition. The response surface method was used to optimize the fermentation medium, and the yield of PB0 shake flask reached 2.01 g/L. The fed-batch culture in a 5 L fermenter was studied, and the fermentation yield of PB0 reached 2.71 g/L by optimizing the supplemental amount of mannitol.

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Preparation and Pharmacokinetic Evaluation of Enteric-coated Capsules Filled with Pristinamycin Nanoparticles

ZHAO Xin, SUN Li'ang, GE Mei, SHEN Qi

2021, 52(05): 661-668. https://doi.org/10.16522/j.cnki.cjph.2021.05.011

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The nanosuspensions of pristinamycins ⅠA and ⅡA were prepared by high pressure homogenization method, then their nanoparticles were obtained by lyophilization. The enteric-coated capsules filled with above freezedried nanoparticles proportionally were prepared during a dipping process. The in vitro release and pharmacokinetic characteristics of the product in rats were evaluated. The mean particle sizes of pristinamycins ⅠA and ⅡA nanosuspensions measured by dynamic light scattering(DLS) were (354.42±80.26) and (370.35±74.92)nm with polydispersion index(PDI) less than 0.3. Under the transmission electron microscope(TEM), both nanoparticles were spherical in shape. The results of in vitro release test showed that the release of pristinamycins ⅠA and ⅡA at 60 min from the enteric-coated capsules were 90.77％ and 78.22％, respectively. And their relative bioavailabilities in rats were 158.27％ and 132.58％, showing a significant increase as compared to the ordinary capsules. In conclusion, the bioavailability of enteric-coated capsules of pristinamycin nanoparticles was significantly improved, which could provide some references for formulation improvement of pristinamycin enteric-coated preparations.

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Key Process Optimization in Preparation of Microspheres Loaded with Highly Water-soluble Drugs

CHEN Wei, LIU Jiwei, LI Xueming

2021, 52(05): 669-676. https://doi.org/10.16522/j.cnki.cjph.2021.05.012

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To solve the problems of low encapsulation of highly water-soluble drugs in microspheres and acylation reaction between peptides and poly(lactic-co-glycolic acid)(PLGA) during the long-term drug release, the key process of PLGA microspheres loaded with octreotide acetate as a model peptide was investigated and optimized. Firstly, the ion-pairing reagent dextran sodium sulfate(DSS) was added to form reversible complexes. Then, calcium phosphate was added to inhibit the acylation side reaction between peptides and PLGA. The final microspheres were obtained by solid-in-oil-in-water double emulsion-solvent evaporation method. Compared with the octreotide acetate microspheres without DSS and calcium phosphate, the occurrence rate of acylation reaction of the final microspheres decreased from 15.12％ to 6.73％, and the encapsulation efficiency increased from 44.85％ to 92.18％. Due to the advantages of our design, the composite strategy comprehensively improved the issues of encapsulation and delivery of water-soluble peptide drugs in PLGA microspheres. This study provides a new perspective to improve the disadvantages of peptide delivery in PLGA microspheres.

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Pharmacokinetics of Brexpiprazole-loaded in situ Gel for Subcutaneous Injection in Rats

WU Wanyan, ZHANG Pei, HUANG Yuan, GONG Tao, ZHANG Zhirong

2021, 52(05): 677-681. https://doi.org/10.16522/j.cnki.cjph.2021.05.013

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The brexpiprazole(BRE)-loaded in situ gel(BRE-GTO-gel) was prepared by stirring and mixing. A LC-MS/MS method for determination of BRE in rat plasma was established and the pharmacokinetic characteristics of the gel after subcutaneous injection in rats were investigated. The results showed that it was linear for BRE in the range of 1 - 1 042 ng/ml with LLOQ of 1 ng/ml. The intra- and inter-day precisions and accuracies, extraction recoveries, matrix effect and stabilities of this method met the requirements of biological sample detection. In order to investigate the pharmacokinetic behavior of BRE in vivo, rats were injected subcutaneously with BRE-GTO-gel or orally administrated of BRE suspension, respectively. There were significant differences between the suspension group and the gel group in t1/2Z, AUC0→t and MRT0→∞(P<0.05). And the release of BRE from the gel reached 30 days.

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SEC-HPLC and MALDI-TOF/TOF-MS Analyses of the Polymer in Thymalfasin and Thymalfasin for Injection

ZHANG Ying, YIN Hongrui, ZHENG Luxia, SHAO Hong, CHEN Gang

2021, 52(05): 682-685. https://doi.org/10.16522/j.cnki.cjph.2021.05.014

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Molecular exclusion chromatography method was used to measure the content of polymer in 10 batches of thymalfasin and 28 batches of thymalfasin for injection collected from different enterprises. The molecular weight of polymer fraction was measured by matrix-assisted laser desorption ionization-time of flight mass spectrometry(MALDI-TOF/TOF-MS). The results showed that the polymer contents were between 0.1％ and 1.6％ in all 38 batches of samples. The relative molecular weight of the polymer was 6 199, which suggested that the polymer would be a dimer of thymalfasin. The samples were collected representatively, based on national drug sampling evaluation in 2018. The method and results are helpful for the optimization of quality standard.

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Quality Evaluation of Azithromycin for Injection and Azithromycin Injection

QIAN Yan, HUANG Yiwen, WU Yang, ZHANG Huafeng

2021, 52(05): 686-692. https://doi.org/10.16522/j.cnki.cjph.2021.05.015

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Special supervision and sampling inspections of the azithromycin(1) for injection and 1 injection were carried out to analyze the current quality status and existing problems of 1 injections. According to the structural characteristics and production process of 1, a number of inspection methods were established in this study for exploratory research on related substances, genotoxic impurities, and elemental impurities. The results showed that most of the domestic 1 for injection products met the current spectifications, and the pass rate was 82.6％. The unqualified items were the clarity of the solution and the related substances, and the control of impurities was generally good. Original product and the product which passed quality consistency evaluation were designed by overfill, so the drug content of both products was obviously higher than that of other generic products. The legal inspection results of the 1 injection were in compliance with the regulations, and the pass rate was 100％. However, the specificity and sensitivity of the legal analysis methods for related substances were not good. After switching to the HPLC method, the number of detected impurities and the amount of impurities increased significantly, and the over-standard impurities were identified as degradation products. Compared with 1 for injection, the related substances in 1 injection, especially for the degradation products, had relatively high risks and poor stability.

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Determination of the Related Substances in Azithromycin Extended Release for Oral Suspension by HPLC-ECD

YIN Xijing, SHI Fangzhen, REN Xia, YU Lihua, ZHAO Yan

2021, 52(05): 693-697. https://doi.org/10.16522/j.cnki.cjph.2021.05.016

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A high performance liquid chromatography-electrochemical detection(HPLC-ECD) method was established for determination of the related substances in azithromycin(1) extended release for oral suspension. The ZirChrom-PBD column was used, with potassium dihydrogen phosphate solution and acetonitrile(213∶87) as mobile phase(isocratic elution). The flow rate was 0.6 ml/min, the column temperature was 30 ℃, and the injection volume was 50 μl. The results showed that 1 and the known impurities[azithromycin N-oxide(2), azithromycin dexsamine(3), N-desmethyl azithromycin(4), azithromycin related substance F(5), azaerythromycin A(6) and azithromycin related substance H(7)], as well as the degradation products produced by the stress tests, were all separated well. And the calibration curves were linear for compounds 1 - 7 in the corresponding ranges(r≥0.996 0). The average recoveries of 1 - 7 were respectively 96.0％, 88.5％, 98.1％, 97.7％, 100.0％, 95.1％ and 98.6％ with the RSDs (n=9) of 1.86％, 3.20％, 1.25％, 2.62％, 4.06％, 1.05％ and 2.95％. The precision test RSDs(n=6) were 4.23％, 2.65％, 2.70％, 4.57％, 4.45％, 0.96％ and 3.91％, respectively. All of the data met the requirements of quantitative analysis. This method has high sensitivity and strong specificity, which can be used for the detection of related substances in 1 extended release for oral suspension.

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Determination of the Intermediate of Nebivolol and Its Three Diastereomers by HPLC

2021, 52(05): 698-702. https://doi.org/10.16522/j.cnki.cjph.2021.05.017

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An HPLC method was established for determination of three diastereomers in an intermediate of nebivolol, named (R)-1-[(R)-6-fluorochroman-2-yl]-2-[(R)-p-tolyl-methyl-sulfinyl]ethanol. A Hypersil? ODS C18 column was used to separate the (RRR) configuration of intermediate and its three diastereomers with mobile phase composed of methanol and water in a gradient elution mode. The detection wavelength was 243 nm. It was linear for the intermediate and its three diastereomers[(SRR)-, (RSR)- and (SSR)-diastereomers] in the range of 0.2 - 10 μg/ml. The detection limits of the three diastereomers were respectively 10.11, 10.22, 10.22 ng/ml, and the quantification limits were respectively 30.33, 30.64, 30.64 ng/ml. The sample recovery rates were 95.6％ - 102.2％, and the RSDs(n=9) were 1.33％ - 1.74％. This method has good specificity and high accuracy, which provides some references for the control of the asymmetric synthesis of nebivolol.

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Pharmaceutical Management & Information

Analysis of Common Problems in Impurity Research in Consistency Evaluation of Generic Drugs

ZHAO Na, SHI Jing

2021, 52(05): 703-708. https://doi.org/10.16522/j.cnki.cjph.2021.05.018

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Pharmaceutical Management & Information

Discussion of Types and Common Problems of On-site GLP Inspection Deficiencies in China

CHEN Yifei, TANG Liming, LI Gang