Chinese Journal of Pharmaceuticals

Select

Synthesis of Febuxostat

XU Bin, CHENG Jintao

2014, 45(11): 1001-1003.

Abstract ( )

Knowledge map

Save

Febuxostat was synthesized from 4-hydroxybenzaldehyde by etherization, bromination, oximation and dehydroation to give 3-bromo-4-(2-methylpropoxy)benzonitrile, which was subjected to reaction with ammonium sulfide in presence of triethylamine and thiazole ring formation to afford ethyl 2-[3-bormo-4-(2-methylpropoxy)phenyl]-4-methylthiazol-5-carboxylate, followed by introduction the cyano group and hydrolysis with an overall yield of 41％.

Select

Synthesis of Antineoplastic Peptide Drug Buserelin Acetate by Solid and Solution Phase Combination Method

LU Dongdong1,2, QIAO Chunhua1*, ZHANG Guoqing2, BAI Juncai2, TAN Ji2

2014, 45(11): 1004-1008.

Abstract ( )

Knowledge map

Save

The fragment Pyr-His(Trt)-Trp-Ser(Trt)-Tyr(Bzl)-D-Ser(tBu)-Leu-OH (2) was synthesized by Fmoc solid-phase synthesis, and the dipeptide H-Arg-Pro-NHEt·2HCl (4) was prepared by solution-phase method to give Boc-Arg(Pbf)-Pro-NHEt which was subjected to deprotection. Buserelin acetate was synthesized by the condensation of 2 with 4, followed by deprotection with Pd/C in the 85％ acetic acid, purification by RP-HPLC with an overall yield of 38.7％ and an HPLC purity over 98％.

Select

Synthesis of Favipiravir

WANG Huan, LI Xingzhou*, ZHONG Wu

2014, 45(11): 1009-1011.

Abstract ( )

Knowledge map

Save

Favipiravir, an antivirus drug, was synthesized from diethyl aminomalonate hydrochloride by ammonolysis and cyclization with glyoxal to give 3-oxo-3,4-dihydropyrazin-2-carboxamide(T1105), which was subjected to bromination with bromine, chlorination and dehydration with POCl3 and halogen exchange with KF to afford 3,6-difluoropyrazin-2-carbonitrile, followed by selective hydrolysis of 3-fluoro and cyano group with an overall yield of about 9％.

Select

Synthesis of (1S,3aR,6aS)-t-Butyl Octahydrocyclopenta[c]pyrrole-1-carboxylate Oxalate

SHI Yubai, MA Shaohua, ZHANG Yulin, WANG Yanfang, LU Jin

2014, 45(11): 1012-1015.

Abstract ( )

Knowledge map

Save

(1S,3aR,6aS)-t-Butyl octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate, the key intermediate of telaprevir, was synthesized from (S)-glycine-nickel-(S)-2-[N-(N'-benzyl-L-proplyl)amino]benzophenone via stereospecific Michael addition with cyclopent-1-enecarbaldehyde and acid hydrolysis to give (3aR,6aS)-1,3a,4,5,6,6ahexahydrocyclopenta[c]pyrrole-1-carboxylic acid, which was subjected to hydrogenation reduction, amino protection, chiral resolution in the presence of (S)-1,2,3,4-tetrahydro-1-naphthylammonium, esterification, amino deprotection and salinization with an overall yield of about 40％.

Select

FAN Shanshan, ZHAO Lin, ZHANG Yong*

2014, 45(11): 1016-1018.

Abstract ( )

Knowledge map

Save

To perform the quality control of olmesartan medoxomil, two related substances recorded in European pharmacopoeia 7.4 were prepared, and their structures were confirmed by 1H NMR, 13C NMR and MS. They were 6,6-dimethyl-2-propyl-3-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-3,6-dihydro-4H-furo[3,4-d]imidazole-4-one (B) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-methylethenyl)-2-propyl-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate (C).

Select

Synthesis and Anti-inflammatory and Analgesic Activities of Ketals(acetals) Derivatives of Pyrrolizinones

WU Liying1,2, WANG Kezhan2, SONG Hongrui2

2014, 45(11): 1019-1021.

Abstract ( )

Knowledge map

Save

Five compounds 1-5 that had not been reported before were prepared from 1,2-dihydro-3Hpyrrolizin-1-one and paraformaldehyde via adol condensation to give 2,2-bis(hydroxymethyl)-1,2-dihydro-1H-pyrrolizin-1-one, which was subjected to condensation with the corresponding ketone(aldehyde). Their structures were confirmed by 1H NMR and MS. The anti-inflammatory and analgesic activities were evaluated by xylene-induced mouse ear edema test and acetic acid-induced mouse writhing test, respectively. The results showed that compound 4 with analgesic percentage of 74.4％ which was closed to ibuprfen had obviously analgesic activity. However, all of these compounds had low antiinflammatory activities.

Select

Isolation, Purification and Structure Elucidation of an Immunosuppressant SIPI-M2 from Actinoplanes

ZHANG Changqing, CHEN Changfa, ZHOU Bin, HU Haifeng*

2014, 45(11): 1022-1025.

Abstract ( )

Knowledge map

Save

The rapamycin-producing Actinoplanes could synthesize not only an immunosuppressant rapamycin but also its analogue. The analogue was named as SIPI-M2 and was purified by acetone and ethyl acetate extraction, silica column chromatography, etc., and samples were obtained with purity over 95％. The structure of SIPI-M2 was elucidated by analyzing its MS and NMR spectra. The results showed that its structure was identical to that of 27-O-demethylrapamycin. This compound might be one of key intermediates of rapamycin biosynthesis pathway in Actinoplanes.

Select

Mutation of Streptomyces aureofaciens with High Yield Demethylchlortetracycline by Atmospheric and Room Temperature Plasma

LIN Guizhen1, YE Ruifang1*, CHENG Lintong2, MAO Quangui2

2014, 45(11): 1026-1031.

Abstract ( )

Knowledge map

Save

Atmospheric and room temperature plasma (ARTP) mutation technique was used and combined with high-throughput screening based on 96 well plates and HPLC to obtain Streptomyces aureofaciens mutants with high demethylchlortetracycline (1) productivity. A mutant A6-6-9 was screened and showed high genetic stability after four subcultures. Compared with the original strain under the same flask fermentation process, the mutant A6-6-9 showed faster aminonitrogen consumption, slower growth rate and glucose consumption rate, and enhanced productivity of 1 with an increase of 22.5％. The changes of organic acids were also studied. Compared with the original strain, the mutant accumulated more precursor organic acids such as oxaloacetic acid and malonic acid which entered into the synthesis of malonyl-CoA, finally enhanced the production of 1. 2D electrophoresis (2-DE) and protein points by MS showed that malate dehydrogenase, glutamine synthetase and 6-hydroxylation enzyme expressed more in the mutant strain, which might be an important reason for the enhancement of 1 productivity.

Select

Optimization of Extraction Technology of Puyi Granules

ZHANG Jie1, CAO Xu1, ZHU Di1, XIE Yumin1, ZHENG Lin1,2*

2014, 45(11): 1032-1035.

Abstract ( )

Knowledge map

Save

Multi-chemical indexes combined with pharmacodynamics index were used to optimize the extraction technology of Puyi granules. Four kinds of extraction technology were investigated, which were water extraction, water extraction with ethanol precipitation, alcohol extraction, and alcohol-water double extraction. The content of caffeic acid, emodin and 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glucoside were determined by HPLC, while polysaccharide and oleic
acid were measured by UV and TLC, respectively. The pharmacodynamic effects of samples obtained from the above four processes on the survival time of mice bearing Ehrlich ascites carcinoma were compared. The results showed that alcoholwater double extraction was superior to other extractions in indicative ingredients and pharmacological effects.

Select

Preparation of Tetra-acetylated Paeoniflorin Polymeric Micelles and Their Protective Effects against Rat Cerebral Ischemia-reperfusion Injury

ZHANG Yun, AN Dianyun, SHEN Teng*, WANG Jianxin, JIANG Chen

2014, 45(11): 1036-1041.

Abstract ( )

Knowledge map

Save

Tetra-acetylated paeoniflorin (1) loaded polymeric micelles were prepared by solid-dispersing and hydration method with Pluronic P123 as the carrier. The formulation was optimized by central composite design-response surface method. The results showed that the entrapment efficiency and drug loading of the optimized micelles were 97.4％ and 10.5％ with the average diameter of 20.5 nm. Moreover, polymeric micelles increased the solubility of 1 to 585 times as against the bulk drug. Focal cerebral ischemia-reperfusion (I/R) injury model was induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. In I/R injury model rats, polymeric micelles showed significant accumulation of 1 in the brain, especially in the ischemic hemisphere. Furthermore, 1-loaded micelles
significantly reduced infarct size by 40％ and ameliorated neurological deficit scores. In conclusion, 1-loaded polymeric micelles succeed in preventing the biopharmaceutical disadvantage of paeoniflorin and the side effects of 1 injection using solubilizers, and exerting protective effects against cerebral ischemia-reperfusion injury.

Select

Optimization of Preparation of Nanostructured Lipid Carriers Loaded with Cucurbitacin B by Central Composite Design and Response Surface Methodology

LI Yao1,2, HAN Cuiyan2*, LI Jinming3, QIN Lu2, TANG Shujie4

2014, 45(11): 1042-1045.

Abstract ( )

Knowledge map

Save

The nanostructured lipid carriers loaded with cucurbitacin B were prepared by melt-emulsification method. Central composite design-response surface methodology (CCD-RSM) was utilized to optimize the formulation with average particle size, entrapment efficiency and drug loading as evaluation indexes. The optimal formulation was as follows: glycerin monostearate was 0.3 g, lecithin was 0.125 g, soybean oil of injection was 0.075 g and polyethylene
glycol 40 stearate was 0.2 g. The measured values of average particle size, entrapment efficiency and drug loading for the optimal product were 120.8 nm, 83.3％ and 0.83％, respectively. And these measured values were close to the predicted values. The cumulative amount at 45.5 h was (87.1±3.5)％ and the first-order kinetic model gave a good fit to the in vitro release data.

Select

Preparation and Evaluation of Vinorelbine Tartrate Liposomes with Different PEG2000-DSPE Contents

WANG Donghai1,2, XIE Lili 2*, ZHANG Yong1, YANG Qingmin1

2014, 45(11): 1046-1049.

Abstract ( )

Knowledge map

Save

The vinorelbine tartrate (1) liposomes with 6％, 3％ and 1％ molar ratios of polyethylene glycol 2000-distearoyl phosphatidyl ethanolamine (PEG2000-DSPE) were prepared by sucrose octasulfate gradient method. The particle size, ζ potential, entrapment efficiency, in vitro release and stability of the three types of liposomes were detected. The growth inhibition effects of three types of liposomes on SW620 cells transplanted into nude mice were investigated
with 1 injection as the contrast. The results showed that the in vitro characteristics of the three types of liposomes were similar. Moreover, the main quality indicators of the three types of liposomes stored at 4 ℃ for 6 months had no significant changes. The tumor growth inhibition effects of the liposomes with 6％, 3％ and 1％ of PEG2000-DSPE were 52.8％, 72.1％ and 61.8％, respectively. Meanwhile, the tumor inhibition of 1 injection was only 47％.

Select

Determination of Ticagrelor and Its Active Metabolite in Dog Plasma by LC-MS/MS

WANG Manman1, GAO Na1, LI Qingjuan1, LIU Sha2, YANG Hanyu1*

2014, 45(11): 1050-1052.

Abstract ( )

Knowledge map

Save

A LC-MS/MS method was established for the determination of ticagrelor(1) and its active metabolite AR-C124910XX(2) in dog plasma with diazepam as the internal standard. A C18 column was used, with the mobile phase of acetonitrile∶2 mmol/L ammonium acetate solution (70∶30). An electrospray ionization source (ESI) was operated in positive ion mode and multiple reaction monitoring (MRM) mode with the transitions of m/z 523.3→m/z 127.1 (1), m/z 479.3→m/z 153.1 (2) and m/z 284.9→m/z 193.0(diazepam), respectively. It was linear for 1 and 2 in the range of 50 - 10 000 ng/ml. Their extraction recoveries were 109.8％ - 115.1％ and 109.3％ - 114.5％, with the intra-day RSDs no more than 6.8％ and inter-day RSDs no more than 14.2％.

Select

Pharmacokinetics and Bioavailability of Sustained-release Multivesicular Liposome of Tramadol in Rats

HE Shengjiang 1, NIE Yang 1*, ZHANG Xiantao1, SONG Li2

2014, 45(11): 1053-1056.

Abstract ( )

Knowledge map

Save

An HPLC method with fluorescence detection was established for the determination of tramadol (1) in rat plasma. The pharmacokinetic behaviors of the self-made liposomes (1-Lip) and multivesicular liposomes (1-MVLs) after im injection to SD rats were investigated with the commercial injection as the reference. The main
pharmacokinetic parameters of the injection, 1-Lip and 1-MVLs were as follows: tmax (0.69±0.19), (2.06±0.68) and (4.29±1.63)h, cmax (5.08±0.86), (3.02±0.48) and (2.27±0.24)mg/ml, AUC0→t (37.34±9.77), (46.76±15.14) and (67.10±24.53)mg·h·ml-1, respectively. The relative bioavailabilities of 1-Lip and 1-MVLs were 125.2％ and 179.7％. Compared with 1-Lip, the sustained-release property of 1-MVLs was more pronounced.

Select

Quality Standard of Qingwei Granules

LI Moying1, YUE Xinyi1, LIANG Wei2, WANG Huijun2, WANG Songpo2*

2014, 45(11): 1057-1060.

Abstract ( )

Knowledge map

Save

The quality standard of Qingwei granules were preliminarily investigated. An HPLC method was established for the determination of paeonol and tanshinone IIA. A Hedera C18 column was used, with the mobile phase of acetonitrile∶water by gradient elution. The calibration curves for paeonol and tanshinone IIA were linear in the ranges of 4 - 80 μg/ml and 0.1 - 2 μg/ml. Their average recoveries were 99.9％ and 98.9％, with RSDs of 2.9％ and 2.8％, respectively. TLC methods were developed for the identification of paeoniflorin, phillyrin, ammonium glycyrrhetate and tetrahydropalmatine, with the developers of chloroform∶ethyl acetate∶methanol∶formic acid(40∶5∶10∶ 0.2, paeoniflorin and phillyrin), ethyl acetate∶formic acid∶glacial acetic acid∶water (15∶1∶1∶2, ammonium
glycyrrhetate) and n-hexane∶chloroform∶methanol (10∶6∶1, tetrahydropalmatine), respectively. TLC results of the four ingredients exhibited that the bands in the chromatogram obtained with the test solutions corresponded in positions and colors to the bands with the reference solutions. The negative samples displayed no interference.

Select

Determination of L-Lysine in Bendazac Lysine Eye Drops by HPLC

SUN Xiao, SHI Yunfeng

2014, 45(11): 1061-1062.

Abstract ( )

Knowledge map

Save

An HPLC method was established for the determination of L-lysine in bendazac lysine eye drops. An amino column was used, with the mobile phase of acetonitrile∶0.04 mol/L potassium dihydrogen phosphate solution (45∶55, pH 6.5, adjusted with potassium hydroxide solution), at the detection wavelength of 200 nm. It was linear in the range of 0.2 - 2.5 mg/ml. The average recovery was 99.04％,with RSD of 1.28％.

Select

Determination of PEGylated Arginine Deiminase by HPLC

LIU Ying, SHAO Yu, HU Haifeng*

2014, 45(11): 1063-1065.

Abstract ( )

Knowledge map

Save

A size exclusion chromatography(SEC)-HPLC method was established for the determination of the PEGylated arginine deiminase (PEG-1). A gel column was used with the mobile phase of 0.05 mol/L phosphate buffer (pH 7.3)∶methanol (80∶20) at the detection wavelength of 220 nm. The calibration curve of PEG-1 was linear in the range of 0.2 - 1.2 mg/ml. The recovery was 96.32％, with RSD of 1.74％.

Select

Determination of Related Substances in Biotin by HPLC

CHEN Xuefan1,3, HU Chuchu2, ZHAO Panpan2, ZHENG Guogang2

2014, 45(11): 1066-1068.

Abstract ( )

Knowledge map

Save

An HPLC method was established for the determination of the related substances in biotin. A C18 column was used, with the mobile phase of PBS (16.7 mmol/L, pH 2.9)∶methanol by gradient elution, at the detection wavelength of 210 nm. Biotin and the related substances were well separated. The calibration curves for related substances A - D were linear in the range of 1 - 20 μg/ml. Their average recoveries were 93.3％ - 99.3％, and the low limits of detection were 0.365, 0.280, 0.255 and 0.480 μg/ml, respectively.

Select

Determination of Methylmesylate and Ethylmesylate in Dronedarone Hydrochloride by GC-MS

DING Yimei1,2, WU Juan2, LU Chunxiao2, CUI Ping1,2, WANG Decai2

2014, 45(11): 1069-1071.

Abstract ( )

Knowledge map

Save

A GC-MS method was established for the determination of methylmesylate (MMS) and ethylmesylate (EMS) in dronedarone hydrochloride. A TR-5MS capillary column was used, with helium as the carrier gas. Electron impact ionization (EI) source was employed and two analytes were detected under the positive ion mode. The calibration curves of MMS and EMS were linear in the range of 0.7 - 10 μg/ml. Their average recoveries were 94.21％ and 95.35％, with RSDs of 3.79％ and 2.67％, respectively.

Select

Research Progress in Stability of Recombinant Human Growth Hormone in Preparation Process

TANG Shu, CHEN Zhixiang, LU Weigen*

2014, 45(11): 1072-1077.

Abstract ( )

Knowledge map

Save

Recombinant human growth hormone is a protein drug widely used in clinic. However, the development and application of long-acting preparation of the drug are limited due to protein aggregation as well as other physical and chemical instability. The influence of formulation factors and preparation process on the stability of these long-acting preparations of recombinant human growth hormone, stability improvement methods and determination measures for protein structure and degradation products are introduced in this paper.

Select

Research Progress of Bioreducible Polymers in Gene Delivery System

WU Shan, ZHONG Yanqiang, ZOU Hao*

2014, 45(11): 1078-1085.

Abstract ( )

Knowledge map

Save

Gene therapy is a kind of biotechnology which transfers genes into cells to express specific proteins to cure diseases. Superior gene delivery vectors play an important role in gene delivery. Bioreducible polymers, which mainly possess disulfide linkages in the polymer structures, are ideal gene delivery carriers due to the high stability in extracellular physiological condition but bioreduction-triggered release in intracellular reducing environment. They have been widely investegated for their low cytotoxicity and high gene transfection efficiency. This review summarizes recent advances in the development of bioreducible polymers during the past decades including cationic liposomes, polymeric micelles, polymers (chitosan, gelatin, polyethyleneimine, polyamide-amine, dendrimer) and polypeptides, etc.

Select

Application of Powder Characterisation to Implementation of Quality by Design (QbD)

WANG Lei1, CHEN Fangxiao1, ZENG Huanxiang1, ZHAO Wanli1, FU Xiaowei2

2014, 45(11): 1086-1089.

Abstract ( )

Knowledge map

Save

The behavior of powder for injection during the vacuum filling process had been systematically investigated in this paper, and key powder properties which influenced the filling weight variation were identified. This study revealed how real processing challenges in pharmaceutical industry could be successfully resolved by using the quality by design (QbD) concept, based on acquired correlation between powder properties and real performance in the production.

Select

Graphical Synthetic Routes of Cabazitaxel

WANG Yi, LIU Wenjie, ZONG Zaiwei, DU Youguo

2014, 45(11): 1090-1092.

Abstract ( )

Knowledge map

Save

Select

Graphical Synthetic Routes of Linagliptin

WANG Yue, GUO Heng, CEN Junda*

2014, 45(11): 1093-1096.

Abstract ( )