主办:上海医药工业研究院
   中国药学会
   中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA

Archive

  • 2014 Volume 45 Issue 5
    Published: 10 May 2014
      

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  • CHEN Zhuo, YU Gang, ZHANG Qingwen*
    2014, 45(5): 401-403.
    Abstract ( )   Knowledge map   Save
    4,5-Dimethoxy-2-nitroacetophenone (2) was catalytically hydrogenated at atmospheric pressure in the presence of 5% palladium on carbon, cyclized with ethyl formate, chlorinated with phosphorus oxychloride, and substituted with 4-aminophenol to give 4-(4-aminophenoxy)-6,7-dimethoxyquinoline (6). Compound 6 was condensed with 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (8) to yield cabozantinib (9), then reacted with (S)-malic acid to deliver cabozantinib (S)-malate (1) with an overall yield of 52% based upon 2.
  • ZHANG Mingguang, MA Yanqi, XIA Zhengjun, CHEN Zaixin*
    2014, 45(5): 404-408.
    Abstract ( )   Knowledge map   Save
    To perform the quality control of moxifloxacin hydrochloride, three related substances were prepared, and their structures were confirmed by MS and 1H NMR. These substances were 1-cyclopropyl-6-fluoro-7-amino-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(S,S)-2-methyl-2,8-diazabicyclo[4.3.0]non-8-yl]-4-oxo-quinoline-3-carboxylic acid and 1-cyclopropyl-7-(1-amino-8-azabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.
  • XU Tao, QU Boyi, HAI Li, WU Yong*
    2014, 45(5): 409-411.
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    Valganciclovir hydrochloride(1) was synthesized from ganciclovir by condensation, selective hydrolysis and hydrogenation with an overall yield of 29.7%. The purity of final product and the ratio of the diastereomeric isomers were in accordance with the requirements of US pharmacopeia (USP35). Three related substances including ganciclovir monoacetate, ganciclovir monopropionate and bis-valine easter of ganciclovir were successfully synthesized, which provided the basis for the quality control and purification of 1.
  • CHEN Yilang, GAO Fei, CHEN Youxi*
    2014, 45(5): 412-414.
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    1-(2-Bromoethoxy)-3-iodobenzene (4) was prepared from 3-iodophenol and 1,2-dibromoethane. And ethyl 5-bromo-2-penenoate (7) was prepared from propylene glycol by reduction with MnO2, Wittig reaction with ethyl (triphenylphosphoranylidene)acetate and bromonation. Ethyl 2-[6,7-dihydro-1H-indeno[5,4-b]furan-8(2H)-ylidene]acetate, the intermediate of ramelteon, was synthesized from 4 and 7 in the presence of palladium acetate/triphenylphosphine/norbornene with an overall yield of about 51%.
  • TU Guoliang, HUANG Shengping
    2014, 45(5): 415-416.
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    t-Butyl 4'-bromomethylbiphenyl-2-carboxylate, the intermediate of telmisartan, was synthesized from t-butyl 4'-methylbiphenyl-2-carboxylate by bromination with bromine and hydrogen peroxide with a yield of 73.4%. After separation, the liquor which contained the product, the starting material and by-product t-butyl
    4',4'-dibromomethylbiphenyl-2-carboxylate was recovered to the starting material with a purity of 98% by the reduction with ammonium chloride and zinc dust.
  • XIONG Lei, GAO Pin, ZHOU Bin, HU Haifeng*
    2014, 45(5): 417-419.
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    SIPI-228 is a cyclic peptide antibiotic with anticancer and antifungal activities. In this paper, a Chromobacterium violaceum named as SIPI-820 kept in our lab. was used as the starting strain. By UV mutation and UV combined with diethyl sulfate treatment, a mutant named as SIPI-LH7-16 was selected and its productivity of SIPI-228 was 354% higher than that of the original strain. After improving its fermentation process, the yield of SIPI-228 in the optimal conditions of shake flask reached to 531 mg/L, which was 254% higher than the initial process. The yield of SIPI-228 reached to 810 mg/L in a 5 L fermentor.
  • CAO Qian1, YANG Ling2, LIU Guosheng1*, LI Jinxin1, XING Shantao3
    2014, 45(5): 420-423.
    Abstract ( )   Knowledge map   Save
    2,6-Diaminopurine arabinoside, the intermediate of guanine arabinoside, was biosynthesized from uracil arabinoside and 2,6-diaminopurine by Escherichia sp. AEM0812. The optimal reaction conditions were as follows: adding 15% Escherichia sp. AEM0812 bacterium cells into 60 mmol/L phosphate buffer (pH 7.0) with substrates of 60 mmol/L uracil arabinoside and 60 mmol/L 2,6-diaminopurine, then the reaction was carried out at 60 ℃ for 48 h. The conversion rate of uracil arabinoside was 95.2% under the above conditions. 
  • QU Xiaosheng1,2, YANG Yifang1*, ZHANG Jing1, HU Xiao2, LUO Yongming2
    2014, 45(5): 424-427.
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    Based on the fusion of water decoction method and the supercritical extraction method, ten extraction methods were designed to get Zhi-Zi-Hou-Pu decoction intermediates. The fingerprint chromatograms of ultra fast liquid chromatography (UFLC) were studied. A mice forced swimming test (FST) was explored to identify the relationship between the fingerprint and antidepressant regression with double variable correlation analysis and multiple linear correlation analysis. The assignment of antidepressant peaks was conducted. It suggested that the synergism from peak 1 (synephrine), 2, 7, 15, 16, 18, 20 (honokiol), 21 (magnolol), 24 and 27 might be related to the antidepressant effect, of which peak 20 and 21 were significant related peaks.
  • WU Mingxia, CUI Yongxia, XU Min
    2014, 45(5): 428-430.
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    The effects of different processing methods on the contents of buddleoside, chlorogenic acid and 3,5-O-dicaffeoylquinic acid in Flos Chrysanthemi indici were investigated and their concentrations were determined by HPLC. A Diamonsil C18 column was used, with the mobile phase of acetonitrile︰0.2% phosphoric acid by gradient elution, at the detection wavelength of 330 nm. The calibration curves for buddleoside, chlorogenic acid and 3,5-O-dicaffeoylquinic acid were linear in the ranges of 0.08 - 0.8, 0.046 - 0.46 and 0.066 - 0.66 µg. Their recoveries were 98.9%, 98.3% and 98.1%, with RSDs of 2.07%, 1.47% and 1.19%, respectively
  • GUO Xiaoheng1, WU Yongyan2, SONG Dengmin1, YAN Zhuyun3*, LIU Tao1
    2014, 45(5): 431-433.
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    The compounds from the chloroform active part of Bombyx batryticatus were isolated and their anticonvulsive effects were investigated. A silica gel column chromatography was used to isolate and purify the compounds and their structures were identified by MS and NMR analysis. Five compounds were identified as β-sitosterol, ergost-6,22-dien-3β,5α,8α-triol, beauvericin, 6,9-epoxy-ergosta-7,22-dien-3-ol and β-daucosterol. Among them, 6,9-epoxy-ergosta-7,22-dien-3-ol was isolated from Bombyx batryticatus for the first time. The anticonvulsive effects were tested and the results showed that beauvericin had anticonvulsive effect, suggesting beauvericin could be served as the internal detective index for the quality control of Bombyx batryticatus.
  • SHAO Zhihui, GUO Jiawang, WANG Jian*
    2014, 45(5): 434-438.
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    The betaxolol hydrochloride-loading resins were prepared with self-made sodium polystyrene sulfonate ion-exchange resins as carriers, then the sustained-release suspension for ophthalmic delivery containing the above drug-loading resins was developed. The drug-loading resins were in spherical shape with an average particle size of 26.4 µm. The test of in vitro drug release from the suspension was performed in Franz diffusion cell with simulated tear fluid as release medium. The results showed that the cumulative release of the drug from the prepared suspension at 0.5 and 10 h were 26.4% and 97.8%. The rheological investigation of the suspension showed that the product presented a liquid gel property and was suitable for ophthalmic drug delivery.
  • ZHANG Wenjian, WEI Gang*, LU Weiyue
    2014, 45(5): 439-443.
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    A novel eye ointment-contained cyclosporine A (1) lipid nanodispersion (1-EOCLN) for the treatment of severe dry eye syndrome accompanied with inflammation was prepared by solvent evaporation method coupled with high pressure homogenization method with medium chain triglycerides (MCT) as a liquid lipid in the formulation. The prepared 1-EOCLN had a mean particle size of about 90 nm, with a polydispersity index less than 0.2 and a ζ potential lower than -25 mV. The entrapment efficiency of 1 in EOCLN was above 99%. The image of TEM showed that 1-EOCLN had a spherical shape and the ointment matrix was evenly entrapped in the nanoemulsion of MCT, which was mostly locating at the interface between oil and aqueous phase. Particle size and ζ potential of 1-EOCLN were sensitive to higher temperature and stronger illumination. The optimized formulation was rather stable when it was stored at 4 ℃ for 6 months. The EOCLN remained the functions of eye lubrication and tear film restoration, and at the mean time avoided the poor compliance of eye ointment. For hydrophobic medicines, EOCLN could be a promising ocular delivery carrier for clinical application.
  • ZHAO Ligang1, LI Yan2, Lü Lixun1, ZHAO Linlin1
    2014, 45(5): 444-448.
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    The drug-in-adhesive patches loaded with selegiline hydrochloride with azone, oleic acid, N-methylpyrrolidone(NMP), menthol, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP) or (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) as penetration enhancer were prepared, respectively. The in vitro permeability test was carried out with two-chamber cells and excised rat skin to investigate the effects of the types and concentrations of pressure sensitive adhesive (PSA) and enhancer on permeation behavior of the drug in patches. The results showed that the optimal patches with Duro-Tak 87-2677 as the matrix, 3% menthol and 10% azone as combined enhancers had a higher penetration amount and no time lag in release. The results of preliminary stability test showed that the adhesion and in
    vitro transdermal property of the product stored at 30 ℃ and relative humidity of 60% for 6 months had no significant changes.
  • ZOU Qing, WANG Bo*
    2014, 45(5): 449-453.
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    The timed- and controlled-release isosorbide mononitrate osmotic pump tablets were prepared on the basis of the principle of osmotic pump. To achieve the goals such as 4 h lag time, zero-order in vitro release kinetics and complete release, hypromellose-based isolation layer and cellulose acetate-based semi-permeable layer were deposited on the cores. And the formulation was optimized by the central composite design-response surface methodology with 4 h and 16 h cumulative release and correlation coefficient of drug release profile as dependent factors and semi-permeable coat weight gain, pore-former amount, isolation layer weight gain and osmotic agent amount as independent factors. The results showed that the lag time was mainly decided by the hydration time of semi-permeable and isolation layer. The optimal formulations had a 4 h lag time (4 h cumulative release below 10%) and 16 h cumulative release above 90% in media with different pH values. Moreover, it showed that the osmotic pressure-controlled delivery was greatly responsible for the release of the developed tablets.
  • ZHANG Jinkun1, YANG Yang1, XU Bei2, HE Yingju1, SONG Xiangrong2*
    2014, 45(5): 454-459.
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    The liver-targeting liposomes loaded with sorafenib (1) were prepared by thin-film dispersion method with glycyrrhetinic acid modified cholesterol (GA-PEG-Chol) as targeting agent. The related pharmaceutical properties, in vitro antitumor activity and in vitro uptake efficiency were investigated. The results showed that the mean size and the entrapment efficiency of the product were (89.79±6.20)nm and (86.13±2.75)%. The cumulative release of 1 from the product at 48 h was 80% in pH 7.4 phosphate buffer containing 0.6% Tween-80. The in vitro antitumor activity study showed that the product inhibited the growth of two human hepatoma cell lines (SMMC-7721 and Bel-7402) more effectively than the free drug and non-targeting 1 liposomes (P<0.05) when the drug concentration was 10 µg/ml. In the in vitro uptake assay, the liver-targeting liposomes loaded with coumarin presented the fluorescence intensity far higher than the free coumarin in both SMMC-7721 and Bel-7402 cells (P<0.05). These findings indicated that the enhanced antitumor activity of 1 liver-targeting liposomes probably attributed to the increasing intracellular concentration of 1.
  • OUYANG Danwei, XIAO Feng, QIN Yan, SHAO Yan, KONG Deyun*
    2014, 45(5): 460-465.
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    An LC-MS method was established for the determination of the triterpenoid saponins in Centella total glucosides (CTG) in rat plasma and the pharmacokinetic properties of CTG in rats were studied after oral and intravenous administrations. A Kromasil C18 column was used with the mobile phase of 0.1% formic acid solution (containing 10 mmol/L ammonium formate)∶methanol by gradient elution. A mass spectrometry was applied with ESI ion source in the positive ion multiple reaction monitoring (MRM) mode. All pharmacokinetic parameters were processed by noncompartmental analysis with DAS 2.0 software. After CTG was intravenously administered at 5 mg/kg dose, the main pharmacokinetic parameters of asiaticoside, madecassoside+asiaticoside B, asiatic acid and madecassic acid were as follows: t1/2 (1.65±0.80), (3.02±0.55), (3.75±1.93) and (0.31±0.08)h; cmax (2 622±555), (23 800±2 138), (483±128) and (605±124)ng/ml; AUC0→t(572±125), (7 703±639), (185±32) and (100±22)ng·h·ml-1; AUC0→∞(581±127), (7 722±639), (206±37) and (101±22)ng·h·ml-1. While after CTG was orally administered at 150 mg/kg dose, the main pharmacokinetic parameters of madecassoside+asiaticoside B and asiatic acid were as follows: t1/2 (3.41±1.27) and (5.25±2.50)h, cmax (97.6±38.2) and (42.3±14.0)ng/ml, AUC0→t(435±38) and (377±52)ng·h·ml-1, AUC0→∞(446±38) and (427±72)ng·h·ml-1. The concentration-time profiles of madecassoside+asiaticoside B and asiatic acid showed double-peak phenomenon after oral administration, inferring that there might be a hepato-enteral circulation. The absolute bioavailability of CTG was (0.081±0.011)%.
  • CHEN Shanshan1, WANG Ting1,2, ZHU Tengwei1, WANG Feng3, DING Jinsong1*
    2014, 45(5): 466-469.
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    The in vitro release of thermo-sensitive methotrexate-loaded in situ gel was evaluated by membranefree release model. The results showed that the gel had a biphasic release process in phosphate buffer. The cumulative release at 4 and 24 h were 20% and 50%. The drug concentration in rabbit plasma was determined by LC/LC-UV. The pharmacokinetics in rabbits after subcutaneous injection of methotrexate injection or the gel was investigated. In comparison with the injection group, the cmax of the gel group was significantly decreased while the AUC0→t and MRT0→twere significantly increased (P<0.01). The maintenance time of the drug concentration above 0.02 µmol/L (MEC) in the gel group was prolonged to 116 h. The relative bioavailability of the product was 341%.
  • QIAO Shi, LI Qingyan*, SUN Ruifang, WANG Wei, XU Haishan
    2014, 45(5): 470-473.
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    An UPLC-MS/MS method was established for the determination of seven compounds in compound glycyrrhiza oral solution. An Acquity UPLC HSS C18 column was used with the mobile phase of 5 mmol/L ammonium acetate water solution (containing 0.08% formic acid)︰0.1% formic acid acetonitrile solution by gradient elution. A multiple reaction monitoring scanning mode was performed combined with the ion switching technology for quantification in six sections. Glycyrrhizic acid and glycyrrhizin were detected by the negative ion scanning mode, while morphine, codeine, thebaine, noscapine and papaverine were detected by the positive ion scanning mode. All calibration curves were linear in the corresponding concentration ranges. Their average recoveries were 93.8% - 109.5%, with RSDs of 2.4% -
    4.8%.
  • SONG Yuqin
    2014, 45(5): 474-475.
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    A dual-wavelength HPLC method was established for the determination of amidopyrine, phenacetin and caffeine in compound aminopyrine phenacetin and caffeine tablets. An Inertsil ODS-SP column was used with the mobile phase of acetonitrile︰water (25︰75) at the detection wavelengths of 249 and 272 nm. The calibration curves for amidopyrine, phenacetin and caffeine were linear in the concentration ranges of 10 - 200, 15 - 300 and 4.5 - 90 µg/ml, respectively. Their average recoveries were 99.8%, 99.6% and 100.4%, with RSDs of 0.8%, 0.7% and 1.3%, respectively.
  • CHEN Yang, GUO Dan, LIU Qian, YANG Yongjian*
    2014, 45(5): 476-478.
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    An inductively coupled plasma-atomic emission spectrometry (ICP-AES) method was established for the determination of calcium, potassium, magnesium and sodium in enteral nutritional emulsion (TP). The samlpes were treated with wet digestion. The emission lines of Ca, K, Mg and Na were 422.7, 766.5, 285.2 and 589.6 nm, respectively. Their calibration curves were linear in the concentration ranges of 0.4 - 1.6, 1 - 4, 0.15 - 0.6 and 0.6 - 2.4 µg/ml. The recoveries of these four elements were (101.6±1.6)%, (98.9±0.9)%, (101.0±0.6)% and (99.9±1.5)%, respectively. Their low limits of quantification were 3, 2, 1 and 2 ng/ml, respectively
  • CHEN Yunyan1,2, SHAO Yan2, OUYANG Danwei2, KONG Deyun2*
    2014, 45(5): 479-480.
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    With the addition of β-cyclodextrin (β-CD) in the mobile phase, the inclusions of asiaticoside B and madecassoside with β-CD were collected by preparative HPLC. The mixture powder was extracted with n-butanol∶water (2∶1) to remove β-CD. Thus, the preparative method of asiaticoside B and madecassoside as the references in the extract of Centella triterpenes was established.
  • GAN Yongqi, LIU Tao, HUANG Ju, ZHU Bin*
    2014, 45(5): 481-484.
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    A routine method was used for bacteria, total combined moulds and yeasts count and the control bacteria test of lactasin tablets. The validation method was used for the determination of 492 batches of samples from 8 manufacturers. Lactasin tablets were antibacterial for Staphylococcus aureu. The pH 7.0 phosphate buffer nutrient agar was used for the elimination of antibacterial activity and bacterial counts. The acceptability result of microbial limit test of 492 samples was 100%.
  • LIN Huangjing, ZHANG Yilan*
    2014, 45(5): 485-490.
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    Due to the more widely use of the non-polyvinyl chloride (PVC) multilayer co-extrusion infusion bags, the safety issues, especially the compatibility with the pharmaceutical products, are receiving greater attention. As one of the most important aspects of compatibility evaluation, the potential extractables and leachables related to such materials have also become research hotspots. The research thinkings and contents as well as the analytical methods for the extractables and leachables from the non-PVC multilayer co-extrusion infusion bags are reviewed in this paper. In addition, the progress on several known extractables and leachables have been discussed in detail.
  • XU Lanxia, ZHAO Chuanmeng, ZHANG Fuli*
    2014, 45(5): 491-494.
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  • XIE Mufeng
    2014, 45(5): 495-497.
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