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

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    Perspectives & Review
  • Perspectives & Review
    DING Yuan, LU Weiyue
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    With the increase of clinical demand and the improvement of nanotechnology, researches on nanodrug delivery systems(NDDS) have become increasingly in-depth. As a new type of NDDS, lipid nanodiscs(LND) show the advantages of desirable biocompatibility, high drug loading capacity, and the ability of long circulation, which can be used in the targeted delivery of antineoplastic and antibacterial drugs. This review summarizes the structural characteristics, superiority, classification, and applications of LND. Furthermore, the advantages and challenges are discussed, thereby providing approaches for promoting the formulation improvement of such preparations.
  • Perspectives & Review
    WANG Li, YUAN Penghui, YANG Dezhi, ZHANG Li, LYU Yang
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    Drug cocrystals generally refer to the multi-component drug system composed of active pharmaceutical ingredients and cocrystal formers, which are bound by non-covalent bonds. The formation of cocrystal can effectively improve the physicochemical properties of solid chemical drugs such as solubility and stability, and thus enhance their bioavailability, which has become a hot spot in the field of crystalline drug research. Thermal analysis techniques are a class of techniques that observe and record the temperature-dependent thermodynamic or physical parameters of a substance under a controlled temperature program, and play an important role in drug development and quality control. Thermal analysis techniques have been widely used as effective analytical characterization methods in the screening of drug cocrystal, and the application of various thermal analysis techniques enables in-depth studies of the physicochemical properties and thermodynamic behaviors of drug cocrystals. In order to provide some references for the application of thermal analysis techniques in the study of drug cocrystals, the recent progress in the application of various thermal analysis techniques in research of drug cocrystals is reviewed in this paper.
  • Perspectives & Review
    HE Chiyu, HU Yuxi
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    Tablets and capsules with the advantages of being easy to use, storage, and carrying are common clinical drug dosage forms. However, swallowing tablets or capsules may cause discomfort or difficulty swallowing(dysphagia). The size, shape, and other physical attributes of pharmaceutical preparations are essential factors that affect the ability of patients to swallow drugs. Differences in their physical attributes may affect patient compliance and may even lead to medication errors, thereby reducing the durability and efficacy of treatment. From the perspective of drug safety design, this review discusses the influences of the size, shape, and other physical attributes of generic drugs on taking drugs and provides a reference for the development of generic drugs for tablets and capsules.
  • Perspectives & Review
    LI Wenjie, XIE Liping
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    Saccharopolyspora spinosa is a member of soil actinomycetes family. The secondary metabolite spinosad(1) is a broad-spectrum macrolide biological insecticide, which has been widely used all over the world because of its unique insecticidal mechanism, safety and high efficiency. The molecular synthesis pathway of 1 and the genes involved are briefly introduced in this study, and the research progress of strain selection and genetic modification methods of Saccharopolyspora spinosa is reviewed, including the research progress of traditional breeding, metabolic regulation and synthetic biology, which can provide a reference for the industrialization research of 1.
  • Paper
  • Paper
    CHU Yanjun, TI Wenli, CHENG Lei, ZHANG Guimin
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    5-Methylpyrazine-2-carboxylic acid(2) was oxidated with hydrogen peroxide/sodium tungstate to produce acipimox. In the process, the pH value was adjusted to 3 - 5 with sodium hydroxide to increase the solubility of compound 2, so that the reaction was complete. After the filtration in heating with activated carbon, followed by the reslurry with the mixed solution of acetone and water, the target compound with purity of 99.93%(with no more than 0.03% of 2, and no more than 0.01% of the peroxide impurity) was obtained, and the total yield was about 84%. The improved process with simple operations was suitable for industrial application.
  • Paper
    JIANG Yanan, LI Linji, LI Xiang,MO Jinqiu, ZHANG Weidong
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    With 2-chlorotriphenyl chloride(CTC) resin as the solid support, Fmoc-Phe-OH as the starting material, and 1-hydroxybenzotriazole(HOBt)/N,N′-diisopropylcarbodiimide(DIC) as the condensation reagent, the protected peptides were assembled through Fmoc-based solid-phase peptide synthesis(SPPS) and cyclized in liquid phase. Trifluoroacetic acid(TFA) was then used to remove the side chain protection to afford the title cyclic peptides. Then they were purified by preparative liquid chromatography. The HPLC, MS and 1 H NMR were used to characterize the pure products. The results showed that the purity of asperheptatides A was 97% with total yield of 7.29% and the purity of asperheptatides B was 95% with total yield of 6.57%.
  • Paper
    LUO Kaihong, DAI Yuhao, MA Xiao, LI Jianqi, LIU Yu
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    [(3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl](morpholino)- methanone(2), the key intermediate of sotagliflozin, was synthesized from L-xylose(4) by acetonylidene protection, selective hydrolysis, oxidation of the primary alcohol, salification with morpholine, and amidation. The reaction conditions were optimized as the following: ① selective hydrolysis with phosphoric acid / water system; ② the conditions of oxidation of primary alcohol were selected to greatly increase the operability and the yield; ③ the work-up of crude product 2 was simplified with n-heptane as solvent to solidify the product. The optimized process overcame the problems that the compound was difficult to extract due to its good water solubility. The total yield was 44% and the purity was 100%, which was more suitable for industrial production.
  • Paper
    HAN Bo, GU Xiu, JIAO Minru, ZHANG Hao, ZHANG Qingwei
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    Using the reported histone deacetylase(HDAC)6 inhibitor SW-100 as the lead compound, a series of novel HDAC inhibitors were designed based on the scaffold hopping strategy. A total of 8 new compounds of classes Ⅰ and Ⅱ were designed and synthesized, and their structures were confirmed by MS and 1 H-NMR. The results of in vitro inhibition assays against HDAC6 and HDAC1 showed that the inhibitory activities of compounds Ⅰa and Ⅱa against HDAC6 were slightly lower than that of the positive control compound SW-100, and their selectivities for HDAC6 were also weaker than that of SW-100. Molecular docking showed that compounds Ⅰa and Ⅱa could well interact with key amino acids in the cavity of HDAC6 protein.
  • Paper
    ZHANG Ying, XU Xiaqing, HE Meng, ZHANG Yueli, YANG Xiaorui, ZHANG Zhenzhong, GUO Xinhong
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    The photosensitive liposomes co-loaded with docetaxel(1) and fullerene C60 malonic acid derivative(2), a photosensitizer, were constructed by thin film dispersion method. The particle size, ζ potential, appearance, encapsulation efficiency, in vitro release, cytotoxicity of the prepared liposomes(1-2-LP) were characterized. The effects on reactive oxygen species(ROS) expression, cell cycle and apoptosis of the tumor cells, and in vivo antitumor activity in mice were also performed. The results showed that the particle size and ζ potential of the 1-2-LP were (170.4±1.3)nm and (–31.28±1.09)mV. The observation of transmission electron microscopy revealed that the product was quasi-spherical and uniform. The encapsulation efficiencies of 1 and 2 were (86.38±0.99)% and (93.81±1.06)%. The release of 1 from the 1-2-LP was unaffected by the addition of 2, and the cumulative release of 1 within 50 h was 78%. The 1-2-LP could significantly inhibit the proliferations of human cervical cancer(HeLa) cells and mouse melanoma(B16-F10) cells under the irradiation of laser at 532 nm for 3 min. The detection results of ROS showed that 1-2-LP enhanced the fluorescence intensities of HeLa and B16-F10 cells under the laser irradiation. The results of flow cytometry showed the 1-2-LP combined with laser irradiation changed the cell cycle of the tumor cells and promoted their early apoptosis. The in vivo test in B16-F10 tumor-bearing mice showed that the tumor growth of the mice in 1-2-LP combined with laser irradiation group was significantly inhibited with the inhibitory rate of 85.33%, showing a synergistic antitumor effect of the liposomes co-loaded with 1 and 2 in combination with laser irradiation.
  • Paper
    YANG Xuanlin, XU Xiaozhen, HAO Yue, WENG Weiyu
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    This study aims to synthesize double-tailed surfactants(DTS) composed of polyethylene glycol monomethyl ether(mPEG) and stearate and evaluate their applications in micellar drug delivery system. Three mPEGoxycarbonyl-3-amino-1,2-propanediol distearates(mPEG-DSs) were synthesized by using (R)-3-amino-1,2-propanediol as the linker to connect stearate with mPEGs of different molecular weights(1 000, 2 000, and 5 000). The critical micelle concentrations of three synthesized mPEG-DSs were lower than 10 μg/ml, and the hemolysis rates were less than 5% at 20 mg/ml of concentration. The solubilization effects of mPEG-DSs on docetaxel were better than that of Tween-80 at the same concentration, and their effects increased with decreasing molecular weight of mPEGs. The particle size of docetaxel-loaded micelles prepared with mPEG1000-DS and mPEG2000-DS were (22.17±1.83) and (62.24±2.73)nm, respectively. Both drug-loaded micelles exhibited neutral charge and high encapsulation efficiency(>95%). The pharmacokinetics was carried out with SD rats as animal models. After intravenous injection, the pharmacokinetic profiles of the docetaxel-loaded mPEG2000-DS-based micelles were similar to those of the commercially available docetaxel injection(Taxotere). In contrast, the docetaxel-loaded mPEG1000-DS-based micelles showed prolonged blood circulation time. In conclusion, the mPEG-DSs showed a good prospect for micellar drug delivery system application.
  • Paper
    LIAO Shiji, LIAO Langkun, HU Yanping, QIU Yuqin
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    The colchicine niosomes(1-NS) were prepared by pH gradient method and the formulation parameters, namely the composition of non-ionic surfactants and amount of cholesterol, were optimized by single factor experiment with encapsulation efficiency(EE) as the indicator. The mean particle size, ζ potential and EE of the optimal 1-NS with the carrier consisted of Span-60, Tween-80 and cholesterol at a mass ratio of 2∶2∶1 were (689.0±3.7)nm, (–14.11±0.45)mV and (78.82±0.64)%, respectively. Preliminary stability test showed that the EE of the optimal 1-NS had no obvious changes during the storage at 4 ℃ for 90 d, and the leakage rate was lower than 10%. A modified Franz diffusion cell test was carried out to compare the transdermal performances of 1 aqueous solution and 1-NS in vitro. The results showed that the cumulative amount, steady-state permeation rate and skin retention of 1-NS in vitro were 2.08, 1.74 and 1.69 times as high as those of the aqueous solution. The results of percutaneous absorption in rats showed that 1-NS could significantly enhance the transdermal property of 1 and had a certain sustained-release effect compared with 1 aqueous solution.
  • Paper
    YU Shaowen, GUO Yajuan, HU Shujun, CHEN Ying
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    The particle morphology of D-mannitol(1) may affect its physicochemical properties and functional indicators. In this study, the morphology, crystal form changes, powder properties, and moisture adsorption properties of 1 particles were investigated, and the influence of 1 particle morphology on its properties and functions was discussed. The results showed that the particle morphology of 1 could affect its compressibility, fluidity and other functional indicators, as well as water adsorption capacity and other properties, which suggested that during the screening of excipients in the early stage of formulation development, attention should be paid to the effects of different crystal forms and granulation processes on the properties and functions of 1 to ensure the stability of formulation quality.
  • Paper
    JI Xiaoli, SHENG Yunhua, LI Yinxia, HU Yue, TANG Liming
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    A human type Ⅱ alveolar epithelial cell line A549-inflammation injury model exposed to air-liquid interface(ALI) cultivation mode was established using lipopolysaccharide(LPS) as an inflammatory stimulator. The effects of different mass concentrations(0, 10, 30, 50 μg/ml) and durations(1, 3, 5 h) of LPS on the gene expression of interleukins(IL-1β, IL-6, IL-8, IL-18), tumor necrosis factor-α and transorming growth factor-β were investigated. The results showed that the expressions of the above-mentioned inflammatory factors were increased in all dose groups except IL-6 when LPS acted for 1 h. The expressions of inflammatory factors were independent of the mass concentration of LPS, but related to its action time, which provided an experimental basis for determining the optimal concentration and time of ALI cultured inflammatory cell model.
  • Paper
    LIU Yuhong, JIANG Yu, HAO Guizhou, LIU Shankui
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    Cabazitaxel(1) liposomes were prepared by ethanol injection method, and a centrifugal-microporous membrane filtration method was established to separate liposomes and free crystalline drug, and an HPLC method was used to determine the encapsulation efficiency of 1 in liposomes. The results showed that under the established chromatographic conditions, the specificity of 1 was good, and it was linear for 1 in the range of 1 - 20 μg/ml. The intraand inter-day precisions both met the requirements, and the repeatability was good. The measuring results showed that the average encapsulation efficiency of 1 liposomes in three batches was 99.24%, with the RSD of 1.00%, which could be used to accurately determine the encapsulation efficiency of 1 liposomes.
  • Paper
    LI Ming, XU Haiyun, ZHAO Kailou
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    In order to detect the cysteine hydrochloride in compound amino acid injection, γ-Al2O3/SiO2 coreshell structure adsorbent was synthesized in this study, and cysteine hydrochloride was pre-separated and enriched by isoelectric point difference. In addition, a chemiluminescent probe was synthesized that could achieve the specific detection of cysteine hydrochloride. The test results showed that the pre-separation and enrichment of cysteine hydrochloride by isoelectric point method, combined with chemiluminescent probe, could realize the rapid separation and detection of cysteine hydrochloride in compound amino acid injection. And the method had good selectivity and sensitivity, with a simple preparation of sample. It was linear for cysteine hydrochloride with the luminous intensity in the range of 1–20 μg/ml, with the pH value of the luminescence solution was 12.5, the concentration of chemiluminescent probe was 1.5×10–4 mol/L, the volume fraction of H2O2 was 0.3%, and the concentration of Cr3+ was 2.5×10–4 mol/L. The method had good repeatability and reproducibility, which provided a reference for the rapid detection of cysteine hydrochloride in compound amino acid injection.
  • Paper
    LU Honghua, WEI Ruixia, HAO Guizhou, SUN Jianhe, ZHANG Guimin
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    A gas chromatography-mass spectrometry(GC-MS) method was established for the determination of genotoxic impurities, N-nitrosopyrrolidine(2), N-nitrosomorpholine(3) and oxole(4), in ketorolac tromethamine(1). A ZB-1MS capillary column(30 m×0.25 mm×0.25 μm) was used for the determination in multiple reaction monitoring mode. The results showed that it was linear for 2, 3 and 4 in the ranges of 33.48 - 100.44, 4.96 - 14.88 and 19.28 - 57.84 ng/ml, respectively. The limits of quantification were 25.11, 3.72, and 14.46 ng/ml, and the limits of detection were 8.54, 1.26, and 4.92 ng/ml, respectively. The average recoveries(n=9) were 96.98%, 98.17%, and 98.50%, with the RSDs of 5.42%, 4.30%, and 1.93%, respectively. This study can provide a reference for the quality control of 1.
  • Paper
    SONG Hang, YANG Hanyue, YAN Xianguang, ZENG Yinhai, LI Runlai, LI Shu'an
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    Based on the crystalline form transformation, preparation of febuxostat crystal form A in both laboratory- and kilogram-scales were investigated. Orthogonal experiments were employed to distinguish the effects of solvents and dosage, dissolving temperature, crystallization temperature and time, and other factors on formation and yield of febuxostat crystal form A yield. The optimized process was as follows: febuxostat was dissolved in 8 times of absolute ethanol at 75 ℃ for 10 min, then the solution was slowly cooled to 10 ℃ at 0.5 - 1 ℃/min, followed by stirring for 4 h at a low speed(below 100 r/min) to form febuxostat crystal form A precipitate with the yield of 93% - 96%; the solvent could be recycled twice. This preparation approach of febuxostat crystal form A with short crystallization time was facile, robust, and environmentally friendly, which was suitable for industrialization.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    ZHU Xin, CHEN Guiliang, CAO Meng
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  • Pharmaceutical Management & Information
    CHEN Wei, YANG Kai, XU Yiming, WU Mingyang, LIANG Yi
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  • Pharmaceutical Management & Information
    SI Xiaofei, LI Wuchao, JIANG Dianzhuo
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  • Pharmaceutical Management & Information
    ZHANG Ling, WANG Yanan, ZHU Jiawen, SHAO Rong
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  • Pharmaceutical Management & Information
    ZANG Kecheng, JIANG Rong, ZHANG Xuerui, SHAO Rong
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