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
    SHEN Jie1,2, LI Yan1, LU Zhiguo1,2, ZHANG Tianlu1, ZHANG Xin1*
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    CRISPR (clustered regularly interspaced short palindromic repeats) has emerged as a new gene editing technique. It can be used to cure cancer, AIDS, and other diseases by modifying gene accurately. Some vaccines and drugs can be exploited by CRISPR. However, there were some problems existing in gene drugs, such as instability, easy degradability and poor membrane penetrability. These problems have limited the development of CRISPR applications. So it is important to find proper vectors, which can effectively deliver drugs to target cells, and improve the efficiency and specificity of CRISPR technology. This paper focuses and summarizes the current developments in gene delivery systems of CRISPR, including the advantages and disadvantages, the current states and the future trends of viral and non-viral vectors, providing some references for the application of drug delivery system in biomedical treatments.
  • Perspectives & Review
    ZOU Ye, SU Weike*
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    L-ribose is a key intermediate of antiviral drugs (such as maribavir). It does not exist in nature and needs to be artificially synthesized. The synthetic methods mainly include chemical synthesis and microbial synthesis. This paper summarizes the synthetic methods according to different starting materials, compares the advantages and disadvantages between the 2 methods, and proposes some suggestions for their future development.
  • Perspectives & Review
    WANG Jiaxin, LUAN Hansen*, WANG Hao
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    Most of the drugs have the disadvantages of poor solubility and low bioavailability. Chemical and physical properties of the stable new structure, which is formed by drug and excipients, are predicted by computer simulation technology. It is helpful to screen and optimize the formulation and to clearly understand the stability mechanism of the new structure. The combination and confirmation of experimental technology with computer simulation technology are achieved finally. Making inclusion complexes and solid dispersions are two effective methods to improve the solubility of insoluble drugs. The ability of the combination of drugs with cyclodextrin ( CD) can be predicted by molecular dynamics simulation and docking. A new model of amorphous solid dispersions simulated with low temperature annealling model indicates that the drug molecules at the surface of the polymer coils are able to easily move and aggregate together, which may explain the physical instability of solid dispersions. The calculation of solubility parameter is an important quota to predict the solubility of insoluble drugs. At the same time, microstructure is given by dissipative particle dynamics simulation. The solubility is predicted from the micro point of view consequently.
  • Perspectives & Review
    LIU Yang, XIE Jin, XU Junnan, YUE Pengfei*, YANG Ming*
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    Solid nanocrystals are a new type of nanotechnology based on the nanosuspensions, which can redisperse into colloid suspensions after rehydration. Solid nanocrystals exhibit large surface area so as to significantly improve the dissolution rate and bioavailability of poorly soluble drugs. Development of solid nanocrystals has become a hot spot of drug delivery system. Stability is an important difficulty that affecting production and application of nanocrystals. It is well known that process parameters are key factors influencing stability of solid nanocrystals. However, the impacts of the properties of drugs, stabilizers and matrix formers on stability of solid nanocrystals are scarcely reviewed. In this paper, the research progress of the key factors affecting the stability of nanocrystals during the nanocrystallization and solidification is systemically summarized. It is expected to provide references for the development of the solid nanocrystals for poorly soluble drugs.
  • Perspectives & Review
    WANG Jue1, ZHU Zhuangzhi2, ZHANG Xiaohong3*
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    Preparations for inhalation have been increasingly widely used in recent years because of their safety and high efficiency. To achieve an effective pulmonary deposition, inhalable drug particles should have an aerodynamic diameter below 6 μm. Spray freeze drying (SFD) technology is a relatively new dry powder formation technique that involves a three-step process of atomization, freezing and drying. As a combination of conventional spray drying with freeze drying, SFD technology has several advantages: ① no heat treatment in the process, which is applicable to thermally labile ingredients; ② ultra-fast freezing of fine droplets minimizes the crystallization and phase separation of drug; ③ frozen fine particles are conductive to forming highly porous spherical particles with controllable size during the process of frozen drying. The dry powders obtained by SFD exhibit improved physicochemical characteristics and low aerodynamic diameters, thus rendering it suitable for pulmonary administration. This review describes the process, characteristics and classification of SFD technology, as well as the application in inhalation preparations for small molecules and biomacromolecules in recent years.
  • Paper
  • Paper
    ZOU Ye1, LI Linling2, CHEN Rener2, SU Weike1*
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    The synthetic process of closantel sodium was improved. Commercial p-chlorobenzyl cyanide reacted with 4-chloro-2-nitrotoluene (3) to give 4-chloro-α-(2-chloro-4-oximido-5-methyl-2,5-cyclohexadiene-1- ylidene)phenylacetonitrile, which was followed by reduction to afford 4-amino-2-chloro-5-methyl-α-(4-chlorphenyl)- phenylacetonitrile (5). In this step, catalytic hydrogenolysis was used instead of reduction by iron powder to avoid the discharge of iron sludge, simplify the operation, and increase the yield from 84% to 92%. Then N-[5-chloro-4-[α-(4- chlorophenyl)cyanomethyl]-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide (8) was synthesized by ''one-pot'' reaction of 2-hydroxy-3,5-diiodobenzoic acid and 5 in the presence of triphosgene, the yield was increased from 81% to 94.3%. Finally, 8 was subjected to salification with sodium hydroxide to give the target compound with a total yield of 77% (based on 3) and a purity of 99.3%. The improved synthetic process had some advantages, such as simple operation, mild reaction conditions, high yield and less waste, which made it easy for large scale production.
  • Paper
    BAI Wenqin1, TANG Zhenbo1, SONG Chuanling1, ZHANG Guimin2*
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    The synthetic process of temsirolimus was improved. Sirolimus (2) was subjected to etherification with chlorotrimethylsilane to protect 31- and 42-hydroxyl groups, which was followed by a selective hydrolysis to give siroliums 31-O-trimethylsilane (4). In this step, excessive hydrolysis was avoided through close reaction monitoring by TLC. In addition, after a purification of compound 4, the residue of 2 was further reduced to less than 0.15%, which would reduce the formation of impurities in the following reaction and improve the quality of the final product. Then compound 4 reacted with 2,4,6-trichlorobenzoic 2,2,5-trimethyl-1,3-dioxane-5-carboxylic anhydride to provide 2,2,5-trimethyl-1,3- dioxane-5-carboxylic 31-O-trimethylsilyl siroliums-42-ester (5). Then the latter was subjected to hydrolysis in 2 mol/L H2SO4 to remove 2 protective groups in one time and afford the target compound with a yield of 94%. After the above improvement, the purity of the final product was increased from 98% to 99%, and the total yield was increased from 60% to 84.3% (based on 2). This process has been verified by pilot scale production in kilograms, and the process parameters and yield are stable.
  • Paper
    SHI Kejin, CHEN Lin*, LI Jianghong, REN Fengying, YANG Chen, GOU Xiaojun
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    The synthetic process of empagliflozin (1)was improved. Phenol (2) reacted with (R)-3- hydroxytetrahydrofuran to give (S)-3-phenoxytetrahydrofuran, which was followed by Friedel-Crafts alkylation with 2-chloro-5-iodobenzyl bromide to provide (S)-3-[4-(2-chloro-5-iodobenzyl)phenoxy]tetrahydrofuran (6). In this study, Friedel-Crafts alkylation was used instead of the Friedel-Crafts acylation and carbonyl reduction which usually be used in literatures. Then compound 6 reacted with 2,3,4,6-tetra-O-acetyl-1-α-bromo-D-glucopyranose in the presence of n-butyl lithium and copper iodide to afford (2S,3R,4R,5S,6R)-2-[3-[4-[(S)-tetrahydrofuran-3-yl-oxy]benzyl]-4-chlorphenyl]- 6-acetoxymethyl-3,4,5-triacetyloxy epoxy hexane (8). In this step, the reaction temperature increased from -78 ℃ to -40~-20 ℃ to make it easier to control. Finally, the target compound was obtained via deacetylation of 8 in lithium hydroxide aqueous solution with an overall yield of 43.0%(based on 2) and a purity of 99.21%. The content of the impurity α-empagliflozin was less than 0.1%. The improved route was shorter, and the operation was convenient.
  • Paper
    XING Lihua
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    Budesonide (7) is a glucocorticoid drug, which has been widely used for the treatment of asthma. There were two diasteroisomers, (R)-budesonide (1) and (S)-budesonide. In this study, the synthesis of 1 was improved. Hydrogen peroxide was used instead of potassium permanganate to oxidize 21-acetoxypregna- 1,4,9(11),16-tetraene-3,20-dione (2) to 16α,17α-dihydroxypregna-21-acetoxy-1,4,9(11)-triene-3,20-dione (3), the waste residue was avoided and the work-up was simplified. After a bromination with N-bromosuccinimide, 9α-bromo-11β,16α,17α-trihydroxypregna-21-acetoxy-1,4-diene-3,20-dione (4) was synthesized, then it was subjected to debromination by Pd/C/H2 to afford 11β,16α,17α-trihydroxypregna-21-acetoxy-1,4-diene-3,20-dione (5), the work-up was simplified and the risk of heavy metal residue was reduced. Then after a hydrolysis of 5 by potassium hydroxide, 16α-hydroxyprednisolone (6) was obtained. Then the latter reacted with n-butylaldehyde to give 7. In this step, a green ionic liquid [PSmim][HSO4] was used instead of perchloric acid to increase the yield from 80.7% to 98.5%, and simplify the work-up, in addition, the ionic liquid could be recycled and the cost was reduced. Finally, the target compound was obtained by chiral resolution of 7 with an overall yield of 21.9%(based on 2).
  • Paper
    LU Yang1,2, WANG Pingping1,3, QIAN Chao1*
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    An improved process of 2-trifluoromethylpyridine-3-carboxaldehyde, the key intermediate of azaindole, was reported. Ethyl 3-amino-4,4,4-trifluorocrotonate (3) was prepared via a condensation of NH3 and ethyl trifluoroacetoacetate in methanol. In this step, NH3 was used instead of ammonium acetate in methanol to avoid the hydrolysis of 2 and 3. Then 3 reacted with acraldehyde via a condensation and oxidation by "one pot" method in ethanol to give ethyl 2-(trifluoromethyl)nicotinate (4), which was followed by a reduction with sodium borohydride to afford 2-(trifluoromethyl)pyridin-3-methanol (5). Finally, 5 was oxidized by manganese dioxide to give the target compound with an overall yield of 49%.
  • Paper
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    Avermectin, the main secondary metabolite produced by Streptomyces avermitilis, and its derivatives with structural similarity are a series of 16-membered macrocyclic anthelmintic antibiotics. Because of the high efficiency, low toxicity, and broad-spectrum insecticidal activity, they are widely utilized in agriculture, medicine and animal husbandry. In addition to avermectin polyketide synthase (PKS), there are eleven different PKSs in the genome of Streptomyces avermitilis. In this study, the optimization of some key parameters was carried out in conjugation of the industrial strains on the basis of classical genetic approach, including MgCl2 concentration, time and temperature of heatshock, pre-germination time, ratio of donor to recipient and the timing of antibiotics overlaying. After optimization of all these conditions, the efficiency of conjugation was increased by 2.4 times finally. Deletion mutants of different PKS biosynthesis clusters were performed and constructed by homologous recombination under the optimized condition and finally seven PKS biosynthesis clusters (pks2, pks5, olm, pte, pks9, rpp and pks11) were knocked out successfully. These deletion mutants were named AV002, AV005, AV006, AV007, AV009, AV010 and AV011, respectively. Among them, AV002 and AV005 no longer produced avermectin. Besides, the avermectin production in AV011 decreased by 18% and AV009 showed no remarkable change on avermectin production compared with the parent strain. On the contrary, the avermectin production in AV006, AV007 and AV010 were enhanced to varying degrees.
  • Paper
    HUANG Bei1, HUANG Chuanli2, ZHANG Caifeng2, LU Banyi1, LONG Xiaoying1,3*
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    The preparation process of the vitamin C (1) phospholipid complex (PC-1) was optimized by single factor test with combining ratio as the index. The optimized PC-1 were characterized by ultraviolet-visible spectroscopy, infrared spectroscopy and differential scanning calorimetry. The solubility and stability of PC-1 were compared with 1 and the modified Franz diffusion cell method was used to compare the transdermal performance of PC-1 and 1 in vitro. The results showed that the optimal preparation process of PC-1 was as follows: the concentration of 1 was 10 mg/ml, mass ratio of 1 to phospholipid (PC) was 1∶4, the complex reaction was conducted at 55 ℃ for 1 h in absolute ethanol. The combining ratio of the optimal PC-1 was (96.0±0.1)%. The lipid solubility of PC-1 increased significantly, while its water solubility was decreased significantly compared with 1. The results of high temperature and intense light tests showed that the stability of 1 was significantly enhanced by forming a complex with PC. The cumulative amount penetrated through excised mouse skin at 12 h of PC-1 and 1 were (0.779±0.057) and (0.333±0.014) mg/cm2 respectively, and the amount of skin retention were (0.36±0.05) and (0.06±0.02)μg/cm2, respectively. These results showed that the physicochemical properties and transdermal performance of 1 were significantly improved by PC-1. This change would make the drug more suitable for external use in creams, gels, nanoemulsions, or something else.
  • Paper
    LI Haigang, XU Jiamin, XU Kang
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    Multivesicular liposomes (MVL), an effective sustained-delivery system, consist of numerous nonconcentric closely-packed internal aqueous chambers separated by lipid bilayer. However, the physical and chemical instabilities (leakage of the encapsulated drug, vesicle aggregation and hydrolysis of phospholipids) of multivesicular liposomes are major problems during the preparation, storage and usage due to their aqueous state. In this study, scutellarin was selected as a model drug and scutellarin internal phase thickened multivesicular liposomes (SITMVLs) were prepared by double emulsion method. In this formulation, hydroxypropyl methyl cellulose (HPMC) was encapsulated into its internal aqueous chambers as a thickener, which was supposed to reduce the fluidity of the interior aqueous phase and enhance mechanical strength of internal chambers, thereby avoiding repture/aggregation of internal aqueous chambers. The process and formulation were optimized by single factor test and orthogonal experiment with encapsulation efficiency as the index. The results showed that the encapsulation efficiency was the highest when the first emulsifying time was 8 min and the nitrogen flow rate was 6 L/min. The optimal formulation was as follows: the HPMC concentration in the internal aqueous phase was 0.2%; the concentrations of soy lecithin, cholesterol, triolein, octadecyl amine in oil phase were 1.5%, 1%, 0.7% and 0.45%, respectively; the concentrations of polyvinyl alcohol and glucose in the external water phase was 0.5% and 3%, respectively. The encapsulation efficiency and particle size of SITMVLs and the common scutellarin multivesicular liposomes (SMLVs) which had no HPMC in the internal aqueous chamber were compared to evaluate the preliminary stability of SITMVLs. The results showed that the shapes of SITMVLs were smooth and spherical during the storage at room temperature for 30 d, and no debris was observed in the light micrographs. Moreover, the changes of encapsulation efficiency for SITMVLs was also unobvious. Finally, the drug release from SITMVLs was significantly slower than that of SMLVs in pH 6.8 phosphate buffer containing 3% glucose.
  • Paper
    CAI Jie1,2, GU Wangwen2, DING Yaping1*
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    The properties of the co-processed excipient including microcellulose, EASYtab, were investigated by evaluating fluidity, compressibility and particle size distribution of powder. The results showed that Carr index and repose angle of the co-processed excipient were 16.7% and 30.18 °, respectively. Scanning electron microscopic observation showed that the co-processed excipient was spherical, uniform and porous compared with the corresponding physical mixture containing the same composition. Piroxicam, carbamazepine and itraconazole exhibited the poor blend uniformity, low dissolution and slow disintegration, respectively. In order to investigate the improvements of the co-processed excipient in content uniformity, dissolution and disintegration of tablets prepared with direct compression process, the above three drugs were adopted as the model drugs. The quality attributes of tablets with different drug loadings were compared. As the drug loading was 20%, piroxicam tablets showed a satisfied content uniformity with the A+2.2S value of 6.53; dissolution at 60 min of carbamazepine tablets was 82.3%; itraconazole tablets could quickly disintegrate within 10 s. Compared with the corresponding physical mixture, the co-processed excipient EASYtab could significantly improve the quality attributes of tablets prepared by direct compression. Moreover, the hardness and friability of three kinds of tablets were also with the acceptable pharmacopoeial limits, even though the drug loading amount reached to 40%. These findings showed that the co-processed excipient including microcellulose reflected the excellent dilution potency in the process of direct compression.
  • Paper
    LI Zhihong1, YAN Renjie1, XING Jianguo3, WU Tong2, LIU Li1*
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    Here we investigated the anti-myocardial ischemia components from Dracocephalum moldavica extraction (DME). Twenty-nine phytochemical compounds were primarily pointed out in fingerprints of DME by HPLC. Plasma pharmacochemistry techniques were further employed to screen potential bioactive components in DME. HPLC chromatographic profiles of dosed plasma, blank plasma and DME were acquired, and a total of eight prototype components, including (+)methyl rabdosiin (1), (+)rabdosiin (2), rosmarinic acid (5), tilianin (13), luteolin-7-O- β-D-glucuronide (18), apigenin-7-O-β-D-glucuronide (19), diosmetin-7-O-β-D-glucuronide (20), and acaetin-7-O- β-D-glucuronide (21) were identified by HPLC analysis. These prototype components could be the major bioactive components of DME. Flavone compounds 13, 18, 19, 20 and 21 were tested to inhibit the ADP-induced aggregation of platelets in vitro. The results showed that the platelet aggregation inhibition rate to ADP-induced rat of compounds 13, 18 and 19 were 8.11%, 9.32% and 3.27%, respectively, with a final concentration of 30 μg/ml. Phenolic compounds 1, 2 and 5 were tested to protect the H2O2-induced myocardial cell. The MTT analysis showed that compounds 1, 2 and 5 at 12.5 μg/ml remarkably reduced the cytotoxicity and inhibited cell apoptosis. As a result, the flavone and phenolic compounds of DME may be partially responsible for myocardial ischemia effect.
  • Paper
    NING Shubo, WANG Jiafeng, ZHAN Zhaoshuang, ZHOU Mingbo, XIN Dan, TENG Jialin
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    A quantitative analysis of multicomponents by single marker (QAMS) was established for multicomponents determination of neochlorogenic acid (1), chlorogenic acid (2), cryptochlorogenic acid (3), caffeic acid (4), cynaroside (5), baicalin (6), wogonoside (7), baicalein (8) and wogonin (9) in Yinhuang tablets, with baicalin (6) as the internal reference. An HPLC method was applied, and the separation was carried out on a Zorbax SB-C18 column, with the mobile phase of methanol∶0.4% phosphoric acid solution, at the detection wavelengths of 325 nm (0-35 min, for detection of 1-5) and 280 nm (35-60 min, for detection of 6-9). The relative correction factors (RCFs) of 1-9 were 0.65, 0.66, 0.72, 0.43, 1.54, 1.00, 1.13, 0.73 and 0.92, and their relative retention time (RRTs) were 0.16, 0.27, 0.38, 0.55, 0.86, 1.00, 1.11, 1.16 and 1.28, respectively. It was linear for 1-9 in the ranges of 1.05-10.50, 1.50-15.00, 0.28-2.80, 0.40-4.00, 1.20-12.00, 20.00-200.00, 7.00-70.00, 9.00-90.00 and 7.30-73.00 μg/ml. Their average recoveries were 93.96%-99.28%, with RSDs of 2.14%-3.95%. Ten batches of Yinhuang tablets were quantitatively determined both by QAMS method and the external standard method (ESM). The results showed that there were no significant differences between these two methods.
  • Paper
    SHEN Chen, XIA Xu, GAO Wenyan, ZENG Shanshan, YE Jincui*
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    An HPLC method was established for the chiral separation and determination of ramosetron hydrochloride and its (S)-enantiomer. The effects of temperature, humidity, light, acid, alkali and oxidant on the enantiomeric conversion from (R)-configuration to (S)-configuration in ramosetron hydrochloride active pharmaceutical ingredients (API) were also investigated. A YMC chiral NEA(R) column was used, with the mobile phase of 50 mmol/L sodium dihydrogen phosphate buffer solution (pH 5.2)∶acetonitrile (50∶50), at the detection wavelength of 306 nm. The resolution of the enantiomers was more than 1.5. It was linear for (S)-ramosetron hydrochloride in the range of 0.04-1.00 μg/ml, with LOQ of 0.032 μg/ml. Its average recovery was 100.2%, with RSD of 0.32%. The results of stability test revealed that ramosetron hydrochloride would undergo an enantiomeric conversion from (R)-configuration to (S)-configuration in alkaline environment, which suggested that alkalinity should be avoided during its preparation and formulation process. The established method was accurate and stable, which provided a quality control method for ramosetron hydrochloride.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    LIN Huanyu1, WU Zhenfeng1*, ZENG Lihua1, WANG Xuecheng1, YANG Ming1,2*
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  • Pharmaceutical Management & Information
    ZHUANSUN Yan, YU Jianing, ZHU Jiaxian*
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  • Pharmaceutical Management & Information
    DU Shuang, LIANG Yi*
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  • Pharmaceutical Management & Information
    JIANG Haihong1, LI Jing2*
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  • Pharmaceutical Management & Information
    YU Xiaowen1, DONG Min2, YOU Chunna1*
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  • Pharmaceutical Management & Information
    YUE Zhihua, LI Huiyi
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  • Pharmaceutical Management & Information
    LIU Shu
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  • Pharmaceutical Management & Information
    SHEN Chen, LU Zhengyu, XU Xiuhui, XU Rong, LAI Congcong
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