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
Chinese Journal of Pharmaceuticals

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    Perspectives & Review
  • Perspectives & Review
    Research Progress of Gastroretentive Drug Delivery Systems
    HU Manyu1,2, ZHU Zhuangzhi2, WANG Hao2*
    2019, 50(03): 241-251. https://doi.org/10.16522/j.cnki.cjph.2019.03.001
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    The residence time of drugs at the absorption site is one of the key factors affecting the treatment effect. Conventional oral dosage forms are often eliminated before complete release because of rapid gastric emptying and short gastrointestinal transit time. It causes low bioavailability and frequent dosing. Based on comprehending the physiological parameters of the gastrointestinal tract, the research of gastroretentive drug delivery system (GRDDS) has been nearly 30 years. The development of GRDDS makes it possible for drugs to stay in the stomach for a longer time. It mainly depends on the size growth, the adhesion improving and the density changing of the formulation to resist gastric emptying. Various gastroretentive technologies have been developed, mainly including expandable system, high density system, bio/mucoadhesive system, floating system, superporous hydrogel, magnetic system and dual work system. GRDDS can increase the bioavailability and absorption of drugs at the upper gastrointestinal tract, thus it can reduce dosing frequency, increase patient compliance and improve clinical efficacy. Also, the emergence of multi-unit GRDDS guarantees better effectiveness and safety of drugs. Currently, GRDDS has many related marketed products. This paper reviews the recent development of GRDDS, including the impacts, the classification and in vivo evaluation methods of GRDDS, and then looks forward to the application prospects of GRDDS.
  • Perspectives & Review
    Analysis on Factors Affecting Tablet Dissolution
    LIU Chao1,2, ZONG Jianfei1,2
    2019, 50(03): 252-259. https://doi.org/10.16522/j.cnki.cjph.2019.03.002
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  • Perspectives & Review
    Discussion on Key Factors in Equipment Cleaning for Synthetic APIs
    WANG Qing, ZHU Jianwei*
    2019, 50(03): 260-269. https://doi.org/10.16522/j.cnki.cjph.2019.03.003
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  • Perspectives & Review
    Patent Analysis on Broadly Neutralizing HIV Antibodies
    WU Yadi1, ZHANG Yingshuai2, ZHANG Dongmei1*
    2019, 50(03): 270-279. https://doi.org/10.16522/j.cnki.cjph.2019.03.004
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    By using Derwent Innovation as the search tool, and (broadly neutralizing antibod* or broadlyneutralizing antibod* or bNAb*) and (HIV or human immunodeficiency virus or AIDS or acquired immune deficiency syndrome) and vaccin* as the search words, 309 patents were selected and they belong to 45 patent families. The first patent application was in 1993, and it showed a downward trend after reaching its peak in 2011. The most important target markets are the United States and Europe, while the International AIDS Vaccine Initiative, the Scripps Research Institute, US Health, Duke university, university of California(Santa Cruz), Children's Medical Center and New York university are main players. The top three inventors are Haynes Barton F from Duke university, Phogat Sanjay K and Hoffenberg Simon from the International AIDS Vaccine Initiative. The field has a certain technical foundation and is being improved and is related to treat subject.
    • Paper
  • Paper
    Process Improvement of Tamsulosin Hydrochloride
    ZHU Anguo, WANG Honggang, DONG Weichao, GUO Qinfang, ZHANG Guimin*
    2019, 50(03): 280-283. https://doi.org/10.16522/j.cnki.cjph.2019.03.005
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    An improved synthetic process of tamsulosin hydrochloride was reported. 1-(4-Methoxyphenyl)- propan-2-one was sulfonated by chlorosulfonic acid/sulfoxide chloride in dichloromethane, which was following by an ammoniation with ammonia to give 2-methoxy-5-(2-oxopropyl)benzenesulfonamide in 91％ yield. Then it reacted with (R)-(+)-α-methylbenzylamine catalyzed by Raney Ni to afford 5-[[(2R)-2-[(1R)-N-(1-methylbenzyl)]amino]- propyl]-2-methoxybenzylsulfonamide hydrochloride. In this step, DMF was used instead of methanol as the solvent to improve the dissoluble amounts of materials, reduce the amount of Raney Ni, and increase the yield from 58％ to 90％. Then the latter was subjected to an ammonolysis with 2-(2-ethoxyphenoxy)ethyl 4-methylbenzenesulfonate and a deprotection with Pd-C as the catalyst to produce the target compound with a purity of 99.9％, a chiral purity of 99.9％ and an overall yield of 60.3％. The optimized process has mild reaction conditions and simple operation, which has been verified by kilogram scale-up.
  • Paper
    Improved Synthesis of Cabozantinib (S)-Malate
    ZHANG Lijuan1, HAN Xiao1*, CHEN Rui2, CHEN Huiqiong3
    2019, 50(03): 284-286. https://doi.org/10.16522/j.cnki.cjph.2019.03.006
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    An improved synthesis of cabozantinib (S)-malate (1) was reported. 4-Chloro-6,7-dimethoxyquioline (2) was reacted with N-tert-butyloxycarboryl-4-hydroxyaniline (3) to give tert-butyl [4-[(6,7-dimethoxyquinolin-4- yl)oxy]phenyl]carbamate (4). In this step, compound 3 was used instead of p-aminophenol to avoid the side reaction from the naked amino group, and to simplify the refining process. Compound 4 was converted to 6,7-dimethoxy-4-(4- aminophenoxy)quioline by deprotection. Then the latter was directly condensed with 1-[(4-fluorophenyl)carbamoyl]- cyclopropane-1-carboxylic acid to afford cabozantinib, which was followed by a salification with (S)-malic acid to prepare the target compound with an overall yield of 85.7％(based on 2) and a purity of 99.5％. This improved synthetic route has some advantages such as mild reaction conditions, low cost, and simple operation procedure, which makes it more suitable for industrial production.
  • Paper
    Synthesis of Novel Quinoline Derivatives and Evaluation of Their DPP-4 Inhibition Activities
    MENG Xiangguo1,2, LIN Kuaile3, ZHANG Wei3, ZHOU Weicheng3, XU Yixin1,2*
    2019, 50(03): 287-295. https://doi.org/10.16522/j.cnki.cjph.2019.03.007
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    Dipeptidyl peptidase-4 (DPP-4) inhibitors have been generally considered as one of the most promising targets for treatment of type 2 diabetes. Ten novel 3-aminomethyl-2-(2,4-dichlorophenyl)-4,6-disubstituted quinoline derivatives (B1 - B10) were designed and synthesized with diphenyl compound A7 as the leading compound. The inhibition and IC50 values on DPP-4 of all the compounds were determined. The compounds showed potential activity probably by the interaction of N atom with Arg 125 residue and benzene ring in quinoline with Tyr 547 residue. Compounds B2 - B5 (IC50=0.080 - 0.331 μmol/L) and B7 - B10 (IC50=0.104 - 0.509 μmol/L) displayed the in vitro inhibitory activity similar to the positive control sitagliptin (IC50=0.035 μmol/L).
  • Paper
    Synthesis and in vitro Nephrotoxicity Evaluation of Andrographolide Derivatives
    YU Qingqing1, GU Lili2, HUANG Wenhai2, LU Hong1, ZHANG Xinyue2*
    2019, 50(03): 296-301. https://doi.org/10.16522/j.cnki.cjph.2019.03.008
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    In this study, C3, C14 and C19-hydroxyl groups of andrographolide were modified. Six C14-esterified andrographolide derivatives, six C14-dehydrated andrographolide derivatives, and five C14-dehydrated and C3-oxidized andrographolide derivatives were synthesized. The structures of these seventeen target compounds were confirmed by NMR and MS. The in vitro nephrotoxicity against human normal renal tubular epithelial cell (HK-2) were evaluated by MTT assay. The results showed that, the toxicity of C14-esterified derivatives to HK-2 cell was higher than that of andrographolide, while the toxicity of dehydrated andrographolide derivatives which removed C14-hydroxyl group was significantly lower than that of andrographolide.
  • Paper
    Effect of Shearing Process on Dissolution Properties of Oral Suspensions Containing Xanthan Gum
    YANG Qiuxia, XIAO Yan, LU Weigen, XI Quan*
    2019, 50(03): 302-307. https://doi.org/10.16522/j.cnki.cjph.2019.03.009
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    The aim of this study was to confirm the effect of shearing process on dissolution rate of oral suspensions containing xanthan gum and discuss its mechanism. Using xanthan gum as suspending agent, the oral suspensions of BKZ, a conazole drug, were prepared by different shearing processes. The dissolution, particle size and viscosity of the suspensions were measured. Furthermore, the disperse state and time of aqueous solutions with xanthan gum and the combinations of xanthan gum and other polysaccharides in dissolution medium were investigated. The results indicated that xanthan gum or xanthan gum combination could form gelatin when dispersed in water. What’s more, the stability of gelatin was critical for the dissolution rate of oral suspensions containing xanthan gum. With the increase of the shearing rate and shearing time, the dissolution rate increased, while the viscosity of the suspension decreased continuously. A high-shear process had an irreversible damage to the gelatin structure, so the viscosity of the oral suspensions would not recovered any more even though the shearing process was stopped. According to the principle of quality by design (QbD), it should be paid more attention to the rheological properties of xanthan gum and the effect of shearing process on the dissolution rate in the R&D process of the oral suspension containing xanthan gum. The dissolution rate of oral suspension could be controlled by varying the shearing process. More importantly, shearing parameters could be determined by monitoring the change of the critical quality attribute (COA), therefore, the process design would be optimized and the process stability should be enhanced .
  • Paper
    Effect of Humidity on the Stability of Andrographolide Solid Dispersion
    ZHONG Youquan1, ZHANG Shoude2, ZHAO Guowei2,3*, ZENG Qingyun2, LIN Qing1
    2019, 50(03): 308-314. https://doi.org/10.16522/j.cnki.cjph.2019.03.010
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    In this paper, the effect of relative humidity on the stability of andrographolide solid dispersion was studied to provide a basis for the selection of storage environment. The andrographolide solid dispersions with polyethylene glycol 8000 as a carrier were stored under various humidity conditions [(55±5)％, (75±5)％ and (95±5)％] at 40 ℃ for 30 d. Then, the physical and chemical properties and dissolution behaviors of andrographolide solid dispersions at different sample points were determined. The results of infrared spectroscopy indicated that there were intermolecular interactions between andrographolide and polyethylene glycol 8000 in the solid dispersions stored under various humidity conditions, and the relative humidity could affect the internal interaction. Thermogravimetric analysis showed that the thermodynamic stability of andrographolide solid dispersion decreased gradually with the increasing of humidity and storage time. Differential scanning calorimetry indicated that the humidity could affect the content of the crystalline andrographolide in the solid dispersion. The hygroscopic analysis showed that the hygroscopic rate of andrographolide solid dispersion increased with the increase of humidity. Dissolution test showed that humidity would affect the solubilization effect of the solid dispersion. When the andrographolide solid dispersion was stored under high humidity condition [(95±5)％] up to 30 d, the dissolution rate was greatly reduced. All results indicated that the humidity could significantly affect the stability of the andrographolide solid dispersion. Therefore, the andrographolide solid dispersion should be stored in a low humidity environment below 40 ℃.
  • Paper
    Preparation of High Drug Loading Solid Dispersions of Enzalutamide and Preliminary Evaluation in vitro
    RAO Qiuhong1, QIU Zhenwen1, LUO Dandong1, LI qingguo2, LIU Yingyan3*
    2019, 50(03): 315-319. https://doi.org/10.16522/j.cnki.cjph.2019.03.011
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Enzalutamide solid dispersions with a drug loading up to 60％ were prepared by spray drying, in order to enhance the dissolution extent and rate of the poorly soluble drug, enzalutamide. The solubilization and crystallization inhibition effects of four polymers [polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), methacrylic acid copolymers (Eudragit L100), vinylpyrrolidone-vinyl acetate copolymers (Kollidon VA64), polyvinylpyrrolidone (PVP K30)] were investigated by apparent solubility test. Based on the screening results, a surfactant [sodium lauryl diphenyl ether disulfonate (Dowfax 2A1) or sodium dodecyl sulfate (SDS)] was added to prepare ternary solid dispersions. Then, the in vitro dissolution of binary solid dispersions with different carriers and the above ternary solid dispersions were investigated in phosphate buffer containing 0.1％ Tween-80. The physicochemical properties of the products were characterized by X-ray powder diffraction (XRPD) analysis, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The results showed that enzalutamide existed in an amorphous state form in both binary and ternary solid dispersions prepared with Soluplus. It indicated that Soluplus could significantly improve the dissolution rate and extent of enzalutamide. Compared with the binary solid dispersions, the ternary solid dispersions could further improve the solubility of enzalutamide, and could maintain good crystallization inhibition effect in the supersaturated solution.
  • Paper
    Evaluation of the Livers Protective Effects of Recombinant Human Interleukin-1 Receptor Antagonist in Mice with Acute Hepatic Failure
    ZHU Chencen, ZHENG Ying, XIAO Xinyi, ZHU Jianwei, YUAN Yunsheng*
    2019, 50(03): 320-324. https://doi.org/10.16522/j.cnki.cjph.2019.03.012
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    (+)-D-galactosamine hydrochloride (D-GalN) and lipopolysaccharide(LPS)-induced mouse model of acute hepatic failure (AHF) was used to investigate the livers protective effects of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra). Male specific pathogen-free (SPF) C57BL/6 mice were given a single intraperitoneal injection of rhIL-1Ra (3 or 9 mg/kg) or equal volume of normal saline(NS) 1 h before D-GalN/LPS administration. Samples of blood and liver tissue were collected after 4 h of D-GalN/LPS treatment. The alanine aminotransferase (ALT) activity, aspartate transaminase (AST) activity and total bilirubin (TBIL) level in serum were analyzed. For histological analysis, liver specimen was photographed. Expression of nitricoxidesynthase 2 (NOS2) and interleukin-6 (IL-6) in the livers were detected by quantitative real time-PCR. The data showed that rhIL-1Ra could significantly suppress ALT activity, AST activity and TBIL level in AHF model mice. Histologically, rhIL-1Ra reduced hepatocytes necrosis and protected the cell shape in liver of AHF mice. Besides, NOS2 and IL-6 mRNA level in the liver were much lower in administration of rhIL-1Ra group than in AHF model group. 3 and 9 mg/kg rhIL-1Ra in two treatment groups could dramatically improve the survival rate in AHF model mice. The results showed that rhIL-1Ra has potential value in drug development and clinic application in AHF.
  • Paper
    Vacuum Freeze-drying Characteristics and Quality Evaluation of Bletilla Striata
    XU Lei1,2, WANG Lizhong3, CUI Xiuming1,2, YANG Ye1,2, WANG Chengxiao1,2*
    2019, 50(03): 325-331. https://doi.org/10.16522/j.cnki.cjph.2019.03.013
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    The drying characteristics (drying rate, productivity and area shrinkage rate), contents of the key components (Bletilla striata polysaccharide, Bletilla bibenzyl compounds and alcohol soluble extract) and power consumption were evaluated under different freeze-drying parameters including vacuum pressure, shelf temperature and slice thickness. A multi-indexes analytic hierarchy process combined with the orthogonal experiment were conducted to optimize the drying conditions of Bletilla striata. Furthermore, fourier transform infrared spectroscopy(FTIR) and scanning electron microscopy(SEM) were performed to evaluate the product quality. Under the optimal drying condition (vacuum pressure of 55 Pa, shelf temperature of 58 ℃ and slice thickness of 5 mm), the contents of polysaccharide, bibenzyl compounds, alcohol-soluble extract and power consumption were (11.69±0.13)％, (2.14±0.06)％, (15.98±0.24)％ and 19.0 kW·h-1. The samples after vacuum freeze-drying have less cell damage, loose texture and high commercial value.
  • Paper
    Correlation on HPLC Fingerprint Spectra of Raw Herbs, Standard Decoction, Intermediates and Dispensing Granules of Forsythia Suspense
    CAO Jingya1,2, LI Zhining1,2, LI Feifei1,2, CHEN Ling2,3, WEI Yue1,2*
    2019, 50(03): 332-337. https://doi.org/10.16522/j.cnki.cjph.2019.03.014
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    In this study, the HPLC fingerprint spectra of the raw herbs, standard decoction, intermediates and dispensing granules of Forsythia suspense were established. The correlations among them were analyzed. An Agilent Eclipse XDB-C18 RP column was used with methanol and water as the mobile phase with a linear gradient elution. The flow rate was 1.0 ml/min, the column temperature was 25 ℃ with the detection wavelength of 235 nm. There were ten common characteristic peaks in the fingerprint spectra of the ten batches of raw herbs, standard decoction, intermediates and dispensing granules of Forsythia suspense. The results presented a good correlation. Six peaks were identified from the ten common peaks, including forsythenside F(peak 3), forsythoside Ⅰ (peak 4), (+)-pinoresinol-4-O-β-Dglucopyranoside (peak 5), forsythoside A (peak 7), forsythin (peak 8) and phillygenin (peak 10). The main chemical compositions existing in the raw herbs, standard decoction, intermediates and dispensing granules of Forsythia suspense are basically the same. The established HPLC fingerprints can be used to control the quality in the whole production process of Forsythia suspense dispensing granules.
    • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    Analysis on the Evolution and Evaluation Methods of the Consistency Evaluation
    YANG Qing, LIU Lingling, ZHOU Bin*
    2019, 50(03): 338-344. https://doi.org/10.16522/j.cnki.cjph.2019.03.015
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  • Pharmaceutical Management & Information
    Present Situation and Countermeasures of TCM Pharmaceutical Equipment Development
    DENG Jinsong1, ZHANG Haiyan1*, LI Yan2, WU Shengxing1, YANG Ming1,3
    2019, 50(03): 345-348. https://doi.org/10.16522/j.cnki.cjph.2019.03.016
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  • Pharmaceutical Management & Information
    Introduction of ICH Q4 Guideline
    XU Xinyi1, XU Huayu1, ZHANG Qiming2, HONG Xiaoxu1*
    2019, 50(03): 349-354. https://doi.org/10.16522/j.cnki.cjph.2019.03.017
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  • Pharmaceutical Management & Information
    Research on the Relationship between Input and Output of China's Biomedical Industrial Park Base on Panel Data Model
    XU Kai1,2, SUN Lihua1*
    2019, 50(03): 355-358. https://doi.org/10.16522/j.cnki.cjph.2019.03.018
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