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  • Pharmaceutical Management & Information
    SI Xiaofei, LI Wuchao, JIANG Dianzhuo
  • Perspectives & Review
    DING Yuan, LU Weiyue
    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
    ZHENG Qiwen, CHEN Guiliang,WANG Jian
    Inhaled drugs are drug-device combination products, which require the cooperation of preparations, devices and patients to achieve desired treatment outcome. Common inhalation devices have problems such as difficult operation skill requirements, low drug availability, and long nebulization time due to their nebulization mechanisms. In terms of these issues, several novel techniques and inhalers are put forward in recent years, such as vibration mesh, soft mist, thermal evaporation atomization, and electrohydrodynamic atomization. Fundamental theory of traditional inhalers and these novel techniques are reviewed in this paper, aiming to provide some inspirations for future inhaler development.
  • Paper
    LUO Kaihong, DAI Yuhao, MA Xiao, LI Jianqi, LIU Yu
    [(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
    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.
  • Pharmaceutical Management & Information
    ZHU Xin, CHEN Guiliang, CAO Meng
  • Paper
    CHU Yanjun, TI Wenli, CHENG Lei, ZHANG Guimin
    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.
  • Perspectives & Review
    TANG Yifei, WU Wenzhe, WANG Jian
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1227-1239. https://doi.org/10.16522/j.cnki.cjph.2022.09.001
    The production mode of oral solid dosage forms is gradually changing from batch to continuous manufacturing. Using process analysis technology to analyze and control the critical quality attributes of raw materials, intermediate products and final products can realize high efficiency manufacturing, automatic monitoring, high product quality requirements and real-time release testing. Continuous manufacturing which integrates continuous production lines, process analysis technology and advanced feedback control system is more in line with the concept of pharmaceutical industry 4.0. In this paper, the development and status, the preparation process and application of process analysis technology in oral solid dosage forms are reviewed to provide references for further research.
  • Perspectives & Review
    WANG Li, YUAN Penghui, YANG Dezhi, ZHANG Li, LYU Yang
    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.
  • Pharmaceutical Management & Information
    CHEN Wei, YANG Kai, XU Yiming, WU Mingyang, LIANG Yi
    以安徽某制药企业为实证研究对象,应用新版的失效模式与影响分析 (FMEA) 对原料药生产活动进行风险评估、风险控制和控制后的风险再评价。结果显示,运用新版的 FMEA 进行原料药质量风险管理,有效降低了原料药生产过程中质量风险的发生率,提高了产品质量水平和质量管理体系运行水平。
  • Paper
    SONG Hang, YANG Hanyue, YAN Xianguang, ZENG Yinhai, LI Runlai, LI Shu'an
    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.
  • Paper
    MAO Yuanhu, CHENG Fei, HE Qing, LIU Bin, TANG Lei
    Chinese Journal of Pharmaceuticals. 2022, 53(09): 1270-1273. https://doi.org/10.16522/j.cnki.cjph.2022.09.005
    In this paper, the drug finerenone for diabetic nephropathy treatment was synthesized. Firstly, the intermidate ethyl 2-cyanoacetoacetate(6) was prepared with 3,5,5-trimethyl-4,6-dioxacyclohex-2-en-1-one(16) and 3-hydroxypropionitrile, and then react with 4-cyano-2-methoxybenzyaldehyde and 4-amino-5-methylpyridin-2-ol via continuous Knoevenagel condensation and Hantzsch cyclization, respectively. Finally, finerenone was obtained via O-alkylation, hydrolysis, ammonolysis and chiral column resolution with an overall yield of 30.8%(based on 16), and 99.7% HPLC purity as well as 99.4% ee value. The improved process had the advantages of simple operation, mild condition, high yield and low cost.
  • Paper
    ZHANG Xiaojie, MIAO Qingzhu, JIA Jingyang, DU Chaoyu, HE Feng
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1419-1423. https://doi.org/10.16522/j.cnki.cjph.2022.10.006
    Five related substances of sufentanil citrate, namely N-[4-(methoxymethyl)piperidin-4-yl]-Nphenylpropionamide( related substance A), cis-4-(methoxymethyl)-4-(N-phenylpropionamido)-1-[2-(thiophen-2-yl)- ethyl]piperidine 1-oxide(related substance B), trans-4-(methoxymethyl)-4-(N-phenylpropionamido)-1-[2-(thiophen- 2-yl)ethyl]piperidine 1-oxide(related substance Ⅰ), [4-(phenylamino)-1-[2-(thiophen-2-yl)ethyl]piperidin- 4-yl]methanol(related substance C), and N-[4-(methoxymethyl)-1-[2-(thiophen-2-yl)ethyl]piperidin-4-yl]-Nphenylacetamide citrate(related substance D). Their structures were confirmed by NMR and ESI-MS. These compounds may be used as the references in the quality control of sufentanil citrate.
  • Paper
    LIAO Shiji, LIAO Langkun, HU Yanping, QIU Yuqin
    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.
  • Perspectives & Review
    HE Chiyu, HU Yuxi
    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.
  • Paper
    JIANG Yanan, LI Linji, LI Xiang,MO Jinqiu, ZHANG Weidong
    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%.
  • Perspectives & Review
    HAO Mengya, ZHU Peixi, SU Feng, SU Weike
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1377-1385. https://doi.org/10.16522/j.cnki.cjph.2022.10.001
    Natural products are physiologically active chemical components extracted from natural resources. The key issue to enhance the utilization efficiency of natural products is to explore rapid, efficient and environmentally friendly extraction technologies. Mechanochemical-assisted extraction technology has the advantages of high yield, short extraction time and environmental-friendly. Thus, it has broad application prospects in the field of natural product extraction. This paper mainly introduces the method procedure, process principle, application mode and future trend of mechanochemical-assisted extraction technology. Meanwhile, the limitations of current mechanochemistry in industrial extraction applications are also discussed. Furthermore, the countermeasures are put forward. It could provide new research ideas for promoting the improvement and industrial applications of mechanochemical-assisted extraction technology.
  • Paper
    BAO Guanglong, ZHANG Naihua, ZHANG Li, ZHU Anguo, ZHANG Guimin
    A novel synthetic process of ethyl (2R,4R)-4-methylpiperidine-2-carboxylate(1), the key intermediate of thrombin inhibitor argatroban, was reported in this paper. 4-Methylcyclohexan-1-one(2) was reacted with hydroxylamine hydrochloride to obtain 4-methylcyclohexan-1-one oxime(3). Compound 3 transformed into 5-methylazepan-2-one(4) through Beckmann rearrangement under p-toluenesulfonamide(p-TSA)/ZnCl2 condition. Compound 4 was treated with cupric bromide to prepare 3-bromo-5-methylazepan-2-one(5). Ethyl 4-methylpiperidine- 2-carboxylate(6) was available from 5 via Favorski rearrangement on exposure to sodium ethoxide. Fractionation of 6 under reduced pressure to separate ethyl trans-4-methylpiperidine-2-carboxylate(7). Finally, the target compound 1 was obtained from 7 through resolution by L-(+)-tartaric acid with a purity of 99.58%, a chiral purity of 99.13% and an overall yield of about 9%(based on 2). The new route was easy to operate, safe in production process, which was suitable for industrial production.
  • Perspectives & Review
    LI Wenjie, XIE Liping
    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
    CAI Jianguang, LIN Tanghuan, ZHANG Heng, CHEN Yan'an, CHEN Liru
    In order to perform the quality control of posaconazole, the two process impurities were synthesized, namely 4-[4-[4-[4-[[(3R,5R)-5-[2-fluoro-4-(1H-1,2,4-triazol)phenyl]-5-(1H-1,2,4-triazol-1-ylmethy1)-3-furanyl]- methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(2S,2S)-2-hydroxy-3-pentyl]-1,2,4-triazol-3-one(the related substance A)- and 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,3,4-triazol-1-ylmethy1)-3-furanyl]methoxy]phenyl]-1- piperazinyl]phenyl]-2-[(2S,2S)-2-hydroxy-3-pentyl]-1,2,4-triazol-3-one(the related substance B). The synthesis routes of the related substance A and the related substance B were first reported. The structures of the products were confirmed by 1 H NMR and HRMS, which could be used as the references for quality control of posaconazole.
  • Paper
    YU Shaowen, GUO Yajuan, HU Shujun, CHEN Ying
    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.
  • Pharmaceutical Management & Information
    ZANG Kecheng, JIANG Rong, ZHANG Xuerui, SHAO Rong
    通过查阅文献资料和专家访谈,运用德尔菲法进行两轮指标筛选,采用层次分析法确定指标权重,该文构建了包含检查依据、检查组织机构体系、检查程序、检查结果、检查信息化水平 5 个评价维度,并进一步细化为 23 个二级指标的指标评价体系,可作为定量评价中国药品生产检查制度实施成效的测量工具,为评价中国药品生产检查制度实施成效提供参考。
  • Paper
    ZHANG Zhen, WANG Guan, QIU Yongfu, LIU Xuyan, LI Jianqi
    In order to control the quality of ivabradine hydrochloride, five related substances were prepared: 7,8-dimethoxy-3-propyl-1,3-dihydro-2H-benzo[d]azepin-2-one(related substance A), 3-allyl-7,8-dimethoxy-1,3-dihydro- 2H-benzo[d]azepin-2-one(related substance B), 3,3'-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3-dihydro-2H-benzo[d]- azepin-2-one)(related substance C), (S)-[2-[2-[[3-[[[3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl]methyl]- (methyl)amino]propyl]amino]ethyl]-4,5-dimethoxyphenyl]acetic acid(related substance D), 3-(7,8-dimethoxy-2-oxo- 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-N-[[(S)-3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-triene-7-yl]methyl]- N-methylpropan-1-amine oxide(related substance E). The structures were confirmed by MS and 1 H NMR. Among them, both related substance A and B have not found in literature.
  • Paper
    LU Honghua, WEI Ruixia, HAO Guizhou, SUN Jianhe, ZHANG Guimin
    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.
  • Pharmaceutical Management & Information
    LI Qing, WU Lihua, GE Yuanyuan
  • Paper
    ZHU Ranran, TIAN Tianen, WANG Jianyao, DONG Zhikui
    In order to control the quality of minodronic acid, this study determined the dimer, [2,5-dihydroxy- 3,6-bis(imidazole[1,2-a]pyridin-3-ylmethyl)-2,5-dioxo-1,4,2,5-dioxodiphosphine-3,6-diacyl]bis(phosphonic acid), a relative substance of minodronic acid based on the production process of minodronic acid. It was obtained by the new strategy by reaction of 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid with phosphorus trichloride in methanesulfonic acid(5.5 times amount of substance). The yield was more than 50%, and the purity was not less than 99.0%. The structure of the dimer was confirmed by 1 H NMR, 13C NMR, 31P NMR and high resolution mass spectrometry(HRMS), which could be used as a standard for the quality study of minodronic acid.
  • Paper
    LIU Yuhong, JIANG Yu, HAO Guizhou, LIU Shankui
    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
    TANG Han, SUN Yani, MING Yuan, GE Yuebin
    Using spherical porous aluminum magnesium silicate(Neusilin? US2) as the carrier, the solid dispersions of trimetazidine hydrochloride with different drug loadings were prepared by solvent dispersion method. Then, these products were characterized by powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy and dynamic water adsorption. The stability, flowability and compressibility of physical mixtures, different solid dispersions and their mixtures with other excipients were investigated. The results showed that the drug in the solid dispersion prepared with spherical porous aluminum magnesium silicate existed in an amorphous form, and no crystalline form was found in the solid dispersions under the accelerated conditions for 1 month and room temperature for 18 months. Compared with the bulk drug, the fluidity of the solid dispersion was significantly improved, and the compressibility after mixing with other excipients(such as microcrystalline cellulose) was also increased. After mixing the solid dispersion with a drug-carrier ratio of 3∶10 and different amounts of croscarmellose sodium(as a disintegrant), the title tablets were prepared by direct powder compression. The results showed that the dissolution behavior of the solid dispersible tablets with the 2% disintegrant was similar to that of the commercially available trimetazidine hydrochloride tablets(the similarity factor f2 was 59.94).
  • Paper
    YANG Xuanlin, XU Xiaozhen, HAO Yue, WENG Weiyu
    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
    LI Ming, XU Haiyun, ZHAO Kailou
    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.
  • Perspectives & Review
    GE Fan, SUN Jian, HUANG Lu
    In this study, five small-molecule cyclin-dependent kinase 4/6(CDK4/6) inhibitors, marketed at home and abroad, are analyzed and researched in detail, so does their patent information. To provide practical patent information and references for Chinese pharmaceutical companies to establish and develop projects of CDK4/6 inhibitors for innovative or generic drugs, as well as new patent mining, patent protection and layout, this study mainly focuses on the patents of product, crystalline form, salt form, process, formulation, drug combination, new use and development derivatives.
  • Paper
    ZHANG Ying, XU Xiaqing, HE Meng, ZHANG Yueli, YANG Xiaorui, ZHANG Zhenzhong, GUO Xinhong
    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.
  • Perspectives & Review
    FAN Ning, YIN Dongfeng
    Central nervous system disease is one of the major diseases that significantly affect human health and quality of life. Most drugs cannot cross the blood-brain barrier(BBB), so that their concentrations are too low to completely produce therapeutic effects. Liposomes with special surface modifications can be used as brain-targeted drug carriers to effectively deliver drugs to the brain. This review summarizes the biological properties, BBB crossing mechanisms, and the application of nose-to-brain delivery of brain-targeted liposomes to provide new ideas for drug brain targeting strategies.
  • Pharmaceutical Management & Information
    ZHANG Ling, WANG Yanan, ZHU Jiawen, SHAO Rong
  • Perspectives & Review
    CHEN Wei, FENG Mingjie, XU Bo, PAN Yi, CHEN Hua, TANG Lida
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1386-1393. https://doi.org/10.16522/j.cnki.cjph.2022.10.002
    Continuous flow chemistry is a promising new pharmaceutical technology, which has the advantages of reducing production cycle, higher automation, more environmentally friendly, energy-saving and emission reduction, and it also has the ability to perform chemical reactions that are difficult or impossible to do in batch manufacturing. It is the trend of active pharmaceutical ingredient(API) technology innovation. However, it has been slowly popularized in the pharmaceutical industry for a long time. With publication of ICH guideline Q13 on continuous manufacturing of drug substances and drug products, the key points of process development and control strategies have been put forward, and the regulatory expectation will gradually become clear. The characteristics, application scenarios and quality considerations of continuous flow chemistry are reviewed in this paper based on ICH Q13. Through literature research, the research points and control strategies of continuous flow chemistry are discussed, so as to promote the application of continuous flow chemistry in domestic pharmaceutical enterprises, improve the manufacturing level of the industry, strive to achieve carbon peaking and carbon neutrality goals.
  • Perspectives & Review
    CAO Meng, GE Yuanyuan, HU Yanchen, WANG Yamin, CAO Yi
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1394-1401. https://doi.org/10.16522/j.cnki.cjph.2022.10.003
    With the release of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) Q13 guideline and the approval of several oral solid dosage form drug products adopting continuous manufacturing techniques, the regulatory development in this area is receiving increasing attention. Material handling is an important part of a continuous manufacturing platform. In this paper, the material handling for continuous manufacturing of oral solid dosage forms is introduced through analyzing the technical characteristics of material input, continuous feeding and continuous mixing. Also, the concerns of supervision and inspection are studied from the aspects of process validation, robustness, facilities and equipment, process control, quality assurance and cleaning. For technical consideration, process equipment should handle materials continuously and stably, with risks controlled and losses reduced as much as possible, so it is necessary to have a deep understanding of material characteristics, scientifically design process equipment and carry out qualification and verification; while regulatory inspections may focus on continuous process-specific risks and their possible effects on product quality. Hopefully this paper could accelerate the application of continuous manufacturing in pharmaceutical industry together with the aid of cooperation of regulation agencies, industrial community as well as the whole society, making full use of process analysis technology, innovative testing methods and digital quality assurance to steadily manufacture qualified products, thus promote domestic pharmaceutical industry to a high level of modernization.
  • Paper
    JI Xiaoli, SHENG Yunhua, LI Yinxia, HU Yue, TANG Liming
    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.
  • Perspectives & Review
    WANG Xuecheng, WU Zhenfeng, XU Shijun, WU Zhicheng, YANG Ming
    Drying is one of the most important processes in the manufacture of traditional Chinese medicines, including drying of herbs, extracts and preparations. It is an important research direction of drying of traditional Chinese medicines to explore the drying technology and process that is fast, efficient and can guarantee the quality and clinical efficacy of traditional Chinese medicines. The advantages of low-frequency and high-power ultrasound in enhancing the drying heat and mass transfer process are gradually highlighted, and this technique has a broad application prospect in the field of high quality drying of traditional Chinese medicines. In this paper, the influences of key technological parameters of ultrasonic drying on the drying process and the research status and development trend of typical equipment are analyzed. Meanwhile, the application status and problems of ultrasonic drying in the field of traditional Chinese medicines are discussed and the countermeasures are put forward. It is hoped to provide some references for promoting the theoretical development and industrial application of ultrasound-assisted drying technology.
  • Paper
    JIANG Shaobo, YANG Lei, WEI Xiaohui
    Chinese Journal of Pharmaceuticals. 2022, 53(10): 1446-1452. https://doi.org/10.16522/j.cnki.cjph.2022.10.010
    This study aimed to establish a top spray granulation for ibuprofen arginine(Ibu-Arg) granules by fluid-bed technology based on Quality by Design(QbD) concept and approach. The quality target product profile(QTPP) and critical quality attributes(CQAs) of Ibu-Arg granules were firstly identified. The relevant CQAs for top spray granulation process were screened out by risk assessment. The percent of the labeled content and particle size distribution(PSD) were selected as the key responses. Risk assessment on critical process parameters(CPPs) was performed by failure mode and effect analysis(FMEA) methodology. By the results of FMEA, spray rate and atomization pressure were screened out as the high-risk process variables to be further studied. A center composite design(CCD) was employed for process optimization. Experimental results were analyzed by response surface methodology(RSM), process parameters model was established for exploration of design space and optimized operation conditions by Design Expert 10 software. The optimized process parameters were established as follows: inlet air volume 55 – 70 m3/h, product temperature 40 – 45 ℃, atomization pressure 80 - 120 kPa and spray rate 17.5 – 18.5 g/min. By implementing validated experiments, the process was confirmed to be robust with high yield, the product CQAs such as the percent of the labeled content and PSD complied with quality requirements.
  • Paper
    WANG Yaqing, HAO Guizhou, LI Qian, CHEN Yuqing, ZHANG Guimin
    The nanosuspension of phillygenin(1) was prepared by wet grinding technique, then the pellets were prepared with coating liquid consisted of the above nanosuspension, hydroxypropyl methylcellulose, lactose and mannitol by the bottom-spray fluid bed method to improve the stability. The parameters of the coating process were optimized by single factor test and central composite design-response surface methodology. The obtained optimal parameters were as follows: the viscosity of coating solution was 130 mPa·s; the temperature of inlet air was 50 ℃; and the rate of feed was 12 r/min. The average particle size of the optimal nanosuspension and pellets(the redispersed suspension) stored at room temperature for three months were (265.5±5.9) and (220.6±3.8)nm, and polydispersity index were 0.253±0.071 and 0.199±0.069, indicating the stability of nano-sized crystals of 1 was improved by solidification process. The results of in vitro dissolution test showed that the dissolution profiles of nanosuspension and pellets in various pH media were significantly enhanced, compared with the micronized bulk drug.