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??OBJECTIVE To investigate the stability of etanercept in vacuum and water to lay foundation for study on its bioactiveprotection. METHODS Umbrella sampling and steered molecular dynamics simulation aqueous solution adopted to study the dissociation process of dimer etanercept with Gromacs software and amber99sb-ildn force field. RESULTS Potential of mean forcel(PMF) free energy of etanercept dissociation in vacuum was approximately three times of that in aqueous solution. And the maximum barrier force of etanercept dissociation in vacuum was approximately ten times of that in aqueous solution. The solvation environment had effect on the stability of antibody protein. Freeze-drying in vacuum could improve the stability of antibody protein. CONCLUSION In the process of steered molecular dynamics simulation, the pulling force can be got easily and is less affected by other factors, which can be used to characterize the stability of active structure of antibody protein dimer.     

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??OBJECTIVE To investigate the mechanism of nucleophosmin (NPM) in the formation of breast cancer drug resistance. METHODS The methotrexate- resistant breast cancer cells (MCF-7/MTX) was established by escalating the concentrations of methotrexate to drug-sensitive MCF-7 cells (MCF-7/S). The cells viability of MCF-7/MTX was detected by MTT test, cell growth curve was drawn and doubling time was calculated. The cell morphology and ultrastructure were observed using optical and transmission electron microscopy. The expression of NPM and factors related to drug resistance were tested by Real-time PCR and Western blot assay. Then the NPM level was attenuated by RNA interfering technology, and the resistance mechanism was explored in MCF-7/MTX cells. RESULTS The MCF-7/MTX cell line was successfully established and resistance factor was 64. The resistant cells has spindle shaped morphology and tended to grow slowly, and the variations appeared in the internal structure of cells. MCF-7/MTX cells possessed cross-resistance to various chemotherapeutic drugs. The expressions of NPM and multidrug-resistant factors P-gp, MRP1, BCRP were up-regulated in the resistant cells. Further, the overexpression of NPM activated PI3K/Akt signaling pathway and inhibited downstream apoptotic factors. Then knockdown of NPM by siRNA significantly decreased the drug resistance of MCF-7/MTX cells, suppressed PI3K/Akt pathway and promoted the downstream cells apoptosis. CONCLUSION The high expression of NPM has an important role in the formation of breast cancer drug resistance, and it is expected to be a novel molecular target for breast cancer treatment in clinical.     

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??Dengue fever is one of the most important vector-borne human diseases caused by mosquito vector Aedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome. There are no approved drugs for the treatment of dengue disease so far. According to the mechanism of anti-dengue virus(anti-DENV) action, drugs under development for dengue disease can be divided into two categories:viral replication inhibitors and anti-cell factor pathway inhibitors. The former is further divided into DENV entry inhibitors, capsid protein inhibitors, NS3 protein inhibitors, NS5 protein inhibitors, and NS4B protein inhibitors; the latter is further divided into cell receptor inhibitors, lipid synthesis and metabolism inhibitors, and glucosidase inhibitors. The R&D of anti-DENV drugs is facing enormous challenges. Development of effective drugs which can be used for the treatment of four serotypes of dengue has a broad application prospect, and it will bring new hopes for dengue fever prevention and therapy.     

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??OBJECTIVE To synthesize low molecular weight chitosan-acetylcysteine (LMWC-NAC) conjugate and investigate its renal targeting profile and the rapeutic effects in model mice with acute kidney injury (AKI).METHODS NAC was conjugated to LMWC by EDC/NHS reaction and the LMWC-NAC conjugate was identified by ¹H-NMR. The cellular uptake of LMWC-NAC conjugate and megalin receptor involved in this process was investigated in vitro. In addition, the tissue distribution of ICG-labelled LMWC-NAC conjugate was investigated in nude mice. AKI were induced by LPS intraperitoneal injection (20 mg??kg^-1).The parameters including Scr, BUN, inflammatory factors (TNF-?? and IL-1??),and oxidative stress (MDA) were determined and renal histology was observed.RESULTS LMWC-NAC conjugate was successfully synthesized by the amide interaction.The in vitro studies demonstrated that the uptake of LMWC-NAC conjugate was mediated by the megalin receptor on HK-2 cells, and the tissue distribution experiment indicated that LMWC-NAC conjugate was mainly accumulated in the kidney.LMWC-NAC conjugate significantly suppressed Scr, BUN, inflammatory factors and oxidative stress (P<0.01) and improved kidney injury. CONCLUSION LMWC-NAC conjugate showed good renal targeting profile and effect in recovering renal functions, which indicates the potential of LMWC-NAC conjugate as a safe and efficient drug delivery system for the treatment of AKI.     

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??OBJECTIVE To study the pharmacokinetics of hot-melt spray-dried andrographolide granules and compare it with andrographolide bulk drug. METHODS A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for determination of the concentration of andrographolide in plasma of rats which were respectively given micronized andrographolide and hot-melt spray-dried andrographolide granules, then the pharmacokinetic parameters were calculated. RESULTS The pharmacokinetic parameters of andrographolide after a single dose administration of micronized andrographolide and hot-melt andrographolide were as following: t_1/2 were (347.33??9.32) and (390.82??8.78) min, t_max were (30.00??5.94) and (60.00??3.48) min, ??_max were (1 940.14??21.21) and (1 818.22??23.64) ng??mL^-1, AUC_0-t were (427 515.71??37 350.03) and (426 406.31??20 577.75) ng??min??mL^-1, AUC_0-inf were (545 423.14??47 969.18) and (593 569.87??30 247.35) ng??min??mL^-1, Vz/F were (43.48??4.75) and (44.96??3.81) kg??L^-1, CL/F were (86.78??3.35) and (79.74??2.89) kg??L^-1??min^-1, respectively. CONCLUSION Compared with the bulk drug, the hot-melt spray-dried andrographolide granules have a longer t_1/2, lower ??_max and delayed t_max in rats.     

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??OBJECTIVE To establish dose-related lung inflammatory injury in rats model with intratracheal atomization of lipopolysaccharide (lipopolysaccharides, LPS). METHODS Four groups of 4 rats were subjected to solvent or a single dose of LPS by intratracheal route using a IA-1B-2 inches-microsprayer. The male rats received 200 ??L solvent (control), LPS solutions (15, 5, 0.5 mg??kg^-1). All rats were sacrificed 24 h after dose administration, biochemical analysis and cell counts on bronchoalveolar lavage fluid (BALF) were performed on each rat. Lung, trachea and kidney were examined histologically. Serum chemistry profiles of creatinine, ALB, Na, K, Cl^- were detected. RESULTS Cell counts in BALF showed LPS groups had different degrees of inflammatory reaction. The alkaline phosphatase and total protein concentration were higher in LPS high dose group compared with other groups. In addition, the concentration of TNF-?? increased consistently with LPS dose and has statistical significance compared with the control group. Histopathology findings demonstrated that LPS produced an accumulation of foamy macrophages in the lungs and high degree of inflammation. CONCLUSION The results recommends intratracheally atomizing doses of LPS in rats model produced ranks of lung inflammatory injury.     

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??OBJECTIVE To prepare sulfadiazine solid dispersion, determine its solubility and dissolution in vitro, and investigate its physical properties. METHODS Using in vitro dissolution as an index, single factor test and orthogonal design were used to optimize the preparation process of sulfadiazine solid dispersion. The existing state of sulfadiazine was identified by DSC, IR spectroscopy, and powder X-ray diffraction. RESULTS The solubility and dissolution rate of sulfadiazine solid dispersion prepared by the optimized preparing process were increased by 17 times and 3 times respectively than crude sulfadiazine. Sulfadiazine existed in an amorphous state as shown by phase identification. CONCLUSION The solid dispersion prepared by the solvent-molten method with PEG4000 as the carrier can significantly improve the solubility and the dissolution rate of sulfadiazine.     

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??OBJECTIVE To optimize the formula of celecoxib gel by studying the effects of different doses of penetration enhancers on the penetration of celecoxib through skin in vitro. METHODS With sodium alginate as the gel base, factorial design method was used to choose the optimal formula of penetration enhancers among four different formulas to prepare celecoxib gels. The release rate of celecoxib in the release media was detected by modified Franz diffusion cells method, and the steady percutaneous speed (J), permeability coefficient (K_p) and the accumulative permeation quantity (Q) in 12 h were calculated. RESULTS The accumulative permeation quantity (Q) in 12 h of celecoxib from the gels made with the four different formulas were 27.93,25.12,18.79 and 19.35 ??g??cm^-2, respectively. The gel with 1% azone and 1% menthol as penetration enhancers had the maximum Q value, 27.93 ??g??cm^-2, its penetration process conformed to Higuchi equation, and the steady percutaneous speed (J) and permeability coefficient(K_p)were also higher than the other three experimental groups. CONCLUSION With sodium alginate as the gel base, azone and menthol have a synergistic effect on the percutaneous penetration of celecoxib gels, and the best formula is 1% azone and 1% menthol.     

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??OBJECTIVE To explore the synthesis of novel phenylalanine dipeptide derivatives and their inhibitory effects on tumor cells. METHODS Starting from L-phenylalanine or L-tyrosine, a series of derivatives were synthesized by reaction with chloroacetyl chloride, followed by condensation with L-phenylalaninol or L-phenylalanine methyl ester hydrochloride and nucleophilic substitution reaction with differently substituted phenol.The cell proliferation inhibiting activities of the derivatives were evaluated by thiazolyl blue tetrazolium bromide(MTT)method.RESULTS Some of the target compounds showed certain inhibitory effect for leukemia cell lines K562 and HEL in vitro.Furthermore, the derivatives 3f and 3q had preferably inhibitory effect on K562 cell line prostate cancer PC3 cells in vitro.CONCLUSION Phenylalanine dipeptide derivatives possess good effect on the leukemia and prostate cancer cells and are worth of further research.     

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??OBJECTIVE To study the anti-cancer components of Calotropis gigantean L.METHODS The powdered whole plants of C. gigantea were extracted with 95% alcohol. After removal of the solvent, the residue was extracted with petroleum ether and chloroform, and the compounds in the chloroform extract were isolated and purified by different column chromatograghies carried out on silica gel, RP-18, MCI, and Sephadex LH-20 and their structures were elucidated by spectral data. RESULTS Thirteen compounds were isolated and their structures were characterized as gofruside(1), uzarigenin(2), arjunolic acid(3), 3??-(1??-hydroxyethyl)-7-hydroxy-1-isobenzofuranone(4), daucosterol(5), syringaresinol(6),12-O-benzoyl-deacylmetaplexigenin(7), 3-hydroxy-4-methoxybenzoic acid(8), oleanolic acid(9),??-sitosterol(10), methyl 1-naphthaleneacetate(11), butylparaben(12),??-D-oleandropyranoside(13), and compounds 2-4,6-9, and 11-13 were isolated from this plant for the first time. Compounds 1 and 2 showed cytotoxicity against HLE, K562, RPMI8226, MCF7, MDA, and WM9 cell lines, with K562 and RPMI8226 being the most sensitive cells.CONCLUSION Compounds 1 and 2 are premilinarily judged as the anti-cancer components in C. gigantean.     

甲硝唑结肠缓释片的药动学研究

 目的研究甲硝唑结肠缓释片的缓释特征和结肠靶向特征。方法采用家犬考察甲硝唑结肠缓释片口服后的血药浓度变化,并与甲硝唑普通片进行比较。采用大鼠口服受试药物,考察药物在大鼠消化道各段的释放情况。结果结肠缓释片的ρ_max为(4.94±2.79)mg·L^-1,t_max为(12.7±0.5)h,t_1/2β为(5.65±4.5)h,MRT为(16.65±5.1)h,AUC_0-τ为(36.09±12.81)mg·h·L^-1,AUC_0-∞为(37.63±11.92)mg·h·L^-1。与普通片比较,ρ_max显著降低,t_max显著延长,显示出缓释效果。大鼠口服甲硝唑结肠缓释片后主要在结肠段释放药物,在胃和其他肠段基本无药物释放。结论甲硝唑结肠缓释片具有结肠靶向和缓释的特征。     

结肠靶向牛血清蛋白缓释片的研制和体外评价

目的 制备牛血清蛋白(BSA)缓释片并对其体外释放进行考察.方法 以BSA为模型药物,烷基果胶为骨架材料制备BSA缓释片并考察其体外释放的影响因素.研究了稳定性实验,并进行精密度测定,考察释放介质pH值(1.0,6.86,7.8)、转篮转速(50,100,150 r·min-1)、压片压力(6,8,10 kg·mm-2...     

基于药物仿生系统分析雷公藤双层片的释药特征

目的: 应用药物溶出/吸收仿生系统(DDASS)研究雷公藤双层片的体外释放和跨膜透过特征,并考察其与该制剂在Beagle犬体内过程特征的体内外相关性。 方法: 以雷公藤定碱为指标成分,考察雷公藤片及雷公藤双层片在转篮法中的释药特征,研究其在DDASS模型体外连续、动态、实时的释放和跨膜透过特征;考察2种制剂在Beagle犬体内的药代动力学特征及其相应的体内外相关性。 结果: 雷公藤双层片中雷公藤定碱在转篮法和DDASS中释药过程均符合一级动力学方程,呈溶蚀释放机制。与雷公藤片相比,雷公藤双层片中雷公藤定碱在Beagle犬体内具有明显的缓释作用,相对生物利用度174.88%。在DDASS模型释放/跨膜透过特征与Beagle犬体内吸收特征存在极显著的相关性,优于转篮法溶出特征与Beagle犬体内吸收特征之间的相关性。 结论: DDASS模型可有效评价雷公藤双层片中雷公藤定碱的体外释放及体内吸收动力学特征。     

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??OBJECTIVE Taking aspirin as a model drug, the feasibility of the controlled release of aspirin tablets was discussed, which was based on the individual demand of 3D printing technology. METHODS The experiment selected 10 000 mPa??s hydroxypropyl methyl cellulose (HPMC10000) and polyacrylic acid (PAA) as a hydrophilic matrix sustained-release layer; hydroxypropyl methyl cellulose 100 mPa??s (HPMC100) as a quick release layer binder, sodium carboxymethyl starch (CMS-Na) and sodium carboxymethyl starch (SSG) as a quick release layer disintegrating agent, the use of 3D printer to print the slow release of aspirin tablets. Select 100 mg??mL^-1 and polyvinylpyrrolidone (PVPK30) as a quick release layer binder, crosslinking sodium carboxymethyl cellulose (CC-Na) as a quick release layer disintegrating agent, hydroxypropyl methyl cellulose (HPMC100) as the matrix material release layer, with the traditional press pressing speed of aspirin sustained-release tablet, as contrast agents. The physical and chemical properties of tablets produced in two different modes of production (film weight difference, hardness and thickness) and release profile were investigated. RESULTS The physical and chemical properties of the two tablets are all in the Pharmacopoeia. Comparison of two kinds of drug release curve showed that the ASA-HPMC (14%, ??) and the press release curve of double layer tablets printing film is similar, and the release rate is higher than the tablet (6% ??.ASA-HPMC double layer tablets), ASA-HPMC (8%, ??) and ASA-HPMC (10%, ??) printing film final release amount increased with hydrophilic matrix HPMC. CONCLUSION 3D printers print different shapes of tablets with different release profiles, in which the release of the package is higher than the other tablets.     

肿节风分散片的研制

目的:研制肿节风分散片。方法:以崩解时间为指标,采用正交实验法优选肿节风分散片处方。结果:选择16%的交联聚乙烯吡咯烷酮(PVPP)、7%的低取代羟丙基纤维素(L-HPC)为崩解剂,40%的微晶纤维素(MCC)为填充剂,所制得的分散片3min内全部崩解。结论:优选处方辅料种类及比例适宜,崩解时间符合要求,可为工业化生产提供依据。     

银杏内酯缓释片的制备工艺筛选及体外释放度评价

目的:研究银杏内酯缓释片的制备方法,并考察其体外释放特性。方法:以银杏内酯A(GA)和银杏内酯B(GB)释放度为考察指标,采用单因素试验法,考察了羟丙基甲基纤维素(HPMC)不同规格及用量,乳糖用量、低取代羟丙基纤维素(L-HPC)、羧甲基淀粉钠(CMS-Na)的用量对药物体外释放行为的影响,并采用正交设计实验对处方进行优化,确定最佳制备工艺条件。结果:以羟丙基甲基纤维素(HPMCK4M)为骨架材料,低取代羟丙基纤维素(L-HPC)为崩解剂,微晶纤维素和乳糖为填充剂,制备了每天给药1次的银杏内酯缓释片。该制剂2 h释放约30%,6 h释放约60%,12 h释放90%以上,满足缓释片释放要求。结论:本方法制备的银杏内酯缓释片外观及可压性良好,具有良好的释放性能。且工艺简单易行,生产成本低。     

泼尼松脉冲片的制备研究

目的：制备泼尼松脉冲片并考察其在体外的释放特性。方法采用粉末直接压片法制备速释片芯,以羟丙甲纤维素（HPMC）为溶胀层包衣材料,以乙基纤维素（EC）为控释层包衣材料,采用多层包衣技术制备泼尼松脉冲片。考察了致孔剂PEG 400、增塑剂PEG 6000比例与用量以及控释层包衣增重对释放的影响。以迟滞时间和累积释放度为指标,考察泼尼松脉冲片的体外释放特性。结果以片芯崩解剂用量为11%,致孔剂用量为10%,增塑剂用量为1%,溶胀层和控释层包衣分别增重为5%、10.5%制备的泼尼松脉冲片效果最佳。按照最优处方工艺制备的泼尼松脉冲片体外释放迟滞时间为4 h,时滞后0.5~1.0 h累积释放度达95%以上。结论泼尼松脉冲片处方组成合理,工艺简便可行,体外释放特性符合脉冲释放设计要求。     

宫颈炎康泡腾片的研制

各种妇科疾病尤其是子宫疾病严重影响女性的健康和生活质量，局部用药可以直接作用于病害部位，快速缓解起效。因此，研究开发宫颈炎康泡腾片，显得非常迫切且具有非常重要的现实意义。     

弥罗松酚胃漂浮片的制备

目的研究弥罗松酚胃漂浮片制备工艺。方法通过考察不同处方的休止角、片剂的体外释放度和体外漂浮性,确定最优处方,并制备该片剂。结果最优处方为:弥罗松酚(纯度95.7%)20 g,pH依赖型丙烯酸树脂Ⅱ号(EudragitⅡ)200 g、羟丙甲纤维素400 g、微晶纤维素126 g、硬脂酸250 g,硬脂酸镁4 g,用直接粉末压片法制备了弥罗松酚胃漂浮片。结论制备弥罗松酚胃漂浮片的工艺简单合理,具有较好的体外漂浮性和合适的体外释放度。