利巴韦林的多晶型研究及药动学评价

 目的 研究利巴韦林多晶型状态,建立不同晶型物质状态的有效制备技术及晶型检测方法,评价不同晶型状态的利巴韦林药代动力学特点。方法 通过晶型筛查技术,发现利巴韦林存在4种晶型物质状态（晶A型、晶B型、晶C型、晶D型）,制备获得了4种晶型纯品,采用单晶X射线衍射技术（SXRD）、粉末X射线衍射技术（PXRD）、差示扫描量热技术（DSC）、红外光谱分析技术（IR）与熔点技术（MP）对利巴韦林4种晶型物质状态进行了表征;SD大鼠灌胃给予不同晶型利巴韦林固体后,采用液质联用技术检测不同时间大鼠血药浓度变化、比较不同晶型的生物利用度。结果 利巴韦林药物存在多晶型现象,其中晶C型和晶D型为首次发现并报道;研究证明粉末X射线衍射技术法、差示扫描量热技术法、红外光谱分析技术法、熔点技术法均可实现对不同晶型物质状态的表征和鉴别;发现使用利巴韦林不同晶型物质作为药物原料会对药物临床治疗作用产生影响。结论 发现了利巴韦林新晶型物质状态,获得对晶型物质的有效鉴别分析方法;通过生物学实验证明晶型物质状态会对药物临床作用产生影响。     

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??OBJECTIVE To analyze the relationship between hygroscopicity and water solubility of chemical drugs by using nonparametric test. METHODS Dynamic vapor sorption (DVS) analysis was adopted to determine the hygroscopicity of 515 chemical drugs, and solubility test method was adopted to determine the water solubility of these drugs. All samples were divided into four levels according to their water solubility, and the relationship between hygroscopicity and water solubility was investigated by using Kruskal-Wallis ??Wilcoxon rank sum test. RESULTS There were significant differences in the hygroscopicity of drugs with different levels of water solubility, and the hygroscopicity of level 4 was significantly higher than that of level 1. Hygroscopicity was positively correlated with water solubility. CONCLUSION The hygroscopicity of chemical drugs is interpreted in terms of a physical property in this study, and the results provide an experimental foundation for further studies on the mechanism of hygroscopicity.     

莽草酸多晶型研究

系统研究莽草酸的多晶型现象,发现该化合物可能存在的不同晶型。通过优化重结晶溶剂种类、数量、温度、时间、压力等参数,发现并制备获得3种莽草酸晶型,利用差示扫描量热法(DSC)、粉末X射线衍射法(PXRD)等方法对各种晶型进行表征分析,通过影响因素实验探索溶剂合物晶型的稳定性及晶型转变规律。最终制备获得A,B,C共3种晶型,均为首次发现的新晶型物质;检测分析结果表明莽草酸3种晶型均不含有结晶溶剂,仅PXRD图间存在显著差异。该研究阐明了莽草酸3种晶型的制备方法、热力学稳定性质、晶型转变规律等,并建立晶型物质的有效定性分析方法。     

中药颗粒剂的水分吸附和扩散测定：糊精为辅料进行流化床制粒的防潮效果

目的：采用流化床制粒法以糊精为辅料制备了泽泻汤颗粒,研究其水分吸附和扩散特征。方法：采用粒径、扫描电镜法（SEM）、差示扫描量热法（DSC）和傅里叶变换红外光谱法（FTIR）对泽泻汤颗粒进行表征,采用饱和盐溶液法测定泽泻汤颗粒的吸湿等温线、平衡吸湿量、水分扩散系数和扩散能量。 结果：粒径大小从6.04 μm（泽泻汤浸膏粉）增加到 1201.47 μm（泽泻汤颗粒）;糊精、泽泻汤浸膏粉和泽泻汤颗粒的玻璃态转变温度（Tg）分别为107.13 ℃, 94.82 ℃和126.25 ℃。制粒后,泽泻汤颗粒的平衡吸湿量和水分扩散系数均显著降低（p<0.01）,临界相对湿度和水分扩散能量均高于泽泻汤浸膏粉,能量壁垒的提高阻碍水分在颗粒中的扩散。结论：以糊精为辅料进行流化床制粒能够降低泽泻汤浸膏粉的吸湿性,抑制水分扩散,这可能与流化床制粒改变颗粒的微观组织结构和糊精的抗塑化作用有关。     

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??OBJECTIVE To investigate the effects of interference of riboflavin (RIB) metabolic pathways on adhesion and migration to cisplatin (DDP) in ovarian cancer HO8910 cells. METHODS Intervention RIB metabolic pathways by lentiviral vector harboring shRNA of riboflavin transporter 2 (RFT2) and chlorpromazine (CHL), a competitive inhibitor of RIB. HO8910 ovarian cancer cell line was divided into normal control group, shRNA control group, RFT2 shRNA group, CHL (50 ??mol??L^-1) group, DDP (20 ??mol??L^-1) group, RFT2 shRNA+DDP group, CHL + DDP group and DDP + RIB (20 ??mol??L^-1) group. Each group cells were collected after treatment 48 h according to the design. And then cell adhesive abilities were detected by adhesion experiment, the cells invasive abilities were observed by transwell method, the protein expressions of VEGF, MMP9 and MMP2 were detected by Western blot, and the expressions of TNF-??, NF-??B/p65 were assayed with laser confocal microscopy. RESULTS Compared with the sole DDP treatment group, RFT2 shRNA or CHL combination with DDP had great advantages in reducing cell adhesion and migration viabilities, deceasing expressions of MM9 and MMP2, reducing cell expressions of TNF-?? and NF-??B/p65. However, the RIB could weaken the effects of DDP on HO8910 cell. CONCLUSION Interference metabolic pathway of RIB can enhance DDP effects on adhesion and migration viabilities of ovarian cancer HO8910 cell lines, and the effects are associated with blocking the pathway of TNF-??/NF-??B; However, RIB could attenuate the anti-tumor effects of cisplatin on HO8910 cell.     

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??OBJECTIVE To optimize the preparation process conditions of fanhuncaoin dry powder for inhalation by orthogonal design. METHODS Fanhuncaoin dry powder was prepared by spray-drying method. Following spray-drying, particle size analysis was performed by laser diffraction. Resultant powders were characterized using scanning electron microscopy. The aerosolisation performance was determined using twin-stage liquid impinger. And moisture content was examined by thermogravimetric analysis. The preparation process conditions were optimized with orthogonal design combined with multi-index test. The powder yield, aerodynamic diameter, moisture content and respirable fraction were used as indices for orthogonal design. RESULTS The results of optimized process parameters were confirmed with atomization pressure of 210 kPa, feed flow rate of 9.1 mL??min^-1, aspiration speed of 0.6 m³??min^-1 and inlet temperature of 130 ??. As a result,51.19% yield, 2.92 ??m aerodynamic diameter,4.18% moisture content and 54.45% respirable fraction are obtained by the optimal process conditions. CONCLUSION Orthogonal design combined with multi-index test can be used to optimize the preparation process of fanhuncaoin dry powder for inhalation.     

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??OBJECTIVE To analyze the polymorphism of furosemide by Raman spectroscopy and establish the quantitative model.METHODS The reference Raman spectra of the three crystal forms of furosemide were established, and a quantitative model wasestablished by TQ Analyst data analysis system.RESULTS Partial least-squared (PLS) regression models were developed, and different data preprocessing algorithms such asmultiplicative signal correction (MSC), standard normal variate (SNV) and the 1st to 2nd derivatives were applied to reduce the influence of systematic disturbances. The root mean square errors of calibration (RMSEC) of the quantitative model established for form ??, ??, and ?? were 0.098 6,0.366 0, 0.051 7, and the correlation coefficients(r) were 1.000 0, 0.999 9, and 1.000 0, respectively; the root mean square errors of prediction (RMSEP) between the predicted value of the sample and its actual value were 0.059 0, 0.070 4, 0.045 1, and the factors were 8,8, and 9, respectively.CONCLUSION Raman spectroscopy can be used to analyze the polymorphism of furosemide and the quantitative model can be used for quantitative determination of furosemide crystal form.     

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??OBJECTIVE To study the monthly dynamics of physical and chemical indexes in Achyranthis Bidentatae Radix(ABR, the dried root of Achyranthes bidentata Bl.) stored in simple and cool warehouses. METHODS ABR was stored in simple and cool warehouses for 27 months. The color was observed. The water content was determined based on the drying method. The contents of ??-ecdysone and 5-hydroxymethylfurfural (5-HMF) were determined by HPLC method. The accumulation of temperature difference between the simple and cool warehouses was evaluated with a relative temperature cumulation (RTC) method. The monthly dynamics of physical and chemical indexes of ABR was analyzed with RTC. RESULTS As the extension of storage time, the ABR stored in the simple warehouse showed deeper color and harder texture, but the ABR stored in the cool warehouse still had soft texture without significant color change. The contents of ??-ecdysone in ABR stored in the two warehouses both gradually decreased and dropped to lower than the limit of 0.030% ruled by China Pharmacopoeia when being stored for up to 27 months. The contents of 5-HMF of ABR stored in the two warehouses both increased and were higher for the sample in the simple warehouse than that in the cool warehouse. CONCLUSION The concept of RTC is put forward and used to study the monthly dynamics of chemical constituents in traditional Chinese medicine during storage for the first time. The physical and chemical indexes of ABR varies during storage. Two years of storage time of ABR is suggested.     

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??OBJECTIVE To select excipients and optimize preparation for the ambroxol hydrochloride/levosalbutamol sulfate dry powder inhalation. METHODS Drug and different excipients in the same ratio were prepared by spray drying to obtain a certain particle size as drug particles or carriers for dry powder inhalation, respectively. Study and compare the parameters of powders of the dry powder inhaler, such as the angle of repose, moisture content, and emptying rate, etc, to screen the excipient of the vectors. Afterward, Box-Behnken design method was adopted to optimize of preparation parameters. RESULTS When lactose-high branched cyclodextrin compounds were used as composite carriers, their powder properties meet the requirements of dry powder inhaler, such as the repose angle was 39.69 degrees, the bulk density was 0.37 g??mL^-1, the tap density was 0.66 g??mL^-1, the evacuation rate of drug-carrier powders in capsules was 93.12%, and the water content was 0.10% and the simulated lung deposition rate was 14.63%. The preparation parameters, such as sample concentration, inlet air temperature, nozzle diameter parameters, theirs values were 50 mg??mL^-1, 110 ??, 1 mm, respectively, were opmized by Box-Behnken design method, which could obtain the carrier particle size of 30.33 ??m. CONCLUSION Lactose-high branched cyclodextrin complexes can be used as carrier for levosalbutamol sulfate-ambroxol hydrochloride compound dry powder inhaler, which could meet the requirements of dry powder inhaler by spray-drying preparation method.     

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??OBJECTIVE To investigate the influence of moisture including water content and water activity on the stability of amoxicillin and potassium clavulanate granules according to the characteristics of the granules, and reveal the key quality control property in the preparation process with stability as an indicator. METHODS Under the condition of (25??2)?? and (75??5)?? RH, the water content, active ingredient contents, related substances and characteristics of crystal form of amoxicillin and potassium clavulanate granules were studied. RESULTS The stability of amoxicillin and clavulante potassium granules was positively correlated with water activity in the samples, but was not related to water content closely. The sample with lower water activity was of higher stability. CONCLUSION The key quality control property of amoxicillin and potassium clavulanate granules is the moisture, and the key process parameter in the preparation is the water activity.