1,4-噻嗯并二氮杂类药的IR和NMR光谱研究

作者选择三个1.4-噻嗯并二氮杂(艹卓)类药物(1.4-Thienodiazepines)进行研究:(1)TDO,即5-(2-氯苯基)-1.3-二氢-2H-噻嗯并[2,3-e][1,4]二氮杂(艹卓)-2-酮;(2)BrTDO,即7-溴-5-(2-氯苯基)-1,3-二氢-2H-噻嗯并[2,3-e][1,4]二氮杂(艹卓)-2-酮;和(3)TDT,即F-氯5-(2-氯苯基)-1,3-二氢-2 H-噻嗯并[2,3-e][1,4]二氮杂(艹卓)-2-硫酮。分别取1.5mg 各     

花生锈病最终病情严重度的长期测报

本研究分析了广东省湛江市和电白县花生锈病最终病情严重度和气象因子的回归关系,结果表明:4月下旬至5月下旬的旬平均气温X_1,旬平均相对湿度X_2和日平均降雨量X_3,对春花生的锈病最终病情严重度Y有显著影响,9月中旬至10月中旬的相应气象因子影响秋花生的锈病最终病情严重度(α=0.005)。这些因素与病情有如下关系: Y=(-2.70884×10~(-7)expX_1 2266970.51lnX_2 5.516×10~(3)expX_3-9501060.363)(1/3)     

高速剪切湿法制粒工艺制备氯沙坦钾片

目的通过优化高速剪切湿法制粒工艺参数制备氯沙坦钾片。方法采用高速剪切湿法制粒工艺制备氯沙坦钾片,通过对制备工艺参数优化:搅拌桨转速(X_1,r·min~(-1))、加水量(X_2,%)和制粒时间(X_3,s)为考察对象,以颗粒粒径大小(D50,Y_1,μm)、片剂硬度(Y_2,N)、15min药物溶出度(Y_3,%)为评价指标,利用Box-Behnken效应面法优化高速剪切湿法制粒工艺参数。结果方差分析结果显示:搅拌桨转速、加水量和制粒时间对颗粒粒径影响较显著(P<0.05);加水量、制粒时间对片剂的硬度影响较显著(P<0.05);加水量、制粒时间对药物的溶出度影响较显著(P<0.05)。结论通过Box-Behnken实验设计法优化高速剪切湿法制粒工艺,可以提高工艺过程的稳健性和灵活性。     

氮钾肥配施对赤红壤上甜玉米生长影响的研究

本文研究氮、钾肥配施对赤红壤上甜玉米生长的影响,于1986年秋作和1987年春作进行两次盆栽试验及植株和土壤的化学分析。结果表明:氮、钾肥配施可增加供试土壤有效氮和速效钾含量,可增加甜玉米穗叶(吐丝明)含N量和含K量,降低穗叶含P量、含Ca量和含mg量。不施钾肥处理的甜玉米穗叶含K量≤1.30％,吐丝前有明显的缺K症。施高量钾肥(0.33克KCl/公斤土)处理的穗叶含Mg量≤0.15％;吐丝后出现明显的缺Mg症;施K_1水平(0.17克KCl/公斤土)的钾肥较适宜。单施氮肥处理,甜玉米果穗和籽粒的产量随施氮量增加而显著降低。配施钾肥处理,甜玉米增产率随施氮量增加而增大。增施氮肥可明显增加籽粒粗蛋白质含量,降低水溶性糖含量。施钾肥与不施钾肥比可明显增加水溶性糖含量,增加粗蛋白质总量(克/盆),但降低租旦白质含量。在供试赤红壤盆栽甜玉米条件下,氮钾肥配施以N_2K_1处理为宜     

大蒜测土配方营养套餐施肥技术

介绍大蒜测土配方套餐施肥方案的设计原则及施肥的具体技术方案.根据大蒜喜钾、喜硫的需肥特点,除基肥施(667 m2)2 000 kg农家肥、50 kg生物有机肥及16-10-22的复混肥100 kg外,并追施(随水冲施)高氮全营养肥(21-8-11)2.5 kg、高钾全营养肥(12-12-17)12.5 kg各2次,叶面肥喷施若干次,并使用大蒜凯普克促进根系生长.通过3年大面积示范试验,与常规施肥对照,大蒜年平均增产14.4%,667 m2净增产量约235kg,净增产值约643元.     

头孢丙烯片在健康人体的药代动力学和生物等效性

目的研究2种国产头孢丙烯片(头孢类抗生素)在健康人体内的药代动力学过程,并评价这2种制剂的生物等效性。方法20例健康成年男性受试者随机分组,自身对照,单次口服头孢丙烯片1 g后,用高效液相色谱法测定头孢丙烯顺式及反式异构体的血浆浓度,用非房室模型法计算各主要药代动力学参数,并进行方差分析和生物等效性评价。结果顺式异构体:参比制剂与受试制剂的tm ax分别为(2.4±1.0),(2.3±0.8)h;Cm ax分别为(15.4±3.5),(14.8±2.8)μg.mL-1;t1/2分别为(1.4±0.1),(1.4±0.1)h;MRT分别为(3.4±0.6),(3.4±0.6)h;AUC0-t分别为(61.2±10.6),(60.3±11.4)μg.h.mL-1;AUC0-∞分别为(64.7±11.2),(64.5±11.7)μg.h.mL-1;受试制剂相对于参比制剂的生物利用度为(99.3±14.5)%。反式异构体:参比制剂与受试制剂的tm ax分别为(2.4±0.9),(2.4±0.9)h;Cm ax分别为(1.6±0.3),(1.5±0.3)μg.mL-1;t1/2分别为(1.2±0.2),(1.5±0.6...     

多标志物联合检测肺癌及其对肺癌病理类型预测的价值分析

目的研究CEA、CYFRA21-1、NSE和SCC四种肿瘤标志物(TM)对肺癌的诊断价值及其与病理类型的关系。方法回顾性分析2017年1月～2018年12月在我院首诊245例肺癌及100例良性肺部疾病患者的临床资料。其中鳞癌(SC)79例,腺癌(AC)127例,小细胞肺癌(SCLC)39例。比较四种TM在不同病理类型肺癌患者中的血清学水平及阳性率,采用判别分析法建立Fisher判别函数诊断肺癌并预测肺癌病理类型。结果三个肺癌组CEA、CYFRA21-1、NSE和鳞癌组SCC血清学水平和阳性率均显著高于对照组(P 0.05)。四种TM联合诊断肺癌的敏感度为94.09%、特异度为79.63%、诊断正确率为89.57%。F1=-0.664+0.004 X_1+0.027 X_2+0.017X_3+0.092X_4(F1 0为肺癌,F1 0为良性)、F2=1.522+0.002X_1+0.032X_2-0.044X_3+0.075X_4(F2 0为NSCLC,F2 0为SCLC)、F3=0.045-0.004X_1+0.003X_2-0.015X_3+0.203X_4(F3 0为鳞癌,F3 0为腺癌)诊断准确率分别为90.43%、89.80%、74.76%。结论肿瘤标志物判别分析法进行肺癌诊断和病理类型预测有一定的临床应用价值。     

西他沙星合成路线图解

西他沙星(sitafloxacin,1),化学名为7-[(7S)-7-氨基-5-氮杂螺[2.4]庚-5-基]-8-氯-6-氟-1-[(1R,2S)-cis-2-氟环丙基]-1,4-二氢-4-氧代-3-喹啉羧酸,是由日本第一制药公司研发的氟喹诺酮类抗菌剂,临床用其一水合物,已在日本完成Ⅲ期临床,2001年11月提交新药申请.按起始原料不同,主要有2条合成路线.关键中间体(1R,2S)-(-)-cis-1-叔丁氧羰基氨基-2-氟环丙烷(2)和(S)-(-)-7-叔丁氧羰基氨基-5-氮杂螺[2.4]庚烷(3)有多种合成方法.2和3也可用于制备其它喹诺酮类衍生物.现将合成方法归纳如下.     

稻田有机肥的分解动态研究

用网袋法研究了早稻稻杆,晚稻稻杆,红萍(Azolla imbricata (Roxb)Nakai)及紫云英(Astragalus sinicus L.)在水田耕作层的分解动态,结果表明干物重、含氮量、含磷量和含钾量的残存百分率(y)均可用y=a·t描述,其中t为分解时间,a、b为回归系数,有机物中氮的释放速度慢于磷钾的释放速度,分解残留物的氮含量趋向1％。有机物氮含量(％)与干物重消失50％所需时间之间的相关系数R=-0.997 5。     

高产高效栽培下春玉米生育后期冠层结构及其光合特性的研究

以郑单958为供试品种,设高产高效栽培(GCGX)和农户传统栽培(CK)2个处理,于2012年和2013年连续2 a进行田间试验,测定春玉米生育后期冠层结构及其光合特性的变化规律。结果表明：吐丝期和乳熟期株高、穗位高产高效栽培略高于农户传统栽培。与农户传统栽培相比,高产高效栽培春玉米叶面积指数较大,在生育期上表现为吐丝之后更为明显,在叶位上表现为棒三叶以下叶片最为突出;不同叶位的叶倾角高产高效栽培显著小于农户传统栽培,而叶向值均显著大于农户传统栽培,在棒三叶表现最为明显;高产高效栽培生育后期净光合速率显著高于农户传统栽培,冠层光合能力极显著高于农户传统栽培。高产高效栽培下春玉米产量为14.009 t·hm^-2(2012)和13.255 t·hm^-2(2013),均极显著高于农户传统栽培。     

Response surface methodology to obtain beta-estradiol biodegradable microspheres for long-term therapy of osteoporosis

The purpose of this work was to evaluate the main and interaction effects of formulation factors on the drug encapsulation efficiency of beta-estradiol biodegradable microspheres by applying response surface methodology. A secondary purpose was to obtain an optimized formula for long-term therapy of osteoporosis. A three factor, three level Box-Behnken experimental design was used to get 15 experimental runs. The independent variables were drug/polymer ratio (X1), dispersing agent concentration (X2), and deaggregating agent concentration (X3). The dependent variables were percentage encapsulation efficiency (Y1), cumulative percent drug released (Y2), and percentage yield of the microspheres (Y3). The formulations were prepared by emulsion solvent evaporation technique using ethyl acetate as organic solvent. The optimized formulation was maximized for encapsulation efficiency and further characterized for the particle size distribution, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR). The mathematical relationship obtained between X1, X2, X3, and Y1 was: Y1 = -129.85 + 29.35X1 + 129.99X2 + 64.82X3 - 3.2X1X2 - 0.29X1X3 - 35.83X2X3 - 2.05X(2)(1) - 13.23X(2)(2) - 5.92X(2)(3) (R2 = 0.99) The equation showed that X1, X2, and X3 affect Y1 positively but interaction between any two of these factors affects Y1 negatively. The most significant interaction was between X2 and X3. The finding indicated that controlled releases beta-estradiol biodegradable microspheres with high encapsulation efficiency and low pulsatile release can be prepared and the quantitative response surface methodology applied helped in understanding the effects and the interaction effects between the three factors applied.     

含稀土有机复混肥的研制及其在甘蔗上的应用研究

在考虑土壤肥力、甘蔗营养特性的基础上,研制出含有改性配方稀土、甘蔗滤泥和氮、磷、钾的甘蔗专用肥。３年９个大田试验的平均结果表明：甘蔗施用含稀土有机复混肥后,平均产量为８８ ６８０ ｋｇ／ｈｍ２,平均田间锤度为 １９． ８％,理论产糖量平均为 １０ ５３０ ｋｇ／ｈｍ２,比不含稀土,但含等量氮、磷、钾、有机质的有机复混肥增产 ８ ４１５ ｋｇ／ｈｍ２,增产率为１０．５％,田间锤度提高１％,增糖１６．４％。     

Response surface methodology to obtain naproxen controlled release tablets from its microspheres with Eudragit L100-55

PURPOSE: Naproxen CR tablets have been obtained from its microspheres prepared by coprecipitation with Eudragit L100-55. The purpose of this work was to evaluate the main and interaction effects of deaggregating agent concentration (X1), compression pressure (X2) and amount of precipitating water (X3) on naproxen release. A secondary purpose was to obtain an optimized naproxen controlled release solid oral dosage form with a predictable 12 h drug release. METHOD: Eudragit L100-55 (10 g) was dissolved in 100 ml of ethyl alcohol, and 30g of naproxen was dispersed in it with stirring. Purified water (100mL, cooled to 4 degrees C) containing calcium chloride as a deaggregating agent was added to an alcoholic solution and homogenized. The mixture was filtered to obtain microspheres. Drug content analysis was performed spectrophotometrically at 332 nm. Tablets were prepared by compressing microspheres containing 500mg of naproxen after adding 1% magnesium stearate. Dissolution was performed by the USP specifications of naproxen tablets. A 3-factor 3-level Box-Behnken design was employed to get 15 experimental runs. The independent variables used were X1, X2 and X3. The dependent variables were dissolution at different time points with constraints on yield value and angle of repose of the microspheres, and hardness and thickness of the tablets. The dissolution constraints were placed such that the naproxen is released for 12 h by Higuchi's square root of time kinetics. RESULTS: The mathematical relationship obtained between X1, X2, X3 and the cumulative per cent of naproxen dissolved in 12 h with various constraints (Y5) was Y5 = 92.39 - 1.13X1 - 4.84X2 - 2.12X3 - 2.26X1X2 - 0.5X1X3 - 0.4X2X3 + 2.4X(1)(2) - 0.4X(2)(2) (R2 = 0.9). The equation shows that X1, X2 and X3 affected the release inversely, and the most significant interaction was between X1 and X2. Y5 has been maximized for optimization of naproxen release. CONCLUSIONS: Controlled release tablets of naproxen with predictable drug release characteristics were obtained by compressing its microspheres with Eudragit L100-55.     

Release modulating hydrophilic matrix systems of losartan potassium: optimization of formulation using statistical experimental design.

The aim of the present research work was to systemically device a model of factors that would yield an optimized sustained release dosage form of an anti-hypertensive agent, losartan potassium, using response surface methodology by employing a 3-factor, 3-level Box-Behnken statistical design. Independent variables studied were the amount of the release retardant polymers - HPMC K15M (X(1)), HPMC K100M (X(2)) and sodium carboxymethyl cellulose (X(3)). The dependent variables were the burst release in 15 min (Y(1)), cumulative percentage release of drug after 60 min (Y(2)) and hardness (Y(3)) of the tablets with constraints on the Y(2)=31-35%. Statistical validity of the polynomials was established. In vitro release and swelling studies were carried out for the optimized formulation and the data were fitted to kinetic equations. The polynomial mathematical relationship obtained Y(2)=32.91-2.30X(1)-5.69X(2)-0.97X(3)-0.41X(1)X(2)+0.21X(1)X(3)-0.92X(1)(2)-1.89X(2)(2) (r(2)=0.9944) explained the main and quadratic effects, and the interactions of factors influencing the drug release from matrix tablets. The adjusted (0.9842) and predicted values (0.9893) of r(2) for Y(2) were in close agreement. Validation of the optimization study indicated high degree of prognostic ability of response surface methodology. Tablets showed an initial burst release preceding a more gradual sustained release phase following a non-fickian diffusion process. The Box-Behnken experimental design facilitated the formulation and optimization of sustained release hydrophilic matrix systems of losartan potassium.     

Response Surface Methodology to Obtain β-Estradiol Biodegradable Microspheres for Long-Term Therapy of Osteoporosis

The purpose of this work was to evaluate the main and interaction effects of formulation factors on the drug encapsulation efficiency of β-estradiol biodegradable microspheres by applying response surface methodology. A secondary purpose was to obtain an optimized formula for long-term therapy of osteoporosis. A three factor, three level Box-Behnken experimental design was used to get 15 experimental runs. The independent variables were drug/polymer ratio (X1), dispersing agent concentration (X2), and deaggregating agent concentration (X3). The dependent variables were percentage encapsulation efficiency (Y1), cumulative percent drug released (Y2), and percentage yield of the microspheres (Y3). The formulations were prepared by emulsion solvent evaporation technique using ethyl acetate as organic solvent. The optimized formulation was maximized for encapsulation efficiency and further characterized for the particle size distribution, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR). The mathematical relationship obtained between X1, X2, X3, and Y1 was:

Y1 = ?129.85 + 29.35X₁ + 129.99X₂ + 64.82X₃ ? 3.2X₁X₂ ? 0.29X₁X₃ ? 35.83X₂X₃ ? 2.05X₁² ? 13.23X₂² ? 5.92X₃² (R2 = 0.99)

The equation showed that X1, X2, and X3 affect Y1 positively but interaction between any two of these factors affects Y1 negatively. The most significant interaction was between X2 and X3. The finding indicated that controlled releases β-estradiol biodegradable microspheres with high encapsulation efficiency and low pulsatile release can be prepared and the quantitative response surface methodology applied helped in understanding the effects and the interaction effects between the three factors applied.     

Response surface methodology for the development of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate

The purpose was to prepare, characterize, and optimize a self-nanoemulsified drug delivery system (SNEDDS) of a model lipophilic compound, all-trans-retinol acetate. As part of the optimization process, the main effects, interaction effects, and quadratic effects of the formulation ingredients were investigated. METHOD: A three-factor, three-level Box-Behnken design was used to explore the quadratic response surfaces and construct a second-order polynomial model in the form: Y = A + A1X1 + A2X2+ A3X3 + A4X1X2 + A5X2X3 + A6X1X3+ A7X1(2) + A8X2(2) + A9X3(2) + E. Amount of added oil (X1), surfactant (X2), and cosurfactant (X3) were selected as the factors. Particle size (Y1), turbidity (Y2), and cumulative amount of the active ingredient emulsified after 10 (Y3) and 30 (Y4) min were the observed variables. Response surface plots were used to demonstrate the effect of factors (X1), (X2), and (X3) on the response (Y4). Amount of added soybean oil (X1), Cremophor EL (X2), and Capmul MCM-C8 (X3) showed a significant effect on the emulsification rates, as well as on the physical properties of the resultant emulsion (particle size and turbidity). Observed and predicted values of Y4 obtained from the constructed equations were in close agreement. Response surface methodology was then used to predict the levels of factors X1, X2, and X3 under the constrained variables for an optimum response. Applied constraints were 0 < Y1 < 0.5, 1 < Y2 < 20, 60 < Y3 < 80, and 90 < Y4 < 100. The predicted values were 0.0704 microm for particle size (Y1), 18.95 NTU for turbidity (Y2), 88.88% for drug release after 10 min (Y3), and 110.7% drug release after 30 min (Y4). Two new formulations were prepared according to the predicted levels. The observed and predicted values were in close agreement.     

Quality by design: understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function

Quality by design (QBD) refers to the achievement of certain predictable quality with desired and predetermined specifications. A very useful component of the QBD is the understanding of factors and their interaction effects by a desired set of experiments. The present project deals with a case study to understand the effect of formulation variables of nanoemulsified particles of a model drug, cyclosporine A (CyA). A three-factor, three-level design of experiment (DOE) with response surface methodology (RSM) was run to evaluate the main and interaction effect of several independent formulation variables that included amounts of Emulphor El-620 (X(1)), Capmul MCM-C8 (X(2)) and 20% (w/w) CyA in sweet orange oil (X(3)). The dependent variables included nanodroplets size (Y(1)), nanoemulsions turbidity (Y(2)), amounts released after 5 and 10min (Y(3), Y(4)), emulsification rate (Y(5)) and lag time (Y(6)). A desirability function was used to minimize lag time and to maximize the other dependent variables. A mathematical relationship, Y(5)=9.09-0.37X(1)+0.37X(2)-0.45X(3)+0.732X(1)X(2)-0.62X(1)X(3)+0.3X(2)X(3)+0.02X(1)(2)-0.28X(2)(2)+0.471X(3)(2) (r(2)=0.92), was obtained to explain the effect of all factors and their colinearities on the emulsification rate. The optimized nanodroplets were predicted to yield Y(1), Y(2), Y(3), Y(4), Y(5) and Y(6) values of 42.1nm, 50.6NTU, 56.7, 107.2, 9.3%/min and 3.5min, respectively, when X(1), X(2), and X(3) values were 36.4, 70 and 10mg, respectively. A new batch was prepared with these levels of the independent variables to yield Y(1)-Y(6) values that were remarkably close to the predicted values. In conclusion, this investigation demonstrated the potential of QBD in understanding the effect of the formulation variables on the quality of CyA self-nanoemulsified formulations.     

Optimization and characterization of controlled release multi-particulate beads coated with starch acetate

The objectives of the present study were (1) to model the effects of process and formulation variables on in vitro release profile of a model drug dyphylline from multi-particulate beads coated with starch acetate (SA); (2) to validate the models using R2 and lack of fit values; (3) to optimize the formulation by response surface methodology (RSM); (4) to characterize the optimized product by thermal, X-ray and infrared spectroscopic analyses. Dyphylline loaded inert beads were coated using organic solution of SA with high degree of substitution. A three-factor, three-level Box-Behnken design was used for the optimization procedure with coating weight gain (X1), plasticizer concentration (X2) and curing temperature (X3) as the independent variables. The regression equation generated for Y5 (cumulative percent drug released after 12 h) was Y5 = 89.83-11.98X1 + 2.82X2 - 4.31X1(2) + 1.90X1X2. Optimization was done by maximizing drug release in 12 h and placing constraints at dissolution time points of 0.5, 1, 4 and 8 h. The drug release data of the optimized product were close to that predicted by the model. The models could explain 99% of variability in responses. Thermal, X-ray and infrared analyses suggested absence of any significant interaction of the drug with the excipients used in the formulation. SEM photographs showed the integrity of the coating layer.     

血浆分离组分V沉淀收率数学模型的建立

目的 建立组分V沉淀收率与原料血浆蛋白质含量关系的数学模型.   方法 利用SPSSl3.0软件包对553批经低温乙醇蛋白分离法分离的人血浆组分V沉淀收率资料进行回归分析,拟合曲线方程,并用所建模型对77批血浆分离组分V沉淀收率进行实例验证.   结果 当原料血浆蛋白质含量范围为49.0～62.9 g/L时,采用三次方程曲线拟合方法建立的方程为(Y)=82.522+6.148X-0.626X²+0.023X³,作拟合优度检验,决定系数R²=0.947,自变量X能在94.7%的程度上对应变量(Y)作出解释,模型拟合非常好,方差分析表明:F=59.193,P=0.000,模型成立,对组分V沉淀收率的预测值符合实际组分V沉淀收率的分布.   结论 处于不同范围内的原料血浆蛋白质含量与组分V沉淀收率之间的曲线关系成立,理论估计值与观察值分布一致,此模型的建立有利于血液制品生产过程中物料平衡的控制.     

Optimization of formulation components and characterization of large respirable powders containing high therapeutic payload

The aim of the study was to optimize and characterize high therapeutic payload large respirable powders prepared by spray-drying technique for maximum fine particle fraction with minimum quantities of excipients. Influence of formulation components was optimized by a three-factor, five-level central composite design having different proportions of L-leucine (X1), tobramycin sulfate (X2), and poloxamer-188 (X3) as the independent variables and fine particle fraction as a response variable (Y). Large respirable powders were characterized for particle size, size distribution, moisture, crystallinity, and morphology. In vitro aerosol performance of powders was determined by an eight-stage Andersen cascade impactor using the Rotahaler. Mathematical model elucidated for Y was Y = 56.2068 + 5.7481 X1 - 3.0531 X2 + 0.8468 X3 + 1.1737 X1 X2 - 0.5012 X1 X3 - 0.7412 X2 X3 - 0.7149 X1(2) - 1.9212 X2(2) - 1.6187X3(2). The component of greatest influence on product performance (response variable) was found to be L-leucine. Lack of fit was not significant (p = 0.08), and regression equation predicted response for Y was in reasonably good agreement with experimental values (p = 0.01; R2 = 0.92). The optimal model predicted with a fine particle fraction of 62.8 +/- 2.6% with X1, X2, X3 levels of 20, 45.71, and 5.51 respectively. Large respirable powders with TB load of 45.7% w/w were prepared; they had smooth surface texture, dimpled spherical shape, roundness value close to 1(1.048 +/- 0.032) and were found to possess bulk tap densities of 0.04 g/cc, geometric particle sizes of 6-7 micro m, and emitted dose of 92%. The results of the studies suggest that in vitro aerosol performance was affected significantly by small and deliberate change of specific formulation components and its proportions. It may be concluded that appropriate type and proportion of excipients is necessary to obtain maximum fine particle fraction of large respirable powders containing high therapeutic payloads.