克拉霉素缓释片释放度研究

目的:研究自制克拉霉素缓释片的体外释放度。方法:以紫外分光光度法测定自制克拉霉素体外释放度。结果:释放度曲线经Weibull分布拟合,自制缓释片为lnln 1/(1-F(t))=1.5 291 lnt-3.7 539(r=0.9 842);进口缓释片为lnln 1/(1-F(t))=1.5 216 lnt-3.6 759(r=0.9 830)。自制和进口克拉霉素缓释片的释放度基本一致。结论:自制克拉霉素缓释片有较好的释药性能。本文建立的释放度测定方法可作为该制剂的质控方法。     

多元线性模型预测药物的稳定性

首次提出了预测药物稳定性的多元线性模型。该模型指出,任何满足恒温降解动力学公式和Arrhenius公式的药物,都可在3维坐标系中以药物平面形式表示。以药物的浓度函数ln[f(c₀)-f(c)]和绝对温度的倒数1/T为变量,对时间的对数ln(t)进行多元线性回归,可以计算得到药物的活化能和室温贮存期。应用多元线性模型和经典恒温法对替诺昔康注射液(自制)、抗坏血酸注射液及盐酸丁卡因水溶液的室温贮存期预测的结果表明:两者无显著性差异,而本模型可大大减少实验次数,应用SAS软件使数据处理更简便。     

同时包载孕二烯酮和炔雌醇的PLGA微球的制备

目的探索制备皮下注射用孕二烯酮/炔雌醇复方微球的可行性。方法以乳酸-羟基乙酸共聚物共聚物(PLGA)为载体材料,孕二烯酮、炔雌醇为模型药物,采用乳化溶剂挥发法制备皮下注射用复方微球,观察微球表面形态,检测所制微球的稳定性,检测微球的有机溶剂残留和体外释放特性。结果所得微球中孕二烯酮和炔雌醇的包封率分别为(69.9±6.6)%和(60.5±1.5)%;微球形态良好,粒径分布窄,平均粒径为(65.62±4.56)μm;微球中有机溶剂残留为(154.84±16.84)mg.L-1;体外释放过程中,2种药物能够持续稳定释放30 d,两药的体外释放行为符合Weibull方程,孕二烯酮和炔雌醇的释药方程分别为:ln[ln1/(1-F(t)]=0.625 8lnt-1.826(r=0.992 1)和:ln[ln1/(1-F(t)]=0.855 2lnt-2.850 1(r=0.991 4);制备的微球在高温、光照条件下均不稳定,在常温下长时间放置也不稳定,但在避光冷藏条件下稳定。结论所用制备工艺稳定,微球包封率较高,粒度均匀,有机溶剂残留符合国家标准,释药平稳,释药时间较长,可以进行进一步的体内研究。     

经典恒温法和多元线性模型预测药物稳定性的空间解析

应用三维坐标系,以图示方式解析药物稳定性预测法中经典恒温法数据处理的复杂性,提出一个简便的药物稳定性预测方法多元线性模型。此模型是以药物的浓度函数ln[f(c₀)-f(c)]和绝对温度的倒数1/T为变量,对时间的对数ln(t)进行多元线性回归,以此计算药物的活化能和室温贮存期。结果表明:多元线性模型可以简化数据处理,明显减少实验工作量和误差。     

健康男青年替硝唑片的生物等效性研究

目的 评价两种替硝唑片的生物等效性.方法 以HPLC法测定18名男性健康志愿者单剂量口服两种替硝唑片2g后血清中替硝唑浓度,3p97程序求算药动学参数.AUC0→t、AUC0→∞和Cmax数据对数转换后用3p97程序进行多因素方差分析及双单侧t检验判断90%可信限,tmax用非参数统计Wilcoxon法进行检验.结果 供试制剂和参比制剂的实测tmax分别为(1.7±0.6)和(1.8±0.8)h,实测Cmax分别为(44.5±6.2)和(45.0±6.6)mg/(L,t1/2)分别为(14.2±2.9)和(15.6±3.5)h,梯形法算得AUC0→t分别为(958.3±149.4)和(1 003.6±184.5)mg/(h·L),AUC0→∞分别为(994.8±163.4)和(1 047.7±206.0)mg/(h·L).以市售广东彼迪药业有限公司产替硝唑片为参比,河南省天工制药厂生产的替硝唑片相对生物利用度F0→t为(96.8±13.3)%,F0→∞为(96.5±14.5)%.结论 两种制剂具有生物等效性.     

奥硝唑片人体生物等效性研究

目的比较口服奥硝唑片试验制剂与国产上市制剂的药代动力学参数,进行生物利用度和生物等效性评价。方法开放、随机、单次给药、双周期交叉临床研究。共20例健康受试者。结果试验制剂和参比制剂的药代动力学结果:T1/2分别为(17.010±2.682)h和(17.446±2.519)h;Tmax分别为(1.550±0.759)h和(1.250±0.526)h;Cmax分别为(9.476±1.083)μg/μL和(9.592±1.251)μg/μL;AUC0-t分别(225.604±44.327)μg/(μL?h)和(213.880±43.834)μg/(μL?h);AUC0-∞分别为(231.269±48.014)μg/(μL?h)和(219.655±46.518)μg/(μL?h)。试验制剂对于参比制剂的平均相对生物利用度F值(106.9±15.4)%。两种制剂的AUC0-t、AUC0-∞及Cmax经对数转换后双单侧t检验结果P<0.05,接受两种制剂生物等效的假设。90%置信区间的计算结果:Cmax为93.7%¹04.5%,AUC0-t为100.0%104.5%,AUC0-t为100.0%¹12.1%,AUC0-∞为99.7%112.1%,AUC0-∞为99.7%¹11.9%,按照生物等效性判定标准,可判定两种制剂生物等效。结论两制剂间无显著性差异,两制剂具有生物等效性。适用与Ⅰ期临床研究。     

SUR1和KCNJ11基因多态性与磺脲类药物继发性失效的相关性研究

目的探讨磺脲类药物受体1(SUR1)基因的外显子16-3c/t、内向整流性钾通道(potassium inwardly-rectifying channel subfamily J,member 11,KCNJ11)基因的E23K变异与2型糖尿病(type 2 diabetes mellitus,T2DM)患者磺脲类药物继发性失效(secondary failure of sulfonylurea,SFS)的关系。方法选取山东地区T2DM患者200例,其中磺脲类药物有效者114例,SFS者86例,运用SNaPshot技术(ABI Biosystem,USA)对SUR1 16-3c/t、KCNJ11 E23K进行基因分型。结果 SUR1 16-3c/t和KCNJ11 E23K等位基因的发生频率均符合Hardy-Weinberg平衡;KCNJ11 E23K各基因型的分布在SFS组及有效组之间差异无统计学意义(P>0.05);SUR116-3c/t各基因型的分布在SFS组和有效组之间差异有统计学意义(P<0.01),且"t"等位基因的频率在SFS组明显增高[比值比(OR)=1.87,95%可信区间(CI)为1.23～2.85,P<0.01]。Logistic回归分析中,校正性别、年龄、BMI、F-C肽、TG、TC、HDL-C、LDL-C后,SUR1 16-3c/t的t/t基因型是SFS发生的独立危险因素[比值比(OR)=2.82,95%可信区间(CI)为1.57～5.07,P<0.01]。结论 SUR1外显子16-3c/t多态性可能与山东地区磺脲类药物继发性失效有明显相关性。     

用SPSS拟合药物溶出度Weibull参数

目的介绍用SPSS拟合药物溶出度Weibull参数。方法采用SPSS软件经非线性回归拟合Weibull模型(Y=1—e-(t-τ)m/t0)处理药物溶出度数参数。结果SPSS与目前其它方法拟合的Weibull模型处理药物溶出度参数比较,其准确性高,计算过程简便、快速。结论本方法拟合药物Weibull参数操作简单,计算结果准确。     

舒巴坦钠/头孢哌酮钠降解产物测定方法研究

目的　建立高效液相色谱法、紫外扫描法对头孢哌酮钠/舒巴坦钠降解产物(氨基烷酸、T - 15 5 1B、T - 15 5 1F、T - 15 5 1E .Na)的测定方法。根据规定对降解产物进行鉴定和分析,结果要符合《中国药典》(2 0 0 0年版)杂质测定相的要求。其验证内容包括:准确度、重复性、中间精密度、重现性、定量限、专属性、以及线性、定量范围和耐用性。方法　进行高效液相色谱分析时条件如下:采用MicrobondapakC18柱,规格3.9mm×30 0mm。流动相配比为乙睛/水(2 2 / 78体积/体积,PH值等于4 ) ,流速为1.5ml/min ,进样体积为10 μl,紫外检测波长为2 30nm。结果　舒谱深降解产物的保留时间与标准品相一致。根据设计的线性试验范围,相关系数大于0 .9998(标准值>0 .995 ) ,斜率标准偏差小于0 .34% (标准值≤±5 % )。选取各自适合的浓度点,平均回收率不超过(10 0±5 ) % (标准值≤(10 0±10 ) % ) ,各浓度点的相对标准偏差小于4 .7% (标准值≤5 % )。对降解产物T - 15 5 1B ,T- 15 5 1F各自精密度的相对标准偏差小于10 % (标准值≤10 % )。分析表明几种物质在测定过程中均无干扰。结论　本方法适用于对药品舒谱深的生产过程及药物稳定性的跟踪监测。     

经典恒温法和多元线性模型预测氯霉素亚砜涂剂的有效期

目的:研究氯霉素亚砜涂剂(氯霉素-二甲基亚砜)的热降解动力学过程,并预测其有效期。方法:采用高效液相色谱法测定氯霉素亚砜涂剂在75、80、85、95℃恒温水浴中放置0、8、16、20、24 h的氯霉素含量;采用经典恒温法和多元线性模型两种方法预测制剂的有效期,同时比较两种方法的特点。结果:经典恒温法取20个数据经5次拟合可得回归方程为lg K=-4 825.3×(1/T)+11.349(r=0.999 0),K25℃为1.470 88×10-5h-1,t0.9为7 165.76 h,活化能为92.46 k J/mol。多元线性模型取8个数据经1次拟合可得回归方程为lnt=1.016 1ln(lnc0-lnc)+11 026.550 1×1/T-25.866 3(r=0.994 2),t0.9为6 794.18 h,活化能为91.73 k J/mol。氯霉素亚砜涂剂降解符合一级动力学方程。用经典恒温法和多元线性模型预测氯霉素亚砜涂剂的有效期分别为9.8、9.3个月。结论:氯霉素亚砜涂剂的有效期约为9.5个月;采用多元线性模型法预测有效期更简便。     

法莫替丁缓释片的实验研究

用紫外分光光度法测定法莫替丁缓释片的体外释放。体外释放数据表明该缓释片在模拟人工胃液中缓慢释放药物,维持8小时以上。分别用单指数分布模型、威布尔分布模型和希古契方程进行拟合,得出t_0、t_(50)值及拟合方程的相关系数。结果表明3种模型都可以较好地反映该缓释片的释放过程,其中以单指数分布模型为最佳。     

Effect of particle size on the available surface area of nifedipine from nifedipine-polyethylene glycol 6000 solid dispersions

Solid dispersions containing 5%, 10%, 20%, 30% and 50% of nifedipine were prepared with polyethylene glycol (PEG) 6000 as carrier, respectively, by the fusion method. Drug release from four different size fractions of nifedipine-polyethylene glycol 6000 solid dispersions were examined. The probability parameters of Weibull distribution or log-normal distribution could be obtained from linear regression of the dissolution data. The effects of particle size on the dissolution rate of nifedipine were evaluated in terms of the time course of the available surface area (S(t)). The X-ray diffraction patterns showed that nifedipine was dispersed homogeneously in an amorphous state in the solid dispersions with nifedipine concentration up to 10%. The initial values and faster rate of decrease of S(t) during the dissolution process were markedly enhanced in the solid dispersions with lower contents of nifedipine (5% and 10%) due to the formation of high energy metastable (amorphous) states of the drug and differences in the particle sizes had little effect on the values of the available surface area and the dissolution of the drug. Values of available surface area were particle size dependent for the solid dispersions with higher contents of nifedipine (20%, 30% and 50%) and the rate of decrease of S(t) was enhanced as the particle size reduced.     

Pharmacokinetic stochastic model with Weibull-distributed residence times of drug molecules in the body

The use of a function to fit blood concentration-time data points is equivalent, under certain assumptions, to specifying a model of the distribution of residence times of the drug molecules in the body (stochastic pharmacokinetic model). An empirical density function of the Weibull type is offered to describe this distribution. The model gives the following disposition function describing the time course of the drug concentrations in blood after an intravenous bolus input: C delta (t) = D/CLs lambda ts-1exp(-lambda ts). It contains only three parameters: lambda is like an 'elimination rate constant' in the single-exponential model into which the Weibull function reduces when the shape parameters becomes equal to unity; CL is the conventional systemic drug clearance, and, D is the dose injected. The Weibull function gives an analytical solution of the convolution integral for zero-order input, thereby permitting use of the model for intravenous infusion data and for extravascular administration, when the absorption may be considered to be zero-order. Using examples from the literature it is shown that in some cases the Weibull function gives a better fit than may be obtained with two- and three-exponential or gamma functions.     

Haemoglobin A1c goal attainment in relation to dose in patients with diabetes mellitus taking metformin: a nested, case-control study

BACKGROUND AND OBJECTIVE: Conclusions from clinical trials suggest possible therapeutic advantages for once-daily agents over twice-daily agents in the treatment of type 2 diabetes mellitus. This study set out to investigate the relationship between metformin dosing frequency and glycosylated haemoglobin (HbA1c)-goal attainment in daily practice. METHODS: This was a nested case-control study. Data were obtained from the PHARMO Record Linkage System, which includes linked drug-dispensing and clinical-laboratory records for approximately three million individuals in defined areas of the Netherlands. The study cohort included new users of oral antihyperglycaemic drugs between 1999 and 2005 with a baseline HbA1c> or =7% and at least one further HbA1c measurement within 18 months after the index date. Cases attained HbA1c goal (<7%) within 18 months; controls did not attain this HbA1c goal. Compliant cases and controls taking metformin monotherapy were included in the analyses. Dosing frequency was dichotomized into once daily and twice daily or more frequently. In the multivariate analysis we considered oral antihyperglycaemic dose, baseline HbA1c, first prescriber and number of HbA1c measurements. RESULTS: The study cohort included 3107 new oral antihyperglycaemic drug users. The analyses included 753 cases and 477 controls taking metformin. Dosing twice daily or more was associated with a 71% higher probability of attaining goal (odds ratio 1.71 [95% CI 1.31, 2.24]) compared with once-daily dosing, after adjustment for baseline HbA1c, first prescriber, sex and age. We could not distinguish between the effect of dose and dosing frequency as these were closely related. Statistical testing in the analyses stratified by dose was prohibited by small numbers. CONCLUSION: About 40% of compliant metformin users did not achieve their HbA1c goal within 18 months because of dosing problems. However, the strong correlation between total daily dose and dosing frequency did not permit identification of which of these dosing issues was the most important contributor to not achieving HbA1c goal.     

三点法测定一室模型血管外给药的药动学参数

目的获得一室模型药物血管外给药的药动学参数;方法给予单次剂量X0,3个采样点时间为t、2t和3或4t,根据给定的药动学参数（ka、k和V/F）计算各取样点的理论血药浓度（c1、c2和c3）,推算ka、k和V/F值。结果参数推算值与给定值一致。结论三点法可以用于获取一室模型血管外给药的药动学参数。     

Effect of the spinal drug tramadol on the fatty acid compositions of rabbit spinal cord and brain

Tramadol is an important spinal drug which produces analgesia following intrathecal injection. It is well known that fatty acids (FAs) play an important role in membrane fluidity of the blood-brain barrier (BBB) tissue, which blocks and/or controls the transportation of toxic substances into the brain. The aim of this study was to investigate the effect of a spinal drug (tramadol) on the concentrations and compositions of fatty acid in BBB tissues of New Zealand male rabbits. The total cellular fatty acid profiles of the tissues in three spinal cord sections (cervical, thoracal and lumbar) and in the brain of rabbits with or without drug administration were determined by gas chromatography using Sherlock Microbial Identification System (MIS) software (Microbial ID, Newark, DE, U.S.A.) with a database of FAME profiles for eukary. The relative percentage of the fatty acid methyl ester (FAME), 24 : 1 omega9c nervonic and 17 : 1 omega8c, did not change with tramadol treatments. However, there was an increase in the concentration of the FA 16 : 0, 18 : 1 omega7c DMA, 18 : 1 omega9c, sum in future 4, sum in future 8, sum in future 9, 18 : 0, 20 : 4 omega6c, sum in future 14, 22 : 4 omega6c, in contrast to a decrease in the percentages of the following FAMEs; 20 : 0, 20 : 1 omega9c. In the brain, there was an increase in the concentration of the FA 18 : 1 omega9c, sum in future 8 and 18 : 0, in contrast to a decrease in the percentages of two FAMEs, 16 : 0, 20 : 4 omega6c and 22 : 6 omega3c. The number of fatty acids were 20 in the spinal cord sections and 8 in the brain tissues of control animals compared to 15-18 fatty acids in the spinal cord section and 7 in the brain tissues of drug administered animals. The overall changes in the concentrations and numbers of FAs suggest that the spinal drug tested in this study has a side effect of disrupting of membrane fluidity of the BBB, which may cause neurotoxicity.     

Synthesis and biological evaluation of orally active prodrugs of indomethacin

Synthesis and biological evaluation of orally active prodrugs (1a-d) of indomethacin are described. Prodrugs 1a-c showed a similar degree of anti-inflammatory activity, and prodrug 1d was found to be less potent than the parent drug indomethacin (1). Ulcer index (UI) data indicated that 1a (UI = 19), 1c (UI = 0), and 1d (UI = 0) were substantially less ulcerogenic and 1b (UI = 62) was more ulcerogenic than parent drug 1 (UI = 47). These prodrugs demonstrated good stability at acidic and basic pH and found to be more lipophilic than parent drug compound 1, indicated by partition coefficients measured in octanol-buffer system at pH 7.4 and 3.0. On the basis of in vivo studies, 1a and 1c compounds were selected for metabolic stability in rat liver microsome (RLM) and rat plasma (RP), and both were found to be enzymatically labile. Prodrugs 1a and 1c emerged as potent anti-inflammatory agents with a lesser potential for ulcer than the parent drug indomethacin.     

Typologies of drug dependence: comparative validity of a multivariate and four univariate models

Data from a longitudinal cohort study were used to directly compare the concurrent and predictive validity of four univariate typologic approaches with a multivariate approach in subtyping drug dependence. The four univariate typologies were based upon: (a) age-of-onset of drug abuse/dependence, (b) presence of drug abuse in first-degree relatives, (c) presence of antisocial personality disorder, and (d) sex. The multivariate typologic approach was based on indices of vulnerability, chronicity, consequences, and psychopathology, yielding the Type A/B dichotomy first demonstrated in alcohol dependence. Subtypes generated from the univariate typologies were then each compared with the multivariate typology on measures of concurrent and predictive validity, and the strength of association was compared statistically. There was evidence of significantly greater concurrent validity of the Type A/B typology compared with the univariate typologies across all the domains of validation (risk, substance use, psychopathology, personality, and overall functioning). The multivariate typology also fared better than the univariate ones in all three domains on which predictive validity was evaluated: substance use, psychopathology, and overall functioning, as well as the degree of change in several composite scores (drug, medical, legal, and psychiatric) and the global psychiatric symptom index. This direct method of comparison seemed to demonstrate the superior validity of the multivariate cluster-analytic approach over the univariate approaches to classifying subjects with drug dependence.