HPLC法测定双唑乳膏中克霉唑与硝酸益康唑的含量

目的：建立高效液相色谱法测定双唑乳膏中克霉唑与硝酸益康唑的含量.方法：采用高效液相色谱法,色谱柱为Alltech Alltima C18色谱柱（150 mm×4.6 mm,5 μm）,流动相为磷酸盐缓冲液（取磷酸二氢钾与磷酸氢二钾各2.5 g,加水溶解并稀释至1000 ml）-甲醇（25∶75）,流速为1.0 ml/min,柱温为35 ℃,检测波长为232 nm.结果：克霉唑与硝酸益康唑在0.25~100 μg/ml范围内,浓度与其峰面积呈良好线性关系（r=0.9999,n=9）,平均回收率分别为99.87%与101.11%,RSD%分别为1.4%与1.8%.结论：为双唑乳膏中克霉唑与硝酸益康唑联合用药的新剂型建立了简单、快速、专属性强、重现性好的含量测定方法,可用于双唑乳膏中克霉唑与硝酸益康唑的测定.     

硝酸益康唑纳米乳滴眼剂的制备及理化性质研究

目的:制备硝酸益康唑(ECZ)纳米乳并对其性质进行考察。方法:在制备三元相图的基础上,优选硝酸益康唑纳米乳的最佳处方及制备工艺,并通过形态观察、ξ电位的测定、稳定性的考察等研究了硝酸益康唑的性质。结果:硝酸益康唑纳米乳的最佳处方工艺组合为聚氧乙烯40氢化蓖麻油(PEG-40氢化蓖麻油)/辛酸/癸酸三甘酯(M-812)/水,ξ电位为1.968 mV,平均粒径为64.06 nm。稳定性考察表明纳米乳在强光及高温加速试验中均较稳定。结论:硝酸益康唑纳米乳增加了益康唑的溶解度,而且剂型稳定,HPLC法检测方便。     

硝酸益康栓制备工艺与质量控制

目的研制硝酸益康栓工艺,并制定合适的定量分析方法。方法以半合成脂肪酸甘油脂为基质制备硝酸益康唑栓,以HPLC法测定本品中硝酸益康唑的含量。结果硝酸益康唑的平均回收率为100.1%,RSD为1.13%。结论硝酸益康唑栓工艺可行,HPLC法测定本品中硝酸益康栓的含量可作为控制本品质量的指标。     

Effects of econazole nitrate on yeast cells and mitochondria

The inhibitory effect of econazole nitrate on the growth of yeast Saccharomyces cerevisiae is proportional to the concentration of the product. It depends on the phase of culture and on the number of cells present at the moment of econazole addition into the medium. The most important inhibition is obtained in the exponential phase of growth with a low concentration of cells. It is enhanced with cells which were previously in contact with the product. There is no adaptation of the yeast toward increased concentrations of econazole. The product penetrates the cells and attaches first to particular fractions, later to soluble fractions. The highest concentration of econazole nitrate in cells lies in the mitochondria. No product of econazole metabolism by S. cerevisiae was uncovered. Econazole nitrate does not slow down the in vivo activities of mitochondrial enzymes (cytochrome c oxidase, succinate dehydrogenase and phenylalanyl-tRNA synthetase), but inhibits the biosynthesis of mitochondrial membrane enzymes without affecting that of the synthetase, a matrix enzyme.     

硝酸益康唑克霉唑乳膏的制备及质量控制

目的 研制硝酸益康唑克霉唑乳膏,并对其进行质量控制.方法 以硝酸益康唑、克霉唑为主药制备乳膏,采用HPLC法进行含量测定.结果 所制制剂为白色均匀细腻乳膏.克霉唑的含量为标示量的90%~110%,硝酸益康唑的含量为标示量的90%~110%,平均回收率分别为99.87%、101.11%,RSD分别为1.4%、1.8%.结论 该乳膏制备工艺简单,性质稳定,质量可控.     

The disposition of cytosine arabinoside and its metabolite after single doses to rabbits

Cytosine arabinoside (ara-C) is rapidly deaminated in vivo to ara-U by cytidine-deoxycytidine deaminase. The purpose of this study was to determine the contribution of the deamination pathway to the overall clearance of ara-C after a single dose to rabbits, as well as to determine the pharmacokinetics of ara-U itself. Male rabbits were cannulated in the marginal ear vein and received a single IV bolus dose (50 mg kg-1) of either ara-C (n = 10) or ara-U (n = 10). Blood samples were collected for up to 24 h. One week later, the rabbits received the opposite treatment. Plasma samples were analyzed by reversed-phase HPLC. The plasma clearance of ara-C (8.16 +/- 2.43 ml min-1 kg-1) was significantly higher than the clearance of ara-U (5.66 +/- 2.59 ml min-1 kg-1). The volume of distribution of ara-C was 0.64 +/- 0.16 l kg-1 (mean +/- SD) and was significantly smaller (p less than 0.05) than that of ara-U (1.22 +/- 0.70 l kg-1). As a result, the elimination rate constant of ara-C was significantly larger than that of ara-U (0.602 +/- 0.097 h-1 vs 0.258 +/- 0.05 l h-1). In the rabbits that received both treatments (n = 7), the fraction of the ara-C dose metabolized to ara-U (fm) was 0.53 +/- 0.20. Qualitatively, the pharmacokinetics of ara-C and ara-U resemble those in humans. This study provides the basis for further work into the modulation of ara-C disposition either by ara-U or other agents.     

Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate

Objectives The aims of this study were to evaluate the suitability of the spray congealing technique to produce solid lipid microparticles (SLMs) for topical administration and to study the skin permeation of a drug from SLMs compared with solid lipid nanoparticles (SLNs). Methods Econazole nitrate was used as model drug and Precirol ATO 5 as the lipidic carrier. SLMs and SLNs were both prepared at 5: 1, 10: 1 and 12.5: 1 lipid: drug weight ratios and characterised in terms of particle size, morphology, encapsulation efficiency and chemical analysis of the particle surface. SLMs and SLNs were also incorporated into HPMC K 100M hydrogels for ex‐vivo drug permeation tests using porcine epidermis. Key findings SLMs had particle sizes of 18–45 μm, while SLNs showed a mean diameter of 130–270 nm. The encapsulation efficiency was 80–100%. Permeation profiles of econazole nitrate were influenced by both particle size (significant difference until 9 h) and the amount of lipid. Conclusions The results confirm the usefulness of SLNs as carriers for topical administration and suggest the potential of SLMs for the delivery of drugs to the skin.     

正交设计法优化硝酸益康唑的合成工艺

目的:优化抗真菌药物硝酸益康唑的合成工艺。方法:采用正交设计法,重点考察反应温度、催化剂、反应时间及溶剂四个因素对收率的影响。结果:溶剂对反应收率的影响最为显著,其次是反应时间和催化剂。结论:新工艺原料价廉易得,反应条件温和,后处理简便,收率高。     

硝酸益康唑脂质体凝胶的释放和经皮渗透性研究

目的：比较自制硝酸益康唑脂质体凝胶与市售硝酸益康唑霜剂的离体皮肤渗透性,探讨脂质体作为硝酸益康唑的载体对皮肤的渗透机制。方法：测定硝酸益康唑脂质体的体外释放百分率,采用双室渗透池作为离体皮肤的渗透试验装置,测定硝酸益康唑在接受液内的累计渗透百分数和在皮肤内的滞留百分数。结果：硝酸益康唑脂质体的体外释放速度较慢,其凝胶和霜剂透过皮肤进入接受液中的药物量都很少,累计渗透百分数均小于硝酸益康唑给药量的5%;其凝胶制剂的皮肤层内的滞留百分数（26%）高于其霜剂在皮肤层内的滞留百分数（11%）,2种不同制剂的经皮渗透性均符合Higuchi方程。结论：脂质体有促进药物进入皮肤的能力,而药物进入血循环的量并不增加。     

硝酸益康唑温度敏感型凝胶的制备及体外评价

目的:制备含硝酸益康唑-HP-β-CD的温度敏感型凝胶,评价其体外制剂学特征.方法:冷冻干燥法制备硝酸益康唑的HP-β-CD包合物并进行表征制备温度敏感型凝胶,考察处方因素泊洛沙姆407、泊洛沙姆188、HP-β-CD、HPMC和PEG400对凝胶胶凝温度和相变时间的影响.制备含硝酸益康唑或其HP-β-CD包合物的温度敏感性凝胶并进行体外释放特性评价.结果:红外光谱和X-射线粉末衍射结果表明硝酸益康唑与HP-β-CD形成了包合物,蒸馏水中溶解度增加38倍,相溶解度实验结果显示硝酸益康唑和HP-β-CD是按1:n(n＞1)形成包合物,提高温度有利于包合物形成.处方中泊洛沙姆407和泊洛沙姆188用量增加,凝胶的相转变温度降低,且相变时间缩短;HP-β-CD使凝胶的LCST升高.含硝酸益康唑或硝酸益康唑包合物凝胶的体外释放速度缓慢,凝胶中加入HPMC可使药物释放速度进一步延迟.结论:初步制备同时具有溶解度改善和缓释作用特征的硝酸益康唑温度敏感性凝胶.     

Stereoselectivity in the disposition of chloroquine and desethylchloroquine in rabbits.

Stereoselective pharmacokinetic properties of chloroquine (CAS 54-05-7) and desethylchloroquine were investigated in rabbits by administration of the separate enantiomers according to a cross-over design. The terminal half-life was longer for (R)-chloroquine than for (S)-chloroquine. A striking difference was revealed in the concentrations of metabolites. The levels of (R)-desethylchloroquine were higher than those of (S)-desethylchloroquine, resulting in a statistically significant higher AUC for the (R)-metabolite than for the (S)-metabolite.     

Absorption and disposition of aluminum in the rat

The kinetics of aluminum were determined in the rat. Intravenous bolus and oral doses of 8.1-mg/kg of aluminum as the chloride salt were administered to six rats. Serial blood samples and total urine and feces were collected and assayed for aluminum by atomic absorption spectrophotometry. The fraction absorbed orally (mean +/- SEM) was 0.27 +/- 0.03; the half-life was 5.29 +/- 0.47 h; the steady-state volume of distribution was 38.4 +/- 6.4 mL/kg, and the clearance was 8.87 +/- 1.76 mL X h-1 X kg-1. It was found that aluminum did not significantly penetrate the cellular components of blood. Plasma protein binding was determined to be approximately 98%. Sixty percent of the intravenous dose was excreted in the urine and the remaining 40% was excreted in the feces.     

Absorption and disposition of ampicillin in the elderly

Summary Ampicillin (500 mg) was administered intravenously (i. v.) and orally to a small panel of young and elderly subjects in a cross-over fashion. Plasma concentrations of ampicillin were measured by a fluorimetric technique for 8 h following dosage. A two compartment-open model was used to characterise the plasma concentration-time data for the intravenous study, and a one compartment-open model incorporating an absorption lag time and a first-order absorption rate constant for the oral data. Plasma clearance after i. v. ampicillin was found to be significantly decreased in the elderly (P<0.05, 0.08 1 h^–1kg^–1 versus 0.18 1 h^–1kg^–1), and half life and area under the plasma level-time curve were significantly increased (P<0.05, 6.70 h versus 1.68 h, t_1/2; p<0.01, 176.51 µg·h ml^–1 versus 37.88 µg·h ml^–1, AUC _o ) as compared to the young. No sigificant differences were observed between the age groups for the volume of distribution terms and the changes in drug handling noted in the elderly were attributed to a decrease in the renal elimination of ampicillin. Following oral administration a significant increase in t_1/2, AUC _o and the maximum plasma concentration (C_pmax P<0.01, 6.59 µg ml^–1 versus 3.42 µg ml^–1) of ampicillin was found in the elderly subjects. These findings were similarly attributed to a decrease in drug elimination in the aged, since no apparent age differences were noted in the pharmacokinetic parameters governing both rate and extent of ampicillin absorption.     

Stability indicating HPLC-method for the determination of econazole nitrate in cream and lotion formulations

A simple, fast HPLC-method for the determination of econazole nitrate in cream (Pevaryl, Pevisone) and lotion formulations (based on polyethylenic oleic glycerides and mono/di-stearic esters of ethylene- and polyethylene glycol) is described. The method is stability indicating as well as linear (range 5-15 mg econazole nitrate/g) and shows a good recovery (98.7-100.2%) and a good reproducibility (cv less than 1%, n = 10). The chromatographic separation is achieved on a RP-18 column using methanol/aqueous ammoniumcarbonate solution/tetrahydrofurane as the mobile phase. Quantification of the chromatograms is done by internal standard method using peak areas.     

HPLC法测定派瑞松乳膏中曲安奈德和硝酸益康唑的含量

目的 HPLC法测定派瑞松乳膏中曲安奈德和硝酸益康唑的含量。方法色谱柱为Dionex C18(200 mm×4.6 mm,5μm);流动相为质量分数为0.5%的三乙铵溶液(乙酸调节pH为3.0)(A)-乙腈(B),线性梯度洗脱;流速为1.0 mL·min-1;柱温为30℃;检测波长为235 nm。结果曲安奈德和硝酸益康唑在13.57⁴2.28 mg·L-1和131.342.28 mg·L-1和131.3⁴25.4 mg·L-1内,两者峰面积线性良好,R分别为0.999 8和0.999 0。平均回收率分别为99.8%和100.4%,RSD分别为0.99%和0.86%(n=9)。结论 HPLC法可用于派瑞松乳膏中曲安奈德和硝酸益康唑的含量测定。     

曲安奈德益康唑乳膏含量和有关物质检测方法的建立

目的：建立反相高效液相色谱法测定曲安奈德益康唑乳膏的有关物质和含量。 方法：采用Agilent Infinity C18柱（4.6 mm×150 mm,4 μm）;以乙酸盐缓冲液（取0.585 g乙酸铵,加500 mL水溶解,再加入1%乙酸溶液9 mL,加水至1 000 mL）-乙腈（95:5）为流动相A,以异丙醇为流动相B,以乙腈为流动相C,梯度洗脱;流速为0.42mL·min-1;柱温为35 ℃;检测波长为225 nm（硝酸益康唑）和240 nm（曲安奈德）,进样量：10 μL。 结果：有关物质曲安奈德的检测限为0.12 μg·mL-1,硝酸益康唑的检测限为0.40 μg·mL-1;含量测定线性范围曲安奈德为4.78～95.6μg·mL-1,r=1.000 0硝酸益康唑为51.8～1 036 μg·mL-1,r=0.999 5;精密度、稳定性、重复性试验的RSD≤0. 8%;曲安奈德的平均回收率为101.5%, RSD为1.3% （n=9）,硝酸益康唑的平均回收率为99.6%,,RSD为1.4% （n=9）。 曲安奈德含量分布于90.8%~109.6%之间,不呈正态分布（P＜0.05）,硝酸益康唑含量分布于95.0%~107.2%之间,呈正态分布（P＞0.05）。 结论：本法更加简便、准确,专属性好,可用于测定曲安奈德益康唑乳膏的含量和有关物质。     

Absorption of bendazac lysine after topical application to the rabbit eye

A water solution of 0.5% 14C-3-bendazac lysine was administered to the rabbit eye. Following single application to the cornea, the drug was found in different ocular compartments including the lens. Although in the lens the concentrations are lower as compared to the iris, retina ciliary bodies and aqueous humor, they last longer.     

In-situ gel formulations of econazole nitrate: preparation and in-vitro and in-vivo evaluation

Objectives This study describes the in‐situ gelling of econazole nitrate containing thermosensitive polymers composed of poloxamer 407 and 188 as a novel treatment platform for vaginal candidiasis. Methods Aqueous thermosensitive formulations containing 1% of econazole nitrate and poloxamer 407 and/or 188 were prepared and their rheological, mechanical and drug‐release properties determined at 20 ± 0.1°C and/or 37 ± 0.1°C. Based on their biologically suitable thermorheological properties, formulations containing the mixtures of poloxamer 407 and 188 in ratios of 15:15 (F1), 15:20 (F2) and 20:10 (F3) were chosen for comprehensive analysis. Key findings Formulations based on F3 exhibited typical gel‐type mechanical spectra (G′ > G″) at 37°C whereas formulations based on F1 and F2 exhibited properties akin to weakly cross‐linked gels. Texture profile analysis demonstrated that F3 showed the highest cohesiveness, adhesiveness, hardness and compressibility. No statistically significant differences (P > 0.5) were observed in the release of econazole nitrate from the formulations at pH 4.5, which in all cases followed anomalous diffusion kinetics. Formulations based on 20% poloxamer 407:10% poloxamer 188 were chosen for in‐vivo studies and were shown to be effective for the treatment of the vaginal candidiasis. Histopathologic evaluation also supported the effectiveness of the thermosensitive formulation administered intravaginally. Conclusion By careful engineering of the rheological properties, in‐situ thermosensitive gel formulations of econazole nitrate were prepared and were shown to be efficacious in the treatment of vaginal candidiasis.     

曲安奈德益康唑乳膏处方及微观结构特性评价的比较研究

摘要：目的 为曲安奈德益康唑乳膏一致性评价参比制剂(reference listed drug, RLD)的选择及质量等同性评价提供依据。方法 采用逆向工程解析不同产地上市的原研产品、地产化产品派瑞松®和国产仿制药产品邦力®处方,比较处方(Q1)和关键功能性辅料的处方用量(Q2)的差异;并采用光学显微镜和冷镜露点法考察微观结构特性(Q3)差异。结果 地产化产品派瑞松®与法国上市产品Pevisone®Q1相同但Q2不同;国产仿制药产品邦力®与地产化产品派瑞松® Q1、Q2及Q3均不一致,两者产品Q3的差异可能是由于Q1和Q2不同引起的。结论 地产化产品派瑞松®不适宜作为本品一致性评价的RLD,建议国内生产企业选择Pevisone®为RLD,实现与参比制剂的Q1、Q2及Q3一致,从而豁免生物等效性研究。