星点设计-效应面法优化盐酸溴己新吸入粉雾剂的处方

摘 要 目的：优化盐酸溴己新吸入粉雾剂的处方。方法: 采用冷冻干燥 气流粉碎法制备盐酸溴己新吸入粉雾剂,通过星点设计考察甘露醇（X1）,亮氨酸（X2）和泊洛沙姆188（X3）在辅料中的用量对盐酸溴己新吸入粉雾剂的休止角（Y1）、细微粒子剂量（Y2）和空气动力学粒径（Y3）的影响。根据最佳数学模型绘制效应面,通过重叠等高线图确定最优处方。结果:影响因素和考察指标之间存在定量关系,优化处方为甘露醇：亮氨酸：泊洛沙姆188在处方中的比例为2.4∶〖KG-*2〗2.22∶〖KG-*2〗0.05。较优处方的各指标实测值与预测值较接近。结论:采用星点设计 效应面法完成了盐酸溴己新吸入粉雾剂的多目标同步优化。     

格隆溴铵吸入喷雾剂的雾化特性研究

目的 考察格隆溴铵吸入喷雾剂的雾化特性。方法 采用激光成像系统和新一代撞击器等测定格隆溴铵吸入喷雾剂的喷雾模式、喷雾形态、递送剂量均一性和空气动力学粒径分布。结果 样品的椭圆度均符合美国食品药品管理局指导原则建议，不同样品喷雾模式和喷雾形态同一参数之间RSD值均小于7%，样品的罐间和罐内递送剂量均一性良好。格隆溴铵吸入喷雾剂与雾化吸入溶液的质量中值、几何标准偏差值基本一致，在肺内沉积方面上高于雾化吸入溶液。结论 格隆溴铵吸入喷雾剂具备良好的雾化特性。     

利巴韦林脂质体吸入粉雾剂的研制与初步评价

目的 为解决利巴韦林存在的明显不良反应问题,研制利巴韦林脂质体吸入粉雾剂,并初步评价其质量特性。方法 采用薄膜分散法制备利巴韦林脂质体,再冻干制备成利巴韦林脂质体粉雾剂,并考察制剂的外观形态、流动性、松密度、包封率、复溶液粒径、聚合物分散指数、电位及亲水性。结果 利巴韦林脂质体粉雾剂形态、粒径、电位、流动性与亲水性均较好,能满足粉雾剂給药的基本要求。结论 应用该方法制备利巴韦林脂质体粉雾剂的制剂技术是可行的,为后续体内外研究提供制剂学技术依据。     

扎那米韦鼻用粉雾剂粉体性质研究

目的 考察3种方法制备扎那米韦鼻用粉雾剂粉体的性质。方法 分别采用研磨法、气流粉碎法和喷雾干燥法制备不同粒径扎那米韦的粉体,并与吸入乳糖混合,对混合粉体的粒径、微观形态、流动性、堆密度和吸湿性进行考察。结果 研磨法、喷雾干燥法和气流粉碎法得到的扎那米韦原料粉末粒径依次减小;与乳糖相比,3种混合粉体松密度逐渐减小,振实密度依次增加,流动性仅喷雾干燥略增加,研磨法和气流粉碎法无影响; 3种方式得到的混合粉末均没有明显的吸湿性。结论 研磨筛分法比较适合扎那米韦鼻用粉雾剂的进一步开发。     

鲑降钙素吸入粉雾剂的制备及其药剂学性质研究鲑降钙素吸入粉雾剂的制备及其药剂学性质研究

目的喷雾干燥法制备鲑降钙素吸入粉雾剂,考察其主要药剂学特性。方法按中国药典2000年版方法测定鲑降钙素吸入粉雾剂排空率及有效部位沉积量,扫描电镜观察粉粒的形态,激光粒度测定仪测定粉粒的粒径大小及分布,差热分析及X射线粉末衍射考察吸入粉雾剂载体的晶型。结果有效部位鲑降钙素沉积量均在10%以上,排空率均在90%以上;相对湿度在52%以下,粉粒呈圆整的分散状态;当RH=75%时粉粒发生较多的粘连和聚集;粉体平均粒径为1.67 μm;差热分析结果显示:吸入粉雾剂中L-亮氨酸的熔融热较单一组分在喷雾干燥后显著下降;X射线粉末衍射图谱中,吸入粉雾剂载体的衍射峰强度较喷雾干燥前显著下降。结论在鲑降钙素吸入粉雾剂载体系统中加入甘露醇,粉粒圆整,加入L-亮氨酸可形成超低密度载体;扫描电镜的结果提示,应严格控制吸入粉雾剂贮存时环境的湿度;喷雾干燥复合载体更有助于无定形的形成。     

盐酸溴己新滴鼻剂的研制及含量测定与透皮性能评价

目的 研究盐酸溴己新滴鼻剂的制备工艺,采用HPLC法测定主药盐酸溴己新的含量并考察其体外透皮效果。方法 采用分散法制备盐酸溴己新滴鼻剂;流动相为甲醇-醋酸溶液（55：45）,流速1.0 ml/min,检测波长为247 nm,柱温30℃;以KM小鼠为模型进行体外透皮试验。结果 盐酸溴己新滴鼻剂为混悬型液体制剂,在37.44~187.2 μg/ml范围内,盐酸溴己新线性关系良好,回归方程为Y=11.996X+124.6（r=0.999 9）,低、中、高三种浓度的平均回收率分别为104.00%、101.59%、98.51%,RSD为0.89%、1.35%、0.35%（n=9）;24 h体外透皮试验累积透过率为60.29%。结论 该制剂处方合理,工艺可行,含量测定方法准确可靠。     

沙美特罗替卡松吸入粉雾剂递送剂量均一性的测定

目的：使用递送剂量均一性测定装置(DUSA管)方法对沙美特罗替卡松吸入粉雾剂的递送剂量均一性进行研究。分析和比较递送剂量均一性与排空率和含量均匀度数据的区别与关系。方法: 沙美特罗替卡松吸入粉雾剂连接DUSA管,调节真空泵控制空气流速为90L/min,采用高效液相色谱法测定9批样品的递送剂量均一性。结果:采用DUSA管方法测定了沙美特罗替卡松吸入粉雾剂中沙美特罗及氟替卡松的递送剂量均一性,并与排空率及含量均匀度测定结果比较。结论:与排空率及含量均匀度相比,DUSA管法测定递送剂量均一性,更符合患者用药的实际剂量。     

盐酸氨溴索干粉吸入剂理化性质及其初步稳定性考察

目的:研究盐酸氨溴索干粉吸入剂的理化性质并考察其稳定性。方法:采用喷雾干燥法制备盐酸氨溴索干粉吸入剂;考察其吸湿性及临界相对湿度;观察其粒径分布、粉末形态;差示扫描量热(DSC)法分析吸入剂及其原料药和各辅料的特征峰;检测其排空率和沉积率;对制剂进行加速试验和长期试验以考察其稳定性。结果:所得干粉吸入剂的临界相对湿度约为64%,平均空气动力学径小于5μm,形态为粒径均匀的球形;DSC提示各样品特征峰未发生明显变化,即在喷雾干燥过程主药与辅料之间未发生相互作用;3批干粉吸入剂排空率均>90%,沉积率均>30%;稳定性试验中各指标在观察期内无明显变化。结论:所制盐酸氨溴索干粉吸入剂适合肺部吸入给药,且具有较好的稳定性。     

4-邻甲苯磺酰氧基苯并噁唑酮脂质体的制备及其质量评价研究

目的 制备新型抗炎镇痛化合物4-邻甲苯磺酰氧基苯并噁唑酮（MBB）脂质体并对其进行质量控制方法研究。方法 采用薄膜分散法制备MBB脂质体,观察脂质体的形态,测定其粒径与电位,采用HPLC法测定其含量,并考察其包封率、渗漏率、稳定性等。结果 制备的MBB脂质体平均粒径为46.3 nm,电位为-60.25 mV,包封率为94%,且于4 ℃下储存较稳定。结论 所制备的脂质体粒径均一,包封率高,稳定性好,所建立的HPLC分析方法准确可靠、重复性好、操作简便、专属性强,符合质量测定要求。     

粉末直接压片法制备盐酸丙哌维林片及其稳定性考察

摘 要 目的:优选盐酸丙哌维林片粉末直接压片法最佳制备工艺,并考察其稳定性。方法: 采用粉末直接压片法,以粉末休止角、片剂脆碎度及溶出度为评价指标,制备样品并进行质量考察。结果:所选处方粉末流动性良好,有效成分溶出速率高,各项指标均符合规定。经6个月加速及室温留样考察,样品的外观、含量、有关物质及溶出度均未发生明显变化。结论:优选的处方工艺操作简便、经济、生产周期短,制备的产品质量稳定     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.