硝苯地平不同粒度对其缓释片剂质量的影响

摘 要 目的：建立硝苯地平原料药粒径测定方法,研究不同粒径硝苯地平原料药对其缓释片（I）体外溶出行为的影响。方法: 采用光散射法对硝苯地平原料药粒径测定进行方法学考察;采用高速万能粉碎机制备不同粒径的硝苯地平原料药样品,用高效液相色谱法测定硝苯地平缓释片（I）的体外溶出曲线,并以国外原研制剂硝苯地平缓释片（商品名：Adalat L,规格：10 mg）为参比制剂,用相似因子f2法进行溶出曲线的相似性比较。结果:粒度测定条件为：粒度分析仪的泵速为1 800 r·min^-1,遮光比为8%～20%,背景与样品的扫描时间为0 s,介质溶液为0.3%吐温80,样品超声时间为1 min。溶出曲线结果表明,硝苯地平原料药粒径越小,溶出越好。Dv90（占总粒子量90%的粒子对应的粒径）从118.781 μm减小至3.471 μm时,自制硝苯地平缓释片在0.25 h时的累积溶出度从11.2%增加至44.0%,溶出曲线与原研制剂溶出曲线相似因子f2先增大后降低,Dv90为29.823 μm时,f2值为77,表明自制片与原研片溶出曲线具有较高的相似度。结论:原料药微粉化技术可显著提高硝苯地平缓释片的体外溶出度,但粒度过细会影响硝苯地平缓释片的缓释效果。为获得与原研品生物等效的制剂,硝苯地平原料药应控制15 μm≤Dv90≤45 μm。     

中心复合设计-效应面法优化盐酸米诺环素缓释片处方

摘 要 目的：制备盐酸米诺环素缓释片并优化处方。方法: 采用干法制粒压片工艺制备盐酸米诺环素缓释片,以羟丙甲纤维素E50（HPMC E50）和羟丙甲纤维素K100LV（HPMC K100LV）的用量为考察因素,1,2,4,8 h的累积释放度为评价指标,采用中心复合设计 效应面法优化盐酸米诺环素缓释片的处方,并通过体外释放度比较自研片剂和原研片剂在4种释放介质中的溶出相似性。结果: 盐酸米诺环素缓释片处方中HPMC E50和HPMC K100LV的用量分别为35 mg和70 mg,制得的缓释片在各时间点的释放度与原研片剂相似,4种释放介质中自研片剂和原研片剂的溶出相似因子f₂分别为79.06、84.62、75.46和72.95。结论:采用中心复合设计 效应面法优化的盐酸米诺环素缓释片处方制得的片剂体外释放度符合要求,为下一步的工业化生产提供依据。     

光纤法考察呋塞米片仿制药与原研药的体外溶出一致性

摘 要 目的： 建立实时监测呋塞米片溶出过程的方法,比较11个不同仿制药厂家与原研药厂家生产的呋塞米片在4种溶出介质中溶出曲线的相似性,评价我国呋塞米片的体外溶出过程。方法: 采用光纤药物溶出度实时测定仪监测11个厂家的仿制药与原研药的溶出过程;采用桨法,转速50 r·min^-1,分别以900 ml pH 1.2盐酸溶液、pH 4.0醋酸盐缓冲液、pH 6.8磷酸盐缓冲液和水为溶出介质,在277 nm波长处测定吸光度,绘制溶出曲线,并采用溶出曲线f 2相似因子法考察其相似性。结果: 光纤溶出度法的辅料和溶出介质不干扰测定。呋塞米在4.44～26.66 μg·mL^-1浓度范围内线性关系良好（r=0.999 7）。呋塞米的平均回收率为101.26%,RSD%为1.84%（n=9）。11个厂家中只有1个厂家仿制药与原研药的相似度均能达到要求。结论:建立了一个简便、快捷、准确的光纤溶出度实时测定方法,该方法能够有效监测药物的体外溶出过程,为改进药物制剂工艺、监控工艺稳定性、提高药品分析能力提供参考。     

国产硝苯地平缓释片的体外溶出度和虚拟生物等效性研究

摘 要 目的：通过体外溶出试验考察4种国产硝苯地平缓释片的质量一致性,并利用GastroPlus软件进行虚拟生物等效性研究。方法: 采用日本橙皮书和中国药典的溶出方法,测定不同厂家硝苯地平缓释片的溶出曲线,利用溶出曲线相似性f2因子法比较溶出曲线相似性。将原研制剂的体外溶出度数据与GastroPlus软件结合计算得到模拟的药物体内吸收曲线,通过与文献实测值比较,选择体内外相关性良好的溶出介质;采用选定的溶出介质进行国产硝苯地平缓释片的溶出试验,得到模拟的体内吸收参数,与原研制剂比较,进行虚拟生物等效性评价。结果: 两种溶出方法的考察结果显示,4种国产制剂与原研制剂的f2因子均小于50;与日本橙皮书方法相比,采用中国药典方法得到的原研制剂溶出曲线的体内外相关性更好。4种国产硝苯地平缓释片的药动学参数Cmax及AUC0~∞模拟值与原研药的实测值相差在±20%以内。结论:4种国产硝苯地平缓释片与原研制剂相比,体外溶出曲线不相似,但体内模拟生物等效。     

草乌甲素胶丸的体外溶出度考察

摘 要 目的： 建立草乌甲素胶丸的溶出度测定方法。方法: 采用小杯法,以pH1.2的人工胃液（含0.25%十二烷基硫酸钠溶液）、pH4.0醋酸盐缓冲液（含0.5%十二烷基硫酸钠溶液）、pH6.8磷酸盐缓冲液（含0.5%十二烷基硫酸钠溶液）及水（含0.25%十二烷基硫酸钠溶液）为溶出介质,转速50 r·min^-1,取样时间30 min测定溶出度,采用高效液相色谱法测定草乌甲素的溶出量,绘制溶出曲线。结果: 草乌甲素胶丸批内批间的溶出度结果差异较小,15 min 后样品的释放百分率趋于平稳。草乌甲素的检测浓度在2~20μg·ml^-1(r=0.999 2)范围内呈良好的线性关系,在4不同溶出介质中的回收率均在99%以上。结论: 该方法简便、准确, 重复性好, 可用于该胶丸的溶出度测定。     

自制与原研托拉塞米缓释片体外释放行为的一致性评价

目的 建立托拉塞米缓释片的体外释放度检测方法并进行方法学研究,以所建立方法对自制与原研托拉塞米缓释片体外释放行为的一致性进行评价。方法 采用HPLC法分别测定托拉塞米自制片与原研制剂在水、0.1 mol/L盐酸溶液、pH4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液以及0.1 mol/L盐酸溶液转pH6.8磷酸盐缓冲液中的累积释放度,并用相似因子（f₂）法对释放曲线的相似性进行评价。结果 当托拉塞米质量浓度在1.0~12.0 μg/mL时,其质量浓度与峰面积呈现良好的线性关系（r=0.999 5）;精密度试验、溶液稳定性试验良好,供试液色谱峰峰面积的相对标准偏差均小于2.0%;准确度试验平均回收率为100.04%,相对标准偏差为0.54%（n=12）;自制片的批内均一性符合技术要求,6个溶出杯内各取样点的相对标准偏差均<10%;托拉塞米缓释自制片与原研制剂在5种不同的释放介质中f₂因子分别为72、60、77、66、60。结论 本文所建立方法可用于托拉塞米缓释片释放度的检测,托拉塞米缓释片自制产品与原研产品体外释放行为一致。     

丙泊酚乳状注射液体外释放一致性评价

摘 要 目的：建立丙泊酚乳状注射液体外释放度的测定方法,并比较与丙泊酚乳状注射液参比制剂在释放介质中的体外释放行为。 方法: 采用反向透析技术,释放介质为pH 7.4并含30%无水乙醇的磷酸盐缓冲液,转速为100 r·min-1,温度为37℃,以HPLC法测定丙泊酚的浓度,计算累积释放度,绘制释放曲线,以丙泊酚乳状注射液为受试制剂,以原研制剂（得普利麻）为参比制剂,采用差异因子（f1）和相似因子（f2）法评价释放曲线的相似度。 结果: 丙泊酚乳状注射液与原研制剂在pH 7.4并含30%无水乙醇的磷酸盐缓冲液中释放曲线的f1＜5,f2＞80,两种制剂体外释放行为相似。     

盐酸哌甲酯双相控释渗透泵片释放度测定方法的建立

摘 要 目的： 建立盐酸哌甲酯双相控释渗透泵片释放度的测定条件和释放度的测定方法。方法: 采用HPLC法测定盐酸哌甲酯双相控释渗透泵片的释放度,色谱条件：Diamonsil C18(250 mm×4.6 mm,5 μm)为色谱柱,流动相为0.02 mol·L^-1磷酸二氢钾溶液（用1%磷酸溶液调节pH为3.0）∶乙腈=70∶30,检测波长为220 nm,流速为1.0 ml·min^-1,柱温为35℃,进样量为20 μl;考察释放介质、不同释放装置和转速对盐酸哌甲酯双相控释渗透泵片释放度的影响。结果: 建立的释放量测定方法在1.0～24.0μg·ml^-1线性关系良好,r=0.999 5,平均回收率为100.5%,RSD为1.58%(n=6);以900 ml pH3.0磷酸盐缓冲溶液作为释放介质,转速为50 r·min^-1,加沉降篮的释放条件下,本品在0~2 h内快速释放,2~10 h符合零级释放,释药方程为Q=5.505t＋44.221（r=0.994 5）。结论:本方法简便、准确、可靠,可用于盐酸哌甲酯双相控释渗透泵片释放度的质量控制。     

不同厂家复方银翘氨敏胶囊溶出度比较

摘 要 目的：比较7个厂家复方银翘氨敏胶囊在4种溶出介质中的溶出曲线,以评价其质量。方法: 采用篮法、转速100 r·min-1、溶出介质900 ml进行体外溶出试验,分别考察不同厂家复方银翘氨敏胶囊在盐酸溶液、pH 4.5醋酸盐缓冲液、水和pH 6.8磷酸盐缓冲液4种溶出介质中的体外溶出行为,测定溶出曲线并采用相似因子法进行比较分析。结果: 7个厂家复方银翘氨敏胶囊在盐酸溶液中30min时累积溶出度均大于70%,在pH 4.5醋酸盐缓冲液、水和pH 6.8磷酸盐缓冲液中溶出结果差;4种溶出介质中的溶出曲线均存在不同程度的批间差异。结论: 各厂家复方银翘氨敏胶囊的质量存在差异,在确保产品具有良好溶出的同时应着力提高制剂的稳定性。     

光纤法与进口药品注册标准法测定甲磺酸多沙唑嗪缓释片释放度的比较

摘 要 目的： 比较光纤法与进口药品注册标准法对甲磺酸多沙唑嗪缓释片的释放度测定结果。方法: 采用 FODT-601型光纤药物溶出度实时测定仪,以氯化钠的盐酸水溶液为溶出介质,桨法,转速75 r·min^-1,246 nm作为测定波长,550 nm作为参比波长,测定光程为5.0 mm。比较光纤法与进口药品注册标准法的释放度。结果: 甲磺酸多沙唑嗪在0.468 1～11.700 0 μg·mL^-1浓度范围内线性关系良好,r均大于0.999 5,日内、日间精密度RSD(n=6)分别为1.6%和2.0%,平均加样回收率为99.0%,RSD为1.4%(n=9);比较光纤法与进口药品注册标准法,两者的释放度测定结果有一定差异。结论:光纤法获得的数据信息完整,实时反映,药物的体外溶出过程,在速释和缓、控释制剂的释放度测定中优势尤为突出,但该方法尚不能替代进口药品注册标准法。     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.