伊维菌素长效透皮剂和普通注射剂在家兔体内的药代动力学比较研究

为比较研究制备的伊维菌素长效透皮制剂与普通伊维菌素注射剂药物代谢及药效时间,本研究制备伊维菌素含量分别为0.5%、1.0%和1.5%的长效透皮制剂,采用高效液相色谱法检测不同药量相同体积伊维菌素长效透皮制剂和普通伊维菌素注射剂（1.0%）在家兔体内的药代动力学,并通过PKSolver药代动力学处理软件对数据进行分析。结果显示,0.5%、1.0%、1.5%伊维菌素长效透皮剂和1.0%普通注射剂吸收半衰期分别为0.81、0.52、1.02和0.12 d;达峰时间为1.55、0.97、1.62和0.42 d;峰浓度为47.36、72.02、115.30和99.53 ng/mL;消除半衰期为3.61、5.92、5.59和1.79 d;平均滞留时间为5.27、7.37、5.13和2.16 d;药时曲线面积为1 488.70、3 081.98、3 161.20和480.00 ng·d/mL,伊维菌素长效透皮剂体内维持有效药物浓度的时间长达35 d,普通注射剂仅为9 d。结果表明,伊维菌素长效透皮剂效果稳定,可进行更深入的研究。     

伊维菌素长效透皮剂和普通注射剂在家兔体内的药代动力学比较研究

为比较研究制备的伊维菌素长效透皮制剂与普通伊维菌素注射剂药物代谢及药效时间,本研究制备伊维菌素含量分别为0.5%、1.0%和1.5%的长效透皮制剂,采用高效液相色谱法检测不同药量相同体积伊维菌素长效透皮制剂和普通伊维菌素注射剂(1.0%)在家兔体内的药代动力学,并通过PKSolver药代动力学处理软件对数据进行分析。结果显示,0.5%、1.0%、1.5%伊维菌素长效透皮剂和1.0%普通注射剂吸收半衰期分别为0.81、0.52、1.02和0.12 d;达峰时间为1.55、0.97、1.62和0.42 d;峰浓度为47.36、72.02、115.30和99.53 ng/mL;消除半衰期为3.61、5.92、5.59和1.79 d;平均滞留时间为5.27、7.37、5.13和2.16 d;药时曲线面积为1 488.70、3 081.98、3 161.20和480.00 ng·d/mL,伊维菌素长效透皮剂体内维持有效药物浓度的时间长达35 d,普通注射剂仅为9 d。结果表明,伊维菌素长效透皮剂效果稳定,可进行更深入的研究。     

伊维菌素纳米乳注射液的研制与质量安全性评价

本研究旨在研制伊维菌素纳米乳注射液(5%)并对其理化性能、载药量、稳定性和急性毒性进行评价。采用伪三元相图法进行处方筛选,在常温下,以黏度、电导率、折光率、Z电位、平均粒径为指标考察纳米乳的理化性能;在不同的温度、光照和湿度条件下以药物含量为指标考察纳米乳的稳定性;采用HPLC法测定载药量,用小鼠灌胃的方法进行急性毒性研究。结果表明,该纳米乳在透射电镜下观察其乳滴呈球状,平均粒径为70 nm;不同温度、光照和湿度条件下含量无明显变化,稳定性良好;小鼠急性毒性试验表明该纳米乳注射液(0.1%)属于实际无毒。结果提示,本研究研制的伊维菌素纳米乳注射液(5%)制备简单,是一种质量稳定、安全性高的新制剂。     

伊维菌素微胶囊的制备及其体外释放的研究

市售伊维菌素制剂存在生物利用度低,释药峰谷浓度差异大等问题,本文以明胶为囊材,采用单凝聚法制备伊维菌素长效注射微胶囊油混悬剂。以微胶囊的粒径、载药量和包封率为制备工艺的优化指标,采用分光光度法测定微胶囊内药物含量及包封率。结果显示：最佳工艺制备的微胶囊的平均包封率为63.2%,载药量为18.3%,微胶囊的正圆度高、表面平滑,粒径分布在20~50 μm,药物呈缓慢持续释放,体外累计释放率18 h为30.0%,44 h后仅为51.0%。伊维菌素微胶囊制剂可大大增加体内留存时间,提高生物利用度,缓释效果显著。     

伊维菌素微乳制剂的溶血性试验

为了观察新型兽药制剂伊维菌素微乳是否具有溶血和红细胞凝聚等反应,试验以《化学药物刺激性、过敏性和溶血性研究技术指导原则》为指导,取兔血,采用常规体外试管法,观察伊维菌素微乳制剂是否出现溶血现象。结果表明:伊维菌素微乳制剂未出现溶血和红细胞凝聚现象,可供注射使用。说明伊维菌素微乳制剂无溶血性,安全可靠。     

伊维菌素纳米乳剂的研制及其评价

为了研制成伊维菌素纳米乳制剂,试验建立了由油酸乙酯、Cremophor RH-40为乳化剂、Transcutol.V、纯化水组成的空白纳米乳体系,选取适宜比例的油相、乳化剂和助乳化剂将伊维菌素溶于其中,通过逐滴加水的方式,可形成2%以上浓度的伊维菌素纳米乳剂。试验以粒度、黏度、电导率、折光率、有效药物含量为对象,考察了1%伊维菌素纳米乳的理化性质和稳定性。结果表明:1%伊维菌素纳米乳的配方为,伊维菌素1%、油酸乙酯2.2%、Cremophor RH-40 14.8%、Transcutol.V5%、纯化水77%。这种伊维菌素微乳理化性质稳定,可保持1年以上。说明该制剂理化指标合格,稳定性良好。     

伊维菌素微乳制剂的过敏性研究

本试验旨在观察伊维菌素微乳制剂对动物的过敏性反应。以《化学药物刺激性、过敏性和溶血性研究技术指导原则》为指导,选用豚鼠及Wistar大鼠为试验动物,采用全身主动过敏试验和被动皮肤过敏试验观察伊维菌素微乳制剂对动物的致敏作用。结果显示伊维菌素微乳制剂对豚鼠和Wistar大鼠的过敏性反应均为阴性。本试验为伊维菌素微乳制剂的安全性评价提供了试验依据。     

伊维菌素微乳的研制及质量评价

研制伊维菌素微乳剂,并对其特性、稳定性进行评定。依据伊维菌素的溶解度,选择适宜的油相和表面活性剂;依据维持微乳体系稳定性的能力,筛选助表面活性剂;利用伪三元相图,确定表面活性剂与助表面活性剂的质量比(Km值),筛选伊维菌素微乳剂的配方,并进行微乳的特性和稳定性分析。结果表明,伊维菌素微乳剂各组分质量分数为伊维菌素5%(50 mg/mL)、油6.79%、乳化剂13.58%、辅助乳化剂54.27%、超纯水20.36%,运动黏度为610.50 mm~2/s,动力黏度为714.28 mPa·s,乳滴平均粒径为6.30nm,光照试验、加速试验、长期试验等证实,微乳剂外观性状未见异常变化,药物含量符合质量规定,伊维菌素微乳剂稳定性良好,说明伊维菌素微乳剂是一种稳定性良好的制剂。     

伊维菌素透皮溶液驱猪线虫效果试验

目前,驱除体内寄生虫的药物很多,给药途径多为注射或口服.伊维菌素是一种高效广谱驱虫药,为扩大给药途径,简化使用方法,浙江海正化工股份有限公司研制了0.5%伊维菌素透皮溶液.为探讨该制剂对猪消化道线虫的疗效,设计了本试验. 1 材料与方法 1.1 供试药物 0.5%伊维菌素透皮溶液,浙江海正化工股份有限公司生产,对照药物为15%盐酸左旋咪唑擦剂.     

羊体内寄生虫的驱虫试验

为进一步做好寄生虫病防控工作,保证驱虫药品的生物安全,确保驱虫药品防治效果。本试验采用口服伊维菌素溶液、阿苯达唑混悬液、吡喹酮片、伊维菌素-阿苯达唑混悬液和伊维菌素-吡喹酮纳米乳等5种驱虫药的方式,对羊体内寄生虫进行了驱虫试验。结果表明:5种药物的虫卵减少率达83%以上,且伊维菌素-阿苯达唑混悬液和伊维菌素-吡喹酮纳米乳虫卵减少率分别为96.07%和95.56%,对照组前后两次粪检虫卵数无明显变化。说明5种药物均具有良好的驱虫效果,且复方制剂驱虫效果优于单方制剂驱虫效果,羊体重增重效果更佳。复方制剂具有疗效更佳、安全性高、价格低廉、驱虫谱更广等特点,具有更好的经济效益。     

痢菌净纳米乳的制备及体外释放度测定

为减少痢菌净的毒副作用及临床用药次数,用水包油法制备了痢菌净纳米乳,并对其形态、粒径、稳定性及体外释放等性能进行了研究。结果显示,纳米乳的稳定性较好,平均粒径在50nm左右,80 h体外释放率达到70%,具备明显的缓释功能,说明痢菌净纳米乳的制备工艺可行。     

氟苯尼考纳米乳制备及其抑菌效果观察

为制备氟苯尼考纳米乳并了解其抑菌效果,本试验进行了处方筛选、物理性质考察、抑菌圈试验,通过测定氟苯尼考在多种油相中的溶解度,确定最佳油相;再以乳化剂-助乳化剂（Smix）体积比Kv值及Smix-油相体积比为考察指标,结合伪三元相图筛选最佳处方组成;利用染色法鉴别纳米乳类型,通过透射电镜观察纳米乳微观形态;通过激光粒度分析仪测定粒度分布、Zeta电位;采用离心及长期试验考察其稳定性;经抑菌圈试验观察氟苯尼考纳米乳对金黄色葡萄球菌、大肠埃希菌、微杆菌、枯草芽孢杆菌的体外抑菌效果。结果显示,橄榄油为最佳油相,EL-40为最佳乳化剂,丙三醇为最佳助乳化剂,优选的Smix体积比Kv值为2.0,Smix-油相体积比为8：2。氟苯尼考纳米乳最佳处方组成为：氟苯尼考120 mg,N,N-二甲基甲酰胺0.1 mL,橄榄油2 mL,EL-40 5.7 mL,丙三醇2.3 mL,水6 mL。氟苯尼考纳米乳为水包油（O/W）型,外观呈球形,大小均匀无黏连,平均粒径28 nm,粒径呈正态分布,Zeta电位为-0.454 mV,经离心试验及长期试验样品稳定,对4种常见菌体外抑菌效果强于同浓度氟苯尼考溶液。本试验结果表明,氟苯尼考纳米乳制备方法简单、可行,且纳米乳稳定,抑菌效果良好,在畜牧养殖中具有潜在应用价值。     

The effect of protein binding on ivermectin uptake by bovine brain microvessel endothelial cells

The effect of albumin binding on ivermectin uptake and transfer across the endothelial component of the blood-brain barrier (BBB) was determined with anin vitro model comprised of bovine brain microvessel endothelial cell (BMEC) monolayers. Cellular uptake of ivermectin was limited in the absence of albumin and 90% inhibited in the presence of 10% albumin. Cell membrane association of ivermectin, as followed by fluorescent probe labelling, was observed only at high (micromolar) concentrations of the drug. Membrane association was about 75% inhibited in the presence of albumin. Similarly, transfer across BMEC monolayers was restricted, equivalent to that of BBB impermeant markers. Unlike the uptake studies, however, albumin had little effect on the transfer of ivermectin across BMEC monolayers. These results support recentin vivo findings on the distribution of ivermectin into the brain and suggest that ivermectin has only a limited affinity for the endothelial component of the normal BBB.     

复方利福昔明纳米乳的制备及质量评价

旨在制备复方利福昔明纳米乳,并对其理化性质进行评价。以纳米乳的载药量、稳定性为考查指标,筛选油相、表面活性剂、助表面活性剂;绘制伪三元相图确定最佳配方;利用透射电子显微镜、激光粒度测定仪考查其微观形态和粒径,采用染色法鉴别纳米乳的类型;经光照试验、温度试验、高速离心试验考查纳米乳的稳定性。结果表明,复方利福昔明纳米乳的最佳配方为利福昔明1%、肉桂醛2.44%、聚乙二醇-2004.88%、聚氧乙烯醚-40-蓖麻油19.51%、蒸馏水72.17%;复方利福昔明纳米乳为水包油型(O/W),可以无限稀释;在透射电镜下观察,纳米乳呈圆球形,无粘连,平均粒径为11.8nm;光照试验、温度试验、长期试验显示,纳米乳稳定性良好。复方利福昔明纳米乳制备方法简单,质量可控,为利福昔明广泛应用于畜禽肠道细菌感染的治疗提供了理论依据。     

In vitro and in vivo evaluation of an in situ forming gel system for sustained delivery of Florfenicol

The objective of this study was to develop an injectable in situ forming gel system based on Poloxamer for sustained release of Florfenicol (FFC). The formulations were prepared containing certain amounts of Poloxamer 407 (P407) and Poloxamer 188 (P188) alone or with hydroxylpropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC‐Na), or polyvinyl pyrrolidone (PVP) as polymer additives. The optimal formulation was chosen according to in vitro parameters (gelation temperature, gelation time, pH value, viscosity, and in vitro release). Then the FFC in vivo pharmacokinetic character of the optimal formulation was investigated in dogs with a single dose of 50 mg/kg b.w. under s.c. injection. In vitro release studies, all formulations containing polymer additives had prolonged release time and decreased initial burst to some extent. The optimal formulation containing 0.15% HPMC showed a best sustained release profile for about 128 h with the lowest initial burst in vitro (<40% in 24 h). In vivo, the 20% FFC in situ forming gel provided prolonged drug release time within the therapeutic range for about 100 h, with stable plasma levels and elimination half‐life (t_1/2λz) nine times higher than the control formulation. In conclusion, in situ forming gel is an attractive alternative for FFC sustained release system.     

伊维菌素小单室脂质体工艺配方优化及质量分析

为获得高包封率的伊维菌素小单室脂质体,本研究对其制备工艺进行了优化,并选取超声波频率、超声时间、卵磷脂与胆固醇质量比、伊维菌素与卵磷脂质量比各因素进行正交交互作用考察,同时利用反相高效液相色谱法对各工艺配方组合下伊维菌素小单室脂质体的包封率进行了测定。结果显示,伊维菌素小单室脂质体的制备最佳配方和工艺组合为超声波频率200 kHz,超声时间6 min,伊维菌素与大豆卵磷脂质量比为1:10。经过优化组合,得到了较高品质的伊维菌素小单室脂质体,平均载药量达到(92.35±0.61)%,药物品质优良,且制备工艺简单可行。     

妥曲珠利纳米乳的制备及质量评价

为了确定妥曲珠利纳米乳的处方和制备工艺,选用液体石蜡、乙酸乙酯、大豆油、IPM、油酸为油相,RH-40、EL-40、OP-10、吐温-80、司盘-80为表面活性剂,乙醇、1,2-丙二醇、异丙醇、丙三醇、PEG-400为助表面活性剂,通过伪三元相图筛选制备妥曲珠利纳米乳的最佳处方.结果表明,油相为乙酸乙酯、表面活性剂为吐温-80,助表面活性剂为1,2-丙二醇可形成纳米乳.优化处方为表面活性剂∶助表面活性剂∶油相∶水相=2∶1∶2∶5,增溶剂添加量为10％,在该处方下制备的妥曲珠利纳米乳稳定性良好.     

Evidence of Ivermectin Resistance by Parascaris equorum on a Texas Horse Farm

By collecting fecal samples every 2 weeks beginning at 2 months of age, 32 foals from a single Texas farm were monitored. The foals were administered ivermectin paste at the time of the first collection and again monthly. When foals had Parascaris egg counts higher 2 weeks after ivermectin treatment than at treatment, they were administered pyrantel pamoate at the manufacturer's recommended dose (6.6 mg/kg) or at twice the recommended dose (13.2 mg/ kg) when tapeworm eggs were also detected. An elevation or only minimal reduction (less than 75%) in Parascaris egg counts was seen 2 weeks after ivermectin treatment until the foals were 8 months of age, at which time there was an 85% reduction in fecal egg count after treatment. When pyrantel was administered at the manufacturer's recommended dose, a 42% to 84% reduction in egg counts occurred, but at 13.2 mg/kg there was a 98% to 100% reduction in fecal egg counts 2 weeks posttreatment. However, pyrantel failed to control strongylate egg counts even at the elevated dose, whereas ivermectin reduced strongylate fecal egg counts by greater than 99%, determined 2 weeks posttreatment. Pyrantel, but not ivermectin, lowered Parascaris egg counts. Ivermectin, but not pyrantel, lowered strongyle egg counts 2 weeks post administration. A single drug for all ages of horses approach to parasite control requires rethinking. Combinations of drugs or more careful evaluation of anthelmintics in foals may be necessary for continued parasite control.