盐酸咪唑苯脲复乳制备条件的优化研究

为了优化盐酸咪唑苯脲复乳制剂的配方和乳化条件,首先通过单因素筛选试验,确定最佳油相和乳化剂的种类、浓度及油水比例、乳化条件确定初乳制备条件;再通过选择不同外水相乳化剂、外水相与初乳体积比、内水相稳定剂与用量以及乳化条件,确定复乳制备条件。结果表明,选择白油作为油相、10%的OP-10为乳化剂、油相和水相比例7∶3,乳化温度为40℃,乳化时间为3 min,乳化速度为10000 rpm时为制备乳剂的最佳条件;选择7%浓度的外水相乳化剂,外水相与初乳体积比为5∶5,选择10%明胶液稳定剂,采用25℃、1 min、4000 rpm的乳化条件制备的复乳制剂效果最佳,研究初步获得了盐酸咪唑苯脲复乳制剂配方和乳化条件。     

盐酸咪唑苯脲复乳注射液在山羊体内的药动学

<正>为研究盐酸咪唑苯脲复乳注射液在山羊体内的药动学,将12只崂山奶山羊随机分为2组,每组6只,公母各半,分别肌注盐酸咪唑苯脲复乳和盐酸咪唑苯脲粉针剂,给药剂量均为1 mg/kg b.w.。血浆样品经固相萃取柱处理后,采用HPLC法测定山羊血浆中咪唑苯脲的血药浓度,用3P97药动学软件处理药时数据。山羊肌注盐酸咪唑苯脲复乳和粉针剂的药时数据均符合一级吸     

紫外系数倍率法测定盐酸咪唑苯脲缓释剂在健康奶牛中的血药浓度

本试验以261 nm为测定波长,277 nm为参比波长,采用紫外系数倍率法测定盐酸咪唑苯脲缓释剂在健康奶牛体内不同时间的血浆药物浓度,并用药动学计算软件拟合处理得药动学参数。结果表明:此方法能不经分离直接消除血浆的背景干扰,盐酸咪唑苯脲标准品在0.1~5.0μg/mL的范围与ΔA呈良好的线性关系(r=0.999 9),平均回收率96.16%,日内、日间RSD%均小于5.00%。药-时曲线符合一室吸收模型,药动学方程为:C=2.254 0(e-0.008 8t-e-0.422 3t),r=0.998 0。与肌肉注射盐酸咪唑苯脲水剂相比,消除半衰期(t1/2ke)延长了75.402 h,药物峰浓度时间(Tmax)延长了7.631 h。盐酸咪唑苯脲缓释剂优于盐酸咪唑苯脲水剂。     

复方“克清甲”软膏剂的处方筛选

为优化复方＂克清甲＂软膏剂的处方,制得稳定的水包油（O/W）型软膏剂,以软膏的稳定性为指标,对处方的亲水亲油平衡（HLB）值、混合乳化剂及油相用量进行筛选。优选后的制剂处方HLB值为10.5,吐温80、单硬脂酸甘油酯的用量分别为6%、4%,白凡士林、十八醇的用量分别为8%、7%。该处方条件下制得的复方＂克清甲＂软膏剂具有良好的稳定性。     

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。     

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120mg,N,N-二甲基甲酰胺0.1mL,橄榄油2mL,EL-40 5.7mL,丙三醇2.3mL,水6mL。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28nm,粒径呈正态分布,Zeta电位为-0.454mV,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。     

高效液相色谱法测定人参皂苷复乳中人参皂苷含量

将人参皂苷与复乳佐剂结合,制成W/O/W型人参皂苷乳免疫增强剂。利用HPLC对人参皂苷复乳中3种单体成分检测条件进行筛选,确定最佳条件。液相色谱法检测结果表明,人参皂苷浓度为0.5 mg/m L复乳中每毫升含人参皂苷Rg1 17.82~23.68μg、人参皂苷Re 27.82~33.68μg、人参皂苷Rd 16.82~23.08μg,均符合药典对人参皂苷Rg1、Re和Rd的含量要求。说明建立的检测方法稳定可行,可有效控制人参皂苷复乳佐剂注射液的质量。     

紫外系数倍率法测定盐酸咪唑苯脲缓释剂在奶牛中的血药浓度

本试验以261nm为测定波长,277nm为参比波长,采用紫外系数倍率法测定盐酸咪唑苯脲缓释荆在奶牛体内不同时间的血浆药物浓度,并用药动学计算软件拟合处理得药动学参数.结果表明:此方法能不经分离直接消除血浆的背景干扰,咪唑苯脲标准品在0.1～5.0μg/mL的范围与△A呈良好的线性关系(r=0.9999),平均回收率96.16%,日内、日间RSD(%)均小于5.00%.药时曲线符合一室吸收模型.药动学方程为:C=2.2540(e-0.0088t-e-0.4223t),r=0.9980.与肌肉注射咪唑苯脲水剂相比,消除半衰期[T1/2(Ke)]延长了75.402h,药物峰浓度时间[Tmax]延长了7.631h.咪唑苯脲缓释剂优于咪唑苯脲水剂.     

鸡新城疫-传染性支气管炎-产蛋下降综合征三联复乳疫苗的研制

以鸡新城疫病毒 La Sota株、传染性支气管炎病毒H120株和减蛋综合征病毒EDS-76株作为制备疫苗的抗原,以吐温80、油酸和丙二醇作为外部水相乳化剂,采用正交试验法,筛选了外部水相乳化剂的理想配比,并制备鸡新城疫-传染性支气管炎-减蛋综合征三联复乳疫苗,测定了疫苗的性状、黏稠度和稳定性.结果表明,疫苗的黏稠度为6 s±0.5 s,疫苗经3 000 r/min离心20 min,未出现分层现象,研制的疫苗是一种黏稠度较低、稳定性良好的乳白色W/O/W型复乳疫苗.     

咪唑苯脲——一种抗巴贝西虫新药

咪唑苯脲(Imidocarb)为均二苯脲(Carbanilide)类中的联脒(diamidine)的衍生物。商品名为 Imizol。化学名称为#结构式为#本药有两种盐类,即二盐酸盐和二丙酸盐,在10％(w/v)溶液时,后者 pH为6.5,前者 pH 为3.1,并且后者具有较前者易溶于水的优点。咪唑苯脲的抗巴贝西虫的作用最早为Schmidt 等(1969)在应用鼠骆氏巴贝西虫(Babesia rodhaini)筛选一组均二苯脲类化合物时发现,同年 Beveridge(1969)3,3′—双(2-咪唑啉)均二苯脲二盐酸[3,3′-his(2—imidozoline—2—yl)—Carbanilide dihydrochloride]。     

Relationship between antigen release and antibody response of infectious coryza water-in-oil-in-water emulsion vaccines

The relationship between the antigen release from formulations in vitro and the antibody response after administration of water-in-oil-in-water (W/O/W) emulsion vaccines containing Haemophilus paragallinarum (Hpg) was studied in chickens. Increases of sorbitan sesquioleate volume in the formulation led to slower antigen release and tended to induce higher hemagglutination-inhibition (HI) antibody titers. In addition, the vaccines prepared with internal aqueous phase:oil phase:external aqueous phase (A:O:A) ratios of 3:4:3 and 3:3:4 also showed slower release of antigen and higher HI antibody titer compared with those of an A:O:A ratio of 3:2:5. Vaccines prepared with polyoxyethylene (POE)(10) hydrogenated castor oil or POE(40) hydrogenated castor oil instead of sorbitan sesquioleate showed higher release and lower antibody HI titers. As a result, HI antibody titers at 6 wk after vaccination were inversely related to antigen release, as determined by the release test. The correlation coefficient was 0.942. In infectious coryza W/O/W emulsion vaccines, the slow release of antigen from the formulation induced and maintained high HI antibody titers of Hpg.     

The chemotherapeutic efficacy of imidocarb dihydrochloride on concurrent bovine anaplasmosis and babesiosis

Summary The chemotherapeutic efficacy of imidocarb dihydrochloride (3,3′-bis(2-imidazolin-2 yl) carbanilide dihydrochloride) administered as single intramuscular doses of 1·0, 2·0 and 2·5 mg/kg, against concurrent bovine anaplasmosis and babesiosis, is reported. Dosages of 2·0 and 2·5 mg/kg of imidocarb dihydrochloride rapidly inhibited acute ascending concurrent parasitaemias ofAnaplasma marginale, Babesia bigemina andBabesia argentina; however, 1·0 mg/kg had a minimal effect onA. marginale but was very effective againstB. bigemina andB. argentina. Imidocarb dihydrochloride at 1·0, 2·0 and 2·5 mg/kg inhibited the development of immunity of the acuteBabesia spp. infections, making the calves more susceptible to babesiosis upon challenge. The inhibition ofA. marginale parasitaemias was directly related to increasing doses of imidocarb dihydrochloride; however, recrudescing and persisting post-treatment parasitaemias also occurred more frequently at higher doses.

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Sumario La eficiencia quemoterapéutica del imidocarb dihydrochloride (3,3′-bis (2-imidazolin-2 yl) carbanilide dihydro chloride) administrada como dosis intramuscular unica de 1·0, 2·0 y 2·5 mg/kg, en infecciones concurrentes de anaplasmosis y babesiosis es reportada en este trabajo. Dosis de 2·0 y 2·5 mg/kg de imidocarb dihydrochloride, rapidamente inhibieron las parasitemias concurrentes ascendientes y agudas deAnaplasma marginale, Babesia bigemina yBabesia argentina; sin embargo, 1·0 mg/kg tuvo un efecto minimo sobreA. marginale, pero fue muy efectivo contraB. bigemina yB. argentina. El imidocarb dihydrochloride en dosis de 1·0, 2·0 y 2·5 mg/kg inhibió el desarrollo de inmunidad contra la forma aguda deBabesia, haciendo a los terneros mas susceptibles a la babesiosis al desafio. La inhibición de parasitemias deA. marginale estuvo directamente relacionada al aumento de la dosis de imidocarb dihydrochloride; sin embargo, parasitemias debido al recrudecimiento ó a la persistencia despues del tratemiento, tambien ocurrieron mas frecuentemente en dosis altas.

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Résumé L'efficacité de ce produit administré à l'occasion d'une unique injection à la dose de 1,0, 2,0 et 2,5 mg/kg contre l'anaplasmose et la babésiose simultanées est rapportée. La dose de 2 à 2,5 mg/kg inhibe rapidement le développement aigu de parasitémies dues à la fois àAnaplasma marginale, Babesia bigemina etBabesia argentina; cependant la dose de 1 mg/kg n'a qu'un effet modeste surA. marginale, alors qu'il conserve toute sa valeur contreB. bigemina etB. argentina. A la dose de 1,0, 2,0 et 2,5 mg/kg, ce corps entrave le développement de l'immunité dans les accés aigus dus àBabesia spp. rendant les veaux plus sensibles à de nouvelles attaques de babésioses. L'inhibition de parasitémie à base deA. marginale est directement en rapport avec l'accroissement de la dose d'Imidocarb dihydrochloride; toutefois, la recrudescence et la persistance après traitement de parasitémies sont plus fréquentes après usage de doses élevées.

     

A selected water-in-oil emulsion: Composition and usefulness as an immunological adjuvant

A selected water-in-oil (W/O) emulsion was evaluated in terms of stability and antibody-response and side-effects in experimental animals.The results from stability tests performed at 4°C and 37°C indicate a storability of the W/O emulsion of more than a year under normal storage conditions. The antibody-response of rabbits after injection of E.coli K99 antigen and bovine serum albumin (BSA) using the W/O emulsion as vehicle was generally significantly higher than the response to the same antigens injected within incomplete Freund's adjuvant (IFA): twenty days after the first antigen injection the rabbits injected with antigen in the W/O emulsion showed average anti-K99 and anti-BSA titres which were ca 5x as high as the titres in sera from rabbits injected with the antigens in IFA. Thirty-two and forty-two days after the first antigen injections the W/O group showed anti-K99 titres which were respectively ca 3.5x and 2x higher than titres in the IFA group, while anti-BSA titres in the W/O group were respectively ca 13x and 6.5x higher than in the IFA group.Intra-muscular and/or subcutaneous injection of the W/O emulsion in rabbits and pigs resulted in a slight degeneration of local tissue. When antigens were present in the emulsion granulomatas were often observed. The rise in temperature in pigs after injection of killed E.coli 0149:K91,K88 in the W/O emulsion was comparable with that induced by E.coli in physiological saline.From these results it is concluded that the W/O emulsion is likely to be a promising basis for veterinary vaccines and that the application of the W/O emulsion may contribute to the limitation of the number of animals used for raising antibodies for general immunological purposes.     

Efficacy of atovaquone and azithromycin or imidocarb dipropionate in cats with acute cytauxzoonosis

Background: Imidocarb or a combination of atovaquone and azithromycin (A&A) has been suggested for treatment of cats with cytauxzoonosis, but neither has been prospectively evaluated for efficacy. Hypothesis/Objectives: That survival to hospital discharge is improved by treatment with A&A as compared with imidocarb. Animals: Eighty acutely ill cats with Cytauxzoon felis infection treated at one of 18 veterinary clinics in 5 states. Methods: An open‐label, randomized prospective study compared survival in cats treated with atovaquone (15 mg/kg PO q8h) and azithromycin (10 mg/kg PO q24h) or imidocarb (3.5 mg/kg IM). All received heparin, fluids, and supportive care. Clinical and clinicopathologic data from initial presentation were collated. Parasitemia was quantified (n = 79) and pathogens genotyped (n = 60). Logistic regression was used to determine the impact of treatment group on the primary endpoint, survival to hospital discharge or death. Covariants were analyzed by rank‐sum testing. Results: Of 53 cats treated with A&A, 32 (60%) survived to discharge while only 7 of 27 cats (26%) treated with imidocarb survived (P= .0036; odds ratio 7.2, 95% CI 2.2, 24). Cats with a lower parasitemia were more likely to survive, as were cats with higher white blood cell counts and lower total bilirubin. Unique pathogen genotypes were identified from 15 cats, while genotype isolated from 21 cats had been described previously. There were multiple pathogen genotypes identified in 24 cats. Conclusions and Clinical Importance: Survival to discharge was more likely in cats treated with A&A as compared with imidocarb, although case fatality rate remained high.     

Effect of imidocarb and levamisole on the experimental infection of BALB/c mice by Leishmania (Leishmania) amazonensis

The adverse effects from using currently available drugs for the treatment of leishmaniasis have motivated the search for new therapeutical agents. The aim of this work was to evaluate the effect of imidocarb and levamisole on the treatment of BALB/c mice experimentally infected by Leishmania (Leishmania) amazonensis. BALB/c mice were infected with 10(6) promastigotes of L. (L.) amazonensis (IFLA/BR/67/PH8) and, starting on day 51, mice were treated subcutaneously with imidocarb (IMD, 34 mg/kg), imidocarb plus levamisole (IMD+LVS, 34 and 12 mg/kg, respectively), only levamisole (LVS, 12 mg/kg) or without treatment (control). Lesion size and swelling were weekly monitored for 10 weeks after the beginning of the treatment. On day 121 post-infection, serum levels of specific IgG from infected mice were evaluated, as well as histopathological and morphometric alterations in the footpad, lymph nodes and spleen of these animals. The data obtained in this study demonstrated that, when compared to controls, mice treated with IMD had lower levels of IgG anti-L. (L.) amazonensis (34.45%), smaller vacuolar area in macrophages (3.75%), lower number of megakaryocytes in spleen (63.19%) and lower parasite burden in the footpad (30.2%). Thus, the evaluated parameters suggest the use of imidocarb as a potential drug in the treatment of tegumentary leishmaniasis.     

甘草黄酮纳米乳的制备及其稳定性研究

[目的]通过绘制伪三元相图优选处方的方法,制备了甘草黄酮纳米乳并对其稳定性进行评价。[方法]以EL-40、Span-80为表面活性剂,肉豆蔻酸异丙酯（IPM）为油相,组成混合溶液,以甘油为助表面活性剂制备甘草黄酮纳米乳,将甘草黄酮纳米乳应用高温、高湿、恒温加速试验检验其稳定性。[结果]纳米乳处方为：0.2 g甘草黄酮、1.2 g EL-40、0.3 g Span-80、0.5 g甘油、0.5 g IPM、4.0 g蒸馏水,经试验验证甘草黄酮纳米乳仍为澄清透明纳米乳状液,未出现分层现象,性质稳定。[结论]该方法操作简单,纳米乳稳定性良好。     

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.     

禽霍乱油乳剂灭活菌苗的研究

选用免疫原性好的５Ａ和７Ａ血清型巴氏杆菌菌株，分别接种于马丁肉汤通气培养。要求每ｍｌ的含菌量达１００亿以上。经０．５％福尔马林灭活后，等量混合为水相。１０＃白油为油相，按适当比例制成油乳剂灭活菌苗。与禽霍乱弱毒菌苗和禽霍乱氢氧化铝菌苗，分别接种于同群蛋鸡作对比试验。结果证实油乳剂灭活苗在安全性和免疫原性方面都优于后两种疫苗，５个月的攻毒保护率达８０％。经广泛的区域试用，从反馈信息和实地调查结果说明本菌苗对各种日龄的鸡、鸭、鹅都能有效地预防和控制禽霍乱的发生或流行。     

HPLC-ECD法测定大观霉素的含量

建立了HPLC—ECD法测定大观霉素含量的分析方法。采用高效液相色谱-电化学检测器,Waters XBridge C18色谱柱（4．6mm×250mm,5μm）,以pH3．2的革酸盐缓冲溶液-乙腈（1000：105,V：V）为流动相,流速1．0mL／min;柱后衍生溶液为21g／L的NaOH溶液,流速0．5mL／min;ECD系统参数：极性为阳性,检波＋0．12V,氧化电位＋0．70V,还原电位-0．60V,范围5μA。结果表明,大观霉素及4R一二氢大观霉素在40～320μg／mL范围内呈良好的线性关系（大观霉素r=0．9999,4R-二氢大观霉素r=0．9992）,平均回收率为100．0％（n=9）,RSD为0．2％。该方法解决了微生物效价测定大观霉素含量偏高的难题,且操作简便、结果准确,可用于大观霉素及相关制剂产品的质量控制。     

Comparative efficacy of diminazene diaceturate and imidocarb dipropionate against Babesia equi infection in donkeys

Diminazene diaceturate (Berenil, Hoechst) at 12 mg/kg intramuscularly (i/m) and repeated after 24 hours controlled the rising parasitaemia of Babesia equi infection in four out of five splenectomised donkeys. The drug was more effective in the early stages of the disease and had a prophylactic effect for at least 30–35 days.A new babesicide, imidocarb (Imizol, Burroughs Wellcome), was 100% effective in three splenectomised donkeys at 5 mg/kg, i/m and repeated after 48 hours. However, imidocarb at 5 or 2 mg/kg i/m with a single injection was only partially effective or ineffective.