替米考星肠溶微丸的制备及其评价

采用挤出滚圆法制备含药微丸,药物以固体分散体的形式存在微丸中,流化床进行肠溶包衣,制得替米考星肠溶微丸。通过不同的工艺处方筛选,考察其理化性质及体外释放特性。分别采用紫外分光光度计测定替米考星的含量,电子显微镜、红外分光光度法和差示扫描量热法确证微丸的特性。结果显示,微晶纤维素在一定程度上对微丸骨架的成型有影响,而包衣的厚度影响微丸的体外释放行为。释放度实验表明替米考星肠溶微丸能达到肠溶制剂的效果。     

替米考星肠溶微丸的质量评价

采用高效液相色谱法和体外溶出度试验测定替米考星肠溶微丸的载药量和溶出度,对自行研制的替米考星肠溶微丸进行初步质量评价。结果显示,制剂含量平均在20%,在人工胃液中不溶出,在人工肠液中溶出度达90%以上,达到了肠溶效果。     

盐酸沃尼妙林肠溶微丸的制备及质量评价

采用挤出滚圆法制备盐酸沃尼妙林微丸,将含不同比例丙烯酸树脂Ⅱ和Ⅲ及不同包衣增重的几种微丸进行体外释放度试验,选择合适的丙烯酸树脂Ⅱ和Ⅲ比例及包衣增重,同时对制剂的稳定性进行考察,以对自行研制的盐酸沃尼妙林质量进行初步评价.结果显示:丙烯酸树脂Ⅱ和丙烯酸树脂Ⅲ的比例为2∶1、包衣增重为15%时,包衣样品具有典型的肠溶特征,在模拟胃部环境中前2h累积释放量均小于标示量10%,进入肠道内45min的累积释放量大于70%,具有明显的定位释放功能.稳定性试验结果表明,在模拟市售包装的条件下,本品外观、含量等指标均保持稳定,说明微丸具有良好的稳定性、制备工艺可靠.     

肠溶制剂在兽药领域的研发和应用

本文从肠溶制剂的包衣原理、制剂类型及检测方法等方面阐述了肠溶包衣技术的主要特点,对兽用肠溶制剂的研发现状以及国内外首个上市的"替米考星肠溶颗粒"产品的特点及药效评价做简要概述。     

味连须肠溶微丸包衣处方的筛选

以挤出滚圆法制备味连须微丸为载药丸芯,以丙烯酸树脂Ⅱ和Ⅲ为包衣材料,利用多功能造粒包衣机对丸芯进行包衣。以味连须微丸体外释放度为指标,通过单因素试验考察丙烯酸树脂Ⅱ和Ⅲ的比例、增塑剂用量、抗静电剂用量和包衣增重,探讨不同包衣处方对药物释放度的影响。结果表明,Ⅱ、Ⅲ号丙烯酸树脂比例为2∶1,增塑剂用量为聚合物用量的20%,滑石粉为聚合物用量的0.3%,包衣增重10%为优化处方。     

替米考星固体分散体的制备与物相鉴定

为改善替米考星的水溶性，提高其生物利用度，试验选用聚乙二醇6000和泊洛沙姆188作为载体，采用熔融法制备替米考星固体分散体。以体外累积溶出度为评价指标，通过正交试验筛选最佳制备工艺，选用X-射线衍射法、傅里叶红外光谱法、扫描电镜法进行物相鉴定。结果显示，替米考星固体分散体最佳制备工艺为联合载体PEG6000：P188=20:1、药载比1:3、搅拌时间1 h、固化时间12 h；物相鉴定表明，替米考星为非晶态，固体分散体为晶体结构，替米考星以无定形态分散于载体中；替米考星固体分散体在2 min时溶出度达到71.8%，15 min时完全溶解，显著提高了替米考星的溶出速率。该制备工艺简单，选用联合载体制备替米考星固体分散体，能够有效避免单一载体制备替米考星固体分散体出现的缺陷，有效提高溶出度，方便临床饮水用药。     

替米考星水溶性粉在家兔体内的药动学研究

为了考察替米考星水溶性粉在家兔体内的药动学特征,本试验分别给受试家兔灌服替米考星、替米考星肠溶微丸、替米考星水溶性粉,以12.5 mg/kg体重剂量给药,采用HPLC方法分析不同时间点受试家兔血浆中替米考星的药物浓度。试验结果显示,新研制的20%替米考星水溶性粉经口服后,药物在家兔体内可被快速吸收达到较高的血药浓度0.413±0.148μg/m L,血药浓度-时间曲线下的面积(AUC)为4.334±0.620μg/m L·h,相对生物利用度(F)达到86.99%,说明替米考星水溶性粉经口服后的生物利用度较高,有利于致病菌细菌的抑制或杀灭。     

盐酸沃尼妙林肠溶微丸的研制

沃尼妙林是新一代截短侧耳素(pleuromutilin)类抗生素。试验以丙烯酸树脂水分散体为肠溶包衣材料,单因素与正交试验筛选处方及工艺条件,用流化床包衣技术及挤出-滚圆法制备10%盐酸沃尼妙林肠溶微丸。研制的肠溶微丸外观、含量和释放度在加速试验条件下均保持稳定;以75~150 g/t饲料混饲给药,10%盐酸沃尼妙林肠溶微丸对猪痢疾有良好治疗效果,明显优于痢菌净。研究表明,盐酸沃尼妙林肠溶微丸质量符合药学要求,具有良好的体外肠靶向性,可用于猪肠道疾病的防制。     

替米考星在酸碱溶液中的稳定性研究

为探讨替米考星在酸碱溶液中的稳定性,配制不同pH溶液,采用高效液相色谱法测定在一定时间内替米考星的含量,观察不同的pH条件下替米考星的降解情况。结果显示,在pH为2～7.4时,替米考星较稳定,在pH为0.5、13的溶液中,替米考星分别降解了11.4%、50.2%。结果证明,替米考星在浓酸、强碱的条件下不稳定,会部分降解。     

不同工艺制备的替米考星颗粒体外释放度研究

通过考察3种替米考星颗粒制剂在酸性溶液和缓冲液中的释放情况，为新制剂的进一步研发和临床应用提供理论依据。采用高效液相色谱法对3种不同制剂中替米考星的含量及其体外溶出度进行测定。色谱柱选择Hypersil ODS-2 C18(4.6 mm×250 mm, 5μm),以水∶乙腈∶四氢呋喃∶磷酸二丁胺(790∶130∶55∶25)为流动相，流速1.0 mL/min,检测波长290 nm,柱温30℃。分别以盐酸溶液和磷酸盐缓冲液为溶出介质，测定3种新研制的替米考星不同制剂体外溶出曲线，溶出方法选用浆法，转速为75 r/min,温度为37℃±0.5℃。在所建立的方法学基础上，替米考星在10μg/mL～1000μg/mL范围内与峰面积呈良好的线性关系，在90 min时3种新研制的替米考星不同制剂在酸性溶液中的溶出度分别为100%、5.73%和8.29%,供试品1与供试品2、供试品3及对照品之间差异显著(P<0.05),供试品2、供试品3与对照品之间无明显差异；120 min时3种新研制的替米考星不同制剂在磷酸盐缓冲液中的累积溶出度分别为100%、97.53%和93.60%,3种供试品与对照品...     

口服肠溶制剂在兽药领域中的应用前景

介绍了肠溶制剂的制剂特点、肠溶制剂包衣原理、肠溶包衣材料和肠溶制剂类型等内容。结合规模化养殖场对药物饮水给药的需求,从兽用肠溶制剂的药物开发特点及近几年的国内外研究情况等两方面做以阐述,以期为兽用肠溶微丸、肠溶微囊制剂研发提供新的思路。     

Gastric retention of enteric-coated aspirin tablets in beagle dogs

Administration of acetylsalicylic acid (ASA) in the dog may cause gastric mucosal damage. Enteric-coated tablets protect the canine stomach during oral ASA medication. A therapeutic plasma salicylate concentration can be attained using enteric-coated ASA tablets at a dose rate of 25 mg/kg body wt, administered every 8 h. Six beagle dogs were given enteric-coated ASA tablets (500 mg) orally, in a 5-day cross-over experiment on two different feeding regimens: i.e. feeding once daily (Group I) or 8 hourly (Group II). Results demonstrate that feeding regimen strongly influences the plasma salicylate concentration pattern. Subtherapeutic mean plasma salicylate concentrations were found in both groups. In Group II the standard deviation (SD) of the mean plasma salicylate concentration was larger than that of Group I. The minimal plasma salicylate concentration never reached detectable levels in Group II. In both groups large numbers of tablets were vomited. Gastric evacuation of the ASA tablets is comparable to indigestible solid particles; their removal was dependent on the interdigestive gastric motility. It is concluded that large enteric-coated ASA tablets are not suitable for therapeutic use in small dogs.     

纳米丝素颗粒药物缓释剂的研制及在治疗小鼠溃疡性结肠炎中的药物控制释放作用

利用天然丝素良好的生物相容性和生物可降解性,制备纳米丝素颗粒作为药物缓释载体。通过磷酸盐缓冲液及乙醇综合处理1 mg/mL丝素蛋白溶液得到颗粒直径比较均匀的纳米级丝素颗粒。电子显微镜下观察到丝素蛋白在pH 8.0的磷酸盐缓冲液作用下其链状胶束结构发生聚集而将药物包裹,自组装形成规则的直径为200～600 nm的球形颗粒,完成与药物的结合,即药物的搭载。在pH 8.0的缓冲液中,单纯柳氮磺吡啶(SASP)药物粉末在1 h左右即将药量的90%释放出来,而加入纳米丝素蛋白的丝素载体药物2 h释放出约60%的药物量,使达到最高药物浓度的时间比单纯药物粉末延长,从而延长药物作用时间,有利于机体对药物的有效吸收利用。将丝素载体药物用于治疗人工诱导小鼠慢性溃疡性结肠炎,结果丝素载体药物治疗组小鼠6～12 h血液药物浓度和结肠组织中的药物浓度降低幅度要低于单纯SASP药物治疗组小鼠,证实了纳米丝素蛋白具有良好的载药、释药功能。     

Protective effects of oral microencapsulated Mycoplasma hyopneumoniae vaccine prepared by co-spray drying method

The efficacy of Mycoplasma hyopneumoniae oral vaccine was investigated in microsphere dosage form. A co-spray drying process was used to apply an encapsulating material, Eudragit L30 D-55, to microspheres containing Mycoplasma hyopneumoniae antigens. The microspheres were generally effective (>93%) with protein release at pH 7.4, but almost none were released at pH 1.2, for 3 hr in an in vitro dissolution test. An SPF-swine model was used to evaluate the effectiveness of the microspheres as an oral vaccine, and the related immune responses. The serum's systemic IgG against M. hyopneumoniae was evoked by ELISA analysis, after a 2nd immunization of all pigs. The vaccinated groups' mean lesion score was significantly lower after the Mycoplasma hyopneumoniae challenge than that of the nonvaccinated/challenged groups (P<0.05). This study strongly suggests that the oral microspheres vaccine prepared by a co-spray drying method can provide effective protection against M. hyopneumoniae infection in pigs.     

Effect of the pH value when treating concentrate protein with formaldehyde on protein protection in the rumen

Nine samples of soybean extracted meal were treated by fumigation in plastic bag with 0.5 g formaldehyde/100 g crude protein, the pH ranging from 2.1 to 10.7. The studies showed that with rising pH (x) the proportion of totally bound (y1, % of formaldehyde amount used) and irreversibly bound (y2) formaldehyde increased (y1 = 77.7 + 1.56x, y2 = 28.2 + 2.04x), whilst the reversible proportion remained constant (45.4% of formaldehyde amount used). The lysine detectable (g/16 g N) after HCl hydrolysis was reduced due to pH raising (y = 101 - 0.67x). Solubility and fermentability of the soybean protein in the rumen were found to rise though. Consequently, the formaldehyde content of the protein was positively correlated with the content of soluble N and fermentable N, respectively, and negatively correlated with the lysine content. These experimental results allow to conclude that the desired protein protection to be attained by treating soybean extracted meal with formaldehyde, is greatly influenced by the respective pH value. To reach maximum protection of the protein against microbial degradation in the rumen (N degradation after 12 hours incubation less than or equal to 20% of total N), the pH value should be below 5. The contents of totally, reversibly or irreversibly bound formaldehyde does not allow any conclusion regarding the protein protection attained. The apparently increased binding rate of formaldehyde is presumably due to the fact that here the reaction stops at the stage of methylol formation (molar proportion 1:1). Under the conditions of acid protein hydrolysis for lysine determination, the released formaldehyde obviously reacts irreversibly with the E-NH2 group of lysine.     

微囊化沙门菌SP4噬菌体的制备及其缓释特性分析

通过采用阳离子醚化淀粉/海藻酸钠/黄原胶/纳米TiO₂/壳寡糖为原料制备微囊化SP4噬菌体,为控制沙门菌感染提供生物制剂。选用沙门菌SP4噬菌体,采用液滴法来制备微囊化SP4噬菌体,并对其效价、阳离子醚化淀粉浓度、海藻酸钠浓度、黄原胶浓度、壳寡糖浓度、pH稳定性、热稳定性、模拟胃液稳定性、模拟肠液释放行为以及保存稳定性进行分析。结果显示,当阳离子醚化淀粉浓度为2.4%、海藻酸钠浓度为2%、黄原胶浓度为1%、壳寡糖浓度为0.6%时,微囊化SP4噬菌体微球外形规则,包封率为97.5%,在pH5.0~8.0、温度10~30℃、模拟胃液pH2.0、0~30 min和pH3.0、0~150 min噬菌体保持较高的生物学活性,模拟肠液中4 h,噬菌体完全释放,4℃环境下保存6周噬菌体效价无明显降低。综上表明,微囊化沙门菌SP4噬菌体显著提高了噬菌体的稳定性和缓释性能,其耐酸特性利于抵御胃酸的分解,具有应用于生物防治的潜力,为进一步采用多因素试验制备微囊化沙门菌SP4噬菌体奠定了基础。     

Reproduction and Development of the Released Przewalski’s Horses (Equus przewalskii) in Xinjiang,China

In China, the first Przewalski’s horse (Equus przewalskii) group was released in Kalamaili Ungulate Protected Area in Xinjiang, in August 2001. The objective of this study was to investigate reproduction and development of released Przewalski’s horses in Xinjiang, China from 2002 to 2006. Twenty-four descendants were naturally born, average reproduction rate was 38.7%, and average survival rate of foals was 69.1% in this interim. Frequent alternation of the leading stallion and infertility in female horses due to environmental factors were main causes for the low reproduction rate. The infant mortality rate of released Przewalski’s horses was 25.0%, and 83.3% of death in infants was due to the leading stallion infanticide. The released Przewalski’s horses exhibited seasonal breeding, 70.8% of infants were born in May and June. The fertility rates were 8.3% in April and 37.5% in May, which were lower compared to those of the captive Przewalski’s horse groups (18.3% and 44.3%, respectively). Furthermore, the fertility rate in June was 33.3% and higher than the captive groups (18.3%). These findings showed that the breeding peak of the released Przewalski’s horse groups was later than the captive groups, and suggested that the altered survival environment and food supplies were the main reasons contributing to the delayed breeding peak.     

Changes in rumen microbial fermentation are due to a combined effect of type of diet and pH

Low ruminal pH may occur when feeding high-concentrate diets. However, because the reduction in pH occurs at the same time as the amount of concentrate fed increases, the changes observed in rumen fermentation may be attributed to pH or the type of substrate being fermented. Our objective was to determine the contribution of pH and type of substrate being fermented to the changes observed in rumen fermentation after supplying a high-concentrate diet. Eight dual-flow, continuous culture fermenters (1,400 mL) were used in 4 periods to study the effect of pH and type of diet being fermented on rumen microbial fermentation. Temperature (39 degrees C), solid (5%/h), and liquid (10%/h) dilution rates, and feeding schedule were maintained constant. Treatments were the type of diet (FOR = 60% ryegrass and alfalfa hays and 40% concentrate; CON = 10% straw and 90% concentrate) and pH (4.9, 5.2, 5.5, 5.8, 6.1, 6.4, 6.7, and 7.0). Diets were formulated to have similar CP and ruminally undegradable protein levels. Data were analyzed as a mixed-effects model considering the linear, quadratic, and cubic effects of pH, the effects of diet, and their interactions. Semipartial correlations of each independent variable were calculated to estimate the contribution of each factor to the overall relationship. True digestion of OM and NDF were affected by pH, but not by type of diet. Total VFA were reduced by pH and were greater in CON than in FOR. Acetate and butyrate concentrations were reduced by pH but were not affected by diet. Propionate concentration increased as the pH decreased and was greater in CON than in FOR. Ammonia-N concentration decreased with decreasing pH and was lower in CON than in FOR. Microbial N flow was affected by pH, diet, and their interaction. Dietary N flow increased as pH decreased and was greater in CON than in FOR. The degradation of CP followed the opposite pattern, increasing as pH increased, and was less in CON than in FOR. The efficiency of microbial protein synthesis (g of N/kg of OM truly digested) was slightly reduced by pH and was less in CON than in FOR. These results indicate that the effects of feeding a high-concentrate diet on rumen fermentation are due to a combination of pH and substrate. Furthermore, the digestion of OM in high-concentrate diets is likely limited by the pH-induced effects on the microbial population activity.     

仿生消化法测定猪饲料原料还原糖释放量的重复性和可加性研究

本试验旨在建立单胃动物仿生消化系统模拟猪饲料原料消化后还原糖释放量的测定方法,为饲料养分生物学效价的评估提供参考。还原糖释放量与上样量的线性关系研究以玉米-豆粕混合物(75%玉米+25%豆粕)为研究对象,上样量设0.2、0.4、0.6、0.8和1.0 g 5个处理,每个处理4个重复,每个重复1根消化管;方法的重复性检验以玉米-豆粕混合物、大麦、花生粕和米糠为研究对象,每个样品设3个批次,每个批次4个重复;方法的可加性检验设19个处理,其中处理1~7分别为玉米、大麦、高粱、大豆粕、花生粕、棉籽粕和米糠,处理8~19为2种或2种以上饲料原料按不同比例组合制备的12种混合饲料,每个处理4个重复,每个重复1根消化管,在仿生消化系统中模拟猪消化后测定各处理的还原糖释放量。结果表明:上样量在0.2~0.8 g时,还原糖总释放量与上样量呈显著的线性关系(R2=0.999 2),还原糖相对释放量在559.56~582.70 mg/g DM变化,变异系数为1.66%,而上样量为1.0 g时,还原糖相对释放量比上样量为0.2~0.8 g时的平均值下降5.37%;3个批次的大麦、花生粕、米糠和玉米-豆粕混合物的还原糖释放量的批内变异系数、批间变异系数和总变异系数均不大于1.68%,批间最大相对偏差分别为0.68%、1.50%、1.39%和0.29%;12种混合饲料还原糖释放量的实测值显著高于计算值(P0.05),而还原糖释放量的计算值与实测值的线性回归模型与y=x相重合(截距P=0.480 5;斜率P=0.514 1)。由此得出,当上样量在0.2~0.8 g时,上样量与还原糖释放量呈显著线性关系;仿生消化法测定猪饲料原料还原糖释放量的重复性和可加性满足定量分析的基本要求。