恩诺沙星纳米混悬注射剂的制备及在猪体内药动学研究

采用高压均质法制备恩诺沙星纳米混悬注射剂并对其制备工艺和质量进行考察、评价;采用高效液相色谱法测定猪血浆中恩诺沙星的浓度,以拜有利注射剂为参照考察恩诺沙星纳米混悬注射剂在猪体内的药动学。结果显示:制备的恩诺沙星纳米混悬注射剂,恩诺沙星的含量为97.9%,平均粒径为(613.21±5.78)nm、PDI(0.22±0.02)、Zeta电位为-2.02mV。恩诺沙星纳米混悬注射剂和拜有利注射剂在猪体内的达峰浓度(Cmax)分别为(0.32±0.12)、(0.67±0.09)mg/L,达峰时间(Tmax)分别为(2.88±0.96)、(0.79±0.26)h,消除半衰期(t1/2ke)分别为(5.99±1.37)、(4.49±1.25)h,AUClast分别为每小时(4.63±1.30)、(4.40±0.45)mg/L,MRTlast分别为(9.59±2.34)、(5.41±1.10)h;与拜有利注射剂相比,恩诺沙星纳米混悬注射剂相对生物利用度为105.2%。结论:高压均质法制备的恩诺沙星纳米混悬注射剂操作简单、不易沉降、再分散性好,理化性质较稳定;与拜有利注射剂相比其Tmax、t1/2k明显增加(P<0.01),MRT显著延长(P<0.01)表明恩诺沙星纳米混悬注射剂具有明显缓释作用且消除缓慢。     

磺胺间甲氧嘧啶混悬注射液在猪体内的药动学研究

本文比较了磺胺间甲氧嘧啶(SMM)和SMM-Na两种混悬注射液与SMM-Na注射液在猪体内的药物代谢动力学特征,旨在为SMM混悬注射液的开发和注册提供依据。将18头猪随机分成SMM混悬注射液、SMM-Na混悬注射液和SMM-Na注射液3个试验组,按100 mg/kg BW单次肌注给药。HPLC分析血浆中的药物浓度,用MCPKP程序计算动力学参数。3种制剂在猪体内的动力学过程都符合一级吸收二室模型,主要药动学参数如下,SMM混悬注射液:t1/2α(2.86±0.85)h,t1/2β(45.57±8.06)h,AUC(712.04±108.20)mg.L-1.h,Cmax(12.16±0.52)mg/L;SMM-Na混悬注射液:t1/2α(7.90±1.21)h,t1/2β(24.87±12.92)h,AUC(1 489.78±164.63)mg.L-1.h,Cmax(97.86±10.24)mg/L;SMM-Na注射液:t1/2α(0.10±0.04)h,t1/2β(6.20±0.57)h,AUC(1080.83±93.78)mg.L-1.h,Cmax(84.30±4.26)mg/L。SMM混悬注射液虽然消除缓慢,但血药浓度低,有效血药浓度时间短,很难达到临床治疗的要求;SMM-Na混悬注射液血药浓度高,有效血药浓度时间长,是一种较理想的缓释制剂。     

吡喹酮混悬注射剂的研制及其稳定性刺激性试验研究

通过处方与工艺的研究,制备吡喹酮混悬注射剂并对其稳定性及刺激性进行评价。以吡喹酮为主药,通过筛选不同的溶媒、助悬剂、润湿剂、抗氧剂以及正交试验的设计,最终成功研制出30%吡喹酮混悬注射液。试验结果表明,该制剂稳定性良好,主要指标均符合质量标准的要求,且刺激性较弱,可供肌肉注射使用。     

正交设计优选复方恩诺沙星混悬型注射剂处方的研究

恩诺沙星属氟喹诺酮第三代产品,具有抗菌谱广,杀菌活性强,体内分布广,抗菌作用独特,与其他抗菌药无交叉耐药性等特点。它对大部分革兰阴性菌、部分革兰阳性菌及某些支原体、衣原体、立克次体均有效。目前,临床上使用的恩诺沙星剂型主要有片剂、普通注射剂、散剂、溶液剂等。混悬剂是指难溶性固体药物以微粒状态分散于液体介质中而形成的非均相液体制剂,注射用的混悬剂要求颗粒大小适宜,具有良好的通针性和再分散性,而且不能沉降太快。将药物制成混悬型注射剂不仅解决了难溶性药物注射给药的问题,而且混悬剂注射给药后吸收延缓,可显著延长疗…     

纳米混悬制剂在兽药中的研究进展

部分兽药原料药由于水溶性较差或渗透性较低，导致生物利用度低，不能发挥良好的疗效。将药物制成纳米混悬制剂，能够减小药物粒度，改善药物溶解度，增加药物溶出度，并改变药物在生物体内的药代动力学特征，有效提高生物利用度。另外，纳米混悬制剂具备制造方法简单、条件温和等优势，满足理想的兽药开发条件。本文就纳米混悬制剂的制备方法，及其在兽药应用领域给药途径进行了综述，为纳米混悬制剂在兽药领域的研制提供参考及借鉴。     

硫酸头孢喹肟混悬注射剂对奶牛大肠杆菌性乳房炎的治疗试验

结合硫酸头孢喹肟药效学文献资料,试验选取了24头大肠杆菌性显性乳房炎病牛,一组肌内注射硫酸头孢喹肟混悬注射剂作治疗试验组,另一组肌内注射氨苄西林钠作药物对照组,结果表明,硫酸头孢喹肟混悬注射剂与注射用氨苄西林钠对奶牛大肠杆菌性乳房炎均有较好的治疗效果,在控制病程和产奶量方面头孢喹肟混悬注射剂明显优于注射用氨苄西林钠,肌内注射1mg/kg.bw硫酸头孢喹肟混悬注射剂,其临床治愈率可达90%以上,细菌学治愈率可达80%以上。     

恩诺沙星长效混悬剂对人工诱发鸭大肠杆菌病的疗效

大肠杆菌病是鸭的一种常见多发病，对雏鸭及成鸭危害极大，可单独感染，也可与其他疾病混合感染。大肠杆菌对氯霉素、磺胺类及氨基苷类等抗菌药物容易产生耐药性，导致疗效降低或治疗失败。目前临诊上常用氟喹诺酮类药物如恩诺沙星等进行治疗，对于非耐药菌株感染疗效确实，给药方法以混饲给药、饮水给药和注射给药为多见。由于鸭的饲养有别于鸡，混饲给药和饮水给药对于严重感染和急性感染疗效较差；普通注射剂需要多次注射，给药不方便且易造成应激。有鉴于此，笔者研制了恩诺沙星长效混悬注射剂，通过治疗人工诱发鸭大肠杆菌病以初步评价…     

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。     

缓释制剂的开发现状及其在兽药中的应用与展望

缓释制剂又称缓释药系统,即通常所说的长效制剂.早在我国古代,就有关于缓释制剂的记载和描述.如李杲的"丸者缓也,舒缓而治"是关于缓释制剂的较早的记载.随着现代兽医药学的发展,缓释制剂得到了越来越广泛的应用,为了使更多的人了解缓释制剂,本文对缓释制剂的基本知识和特点、缓释制剂的研究开发现状及发展前景进行了综述.     

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。     

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.     

Enhancement of antibacterial activity of tilmicosin against Staphylococcus aureus by solid lipid nanoparticles in vitro and in vivo

This study aimed to enhance the antibacterial activity of tilmicosin by solid lipid nanoparticles (SLN). Tilmicosin-loaded hydrogenated castor oil (HCO)-SLN was prepared using a hot homogenisation and ultrasonication method. The physicochemical characteristics of SLN were investigated by scanning electron microscopy (SEM) and photon correlation spectroscopy (PCS). The antibacterial activity of tilmicosin-SLN against Staphylococcus aureus was evaluated by growth inhibition and colony-counting method. A therapeutic study of tilmicosin-SLN was conducted by subcutaneous injection in a mouse mastitis model infected with S. aureus by teat canal infusion. Therapeutic efficacy was assessed by physical appearance of the mammary gland and measurement of colony-forming units (CFU) per gland. The results showed that the diameter, polydispersivity index, zeta potential, encapsulation efficiency and loading capacity of the nanoparticles were 343±26 nm, 0.33±0.08, -7.9±0.4 mV, 60.4±3.3% and 11.2±0.47%, respectively. Tilmicosin-SLN showed a sustained-release effect and sustained and enhanced antibacterial activity in vitro. SLN significantly enhanced the therapeutic efficacy of tilmicosin determined by lower CFU counts and a decreased degree of inflammation. These results demonstrated that the HCO-SLN is an effective carrier to enhance the antibacterial activity of tilmicosin.     

Safety evaluation of moxidectin sustained-release injectable in 10-week-old puppies

A study was conducted to evaluate the safety of a commercial formulation of moxidectin sustained-release injectable for dogs (ProHeart 6, Fort Dodge Animal Health) administered as a single subcutaneous dose to 10-week-old puppies. Twelve male and 12 female purpose-bred beagles 10 weeks of age were blocked by weight within gender and randomly allocated to three treatment groups. Puppies in two groups were treated with moxidectin sustained-release injectable for dogs at three or five times the labeled dose rate of 0.17 mg moxidectin/kg. The third group was treated with saline solution as controls. Physical and neurologic status, hematologic parameters, clinical chemistries, urine samples, body weight, and food consumption were evaluated before and up to 12 weeks after treatment. When compared to controls, mild depression of erythropoiesis, characterized by reduced hemoglobin, reticulocytes, erythrocytes, and hematocrit, was noted in puppies treated with five times the label dose of moxidectin sustained-release injectable. Values for these parameters remained within normal ranges and increased during the study, but at a reduced rate relative to saline-treated controls. Other parameters evaluated remained within normal limits for all treatment groups. Based on results of this study, the no observed adverse effect level for moxidectin sustained-release injectable (ProHeart 6) treatment in 10-week-old puppies was determined to be three times the recommended rate.     

Hydrogenated castor oil nanoparticles as carriers for the subcutaneous administration of tilmicosin: in vitro and in vivo studies

Tilmicosin-loaded solid lipid nanoparticles (SLN) were prepared with hydrogenated castor oil (HCO) by o/w emulsion–solvent evaporation technique. The nanoparticle diameters, surface charges, drug loadings and encapsulation efficiencies of different formulations were 90∼230 nm, −6.5∼−12.5 mV, 40.3∼59.2% and 5.7∼11.7% (w/w), respectively. In vitro release studies of the tilmicosin-loaded nanoparticles showed a sustained release and the released tilmicosin had the same antibacterial activity as that of the free drug. Pharmacokinetics study after subcutaneous administration to Balb/c mice demonstrated that a single dose of tilmicosin-loaded nanoparticles resulted in sustained serum drug levels (>0.1 μg/mL) for 8 days, as compared with only 5 h for the same amount of tilmicosin phosphate solution. The time to maximum concentration (Tmax), half-life of absorption (T½ ab) and half-life of elimination (T½ el) of tilmicosin-loaded nanoparticles were much longer than those of tilmicosin phosphate solution. Tissue section showed that drug-loaded nanoparticles caused no inflammation at the injection site. Cytotoxicity study in cell culture and acute toxicity test in mice demonstrated that the nanoparticles had little or no toxicity. The results of this exploratory study suggest that the HCO–SLN could be a useful system for the delivery of tilmicosin by subcutaneous administration.     

Pharmacokinetics of an injectable sustained-release formulation of morphine for use in dogs

This study investigated the pharmacokinetics of morphine sulphate in an injectable chitosan-based gel. Gels were made from a combination of N-O-carboxymethylchitosan (NOCC) and chitosan and were easily injectable via a 22 gauge needle and appeared stable during long-term storage. Groups of six beagles were injected subcutaneously (s.c.) with 1.2 mg/kg morphine sulphate, either in sterile saline or in sterilized gels, and serial blood samples were withdrawn via a jugular catheter and later analysed for morphine concentrations using radioimmunoassay. Data were analysed according to non-compartmental pharmacokinetics. NOCC-based gels resulted in significantly lower serum morphine concentrations at 10 and 30 min following injection but significantly higher concentrations at all points from 120 to 480 min post-injection. Dogs receiving morphine gel exhibited equivalent or lesser variability in serum morphine concentrations than dogs receiving conventional morphine sulphate. Pharmacokinetic analysis revealed that morphine release from the gel matrix was significantly prolonged but fully bioavailable. There were no significant differences in either distribution ( V _d) or terminal elimination ( t _1/2). Dogs experienced no adverse effects other than those normally associated with morphine administration at the time of injection but all dogs receiving the gel presented with an undefined stiffness the next day that resolved spontaneously within 48 h. We conclude that carboxymethylchitosan-based gels hold considerable promise for the development of injectable sustained-release formulations of opioid analgesics.     

Efficacy of a long-acting formulation of ivermectin against Psoroptes ovis (Hering, 1838) on cattle

A study was conducted in cattle experimentally infested with Psoroptes ovis to compare the prophylactic control against P. ovis provided by a long-acting injectable formulation of ivermectin to that of a commercially available injectable formulation of doramectin. Thirty Holstein steers were used. Animals were allocated by restricted randomization based on Day 0 body weight, forming six replicates of five animals each. Within each replicate, one animal was randomly allocated to one of the following treatment groups, with ivermectin and doramectin administered subcutaneously where indicated: (1) untreated controls; (2) ivermectin long-acting injectable (LAI) 630 mcg/kg, 56 days before challenge; (3) ivermectin LAI 630 mcg/kg, 42 days before challenge; (4) ivermectin LAI 630 mcg/kg, 35 days before challenge; or (5) doramectin 200 mcg/kg, 35 days before challenge. Animals were housed in individual pens 1 week prior to treatment. All animals were experimentally infested with P. ovis mites in the area between the shoulders, on the same day. Live mites were counted in scrapings from mange lesions at 2 sites on each animal 14, 21 and 28 days after challenge. Live mites were found in 33, 67 and 83% of the untreated controls on each respective evaluation. No P. ovis mites were found in steers treated with ivermectin LAI. Those animals showed lower (P < 0.05) mite counts than untreated controls on evaluations conducted 21 and 28 days after challenge. These results indicate that the ivermectin long-acting injectable formulation prevents induced infestations by P. ovis for at least 56 days after treatment. Doramectin injectable formulation, used at 200 mcg/kg, did not have a prophylactic effect 35 days after treatment.     

Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats

OBJECTIVE: To determine whether particular vaccine brands, other injectable medications, customary vaccination practices, or various host factors were associated with the formation of vaccine-associated sarcomas in cats. DESIGN: Prospective multicenter case-control study. ANIMALS: Cats in the United States and Canada with soft tissue sarcomas or basal cell tumors. PROCEDURE: Veterinarians submitting biopsy specimens from cats with a confirmed diagnosis of soft tissue sarcoma or basal cell tumor were contacted for patient medical history. Time window statistical analyses were used in conjunction with various assumptions about case definitions. RESULTS: No single vaccine brand or manufacturer within antigen class was found to be associated with sarcoma formation. Factors related to vaccine administration were also not associated with sarcoma development, with the possible exception of vaccine temperature prior to injection. Two injectable medications (long-acting penicillin and methyl prednisolone acetate) were administered to case cats more frequently than to control cats. CONCLUSIONS AND CLINICAL RELEVANCE: Findings do not support the hypotheses that specific brands or types of vaccine within antigen class, vaccine practices such as reuse of syringes, concomitant viral infection, history of trauma, or residence either increase or decrease the risk of vaccine-associated sarcoma formation in cats. There was evidence to suggest that certain long-acting injectable medications may also be associated with sarcoma formation.     

Adjuvant effect enhancement of porcine interleukin-2 packaged into solid lipid nanoparticles

In this paper, we investigated the enhancement of adjuvant effects of porcine IL-2 (pIL-2) by packaging it into a solid lipid nanoparticle (SLN) delivery system. SLN–pIL-2 was prepared using hydrogenated castor oil and Polylactide-co-glycolide by double emulsion solvent evaporation methods (w/o/w). In animal trials, BALB/c mice were immunized with inactivated foot and mouth disease virus (FMDV) antigen combined with the SLN–pIL-2 adjuvant on days 0 and 14. Antibody titer, splenocyte proliferation, and secretion of IFN-γ and IL-4 cytokines were determined. Our results showed that SLN–pIL-2 could significantly enhance FMDV-specific antibody level compared with recombinant pIL-2 alone (p < 0.05). In addition, SLN–pIL-2 significantly increased the proliferative responses of antigen-specific spleen cells. Furthermore, SLN–pIL-2 induced the secretion of IFN-γ at a level higher than that induced by recombinant pIL-2 alone. Our results indicate that packaging recombinant pIL-2 in SLNs can be an effective way of boosting the effectiveness of pIL-2 as an adjuvant to enhance immune responses of vaccines.     

A field trial evaluation of the effectiveness and benefit of cydectin long-acting injectable and ivomec injectable as used one time in grazing stocker cattle

Use of moxidectin long-acting injectable and ivermectin injectable in female Bos taurus beef-type calves was evaluated in terms of efficacy (fecal egg counts) and performance parameters (weight gain). In this 150-day study, moxidectin-treated calves gained 20% more weight than did ivermectin-treated and control calves. Mean fecal egg count reductions ranged from 76.7 to 99.0 for moxidectin and -0.8 to 83.4 for ivermectin. Moxidectin long-acting injection provided efficacious (immediate as well as long-term) egg count suppressions as well as enhanced animal productivity (weight gains). The study also showed that Cooperia spp appear poised to present the most immediate challenges once long-acting macrocyclic lactone treatments become available.     

乙酰氨基阿维菌素注射用缓释剂质量标准与药学等效研究

依据《中华人民共和国兽药典》与《兽药研究技术指导原则汇编》等相关指导要求,对乙酰氨基阿维菌素（EPR）注射用缓释剂进行外观、黏度、pH、水分、密度、内毒素、含量及有关物质检测,建立EPR注射用缓释剂的质量标准并比较与参比制剂的药学等效性。含量与有关物质检测方法为使用ZORBAX Eclipse Plus C18柱（2.1 mm×50 mm,1.8 μm）;流动相：甲酸：水：乙腈（0.04 mL：40 mL：60 mL）;流速：0.4 mL/min;检测波长：245 nm;柱温：35 ℃;进样量：2 μL。在37 ℃,转速为50 r/min,0.5% SDS的PBS缓冲液条件下,比较自研与原研EPR注射用缓释剂的药学等效性。EPR注射用缓释剂外观澄清透明,平均相对黏度为46.45 mPa·s,平均pH为6.88,制剂中不含水分,密度为1.13 g/cm³,内毒素满足<0.1 EU/mL限度,含量>5%的标示值,有关物质的量<5%,检测结果均符合注射剂制剂要求;在同一条件下释放31 d后,自研与原研EPR注射用缓释剂累积释放量均超过80%,且自研与原研的相似因子（f2）值>50。自研EPR注射用缓释剂的检测结果均符合注射剂标准,自研与原研EPR注射用缓释剂具有药学等效。