甲砜霉素纳米乳的制备及其在家兔体内的药物动力学研究
|
摘要
本研究旨在研制出包封率高、稳定性好、安全、高效的甲砜霉素纳米乳,并研究其在家兔体内的药物动力学过程。
1.甲砜霉素纳米乳的制备本试验通过以聚氧乙烯氢化蓖麻油(RH-40),吐温-80,司班-80,无水乙醇,正丁醇,丙二醇,丙三醇,肉豆蔻算异丙酯(IPM),蓖麻油,石蜡油,乙酸乙酯为原料制备空白纳米乳。采用伪三元相图,考察纳米乳体系中不同的表面活性剂、助表面活性剂、Km值、油相、水相对纳米乳形成区域的影响,结合origin 7.0软件分析,筛选出最佳的制备配方。结果显示,以RH-40/IPM/蒸馏水为药用载体,制得的纳米乳形成区域的面积最大,可以作为甲砜霉素纳米乳的处方。
2.甲砜霉素纳米乳理化性质用透射电镜、激光粒度分布仪等对其理化性质进行研究。结果表明,甲砜霉素纳米乳是无色澄清透明的液体,其平均粒径为18.5 nm,粒径分布范围窄,且比较均匀。
3.甲砜霉素纳米乳稳定性考察用紫外可见分光光度法测定甲砜霉素纳米乳中甲砜霉素的含量,并通过离心、加速、留样和光照考察其稳定性。试验结果表明,甲砜霉素在232 nm处有最大吸收,在1μg/mL～50μg/mL范围内线性关系良好,其平均回收率为97.60%,平均包封率为88.17%,该方法可用于甲砜霉素纳米乳的包封率和含量的测定;高速离心、恒温加速、留样观察,外观和含量未发生明显变化。
4.甲砜霉素纳米乳安全性评价通过急性毒性试验、皮肤刺激实验和眼部刺激试验对甲砜霉素纳米乳进行安全性评价。结果表明,甲砜霉素纳米乳对小鼠的LD_(50)为1342 mg/kg,属于低毒;对家兔皮肤和眼部均无刺激。
5.甲砜霉素纳米乳体外抑菌试验选取临床常见致病菌,以试管二倍稀释法对甲砜霉素纳米乳进行体外抑菌实验。结果表明,甲砜霉素纳米乳对致病性大肠埃希菌、金黄色葡萄球菌、无乳链球菌的MIC和MBC都分别为游离甲砜霉素的1/2、1/4和1/2。
6.甲砜霉素纳米乳在家兔体内的药物动力学试验健康家兔口服甲砜霉素纳米乳20 mg/kg,36 h内不同时间10次心脏采血,高效液相色谱法测定血药浓度,残数法拟合药时曲线,计算药动学参数。结果表明,6只家兔口服甲砜霉素纳米乳(20 mg/kg)后,其药动学配置符合有吸收因素一室模型特征。最佳药时曲线方程为:C = 9.0972(e~(-0.2214t)-e~(-1.4944t))。甲砜霉素在家兔体内的吸收半衰期(t_(1/2Ka))为0.48±0.08 h,消除半衰期(t_(1/2Ke))为3.13±0.05 h,药时曲线下面积(AUC)为34.83±0.72 (mg/L)·h。表明甲砜霉素纳米乳在家兔体内吸收迅速,消除相对较慢。
The purpose of this study was to prepare a high encapsulation efficiency, stability, security and efficient thiamphenicol nanoemulsion and to study pharmacokinetics process in the rabbits.
1. Preparation of thiamphenicol nanoemulsion: Blank nanoemulsion was prepared using RH-40, Tween-80,Span-80,IPM, dehydrated alcohol, propylene glycol, glycerine, castor oil, paraffin oil, acetoacetate as raw material. The nanoemulsion was evaluated by using artifical three initiatives phase diagram, and to study the effect of surfactants , aid- surfactant, Km, oils and water on the area of nanoemulsion forming. What is more, with the help of the software origin 7.0, The best prescription and craft was selected.The results showed that using RH-40/IPM/water as nanoemulsion area to prepare nanoemulsion, the area of the nanoemulsion was maximum. So that, RH-40/IPM/water was selected as the prescription of thiamphenicol nanoemulsion.
2. The physico-chemical property of thiamphenicol nanoemulsion: The physico-chemical property was detected by electron microscope, photon correlation spectroscope. The results showed that thiamphenicol nanoemulsion was clarified and transparent liquid. Its average diameter was 18.5 nm. The disposition of diameter was narrow and uniformity.
3. The stability of thiamphenicol nanoemulsion: The content of thiamphenicol were measured by ultraviolet spectrophotometer .The stability of thiamphenicol nanoemulsion was evaluated by centrifuging, acceleration, light and long-term. The results showed that thiamphenicol had the maximal absorption in 232nm. It had a good linear range in 1μg/mL～50μg/mL, its mean recovery was 97.60%, and its mean entrapment efficiency was 88.17%. The method of determining was convenient, sensitive, accurate and suitable for determining the entrapment efficiency and content of the nanoemulsion. The appearance and content of nanoemulsion did not change by high-speed centrifuging, constant temperature acceleration and long-term.
4. The safety evaluation of thiamphenicol nanoemulsion: The safety of thiamphenicol nanoemulsion was evaluated by acute toxicity, skin irritation, eye irritation experiment.The results showed that the accmumulation LD50 of the thiamphenicol nanoemulsion test on mouse was 1342mg/kg. The stimulation to the skin and eye of domestic rabbits were all nontoxic,no skin allergy response.
5. Antibacterial effect in vitro of thiamphenicol nanoemulsion: Antibacterial activity in vitro of the nanoemulsion to 3 common strains in veterinarian clinical practice was tested by tube double dilution method. Minimal inhibitory concentration and minimal bactericidal concentration of the nanoemulsion was 1/2, 1/4 and 1/2 to that of free thiamphenicol for Escherichia coli, Staphylococcus aureus and Streptococcus agalactiae in vitro.
6. Pharmacokinetics in rabbits of thiamphenicol nanoemulsion: Rabbits were treated with thiamphenicol nanoemulsion (20 mg/kg) for oral use , while the blood samples were collected from coeur within 36 hour post giving drug. The concentrations of thiamphenicol nanoemulsion in blood were determined by high performance liquid chromatography (HPLC). Concentration-time is fitted by method of residual And pharmacokinetic parameters is calculated.The results showed that the one-compartment open model with first-order absorption factor adequately describes concentrations of thiamphenicol nanoemulsion(20 mg/kg) for PO in 6 rabbits’blood disposition and the best concentration-time equations are: C = 9.0972( e~(-0.2214t) - e~(-1.4944t) ) . The primary pharmacokinetic parameters of thiamphenicol nanoemulsion are: t1/2Kα=0.475±0.077 h, t_(1/2Ke)=3.132±0.051 h, AUC=34.825±0.720μg·mL~(-1)·h, T_(max)=1.519±0.164 h., C_(max)=5.575±0.515μg·mL~(-1). It will be seen that the distribution of thiamphenicol nanoemulsion in vivo is rapid, and the elimination of thiamphenicol nanoemulsion in vivo is slowly. relatively.
1.甲砜霉素纳米乳的制备本试验通过以聚氧乙烯氢化蓖麻油(RH-40),吐温-80,司班-80,无水乙醇,正丁醇,丙二醇,丙三醇,肉豆蔻算异丙酯(IPM),蓖麻油,石蜡油,乙酸乙酯为原料制备空白纳米乳。采用伪三元相图,考察纳米乳体系中不同的表面活性剂、助表面活性剂、Km值、油相、水相对纳米乳形成区域的影响,结合origin 7.0软件分析,筛选出最佳的制备配方。结果显示,以RH-40/IPM/蒸馏水为药用载体,制得的纳米乳形成区域的面积最大,可以作为甲砜霉素纳米乳的处方。
2.甲砜霉素纳米乳理化性质用透射电镜、激光粒度分布仪等对其理化性质进行研究。结果表明,甲砜霉素纳米乳是无色澄清透明的液体,其平均粒径为18.5 nm,粒径分布范围窄,且比较均匀。
3.甲砜霉素纳米乳稳定性考察用紫外可见分光光度法测定甲砜霉素纳米乳中甲砜霉素的含量,并通过离心、加速、留样和光照考察其稳定性。试验结果表明,甲砜霉素在232 nm处有最大吸收,在1μg/mL～50μg/mL范围内线性关系良好,其平均回收率为97.60%,平均包封率为88.17%,该方法可用于甲砜霉素纳米乳的包封率和含量的测定;高速离心、恒温加速、留样观察,外观和含量未发生明显变化。
4.甲砜霉素纳米乳安全性评价通过急性毒性试验、皮肤刺激实验和眼部刺激试验对甲砜霉素纳米乳进行安全性评价。结果表明,甲砜霉素纳米乳对小鼠的LD_(50)为1342 mg/kg,属于低毒;对家兔皮肤和眼部均无刺激。
5.甲砜霉素纳米乳体外抑菌试验选取临床常见致病菌,以试管二倍稀释法对甲砜霉素纳米乳进行体外抑菌实验。结果表明,甲砜霉素纳米乳对致病性大肠埃希菌、金黄色葡萄球菌、无乳链球菌的MIC和MBC都分别为游离甲砜霉素的1/2、1/4和1/2。
6.甲砜霉素纳米乳在家兔体内的药物动力学试验健康家兔口服甲砜霉素纳米乳20 mg/kg,36 h内不同时间10次心脏采血,高效液相色谱法测定血药浓度,残数法拟合药时曲线,计算药动学参数。结果表明,6只家兔口服甲砜霉素纳米乳(20 mg/kg)后,其药动学配置符合有吸收因素一室模型特征。最佳药时曲线方程为:C = 9.0972(e~(-0.2214t)-e~(-1.4944t))。甲砜霉素在家兔体内的吸收半衰期(t_(1/2Ka))为0.48±0.08 h,消除半衰期(t_(1/2Ke))为3.13±0.05 h,药时曲线下面积(AUC)为34.83±0.72 (mg/L)·h。表明甲砜霉素纳米乳在家兔体内吸收迅速,消除相对较慢。
The purpose of this study was to prepare a high encapsulation efficiency, stability, security and efficient thiamphenicol nanoemulsion and to study pharmacokinetics process in the rabbits.
1. Preparation of thiamphenicol nanoemulsion: Blank nanoemulsion was prepared using RH-40, Tween-80,Span-80,IPM, dehydrated alcohol, propylene glycol, glycerine, castor oil, paraffin oil, acetoacetate as raw material. The nanoemulsion was evaluated by using artifical three initiatives phase diagram, and to study the effect of surfactants , aid- surfactant, Km, oils and water on the area of nanoemulsion forming. What is more, with the help of the software origin 7.0, The best prescription and craft was selected.The results showed that using RH-40/IPM/water as nanoemulsion area to prepare nanoemulsion, the area of the nanoemulsion was maximum. So that, RH-40/IPM/water was selected as the prescription of thiamphenicol nanoemulsion.
2. The physico-chemical property of thiamphenicol nanoemulsion: The physico-chemical property was detected by electron microscope, photon correlation spectroscope. The results showed that thiamphenicol nanoemulsion was clarified and transparent liquid. Its average diameter was 18.5 nm. The disposition of diameter was narrow and uniformity.
3. The stability of thiamphenicol nanoemulsion: The content of thiamphenicol were measured by ultraviolet spectrophotometer .The stability of thiamphenicol nanoemulsion was evaluated by centrifuging, acceleration, light and long-term. The results showed that thiamphenicol had the maximal absorption in 232nm. It had a good linear range in 1μg/mL～50μg/mL, its mean recovery was 97.60%, and its mean entrapment efficiency was 88.17%. The method of determining was convenient, sensitive, accurate and suitable for determining the entrapment efficiency and content of the nanoemulsion. The appearance and content of nanoemulsion did not change by high-speed centrifuging, constant temperature acceleration and long-term.
4. The safety evaluation of thiamphenicol nanoemulsion: The safety of thiamphenicol nanoemulsion was evaluated by acute toxicity, skin irritation, eye irritation experiment.The results showed that the accmumulation LD50 of the thiamphenicol nanoemulsion test on mouse was 1342mg/kg. The stimulation to the skin and eye of domestic rabbits were all nontoxic,no skin allergy response.
5. Antibacterial effect in vitro of thiamphenicol nanoemulsion: Antibacterial activity in vitro of the nanoemulsion to 3 common strains in veterinarian clinical practice was tested by tube double dilution method. Minimal inhibitory concentration and minimal bactericidal concentration of the nanoemulsion was 1/2, 1/4 and 1/2 to that of free thiamphenicol for Escherichia coli, Staphylococcus aureus and Streptococcus agalactiae in vitro.
6. Pharmacokinetics in rabbits of thiamphenicol nanoemulsion: Rabbits were treated with thiamphenicol nanoemulsion (20 mg/kg) for oral use , while the blood samples were collected from coeur within 36 hour post giving drug. The concentrations of thiamphenicol nanoemulsion in blood were determined by high performance liquid chromatography (HPLC). Concentration-time is fitted by method of residual And pharmacokinetic parameters is calculated.The results showed that the one-compartment open model with first-order absorption factor adequately describes concentrations of thiamphenicol nanoemulsion(20 mg/kg) for PO in 6 rabbits’blood disposition and the best concentration-time equations are: C = 9.0972( e~(-0.2214t) - e~(-1.4944t) ) . The primary pharmacokinetic parameters of thiamphenicol nanoemulsion are: t1/2Kα=0.475±0.077 h, t_(1/2Ke)=3.132±0.051 h, AUC=34.825±0.720μg·mL~(-1)·h, T_(max)=1.519±0.164 h., C_(max)=5.575±0.515μg·mL~(-1). It will be seen that the distribution of thiamphenicol nanoemulsion in vivo is rapid, and the elimination of thiamphenicol nanoemulsion in vivo is slowly. relatively.
引文
[1]陈杖榴.兽医药理学[M].第2版.北京:中国农业出版社,2002,218-220.
[2] Lorenzo Drago, Elena De Vecchi, Maria Cristina Fassina, et al.Serum and lung levels of thiamphenicol after administration of its glycinate N-acetylcysteinate ester in experimentally infected guinea pigs [J]. International Journal of Antimicrobial Agents, 2000, 13(4):301-303.
[3] Castells G., Prats C., Korchi G. E. L., et al.Thiamphenicol disposition in pigs [J]. Research in Veterinary Science, 1999, 66(3):219-222.
[4]汤光,李大魁.现代临床药物学[M].北京:化学工业出版社,2003,77-79.
[5] Vivian Tullio, Annamaria Cuffini, Narcisa Mandras, et al. Influence of thiamphenicol on the primary functions of human polymorphonuclear leucocytes against Streptococcus pyogenes [J]. International Journal of Antimicrobial Agents, 2004, 24(4):381-385.
[6] Lettresàla redaction. Thiamphenicol susceptibility of S. pneumoniae, H. influenzae and B. catarrhalis strains identified in a pediatric unit [J]. Médecine et maladies infectieuses, 2003, 33(5):276-279.
[7] Turton J. A., Havard A. C., Robinson S., et al. An assessment of chloramphenicol and thiamphenicol in the induction of aplastic anaemia in the BALB/c mouse [J]. Food and Chemical Toxicology, 2000, 38(10):925-938.
[8]王涛.甲砜霉素顿服治疗淋病及非淋菌性尿道炎疗效观察[J].临床误诊误治,2007,20(1):85.
[9]何湘.甲砜霉素与强力霉素联合治疗支原体感染的疗效观察[J].中国现代医药,2007,9(1):89-90.
[10]尹仲.甲砜霉素与司巴沙星治疗尿道(宫颈)解脲支原体疗效比较[J].华夏医学,2004,17(3):384-385.
[11]葛正义.甲砜霉素治疗耐药淋病60例疗效观察[J].浙江临床医学,2002,4(10):788.
[12]叶一萍.甲砜霉素治疗支原体感染耐药病例16例效果观察[J].齐齐哈尔医学院学报,2003,24(3):277.
[13]赵飞,李红文,何秋波.甲砜霉素对小儿泛发性脓疱型银屑病的治疗观察[J].中国麻风皮肤病杂志,2004,20(3):240-241.
[14]潘虎,顾加红,郝飞.甲砜霉素治疗掌跖脓疱病疗效观察[J].中华皮肤科杂志,2006,39(11):668.
[15]马绍云.甲砜霉素联合雷公藤治疗掌跖脓疱病疗效观察[J].皮肤病与性病,2003,25(1):34-35.
[16]周振新,严明,陈洪.复方甲砜霉素注射液对人工感染鸡巴氏杆菌病的临床疗效试验[J].河北畜牧兽医,2000,19(8):20-21.
[17]陈平,罗淑琼,黄庆洲,等.仔猪黄白痢大肠杆菌病原的分离鉴定及其药效试验[J].四川畜牧兽医,2002,29(6):19,22.
[18]黄庆洲,郭定章,但麒麟,等.川渝两地鸭疫里氏杆菌分离鉴定及药效试验[J].四川畜牧兽医,2002,29(1):19-20.
[19]刘富来,冯翠兰,王林川.番鸭感染肠炎沙门氏菌的分离鉴定[J].畜牧与兽医,2004,36(8):37-38.
[20]黄正才,吴绍容.甲砜霉素对牛细菌性呼吸器病的效果研究[J].黑龙江畜牧兽医,1999,(11):24-26.
[21]朱方容,田智得,石美宁.家蚕细菌病治疗药物的研究[J].广西蚕业,2003,40(2):4-9.
[22]吴俊伟,曾忠良,罗音久,等.甲砜霉素注射液的研制及稳定性实验[J].四川畜牧兽医学院学报,2000,14(4):1-5.
[23]吴俊伟,陆彬.甲砜霉素β-环糊精包合物的研制[J].华西药学杂志,2000,15(6):420-422.
[24]黄春玉,周建平,姚静,等.尼莫地平微乳及自微乳的家兔口服生物利用度研究[J].中国药科大学学报,2004,35(5):409-412.
[25]阎家麒,王惠杰,童岩,等.紫杉醇微乳的研究[J].中国药学杂志,2000,35(3):173-176.
[26]刘英,蒋雪涛,鲁莹,等.紫外分光光度法测定5-氟尿嘧啶微乳的含量研究[J].中国新药杂志,2000,9(7):464-465.
[27]姚静,周建平,卢韵,等.聚氧乙烯蓖麻油微乳对血脑屏障通透性的影响[J].中国药科大学报,2005,6(1):27-30.
[28]张小华,张龙,范斌.紫外分光光度法测定甲砜霉素片的含量[J].化学分析计量,2002,11(1):16.
[29]王建华,陈世山.同时测定鱼肉中氯霉素和甲砜霉素残留量的毛细管气相色谱法[J].分析测试学报,2001,20(3):89.
[30]寇晋萍,王国兰,余立.HPLC法测定甲砜霉素胶囊含量[J].首都医药,2004,(18):52.
[31] Mestorino N, Landon M F, Alt M,et al. The pharmacokinetics of thiamphenicol inlacting cows.J Vet Pharmacol Ther.1993, 295-303.
[32] Abdennebi EH, Sawchuk RJ, Stowe CM. Thiamphenicol pharmacokinetics in beef and dairy cattle. J Vet Pharmacpl Ther., 1994, 17(5):365-368.
[33] Abdennebi,E H and Stowe,C M.Pharmacokinetics and distribution of thiamphenicol in sheep given repeated intramuscular dose.Vet.Res, 1994, 25:489-494.
[34] Castell, Intorre L, Franquelo C, Cristofol C, et al. Pharmacokintics of thiamphenicol in dogs. Am J Vet Res, 1998, 59(11):1473-1475.
[35] Darwin L.P,Agamemnon D, Eppie D R. Induction of Chloramphenicol Metabism by Phenobarbital. Antimicrob. Agents Chemother, 1972, 1(2):112-115.
[36]陈晓兰.甲砜霉素在鸡的药动学及组织残留HPLC检测方法的研究[D].扬州大学,2006,15-22.
[37]周志凌,梁净.甲砜霉素胶囊含量测定方法的改进[J].中国药品标准,2005,6(6):35-37.
[38]陆广富,陈晓兰,卜仕金.鸡组织中甲砜霉素残留HPLC检测方法[J].中国兽医杂志,2008,44(2):85.
[39]徐楚鸿,吕永宁,韩召敏.HPLC法测定人血清中甲砜霉素浓度[J].中国医药,2006,12:24.
[40]杨亚军,李引乾.甲砜霉素脂质体制备和体外抑菌效果[J].西北农业学报2007,16(4):213-215.
[41] Kowalski P., Capillary electrophoretic determination of thiamphenicol in turkeys serum and its pharmacokinetic application [J]. Journal of Pharmaceutical and Biomedical Analysis, 2007, 43(1):222-227.
[42] Ando J., Ishihara R., Imai Sh., et al. Thirteen-week subchronic toxicity study of thiamphenicol in F344 rats [J]. Toxicology Letters, 1997, 91(2):137-146.
[43]杜向党,阎若潜,沈建忠.氯霉素类药物耐药机制的研究进展[J].动物医学进展,2004,25(2):27-2.
[44] Kitamura T., Ando J., Ishihara R., Takano S., et al. Lack of Carcinogenicity of Thiamphenicol in F344 Rats [J]. Food and Chemical Toxicology, 1997, 35(10, 11):1075-1080.
[45] Nobile L., Cavrini V., Raggi M. A., et al. Analysis of thiamphenicol glycinate salts in pharmaceutical formulations by derivative UV spectroscopy [J]. International Journal of Pharmaceutics, 1987, 40(1, 2):85-91.
[46]寇贺红.丁香酚纳米乳的研制[D].西北农林科技大学,2006.
[47]张文娟.利福平微乳的研制[D].西北农林科技大学,2006.
[48]张阳德.纳米药物学[M].北京:化学工业出版社,2006,163.
[49]刘程.表面活性剂大全田.北京:北京工业大学出版社,1994.
[50] KohsakuK awakami, Ta kayoshiYo shikawa, Ya sushiM oroto, et al. Microemulsion formulationfo renh anced a bsorptionof po orlyso luble drugs. IP rescriptiond esign.J control Re l, 2002, 81(22):65 -7 4.
[51]杨惊宇.隐丹参酮微乳的制备工艺及相对生物利用度的测定[D].湖南中医学院,2005.
[52] E C Swenson, WJCuratolo.Adv.DrugDeliv, 1992, 8(1):39-92.
[53]吴顺芹,李三鸣,郎轶咏,等.水包油型微乳形成因素的考察[J].沈阳药科大学学报,2005,2:96-99.
[54] Sanchez L, Mitjans M, Infante MR,etal, Potential irritationof lysine derivative surfactants by hemolysis and HaCaT cellviability[J]. Toxicology Letters. 2006,(161):53-60.
[55]潘国梁,魏惠华,陈彦,贾晓斌.葛根素微乳的质量评价[J].时珍国医国药,2005,16(7):582-583.
[56]于力,张钧寿,周建平.纳米乳的研究及其在制剂学领域的应用[J].药学进展,2006,30(11):491-498.
[57] Robbins M L. Microemulsion Solubilization and Microemulsion[M]. Plenum Press, New York, 1997, 713.
[58] Mukherjee K, M ukherjee DC, Moulik SP. Thermodynamics of microemulsion formation(?. enthalpies of solution of water inch loroform as well as chloroform in water aided bycationic, anionic, and nonionic surfactants) [J]. J Colloid Interface Sci, 1997, 187:327-333.
[59] Munsh iN , De TK, M aitra A. Size modulation of polymericnano particles under controlled dynamics of microemulsion droplets[J]. J Colloid Interface Sic, 1997, 190:387-392.
[60] Cottens S, Haeberlin B, Sedrani R, etal. Pharmaceaticecl microemulsion preconcent rates containing cyclosporings and macrecides. Swifz, WO 96132739 May 1996.
[61] Kim CK, Cho YJ, Gao ZG. Preparation and evaluation ofbiphenyl dimethyl dicarboxylate microemulsions for oral delivery[J]. J Controlled Release, 2001, 70(1-2):149-155.
[62] Constantinides PP, Yiv SH. Pharmaceutical selfemulsifying microemulsion comp rising surfactants [P]. WO9408610, 1994-04-28.
[63]朱盛山.药物新剂型[M].北京:化学工业出版社,2003,408-470.
[64]温清.甲砜霉素胶囊人体生物等效性研究[J].中国新药与临床杂志.2005,24(7):518.
[65]寇欣.微乳给药系统的研究进展[J].天津药学,2005,17(6):52-55.
[66]汪龙,邓瑾,金玉燕,等.低分子肝素微乳及其纳米脂质体作大鼠口服抗凝效果的比较[J].江苏药学与临床研究,2005,13(2):4-6.
[67]奉建芳.我国纳米给药系统的研究与应用[J].中南药学,2004,2(1):29-33.
[68]陈华兵,翁婷,杨祥良.微乳在现代药剂学中的研究进展[J].中国医药工业杂志,2004,35(8):502-506.
[69]中国药典委员会.中国药典2005年版二部[S].北京:化学工业出版社,116,附录85.
[70]顾憋瑜,李虹影,吴秀英,等.纳米技术在药学研究领域中的应用[J].药品评价,2005,3(2):170-172.
[71]王汝兴,刘翠哲,刘喜纲,等.纳米技术及其在药学研究中的应用[J].承德医学院学报,2005,22(3):248-249.
[72]张文萍,张志耘.我国纳米技术在药学领域中应用现状[J].天津药学,2002,14(5):17.
[73]毕肖林,狄留庆.纳米技术及其在医药学中的应用研究[J].中医药学报,2004,22(6):1064.
[74]胡志洁,张志耘.纳米技术在医药学领域中研究应用进展[J].天津药学,2001,13(5):10-15.
[75]于巍,王春龙,赵广荣,等.微乳给药系统研究进[J].医药导报,2006,25(11):1177-1179.
[76] Lawrence M J, Gareth D R. Microemulsion based media as novel drug delivery systems[J]. Adv Drug Delivery Rev, 2000, 45:89 -121.
[77] LU Y, JI XX,GAO S, et a1.Studies of lidocaine-lecithin micrcemulsion[J]. J Pharm practice, 2004, 22(3):141-143.Chinese.
[78] Milan Johann Schwuger, Katrin Stickdom. Microemulsion in technical processes[J]. American Chemical Society, 1995, 95:849- 864.
[79] Dreher F, Walde P, Walther P, et al . Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport[J]. J Control Release, 1997, 45(2):131-140.
[80]廉云飞,李娟,平其能,等.吲哚美辛微乳的制备及经皮吸收研究[J].中国医药工业杂志,2005,36(3):148-170.
[81]茆同江.人参皂苷Rg3微乳剂的制备及其质量评价[D].扬州大学,2005.
[82]赵建,张钧寿,张瑛,等.胰岛素微乳大鼠结肠给药的药效学研究[J].中国药科大学学报,2004,35(6):491.
[83] Kreilgaard M,Pedersen E J,Jaroszewski J W.NMR characterisation and transdermal drug delivery potential of microemulsion systems[J] . J Control Release, 2000, 69(3):421-433.
[84] Kemken J, Ziegler A, Muller BW. Investigations into the pharmacodynamic effects of dermally administered microemulsions containingβ-blockers [J]. J Pharm Pharmacol, 1991, 43(10):679-684.
[85] Schmalfu U , Neubert R , Wohlrab W. Modification of drug penetration into human skin using microemulsions [J] .J Control Release ,1997, 46(1):279- 285.
[86]鲁莹,刘英,蒋雪涛.新型药物载体:微乳[J].国外医药-合成药生化药制剂分册,1999,20(4):253-258.
[87]张正全,陆彬.微乳给药系统研究概况[J].中国医药工业杂志,2001,32(3):139-142.
[88]汪龙,邓瑾,金玉燕,等.低分子肝素微乳及其纳米脂质体作大鼠口服抗凝效果的比较[J].江苏药学与临床研究,2005,13(2):4-6.
[89]孙玉静,隋延仿,吴道澄,等.肿瘤特异性抗原纳米乳剂的制备及抗肿瘤免疫效应[J].中国药理学通报,2005,21(3):288-911.
[90]张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4):294-298.
[91] CAOZ S,LU F Q,Microemulsion and their apphcation for thednlgs[J].World Pharmacy, 1993, 14(5):289-293. Chinese.
[92] TDOKA HIDEMI, OGAW A, ETSUKO et a1. Formulation of W/O type microemulsion in biocompatible surfactant systems[J]. NihonYukagakkaishi, 1997, 46(12):1475-1479.
[93] Zhinan Mei, Huabing Chen,Ting Weng, et al. Solid lipid nanoparticle and microemulsion for topical delivery of triptolide. Euro. Jour. of Pharm. and Biop. 2003,56):189-196.
[94]沈海蓉,李中东,钟明康.自微乳释药系统及其制剂的研究进展[J].中国新药与临床杂志,2005,24(5):409-412.
[95]沙先谊,陈小飞.9-硝基喜树碱自微乳化给药系统研究[J].中国医药工业杂志,2004,35(8):469-472.
[96]潘国梁,魏惠华,陈彦,等.葛根素微乳的质量评价[J].时珍国医国药,2005,16(7):582-583.
[97]张柯萍,蔺胜照,陈国广,等.鸦胆子油微乳的制备及稳定性研究[J].华西药学杂志,2005,(20)3:l99-20l.
[98] JUNPING W, TAKAYAMA K, NAGAI T, et a1. Pharmacokinetics and antitumor effects of vincristineeaied by mieroemulsions composed of PEG lipid oleic acid, vitamin E and cholesterol[J]. Int J Pharm, 2003, 251(1-2):13-16.
[99] Baroli B, Lopez-Quintela MA, Delgado-Charro MB, et al. Microemulsions for topical delivery of 8-methoxsalen[J]. J Control Release, 2000, 69(1):209-218.
[100] Arturo M Lopez-Quintela and Jose Rivas. Chemical reaction in microemulsions:A powerful method to obtain ultrafine particles[J]. Journal of Colloid and Interface Science, 1993, 158:446-451.
[101] Shinoda k, Araki M, Sadaghiani A, et al. Lecithinbased microemulsions:phase behavior and microstructure[J]. J Phys Chem, 1991, 95:989-993.
[102] Cheng T H, Gan L M and Chem C H. Morphology of microporous polymeric materials by polymerization of methyl methacrylate and 2-hydroxyethyl methacrylate in microemulsions[J]. Polymer, 1995, 36:1941-1946.
[103]中国兽药典委员会.中国兽药典兽药使用指南——化学药品卷[S].2005年版.中国农业出版社,2005,50-51.
[104]徐叔云,卞如濂,陈修.药理实验方法学[M]第三版.北京:人民卫生出版社,2003,1647-1660.
[105]周力国主编.药物毒理学[M].北京:中国医药科技出版社,2001.9.
[106]谢沄.甲磺酸培氟沙星的药动学及药效学研究[D].西北农林科技大学,2007.
[107]黄勇旗.乙酰甲喹在山羊和绵羊体内的药动学及其抗菌后效应研究[D].西北农林科技大学,2008.
[108]陆晨薇.乙酰甲喹在实验性肝和肾功能损害家兔体内的药动学研究[D].西北农林科技大学,2008.
[2] Lorenzo Drago, Elena De Vecchi, Maria Cristina Fassina, et al.Serum and lung levels of thiamphenicol after administration of its glycinate N-acetylcysteinate ester in experimentally infected guinea pigs [J]. International Journal of Antimicrobial Agents, 2000, 13(4):301-303.
[3] Castells G., Prats C., Korchi G. E. L., et al.Thiamphenicol disposition in pigs [J]. Research in Veterinary Science, 1999, 66(3):219-222.
[4]汤光,李大魁.现代临床药物学[M].北京:化学工业出版社,2003,77-79.
[5] Vivian Tullio, Annamaria Cuffini, Narcisa Mandras, et al. Influence of thiamphenicol on the primary functions of human polymorphonuclear leucocytes against Streptococcus pyogenes [J]. International Journal of Antimicrobial Agents, 2004, 24(4):381-385.
[6] Lettresàla redaction. Thiamphenicol susceptibility of S. pneumoniae, H. influenzae and B. catarrhalis strains identified in a pediatric unit [J]. Médecine et maladies infectieuses, 2003, 33(5):276-279.
[7] Turton J. A., Havard A. C., Robinson S., et al. An assessment of chloramphenicol and thiamphenicol in the induction of aplastic anaemia in the BALB/c mouse [J]. Food and Chemical Toxicology, 2000, 38(10):925-938.
[8]王涛.甲砜霉素顿服治疗淋病及非淋菌性尿道炎疗效观察[J].临床误诊误治,2007,20(1):85.
[9]何湘.甲砜霉素与强力霉素联合治疗支原体感染的疗效观察[J].中国现代医药,2007,9(1):89-90.
[10]尹仲.甲砜霉素与司巴沙星治疗尿道(宫颈)解脲支原体疗效比较[J].华夏医学,2004,17(3):384-385.
[11]葛正义.甲砜霉素治疗耐药淋病60例疗效观察[J].浙江临床医学,2002,4(10):788.
[12]叶一萍.甲砜霉素治疗支原体感染耐药病例16例效果观察[J].齐齐哈尔医学院学报,2003,24(3):277.
[13]赵飞,李红文,何秋波.甲砜霉素对小儿泛发性脓疱型银屑病的治疗观察[J].中国麻风皮肤病杂志,2004,20(3):240-241.
[14]潘虎,顾加红,郝飞.甲砜霉素治疗掌跖脓疱病疗效观察[J].中华皮肤科杂志,2006,39(11):668.
[15]马绍云.甲砜霉素联合雷公藤治疗掌跖脓疱病疗效观察[J].皮肤病与性病,2003,25(1):34-35.
[16]周振新,严明,陈洪.复方甲砜霉素注射液对人工感染鸡巴氏杆菌病的临床疗效试验[J].河北畜牧兽医,2000,19(8):20-21.
[17]陈平,罗淑琼,黄庆洲,等.仔猪黄白痢大肠杆菌病原的分离鉴定及其药效试验[J].四川畜牧兽医,2002,29(6):19,22.
[18]黄庆洲,郭定章,但麒麟,等.川渝两地鸭疫里氏杆菌分离鉴定及药效试验[J].四川畜牧兽医,2002,29(1):19-20.
[19]刘富来,冯翠兰,王林川.番鸭感染肠炎沙门氏菌的分离鉴定[J].畜牧与兽医,2004,36(8):37-38.
[20]黄正才,吴绍容.甲砜霉素对牛细菌性呼吸器病的效果研究[J].黑龙江畜牧兽医,1999,(11):24-26.
[21]朱方容,田智得,石美宁.家蚕细菌病治疗药物的研究[J].广西蚕业,2003,40(2):4-9.
[22]吴俊伟,曾忠良,罗音久,等.甲砜霉素注射液的研制及稳定性实验[J].四川畜牧兽医学院学报,2000,14(4):1-5.
[23]吴俊伟,陆彬.甲砜霉素β-环糊精包合物的研制[J].华西药学杂志,2000,15(6):420-422.
[24]黄春玉,周建平,姚静,等.尼莫地平微乳及自微乳的家兔口服生物利用度研究[J].中国药科大学学报,2004,35(5):409-412.
[25]阎家麒,王惠杰,童岩,等.紫杉醇微乳的研究[J].中国药学杂志,2000,35(3):173-176.
[26]刘英,蒋雪涛,鲁莹,等.紫外分光光度法测定5-氟尿嘧啶微乳的含量研究[J].中国新药杂志,2000,9(7):464-465.
[27]姚静,周建平,卢韵,等.聚氧乙烯蓖麻油微乳对血脑屏障通透性的影响[J].中国药科大学报,2005,6(1):27-30.
[28]张小华,张龙,范斌.紫外分光光度法测定甲砜霉素片的含量[J].化学分析计量,2002,11(1):16.
[29]王建华,陈世山.同时测定鱼肉中氯霉素和甲砜霉素残留量的毛细管气相色谱法[J].分析测试学报,2001,20(3):89.
[30]寇晋萍,王国兰,余立.HPLC法测定甲砜霉素胶囊含量[J].首都医药,2004,(18):52.
[31] Mestorino N, Landon M F, Alt M,et al. The pharmacokinetics of thiamphenicol inlacting cows.J Vet Pharmacol Ther.1993, 295-303.
[32] Abdennebi EH, Sawchuk RJ, Stowe CM. Thiamphenicol pharmacokinetics in beef and dairy cattle. J Vet Pharmacpl Ther., 1994, 17(5):365-368.
[33] Abdennebi,E H and Stowe,C M.Pharmacokinetics and distribution of thiamphenicol in sheep given repeated intramuscular dose.Vet.Res, 1994, 25:489-494.
[34] Castell, Intorre L, Franquelo C, Cristofol C, et al. Pharmacokintics of thiamphenicol in dogs. Am J Vet Res, 1998, 59(11):1473-1475.
[35] Darwin L.P,Agamemnon D, Eppie D R. Induction of Chloramphenicol Metabism by Phenobarbital. Antimicrob. Agents Chemother, 1972, 1(2):112-115.
[36]陈晓兰.甲砜霉素在鸡的药动学及组织残留HPLC检测方法的研究[D].扬州大学,2006,15-22.
[37]周志凌,梁净.甲砜霉素胶囊含量测定方法的改进[J].中国药品标准,2005,6(6):35-37.
[38]陆广富,陈晓兰,卜仕金.鸡组织中甲砜霉素残留HPLC检测方法[J].中国兽医杂志,2008,44(2):85.
[39]徐楚鸿,吕永宁,韩召敏.HPLC法测定人血清中甲砜霉素浓度[J].中国医药,2006,12:24.
[40]杨亚军,李引乾.甲砜霉素脂质体制备和体外抑菌效果[J].西北农业学报2007,16(4):213-215.
[41] Kowalski P., Capillary electrophoretic determination of thiamphenicol in turkeys serum and its pharmacokinetic application [J]. Journal of Pharmaceutical and Biomedical Analysis, 2007, 43(1):222-227.
[42] Ando J., Ishihara R., Imai Sh., et al. Thirteen-week subchronic toxicity study of thiamphenicol in F344 rats [J]. Toxicology Letters, 1997, 91(2):137-146.
[43]杜向党,阎若潜,沈建忠.氯霉素类药物耐药机制的研究进展[J].动物医学进展,2004,25(2):27-2.
[44] Kitamura T., Ando J., Ishihara R., Takano S., et al. Lack of Carcinogenicity of Thiamphenicol in F344 Rats [J]. Food and Chemical Toxicology, 1997, 35(10, 11):1075-1080.
[45] Nobile L., Cavrini V., Raggi M. A., et al. Analysis of thiamphenicol glycinate salts in pharmaceutical formulations by derivative UV spectroscopy [J]. International Journal of Pharmaceutics, 1987, 40(1, 2):85-91.
[46]寇贺红.丁香酚纳米乳的研制[D].西北农林科技大学,2006.
[47]张文娟.利福平微乳的研制[D].西北农林科技大学,2006.
[48]张阳德.纳米药物学[M].北京:化学工业出版社,2006,163.
[49]刘程.表面活性剂大全田.北京:北京工业大学出版社,1994.
[50] KohsakuK awakami, Ta kayoshiYo shikawa, Ya sushiM oroto, et al. Microemulsion formulationfo renh anced a bsorptionof po orlyso luble drugs. IP rescriptiond esign.J control Re l, 2002, 81(22):65 -7 4.
[51]杨惊宇.隐丹参酮微乳的制备工艺及相对生物利用度的测定[D].湖南中医学院,2005.
[52] E C Swenson, WJCuratolo.Adv.DrugDeliv, 1992, 8(1):39-92.
[53]吴顺芹,李三鸣,郎轶咏,等.水包油型微乳形成因素的考察[J].沈阳药科大学学报,2005,2:96-99.
[54] Sanchez L, Mitjans M, Infante MR,etal, Potential irritationof lysine derivative surfactants by hemolysis and HaCaT cellviability[J]. Toxicology Letters. 2006,(161):53-60.
[55]潘国梁,魏惠华,陈彦,贾晓斌.葛根素微乳的质量评价[J].时珍国医国药,2005,16(7):582-583.
[56]于力,张钧寿,周建平.纳米乳的研究及其在制剂学领域的应用[J].药学进展,2006,30(11):491-498.
[57] Robbins M L. Microemulsion Solubilization and Microemulsion[M]. Plenum Press, New York, 1997, 713.
[58] Mukherjee K, M ukherjee DC, Moulik SP. Thermodynamics of microemulsion formation(?. enthalpies of solution of water inch loroform as well as chloroform in water aided bycationic, anionic, and nonionic surfactants) [J]. J Colloid Interface Sci, 1997, 187:327-333.
[59] Munsh iN , De TK, M aitra A. Size modulation of polymericnano particles under controlled dynamics of microemulsion droplets[J]. J Colloid Interface Sic, 1997, 190:387-392.
[60] Cottens S, Haeberlin B, Sedrani R, etal. Pharmaceaticecl microemulsion preconcent rates containing cyclosporings and macrecides. Swifz, WO 96132739 May 1996.
[61] Kim CK, Cho YJ, Gao ZG. Preparation and evaluation ofbiphenyl dimethyl dicarboxylate microemulsions for oral delivery[J]. J Controlled Release, 2001, 70(1-2):149-155.
[62] Constantinides PP, Yiv SH. Pharmaceutical selfemulsifying microemulsion comp rising surfactants [P]. WO9408610, 1994-04-28.
[63]朱盛山.药物新剂型[M].北京:化学工业出版社,2003,408-470.
[64]温清.甲砜霉素胶囊人体生物等效性研究[J].中国新药与临床杂志.2005,24(7):518.
[65]寇欣.微乳给药系统的研究进展[J].天津药学,2005,17(6):52-55.
[66]汪龙,邓瑾,金玉燕,等.低分子肝素微乳及其纳米脂质体作大鼠口服抗凝效果的比较[J].江苏药学与临床研究,2005,13(2):4-6.
[67]奉建芳.我国纳米给药系统的研究与应用[J].中南药学,2004,2(1):29-33.
[68]陈华兵,翁婷,杨祥良.微乳在现代药剂学中的研究进展[J].中国医药工业杂志,2004,35(8):502-506.
[69]中国药典委员会.中国药典2005年版二部[S].北京:化学工业出版社,116,附录85.
[70]顾憋瑜,李虹影,吴秀英,等.纳米技术在药学研究领域中的应用[J].药品评价,2005,3(2):170-172.
[71]王汝兴,刘翠哲,刘喜纲,等.纳米技术及其在药学研究中的应用[J].承德医学院学报,2005,22(3):248-249.
[72]张文萍,张志耘.我国纳米技术在药学领域中应用现状[J].天津药学,2002,14(5):17.
[73]毕肖林,狄留庆.纳米技术及其在医药学中的应用研究[J].中医药学报,2004,22(6):1064.
[74]胡志洁,张志耘.纳米技术在医药学领域中研究应用进展[J].天津药学,2001,13(5):10-15.
[75]于巍,王春龙,赵广荣,等.微乳给药系统研究进[J].医药导报,2006,25(11):1177-1179.
[76] Lawrence M J, Gareth D R. Microemulsion based media as novel drug delivery systems[J]. Adv Drug Delivery Rev, 2000, 45:89 -121.
[77] LU Y, JI XX,GAO S, et a1.Studies of lidocaine-lecithin micrcemulsion[J]. J Pharm practice, 2004, 22(3):141-143.Chinese.
[78] Milan Johann Schwuger, Katrin Stickdom. Microemulsion in technical processes[J]. American Chemical Society, 1995, 95:849- 864.
[79] Dreher F, Walde P, Walther P, et al . Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport[J]. J Control Release, 1997, 45(2):131-140.
[80]廉云飞,李娟,平其能,等.吲哚美辛微乳的制备及经皮吸收研究[J].中国医药工业杂志,2005,36(3):148-170.
[81]茆同江.人参皂苷Rg3微乳剂的制备及其质量评价[D].扬州大学,2005.
[82]赵建,张钧寿,张瑛,等.胰岛素微乳大鼠结肠给药的药效学研究[J].中国药科大学学报,2004,35(6):491.
[83] Kreilgaard M,Pedersen E J,Jaroszewski J W.NMR characterisation and transdermal drug delivery potential of microemulsion systems[J] . J Control Release, 2000, 69(3):421-433.
[84] Kemken J, Ziegler A, Muller BW. Investigations into the pharmacodynamic effects of dermally administered microemulsions containingβ-blockers [J]. J Pharm Pharmacol, 1991, 43(10):679-684.
[85] Schmalfu U , Neubert R , Wohlrab W. Modification of drug penetration into human skin using microemulsions [J] .J Control Release ,1997, 46(1):279- 285.
[86]鲁莹,刘英,蒋雪涛.新型药物载体:微乳[J].国外医药-合成药生化药制剂分册,1999,20(4):253-258.
[87]张正全,陆彬.微乳给药系统研究概况[J].中国医药工业杂志,2001,32(3):139-142.
[88]汪龙,邓瑾,金玉燕,等.低分子肝素微乳及其纳米脂质体作大鼠口服抗凝效果的比较[J].江苏药学与临床研究,2005,13(2):4-6.
[89]孙玉静,隋延仿,吴道澄,等.肿瘤特异性抗原纳米乳剂的制备及抗肿瘤免疫效应[J].中国药理学通报,2005,21(3):288-911.
[90]张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4):294-298.
[91] CAOZ S,LU F Q,Microemulsion and their apphcation for thednlgs[J].World Pharmacy, 1993, 14(5):289-293. Chinese.
[92] TDOKA HIDEMI, OGAW A, ETSUKO et a1. Formulation of W/O type microemulsion in biocompatible surfactant systems[J]. NihonYukagakkaishi, 1997, 46(12):1475-1479.
[93] Zhinan Mei, Huabing Chen,Ting Weng, et al. Solid lipid nanoparticle and microemulsion for topical delivery of triptolide. Euro. Jour. of Pharm. and Biop. 2003,56):189-196.
[94]沈海蓉,李中东,钟明康.自微乳释药系统及其制剂的研究进展[J].中国新药与临床杂志,2005,24(5):409-412.
[95]沙先谊,陈小飞.9-硝基喜树碱自微乳化给药系统研究[J].中国医药工业杂志,2004,35(8):469-472.
[96]潘国梁,魏惠华,陈彦,等.葛根素微乳的质量评价[J].时珍国医国药,2005,16(7):582-583.
[97]张柯萍,蔺胜照,陈国广,等.鸦胆子油微乳的制备及稳定性研究[J].华西药学杂志,2005,(20)3:l99-20l.
[98] JUNPING W, TAKAYAMA K, NAGAI T, et a1. Pharmacokinetics and antitumor effects of vincristineeaied by mieroemulsions composed of PEG lipid oleic acid, vitamin E and cholesterol[J]. Int J Pharm, 2003, 251(1-2):13-16.
[99] Baroli B, Lopez-Quintela MA, Delgado-Charro MB, et al. Microemulsions for topical delivery of 8-methoxsalen[J]. J Control Release, 2000, 69(1):209-218.
[100] Arturo M Lopez-Quintela and Jose Rivas. Chemical reaction in microemulsions:A powerful method to obtain ultrafine particles[J]. Journal of Colloid and Interface Science, 1993, 158:446-451.
[101] Shinoda k, Araki M, Sadaghiani A, et al. Lecithinbased microemulsions:phase behavior and microstructure[J]. J Phys Chem, 1991, 95:989-993.
[102] Cheng T H, Gan L M and Chem C H. Morphology of microporous polymeric materials by polymerization of methyl methacrylate and 2-hydroxyethyl methacrylate in microemulsions[J]. Polymer, 1995, 36:1941-1946.
[103]中国兽药典委员会.中国兽药典兽药使用指南——化学药品卷[S].2005年版.中国农业出版社,2005,50-51.
[104]徐叔云,卞如濂,陈修.药理实验方法学[M]第三版.北京:人民卫生出版社,2003,1647-1660.
[105]周力国主编.药物毒理学[M].北京:中国医药科技出版社,2001.9.
[106]谢沄.甲磺酸培氟沙星的药动学及药效学研究[D].西北农林科技大学,2007.
[107]黄勇旗.乙酰甲喹在山羊和绵羊体内的药动学及其抗菌后效应研究[D].西北农林科技大学,2008.
[108]陆晨薇.乙酰甲喹在实验性肝和肾功能损害家兔体内的药动学研究[D].西北农林科技大学,2008.