伊维菌素亚微乳的制备及药物动力学研究
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摘要
伊维菌素(Ivermectin, IVM)是一种新型的广谱,高效,低毒抗生素类抗寄生虫药。目前,兽医临床应用的伊维菌素制剂体内血药浓度起伏大,导致其安全性和有效性均较低。亚微乳作为一种新型制剂,具有保护被包封药物、载药量大、提高药物稳定性、延长药物作用时间、毒副作用少等特点。伊维菌素难溶于水,并且为了防止兽药滥用,静脉注射给药是一条可以防止兽药滥用的有效途径。本研究将伊维菌素制备成静脉注射用亚微乳,并对其稳定性进行考察,制定了初步的质量标准,并对伊维菌素亚微乳的药代动力学进行了研究。旨在为此类药物的亚微乳剂开发提供一定的基础。
本研究在以往的实验基础上,对伊维菌素亚微乳进行了处方前研究,建立了含量测定方法。采用微射流高压均质方法制备了伊维菌素亚微乳,以亚微乳剂的外观,粒径,电位为主要的评价指标,对伊维菌素亚微乳的处方和制备工艺进行了考察。考察了处方中的大豆油用量,乳化剂用量,辅助乳化剂用量和稳定剂的影响,还考察了工艺中的初乳化温度,乳化转速和时间,高压均质的压力与次数等的影响。初步确定了伊维菌素亚微乳的最优处方和制备工艺。
对伊维菌素亚微乳的稳定性进行了考察,考察了120℃灭菌15min对亚微乳剂的影响,并且开展了影响因素实验,加速实验和长期实验。乳剂在冷藏条件和室温条件下各项指标基本稳定,符合要求。同时在高温,冷冻和光照条件下稳定性较差,应当在存放时避免高温,冷冻和光照。
制定了伊维菌素亚微乳初步的质量标准。考察了伊维菌素亚微乳的含量测定方法。测定了伊维菌素亚微乳的粒径,pH值,有关物质,过氧化值,游离脂肪酸和甘油含量等,制定了伊维菌素亚微乳初步的质量标准。
对伊维菌素亚微乳的大鼠体内药代动力学进行了评价,以1mg/kg进行大鼠尾静脉注射,对比评价了伊维菌素普通制剂和伊维菌素亚微乳的药代动力学特点,符合三室模型特征。伊维菌素普通制剂和伊维菌素亚微乳的T1/2pi分别为0.03±0.013h和0.031±0.002h,T1/2α分别为0.582±0.050h和0.827±0.150h,t1/2β分别为14.082±1.703h和72.474±26.82h,AUC分别为8.115±0.218(mg/L)*h和50.353±13.29(mg/L)*h。伊维菌素亚微乳可以显著延长药物半衰期,并提高生物利用度。
Ivermectin (IVM) is a novel antibiotics insecticide which has a wide antimicrobial spectrum. It is lower toxicity and more effciency. Currently, Plasma concentration changes largely of normal IVM formulations which leading to a lower safety and efficacy in veterinary clinical applications.
Submicron emulsion as a noval formation of drug delivery sysytem, can protect drug, improve drug stability, prolong interaction time and reduce few side-effects. Intravenous injection is a way which can prevent the abuse of veterinary drugs, so we consider made IVM into submicron emulsion which can povide fundmental work for a new dosage of IVM.
Preformulation research of IVM was investigated to develop HPLC method for IVM content determination. IVM submicron emulsion was prepared by high pressure homogenization technique. In order to choose the best formulation and preparation process, the droplet size, PDI, the value of (?) potential and the drug concentration of IVM submicron emulsion were investigated.
The stability of IVM submicron emulsion was also investigated. It included the impact of sterilization and the main emulsifier on its general physico-chemical properties of IVM submicron emulsion. IVM submicron emulsion was stable at4℃and25℃,and it should not be kept at a condition of high temperature and light.
Quality standards were preliminary reseached. The properties include particle size, Zeta potential, pH value, content of IVM and Osmotic pressure were investigated. Besides, free fatty acid, peroxide value and the related substances of the emulsion were examined. The HPLC method was suitable for IVM content determination.
To study its pharmacokinetic characteristics, a HPLC-UV method was validated to quantitatively determine IVM concentration in rat plasma. The pharmacokinetic study was conducted in rats by intravenous (i.v.1mg/kg). The concentration-time profiles of IVM submicron emulsion and general injection in plasma fitted a three-compartment model. IVM submicron emulsion is a good choice for intravenously administrating poorly soluble IVM. The T1/2Pi of general injection and IVM submicron emulsion were0.03±0.013h and0.031±0.002h. The T1/2α of general injection and IVM submicron emulsion were0.582±0.050h and0.827±0.150h. The t1/2β of general injection and IVM submicron emulsion were14.082±1.703h and72.474±26.82h. AUC of general injection and IVM submicron emulsion were8.115±0.218(mg/L)*h and50.353±13.29(mg/L)*h. IN CONCLUSION, IVM submicron emulsion can significantly prolong half-life of IVM and improve the bioavailability.
本研究在以往的实验基础上,对伊维菌素亚微乳进行了处方前研究,建立了含量测定方法。采用微射流高压均质方法制备了伊维菌素亚微乳,以亚微乳剂的外观,粒径,电位为主要的评价指标,对伊维菌素亚微乳的处方和制备工艺进行了考察。考察了处方中的大豆油用量,乳化剂用量,辅助乳化剂用量和稳定剂的影响,还考察了工艺中的初乳化温度,乳化转速和时间,高压均质的压力与次数等的影响。初步确定了伊维菌素亚微乳的最优处方和制备工艺。
对伊维菌素亚微乳的稳定性进行了考察,考察了120℃灭菌15min对亚微乳剂的影响,并且开展了影响因素实验,加速实验和长期实验。乳剂在冷藏条件和室温条件下各项指标基本稳定,符合要求。同时在高温,冷冻和光照条件下稳定性较差,应当在存放时避免高温,冷冻和光照。
制定了伊维菌素亚微乳初步的质量标准。考察了伊维菌素亚微乳的含量测定方法。测定了伊维菌素亚微乳的粒径,pH值,有关物质,过氧化值,游离脂肪酸和甘油含量等,制定了伊维菌素亚微乳初步的质量标准。
对伊维菌素亚微乳的大鼠体内药代动力学进行了评价,以1mg/kg进行大鼠尾静脉注射,对比评价了伊维菌素普通制剂和伊维菌素亚微乳的药代动力学特点,符合三室模型特征。伊维菌素普通制剂和伊维菌素亚微乳的T1/2pi分别为0.03±0.013h和0.031±0.002h,T1/2α分别为0.582±0.050h和0.827±0.150h,t1/2β分别为14.082±1.703h和72.474±26.82h,AUC分别为8.115±0.218(mg/L)*h和50.353±13.29(mg/L)*h。伊维菌素亚微乳可以显著延长药物半衰期,并提高生物利用度。
Ivermectin (IVM) is a novel antibiotics insecticide which has a wide antimicrobial spectrum. It is lower toxicity and more effciency. Currently, Plasma concentration changes largely of normal IVM formulations which leading to a lower safety and efficacy in veterinary clinical applications.
Submicron emulsion as a noval formation of drug delivery sysytem, can protect drug, improve drug stability, prolong interaction time and reduce few side-effects. Intravenous injection is a way which can prevent the abuse of veterinary drugs, so we consider made IVM into submicron emulsion which can povide fundmental work for a new dosage of IVM.
Preformulation research of IVM was investigated to develop HPLC method for IVM content determination. IVM submicron emulsion was prepared by high pressure homogenization technique. In order to choose the best formulation and preparation process, the droplet size, PDI, the value of (?) potential and the drug concentration of IVM submicron emulsion were investigated.
The stability of IVM submicron emulsion was also investigated. It included the impact of sterilization and the main emulsifier on its general physico-chemical properties of IVM submicron emulsion. IVM submicron emulsion was stable at4℃and25℃,and it should not be kept at a condition of high temperature and light.
Quality standards were preliminary reseached. The properties include particle size, Zeta potential, pH value, content of IVM and Osmotic pressure were investigated. Besides, free fatty acid, peroxide value and the related substances of the emulsion were examined. The HPLC method was suitable for IVM content determination.
To study its pharmacokinetic characteristics, a HPLC-UV method was validated to quantitatively determine IVM concentration in rat plasma. The pharmacokinetic study was conducted in rats by intravenous (i.v.1mg/kg). The concentration-time profiles of IVM submicron emulsion and general injection in plasma fitted a three-compartment model. IVM submicron emulsion is a good choice for intravenously administrating poorly soluble IVM. The T1/2Pi of general injection and IVM submicron emulsion were0.03±0.013h and0.031±0.002h. The T1/2α of general injection and IVM submicron emulsion were0.582±0.050h and0.827±0.150h. The t1/2β of general injection and IVM submicron emulsion were14.082±1.703h and72.474±26.82h. AUC of general injection and IVM submicron emulsion were8.115±0.218(mg/L)*h and50.353±13.29(mg/L)*h. IN CONCLUSION, IVM submicron emulsion can significantly prolong half-life of IVM and improve the bioavailability.
引文
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[4]魏永红,李有全,殷洪,等.动物寄生虫病的综合防治研究进展[J].中国动物保健-学术研究,2011,(2)：21-22.
[5]蒲文兵,杨帆,宋刚华,等.伊维菌素(维力加)注射液对羊体内外寄生虫的驱虫试验[J].中国动物传染病学报,2009,17(1)：54-57.
[6]Cully DF, Vassilatis DK, Liu KK, et al. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans[J]. Nature,1994, (371):707-711.
[7]Yates DM, Portillo V, Wolstenholme AJ. The avermectin receptors of Haemonchus contortusand Caenorhabditis elegans[J]. Int.J.Parasitol,2003,33(11):1183-1193.
[8]王广成,张忠明,高立明,等.阿维菌素的作用机理及其应用现状[J].植物医生,2006,19(1)：4-5.
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[10]游锡火.阿维菌素类药物的药理作用及毒理作用[J].吉林农业,2000,(5)：35.
[11]李成命,危杰.伊维菌素类药物的耐药性[J].黑龙江畜牧兽医,2001,(9)：20.
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