纳米粒径和电位对替米考星—氢化蓖麻油纳米悬液性能的影响
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摘要
替米考星常规制剂的生物利用度低、毒性比较大,严重影响其在疾病治疗过程中应用,频繁给药或是高剂量用药会造成药物残留增加和毒副作用增强。固体脂质纳米载体可以有效地促进药物吸收、提高生物利用度、延长药物在体内循环的时间、降低残留和减轻毒性作用,是提高兽药功效非常有效的药物载体。粒径和表面电位作为纳米颗粒的重要参数,对纳米药物载体的性能有很大的影响。
本文以氢化蓖麻油(hydrogenated castor oil, HCO)为脂质材料、聚乙烯醇(polyvinyl alcohol, PVA为表面活性剂、季铵盐为表面电位修饰剂,运用热熔超声乳化技术制备了替米考星-氢化蓖麻油纳米(tilmicosin-loaded hydrogenated castor oil nanoparticle, TMS-HCO-NP)悬液。通过改变PVA的浓度控制纳米颗粒的粒径,用季铵盐进行表面修饰以改变纳米颗粒的表面电位。本实验运用紫外分光光度计对不同粒径和电位的TMS-HCO-NP载药量进行了测定,同时对不同制剂样品体外释放特性进行了研究。此外,在4℃和室温两种储存条件下评价粒径和表面电位对TMS-HCO-NP悬液稳定性的影响。用BHK、Vero和RAW264.7三种细胞系对不同粒径和电位的TMS-HCO-NP悬液进行了体外细胞毒性评价,并通过激光共聚焦对巨噬细胞吞噬纳米颗粒进行观察。通过小鼠皮下注射不同粒径的TMS-HCO-NP悬液,揭示粒径对制剂体内急性毒性的影响。运用肉汤稀释法、琼脂稀释法进行体外抗菌活性研究,建立了适合纳米混悬剂抗菌活性检测的新方法,并对不同粒径和电位TMS-HCO-NP悬液的抗菌活性进行了评价。
研究结果显示,表面活性剂的浓度显著影响纳米颗粒的粒径。以不同PVA浓度(0.2%、1%和5%)制备的纳米悬液纳米颗粒的平均粒径分别为920±35nm、452±10nm和151±4nm。尽管三种不同粒径的TMS-HCO-NP悬液体外释放模式都为双相曲线,但是小粒径的纳米悬液的初始释放速率更快。三种不同粒径的TMS-HCO-NP悬液在低浓度条件下,不会影响BHK和Vero细胞增殖。在较高浓度条件下下,不同粒径TMS-HCO-NP纳米悬液对三种细胞都表现出浓度依赖性细胞毒性作用。细胞吞噬试验表明纳米颗粒的粒径越大越容易被吞噬。最小粒径的fMS-HCO-NP悬液在小鼠体内表现出更显著的急性毒性,主要是由于药物释放更快所致。肉汤稀释法显示粒径越小纳米颗粒的最低抑制浓度(minimal inhibitory concentration, MIC)和最小杀菌浓度(minimal bactericidal concentration, MBC)值越低。时间-杀菌曲线表明,在12小时内150nm的TMS-HCO-NP悬液和替米考星原药表现出最有效的杀菌活性,但在随后的时间点较大粒径纳米悬浮液表现出持续的抗菌活性,新建立的检测方法结果也表明粒径越小抗菌效果越好。三种不同粒径的纳米悬液都显示出良好的稳定性,在4℃和室温下至少可以稳定6个月。季铵盐添加比例对纳米颗粒的表面电位有影响。制备体系中双十八烷基二甲基氯化铵(DDAC)比例为2%,PVA浓度分别为0.2%、1%和5%时,纳米颗粒的电位分别为43.1±1.2mv、38.9±1.5mv和26.6±1.2mv；粒径分别为885±16nm、499±6nm和169±4nm；多分散系数分别为0.344±0.041、0.309±0.012和0.478±0.005。而2%双十二烷基二甲基溴化铵(DDAB)修饰的纳米表征如下：电位分别是48.2±1.5mv、38.6±1.3mv和27.3±1.2my；粒径分别是822±4nm、481±6nm和175±2nm；多分散系数分别是0.427±0.036、0.456±0.076和0.532±0.031。季铵盐比例的增加能显著提高纳米的ζ电位,但是当增加到一定程度后电位不再增大,并且DDAC比例增加会使粒径分布范围变宽。此外,季铵盐的加入会影响载药量,正电位TMS-HCO-NP的载药量高于负电位纳米。正电位TMS-HCO-NP与负电位相比,体外释放模式相似,但是初始释放速率变慢。细胞毒性研究表明低浓度的正电位纳米不会影响BHK和Vero细胞的增殖,但是对巨噬细胞影响较大,可能与不同细胞摄取纳米颗粒的机制有关。细胞吞噬试验表明止电位大粒径的纳米颗粒更容易被巨噬细胞吞噬。通过不同的抗菌实验方法证明,正电位TMS-HCO-NP的抗菌效果要稍高于负电位纳米组。时间-杀菌曲线也表明在同一时间点止电位TMS-HCO-NP组的细菌数比负电位要少。
本论文研究结果表明,通过改变PVA浓度和添加季铵盐可以有效的控制粒径和改变表面电位。纳米颗粒的粒径和表面电位对TMS-HCO-NP悬液的性能有很大影响。粒径和表面电位这两个参数是研发固体脂质纳米药物制剂的重要考虑因素。
Backgroud:Traditional formulations of tilmicosin have drawbacks of high toxic effect, fast metabolism, and low bioavailability. Frequent injection or high doses over the therapeutic period will increase the cost. High doses could also result in drug resistance which poses a threat to human health. Solid lipid nanoparticles (SLN) have lots of advantages, such as enhancing therapeutic effects, reducing the residual of drug, prolonging the circulation time in vivo and decreasing the toxic effects. SLN could be a potential drug carrier system for veterinary drug. Particle size and surface charge are important characteristics of nanoparticles, and have great effect on the property of nanoparticles drug carriers.
Methods:The tilmicosin-loaded hydrogenated castor oil nanoparticle (TMS-HCO-NP) suspensions were prepared with hydrogenated castor oil as lipid material, polyvinyl alcohol as surfactant and quaternary ammonium salt as surface modifier by a hot homogenization and ultrasonic technique. The size of the nanoparticles was controlled by varying the PVA concentration, and the surface charge was modified by adding quaternary ammonium salt. The effects of the size and surface charge on the property of the suspensions were studied. The physicochemical characteristics of TMS-HCO-NP were investigated by optical microscope, scanning electron microscopy (SEM) and photon correlation spectroscopy (PCS). The drug loading of the TMS-HCO-NP was measured by ultraviolet spectrophotometer. The release profiles of TMS-HCO-NP with different particle sizes and zeta potentials were studied. The effects of particle size and surface charge on cytotoxicity of TMS-HCO-NP suspensions were evaluated with BHK, Vero and RAW264.7cell lines, and the macrophage phagocytosis of TMS-HCO-NP was studied through confocal laser system. In vitro antibacterial activity of TMS-HCO-NP suspensions with different particle size and surface charge were investigated using three different methods. The acute toxicity of TMS-HCO-NP suspensions with different particle sizes was evaluated in ICR mice. The stability of TMS-HCO-NP suspensions was studied after stored at room temperature and at4℃for6months.
Results:The surfactant significantly affected the size of nanoparticles. When prepared with PVA concentrations of0.2%,1%and5%, the mean diameters of the nanoparticles in the three suspensions were920±35nm,452±10nm and151±4nm, respectively. The three suspensions displayed similar biphasic release profiles, but the suspension of smaller-sized particle showed faster initial release. None of the three suspensions were cytotoxic at clinical dosage levels on BHK and Vero cell lines. At high drug concentrations, TMS-HCO-NP suspensions with different sizes exhibited a concentration-dependent cytoxicity on the three cell lines. Phagocytosis experiments showed that the larger particles could be uptaken more easily. Time-kill curves showed that within12hours the suspension with150nm particles had the most potent bactericidal activity, but later the suspensions with larger-sized particles showed increased antibacterial activity. The results of the novel method also suggested that smaller-sized particles had better antibacterial effect. The suspension with the smallest-sized particle showed significantly more acute toxicity in mice, due to faster drug release. All three suspensions exhibited good stability at4℃and at room temperature for at least6months. The proportion of quaternary ammonium salt affected the surface charge of nanoparticles. When TMS-HCO-NP suspensions were prepared with2%dioctadecyl dimethyl ammonium chloride (DDAC) and difeeerent concentration of PVA (0.2%,1%and5%), the zeta potential of the nanoparticles were43.1±1.2mv,38.9±1.5mv and26.6±1.2mv; the particle sizes were885±16nm,499±6nm and169±4nm; the polydispersity indexes were0.344±0.041,0.309±0.012and0.478±0.005. While the TMS-HCO-NP suspensions were prepared with2%didodecyldimethylammonium bromide (DDAB), the zeta potential were48.2±1.5mv,38.6±1.3mv and27.3±1.2mv; the particle sizes were822±4nm,481±6nm and175±2nm; the polydispersity indexes were0.427±0.036,0.456±0.076and0.532±0.031. With the increment of the proportion of quaternary ammonium from2%to4%, the zeta potential was increased, but the size distribution became wider. The drug loading of positive charged nanoparticles was slight higher than that of the negatively charged ones. Compared with negatively charged TMS-HCO-NP suspensions, the positively ones showed similar release patterns but slower initial release. Cytotoxicity study showed that low concentration of TMS-HCO-NP suspensions with positive surface charge did not affect proliferation of BHK and Vero but RAW264.7, which could be due to different uptake mechanisms of nanoparticles. The antibacterial activity of TMS-HCO-NP suspension with positive surface charge was slightly higher than that with the negative surface charge.
These results demonstrate that the size and surface charge could be controlled by varying the PVA concentration and adding quaternary ammonium salt. Particle size and surface charge significantly affected the property of TMS-HCO-NP suspensions. Particle size and surface charge are important considerations for the development of drug-SLN formulations.
本文以氢化蓖麻油(hydrogenated castor oil, HCO)为脂质材料、聚乙烯醇(polyvinyl alcohol, PVA为表面活性剂、季铵盐为表面电位修饰剂,运用热熔超声乳化技术制备了替米考星-氢化蓖麻油纳米(tilmicosin-loaded hydrogenated castor oil nanoparticle, TMS-HCO-NP)悬液。通过改变PVA的浓度控制纳米颗粒的粒径,用季铵盐进行表面修饰以改变纳米颗粒的表面电位。本实验运用紫外分光光度计对不同粒径和电位的TMS-HCO-NP载药量进行了测定,同时对不同制剂样品体外释放特性进行了研究。此外,在4℃和室温两种储存条件下评价粒径和表面电位对TMS-HCO-NP悬液稳定性的影响。用BHK、Vero和RAW264.7三种细胞系对不同粒径和电位的TMS-HCO-NP悬液进行了体外细胞毒性评价,并通过激光共聚焦对巨噬细胞吞噬纳米颗粒进行观察。通过小鼠皮下注射不同粒径的TMS-HCO-NP悬液,揭示粒径对制剂体内急性毒性的影响。运用肉汤稀释法、琼脂稀释法进行体外抗菌活性研究,建立了适合纳米混悬剂抗菌活性检测的新方法,并对不同粒径和电位TMS-HCO-NP悬液的抗菌活性进行了评价。
研究结果显示,表面活性剂的浓度显著影响纳米颗粒的粒径。以不同PVA浓度(0.2%、1%和5%)制备的纳米悬液纳米颗粒的平均粒径分别为920±35nm、452±10nm和151±4nm。尽管三种不同粒径的TMS-HCO-NP悬液体外释放模式都为双相曲线,但是小粒径的纳米悬液的初始释放速率更快。三种不同粒径的TMS-HCO-NP悬液在低浓度条件下,不会影响BHK和Vero细胞增殖。在较高浓度条件下下,不同粒径TMS-HCO-NP纳米悬液对三种细胞都表现出浓度依赖性细胞毒性作用。细胞吞噬试验表明纳米颗粒的粒径越大越容易被吞噬。最小粒径的fMS-HCO-NP悬液在小鼠体内表现出更显著的急性毒性,主要是由于药物释放更快所致。肉汤稀释法显示粒径越小纳米颗粒的最低抑制浓度(minimal inhibitory concentration, MIC)和最小杀菌浓度(minimal bactericidal concentration, MBC)值越低。时间-杀菌曲线表明,在12小时内150nm的TMS-HCO-NP悬液和替米考星原药表现出最有效的杀菌活性,但在随后的时间点较大粒径纳米悬浮液表现出持续的抗菌活性,新建立的检测方法结果也表明粒径越小抗菌效果越好。三种不同粒径的纳米悬液都显示出良好的稳定性,在4℃和室温下至少可以稳定6个月。季铵盐添加比例对纳米颗粒的表面电位有影响。制备体系中双十八烷基二甲基氯化铵(DDAC)比例为2%,PVA浓度分别为0.2%、1%和5%时,纳米颗粒的电位分别为43.1±1.2mv、38.9±1.5mv和26.6±1.2mv；粒径分别为885±16nm、499±6nm和169±4nm；多分散系数分别为0.344±0.041、0.309±0.012和0.478±0.005。而2%双十二烷基二甲基溴化铵(DDAB)修饰的纳米表征如下：电位分别是48.2±1.5mv、38.6±1.3mv和27.3±1.2my；粒径分别是822±4nm、481±6nm和175±2nm；多分散系数分别是0.427±0.036、0.456±0.076和0.532±0.031。季铵盐比例的增加能显著提高纳米的ζ电位,但是当增加到一定程度后电位不再增大,并且DDAC比例增加会使粒径分布范围变宽。此外,季铵盐的加入会影响载药量,正电位TMS-HCO-NP的载药量高于负电位纳米。正电位TMS-HCO-NP与负电位相比,体外释放模式相似,但是初始释放速率变慢。细胞毒性研究表明低浓度的正电位纳米不会影响BHK和Vero细胞的增殖,但是对巨噬细胞影响较大,可能与不同细胞摄取纳米颗粒的机制有关。细胞吞噬试验表明止电位大粒径的纳米颗粒更容易被巨噬细胞吞噬。通过不同的抗菌实验方法证明,正电位TMS-HCO-NP的抗菌效果要稍高于负电位纳米组。时间-杀菌曲线也表明在同一时间点止电位TMS-HCO-NP组的细菌数比负电位要少。
本论文研究结果表明,通过改变PVA浓度和添加季铵盐可以有效的控制粒径和改变表面电位。纳米颗粒的粒径和表面电位对TMS-HCO-NP悬液的性能有很大影响。粒径和表面电位这两个参数是研发固体脂质纳米药物制剂的重要考虑因素。
Backgroud:Traditional formulations of tilmicosin have drawbacks of high toxic effect, fast metabolism, and low bioavailability. Frequent injection or high doses over the therapeutic period will increase the cost. High doses could also result in drug resistance which poses a threat to human health. Solid lipid nanoparticles (SLN) have lots of advantages, such as enhancing therapeutic effects, reducing the residual of drug, prolonging the circulation time in vivo and decreasing the toxic effects. SLN could be a potential drug carrier system for veterinary drug. Particle size and surface charge are important characteristics of nanoparticles, and have great effect on the property of nanoparticles drug carriers.
Methods:The tilmicosin-loaded hydrogenated castor oil nanoparticle (TMS-HCO-NP) suspensions were prepared with hydrogenated castor oil as lipid material, polyvinyl alcohol as surfactant and quaternary ammonium salt as surface modifier by a hot homogenization and ultrasonic technique. The size of the nanoparticles was controlled by varying the PVA concentration, and the surface charge was modified by adding quaternary ammonium salt. The effects of the size and surface charge on the property of the suspensions were studied. The physicochemical characteristics of TMS-HCO-NP were investigated by optical microscope, scanning electron microscopy (SEM) and photon correlation spectroscopy (PCS). The drug loading of the TMS-HCO-NP was measured by ultraviolet spectrophotometer. The release profiles of TMS-HCO-NP with different particle sizes and zeta potentials were studied. The effects of particle size and surface charge on cytotoxicity of TMS-HCO-NP suspensions were evaluated with BHK, Vero and RAW264.7cell lines, and the macrophage phagocytosis of TMS-HCO-NP was studied through confocal laser system. In vitro antibacterial activity of TMS-HCO-NP suspensions with different particle size and surface charge were investigated using three different methods. The acute toxicity of TMS-HCO-NP suspensions with different particle sizes was evaluated in ICR mice. The stability of TMS-HCO-NP suspensions was studied after stored at room temperature and at4℃for6months.
Results:The surfactant significantly affected the size of nanoparticles. When prepared with PVA concentrations of0.2%,1%and5%, the mean diameters of the nanoparticles in the three suspensions were920±35nm,452±10nm and151±4nm, respectively. The three suspensions displayed similar biphasic release profiles, but the suspension of smaller-sized particle showed faster initial release. None of the three suspensions were cytotoxic at clinical dosage levels on BHK and Vero cell lines. At high drug concentrations, TMS-HCO-NP suspensions with different sizes exhibited a concentration-dependent cytoxicity on the three cell lines. Phagocytosis experiments showed that the larger particles could be uptaken more easily. Time-kill curves showed that within12hours the suspension with150nm particles had the most potent bactericidal activity, but later the suspensions with larger-sized particles showed increased antibacterial activity. The results of the novel method also suggested that smaller-sized particles had better antibacterial effect. The suspension with the smallest-sized particle showed significantly more acute toxicity in mice, due to faster drug release. All three suspensions exhibited good stability at4℃and at room temperature for at least6months. The proportion of quaternary ammonium salt affected the surface charge of nanoparticles. When TMS-HCO-NP suspensions were prepared with2%dioctadecyl dimethyl ammonium chloride (DDAC) and difeeerent concentration of PVA (0.2%,1%and5%), the zeta potential of the nanoparticles were43.1±1.2mv,38.9±1.5mv and26.6±1.2mv; the particle sizes were885±16nm,499±6nm and169±4nm; the polydispersity indexes were0.344±0.041,0.309±0.012and0.478±0.005. While the TMS-HCO-NP suspensions were prepared with2%didodecyldimethylammonium bromide (DDAB), the zeta potential were48.2±1.5mv,38.6±1.3mv and27.3±1.2mv; the particle sizes were822±4nm,481±6nm and175±2nm; the polydispersity indexes were0.427±0.036,0.456±0.076and0.532±0.031. With the increment of the proportion of quaternary ammonium from2%to4%, the zeta potential was increased, but the size distribution became wider. The drug loading of positive charged nanoparticles was slight higher than that of the negatively charged ones. Compared with negatively charged TMS-HCO-NP suspensions, the positively ones showed similar release patterns but slower initial release. Cytotoxicity study showed that low concentration of TMS-HCO-NP suspensions with positive surface charge did not affect proliferation of BHK and Vero but RAW264.7, which could be due to different uptake mechanisms of nanoparticles. The antibacterial activity of TMS-HCO-NP suspension with positive surface charge was slightly higher than that with the negative surface charge.
These results demonstrate that the size and surface charge could be controlled by varying the PVA concentration and adding quaternary ammonium salt. Particle size and surface charge significantly affected the property of TMS-HCO-NP suspensions. Particle size and surface charge are important considerations for the development of drug-SLN formulations.
引文
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