注射用大蒜油固体脂质纳米粒的研究
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摘要
作为中药现代化的最前沿的创新技术，纳米中药必将成为中药现代化中的重要组成部分，这不仅可以大大提高中药的现代化和标准化，加速中药向国际市场进军的步伐，而且还可以对中药的发展产生革命性的影响。本文以具有抗真菌、抑肿瘤、降血脂等较强药理活性的大蒜油为模型药物，运用高压匀质法和熔融乳化超声法制备了固体脂质纳米粒。利用大蒜油与脂质良好的相容性，既解决了大蒜油水溶性差的问题，又提高了固体脂质纳米粒载药量。本论文首先分离纯化了大蒜油中二烯丙基二硫化物(DADS)和二烯丙基三硫化物(DATS)，制备了大蒜油及其制剂的质量控制用对照品：利用精制大蒜油制备了大蒜油固体脂质纳米粒，并用冷冻干燥技术制备大蒜油固体脂质纳米粒冻干制剂，提高了其贮存稳定性；采用中药指纹图谱作为控制制剂质量的手段；最后通过大鼠体内药动学和组织分布研究揭示了大蒜油固体脂质纳米粒的体内行为的规律。
采用制备液相纯化了GO中二种主要组分DATS和DADS，HPLC、GC-FID和GC-2ECD的纯度均达到95％以上；降解动力学研究表明DATS和DADS在不同pH溶液中有一定的降解，pH＞13时，降解速度加快；DATS和DADS在20％血浆和10％不同组织匀浆液中的降解比非生物样品中的快得多。采用GC-MS法确证了DATS主要降解产物为DADS。
以单硬脂酸甘油酯为脂质材料，卵磷脂和泊罗沙姆188为乳化剂，采用高压匀质法和熔融超声法制备了大蒜油固体脂质纳米粒。二种方法制备的大蒜油固体脂质纳米粒粒径小，包封率均在90％以上。通过单因素实验考察了工艺因素(如加入顺序、匀化压力和次数、超声功率和时间等)和处方因素(脂质相种类和用量、乳化剂浓度、乳化剂比例和大蒜油用量)对GO-SLN粒径大小及分布的影响，并进一步通过正交设计优化了处方。最佳处方的大蒜油固体脂质纳米粒粒径为106.5±40.3nm，包封率为98.6％±1.8％。
利用冷冻干燥技术，通过优化冷冻干燥的工艺和处方，将GO-SLN制备成具有良好外观和再分散性的冻干制剂，GO损失低于10％，提高了制剂的稳定性。冻干保护剂对冻干纳米粒的质量有很大的影响。使用单一保护剂时，再分散性均较差，葡萄糖、果糖、山犁醇的处方则出现了萎缩、起泡，部分产品发生喷瓶，外观很差。使用混合保护剂时，有葡萄糖和果糖的处方依然出现起泡、萎缩的现象，而其他处方的外观均较好。从再分散角度看，海藻糖和麦芽糖有提高再分散速度的作用，海藻糖更为明显。最佳处方为10％海藻糖和10％蔗糖，手摇振动的再分散时间小于10s，再分散后的粒径从106.5nm长至155.3nm，能够满足临床要求。显微摄影技术观察了冻干纳米粒的微观形态。残留水分研究表明，未经过二次升温干燥的冻干品的残余含水量仅占5.4％，自由水基本完全除去。通过室温减压干燥可去除部分结合水(2.2％)，热重分析法的加热条件不同测得残留水分的比例也有所差异。100℃加热使冻干品产生严重的萎缩、变色，所测残留水分比例较大，有可能是GO挥发的结果。稳定性研究表明，GO-SLN制成冻干品后，依然对光和热不稳定。长期留样观察结果表明，在4℃避光条件下，GO-SLN冻干品基本稳定，含量和再分散后粒径基本不变。
从粒子形态、粒径大小及分布、药物分散状态、包封率和体外释放行为方面对GO-SLN进行表征。采用透射电镜观察了自制的GO-SLN和DATS-SLN的形态，结果表明所制得的纳米粒均为表面圆整的类球形粒子。采用光子相关光谱法测定了自制SLN的粒径和分布，相同优化处方的GO-SLN粒径大小顺序为熔融超声法＞高压乳匀法。以电泳法测定了GO-SLN的ζ电位，结果表明本研究制得的纳米粒表面带负电荷，空白SLN的ζ电位为-9.9±6.6mv，3～4天就出现纳米粒的聚集分层，稳定性较差；优化处方的GO-SLN的ζ电位冻干前为-31.9±16mv，能维持40～45天未见可见颗粒，冻干后为-34.7±9.6mv。冻干前后比较可知，冷冻干燥没使ζ电位发生很大变化。
DSC法研究了药物在SLN中的分散状态，结果表明制成SLN后，大部分药物与脂质形成固体溶液，均匀分散在脂质材料中，使脂质的结晶度也有所下降。包封率是SLN的一个重要的测定指标。本研究中比较了葡聚糖凝胶过滤法、超速离心法、超滤法和冷冻聚结过滤法。结果表明，超速离心法和冷冻聚结过滤法的测定结果比较接近，葡聚糖凝胶过滤法结果偏低，超滤法对GO完全截留。体外释放的研究表明GO-SLN在体外经轻微突释后缓慢释放。
分别采用HPLC法和GC法建立了注射用GO-SLN的标准指纹图谱，相似度评价结果良好，相似系数均在0.99以上，可作为控制注射用GO-SLN的质量标准。
最后研究了大鼠颈静脉注射GO-SLN和GO注射液后的体内药动学，并比较了两种制剂的组织分布。药动学研究结果表明，GO制备成SLN后加快了其向组织分布的速度，减少了在血液中驻留时间，GO-SLN~-的MRT(13.8 min)比GO注射液的MRT(19.5 min)短，但C_(max)、AUC均为GO注射液的近两倍，生物利用度有较大的提高。组织分布研究结果表明，GO与脂质结合形成SLN后，在体内有释放的过程，一定程度上减少了体内酶对GO的代谢和破坏，延长了GO在组织中的作用时间。
As the most advancing technology of traditional Chinese drug modernazition, nano traditional Chinese drug will become one of the most parts of traditional Chinese drug modernazition, which not only elevate the modernization and standardization of traditional Chinese drug and accelerate the step into international market, but also have revolutionary influence on the development of it. In this article, garlic oil(GO) was selected as model drug, which exhibit a variety of biological activities including hypolipidemic, antithrombotic, antiatherosclerotic, antimutagenic, anticarcinogenic and antibacterial effects, and solid lipid nanoparticle(SLN) was prepared by high pressure homogenization(HPH) and melt-ultrasound technology. On account of the good compatibility of GO and lipid, the problem of poor solubility of GO and the low drug loading capacity may be solved simultaneously. Firstly, diallyl trisulfide(DATS) and diallyl disulfide(DADS) were separated from GO as the standards of quality control; GO-SLN was prepared by HPH and melt-ultrasound technology and the freeze drying preparation of GO-SLN was prepared by lyophillization to enhance the storage stability. The finger print was made as the method of quality control. Finally, the pharmacokinetics and tissue distribution in rats was studied to reveal the fate in vivo of GO-SLN.DATS and DADS were separated and purified by preparation HPLC. The both contents were evaluated to be >95% by the methods of HPLC, GC-FID and GC-ECD. The results of degradation dynamics showed that both degraded to some extent in different pH solution, while pH was higher than 13, the degradation rate accelerated markedly. Both degraded more quickly in 20% plasma and 10% tissue homogenates than in water solution. The main degradation product of DATS was DADS identified by GC-MS.GO-SLN was prepared by HPH and melt-ultrasound technology, which glyceryl monostearate was lipid material and lecithin and poloxamer 188 as emulsifier. The particle size of GO-SLN by two methods was small and encapsulation efficiency was higher 90%. The single factor experiments were investigated the effects of technology factors (adding order, homogenization pressure and cycles, ultrasound power and time, et al) and formulation factors(the kinds and content of lipid phase, the kind and ratio of emulsifier and the content of GO) on particle size and distribution of GO-SLN. The orthogonal design was carried to optimize the formulation further. The particle size of the best formulation was 106.5±40.3nm and the encapsulation efficiency was 98.6％±1.8％.
GO-SLN was prepared into freeze drying preparation with good appearance and reconstitution by lyophillization after the process and formulation parameters were optimized. The lose of GO was lower 10％and the stability of GO-SLN was highly improved. The cryoprotectants are necessary to protect SLN during lyophillization. The reeonstitution of the freeze drying preparation of GO-SLN with single cryoprotectant was poor and the phenomena of shrinking, bubbling or spurt bottle will happen in the formulations with glucose, fructose and sorbitol as cryoprotectant. However, the mixture of cryoproteetants can notably improve the appearance and reconstitution. Trehalose and maltose can accelerate the reeonstitution rate. The best formulation with 10％trehalose and 10％sucrose can reconstitute in 10s with manual shaking and the particle size increase from 106.5nm to155.3nm, which can reach the requirement. The microform was observed by microphotograph. The study of retained moisture showed that the retained moisture was about 5.4％after sublimation drying and free water in GO-SLN was almost removed. 2.2％of the retained moisture can be removed further by the drying under reduced pressure at room temperature. The retained moisture can be removed wholly by being heated at 100℃. However, the shringkage and change color happened visibly. The results of stability study showed that the freeze drying preparation of GO-SLN are still instable to heat and light, but it is stable away from light at 4℃,
The characters of GO-SLN include the shape, particle size and distribution, drug status in SLN, encapsulation efficiency and release in vitro. In this study, the shape of GO-SLN and DATS-SLN was observed by transmission electron microscope(TEM), which is spherelike. The particle size and distribution was determined by PCS. The particle size of GO-SLN prepared by melt-emulsified ultrasound was higher than that by HPH.ζpotential of GO-SLN was determined by electrophoretic method, which was negative.ζpotential of drug-free SLN and GO-SLN was --9.9±6.6mv and --31.9±16mv, respectively. potential of the freeze drying preparation of GO-SLN was --34.7±9.6mv, which didn't nearly change.
The result of DSC indicated that GO dispersed into lipid uniformly and form solid solution. Encapsulation efficiency is one of important index. In this study, sephadex filtration method, ultraeentrifugalization, ultrafiltration and freeze- coalescence filtration was used to determined encapsulation effieiency(EE). The results showed that EE was alike by ultraeentrifugalization and freeze-coalescence filtration, while the result by sephadex filtration method was lower. GO was wholly entrapped by ultraflltration membrane, so ultrafiltration method is not suitable to determine the EE of GO-SLN. The release study in vitro showed that GO-SLN in vitro first slight burst release, then release slowly.
The standard finger print of GO-SLN was erected by I-IPLC and GC, respectively. Good similarities were found in fingerprints in 10 batches of GO-SLN. The similarity coefficient was higher than 0.99, so it can act the quality control standard of Go-SLN for injection.
A GC-ECD method was developed for the determination of DATS and DADS in the plasma and biological samples of rats. The intravenous pharmacokinetic behaviors of GO solution and GO-SLN were investigated. The results showed that compared with GO solution, MRT of GO-SLN(13.8min) was shorter than that of GO solution(19.5 min). However, C_(max), and AUC of GO-SLN was twice of that of GO solution. GO-SLN significantly enhanced the bioavailability. The results of tissue distribution showed that GO-SLN distributed more quickly into tissues after intravenous injection and maintained a higher concentration and longer time in tissues, which indicated that the target efficiency enhanced.
采用制备液相纯化了GO中二种主要组分DATS和DADS，HPLC、GC-FID和GC-2ECD的纯度均达到95％以上；降解动力学研究表明DATS和DADS在不同pH溶液中有一定的降解，pH＞13时，降解速度加快；DATS和DADS在20％血浆和10％不同组织匀浆液中的降解比非生物样品中的快得多。采用GC-MS法确证了DATS主要降解产物为DADS。
以单硬脂酸甘油酯为脂质材料，卵磷脂和泊罗沙姆188为乳化剂，采用高压匀质法和熔融超声法制备了大蒜油固体脂质纳米粒。二种方法制备的大蒜油固体脂质纳米粒粒径小，包封率均在90％以上。通过单因素实验考察了工艺因素(如加入顺序、匀化压力和次数、超声功率和时间等)和处方因素(脂质相种类和用量、乳化剂浓度、乳化剂比例和大蒜油用量)对GO-SLN粒径大小及分布的影响，并进一步通过正交设计优化了处方。最佳处方的大蒜油固体脂质纳米粒粒径为106.5±40.3nm，包封率为98.6％±1.8％。
利用冷冻干燥技术，通过优化冷冻干燥的工艺和处方，将GO-SLN制备成具有良好外观和再分散性的冻干制剂，GO损失低于10％，提高了制剂的稳定性。冻干保护剂对冻干纳米粒的质量有很大的影响。使用单一保护剂时，再分散性均较差，葡萄糖、果糖、山犁醇的处方则出现了萎缩、起泡，部分产品发生喷瓶，外观很差。使用混合保护剂时，有葡萄糖和果糖的处方依然出现起泡、萎缩的现象，而其他处方的外观均较好。从再分散角度看，海藻糖和麦芽糖有提高再分散速度的作用，海藻糖更为明显。最佳处方为10％海藻糖和10％蔗糖，手摇振动的再分散时间小于10s，再分散后的粒径从106.5nm长至155.3nm，能够满足临床要求。显微摄影技术观察了冻干纳米粒的微观形态。残留水分研究表明，未经过二次升温干燥的冻干品的残余含水量仅占5.4％，自由水基本完全除去。通过室温减压干燥可去除部分结合水(2.2％)，热重分析法的加热条件不同测得残留水分的比例也有所差异。100℃加热使冻干品产生严重的萎缩、变色，所测残留水分比例较大，有可能是GO挥发的结果。稳定性研究表明，GO-SLN制成冻干品后，依然对光和热不稳定。长期留样观察结果表明，在4℃避光条件下，GO-SLN冻干品基本稳定，含量和再分散后粒径基本不变。
从粒子形态、粒径大小及分布、药物分散状态、包封率和体外释放行为方面对GO-SLN进行表征。采用透射电镜观察了自制的GO-SLN和DATS-SLN的形态，结果表明所制得的纳米粒均为表面圆整的类球形粒子。采用光子相关光谱法测定了自制SLN的粒径和分布，相同优化处方的GO-SLN粒径大小顺序为熔融超声法＞高压乳匀法。以电泳法测定了GO-SLN的ζ电位，结果表明本研究制得的纳米粒表面带负电荷，空白SLN的ζ电位为-9.9±6.6mv，3～4天就出现纳米粒的聚集分层，稳定性较差；优化处方的GO-SLN的ζ电位冻干前为-31.9±16mv，能维持40～45天未见可见颗粒，冻干后为-34.7±9.6mv。冻干前后比较可知，冷冻干燥没使ζ电位发生很大变化。
DSC法研究了药物在SLN中的分散状态，结果表明制成SLN后，大部分药物与脂质形成固体溶液，均匀分散在脂质材料中，使脂质的结晶度也有所下降。包封率是SLN的一个重要的测定指标。本研究中比较了葡聚糖凝胶过滤法、超速离心法、超滤法和冷冻聚结过滤法。结果表明，超速离心法和冷冻聚结过滤法的测定结果比较接近，葡聚糖凝胶过滤法结果偏低，超滤法对GO完全截留。体外释放的研究表明GO-SLN在体外经轻微突释后缓慢释放。
分别采用HPLC法和GC法建立了注射用GO-SLN的标准指纹图谱，相似度评价结果良好，相似系数均在0.99以上，可作为控制注射用GO-SLN的质量标准。
最后研究了大鼠颈静脉注射GO-SLN和GO注射液后的体内药动学，并比较了两种制剂的组织分布。药动学研究结果表明，GO制备成SLN后加快了其向组织分布的速度，减少了在血液中驻留时间，GO-SLN~-的MRT(13.8 min)比GO注射液的MRT(19.5 min)短，但C_(max)、AUC均为GO注射液的近两倍，生物利用度有较大的提高。组织分布研究结果表明，GO与脂质结合形成SLN后，在体内有释放的过程，一定程度上减少了体内酶对GO的代谢和破坏，延长了GO在组织中的作用时间。
As the most advancing technology of traditional Chinese drug modernazition, nano traditional Chinese drug will become one of the most parts of traditional Chinese drug modernazition, which not only elevate the modernization and standardization of traditional Chinese drug and accelerate the step into international market, but also have revolutionary influence on the development of it. In this article, garlic oil(GO) was selected as model drug, which exhibit a variety of biological activities including hypolipidemic, antithrombotic, antiatherosclerotic, antimutagenic, anticarcinogenic and antibacterial effects, and solid lipid nanoparticle(SLN) was prepared by high pressure homogenization(HPH) and melt-ultrasound technology. On account of the good compatibility of GO and lipid, the problem of poor solubility of GO and the low drug loading capacity may be solved simultaneously. Firstly, diallyl trisulfide(DATS) and diallyl disulfide(DADS) were separated from GO as the standards of quality control; GO-SLN was prepared by HPH and melt-ultrasound technology and the freeze drying preparation of GO-SLN was prepared by lyophillization to enhance the storage stability. The finger print was made as the method of quality control. Finally, the pharmacokinetics and tissue distribution in rats was studied to reveal the fate in vivo of GO-SLN.DATS and DADS were separated and purified by preparation HPLC. The both contents were evaluated to be >95% by the methods of HPLC, GC-FID and GC-ECD. The results of degradation dynamics showed that both degraded to some extent in different pH solution, while pH was higher than 13, the degradation rate accelerated markedly. Both degraded more quickly in 20% plasma and 10% tissue homogenates than in water solution. The main degradation product of DATS was DADS identified by GC-MS.GO-SLN was prepared by HPH and melt-ultrasound technology, which glyceryl monostearate was lipid material and lecithin and poloxamer 188 as emulsifier. The particle size of GO-SLN by two methods was small and encapsulation efficiency was higher 90%. The single factor experiments were investigated the effects of technology factors (adding order, homogenization pressure and cycles, ultrasound power and time, et al) and formulation factors(the kinds and content of lipid phase, the kind and ratio of emulsifier and the content of GO) on particle size and distribution of GO-SLN. The orthogonal design was carried to optimize the formulation further. The particle size of the best formulation was 106.5±40.3nm and the encapsulation efficiency was 98.6％±1.8％.
GO-SLN was prepared into freeze drying preparation with good appearance and reconstitution by lyophillization after the process and formulation parameters were optimized. The lose of GO was lower 10％and the stability of GO-SLN was highly improved. The cryoprotectants are necessary to protect SLN during lyophillization. The reeonstitution of the freeze drying preparation of GO-SLN with single cryoprotectant was poor and the phenomena of shrinking, bubbling or spurt bottle will happen in the formulations with glucose, fructose and sorbitol as cryoprotectant. However, the mixture of cryoproteetants can notably improve the appearance and reconstitution. Trehalose and maltose can accelerate the reeonstitution rate. The best formulation with 10％trehalose and 10％sucrose can reconstitute in 10s with manual shaking and the particle size increase from 106.5nm to155.3nm, which can reach the requirement. The microform was observed by microphotograph. The study of retained moisture showed that the retained moisture was about 5.4％after sublimation drying and free water in GO-SLN was almost removed. 2.2％of the retained moisture can be removed further by the drying under reduced pressure at room temperature. The retained moisture can be removed wholly by being heated at 100℃. However, the shringkage and change color happened visibly. The results of stability study showed that the freeze drying preparation of GO-SLN are still instable to heat and light, but it is stable away from light at 4℃,
The characters of GO-SLN include the shape, particle size and distribution, drug status in SLN, encapsulation efficiency and release in vitro. In this study, the shape of GO-SLN and DATS-SLN was observed by transmission electron microscope(TEM), which is spherelike. The particle size and distribution was determined by PCS. The particle size of GO-SLN prepared by melt-emulsified ultrasound was higher than that by HPH.ζpotential of GO-SLN was determined by electrophoretic method, which was negative.ζpotential of drug-free SLN and GO-SLN was --9.9±6.6mv and --31.9±16mv, respectively. potential of the freeze drying preparation of GO-SLN was --34.7±9.6mv, which didn't nearly change.
The result of DSC indicated that GO dispersed into lipid uniformly and form solid solution. Encapsulation efficiency is one of important index. In this study, sephadex filtration method, ultraeentrifugalization, ultrafiltration and freeze- coalescence filtration was used to determined encapsulation effieiency(EE). The results showed that EE was alike by ultraeentrifugalization and freeze-coalescence filtration, while the result by sephadex filtration method was lower. GO was wholly entrapped by ultraflltration membrane, so ultrafiltration method is not suitable to determine the EE of GO-SLN. The release study in vitro showed that GO-SLN in vitro first slight burst release, then release slowly.
The standard finger print of GO-SLN was erected by I-IPLC and GC, respectively. Good similarities were found in fingerprints in 10 batches of GO-SLN. The similarity coefficient was higher than 0.99, so it can act the quality control standard of Go-SLN for injection.
A GC-ECD method was developed for the determination of DATS and DADS in the plasma and biological samples of rats. The intravenous pharmacokinetic behaviors of GO solution and GO-SLN were investigated. The results showed that compared with GO solution, MRT of GO-SLN(13.8min) was shorter than that of GO solution(19.5 min). However, C_(max), and AUC of GO-SLN was twice of that of GO solution. GO-SLN significantly enhanced the bioavailability. The results of tissue distribution showed that GO-SLN distributed more quickly into tissues after intravenous injection and maintained a higher concentration and longer time in tissues, which indicated that the target efficiency enhanced.
引文
1．徐辉碧，杨祥良，谢长生．纳米技术在中药研究中的应用．中国药科大学学报[J]，2001，22(1)：82～86
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