复方姜黄素脂质立方液晶的制备、表征与评价
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摘要
姜黄素(curcumin)是从姜黄中提取的一种天然有效成分,同时也广泛存在于姜黄属的其他植物中,目前被广泛用作色素、食品添加剂及调味品,其来源广泛、安全无毒。近年的研究表明,姜黄素具有广泛的药理作用,如抗肿瘤、改善心血管功能、抗炎、抗病毒、保肝、增强免疫力等,具有良好的药理活性和应用前景,但是姜黄素存在疏水性强、口服吸收少、稳定性差以及体内生物利用度低等缺陷,严重影响了其在临床上的使用。
脂质立方液晶纳米粒(cubic liquid crystalline nanoparticles, LCNP)是由两亲性脂质和表面活性剂在水中自发形成的液晶纳米分散体系,具有能够包结各种不同极性和剂量的药物；提高药物的稳定性,免受机体酶和免疫系统的影响；生物亲和性、粘附性好以及控制药物释放和提高药物生物利用度等优点。
本论文从两个方面着手共同提高姜黄素的生物利用度：基于胡椒碱为天然葡萄糖醛酸酶抑制剂,将姜黄素与胡椒碱联合应用,降低姜黄素在体内的生物转化；针对姜黄素在水中溶解度低、稳定性较差、生物利用度低等问题,将姜黄素与胡椒碱制备成立方液晶纳米粒。本论文主要从复方姜黄素理化性质、稳定性、脂质立方液晶制备、结构表征、药剂学特征、药动学及其细胞跨膜吸收机制等方面进行研究,具体如下：
1、姜黄素和胡椒碱理化性质和稳定性研究。采用高效液相色谱法建立了姜黄素和胡椒碱原料的含量测定方法并测定姜黄素和胡椒碱原料的含量,在此基础上,对姜黄素和胡椒碱在有机溶剂中的饱和溶解度、表观溶解度以及汕水分配系数进行了考察,结果表明姜黄素和胡椒碱均为脂溶性药物,在PEG400中饱和溶解度均最高。姜黄素在不同pH值磷酸盐缓冲液中均不溶解,而胡椒碱随着pH值的增加,溶解性逐渐提高。最后对姜黄素和胡椒碱原料热稳定性进行考察,结果表明姜黄素和胡椒碱水溶液对热不稳定,但在乙醇溶液含量未发生显著性变化。
2、复方姜黄素脂质立方液晶的制备与表征。筛选了复方姜黄素脂质立方液晶不同的包封率测定方法,在此基础上选择前体注入法制备了复方姜黄素脂质立方液晶,通过单因素试验,考察搅拌温度、搅拌转速、搅拌时间、超声次数等因素对复方姜黄素脂质立方液晶包封率的影响,确定了复方姜黄素脂质立方液晶最佳制备工艺参数,最后对复方姜黄素脂质立方液晶处方工艺进行了研究,以药物的包封率和载药量为评价指标,采用均匀设计优化处方工艺,得到了包封率和载药量均较佳的脂质立方液晶纳米粒。通过偏)光显微镜、扫描电镜、激光粒度仪、小角度X散射、红外光谱和差式扫描量热分析等方法对复方姜黄素脂质立方液晶光学特性、形貌、晶型结构、分子间作用以及热量变化进行表征。
3、复方姜黄素脂质立方液晶药剂学特性研究。主要从脂质立方液晶纳米粒混悬液的pH、渗漏率、体外释放、生物粘附性以及稳定性等几个方面对复方姜黄素脂质立方液晶的药剂学特性进行考察。结果显示复方姜黄素脂质立方液晶纳米粒pH和渗漏率均较为稳定；与原料药相比,复方姜黄素脂质立方液晶生物粘附性和稳定性也有了较大的提高。在体外释放方面,复方姜黄素脂质立方液晶药物释放均符合Higuchi方程,且pH和无机盐对其体外释放无显著性影响。
4、复方姜黄素脂质立方液晶小鼠体内药动学及组织分布。运用药动学软件对不同时间点的样品浓度进行房室模型拟合,确定最佳房室模型并计算相关药动学参数。结果显示,两给药组中的血液和各组织器官药物药时曲线均符合二室开放模型(C=Ae-α t+Be-βt)。复方姜黄素脂质立方液晶纳米粒给药后达峰浓度显著高于原药组。同时LCNP组药物达峰时间相比原药组显著延后,其相对生物利用度相比原料药提高了近15倍,达到了试验预期要求。药物制备成脂质立方液晶纳米粒后,主要分布于脾脏、肝脏和肺组织中,尤其是脾脏,其组织摄取率相比其他组织增加近20倍。
5、复方姜黄素脂质立方液晶透膜吸收机制研究。建立了Caco-2单层细胞模型并考察了原料药和复方姜黄素脂质立方液晶(LCNP)对细胞存活率的影响,确定了药物安全浓度范围。通过对原料药和LCNP的细胞摄取试验发现,LCNP随着浓度的增加,摄取逐渐增加,而原料药具有饱和现象。加入维拉帕米后,原料药摄取率有一定程度的增加。最后考察不同的孵育时间和维拉帕米对细胞转运的影响,结果与上述结果一致。
综上所述,本文采用了前体法注入法制备了复方姜黄素脂质立方液晶,不仅提高了制备效率,而且制备工艺稳定,重现性良好,质量可控,具有较好的生物粘附性,可以明显提高姜黄素体内生物利用度,达到了试验预期的目的,同时也为其他药物脂质立方液晶纳米粒的制备提供了较好的借鉴作用。
本论文的创新点主要包括以下几个方面：
1、首次将姜黄素和胡椒碱联合制备成脂质立方液晶纳米粒,不仅解决了姜黄素水溶性、稳定性以及生物利月用度差的问题,而且.为脂质立方液晶作为药物载体研究提供了一个新的思路。
2、首次采用多种方法和手段对复方姜黄素脂质立方液晶进行体内外评价。采用了光谱、色谱、DSC、SAXS等方法对复方姜黄素脂质立方液晶进行结构表征,同时对其体外释放,体内生物利用度,细胞吸收和转运机制等方而进行了较为系统和全而的研究。
Curcumin is a natural active ingredient that extracted from the Carcuraa longa, and the other plants with the carcuma species. Curcumin had been widely used as pigment, food additives and spices, which proved to be sufficient and safe. In recent years, the research had shown that curcumin had extensive pharmacological effects, such as anti-tumor, improving cardiovascular function, anti-inflammatory, antiviral,liver protection, boosting immunity, etc. In spite of the good pharmacological activity and application prospects, the curcumin had the problems, such as hydrophobic, oral absorption, poor stability and low bioavailability in vivo,which exerted a serious influence on its clinical use.
Cubic liquid crystalline nanoparticles (LCXP), was spontaneously formed by the amphiphilic lipids and surfactants in the water, which had lots of advantages, such as encapsulation of different polarity and dose of the drug, improvement of the stability of the drug against from the influence of the enzymes and the immune system, good biological affinity and adhesivity, the characteristic of drug controlled release, improvement of drug bioavailability, etc.
This paper was aimed to improve the bioavailability of curcumin from two aspects:based on the piperine was natural inhibitors of glucuronic acid, the curcumin was used with piperine to decrease the biological transformation of curcumin in the body. For the low solubility in the water, poor stability, and low bioavailability, the curcumin with piperine cubic liquid crystalline nanoparticles was established. The content of the paper mainly included: physical and chemical properties of the compound curcumin, preparation and stability of compound curcumin lipid cubic liquid crystalline nanoparticles, characterization of structure, features of pharmaceutics, pharmacokinetic and the absorption mechanism of transmembrane and so on, details as below:
1.The study on the physical and chemical properties and stability of the compound curcumin. High performance liquid chromatography (HPLC) method was established to determine the content of curcumin and piperine. And then, saturated solubility in organic solvent, apparent solubility and oil/water partition coefficient of the curcumin and piperine were investigated. The results showed that both curcumin and piperine were fat soluble drugs, and had the highest saturated solubility in the PEG400. The curcumin was insoluble in different pH phosphate buffer, and the solubility of piperine gradually improved with the increase of pH. From the study on the thermal stability of curcumin and piperine, the results showed that curcumin and piperine was not stable in water, but the content of drugs had no significant change in ethanol solution.
2. Preparation and characterization of compound curcumin lipid cubic liquid crystalnanoparticles. On the basis of screening different coating rate measurement method of compound curcumin lipid cubic liquid crystalline nanoparticles, ethanol injection was selected for the preparation of the compound curcumin lipid cubic liquid crystalline nanoparticles.The influence of stirring temperature, speed, time and ultrasonic frequency on the encapsulation efficiency of the compound curcumin lipid cubic liquid crystalline nanoparticles was investigated by single factor experiment.the optimum preparation technology parameters of compound curcumin lipid cubic liquid crystalline nanoparticles were identified. Finally, the prescription process of compound curcumin lipid cubic liquid crystalline nanoparticles was also studied. With encapsulation efficiency and drug loadings as evaluation index, the prescription was optimized by using uniform design process, and compound curcumin lipid cubic liquid crystalline nanoparticles was achieved with the optimal encapsulation efficiency and drug loadings. And then the polarizing microscope,scanning electron microscopy, laser particle size instrument, small Angle X-ray scattering, infrared spectroscopy and differential scanning calorimetric analysis was adopted to the characterization of Compound curcumin lipid cubic liquid crystalline nanoparticles by the optical properties,morphology, crystalline structure, molecular interaction and heat changes.
3. Characteristic study in pharmacy of Compound curcumin lipid cubic liquid crystalline nanoparticles. The research was conducted mainly including the pH value, leakage,the release rate in vitro,biological adhesion and stability of compound curcumin lipid cubic liquid crystalline nanoparticles. And the results showed that the pH and the leakage rate of compound curcumin lipid cubic liquid crystalline nanoparticles is relatively stable. Compared with the crude ingredients, compound curcumin lipid cubic liquid crystalline nanoparticles had better biological adhesion and stability and in terms of in vitro release, compound curcumin lipid cubic liquid crystalline nanoparticles had the feature of controlled release consistent with Higuchi equation, and would not be impacted by the pH and inorganic salt on the in vitro release.
4. pharmacokinetic and tissue distribution in mice of compound curcumin lipid cubic liquid crystalline nanoparticles. The sample concentrations at different time points was conducted by atrioventricular model fitting using pharmacokinetic software, and the pharmacokinetic parameters of the best atrioventricular models was determined. According to the results of two groups of the drug, the blood and the tissues distributed in accordance with2rooms open model (C=Ae-αt+Be-βt). The peak concentration of compound curcumin lipid cubic liquid crystalline nanoparticles was significantly higher than the crude drug. and tmax was delayed as well. In addition, the relative bioavailability of compound curcumin lipid cubic liquid crystalline nanoparticles increased nearly by15times, which reached the expectation of the cubsomes. Compound curcumin lipid cubic liquid crystalline nanoparticles mainly distributed in the spleen, liver and lung tissues, especially the spleen. The tissue uptake rate increased by nearly20times compared to other groups.
5. The absorption mechanism of compound curcumin cubic liquid crystal. Caco-2monolayer cell model was established and the effect on the cell survival rate of compound curcumin lipid cubic liquid crystalline nanoparticles was investigated to identify the range of the safe concentration. During the cell uptake test, we found that the intake of compound curcumin lipid cubic liquid crystalline nanoparticles gradually increased with the enhancement of concentration, however, the intake of the crude drug showed phenomenon of saturation. After joined verapamil, the intake rate of crude drug had increased to a certain extent. Finally, the influence of the different incubation time and verapamil on the cell membrane was consistent with the results above.
In conclusion, the compound curcumin lipid cubic liquid crystalline nanoparticles was prepared by the ethanol precursor.The method proved to be high efficiency, stable, good reproducibility, quality controlled,and good biological adhesive. The compound curcumin lipid cubic liquid crystalline nanoparticles could obviously increase the bioavailability of curcumin in the body and achieve the aim of the trial. Meanwhile, it also provided a good reference to the other drugs for lipid cubic liquid crystalline nanoparticles.
The innovation of the paper mainly including:
1. The compound curcumin lipid cubic liquid crystalline nanoparticles was prepared for the first time, which not only solved water-soluble problem, poor stability and bioavailability of the curcumin and also provided a new idea for lipid cubic liquid crystalline nanoparticles as drug carrier.
2. A variety of methods and technology was adopted for the evaluation in vivo and in vitro of compound curcumin lipid cubic liquid crystalline nanoparticles for the first time. The structure characterization of compound curcumin lipid cubic liquid crystalline nanoparticles was carried out by the spectroscopy, chromatography, DSC, SAXS, and so on. In addition, in vitro release, in vivo bioavailability, cell absorption and transport mechanism was also been studied systematically and comprehensively.
脂质立方液晶纳米粒(cubic liquid crystalline nanoparticles, LCNP)是由两亲性脂质和表面活性剂在水中自发形成的液晶纳米分散体系,具有能够包结各种不同极性和剂量的药物；提高药物的稳定性,免受机体酶和免疫系统的影响；生物亲和性、粘附性好以及控制药物释放和提高药物生物利用度等优点。
本论文从两个方面着手共同提高姜黄素的生物利用度：基于胡椒碱为天然葡萄糖醛酸酶抑制剂,将姜黄素与胡椒碱联合应用,降低姜黄素在体内的生物转化；针对姜黄素在水中溶解度低、稳定性较差、生物利用度低等问题,将姜黄素与胡椒碱制备成立方液晶纳米粒。本论文主要从复方姜黄素理化性质、稳定性、脂质立方液晶制备、结构表征、药剂学特征、药动学及其细胞跨膜吸收机制等方面进行研究,具体如下：
1、姜黄素和胡椒碱理化性质和稳定性研究。采用高效液相色谱法建立了姜黄素和胡椒碱原料的含量测定方法并测定姜黄素和胡椒碱原料的含量,在此基础上,对姜黄素和胡椒碱在有机溶剂中的饱和溶解度、表观溶解度以及汕水分配系数进行了考察,结果表明姜黄素和胡椒碱均为脂溶性药物,在PEG400中饱和溶解度均最高。姜黄素在不同pH值磷酸盐缓冲液中均不溶解,而胡椒碱随着pH值的增加,溶解性逐渐提高。最后对姜黄素和胡椒碱原料热稳定性进行考察,结果表明姜黄素和胡椒碱水溶液对热不稳定,但在乙醇溶液含量未发生显著性变化。
2、复方姜黄素脂质立方液晶的制备与表征。筛选了复方姜黄素脂质立方液晶不同的包封率测定方法,在此基础上选择前体注入法制备了复方姜黄素脂质立方液晶,通过单因素试验,考察搅拌温度、搅拌转速、搅拌时间、超声次数等因素对复方姜黄素脂质立方液晶包封率的影响,确定了复方姜黄素脂质立方液晶最佳制备工艺参数,最后对复方姜黄素脂质立方液晶处方工艺进行了研究,以药物的包封率和载药量为评价指标,采用均匀设计优化处方工艺,得到了包封率和载药量均较佳的脂质立方液晶纳米粒。通过偏)光显微镜、扫描电镜、激光粒度仪、小角度X散射、红外光谱和差式扫描量热分析等方法对复方姜黄素脂质立方液晶光学特性、形貌、晶型结构、分子间作用以及热量变化进行表征。
3、复方姜黄素脂质立方液晶药剂学特性研究。主要从脂质立方液晶纳米粒混悬液的pH、渗漏率、体外释放、生物粘附性以及稳定性等几个方面对复方姜黄素脂质立方液晶的药剂学特性进行考察。结果显示复方姜黄素脂质立方液晶纳米粒pH和渗漏率均较为稳定；与原料药相比,复方姜黄素脂质立方液晶生物粘附性和稳定性也有了较大的提高。在体外释放方面,复方姜黄素脂质立方液晶药物释放均符合Higuchi方程,且pH和无机盐对其体外释放无显著性影响。
4、复方姜黄素脂质立方液晶小鼠体内药动学及组织分布。运用药动学软件对不同时间点的样品浓度进行房室模型拟合,确定最佳房室模型并计算相关药动学参数。结果显示,两给药组中的血液和各组织器官药物药时曲线均符合二室开放模型(C=Ae-α t+Be-βt)。复方姜黄素脂质立方液晶纳米粒给药后达峰浓度显著高于原药组。同时LCNP组药物达峰时间相比原药组显著延后,其相对生物利用度相比原料药提高了近15倍,达到了试验预期要求。药物制备成脂质立方液晶纳米粒后,主要分布于脾脏、肝脏和肺组织中,尤其是脾脏,其组织摄取率相比其他组织增加近20倍。
5、复方姜黄素脂质立方液晶透膜吸收机制研究。建立了Caco-2单层细胞模型并考察了原料药和复方姜黄素脂质立方液晶(LCNP)对细胞存活率的影响,确定了药物安全浓度范围。通过对原料药和LCNP的细胞摄取试验发现,LCNP随着浓度的增加,摄取逐渐增加,而原料药具有饱和现象。加入维拉帕米后,原料药摄取率有一定程度的增加。最后考察不同的孵育时间和维拉帕米对细胞转运的影响,结果与上述结果一致。
综上所述,本文采用了前体法注入法制备了复方姜黄素脂质立方液晶,不仅提高了制备效率,而且制备工艺稳定,重现性良好,质量可控,具有较好的生物粘附性,可以明显提高姜黄素体内生物利用度,达到了试验预期的目的,同时也为其他药物脂质立方液晶纳米粒的制备提供了较好的借鉴作用。
本论文的创新点主要包括以下几个方面：
1、首次将姜黄素和胡椒碱联合制备成脂质立方液晶纳米粒,不仅解决了姜黄素水溶性、稳定性以及生物利月用度差的问题,而且.为脂质立方液晶作为药物载体研究提供了一个新的思路。
2、首次采用多种方法和手段对复方姜黄素脂质立方液晶进行体内外评价。采用了光谱、色谱、DSC、SAXS等方法对复方姜黄素脂质立方液晶进行结构表征,同时对其体外释放,体内生物利用度,细胞吸收和转运机制等方而进行了较为系统和全而的研究。
Curcumin is a natural active ingredient that extracted from the Carcuraa longa, and the other plants with the carcuma species. Curcumin had been widely used as pigment, food additives and spices, which proved to be sufficient and safe. In recent years, the research had shown that curcumin had extensive pharmacological effects, such as anti-tumor, improving cardiovascular function, anti-inflammatory, antiviral,liver protection, boosting immunity, etc. In spite of the good pharmacological activity and application prospects, the curcumin had the problems, such as hydrophobic, oral absorption, poor stability and low bioavailability in vivo,which exerted a serious influence on its clinical use.
Cubic liquid crystalline nanoparticles (LCXP), was spontaneously formed by the amphiphilic lipids and surfactants in the water, which had lots of advantages, such as encapsulation of different polarity and dose of the drug, improvement of the stability of the drug against from the influence of the enzymes and the immune system, good biological affinity and adhesivity, the characteristic of drug controlled release, improvement of drug bioavailability, etc.
This paper was aimed to improve the bioavailability of curcumin from two aspects:based on the piperine was natural inhibitors of glucuronic acid, the curcumin was used with piperine to decrease the biological transformation of curcumin in the body. For the low solubility in the water, poor stability, and low bioavailability, the curcumin with piperine cubic liquid crystalline nanoparticles was established. The content of the paper mainly included: physical and chemical properties of the compound curcumin, preparation and stability of compound curcumin lipid cubic liquid crystalline nanoparticles, characterization of structure, features of pharmaceutics, pharmacokinetic and the absorption mechanism of transmembrane and so on, details as below:
1.The study on the physical and chemical properties and stability of the compound curcumin. High performance liquid chromatography (HPLC) method was established to determine the content of curcumin and piperine. And then, saturated solubility in organic solvent, apparent solubility and oil/water partition coefficient of the curcumin and piperine were investigated. The results showed that both curcumin and piperine were fat soluble drugs, and had the highest saturated solubility in the PEG400. The curcumin was insoluble in different pH phosphate buffer, and the solubility of piperine gradually improved with the increase of pH. From the study on the thermal stability of curcumin and piperine, the results showed that curcumin and piperine was not stable in water, but the content of drugs had no significant change in ethanol solution.
2. Preparation and characterization of compound curcumin lipid cubic liquid crystalnanoparticles. On the basis of screening different coating rate measurement method of compound curcumin lipid cubic liquid crystalline nanoparticles, ethanol injection was selected for the preparation of the compound curcumin lipid cubic liquid crystalline nanoparticles.The influence of stirring temperature, speed, time and ultrasonic frequency on the encapsulation efficiency of the compound curcumin lipid cubic liquid crystalline nanoparticles was investigated by single factor experiment.the optimum preparation technology parameters of compound curcumin lipid cubic liquid crystalline nanoparticles were identified. Finally, the prescription process of compound curcumin lipid cubic liquid crystalline nanoparticles was also studied. With encapsulation efficiency and drug loadings as evaluation index, the prescription was optimized by using uniform design process, and compound curcumin lipid cubic liquid crystalline nanoparticles was achieved with the optimal encapsulation efficiency and drug loadings. And then the polarizing microscope,scanning electron microscopy, laser particle size instrument, small Angle X-ray scattering, infrared spectroscopy and differential scanning calorimetric analysis was adopted to the characterization of Compound curcumin lipid cubic liquid crystalline nanoparticles by the optical properties,morphology, crystalline structure, molecular interaction and heat changes.
3. Characteristic study in pharmacy of Compound curcumin lipid cubic liquid crystalline nanoparticles. The research was conducted mainly including the pH value, leakage,the release rate in vitro,biological adhesion and stability of compound curcumin lipid cubic liquid crystalline nanoparticles. And the results showed that the pH and the leakage rate of compound curcumin lipid cubic liquid crystalline nanoparticles is relatively stable. Compared with the crude ingredients, compound curcumin lipid cubic liquid crystalline nanoparticles had better biological adhesion and stability and in terms of in vitro release, compound curcumin lipid cubic liquid crystalline nanoparticles had the feature of controlled release consistent with Higuchi equation, and would not be impacted by the pH and inorganic salt on the in vitro release.
4. pharmacokinetic and tissue distribution in mice of compound curcumin lipid cubic liquid crystalline nanoparticles. The sample concentrations at different time points was conducted by atrioventricular model fitting using pharmacokinetic software, and the pharmacokinetic parameters of the best atrioventricular models was determined. According to the results of two groups of the drug, the blood and the tissues distributed in accordance with2rooms open model (C=Ae-αt+Be-βt). The peak concentration of compound curcumin lipid cubic liquid crystalline nanoparticles was significantly higher than the crude drug. and tmax was delayed as well. In addition, the relative bioavailability of compound curcumin lipid cubic liquid crystalline nanoparticles increased nearly by15times, which reached the expectation of the cubsomes. Compound curcumin lipid cubic liquid crystalline nanoparticles mainly distributed in the spleen, liver and lung tissues, especially the spleen. The tissue uptake rate increased by nearly20times compared to other groups.
5. The absorption mechanism of compound curcumin cubic liquid crystal. Caco-2monolayer cell model was established and the effect on the cell survival rate of compound curcumin lipid cubic liquid crystalline nanoparticles was investigated to identify the range of the safe concentration. During the cell uptake test, we found that the intake of compound curcumin lipid cubic liquid crystalline nanoparticles gradually increased with the enhancement of concentration, however, the intake of the crude drug showed phenomenon of saturation. After joined verapamil, the intake rate of crude drug had increased to a certain extent. Finally, the influence of the different incubation time and verapamil on the cell membrane was consistent with the results above.
In conclusion, the compound curcumin lipid cubic liquid crystalline nanoparticles was prepared by the ethanol precursor.The method proved to be high efficiency, stable, good reproducibility, quality controlled,and good biological adhesive. The compound curcumin lipid cubic liquid crystalline nanoparticles could obviously increase the bioavailability of curcumin in the body and achieve the aim of the trial. Meanwhile, it also provided a good reference to the other drugs for lipid cubic liquid crystalline nanoparticles.
The innovation of the paper mainly including:
1. The compound curcumin lipid cubic liquid crystalline nanoparticles was prepared for the first time, which not only solved water-soluble problem, poor stability and bioavailability of the curcumin and also provided a new idea for lipid cubic liquid crystalline nanoparticles as drug carrier.
2. A variety of methods and technology was adopted for the evaluation in vivo and in vitro of compound curcumin lipid cubic liquid crystalline nanoparticles for the first time. The structure characterization of compound curcumin lipid cubic liquid crystalline nanoparticles was carried out by the spectroscopy, chromatography, DSC, SAXS, and so on. In addition, in vitro release, in vivo bioavailability, cell absorption and transport mechanism was also been studied systematically and comprehensively.
引文
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