前体药物—姜黄素二癸酸酯药代动力学研究及其纳米混悬剂工艺探索与评价
摘要
姜黄素是姜黄的主要成分之一,姜黄素作为色素、食品添加剂以及调味品已被广泛使用,各种实验模型证明姜黄素具有抗肿瘤、抗炎、抗氧化、保肝肾等药理活性；北大医学部库宝善等在郁金为主要成分的解郁丸中,发现并率先报道姜黄素具有明显的抗抑郁活性,并开展了深入的研究,认为选用姜黄素作为研究治疗抗肿瘤并伴有抑郁的候选药物具有极大的研究潜力和应用价值。但是由于姜黄素稳定性差,难溶于水,生物利用度低,体内代谢快,吸收过程发生转化,半衰期短等问题而限制了使用。如何解决其稳定性,提高其生物利用度,改善体内代谢及动力学问题成为研究的重点与难点。因此于凤华等人合成了姜黄素的酯类前体药物-姜黄素二癸酸酯(CurDD), CurDD吸收后酶解为姜黄素而发挥活性。本文主要采用高效液相色谱以及液质联用色谱技术,研究以整体实验动物给予姜黄素及其前体药物后的药代动力学特性,进行相关的药代动力学评价,并完成制剂成型与原料药的质量评价。
首先,本文首次建立了高效、灵敏、稳定可靠的同时监测生物样品中姜黄素二癸酸酯和姜黄素的HPLC分析方法。本方法选用大黄素作为内标物,采用液液萃取同时加有高浓度表面活性剂的方法作为前处理步骤。结果显示,姜黄素二癸酸酯和姜黄素在各自的线性范围内呈现良好的线性,精密度、准确度、提取回收率均符合生物样品分析要求。同时,我们建立了HPLC-MS/MS分析方法测定姜黄素在大鼠血浆中的含量,可以检测血浆样品浓度在0.5ng/ml～20ng/ml范围内的低含量样品,且线性、精密度、准确度、提取回收率均符合生物样品分析要求。
第二,我们研究了姜黄素二癸酸酯的体外生物转化。研究结果显示,姜黄素二癸酸酯可以转化为姜黄素,但是姜黄素的含量始终维持在100ng/ml左右,可以表明姜黄素在生成的同时又发生了自身的降解,而姜黄素二癸酸酯则作为姜黄素的一个储存仓库,缓慢释放,使其维持在一个稳定的浓度范围。
第三,本文首次应用已经建立的HPLC方法,研究了姜黄素二癸酸酯和姜黄素在大鼠体内静脉注射后的药代动力学特性。静脉注射药代动力学评价显示姜黄素二癸酸酯可以使姜黄素的半衰期由6.6min延长至6h左右,而AUC值也提高近10倍,说明姜黄素二癸酸酯可以作为姜黄素的一个储存仓库具有缓慢释放姜黄素的作用。本文同时应用已建立的HPLC-MS/MS法,研究了姜黄素二癸酸酯和姜黄素在大鼠体内肌肉注射后的药代动力学特性。肌肉注射药代动力学评价显示姜黄素二癸酸酯可以使姜黄素的半衰期延长。
第四,本文制备了平均粒径在1μm以下的姜黄素二癸酸酯纳米粒,单因素考察了采用单平行星式球磨仪各参数对纳米粒子粒径的影响,优化了工艺参数,并对纳米粒子进行相关的物理性质评价和稳定性评价。
第五,本文研究了姜黄素二癸酸酯纳米／普通混悬注射油剂在大鼠肌肉注射部位的释放与消除。结果显示,姜黄素二癸酸酯纳米／普通混悬注射油剂,15d后释放均超过80%以上,而纳米混悬剂比普通混悬剂更能延长姜黄素二癸酸酯在注射部位的驻留时间。
最后,本文又考察了姜黄素二癸酸酯纳米／普通混悬剂肌肉注射后在脑部的含量,结果发现,姜黄素二癸酸酯纳米混悬剂在脑部姜黄素二癸酸酯的含量显著高于普通混悬剂的含量,AUC值也提高4倍以上。
本论文研究结果发现姜黄素二癸酸酯的药代动力学性质具有缓慢释放姜黄素的作用,能够显著延长姜黄素的半衰期和姜黄素在体内的作用时间,达到长效的作用,并为制剂的研发提供了一定的参考依据；而姜黄素二癸酸酯纳米混悬剂制备与评价结果显示,纳米混悬剂在缓释、长效方面比普通混悬剂具有显著的优势,并解决了姜黄素二癸酸酯在水和有机溶剂都难溶的难题,因此适合于姜黄素二癸酸酯长效抗抑郁制剂的开发和利用。
Curcumin is the major active ingredient of the rhizome of Curcuma longa L, which has been extensively used as a dietary spice and a coloring agent, as well as a medicinal herb in the Chinese and Ayurvedic medical systems for the treatment of flatulence, jaundice, menstrual difficulties, hematuria, hemorrhage and colic. The studies on curcumin and its analogues have drawn increasing attentions in recent years, due to the promising clinical applications and low toxicity and have documented that curcumin possesses various biological and pharmacological activities, including anti-oxidation, anti-inflammation, tumor prevention and anti-depression, etc.. Nonetheless, the pharmaceutical formulation development of curcumin remains to be a challenge due to its poor physicochemical and biopharmaceutical properties. As a polyphenolic compound, curcumin is water insoluble and unstable at aqueous medium, and exhibits very poor oral bioavailability and rapid systemic elimination. In order to improve the bioavailability and/or modify the pharmacokinetic parameters, numerous drug delivery techniques by loading curcumin into liposomes, nanoparticles, solid dispersion or self-microemulsifying system, forming curcumin-phospholipids or cyclodextrins complex, and synthesizing structural analogues of curcumin have been investigated.
Recently, a prodrug of curcumin, curcumin didecanoate (CurDD), was prepared by esterification of the hydroxyl groups of curcumin with capric acid so as to provide sustained plasma levels of curcumin and to achieve long-acting therapeutic effects following administration as a depot.
Firstly, a high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate (CurDD), in rat plasma. The analytes were extracted by ethyl acetate following the addition of sodium dodecyl sulfate, and separated on a reverse phase C18 column using a gradient mobile phase system of acetonitrile-tetrahydrofuran-water containing 0.1% formic acid. Detection by UV absorption at 425 nm gave a lower limit of quantitation (LLOQ) of 5 ng/ml and 10 ng/ml for curcumin and CurDD in 50μl of plasma, respectively. Intra-and inter-day precision of quality control samples except those at LLOQ were within 15% for curcumin and CurDD, respectively, and the accuracy for both compounds were between-6.07 and 8.88%. Meanwhile, an HPLC-MS/MS method has been established for the determination of curcumin in rat plasma. The LLOQ of curcumin were determined to be 0.5 ng/ml. The linearity, precision, accuracy, extraction recoveries were fit for purpose of biological sample analysis.
Secondly, the results of biotransformation of CurDD in vitro showed that CurDD can be transformed into curcumin, and the concentrations of curcumin were maintained at about 100ng/ml. Meanwhile, curcumin may be not only released by CurDD, but also degraded by itself. The results suggested that CurDD may be used as a depot of curcumin to maintain a stable concentration.
Thirdly, a simple HPLC method was applied to determine the plasma concentrations of CurDD and/or curcumin after CurDD or curcumin was intravenously administered to rats at a dose of 1 mg/kg (calculated as curcumin). Following IV administration of curcumin, the plasma concentrations of curcumin rapidly decreased to the LLOQ within 20 min with a t1/2 of-7 min. After IV administration of CurDD, the concentrations of both CurDD and curcumin declined slowly. The plasma concentration of curcumin converted from CurDD was detectable up to 24 h with a t1/2 of～400 min. When the AUC data of curcumin obtained by direct IV administration were compared with those converted from CurDD, the latter were surprisingly 6-fold higher than the former. An HPLC-MS/MS method has also been developed and validated for the determination of curcumin after CurDD or curcumin was intramuscularly administered to rats at a dose of 50 mg/kg (calculated as curcumin). The study also found that when entered into the blood, CurDD was converted to curcumin and markedly extended the apparent elimination half-life. These results suggested that CurDD might be utilized as a prodrug to provide sustained plasma levels of curcumin over a long duration when administered as a depot.
Fourthly, nano-suspensions of CurDD was prepared by planetary ball milling with the median particle size being less than 1μm. The preparation processes were optimized for various parameters of planetary ball milling affecting the particle size. Moreover, the physical properties and stability of the nano-suspensions have also been evaluated.
Fifthly, it has been assessed that the percentage of the dose of CurDD remaining at the injection site after intramuscular administration of CurDD nano-and normal-suspensions in peanut oil. After 15d, only less than 20% of CurDD was remained at the injection site, whether CurDD nano-or normal-suspensions. Compared with CurDD normal-suspensions, CurDD nano-suspensions have extremely extended the dwell time of CurDD at the injection site.
Finally, the concentration of curcumin didecanoate (CurDD) in brain tissues was determined as a function of time following intramuscular of CurDD nano-and normal-suspensions to rats at doses of 50 mg/kg(calculated as curcumin). When the brain concentration and AUC data obtained by CurDD nano-suspensions were compared with normal-suspensions, the former were significantly higher than the latter.
首先,本文首次建立了高效、灵敏、稳定可靠的同时监测生物样品中姜黄素二癸酸酯和姜黄素的HPLC分析方法。本方法选用大黄素作为内标物,采用液液萃取同时加有高浓度表面活性剂的方法作为前处理步骤。结果显示,姜黄素二癸酸酯和姜黄素在各自的线性范围内呈现良好的线性,精密度、准确度、提取回收率均符合生物样品分析要求。同时,我们建立了HPLC-MS/MS分析方法测定姜黄素在大鼠血浆中的含量,可以检测血浆样品浓度在0.5ng/ml～20ng/ml范围内的低含量样品,且线性、精密度、准确度、提取回收率均符合生物样品分析要求。
第二,我们研究了姜黄素二癸酸酯的体外生物转化。研究结果显示,姜黄素二癸酸酯可以转化为姜黄素,但是姜黄素的含量始终维持在100ng/ml左右,可以表明姜黄素在生成的同时又发生了自身的降解,而姜黄素二癸酸酯则作为姜黄素的一个储存仓库,缓慢释放,使其维持在一个稳定的浓度范围。
第三,本文首次应用已经建立的HPLC方法,研究了姜黄素二癸酸酯和姜黄素在大鼠体内静脉注射后的药代动力学特性。静脉注射药代动力学评价显示姜黄素二癸酸酯可以使姜黄素的半衰期由6.6min延长至6h左右,而AUC值也提高近10倍,说明姜黄素二癸酸酯可以作为姜黄素的一个储存仓库具有缓慢释放姜黄素的作用。本文同时应用已建立的HPLC-MS/MS法,研究了姜黄素二癸酸酯和姜黄素在大鼠体内肌肉注射后的药代动力学特性。肌肉注射药代动力学评价显示姜黄素二癸酸酯可以使姜黄素的半衰期延长。
第四,本文制备了平均粒径在1μm以下的姜黄素二癸酸酯纳米粒,单因素考察了采用单平行星式球磨仪各参数对纳米粒子粒径的影响,优化了工艺参数,并对纳米粒子进行相关的物理性质评价和稳定性评价。
第五,本文研究了姜黄素二癸酸酯纳米／普通混悬注射油剂在大鼠肌肉注射部位的释放与消除。结果显示,姜黄素二癸酸酯纳米／普通混悬注射油剂,15d后释放均超过80%以上,而纳米混悬剂比普通混悬剂更能延长姜黄素二癸酸酯在注射部位的驻留时间。
最后,本文又考察了姜黄素二癸酸酯纳米／普通混悬剂肌肉注射后在脑部的含量,结果发现,姜黄素二癸酸酯纳米混悬剂在脑部姜黄素二癸酸酯的含量显著高于普通混悬剂的含量,AUC值也提高4倍以上。
本论文研究结果发现姜黄素二癸酸酯的药代动力学性质具有缓慢释放姜黄素的作用,能够显著延长姜黄素的半衰期和姜黄素在体内的作用时间,达到长效的作用,并为制剂的研发提供了一定的参考依据；而姜黄素二癸酸酯纳米混悬剂制备与评价结果显示,纳米混悬剂在缓释、长效方面比普通混悬剂具有显著的优势,并解决了姜黄素二癸酸酯在水和有机溶剂都难溶的难题,因此适合于姜黄素二癸酸酯长效抗抑郁制剂的开发和利用。
Curcumin is the major active ingredient of the rhizome of Curcuma longa L, which has been extensively used as a dietary spice and a coloring agent, as well as a medicinal herb in the Chinese and Ayurvedic medical systems for the treatment of flatulence, jaundice, menstrual difficulties, hematuria, hemorrhage and colic. The studies on curcumin and its analogues have drawn increasing attentions in recent years, due to the promising clinical applications and low toxicity and have documented that curcumin possesses various biological and pharmacological activities, including anti-oxidation, anti-inflammation, tumor prevention and anti-depression, etc.. Nonetheless, the pharmaceutical formulation development of curcumin remains to be a challenge due to its poor physicochemical and biopharmaceutical properties. As a polyphenolic compound, curcumin is water insoluble and unstable at aqueous medium, and exhibits very poor oral bioavailability and rapid systemic elimination. In order to improve the bioavailability and/or modify the pharmacokinetic parameters, numerous drug delivery techniques by loading curcumin into liposomes, nanoparticles, solid dispersion or self-microemulsifying system, forming curcumin-phospholipids or cyclodextrins complex, and synthesizing structural analogues of curcumin have been investigated.
Recently, a prodrug of curcumin, curcumin didecanoate (CurDD), was prepared by esterification of the hydroxyl groups of curcumin with capric acid so as to provide sustained plasma levels of curcumin and to achieve long-acting therapeutic effects following administration as a depot.
Firstly, a high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate (CurDD), in rat plasma. The analytes were extracted by ethyl acetate following the addition of sodium dodecyl sulfate, and separated on a reverse phase C18 column using a gradient mobile phase system of acetonitrile-tetrahydrofuran-water containing 0.1% formic acid. Detection by UV absorption at 425 nm gave a lower limit of quantitation (LLOQ) of 5 ng/ml and 10 ng/ml for curcumin and CurDD in 50μl of plasma, respectively. Intra-and inter-day precision of quality control samples except those at LLOQ were within 15% for curcumin and CurDD, respectively, and the accuracy for both compounds were between-6.07 and 8.88%. Meanwhile, an HPLC-MS/MS method has been established for the determination of curcumin in rat plasma. The LLOQ of curcumin were determined to be 0.5 ng/ml. The linearity, precision, accuracy, extraction recoveries were fit for purpose of biological sample analysis.
Secondly, the results of biotransformation of CurDD in vitro showed that CurDD can be transformed into curcumin, and the concentrations of curcumin were maintained at about 100ng/ml. Meanwhile, curcumin may be not only released by CurDD, but also degraded by itself. The results suggested that CurDD may be used as a depot of curcumin to maintain a stable concentration.
Thirdly, a simple HPLC method was applied to determine the plasma concentrations of CurDD and/or curcumin after CurDD or curcumin was intravenously administered to rats at a dose of 1 mg/kg (calculated as curcumin). Following IV administration of curcumin, the plasma concentrations of curcumin rapidly decreased to the LLOQ within 20 min with a t1/2 of-7 min. After IV administration of CurDD, the concentrations of both CurDD and curcumin declined slowly. The plasma concentration of curcumin converted from CurDD was detectable up to 24 h with a t1/2 of～400 min. When the AUC data of curcumin obtained by direct IV administration were compared with those converted from CurDD, the latter were surprisingly 6-fold higher than the former. An HPLC-MS/MS method has also been developed and validated for the determination of curcumin after CurDD or curcumin was intramuscularly administered to rats at a dose of 50 mg/kg (calculated as curcumin). The study also found that when entered into the blood, CurDD was converted to curcumin and markedly extended the apparent elimination half-life. These results suggested that CurDD might be utilized as a prodrug to provide sustained plasma levels of curcumin over a long duration when administered as a depot.
Fourthly, nano-suspensions of CurDD was prepared by planetary ball milling with the median particle size being less than 1μm. The preparation processes were optimized for various parameters of planetary ball milling affecting the particle size. Moreover, the physical properties and stability of the nano-suspensions have also been evaluated.
Fifthly, it has been assessed that the percentage of the dose of CurDD remaining at the injection site after intramuscular administration of CurDD nano-and normal-suspensions in peanut oil. After 15d, only less than 20% of CurDD was remained at the injection site, whether CurDD nano-or normal-suspensions. Compared with CurDD normal-suspensions, CurDD nano-suspensions have extremely extended the dwell time of CurDD at the injection site.
Finally, the concentration of curcumin didecanoate (CurDD) in brain tissues was determined as a function of time following intramuscular of CurDD nano-and normal-suspensions to rats at doses of 50 mg/kg(calculated as curcumin). When the brain concentration and AUC data obtained by CurDD nano-suspensions were compared with normal-suspensions, the former were significantly higher than the latter.
引文
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