厚朴酚磷脂复合物的制备、理化性质与生物利用度研究
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摘要
针对厚朴酚水溶性差、口服生物利用度低等难题,本论文对以溶剂法制备的厚朴酚磷脂复合物进行了系统的研究,以期达到增加其口服吸收、提高生物利用度的目的。主要研究内容如下。
(1)建立了厚朴酚磷脂复合物制备条件的评价标准,即厚朴酚与磷脂的复合率,并以其考察反应溶剂的种类、磷脂与原药的投料比、反应物浓度、反应时间及反应温度等制备工艺条件对复合率的影响,并对制备工艺条件进行了验证。结果表明反应溶剂的种类与投料比为制备关键工艺条件；经验证的制备工艺条件为：反应溶剂为四氢呋喃,磷脂与厚朴酚投料比为3：1,40℃条件下反应3h。
(2)采用高效液相色谱法测定厚朴酚磷脂复合物的含量,并根据药品质量标准分析方法验证指导原则对测定方法进行了系统全面的验证。验证结果表明,该方法灵敏度和准确度高,重复性和耐用性好,可作为厚朴酚磷脂复合物的含量测定方法。
(3)采用紫外光谱、扫描量热、X-射线粉末衍射、红外吸收以及核磁共振等手段研究了厚朴酚磷脂复合物的理化性质,并对其形成机理进行了探讨。结果表明与磷脂形成复合物后,厚朴酚的晶型特性消失,表现出无定形特征,并高度分散于磷脂分子中。厚朴酚苯环骨架或其酚羟基与磷脂极性端的相应红外信号发生变化,但磷脂的非极性端仍保持原有红外特征,推测两者结合部位应发生在厚朴酚的苯环骨架或其酚羟基与磷脂的极性碱基部位。厚朴酚磷脂复合物的核磁共振氢谱中厚朴酚的质子信号明显减弱,可推测是由于厚朴酚与磷脂的极性端彼此被固定,其自由转动的脂肪酸链的包覆作用所导致；由于未产生新的质子信号,进一步表明两者是以分子间力结合形成的复合物,而非生成了新的化合物。影响因素和加速试验研究表明,厚朴酚磷脂复合物与原药及其物理混合物相比,复合物中厚朴酚的酚羟基与磷脂的极性端结合后,脂肪酸链减少了氧、光能等对厚朴酚易于氧化部位的影响,热稳定性显著提高。
(4)厚朴酚磷脂物理混合物和厚朴酚磷脂复合物在水中的表观溶解度均有不同程度的提高,但以厚朴酚磷脂物理混合物在水中的表观溶解度更大,其差别说明厚朴酚磷脂复合物中两者分子间力的形成改变了厚朴酚的溶解特征。厚朴酚、厚朴酚磷脂物理混合物和厚朴酚磷脂复合物在pH1.2～8.0范围内,各自的溶解度无明显差异,说明厚朴酚的溶解度在生理酸碱度范围内非pH依赖型。体外溶出实验结果表明,不含表面活性剂不同pH溶出介质对厚朴酚、厚朴酚磷脂物理混合物和厚朴酚磷脂复合物的溶出速率无显著影响；但作为一种外部机械力,不同的溶出转数可影响复合物中药物在溶出介质中的扩散。
(5)分别口服给予Spragu-Dawley大鼠相同剂量的厚朴酚、厚朴酚磷脂物理混合物、厚朴酚磷脂复合物,进行了大鼠体内药代动力学研究,以比较三组药代动力学特征和口服相对生物利用度。结果显示厚朴酚磷脂复合物与原药相比,Cmax、Tmax、AUC、MRT等主要药动学参数均发生了显著变化,在试验测定时间范围内口服生物利用度提高97%,并表现出一定的缓释特征。对体内研究结果的分析表明,厚朴酚与磷脂形成复合物后其分子间力的存在以及厚朴酚的亲脂性使其从磷脂扩散入体液或细胞膜双脂层的作用被延缓,其体内药动学特征区别于单纯以增溶作用增加厚朴酚水溶性的物理混合物,说明磷脂复合物可通过增加其在溶液中的溶解度并延长药物作用时间,达到提高其口服生物利用度的目的。
(6)在已经取得的厚朴酚磷脂复合物体外释放度、体内血药浓度数据的基础上,采用卷积法与反卷积法分别对体内外相关性进行了建立和分析,并比较了两种方法的差异,特别是对于发生实验数据波动的情况,采用卷积分方法比反卷积分方法能有更好的拟合；以此筛选出的体外释放测定条件为：桨法,转数100转,溶出介质为1%SDS的1000mL水溶液,为未来确立厚朴酚磷脂复合物制剂的质量控制指标奠定基础。
综上所述,本文在以下5个方面进行了具有创新性的研究与探索：
(1)将厚朴酚制成磷脂复合物,该研究尚未见国内外相关报道；
(2)对制成的厚朴酚磷脂复合物进行了理化性质分析并分析推测了反应发生的部位；
(3)通过大鼠体内药代动力学研究发现,厚朴酚制成磷脂复合物后,在体内表现出一定的缓释特征,未见国内外相关研究报道；
(4)同时采用卷积分／反卷积分方法对厚朴酚磷脂复合物的体内外相关性进行比较,通过对比证明参比制剂选择的重要性,并提出以缓释与参比制剂AUC比值作为矫正因子对计算过程进行修正；
(5)以体内外相关性研究为基础,筛选和确定了厚朴酚磷脂复合物体外溶出度测定条件,未见相关研究报道。
New approach to increase Magnolol's poor water solubility and to enhance its low oral bioavailability is a constant interest of formulators in the pharmaceutical research area. In this paper, solvent evaporation method was adopted to prepare magnolol-phospholipid complex, aimed to achieve an increase in oral absorption and to improve its bioavailability.
(1) A method to evaluate the binding percentage of magnolol and phospholipid (the binding efficiency) was established. Then the responses of the solvent, the feed ratio of magnolol and phospholipid, reactant concentration, reaction time and reaction temperature were examined and the preparation process was validated. The results indicated that the reaction solvent and the feed ratio of the two reactants were the crucial factors and the manufacture conditions were obtained as following:the feed ratio of phospholopid and magnolol was3:1, reacted in the tetrahydrofuran for3h under40℃.
(2) An RP-HPLC method was developed and validated to determine the content of magnolol in its phospholipid complex. The validated results showed that the method's sensitivity, accuracy, repeatability and durability were in compliance with the requirement for the assay of the magnolol-phospholipid complex.
(3) Ultraviolet spectroscopy, scanning calorimetry, X-ray powder diffraction, infrared spectroscopy and nuclear magnetic resonance were used to study the physicochemical
. properties of the complex; and its formation mechanism was discussed. The results revealed that magnolol was in an amorphous state and was homogeneously dispersed in the phospholipid molecules instead of maintaining its crystal characteristics after the formation of the phospholipid complex. The changes in the corresponding infrared signals indicated that the binding site could occur between the magnolol's benzene group or its phenolic hydroxyl group and the phospholipid's polar base. The'H-NMR spectrum showed that the H-signals'strength of magnolol-phospholipid complex was attenuated, which was probably caused by the fixation effect generated from the combination of the sites mentioned above of the magnolol and the phospholipid. Stability study showed that thermostablity of magnolol could be enhanced when the phospholipid complex formed, which might be explained by the barrier effect of fatty acid chain of the phosphlipid.
(4) The water solubility study showed that both the magnolol phospholipid mixture and their complex could improve the magnolol's apparent solubility in aqueous solution, but the mixture can increase more than that of complex. Such difference might be caused by the formation of the inter-molecular forces in the magnolol-phospholipid complex. Insignificant changes in the apparent solubility of each group in the dissolution media of pH1.2～8.0indicated that the aqueous solubility of magnolol was pH-independent under the physiological conditions, and the dissolution media of different pH without surfactant had no significant influence on the dissolution rate for each group. The stirring rate in the dissolution test had an obvious effect on the dissolution rate of magnolol-phospholipid complex, for that the mechanic force could overcome its inter-molecular forces to increase the diffusion of the complex to the media.
(5) The pharmacokinetic study in Spragu-Dawley rats was conducted by testing plasma concentration of magnolol after oral administration of an equivalent dose of magnolol, magnolol phospholipid mixture and their complex respectively. The results indicated that the pharmacokinetic character of magnolol-phospholipid complex was different from that of the magnolol and its phospholipid mixture. The main pharmacokinetic parameters such as Cmax, Tmax, AUC and MRT changed obviously with a tendency of sustained release and the relative oral bioavailability increased by97%compared to the magnolol. The in vivo study revealed that magnolol-phospholipid complex could assist the magnolol to disperse in aqueous solution; however, due to its lipophilic property of magnolol, the phospholipid could decrease its rate of diffusion from complex to the cell membrane.
(6) Both the convolution and the deconvolution methods were used to study the in vitro-in vivo correlation of magnolol-phospholipid complex, based on the data of accumulated release rate in vitro study, and on the data of the plasma drug concentration in vivo study. The convolution method could have a higher simulation degree compared to the deconvolution method in the case of fluctuations in the experimental data. By comparing in vitro and in vivo drug release profiles, an optimized condition with the dissolution media of1000mL1%SDS at the stirring rate of100r-min-1for in vitro release assay was suggested in order to establish indicators of the quality control of magnolol-phospholipid complex.
In summary, this paper involves the following five points of innovative research and exploration:
(1) It was the first to report in this paper to prepare the phospholipid complex made of magnolol;
(2) The physicochemical properties of magnolol-phospholipid complex were studied and their formation mechanism was discussed in this work.
(3) Pharmacokinetic study found that, the formation of phospholipid complex of magnolol showed a sustained release tendency;
(4) Both the convolution/deconvolution methods were compared for in vitro-in vivo correlation study of magnolol-phospholipid complex, and a corrector based on the AUC ratio was put forward to adjust the calculation.
(5) Consequently, an approach to determine the condition of the in vitro release measurement was studied based on the IVIVC study.
(1)建立了厚朴酚磷脂复合物制备条件的评价标准,即厚朴酚与磷脂的复合率,并以其考察反应溶剂的种类、磷脂与原药的投料比、反应物浓度、反应时间及反应温度等制备工艺条件对复合率的影响,并对制备工艺条件进行了验证。结果表明反应溶剂的种类与投料比为制备关键工艺条件；经验证的制备工艺条件为：反应溶剂为四氢呋喃,磷脂与厚朴酚投料比为3：1,40℃条件下反应3h。
(2)采用高效液相色谱法测定厚朴酚磷脂复合物的含量,并根据药品质量标准分析方法验证指导原则对测定方法进行了系统全面的验证。验证结果表明,该方法灵敏度和准确度高,重复性和耐用性好,可作为厚朴酚磷脂复合物的含量测定方法。
(3)采用紫外光谱、扫描量热、X-射线粉末衍射、红外吸收以及核磁共振等手段研究了厚朴酚磷脂复合物的理化性质,并对其形成机理进行了探讨。结果表明与磷脂形成复合物后,厚朴酚的晶型特性消失,表现出无定形特征,并高度分散于磷脂分子中。厚朴酚苯环骨架或其酚羟基与磷脂极性端的相应红外信号发生变化,但磷脂的非极性端仍保持原有红外特征,推测两者结合部位应发生在厚朴酚的苯环骨架或其酚羟基与磷脂的极性碱基部位。厚朴酚磷脂复合物的核磁共振氢谱中厚朴酚的质子信号明显减弱,可推测是由于厚朴酚与磷脂的极性端彼此被固定,其自由转动的脂肪酸链的包覆作用所导致；由于未产生新的质子信号,进一步表明两者是以分子间力结合形成的复合物,而非生成了新的化合物。影响因素和加速试验研究表明,厚朴酚磷脂复合物与原药及其物理混合物相比,复合物中厚朴酚的酚羟基与磷脂的极性端结合后,脂肪酸链减少了氧、光能等对厚朴酚易于氧化部位的影响,热稳定性显著提高。
(4)厚朴酚磷脂物理混合物和厚朴酚磷脂复合物在水中的表观溶解度均有不同程度的提高,但以厚朴酚磷脂物理混合物在水中的表观溶解度更大,其差别说明厚朴酚磷脂复合物中两者分子间力的形成改变了厚朴酚的溶解特征。厚朴酚、厚朴酚磷脂物理混合物和厚朴酚磷脂复合物在pH1.2～8.0范围内,各自的溶解度无明显差异,说明厚朴酚的溶解度在生理酸碱度范围内非pH依赖型。体外溶出实验结果表明,不含表面活性剂不同pH溶出介质对厚朴酚、厚朴酚磷脂物理混合物和厚朴酚磷脂复合物的溶出速率无显著影响；但作为一种外部机械力,不同的溶出转数可影响复合物中药物在溶出介质中的扩散。
(5)分别口服给予Spragu-Dawley大鼠相同剂量的厚朴酚、厚朴酚磷脂物理混合物、厚朴酚磷脂复合物,进行了大鼠体内药代动力学研究,以比较三组药代动力学特征和口服相对生物利用度。结果显示厚朴酚磷脂复合物与原药相比,Cmax、Tmax、AUC、MRT等主要药动学参数均发生了显著变化,在试验测定时间范围内口服生物利用度提高97%,并表现出一定的缓释特征。对体内研究结果的分析表明,厚朴酚与磷脂形成复合物后其分子间力的存在以及厚朴酚的亲脂性使其从磷脂扩散入体液或细胞膜双脂层的作用被延缓,其体内药动学特征区别于单纯以增溶作用增加厚朴酚水溶性的物理混合物,说明磷脂复合物可通过增加其在溶液中的溶解度并延长药物作用时间,达到提高其口服生物利用度的目的。
(6)在已经取得的厚朴酚磷脂复合物体外释放度、体内血药浓度数据的基础上,采用卷积法与反卷积法分别对体内外相关性进行了建立和分析,并比较了两种方法的差异,特别是对于发生实验数据波动的情况,采用卷积分方法比反卷积分方法能有更好的拟合；以此筛选出的体外释放测定条件为：桨法,转数100转,溶出介质为1%SDS的1000mL水溶液,为未来确立厚朴酚磷脂复合物制剂的质量控制指标奠定基础。
综上所述,本文在以下5个方面进行了具有创新性的研究与探索：
(1)将厚朴酚制成磷脂复合物,该研究尚未见国内外相关报道；
(2)对制成的厚朴酚磷脂复合物进行了理化性质分析并分析推测了反应发生的部位；
(3)通过大鼠体内药代动力学研究发现,厚朴酚制成磷脂复合物后,在体内表现出一定的缓释特征,未见国内外相关研究报道；
(4)同时采用卷积分／反卷积分方法对厚朴酚磷脂复合物的体内外相关性进行比较,通过对比证明参比制剂选择的重要性,并提出以缓释与参比制剂AUC比值作为矫正因子对计算过程进行修正；
(5)以体内外相关性研究为基础,筛选和确定了厚朴酚磷脂复合物体外溶出度测定条件,未见相关研究报道。
New approach to increase Magnolol's poor water solubility and to enhance its low oral bioavailability is a constant interest of formulators in the pharmaceutical research area. In this paper, solvent evaporation method was adopted to prepare magnolol-phospholipid complex, aimed to achieve an increase in oral absorption and to improve its bioavailability.
(1) A method to evaluate the binding percentage of magnolol and phospholipid (the binding efficiency) was established. Then the responses of the solvent, the feed ratio of magnolol and phospholipid, reactant concentration, reaction time and reaction temperature were examined and the preparation process was validated. The results indicated that the reaction solvent and the feed ratio of the two reactants were the crucial factors and the manufacture conditions were obtained as following:the feed ratio of phospholopid and magnolol was3:1, reacted in the tetrahydrofuran for3h under40℃.
(2) An RP-HPLC method was developed and validated to determine the content of magnolol in its phospholipid complex. The validated results showed that the method's sensitivity, accuracy, repeatability and durability were in compliance with the requirement for the assay of the magnolol-phospholipid complex.
(3) Ultraviolet spectroscopy, scanning calorimetry, X-ray powder diffraction, infrared spectroscopy and nuclear magnetic resonance were used to study the physicochemical
. properties of the complex; and its formation mechanism was discussed. The results revealed that magnolol was in an amorphous state and was homogeneously dispersed in the phospholipid molecules instead of maintaining its crystal characteristics after the formation of the phospholipid complex. The changes in the corresponding infrared signals indicated that the binding site could occur between the magnolol's benzene group or its phenolic hydroxyl group and the phospholipid's polar base. The'H-NMR spectrum showed that the H-signals'strength of magnolol-phospholipid complex was attenuated, which was probably caused by the fixation effect generated from the combination of the sites mentioned above of the magnolol and the phospholipid. Stability study showed that thermostablity of magnolol could be enhanced when the phospholipid complex formed, which might be explained by the barrier effect of fatty acid chain of the phosphlipid.
(4) The water solubility study showed that both the magnolol phospholipid mixture and their complex could improve the magnolol's apparent solubility in aqueous solution, but the mixture can increase more than that of complex. Such difference might be caused by the formation of the inter-molecular forces in the magnolol-phospholipid complex. Insignificant changes in the apparent solubility of each group in the dissolution media of pH1.2～8.0indicated that the aqueous solubility of magnolol was pH-independent under the physiological conditions, and the dissolution media of different pH without surfactant had no significant influence on the dissolution rate for each group. The stirring rate in the dissolution test had an obvious effect on the dissolution rate of magnolol-phospholipid complex, for that the mechanic force could overcome its inter-molecular forces to increase the diffusion of the complex to the media.
(5) The pharmacokinetic study in Spragu-Dawley rats was conducted by testing plasma concentration of magnolol after oral administration of an equivalent dose of magnolol, magnolol phospholipid mixture and their complex respectively. The results indicated that the pharmacokinetic character of magnolol-phospholipid complex was different from that of the magnolol and its phospholipid mixture. The main pharmacokinetic parameters such as Cmax, Tmax, AUC and MRT changed obviously with a tendency of sustained release and the relative oral bioavailability increased by97%compared to the magnolol. The in vivo study revealed that magnolol-phospholipid complex could assist the magnolol to disperse in aqueous solution; however, due to its lipophilic property of magnolol, the phospholipid could decrease its rate of diffusion from complex to the cell membrane.
(6) Both the convolution and the deconvolution methods were used to study the in vitro-in vivo correlation of magnolol-phospholipid complex, based on the data of accumulated release rate in vitro study, and on the data of the plasma drug concentration in vivo study. The convolution method could have a higher simulation degree compared to the deconvolution method in the case of fluctuations in the experimental data. By comparing in vitro and in vivo drug release profiles, an optimized condition with the dissolution media of1000mL1%SDS at the stirring rate of100r-min-1for in vitro release assay was suggested in order to establish indicators of the quality control of magnolol-phospholipid complex.
In summary, this paper involves the following five points of innovative research and exploration:
(1) It was the first to report in this paper to prepare the phospholipid complex made of magnolol;
(2) The physicochemical properties of magnolol-phospholipid complex were studied and their formation mechanism was discussed in this work.
(3) Pharmacokinetic study found that, the formation of phospholipid complex of magnolol showed a sustained release tendency;
(4) Both the convolution/deconvolution methods were compared for in vitro-in vivo correlation study of magnolol-phospholipid complex, and a corrector based on the AUC ratio was put forward to adjust the calculation.
(5) Consequently, an approach to determine the condition of the in vitro release measurement was studied based on the IVIVC study.
引文
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