三七总皂苷口服肠溶制剂的研究
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摘要
本课题以广泛应用于临床,对心血管疾病等有显著疗效的血栓通注射液中的三七提取物—三七总皂苷(Panax notoginseng saponins, PNS)为模型药物,以生物药剂学和药物动力学理论为指导,研究其吸收机理和能够避开胃酸及酶破坏的肠溶口服制剂。
论文第一部分,建立了HPLC-UV测定PNS中指标性成分的体内外分析方法,其灵敏度高,分离度和重现性好,可以满足本研究体内外样品分析要求。测定了PNS中活性单体三七皂苷R_1(R_1)、人参皂苷Rb_1(Rb_1)和人参皂苷Rg_1(Rg_1)的百分含量,分别为9.64%、36.38%和51.10%。系统考察了PNS的理化性质和初步稳定性。采用正辛醇—水系统测定了不同pH值条件下PNS中R_1、Rb_1和Rg_1的表观油水分配系数(P_(app)),同时考察了pH值、温度、光照和湿度对PNS中三种单体的影响。结果显示PNS水溶液呈弱酸性,生理pH环境下R_1和Rb_1的P_(app)均在1~2之间,Rg_1的Papp在5~8之间。三种单体对光照和湿度较敏感,在中性及弱碱性条件下相对稳定,在酸性环境中迅速降解。
论文第二部分,建立了适用于PNS吸收机理研究的大鼠在体灌注模型,系统地研究了PNS主要成分在小肠的吸收动力学,并且考察了常用吸收促进剂对其吸收的影响。结果显示,在40.084~400.840μg·mL~(-1)这个浓度范围内,不同的药物浓度对PNS在大鼠小肠全段的吸收无显著影响,PNS主要成分水溶性好,透膜性差,吸收机制主要为被动扩散,同时有细胞旁路转运,存在外排泵消除可能。PNS主要成分口服生物利用度低,透膜吸收是限速过程,与冰片、卡波姆或吐温80联合使用,大鼠小肠吸收速率提高明显,可能与它们能促进细胞旁路转运或降低药物外排泵的作用有关。
论文第三部分,在对PNS吸收机理及药动学进行了初步研究的基础上,以PNS为模型药物,对其普通肠溶胶囊、肠溶微囊(胶囊)和肠溶微丸(胶囊)三种不同肠溶制剂的制备工艺、制剂学性质、体外释药规律和稳定性进行了研究。按正交设计方法得到的最优处方分别制备了三批PNS肠溶胶囊样品,f_2因子评价结果表明,三种肠溶胶囊的三批样品的释放度均有良好的重现性,R_1、Rb_1和Rg_1的释放行为没有显著性差异,只需要监测一种指标成分即可对PNS各主要成分的释放进行评价,并最终选择Rg1为体外释放度监测对象。采用单指数模型、Weibull模型、Higuchi模型、Ritger-Peppas模型、零级释放、一级释放、Hixcon Crowell模型和Niebergull模型对累积释放度数据进行拟合,普通肠溶胶囊、肠溶微囊(胶囊)和肠溶微丸(胶囊)的最佳拟合模型分别为:Hixcon Crowell模型、Weibull模型和Weibull模型。参照中国药典2010版二部附录XIX C“药物稳定性试验指导原则”,对三种PNS肠溶胶囊的稳定性进行了初步研究。结果表明,所考察胶囊完整,无软化塌陷现象,内容物色泽变化不大;释放度、含量和水分考察均符合要求。
论文第四部分,考察了PNS在大鼠体内及三种PNS肠溶胶囊在Beagle犬体内的药代动力学及口服生物利用度。本部分创新性地应用中药多组分整合药代动力学研究新理论,在求得R_1、Rb_1和Rg_1药动学参数后,利用各成分曲线下面积(AUC_(0→∞))百分率作为自定义权重系数,计算PNS动物体内综合血药浓度并建立整合药动学研究模型,进一步估算PNS动物体内整合药动学参数,使得所获参数能够最大程度上表征中药的整体处置规律,为建立符合中医药特点的中药药代动力学研究提供了一种新的研究思路与技术方法。结果表明PNS静脉注射及灌胃后,R_1、Rb_1和Rg_1在大鼠体内的药时曲线均符合二室模型,经过剂量校正后的口服绝对生物利用度分别为1.76%、0.78%和2.44%。分别以市售注射用血栓通(冻干)和市售血栓通胶囊为参比制剂进行了自制PNS肠溶胶囊的药动学和生物利用度初步研究。实验结果表明:单剂量给予Beagle犬供试品和参比制剂后,PNS肠溶胶囊与普通制剂相比,生物利用度提高1.08~5.71倍,有显著性差异,MRT延长,绝对生物利用度也有不同程度提高。采用Wagner-Nelson (W-N)法对自制肠溶胶囊的体内外相关性进行评价,结果表明,各制剂的各成分的体内外相关性结果不一,其原因可能是PNS的吸收过程不仅仅是被动扩散,还包括主动转运过程。体内实验结果进一步证明各肠溶制剂效果确切,达到了课题预期设计的目的。
本课题在生物药剂学和药物动力学理论的指导下,以PNS的胃肠道吸收特性为基础进行制剂研制,减少了制剂开发的盲目性。本课题的研究结果为今后PNS其它剂型设计的处方工艺、质量评价、稳定性、体内动力学等方面提供参考。
Xueshuantong injection has been widely used to treat coronary disease in clinic. In this paper, its main group that is panax notoginseng saponions (PNS) was used as model drug. The objective was to study absorption mechanism of PNS and to develop oral enteric preparation of PNS which could avoid being destroyed by stomach acid and enzymes, on the basis of principles in biopharmaceutics and pharmacokinetics.
This paper fell into four parts.
In partⅠ, HPLC-UV (high-performance liquid chromatography-ultraviolet) method was established to analysis main saponins of PNS. The method which was sensitive, effective and repeatable can meet the requirement to the chemical and biological samples. The content percentages were 9.64%, 36.38% and 51.10% for notoginsenoside R_1 (R_1), ginsenoside Rb_1 (Rb_1) and ginsenoside Rg1 (Rg_1) in PNS, respectively. In additional, physical and chemical properties and stabilities of PNS were investigated. Octanol-water system was used to determine the apparent partition coefficients of R_1、Rb_1 and Rg_1, and the effects of pH, heat, light and humidity on stability of R_1、Rb_1 and Rg_1 were studied. Results showed that PNS was week acid in water, the apparent partition coefficient was between 1 and 2 for both of R_1 and Rb_1, but Rg_1 was between 5 and 8. All of them were sensitive to light, humidity and acid condition, and were relatively stable in normal and alkalescence condition.
In partⅡ, rat in situ intestinal perfusion model which was employed to study the absorption mechanism of PNS was established. It investigated orderly absorptive kinetics of the main components of PNS on small intestine and effects of some common absorptive promoters on the absorptive mechanism of PNS. The results clearly indicated that the concentration of PNS from 40.084 to 400.840μg·mL~(-1) had no distinctive effect on the absorptive kinetics, and the main components of PNS have high solubility and low permeability. The absorption mechanism of PNS across the intestinal epithelium is mainly passive diffusion. Paracellular pathway transportation and drug flux pump may also play a part in this process. The main components of PNS have a low absolute bioavailability, as process of acrossing the intestinal epithelium limits the rate and extent of absorption. Combination of PNS with borneol or carbomer or polysorbate 80 was administered to rats by oral, in which the absorption rate of the main components was improved. It may be related to the increase of paracellular pathway transportation or the inhibition of drug flux pump.
In partⅢ, on the basis of preliminary conclusion of the absorptive mechanism and pharmacokinetics about PNS, it was chosen as drug model for investigation the preparation of process, characters of agents, release characteristics in vitro and stability of common enteric capsules, enteric microcapsules (capsule) and enteric micropellets (capsule). Three samples of enteric capsules of PNS were produced respectively by the optimized prescription. The f_2 factor analysis showed that the reproducibility of release degree of the three samples was stable, and there was no significant difference among R_1, Rb_1 and Rg_1 that only one group that Rg_1 was selected finally needed to be controlled. The release data were intended to be single index model, Weibull model, Higuchi model, Ritger-Peppas model, zero levels release model, first levels release model, Hixcon Crowell model and Niebergull model. The best model of common enteric capsules, enteric microcapsules (capsule) and enteric micropellets (capsule) were Hixcon Crowell model, Weibull model and Weibull model respectively. Referred to appendix of Ch.P. 20_10(Ⅱ)“drug stability in the guidelines”, the stabilities of enteric capsules of PNS were studied elementarily. The results suggested that the shape of enteric capsules were still complete and the color of contents had no changes. Release degree, the content and water content all conformed to the requirements.
In partⅣ, pharmacokinetics and bioavailability of PNS in rat and its enteric capsules in Beagle dog were investigated. This part was designed to develop a novel integrated pharmacokinetic approach to assess the holistic pharmacokinetic properties of traditional Chinese medicines (TCM). After calculating pharmacokinetic parameters of R_1, Rb_1 and Rg_1, a novel approach of self-defined weight coefficient based on the area under the curve from zero to infinity (AUC_(0→∞)) has been created to obtain the holistic pharmacokinetic profiles of PNS. The integrated pharmacokinetic parameters of PNS were then calculated. This study would be useful for guiding the holistic pharmacokinetic study in consistence with the intrinsic theory and characteristics of TCM. A novel integrated pharmacokinetic thought and approach to describe the holistic pharmacokinetic properties of TCM has been successfully developed. The results suggested that after intragastric and intravenous administration of PNS, the concentration-time curve of R_1, Rb_1 and Rg_1 belonged to two compartment model, the absolute bioavailability was 1.76%, 0.78% and 2.44% respectively after correction. Study on pharmacokinetics and bioavailability of PNS enteric capsules in comparison with Xueshuantong injection and Xueshuantong capsule showed significant differences of single dosage. Bioavailabilities of PNS enteric capsules are 1.08~5.71 times as Xueshuantong capsule and MRT is longer. Moreover absolute bioavailability is improved. Evaluation on in vivo-in vitro correlation of the PNS enteric capsules according to Wagner-Nelson (W-N) method proved different correlation results. The reason is possible that the absorption process of PNS is not only passive diffusion but also active transport. The result in vivo further proved exact effects of enteric capsules as we anticipated.
According to principles of biopharmaceutics and pharmacokinetics, we based preparation research on the absorption kinetics of PNS in stomach and intestine that reduced blindness of preparation development. The study provides references for other formulation of PNS in process, quality evaluation, stability, pharmacokinetics in vivo, and so on.
论文第一部分,建立了HPLC-UV测定PNS中指标性成分的体内外分析方法,其灵敏度高,分离度和重现性好,可以满足本研究体内外样品分析要求。测定了PNS中活性单体三七皂苷R_1(R_1)、人参皂苷Rb_1(Rb_1)和人参皂苷Rg_1(Rg_1)的百分含量,分别为9.64%、36.38%和51.10%。系统考察了PNS的理化性质和初步稳定性。采用正辛醇—水系统测定了不同pH值条件下PNS中R_1、Rb_1和Rg_1的表观油水分配系数(P_(app)),同时考察了pH值、温度、光照和湿度对PNS中三种单体的影响。结果显示PNS水溶液呈弱酸性,生理pH环境下R_1和Rb_1的P_(app)均在1~2之间,Rg_1的Papp在5~8之间。三种单体对光照和湿度较敏感,在中性及弱碱性条件下相对稳定,在酸性环境中迅速降解。
论文第二部分,建立了适用于PNS吸收机理研究的大鼠在体灌注模型,系统地研究了PNS主要成分在小肠的吸收动力学,并且考察了常用吸收促进剂对其吸收的影响。结果显示,在40.084~400.840μg·mL~(-1)这个浓度范围内,不同的药物浓度对PNS在大鼠小肠全段的吸收无显著影响,PNS主要成分水溶性好,透膜性差,吸收机制主要为被动扩散,同时有细胞旁路转运,存在外排泵消除可能。PNS主要成分口服生物利用度低,透膜吸收是限速过程,与冰片、卡波姆或吐温80联合使用,大鼠小肠吸收速率提高明显,可能与它们能促进细胞旁路转运或降低药物外排泵的作用有关。
论文第三部分,在对PNS吸收机理及药动学进行了初步研究的基础上,以PNS为模型药物,对其普通肠溶胶囊、肠溶微囊(胶囊)和肠溶微丸(胶囊)三种不同肠溶制剂的制备工艺、制剂学性质、体外释药规律和稳定性进行了研究。按正交设计方法得到的最优处方分别制备了三批PNS肠溶胶囊样品,f_2因子评价结果表明,三种肠溶胶囊的三批样品的释放度均有良好的重现性,R_1、Rb_1和Rg_1的释放行为没有显著性差异,只需要监测一种指标成分即可对PNS各主要成分的释放进行评价,并最终选择Rg1为体外释放度监测对象。采用单指数模型、Weibull模型、Higuchi模型、Ritger-Peppas模型、零级释放、一级释放、Hixcon Crowell模型和Niebergull模型对累积释放度数据进行拟合,普通肠溶胶囊、肠溶微囊(胶囊)和肠溶微丸(胶囊)的最佳拟合模型分别为:Hixcon Crowell模型、Weibull模型和Weibull模型。参照中国药典2010版二部附录XIX C“药物稳定性试验指导原则”,对三种PNS肠溶胶囊的稳定性进行了初步研究。结果表明,所考察胶囊完整,无软化塌陷现象,内容物色泽变化不大;释放度、含量和水分考察均符合要求。
论文第四部分,考察了PNS在大鼠体内及三种PNS肠溶胶囊在Beagle犬体内的药代动力学及口服生物利用度。本部分创新性地应用中药多组分整合药代动力学研究新理论,在求得R_1、Rb_1和Rg_1药动学参数后,利用各成分曲线下面积(AUC_(0→∞))百分率作为自定义权重系数,计算PNS动物体内综合血药浓度并建立整合药动学研究模型,进一步估算PNS动物体内整合药动学参数,使得所获参数能够最大程度上表征中药的整体处置规律,为建立符合中医药特点的中药药代动力学研究提供了一种新的研究思路与技术方法。结果表明PNS静脉注射及灌胃后,R_1、Rb_1和Rg_1在大鼠体内的药时曲线均符合二室模型,经过剂量校正后的口服绝对生物利用度分别为1.76%、0.78%和2.44%。分别以市售注射用血栓通(冻干)和市售血栓通胶囊为参比制剂进行了自制PNS肠溶胶囊的药动学和生物利用度初步研究。实验结果表明:单剂量给予Beagle犬供试品和参比制剂后,PNS肠溶胶囊与普通制剂相比,生物利用度提高1.08~5.71倍,有显著性差异,MRT延长,绝对生物利用度也有不同程度提高。采用Wagner-Nelson (W-N)法对自制肠溶胶囊的体内外相关性进行评价,结果表明,各制剂的各成分的体内外相关性结果不一,其原因可能是PNS的吸收过程不仅仅是被动扩散,还包括主动转运过程。体内实验结果进一步证明各肠溶制剂效果确切,达到了课题预期设计的目的。
本课题在生物药剂学和药物动力学理论的指导下,以PNS的胃肠道吸收特性为基础进行制剂研制,减少了制剂开发的盲目性。本课题的研究结果为今后PNS其它剂型设计的处方工艺、质量评价、稳定性、体内动力学等方面提供参考。
Xueshuantong injection has been widely used to treat coronary disease in clinic. In this paper, its main group that is panax notoginseng saponions (PNS) was used as model drug. The objective was to study absorption mechanism of PNS and to develop oral enteric preparation of PNS which could avoid being destroyed by stomach acid and enzymes, on the basis of principles in biopharmaceutics and pharmacokinetics.
This paper fell into four parts.
In partⅠ, HPLC-UV (high-performance liquid chromatography-ultraviolet) method was established to analysis main saponins of PNS. The method which was sensitive, effective and repeatable can meet the requirement to the chemical and biological samples. The content percentages were 9.64%, 36.38% and 51.10% for notoginsenoside R_1 (R_1), ginsenoside Rb_1 (Rb_1) and ginsenoside Rg1 (Rg_1) in PNS, respectively. In additional, physical and chemical properties and stabilities of PNS were investigated. Octanol-water system was used to determine the apparent partition coefficients of R_1、Rb_1 and Rg_1, and the effects of pH, heat, light and humidity on stability of R_1、Rb_1 and Rg_1 were studied. Results showed that PNS was week acid in water, the apparent partition coefficient was between 1 and 2 for both of R_1 and Rb_1, but Rg_1 was between 5 and 8. All of them were sensitive to light, humidity and acid condition, and were relatively stable in normal and alkalescence condition.
In partⅡ, rat in situ intestinal perfusion model which was employed to study the absorption mechanism of PNS was established. It investigated orderly absorptive kinetics of the main components of PNS on small intestine and effects of some common absorptive promoters on the absorptive mechanism of PNS. The results clearly indicated that the concentration of PNS from 40.084 to 400.840μg·mL~(-1) had no distinctive effect on the absorptive kinetics, and the main components of PNS have high solubility and low permeability. The absorption mechanism of PNS across the intestinal epithelium is mainly passive diffusion. Paracellular pathway transportation and drug flux pump may also play a part in this process. The main components of PNS have a low absolute bioavailability, as process of acrossing the intestinal epithelium limits the rate and extent of absorption. Combination of PNS with borneol or carbomer or polysorbate 80 was administered to rats by oral, in which the absorption rate of the main components was improved. It may be related to the increase of paracellular pathway transportation or the inhibition of drug flux pump.
In partⅢ, on the basis of preliminary conclusion of the absorptive mechanism and pharmacokinetics about PNS, it was chosen as drug model for investigation the preparation of process, characters of agents, release characteristics in vitro and stability of common enteric capsules, enteric microcapsules (capsule) and enteric micropellets (capsule). Three samples of enteric capsules of PNS were produced respectively by the optimized prescription. The f_2 factor analysis showed that the reproducibility of release degree of the three samples was stable, and there was no significant difference among R_1, Rb_1 and Rg_1 that only one group that Rg_1 was selected finally needed to be controlled. The release data were intended to be single index model, Weibull model, Higuchi model, Ritger-Peppas model, zero levels release model, first levels release model, Hixcon Crowell model and Niebergull model. The best model of common enteric capsules, enteric microcapsules (capsule) and enteric micropellets (capsule) were Hixcon Crowell model, Weibull model and Weibull model respectively. Referred to appendix of Ch.P. 20_10(Ⅱ)“drug stability in the guidelines”, the stabilities of enteric capsules of PNS were studied elementarily. The results suggested that the shape of enteric capsules were still complete and the color of contents had no changes. Release degree, the content and water content all conformed to the requirements.
In partⅣ, pharmacokinetics and bioavailability of PNS in rat and its enteric capsules in Beagle dog were investigated. This part was designed to develop a novel integrated pharmacokinetic approach to assess the holistic pharmacokinetic properties of traditional Chinese medicines (TCM). After calculating pharmacokinetic parameters of R_1, Rb_1 and Rg_1, a novel approach of self-defined weight coefficient based on the area under the curve from zero to infinity (AUC_(0→∞)) has been created to obtain the holistic pharmacokinetic profiles of PNS. The integrated pharmacokinetic parameters of PNS were then calculated. This study would be useful for guiding the holistic pharmacokinetic study in consistence with the intrinsic theory and characteristics of TCM. A novel integrated pharmacokinetic thought and approach to describe the holistic pharmacokinetic properties of TCM has been successfully developed. The results suggested that after intragastric and intravenous administration of PNS, the concentration-time curve of R_1, Rb_1 and Rg_1 belonged to two compartment model, the absolute bioavailability was 1.76%, 0.78% and 2.44% respectively after correction. Study on pharmacokinetics and bioavailability of PNS enteric capsules in comparison with Xueshuantong injection and Xueshuantong capsule showed significant differences of single dosage. Bioavailabilities of PNS enteric capsules are 1.08~5.71 times as Xueshuantong capsule and MRT is longer. Moreover absolute bioavailability is improved. Evaluation on in vivo-in vitro correlation of the PNS enteric capsules according to Wagner-Nelson (W-N) method proved different correlation results. The reason is possible that the absorption process of PNS is not only passive diffusion but also active transport. The result in vivo further proved exact effects of enteric capsules as we anticipated.
According to principles of biopharmaceutics and pharmacokinetics, we based preparation research on the absorption kinetics of PNS in stomach and intestine that reduced blindness of preparation development. The study provides references for other formulation of PNS in process, quality evaluation, stability, pharmacokinetics in vivo, and so on.
引文
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