神清滴丸的药学及药代动力学研究
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摘要
本课题组在石菖蒲10年大量研究的基础上,明确发现β-细辛醚和丁香酚配伍能有效治疗AD,通过筛选单体配伍β-细辛醚和丁香酚对β-淀粉样蛋白诱导PCI2细胞损伤的保护作用,结果显示优化成分组合为：β-细辛醚为10μ L、丁香酚为3μ L,所需浓度低仅为各自单个成分剂量的1/5、1/20,但已能发挥显著作用。石菖蒲有效成分的适当配比,能更有效地保护PC12细胞免受β-淀粉样蛋白毒性损伤,不仅明显降低单体的用量,关键还明显降低单体应用的毒性风险,真正体现中药多成分作用的优势。本课题组在此研究基础上采用固体分散技术,以β-细辛醚和丁香酚为原料,制备一种口服有效的神清滴丸,并按照《中国药典》(2010年版)要求,完成工艺、质量标准、初步稳定性及药代动力学研究。通过选用PEG4000和PEG6000载体辅料,提高了难溶性药物的溶出速度,并通过优化制剂工艺条件,提高了药物的稳定性和生物利用度,增强了治疗效果,为抗老年痴呆症新药——神清滴丸的进一步研究开发提供了基础。
目的：
提取纯化β-细辛醚,确定神清滴丸的最佳成型工艺,并对制剂进行质量标准考察、初步稳定性考察及药代动力学研究,为今后神清滴丸的生产和应用提供科学依据。
方法：
(1)从石菖蒲药材提取石菖蒲挥发油,利用冷冻结晶法精制β-细辛醚。
(2)用单因素实验法确定制备工艺条件,通过考察滴丸的圆整度、硬度、拖尾、粘连等指标,分别对冷却剂、基质、药物与基质的配比、滴制温度、冷却剂温度、滴管口径、滴距等进行研究,确定工艺条件。
(3)采用HPLC法测定滴丸中β-细辛醚和丁香酚的含量,并对神清滴丸丸重差异、溶散时限和外观质量指标进行考察。
(4)通过加速实验,对神清滴丸的外观、含量、丸重差异和溶散时限指标进行考察。
(5)通过灌胃给药,考察滴丸中β-细辛醚和丁香酚在大鼠体内的血药浓度、半衰期t1/2、达峰时间Tmax、达峰浓度、Cmax等动力学参数,并与β-细辛醚单体滴丸组在大鼠体内的药代动力学参数进行比较。
结果：
(1)神清滴丸的制备工艺：最佳工艺条件为,β-细辛醚与丁香酚的较优配伍比例为4：1作为原料药物,以PEG4000:PEG6000=1:6为滴丸剂基质,基质与药物比例为7：1,80℃保温,在滴距5cm,滴速为30d/min的条件下滴入梯度冷凝的液体石蜡中。
(2)质量标准研究：神清滴丸中β-细辛醚和丁香酚的含量分别为9.43%和2.18%。滴丸的丸重约为30mg,滴丸的溶散时限符合规定。
(3)初步稳定性研究：在加速实验条件下,神清滴丸外观、丸重、溶散时限和含量均保持稳定。
(4)药代动力学研究：大鼠灌胃β-细辛醚滴丸混悬液后在Tmax=10min达到吸收峰值Cmax=1.3948mg/L,吸收半衰期t1/2α=1.975min,消除半衰期t1/2β=93.286min,血药浓度-时间曲线下面积AUC=48.41mg/L*min。大鼠灌胃神清滴丸混悬液后在Tmax=30min达到吸收峰值Cmax=0.8965mg/L,吸收半衰期t1/2α=13.005min,消除半衰期t1/2β=17.489min,血药浓度-时间曲线下面积AUC=57.747mg/L*min。
结论：
(1)优选的神清滴丸制备工艺稳定性好、成型率高。
(2)已建立神清滴丸含量测定方法；及制定滴丸其余质量方案。
(3)神清滴丸在加速试验条件下基本稳定,达到制剂设计要求。
(4)滴丸组(即β-细辛醚与丁香酚配伍组)达峰时间约为30min分钟,而β-细辛醚单体组达峰时间约为10min,可见与丁香酚配伍后,可明显延长β-细辛醚的达峰时间。
从分布半衰期来看,滴丸组约为13.005min,单体组为1.975min,可见与丁香酚配伍后,可明显增加β-细辛醚的分布半衰期。从消除半衰期来看,滴丸组约为17.489min,单体组为93.286min,可见与丁香酚配伍后,可明显缩短β-细辛醚的消除半衰期。其原因有待进一步探讨。
从达峰浓度来看,配伍组按比例折算成0.8965×1.25=1.1206(mg/L),与单体组1.395相近,提示与丁香酚配伍后,对β-细辛醚的血药浓度的影响不明显。
Objective
Extraction and purification of β-asarone, to determine the best molding process of ShenQing dripping pills, and quality standards inspection preparation, Preliminary investigation of stability and pharmacokinetic studies to provide scientific, production and application in the future ShenQing dripping pills basis.
Methods
(1) To extract the volatile oil from the gramineus herbs, and then use of freezing crystallization purification of β-asarone.
(2) Preparation conditions using a single factor test to determine inspection dripping pills, roundness, hardness, trailing, adhesive and other indicators, respectively, the ratio of the coolant, matrix, drug and matrix, the dripping temperature, coolant temperature, The dropper caliber, drops from the study to determine the process conditions.
(3) Dripping Pills beta-asarone and eugenol content was determined by HPLC, and ShenQing dripping:pills pills weight variation, dissolution time and to inspect the appearance of quality indicators.
(4) By speeding up the experiment, the appearance of ShenQing dripping pills, content, pills, weight variation and dissolution time indicators to inspect.
(5) Dripping Pills plasma concentration of beta-asarone and eugenol in rats by intragastric administration, inspection, and half-life ti/2, time to peak Tmax is the peak concentration, Cmax, and other kinetic parameters, and β-asarone monomer Dripping Pills group pharmacokinetic parameters in rats.
Results
(1) ShenQing dripping pills preparation process:optimal conditions for beta-asarone and eugenol, the better compatibility ratio of4:1as a raw material drugs, drop pills of PEG4000:PEG6000=1:6matrix, matrix anddrug ratio of7:1,80for drops away from5cm drip for30d/min conditions under trickle-down gradient condensation of liquid paraffin.
(2) Quality standards:ShenQing dripping pills of β-asarone and eugenol were9.43%and2.18%. Dripping pills weight about30mg, dropping pills dissolution time required.
(3) Preliminary stability study:In the accelerated test conditions, the appearance of ShenQing dripping pills, pills, weight, dissolution time and content to remain stable.
(4) Pharmacokinetic Study:Rats were β-asarone Dripping Pills suspension absorbed at Tmax=10min to reach peak Cmax=1.3948mg/L, absorption half-life t1/2a=1.975min, elimination half-life t1/2β=93.286min, the area under the plasma concentration-time curve AUC=48.41mg/L*min, After the suspension of the the intragastric ShenQing dripping pills, the absorption peak at Tmax is=30min to reach Cmax=0.8965mg/L, and absorption half-life t1/2a=13.005min, elimination half-life t1/2P=17.489min, the plasma concentration-time The area under the curve AUC=57.747mg/L*min.
Conclusion
(1) The stability of the preparation process of the optimization of ShenQing dripping pills, forming rate.
(2) A method for the determination of ShenQing dripping pills has established; and the development of dripping pills the rest of the quality program.
(3) ShenQing dripping pills in the basic stability of the accelerated test conditions to achieve the preparation design requirements.
(4) Dripping Pills group (ie, β-asarone and eugenol compatibility group) time to peak of about30min, time to peak of β-asarone monomer group of about10min, visible and eugenol compatibility, can significantly extend thetime to peak of β-asarone.
From the distribution half-life, pills group of approximately13.005min, monomer is1.975min, visible compatibility with eugenol, can significantly increase the distribution half-life of β-asarone. From the elimination half-life, pills group of approximately17.489min, the monomer of93.286min, found compatibility with eugenol, can significantly shorten the elimination half-life of β-asarone. The reason to be explored.
From the peak concentration, the compatibility group prorated.8965X1.25=1.1206(mg/L),1.395similar to the monomer group, suggesting that compatibility with eugenol, the plasma concentration of beta-asaronenot obvious.
目的：
提取纯化β-细辛醚,确定神清滴丸的最佳成型工艺,并对制剂进行质量标准考察、初步稳定性考察及药代动力学研究,为今后神清滴丸的生产和应用提供科学依据。
方法：
(1)从石菖蒲药材提取石菖蒲挥发油,利用冷冻结晶法精制β-细辛醚。
(2)用单因素实验法确定制备工艺条件,通过考察滴丸的圆整度、硬度、拖尾、粘连等指标,分别对冷却剂、基质、药物与基质的配比、滴制温度、冷却剂温度、滴管口径、滴距等进行研究,确定工艺条件。
(3)采用HPLC法测定滴丸中β-细辛醚和丁香酚的含量,并对神清滴丸丸重差异、溶散时限和外观质量指标进行考察。
(4)通过加速实验,对神清滴丸的外观、含量、丸重差异和溶散时限指标进行考察。
(5)通过灌胃给药,考察滴丸中β-细辛醚和丁香酚在大鼠体内的血药浓度、半衰期t1/2、达峰时间Tmax、达峰浓度、Cmax等动力学参数,并与β-细辛醚单体滴丸组在大鼠体内的药代动力学参数进行比较。
结果：
(1)神清滴丸的制备工艺：最佳工艺条件为,β-细辛醚与丁香酚的较优配伍比例为4：1作为原料药物,以PEG4000:PEG6000=1:6为滴丸剂基质,基质与药物比例为7：1,80℃保温,在滴距5cm,滴速为30d/min的条件下滴入梯度冷凝的液体石蜡中。
(2)质量标准研究：神清滴丸中β-细辛醚和丁香酚的含量分别为9.43%和2.18%。滴丸的丸重约为30mg,滴丸的溶散时限符合规定。
(3)初步稳定性研究：在加速实验条件下,神清滴丸外观、丸重、溶散时限和含量均保持稳定。
(4)药代动力学研究：大鼠灌胃β-细辛醚滴丸混悬液后在Tmax=10min达到吸收峰值Cmax=1.3948mg/L,吸收半衰期t1/2α=1.975min,消除半衰期t1/2β=93.286min,血药浓度-时间曲线下面积AUC=48.41mg/L*min。大鼠灌胃神清滴丸混悬液后在Tmax=30min达到吸收峰值Cmax=0.8965mg/L,吸收半衰期t1/2α=13.005min,消除半衰期t1/2β=17.489min,血药浓度-时间曲线下面积AUC=57.747mg/L*min。
结论：
(1)优选的神清滴丸制备工艺稳定性好、成型率高。
(2)已建立神清滴丸含量测定方法；及制定滴丸其余质量方案。
(3)神清滴丸在加速试验条件下基本稳定,达到制剂设计要求。
(4)滴丸组(即β-细辛醚与丁香酚配伍组)达峰时间约为30min分钟,而β-细辛醚单体组达峰时间约为10min,可见与丁香酚配伍后,可明显延长β-细辛醚的达峰时间。
从分布半衰期来看,滴丸组约为13.005min,单体组为1.975min,可见与丁香酚配伍后,可明显增加β-细辛醚的分布半衰期。从消除半衰期来看,滴丸组约为17.489min,单体组为93.286min,可见与丁香酚配伍后,可明显缩短β-细辛醚的消除半衰期。其原因有待进一步探讨。
从达峰浓度来看,配伍组按比例折算成0.8965×1.25=1.1206(mg/L),与单体组1.395相近,提示与丁香酚配伍后,对β-细辛醚的血药浓度的影响不明显。
Objective
Extraction and purification of β-asarone, to determine the best molding process of ShenQing dripping pills, and quality standards inspection preparation, Preliminary investigation of stability and pharmacokinetic studies to provide scientific, production and application in the future ShenQing dripping pills basis.
Methods
(1) To extract the volatile oil from the gramineus herbs, and then use of freezing crystallization purification of β-asarone.
(2) Preparation conditions using a single factor test to determine inspection dripping pills, roundness, hardness, trailing, adhesive and other indicators, respectively, the ratio of the coolant, matrix, drug and matrix, the dripping temperature, coolant temperature, The dropper caliber, drops from the study to determine the process conditions.
(3) Dripping Pills beta-asarone and eugenol content was determined by HPLC, and ShenQing dripping:pills pills weight variation, dissolution time and to inspect the appearance of quality indicators.
(4) By speeding up the experiment, the appearance of ShenQing dripping pills, content, pills, weight variation and dissolution time indicators to inspect.
(5) Dripping Pills plasma concentration of beta-asarone and eugenol in rats by intragastric administration, inspection, and half-life ti/2, time to peak Tmax is the peak concentration, Cmax, and other kinetic parameters, and β-asarone monomer Dripping Pills group pharmacokinetic parameters in rats.
Results
(1) ShenQing dripping pills preparation process:optimal conditions for beta-asarone and eugenol, the better compatibility ratio of4:1as a raw material drugs, drop pills of PEG4000:PEG6000=1:6matrix, matrix anddrug ratio of7:1,80for drops away from5cm drip for30d/min conditions under trickle-down gradient condensation of liquid paraffin.
(2) Quality standards:ShenQing dripping pills of β-asarone and eugenol were9.43%and2.18%. Dripping pills weight about30mg, dropping pills dissolution time required.
(3) Preliminary stability study:In the accelerated test conditions, the appearance of ShenQing dripping pills, pills, weight, dissolution time and content to remain stable.
(4) Pharmacokinetic Study:Rats were β-asarone Dripping Pills suspension absorbed at Tmax=10min to reach peak Cmax=1.3948mg/L, absorption half-life t1/2a=1.975min, elimination half-life t1/2β=93.286min, the area under the plasma concentration-time curve AUC=48.41mg/L*min, After the suspension of the the intragastric ShenQing dripping pills, the absorption peak at Tmax is=30min to reach Cmax=0.8965mg/L, and absorption half-life t1/2a=13.005min, elimination half-life t1/2P=17.489min, the plasma concentration-time The area under the curve AUC=57.747mg/L*min.
Conclusion
(1) The stability of the preparation process of the optimization of ShenQing dripping pills, forming rate.
(2) A method for the determination of ShenQing dripping pills has established; and the development of dripping pills the rest of the quality program.
(3) ShenQing dripping pills in the basic stability of the accelerated test conditions to achieve the preparation design requirements.
(4) Dripping Pills group (ie, β-asarone and eugenol compatibility group) time to peak of about30min, time to peak of β-asarone monomer group of about10min, visible and eugenol compatibility, can significantly extend thetime to peak of β-asarone.
From the distribution half-life, pills group of approximately13.005min, monomer is1.975min, visible compatibility with eugenol, can significantly increase the distribution half-life of β-asarone. From the elimination half-life, pills group of approximately17.489min, the monomer of93.286min, found compatibility with eugenol, can significantly shorten the elimination half-life of β-asarone. The reason to be explored.
From the peak concentration, the compatibility group prorated.8965X1.25=1.1206(mg/L),1.395similar to the monomer group, suggesting that compatibility with eugenol, the plasma concentration of beta-asaronenot obvious.
引文
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