雷公藤主成分肠吸收动力学研究
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摘要
口服给药是最常用的临床给药方式,吸收是药物发挥作用、产生疗效或发生毒副反应的前提和关键,研究药物的肠吸收特性对研究口服药物的剂型设计、药物药效及毒性具有重要意义。雷公藤是临床治疗类风湿性关节炎以及其他自身免疫性疾病的常用中药,雷公藤甲素和雷公藤红素是雷公藤的主要有效成分,具有广泛的药理活性,目前对于雷公藤的研究多集中于抗炎、抗肿瘤等药理药效机制,而对其体内过程鲜有报道。本研究对雷公藤提取物及其主成分的肠吸收动力学进行了研究,并通过脂质体技术改善雷公藤红素的肠吸收,为雷公藤新剂型研究以及临床安全合理用药提供依据。
1雷公藤主成分理化性质研究
研究雷公藤中最具代表性的二萜类活性成分雷公藤甲素和三萜类活性成分雷公藤红素的理化性质,通过测定它们的溶解度和油水分配系数,考察溶解性和膜渗透性,为下一步实验提供依据,并对药物的体内吸收做出初步预测。结果雷公藤甲素水溶性较低,log P为0.58,渗透性较好,在pH1.2-9.0范围内的分配系数受pH值的影响不大,根据“五规则”推测其在整个胃肠道均有较好的吸收；雷公藤红素溶解度和渗透性都很差,属BCS分类标准中的Class IV型药物,推测其在体内的吸收可能较差。
2生物样品分析方法学的建立
建立雷公藤提取物及单体的雷公藤甲素、雷公藤红素在外翻肠囊样品和肠灌流液样品中的UPLC分析方法,经方法学考察,专属性、线性、回收率、精密度、稳定性均符合要求,所建方法快速、灵敏、准确,为上述化合物的体内外吸收实验奠定了研究基础。
3雷公藤甲素肠吸收动力学研究
建立大鼠离体外翻肠囊模型和大鼠在体肠灌流模型,通过离体法和在体法相结合,研究并比较了雷公藤甲素单体和提取物两种形式给药下的肠吸收特性与差异。结果表明,雷公藤甲素在大鼠各肠段均有较好的吸收,总趋势按十二指肠、结肠、空肠和回肠的顺序依次降低,但无特殊吸收部位；在试验时间和浓度范围内,符合零级吸收速率,可能为被动扩散；雷公藤提取物中其他成分对雷公藤甲素的肠吸收没有影响,雷公藤甲素在提取物给药下的吸收与单体给药相似。
4雷公藤红素肠吸收动力学研究
通过离体外翻肠囊模型和在体肠灌流模型,研究并比较雷公藤红素在单体和提取物中这两种形式给药下的肠吸收特性与差异。结果表明,雷公藤红素在肠道内吸收较差,不同肠段间的吸收表现为,十二指肠和空肠的吸收明显大于回肠、结肠,十二指肠与空肠之间的吸收无明显差异,其余各肠段之间具有显著性差异；在试验时间和浓度范围内,符合零级吸收速率,可能为被动扩散；提取物中其他成分对雷公藤红素的肠吸收没有影响,与单体相比,提取物中雷公藤红素在肠道内的吸收并无明显差异。
5雷公藤红素脂质体的制备及其肠吸收动力学研究
由于水溶性和渗透性差,雷公藤红素的肠吸收较差,采用脂质体技术改善雷公藤红素在肠道内的吸收,建立雷公藤红素脂质体的制备方法,并进行制剂学表征,对雷公藤红素脂质体的肠吸收特性进行考察。建立了脂质体的药物含量测定方法及微柱离心法测定包封率的方法；采用乙醇注入法制备雷公藤红素脂质体,以包封率为指标,对处方工艺进行单因素考察,正交试验成功优化了制备工艺,确定最佳工艺为：大豆磷脂用量300mg时,雷公藤红素用量为30mg,胆固醇用量为80mg,吐温-80浓度为0.5mg·mL-1,水相体积40mL；制得的脂质体呈不连续球状,粒径均一、电位适中、包封率及载药量高、性质稳定；采用大鼠在体肠灌流模型考察雷公藤红素脂质体的肠吸收特性,结果脂质体在不同肠段间的吸收差异与单体原型相同；对比单体,雷公藤红素脂质体在各肠段中的吸收均显著提高,有效的改善了雷公藤红素在肠道的吸收。
综上,雷公藤中两种主要成分雷公藤甲素在肠道内吸收较好,雷公藤红素的肠吸收较差,通过脂质体技术,有效的改善了雷公藤红素的肠吸收。肠吸收动力学研究为为口服中药剂型设计提供了可靠依据。
Oral administration is the most common clinical drug delivery. Absorption is the prerequisite for drugs to exert therapeutic or toxic effects. Intestinal absorption research is important for dosage form design, efficacy and toxicity study of oral drugs. Triptergium wilfordii Hook.f (TwHf) is used as an herbal remedy to treat arthritis and other autoimmune deseases. Triptolide and tripterine are the major components in TwHf, which possess extensive pharmacological activitities. Currently, the research mostly focuses on the anti-inflammatory and antitumor efficacy mechanism, while their ADME process study is rarely reported. Therefore, the absorption kinetics of main components from TwHf is studied, and the tripterine liposome is prepared to improve the intestinal absorption. It can provide the basis to design new dosage forms and derect safe and reasonable clinical application of TwHf.
1 Physical and chemical properties of main components from TwHf
The physical and chemical properties of triptolide and tripterine, which are the most representative active components of diterpenes and triterpenoids, are studied. The solubility and membrane permeability are determined to provide the basis for further experiments, and their intracorporal absorption are predicted. Triptolide is low water-solubility, but has well membrane permeability with log P of 0.58 in octanol/water system and the pH of buffer solution had no influence to its distribution coefficient. It is speculated that triptolide could be well absorbed in general intestinal according to the "Five Rules". Tripterine has poor solubility and permeability, belonging to class IV of the BCS, which might be poor absorbed in vivo.
2 Establishment of biological sample analytical methods
The analytical methods for triptolide, tripterine and TwHf extracts in biological samples were established. The specialization, linearity, recovery, precision and stability are investigated and results are satisfactory. The methods are rapid, sensitive and accurate, which meet the requirement of the following experiments.
3 The absorption kinetics of triptolide
The in vitro everted rat gut scas model and in situ perfused rat intestinal model are established. The absorption mechanism of triptolide and its in extract is studied and their differences are compared through in vitro and in situ experiments. The results show that triptolide could be well absorbed in general intestinal tract. The absorption tends to be decreased in the order of duodenum, colon, jejunum and ileum, but without specific absorption site. The absorption of triptolide conforms to the zero order rate process and displays the passive diffusion mechanism in the test of time and concentration range. There are no obvious differences between triptolide and its in extract. Other components in the extract of TwHf have no effect on the absorption of triptolide.
4 The absorption kinetics of tripterine
The absorption mechanism of tripterine and its in extract is studied and their differences are compared using everted gut scas model and perfused rat intestinal model. The results show that tripterine is rarely absorbed in the intestine. The absorption in duodenum and jejunum is significantly larger than that in ileum and colon. There are no significant difference between duodenum and jejunum, while other segments of intestine were significant different. The absorption of tripterine conforms to the zero order rate process and displays the passive diffusion mechanism in the test of time and concentration range. There are no obvious differences between tripterine and its in extract. Other components in the extract of TwHf have no effect on the absorption of tripterine.
5 Study of tripterine liposome and its intestinal absorption kinetics
As the poor solubility and permeability, the intestinal absorption of tripterine is poor. We use liposome technology to improve the absoption of tripterine. Tripterine liposome is prepared, and the properies are verified. Finally, the absorption of tripterine liposome is investigated. The method for content determination is established and minicolum centrifugation method is employed to determine the entrapment efficiency. Tripterine liposome is prepared by ethanol injection method with encapsulation efficiency as index. After screened by orthogonal experimental design, the optimized formula is as the follows: 300mg of soybean phosopholipids,30mg of tripterine,80mg of cholesterol, 0.5mg·mL-1 of Tween-80, and 40mL of water. The tripterine liposome is intact spherical or oval shaped ball vesicle, with uniform particle size and moderate potential. The encapsulation efficiency and drug loading of the optimized liposome are high. We use in situ perfused rat intestinal model to study the absorption mechanism of tripterine liposome. Results show that the absorption differences in four intestinal segments of liposome are same as that of tripterine. Compared with tripterine, the absorption of liposome in intestines is significant increased. Tripterine liposome effectively improves tripterine absorption in the intestine.
In conclusion, triptolide is well absorbed in intestine, while of tripterine, the absorption is poor. The absorption is significantly improved by liposome technology. Intestinal absorption kinetics can porvide a method for profound study on new dosage forms.
1雷公藤主成分理化性质研究
研究雷公藤中最具代表性的二萜类活性成分雷公藤甲素和三萜类活性成分雷公藤红素的理化性质,通过测定它们的溶解度和油水分配系数,考察溶解性和膜渗透性,为下一步实验提供依据,并对药物的体内吸收做出初步预测。结果雷公藤甲素水溶性较低,log P为0.58,渗透性较好,在pH1.2-9.0范围内的分配系数受pH值的影响不大,根据“五规则”推测其在整个胃肠道均有较好的吸收；雷公藤红素溶解度和渗透性都很差,属BCS分类标准中的Class IV型药物,推测其在体内的吸收可能较差。
2生物样品分析方法学的建立
建立雷公藤提取物及单体的雷公藤甲素、雷公藤红素在外翻肠囊样品和肠灌流液样品中的UPLC分析方法,经方法学考察,专属性、线性、回收率、精密度、稳定性均符合要求,所建方法快速、灵敏、准确,为上述化合物的体内外吸收实验奠定了研究基础。
3雷公藤甲素肠吸收动力学研究
建立大鼠离体外翻肠囊模型和大鼠在体肠灌流模型,通过离体法和在体法相结合,研究并比较了雷公藤甲素单体和提取物两种形式给药下的肠吸收特性与差异。结果表明,雷公藤甲素在大鼠各肠段均有较好的吸收,总趋势按十二指肠、结肠、空肠和回肠的顺序依次降低,但无特殊吸收部位；在试验时间和浓度范围内,符合零级吸收速率,可能为被动扩散；雷公藤提取物中其他成分对雷公藤甲素的肠吸收没有影响,雷公藤甲素在提取物给药下的吸收与单体给药相似。
4雷公藤红素肠吸收动力学研究
通过离体外翻肠囊模型和在体肠灌流模型,研究并比较雷公藤红素在单体和提取物中这两种形式给药下的肠吸收特性与差异。结果表明,雷公藤红素在肠道内吸收较差,不同肠段间的吸收表现为,十二指肠和空肠的吸收明显大于回肠、结肠,十二指肠与空肠之间的吸收无明显差异,其余各肠段之间具有显著性差异；在试验时间和浓度范围内,符合零级吸收速率,可能为被动扩散；提取物中其他成分对雷公藤红素的肠吸收没有影响,与单体相比,提取物中雷公藤红素在肠道内的吸收并无明显差异。
5雷公藤红素脂质体的制备及其肠吸收动力学研究
由于水溶性和渗透性差,雷公藤红素的肠吸收较差,采用脂质体技术改善雷公藤红素在肠道内的吸收,建立雷公藤红素脂质体的制备方法,并进行制剂学表征,对雷公藤红素脂质体的肠吸收特性进行考察。建立了脂质体的药物含量测定方法及微柱离心法测定包封率的方法；采用乙醇注入法制备雷公藤红素脂质体,以包封率为指标,对处方工艺进行单因素考察,正交试验成功优化了制备工艺,确定最佳工艺为：大豆磷脂用量300mg时,雷公藤红素用量为30mg,胆固醇用量为80mg,吐温-80浓度为0.5mg·mL-1,水相体积40mL；制得的脂质体呈不连续球状,粒径均一、电位适中、包封率及载药量高、性质稳定；采用大鼠在体肠灌流模型考察雷公藤红素脂质体的肠吸收特性,结果脂质体在不同肠段间的吸收差异与单体原型相同；对比单体,雷公藤红素脂质体在各肠段中的吸收均显著提高,有效的改善了雷公藤红素在肠道的吸收。
综上,雷公藤中两种主要成分雷公藤甲素在肠道内吸收较好,雷公藤红素的肠吸收较差,通过脂质体技术,有效的改善了雷公藤红素的肠吸收。肠吸收动力学研究为为口服中药剂型设计提供了可靠依据。
Oral administration is the most common clinical drug delivery. Absorption is the prerequisite for drugs to exert therapeutic or toxic effects. Intestinal absorption research is important for dosage form design, efficacy and toxicity study of oral drugs. Triptergium wilfordii Hook.f (TwHf) is used as an herbal remedy to treat arthritis and other autoimmune deseases. Triptolide and tripterine are the major components in TwHf, which possess extensive pharmacological activitities. Currently, the research mostly focuses on the anti-inflammatory and antitumor efficacy mechanism, while their ADME process study is rarely reported. Therefore, the absorption kinetics of main components from TwHf is studied, and the tripterine liposome is prepared to improve the intestinal absorption. It can provide the basis to design new dosage forms and derect safe and reasonable clinical application of TwHf.
1 Physical and chemical properties of main components from TwHf
The physical and chemical properties of triptolide and tripterine, which are the most representative active components of diterpenes and triterpenoids, are studied. The solubility and membrane permeability are determined to provide the basis for further experiments, and their intracorporal absorption are predicted. Triptolide is low water-solubility, but has well membrane permeability with log P of 0.58 in octanol/water system and the pH of buffer solution had no influence to its distribution coefficient. It is speculated that triptolide could be well absorbed in general intestinal according to the "Five Rules". Tripterine has poor solubility and permeability, belonging to class IV of the BCS, which might be poor absorbed in vivo.
2 Establishment of biological sample analytical methods
The analytical methods for triptolide, tripterine and TwHf extracts in biological samples were established. The specialization, linearity, recovery, precision and stability are investigated and results are satisfactory. The methods are rapid, sensitive and accurate, which meet the requirement of the following experiments.
3 The absorption kinetics of triptolide
The in vitro everted rat gut scas model and in situ perfused rat intestinal model are established. The absorption mechanism of triptolide and its in extract is studied and their differences are compared through in vitro and in situ experiments. The results show that triptolide could be well absorbed in general intestinal tract. The absorption tends to be decreased in the order of duodenum, colon, jejunum and ileum, but without specific absorption site. The absorption of triptolide conforms to the zero order rate process and displays the passive diffusion mechanism in the test of time and concentration range. There are no obvious differences between triptolide and its in extract. Other components in the extract of TwHf have no effect on the absorption of triptolide.
4 The absorption kinetics of tripterine
The absorption mechanism of tripterine and its in extract is studied and their differences are compared using everted gut scas model and perfused rat intestinal model. The results show that tripterine is rarely absorbed in the intestine. The absorption in duodenum and jejunum is significantly larger than that in ileum and colon. There are no significant difference between duodenum and jejunum, while other segments of intestine were significant different. The absorption of tripterine conforms to the zero order rate process and displays the passive diffusion mechanism in the test of time and concentration range. There are no obvious differences between tripterine and its in extract. Other components in the extract of TwHf have no effect on the absorption of tripterine.
5 Study of tripterine liposome and its intestinal absorption kinetics
As the poor solubility and permeability, the intestinal absorption of tripterine is poor. We use liposome technology to improve the absoption of tripterine. Tripterine liposome is prepared, and the properies are verified. Finally, the absorption of tripterine liposome is investigated. The method for content determination is established and minicolum centrifugation method is employed to determine the entrapment efficiency. Tripterine liposome is prepared by ethanol injection method with encapsulation efficiency as index. After screened by orthogonal experimental design, the optimized formula is as the follows: 300mg of soybean phosopholipids,30mg of tripterine,80mg of cholesterol, 0.5mg·mL-1 of Tween-80, and 40mL of water. The tripterine liposome is intact spherical or oval shaped ball vesicle, with uniform particle size and moderate potential. The encapsulation efficiency and drug loading of the optimized liposome are high. We use in situ perfused rat intestinal model to study the absorption mechanism of tripterine liposome. Results show that the absorption differences in four intestinal segments of liposome are same as that of tripterine. Compared with tripterine, the absorption of liposome in intestines is significant increased. Tripterine liposome effectively improves tripterine absorption in the intestine.
In conclusion, triptolide is well absorbed in intestine, while of tripterine, the absorption is poor. The absorption is significantly improved by liposome technology. Intestinal absorption kinetics can porvide a method for profound study on new dosage forms.
引文
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