物质经皮转运的唯象理论研究
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摘要
随着生物技术的发展，以多肽、蛋白质、寡核苷酸等大分子为主的生物制剂愈来愈多，给药途径是生物制剂在临床应用中遇到的一个普遍性问题。因为生物制剂口服时很容易在肝脏和胃肠道中降解，降低生物利用度；注射时又难以保持体内稳定的血药浓度，频繁注射还会给患者造成极大不便和痛苦。因此，经皮给药作为口服、注射之外的另一种给药方式备受关注。
经皮给药是将药物贴敷在皮肤外表面，依靠被动扩散或促进扩散使药物通过皮肤进入皮下毛细血管。由于皮肤角质层的屏障作用，大分子的生物制剂难以靠被动扩散进入，需要借助物理或化学的辅助方法，如离子导入、电穿孔导入、超声导入、电磁导入、光压波导入、化学促渗剂等，此即所谓促进扩散。
在经皮给药系统中，物质转运是一个不可逆非平衡态热力学过程，其渗透率与外力场、皮肤特性、物质理化性质等因素有很大关系。本文在物质通过皮肤角质层转运的生物物理现象研究中，取得了以下三个方面的成果：
1．物质经皮转运的热力学分析。将流动扩散池系统看成由扩散池子系统和漏槽子系统组成，分别对两个子系统列出熵平衡方程，两个子系统通过共有部分供应室联系，并且整个流动扩散池系统中物质不灭，从而得到流动扩散池系统的熵平衡方程，确定系统中扩散流及其推动力之间的唯象关系。以胰岛素、FD-4和FD-20为模式物质，指数衰减电脉冲为促进扩散的外力场，通过漏槽实验得到：(1)唯象系数较小，说明系统中的力和流满足线性唯象关系假设；(2)唯象系数具有可变性，随不同的模式物质、实验角质层样本和取样时间而改变；(3)研究脉冲协议、角质层样本和模式物质对电场力的单因素影响，脉冲协议(主要能量、电压)影响电场力的大小，角质层样本特性影响电场力的变化趋势，模式物质对电场力的大小和变化趋势都有影响。
2．脉冲电场物质经皮转运率和皮肤电导的影响。物质经皮转运率可以作为电脉冲促进物质经皮转运作用的评价指标，角质层电导反映出电脉冲作用下皮肤结构的变化状况。以胰岛素和FD-4作为模式物质，分别进行15和12种脉冲协议的促进扩散，结果表明：角质层电导和物质经皮转运率的变化在时间上并非对应，但在数值的大小方面有内在的联系，较小的电导变化伴随同向的较大的经皮转运率变化，并且对同一模式物质，两者的变化斜率之比较为恒定。
3．物质经皮转运的时变特性。目前检测物质经皮转运率广泛采用求统计平均值的方法，但此法存在很大的均方差，其原因在于忽略了经皮转运的时变性和每个实验个体的差异。我们用胰岛素经皮转运的实验数据和数学模型建立一种描述药物经皮转运的唯象模型，用唯象模型的参数描述药物经皮通透率的时变性和最大转运率。
Recent advances in biotechnology have resulted in a significant increase in the number of therapeutic macromolecules such as peptides, proteins, oligonucleotides and so on. Difficulty of drug delivery prevents these bioactive macromolecules from popular clinical application. For oral use they will be degraded in the liver and gastrointestinal tract, while for injection it is difficult to maintain blood concentration of the drug and patients will suffer inconvenience and pain because of frequently injection. Transdermal drug delivery (TDD) is an alternative method of drug delivery that draws attention as a potential administration of biological pharmacy.
TDD is the method that patching the drug on the skin, the drug molecules permeating through the skin into the subcutaneous capillary vessels by passive diffusion and enhanced diffusion. Very few drugs can be administered transdermally by passive diffusion due to the barrier of stratum corneum (SC), the skin's outer layer. Several physical and chemical methods, including iontophoresis, electroporation, sonophoresis, magnetophoresis, photomechanical wave and chemical enhancers, are applied to improve the permeability of skin, which is called the enhanced diffusion.
In TDD system, substance transport is an irreversible and non-equilibrium thermodynamical process whose penetration is in great relation to the outside force field, skin specialty, physical and chemical properties of drug, etc. Three achievements have been obtained in our study on biophysical phenomena of substance transport through SC, including below:
1. Thermodynamic analysis of substance transport through SC. Considering the diffusion cell system consists of the diffusion cell subsystem and the sink subsystem, the subsystems associated with each other by the receptor which is their mutual part, and the whole diffusion cell system is matter conservation, we derived the entropy equilibrium equation of the diffusion cell system, determined the phenomenological relationship between the diffusion flow and its driving force. Insulin, FD-4 and FD-20 as pattern substances, exponentially decaying electric pulses as the outside force field enhancing diffusion, leakage experiments resulted in: (1) the phenomenological coefficient is small, which proves the hypothesis of linear phenomenological relationship between the flow and force in the system; (2) the phenomenological coefficient varies with pattern substances, SC samples and sampling time; (3) one-factor influence of pulse protocol, SC sample and pattern substance on electric field force is that, pulse protocol (energy, voltage) affects the quantity of electric field force, characteristics of SC sample affect variation of electric field force, while pattern substance effect on both of the quantity and variation of electric field force.
2. Connection between transdermal flux and conductance of SC in electric field enhanced diffusion. Transdermal flux is the index of electric pulses acting on TDD, while SC conductance reflects the variation of skin structure under electric field. Insulin and FD-4 as pattern substances, whose pulse protocols are 15 and 12 types respectively, electric field enhanced diffusions were carried out and results show that SC conductance and transdermal flux seems no temporal correspondence, but they have inherent connection in quantitative change, little SC conductance variation went with large transdermal flux variation, the proportion of their variation slope was relatively invariable as to the same pattern substance.
3. Time variant property of substance transport through SC. The popular method that statistically averaging transdermal fluxes has large mean square deviation, because the time varying property of TDD and the individual difference of SC samples are ignored. Using mathematic method we established a phenomenological model based on transdermal flux data of insulin experiment, time variant property and the maximum flux of TDD are described by parameters of the phenomenological model.
经皮给药是将药物贴敷在皮肤外表面，依靠被动扩散或促进扩散使药物通过皮肤进入皮下毛细血管。由于皮肤角质层的屏障作用，大分子的生物制剂难以靠被动扩散进入，需要借助物理或化学的辅助方法，如离子导入、电穿孔导入、超声导入、电磁导入、光压波导入、化学促渗剂等，此即所谓促进扩散。
在经皮给药系统中，物质转运是一个不可逆非平衡态热力学过程，其渗透率与外力场、皮肤特性、物质理化性质等因素有很大关系。本文在物质通过皮肤角质层转运的生物物理现象研究中，取得了以下三个方面的成果：
1．物质经皮转运的热力学分析。将流动扩散池系统看成由扩散池子系统和漏槽子系统组成，分别对两个子系统列出熵平衡方程，两个子系统通过共有部分供应室联系，并且整个流动扩散池系统中物质不灭，从而得到流动扩散池系统的熵平衡方程，确定系统中扩散流及其推动力之间的唯象关系。以胰岛素、FD-4和FD-20为模式物质，指数衰减电脉冲为促进扩散的外力场，通过漏槽实验得到：(1)唯象系数较小，说明系统中的力和流满足线性唯象关系假设；(2)唯象系数具有可变性，随不同的模式物质、实验角质层样本和取样时间而改变；(3)研究脉冲协议、角质层样本和模式物质对电场力的单因素影响，脉冲协议(主要能量、电压)影响电场力的大小，角质层样本特性影响电场力的变化趋势，模式物质对电场力的大小和变化趋势都有影响。
2．脉冲电场物质经皮转运率和皮肤电导的影响。物质经皮转运率可以作为电脉冲促进物质经皮转运作用的评价指标，角质层电导反映出电脉冲作用下皮肤结构的变化状况。以胰岛素和FD-4作为模式物质，分别进行15和12种脉冲协议的促进扩散，结果表明：角质层电导和物质经皮转运率的变化在时间上并非对应，但在数值的大小方面有内在的联系，较小的电导变化伴随同向的较大的经皮转运率变化，并且对同一模式物质，两者的变化斜率之比较为恒定。
3．物质经皮转运的时变特性。目前检测物质经皮转运率广泛采用求统计平均值的方法，但此法存在很大的均方差，其原因在于忽略了经皮转运的时变性和每个实验个体的差异。我们用胰岛素经皮转运的实验数据和数学模型建立一种描述药物经皮转运的唯象模型，用唯象模型的参数描述药物经皮通透率的时变性和最大转运率。
Recent advances in biotechnology have resulted in a significant increase in the number of therapeutic macromolecules such as peptides, proteins, oligonucleotides and so on. Difficulty of drug delivery prevents these bioactive macromolecules from popular clinical application. For oral use they will be degraded in the liver and gastrointestinal tract, while for injection it is difficult to maintain blood concentration of the drug and patients will suffer inconvenience and pain because of frequently injection. Transdermal drug delivery (TDD) is an alternative method of drug delivery that draws attention as a potential administration of biological pharmacy.
TDD is the method that patching the drug on the skin, the drug molecules permeating through the skin into the subcutaneous capillary vessels by passive diffusion and enhanced diffusion. Very few drugs can be administered transdermally by passive diffusion due to the barrier of stratum corneum (SC), the skin's outer layer. Several physical and chemical methods, including iontophoresis, electroporation, sonophoresis, magnetophoresis, photomechanical wave and chemical enhancers, are applied to improve the permeability of skin, which is called the enhanced diffusion.
In TDD system, substance transport is an irreversible and non-equilibrium thermodynamical process whose penetration is in great relation to the outside force field, skin specialty, physical and chemical properties of drug, etc. Three achievements have been obtained in our study on biophysical phenomena of substance transport through SC, including below:
1. Thermodynamic analysis of substance transport through SC. Considering the diffusion cell system consists of the diffusion cell subsystem and the sink subsystem, the subsystems associated with each other by the receptor which is their mutual part, and the whole diffusion cell system is matter conservation, we derived the entropy equilibrium equation of the diffusion cell system, determined the phenomenological relationship between the diffusion flow and its driving force. Insulin, FD-4 and FD-20 as pattern substances, exponentially decaying electric pulses as the outside force field enhancing diffusion, leakage experiments resulted in: (1) the phenomenological coefficient is small, which proves the hypothesis of linear phenomenological relationship between the flow and force in the system; (2) the phenomenological coefficient varies with pattern substances, SC samples and sampling time; (3) one-factor influence of pulse protocol, SC sample and pattern substance on electric field force is that, pulse protocol (energy, voltage) affects the quantity of electric field force, characteristics of SC sample affect variation of electric field force, while pattern substance effect on both of the quantity and variation of electric field force.
2. Connection between transdermal flux and conductance of SC in electric field enhanced diffusion. Transdermal flux is the index of electric pulses acting on TDD, while SC conductance reflects the variation of skin structure under electric field. Insulin and FD-4 as pattern substances, whose pulse protocols are 15 and 12 types respectively, electric field enhanced diffusions were carried out and results show that SC conductance and transdermal flux seems no temporal correspondence, but they have inherent connection in quantitative change, little SC conductance variation went with large transdermal flux variation, the proportion of their variation slope was relatively invariable as to the same pattern substance.
3. Time variant property of substance transport through SC. The popular method that statistically averaging transdermal fluxes has large mean square deviation, because the time varying property of TDD and the individual difference of SC samples are ignored. Using mathematic method we established a phenomenological model based on transdermal flux data of insulin experiment, time variant property and the maximum flux of TDD are described by parameters of the phenomenological model.
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