| 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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