| Electret is a functional dielectric material that can keep space charge and dipole charge for a long time. Electret, prepared by means of corona charge, plasma charge, thermal poling or electron beam charge, could keep large amount of space charge or polar charge (holding effective surface potential larger than thousands of voltage). If stored properly, electret had much better charge storage stability. For example, the charge storage life of negative corona charged porous polytetrafluoraethylene (PTFE) electret could be more than 105 years.Due to the property of providing electrostatic effect and microcurrent, electret could effectively regulate the electret state of biological tissue and macromolecule, enhance the wound healing, accelerate the nerve regeneration, improve hemorheology, regulate cell growth and cell apoptosis, control bacteria growth, modify the electret state and electric structure of skin, regulate kinetics of transdermal absorption of ionic or no-ionic drugs and enhance drug transdermal delivery. The possible enhancing mechanisms of electret on drug transdermal delivery include (1) disengagement of epidermal cells and formation of transient permeable holes; (2) micro-current produced from the potential difference between electret and skin, therefore to enhance the permeation and diffusion of ionic drug through skin. Besides, the electrostatic effect and micro-current of the electret could work as an external physical factor to effectively regulate cell apoptosis and improve blood circulation, which are beneficial to drug metabolism in vivo.Our previous study indicated that electret could improve transdermal absorption of drug for ionic or non ionic drug, especially for ionic drug. In order to improve the enhancing effect of electret on transdermal delivery, the most important problem is to keep a better charge storage stability and to effectively regulate the electrostatic effect and microcurrent effect during the process of transdermal drug delivery. Also to clearly explain the mechanism of electret on transdermal drug delivery enhancement is of great significance in novel TDDS study. However, there are some problems to be considered, for example, electret transdermal formulation, high humidity of the skin surface, mechanism of electret on transdermal drug delivery.In order to systemically study the influence factors of thickness, drug content, chemical enhancer content and surface potential etc in charge storage stability of electret, the enhancing effect of electret and electret patch on drug transdermal delivery systemically, explore the relationship between enhancing effect and drug property or electret surface potential, explain the enhancing mechanism of electret on transdermal drug delivery and provide fundament of theory and experiment for preparation of new electret transdermal formulation, (1) we use meloxicam as model drug, polypropylene (PP) as electret material ethyl oleate as chemical enhancer to prepare PP electret, meloxicam patch and chemical enhancer containing meloxicam patch by means of corona charging and pharmaceutical methodology. Then PP patch work as charge storage layer was covered to the meloxicam patch and chemical enhancer containing meloxicam patch respectively to prepare the electret meloxicam patch and chemical enhancer containing electret meloxicam patch. The influences effect of PP film, grid voltage, pressure sensitive adhesive (PSA) thickness, chemical enhancer content, meloxicam content on charge storage stabilities were studied. (2) Using meloxicam as model drug, PP as electret material, electret meloxicam patch of different grid voltage were prepared by the same method as mentioned above to study the relationship between transport pattern of drug in skin and surface potential of the electret, the charge storage stability under different application condition, the drug contents in stratum corneum as well as stratum corneum stripped skin and surface charge decay after in vivo and in vitro transdermal administration of electret meloxicam patches. The correlation between in vitro and in vivo experiment results was also studied. The results were as follows.(1) The surface charge decay of PP electret which kept under room temperature (RT) was exponentially and exhibited excellent charge storage stability no mater the surface potential was measured from charging face or back electrode. When the charging face of PP electret was covered by PP film, although the contact effect and interface effect accelerated the rate of surface charge decay, the charge loss was similar to the result when PP electret was kept under RT and normal humidity environment, indicating that negative charged PP electret had excellent charge storage stability and environment resistance.The charge storage stability study for negative PP electret charged at different grid voltage indicated that the higher the surface potential, the more the absolute surface potential decay was, but could still hold higher effective surface potential than that of the electret with lower initial surface potential. The same result was confirmed by TSD experiment. The study also indicated that double naked electret had better charge storage stability than aluminium coated electret.(2) The charge storage stability of PSA PP patch was varied with the thickness of the PSA. The thicker the PSA, the more the surface potential decay was. However, the thickness of the PSA would not play an important role in practice.The study also indicated that meloxicam patch had better charge storage stability than that of PSA patch due to its lower compensation effect of positive ion and negative ion in PSA and meloxicam respectively. Besides, the contents of meloxicam and chemical enhancer also showed no significant effect on electret charge storage stability.(3) Under the in vitro and in vivo experiment condition, moisture, electrolyte, and biomelocules resulted from skin metabolism after close attachment of electret patch to skin would dissociate and polarize to result in the effective surface charge decay because of the compensation effect of these dipole molecules and ions. Therefore, the surface charge decay of -1200V and -2000V electret meloxicam patches was larger than that of the electret meloxicam patch kept under room temperature (RT). However, the -1200V and -2000V electret meloxicam patches could still hold 50%~65% of initial surface potential after in vitro and in vivo experiment, indicating that the application condition had no influence in charge storage stability of the electret and electret patch could be used to enhance transdermal drug delivery both in vitro and in vivo.(4) The in vivo experiment results indicated that electret surface potential had biological window effect on drug transdermal delivery. The drug contents in both stratum corneum and stratum corneum stripped skin were determined after application of -800V, -1200V, -1600V and -2000V electret meloxicam patches respectively. -1200V electret could be more durable to open the stratum corneum structure, form tiny easy-to-permeable pore, increase the mobility of lipid, make drug rapidly delivery into the stratum corneum, and then through the stratum corneum into the dermal, and finally via the capillaries into the systemic circulation, resulting in not only similar drug content variation pattern in stratum corneum and stratun corneum stripped skin but also less drug accumulation in skin. The highest concentrations of meloxicam in serum and liver were also observed by one member of our research group after transdermal application of the electret meloxicam patches with the surface potential ranged from -800V to -2000V. Due to the higher surface potential and charge density, -2000V electret patch could open the stratum corneum structure transiently so that a large number of meloxicam diffused into the stratum corneum. But this skin structure change is short-lived and reversible. Therefore, -1200V electret could greatly propel the drug to skin and system circulation for the small resistance of the stratum corneum. -2000V electret could greatly accelerate the permeation of drug to stratum corneum with the highest velocity and permeation amount.The in vitro experiment results also indicated that -1200V electret had more effective influence in stratum cornem structure than that of -2000V electret.(5) The in vitro drug content in stratum corneum stripped skin had less accumulation as compared with the result observed in vivo because of the improved microcirculation by -1200V electret in vivo to carry more drugs into the system circulation via disrupted stratum corneum, active epidermis and dermis.Due to the short-lived effect of -2000V electret on skin structure, the drug content variation patterns both in stratum cornem and stratum corneum stripped skin were almost the same as control group but with the higher skin contents than that of the control group, indicating that -2000V electret could enhance the skin permeation to play a role in local treatment.(6) Another interesting biological window effect of onset time of electret on drug transdermal permeation was also observed. After one hour's administration of the -1200V and -2000V electret meloxicam patches, the drug contents in stratum corneum and stratum corneum stripped skin were almost the same as that of control group. Then all of them varied differently. The same phenomena was observed in vitro experiment but only with one hour's postpone which can be explained by the effect of electret on microcirculation improvement and skin structure disruption.(7) -1200V electret could be effectively to play a role in systemic treatment, while -2000V electret could be effectively to play a role in local treatment.In conclusion, electret transdermal formulation is of the characteristics of simple manufacturing, easy to use and biological safety. Electret can be used as an exogenous physical factor to not only enhance the system absorption of drug transdermally, but also enhance the skin absorption of the drug locally.The study was supported by Nature Science Foundation of China (50577066, 50977089) and the"Eleven-Five-Year"International Collaboration Project of PLA (06H022). |
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