| Electret is a functional dielectric material that can keep space charge and/or dipole charge for a long time.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,and control bacteria growth.Our previous studies also indicated that electret could modify the ultrastructure of skin and enhance drug transdermal delivery.In this study,we chose meloxicam as model drug and polypropylene(PP) as electret material(storage layer of charge) to prepare the electret patches by method of pharmaceutics and constant voltage corona charging.The charge storage stability of the patch was systemically studied.Then using SD rat as animal model,the HPLC method was established for determination of the concentration of meloxicam in blood and skin after application of negative electret meloxicam patch,control patch(no surface potential and no chemical enhancer) and chemical enhancer containing meloxicam patch(no surface potentia) in vivo.The enhancing effect of electret on meloxicam transdrmal delivery were studied. Besides,the synergistic effect between electret and chemical enhancer was also studied.In this study,the micrographic and ultrastructure of skin were examined by using optical microscope,scanning electron microscopy and transmission electron microscopy for further explanation of the enhancing mechanism of electret on drug transdermal delivery. Furthermore,in order to explain the enhancing mechanism in drug metabolic terms,the variation of SD rat blood viscosity treated with electret was determined by cone- panel viscosimeter.The results indicated that 1) The surface potential decreased exponentially for negative PP electret,negative electret meloxicam patch and chemical enhancer containing negative electret meloxicam patch.When storage layer charged at -600V and -1200V,the surface potential of negative PP electret,negative electret meloxicam patch and chemical enhancer containing negative electret meloxicam patch could keep above 80%of their initial value in 24 hours,respectively,suggesting a better charge storage stability for all the electrets studied here.The same results were confirmed by thermally stimulated discharge(TSD) current experiment.2) The charge loss during compositing of charging surface of PP electret with the patch backing layer,the compensation effect of matrix and ionic drug to surface potential on charging surface,and the influence of patch thickness,resulted in lower surface potential for the above two electret meloxicam patches than that of the PP electret.The surface potential in 4 days was ranged as follows:PP electret＞electret meloxicam patch＞chemical enhancer containing electret meloxicam patch.Negative PP electret could be used to prepare the transdermal formulation and as an excellent enhancer to improve the drug transdermal delivery.3) A simple and sensitive HPLC method was established to examine the meloxicam concentration in blood.The retaining time was 3.4min.When the blood concentration of meloxicam was ranged at 0.05-10μg/ml,the regression equation of blood concentration of meloxicam to peak area was C=0.01444A+0.01072(r=0.99986,P＞0001).The accuracy was around 94.27%-99.48%,precision in 24h was lower than 3.68%,precision between days was around 6.75%-12.80%and the recovery rate of meloxicam was 75%-82%,satisfying the requirement for drug analysis in vivo.Besides,the HPLC method for determination of meloxicam in skin was also established.When the blood concentration of meloxicam was ranged at 0.25-10μg/ml,the regression equation of skin concentration of meloxicam to peak area was C=0.01192A-0.01048(r=0.99994,P＜0001).The accuracy was around 95.65%-101.65%,precision in 24h was lower than 7.19%,precision between days was lower than 5.50%and the recovery rate of meloxicam was larger than 76.88%.4) After applied to skin for 4 hours,-1200V electret meloxicam patch had a higher meloxicam amount both remaining in skin and permeated through skin than that of the control group because of the initiative and passive release of negative polar drug and the influence of electret in skin structure.With the increasing of application time,electret enlarged the venule calibre,reduced the peripheral vascular resistance of microcirculation,which resulted in the increase of blood through microcirculation,improving of microcirculation,increasing of metabolism of meloxicam in system.Therefore,the concentration of meloxicam in blood and skin of electret group was lower than that of control group.Since meloxicam had a longer half life and electret resulted in more transdermal delivery of meloxicam,the recirculation of drug after 10 hours led to a higher blood and skin concentration than that of control group and the tendency of double peak appearance.Both the -600V and -1200V electret meloxicam patches exhibited the same change tendency for skin remaining content and permeated amount of meloxicam during the time interval of study.However,the enhancing effect of-1200V electret meloxicam patch was better as compared with -600V electret meloxicam patch.5) During the time interval of study, the blood concentration of meloxicam for chemical enhancer containing meloxicam patch was higher than that of the patch containing no chemical enhancer,suggesting a better enhancing effect of ethyl oleate on meloxicam transdermal delivery.Also meloxicam concentration for chemical enhancer containing meloxicam patch was higher than that of the negative electret meloxicam patch containing chemical enhancer.We deduced that was because metabolism of meloxicam in SD for the negative electret meloxicam patch containing chemical enhancer was increased in vivo.Besides,the synergistic effect between -1200V electret and 10%ethyl oleate wasn't found during the process of experiment,maybe that was occasioned by the saturated pathway for enhancing drug percutaneous absorption of -1200V electret and 10% ethyl oleate.6) The skin morphological study indicated that by providing stable electrostatic field negative electret meloxicam patch could loosen and separate the lipid arrangement of stratum corneum,and so on,which resulted in the weakening of skin barrier function and increasing of drug permeability.7)Electret didn't change the blood viscosity of SD rat,while it enlarged the venule caliber and increase the blood amount through microcirculation.In hemodynamics,the peripheral vascular resistance was directly proportional to blood viscosity and length of capillary,while inversely proportional to the third power of venule caliber. Therefor,the invariability of blood viscosity and the increase of blood flow facilitated the metabolism of meloxican during the same period.Negative PP electret and electret meloxicam patch not only showed better charge storage stability,but also could improve the ultrastructure of skin and therefore enhance the meloxicam transdermal delivery.In conclusion,electret could be a novel enhancer used in transdermal formulation study.The study was supported by Nature Science Foundation of China(50577066) and the "Eleven-Five-Year" International Collaboration Projict of PLA(06H022).
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