| Electret is a functional dielectric material that can keep space charge and/or dipole charge for a long time. Electret, prepared by means of corona charge, plasma charging, thermal poling and electron beam charging, 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. Transdermal drug delivery system (TDDS) refers to the system that delivery drug in a controlled pattern to the blood system by skin route. It provides several advantages over the conventional dosage forms, such as reducing the gastrointestinal side effect and first-pass metabolism, steady blood level profile, better patient compliance and easy termination of drug. Electret technique originated from our previous study is a physical strategy to enhance the drug transdermal delivery. The electric field and microcurrent produced by electret could result in the structural change of the stratum corneum (SC) and form transient permeable pore for drug to penetrate through the skin. Electret could be a new physical strategy to be used to enhance drug transdermal delivery.In this study, (1) Using SD rats as animal model, the HPLC method was established for determination of the concentration of meloxicam in plasma and liver after application of negative electret meloxicam patch and control patch (no surface potential) in vivo. The enhancing effects of electret on meloxicam transdrmal delivery were studied. (2) The biological safety of electret meloxicam patch was studied. Using ALC-2000 MPA Multi-channel bio-signal analysis system, the breathing rate, blood pressure and electrocardiogram (ECG) of the rats were recorded during 12 hours'application of the patch. (3)The ultrastructural changes of liver, kidney and cardiac muscle tissues of the rats were examined using transmission electron microscope (TEM) after application of negative electret meloxicam patch and control patch in vivo to study the bio-safety of electret meloxicam patch. (4) The animal experiments of skin irritation and allergy were carried out to further verify the medical bio-security of the electret meloxicam patch from a toxicological point of view.The results indicated that (1) A simple and sensitive HPLC method was established to examine the meloxicam concentration in plasma and liver tissue. The retention time of meloxicam and internal standard, piroxicam, was around 8.0 and 10.5 min, respectively and the theoretical plate number was both greater than 4000. No endogenous interference and metabolic product were found at the retention time of meloxicam and the internal standard. When the plasma concentration of meloxicam was ranged from 0.05～5 g/ml, a equation of the standard curve y=1.6581c+0.0720 (R~2=0.9956) was established, where y was the peak area ratio of meloxicam to internal standard and c was the plasma concentration of meloxicam. The accuracy was around 96.1%～101.6%, the intra-day and inter-day precisions were respectively lower than 2.30% and 3.20%, and the recovery rate of meloxicam ranged from 66.1%～73.5%. Besides, the HPLC method for determination of meloxicam in liver tissue was also established. When the liver tissue concentration of meloxicam was ranged from 0.10～4.00μg/g, the equation of the curve was y=0.9423c-0.0540 (R~2=0.9978), where y was the peak area ratio of meloxicam tointernal standard and c was the liver concentration of meloxicam. The accuracy was around 99.2%～99.6%,the intra-day and inter-day precisions were respectively lower than 3.50% and 4.30%, and the recovery rate of meloxicam ranged from 67.0%～74.6%. Both of the HPLC method established here satisfied the requirement for drug analysis in vivo. (2) The results of meloxicam transdermal experiments in vivo indicated that the enhancing effect was related to its surface potential. After transdermal application in 24 hours, the meloxicam plasma concentration as well as liver tissue concentration of -1200V electret meloxicam patch group was significantly larger than that of the control group (meloxicam patch group), suggesting that -1200V electret had significant enhancing effect on the meloxicam transdermal absorption considering both therapeutic level (plasma concentration) and metabolism level (liver concentration). (3) After application of negative electret meloxicam patch in 12 hours, the respiratory waveform, ECG and blood pressure waveform of carotid artery of rats were normal and there were no significant differences in breathing rate, blood pressure and ECG targets among control group, meloxicam patch group and electret meloxicam patch group. The result also indicated that the negative electret could improve not only blood circulation but also cardiac function of rats. (4) In transmission electron microscope (TEM) experiment, we found that tissue structure of control group and electre meloxicam patch group were all normal and no pathological changes at all by observing the ultrastructure of cardiac muscle, liver and kidney tissue of rats after application of negative electret meloxicam patch in 8 hours. These results indicated that electret meloxicam patch has no any adverse impacts on the ultrastructure and physiological function of cardiac muscle, liver and kidney tissue of rats. (5) The results of skin irritation and allergic experiments showed that electret meloxicam patch did not bring any irritating and allergenic to the skin of New Zealand rabbits. Together with the results of electrophysiology, TEM experiments and skin irritation and allergic experiments, we reached a conclusion that negative electret meloxicam patch had biological safety.Both PP electret and electret meloxicam patch showed better biological safety. What's more, negative electret showed significant enhancing effect on the meloxicam transdermal absorption. In conclusion, electret meloxicam patch could be a novel pharmaceutical formulation used in clinical therapy.The study was supported by Nature Science Foundation of China(50577066, 2006~2008; 50977089,2010~2012)and the"Eleven-Five-Year"International Collaboration Projict of PLA(06H022). |
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