| Transdermal drug delivery system (TTDS) is a new formulation which treats or prevents diseases by the skin administration. TTDS can maintain drug blood level, avoid hepatic first-pass elimination, decrease side effects, and extend drug effective time, facilitate and enhance long-term treatment of patients with compliance. However, there are only limited number of chemicals, which have low molecular weight (<500), low melting point (<200℃), low-dose (≤20mg·d-1) and high lipophilicity (log P = 1～3), are suitable for TDDS due to the barrier function of the outmost layer of the skin.Meloxicam is a small molecule and lipophilic drug with the molecular weight of 351.41 and LogP=1.01. Its daily dose is less than 10mg and melting point, determined in our experiment, is 247.1℃.As a whole, meloxicam is suitable for TDDS.However, it is difficult for some drug to achieve therapeutic effect because of physiological barrier function of the stratum corneum. Therefore, it is of much importance to overcome barrier effect of skin and to promote penetration amount of drugs within a certain period of time.Some strategies, consisting of chemical and physical enhancers, have been investigated and developed in order to overcome the barrier properties of the skin and thus enhance drug transdermal absorption. Penetration enhancers, such as Azone, ethyl oleate, menthol, propylene glycol, dimethyl sulfoxidend are commonly used. On the other hand, iontophoresis is an enhancement technique that improves transdermal drug transport through the application of a low-level electric current.Eelectret is the electrostatic equivalent of a permanent magnet and can generate internal and external electric fields. Our previous studies indicated that electret can improve the circulation of blood, enhance the wound healing, regulate the cell growth and apoptosis, modify the electret state of skin, and enhance the transdermal drug delivery.The primary aim of this paper was to characterize enhancing effect of electret on the maloxicam transdermal absorption through rat skin as compared with chemical enhancers, to understand in detail the possible mechanisms by which electret enhances molecular transport across the skin, to investigate the possible synergic effect of the application of chemical enhancers and electret, to prepare a meloxicam electret patch formulation and to study its pharmacodynamics for inflammation and pain.The solubilities of meloxicam in octanol or phosphrte buffer solution (PBS) with different pH were determined by UV method and the partition coefficient was calculated accordingly. The results showed that (1) The octanol-water partition coefficient of meloxicam logP was 0.97 which is similar to the reported value. (2) The solubility of meloxicam increased with the increasing of pH of the buffer solution. The in vitro permeation study indicated that (1) 1%, 3% and 5% azones show a 1.18, 1.33, 1.26 times increase of the cumulated permeation amount of meloxiam in 10h as compared with that of in control group(p<0.05).The enhancing effect was ranged in following order: 3% azone >5% azone >1% azone; (2) Most of the chemical enhancers used in this study were shown to have enhancing effects except for 20% propylene glycol. Among them, 10% ethyl oleate was proved to be the most effective one, showing a 1.86 times increase of the cumulated permeation amount of meloxiam in 10h as compared with that of in control group(p<0.05); (3) Negative electret was more effective than the chemical enhancers used in this study in meloxicam trasdermal delivery, showing a 2.16 times increase of the cumulated permeation amount of meloxiam in 10h as compared with that of in control group(p<0.05); (4) Electret can improve the enhacing effect of chemical enhancers in this study. The cumulated permeation amount of meloxicam for chemical enhancer with electret patchs in 10h were 1.14 to 2.89 times that of the meloxicam patchs with chemical enhancers only(p<0.05); (5) The cumulated permeation amounts of meloxicam for 10% ethyl oleate with negative electret patch was the largest in all of the patchs, showing a 4.53 times increase as compard with that of in control group ( p<0.01). In order to explain and explore the electret enhancing mechanism, electron microscopy specimen was used to observe the rat skin's ultrastructural change and confocal laser scanning microscopy (CLSM) was used to study the mechanisms of drug skin permeation enhancement after the rats skin was treated with electret for 2h. The studies revealed that the enhancing effect of electret on meloxicam transdermal delivery was not only through changing the structure of the stratum corneum cells to achieve, but also to a large extent through broadening the hair follicle to obtain.Based on the above findings, we prepared meloxicam patch combining 10% ethyl oleate with negative electret. The effects of the plasticizer and drug content on adhension of the patches were observed. The study showed that the more the content of plasticizer, the stronger the tack of the patch was, but the waker the cohesion of the patch was. The effect of meloxicam was opposite to plasticizer. Optimal formulation was achieved by orthogonal experiment on considering the factors of cohesion of the patch and cumulated released amount of meloxicam from the patch. The methodology for determination the quality of electret meloxicam patch was studied. The results showed that electret meloxicam patch was of uniform thickness, moderate adhension. The releasing rate, stability, toxicity and irritability studies indicated that electret meloxicam patch was a safe, nontocix and non irritant formulation.In addition, the mice retortion pain models induced by acetic acid and mice auriculate tumefaction models caused by xylene were established in the paper. The results showed that the inhibitory ratio of retortion of mice induced by acetic acid in electret meloxicam patch was 63.30% (p<0.01), which was higher than that in meloxicam patch (55.85%) and oral meloxicam suspension (54.25%). the inhibitory ratio of auriculate tumefaction of mice caused by xylene in electret meloxicam patch was 34.20% (p<0.05), which was also higher than that in meloxicam patch (22.14%) and oral meloxicam suspension (24.60% ).In this paper, the electret meloxicam patch combined both the physical and chemical enhacing methods. Electret demonstrated its unique effect as a new, non-toxic, safe physical method in this paper. The studies proved that electret could be used as excellent enhancer in transdermal permeation of meloxicam. Meanwhile, electret meloxicam patch was a kind of multiple effective anti-inflammatory analgesic patch, which integrated chemical and physical treatment into a one. It took advantage of the pharmacological effects of meloxicam and characteristics of electret which can adjust skin in biological electret state and weakened pain caused by injure and improved the effect of the analgesic drug.
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