Preparation Of Electret Lidocaine Patch And The Comparative Study Of Electret Patch Containing Different Polar Drug

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. However, some pharmacologically effective chemicals, such as ionic chemicals, hydrophilic chemicals and macromolecular chemicals are not suitable for TDDS due to the natural barrier function of the skin. Although, recently many methodologies have been investigated and developed, including the use of chemical enhancers, novel vehicle systems and physical enhancement (iontophoresis, electroporation, ultrasound, microneedle, photomechanical waves, and so on) which makes it possible for those said chemicals to be delivery transdermally, exploring of new methodology to overcome skin barrier function and enhance the drug transdermal delivery still have attracted considerable interest by the researchers.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 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. For example, the charge storage life of negative corona charged porous polytetrafluoraethylene (PTFE) electret could be more than 105 years. Using electret to enhancing the drug transdermal deliver began in 1995. As an electric active functional material, electret could provide electrostatic field and micro-current, modify the electret state and electric structure of skin, regulate kinetics of percutaneous absorption of ionic or no-ionic drugs and enhance drug transdermal delivery. The possible enhancing mechanisms of electret on drug transdermal delivery are including (1) disengagement of epidermal cells, 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 high potential electrostatic effect and micro-current could work as an external physical factor to effectively regulate cell apoptosis and improve blood circulation, which are beneficial to drug metabolism in vivo. Lidocaine hydrochloride, C14H22ON2·HCl·H2O, a moderate local anesthetics, is frequently used as a model drug in study of tansdermal drug delivery system. In order to study 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, we use lidocaine as model drug, polypropylene (PP) as electret material to prepare the electret and electret patch by means of corona charging and pharmaceutical methodology. The charge storage stability of the electret and electret patch were studied by electret experimental technology. The enhancing effects of chemical enhancers and electret on lidocaine transdermal delivery were studied by means of in vitro percutaneous experiment. The optimal electret lidocaine transdermal patch formulation was achieved by orthogonal experiment. Besides, influence of surface potential of electret in transdermal delivery enhancement of drugs with different properties was compared.By using PP as electret and patch backing materials, pressure sensitive adhesive (PSA) patch, lidocaine patch and chemical enhancer containing lidocaine patch were prepared. By means of corona charging at room temperature, PP film and the above said patches were made into PP electret, PSA electret patch, electret lidocaine patch and chemical enhancer containing electret lidocaine patch. By means of isothermal surface potential decay measurement, influence of composition of the electret patch and charging potential in charge storage stability of the above said electret or electret patches were studied. The results indicated that 1) PP electret exhibited excellent charge storage stability no matter which side the effective surface potential measured; 2) The effective surface potential (on charging surface or backing surface) of PP electret and said electret patches decayed exponentially. 3) PP electret and said electret patch had better charge storage stability. Among them, negatively corona charged electret patch had better charge storage ability than that of positively corona charged electret patch. 4) Although the effective surface potential of backing electrode of electret patch was lower than charging voltage (keeping 80% of charging voltage), it still showed better charge storage stability.The in vitro permeation study was carried out using Franz diffusion cells. On basis of the comparative study of effect of positive/negative electret and chemical enhancers on lidocaine transdermal delivery enhancement, the synegestic effect of electret and chemical enhancer on the lidocaine transdermal delivery enhancement was also studied. The results indicated that 1) 1% Azone, 3% Azone, 5% Azone, 10% ethyl oleate and 1% menthol containing lidocaine patch could enhance cumulated percutaneous amount of lidocaine in 10 hours by times of 1.052, 1.123, 1.664, 1.528 and 1.465 (P<0.05), respectively as compared with lidocaine patch. The enhancing effect was ranged in following order: 5% Azone > 10% ethyl oleate > 1% menthol > 3% Azone > 1% Azone. 2) After 10h's application of negative or positive electret on rat skin, positive electret lidocaine patch exhibited a significant increase of cumulated percutaneous amount of lidocaine as compared with lidocaine patch (1.823 time, P<0.05), exceeded to the enhancing effect of all the chemical enhancers studied. However, negative electret lidocaine patch showed no significant enhancement on lidocaine cumulated percutaneous amount as compared with the effect of chemical enhancers. 3) Positive electret and chemical enhancer had a better synegestic effect on lidocaine transdermal delivery enhancement. The most significant enhancing effect was displayed when positive electret combined with 5% Azone. The enhancing ratios were 1.787 (P<0.05) and 2.974 (P<0.05) as compared with 5% Azone lidocaine patch and lidocaine patch.Based on the above findings, we prepared positive electret lidocaine patch using acrylic adhesive as matrix, 5%Azone as chemical enhancer. The effects of plasticizer and cross-linking agent on adhesion were observed. The results indicated that with the increasing of plasticizer content, tack of the patch increased, but decreased the cohesion. On the other hand, with the increasing of cross-linking agent, tack of the patch decreased, but cohesion of the patch increased first and then decreased. In order to decide the patch formulation, we used tack and cohesion as evaluation index to optimize the formulation by means of orthogonal experiment. The quality, release and transdermal behaviour of the patch were studied. The releasing experiment indicated 85% release of lidocaine in 5 hours. The release behaviour of lidocaine from the patch obeyed Higuchi equation. The in vitro rat skin permeation behaviour of lidocaine obeyed zero order pharmacokinetic equation. The static permeation rate was 51.77μg/cm2?h. Under the constant humidity and temperature, patch showed constant surface potential and drug content, appropriate adhesion, no toxic and no irritation to skin. Therefore, electret lidocaine patch was a safe and effective formulation.In order to observe the influence of charging voltage and drug property in the effect of electret transdermal patch on drug percutaneous enhancement, the in vitro skin permeation studies of electret lidocaine patch containing chemical enhancer or not and electret meloxicam patch containing chemical enhancer were proceeded. The results indicated that 1)On combination of different surface potential electret and chemical enhancer (10% ethyl oleate), cumulated percutaneous amount of meloxicam could be ranged from 2.648 to 4.498 (P<0.05) and 1.828 to 3.064 (P<0.05) as compared with meloxicam patch and 10% ethyl oleate meloxicam patch, respectively. The enhancing effect of different potential on meloxicam skin permeation was ranged in following order: -800V>-1000V>-600V>-400V>-200V>+1000V. The synegestic effect of negative electret with chemical enhancer increased with the increase of electret surface potential. 2) On combination of different surface potential electret and chemical enhancer (5% Azone), cumulated percutaneous amount of lidocaine ranged from 1.614 to 2.592 (P<0.05) and 1.058 to 1.700 (P<0.05) as compared with lidocaine patch and 5% Azone lidocaine patch, respectively. The enhancing effect of different potential on lidocaine skin permeation was ranged in following order: +1000V>+800V>+600V>+200V>+400V>-1000V. The synegestic effect of positive electret with chemical enhancer increased with the increase of electret surface potential. 3) The enhancing effect of electret on drug transdermal delivery was not only related to the polar property of electret, but also to drug property.The electret lidocaine patch prepared in this paper combined both chemical and physical enhancer strategies. As a novel, safe and nontoxic physical enhancing method, electret exhibited unique ability in drug transdermal enhancement and could be used as an enhancer in the study of trnasdermal drug delivery system.