Study Of Controlled Release Patch Of Ligustrazine Ethosomes

Backgrounds:Ligustrazine is a primary active alkaloid of Chinese medicine Szechwan Lovage Rhizome, which has many pharmacological actions such as protecting myocardium cells, broadening coronary artery, inhibiting platelet adhesion and aggregation, inhibiting thrombosis, anti-atherosclerosis and removing oxygen-derived free radicals etc, and using for coronary heart disease in clinic. Nanoliposomes as a drug carrier, has many good properties such as degradation in vivo, avirulent, non-immunogenicity, ability to encapsulate drug of water solubility and liposolubility, protecting encapsulated drug, reduce drug dosage and active targeting after modification. And ethosomes, novel liposomes, has better deformability, more advantage to through epidermis barrier into deeper layer of skin, and better permeability.Objective:This study is to prepare Ligustrazine ethosomes for coronary heart disease with good permeability by optimizing different formulations and technology parameters, to prepare controlled release delivery system of Ligustrazine ethosomes dermal patch with stable formulations, better encapsulating efficient, release rate and permeability, and to research novel preparation methods of transdermal drug delivery system for Chinese medicine.Methods:Encapsulating efficiency as index, the effect of phospholipids concentration, ethanol content, sonication time and flexible adjuvants dosage on Ligustrazine ethosomes during preparation was studied. The preparation technology and formulations was optimized. The patch formulations was optimized by orthogonal design which used acrylic resin as major composition, in addition to succinic acid as crosslinking agent and triethyl citrate as plasticizer. Transdermal experiment and release rate in vitro of The Ligustrazine ethosomes patch was detected by high-performance liquid chromatography (HPLC). The drug concentration-time curve was detected for group A (intragastric administration for rats), group B (transdermal delivery of Ligustrazine ethosomes) and group C (common transdermal delivery), and the pharmacokinetics characteristics and relative bioavailability of Ligustrazine ethosomes on rats was analyzed by pharmacokinetics software 3p97. The protection effect of Ligustrazine ethosomes patch for ischemia myocardium and reperfusion injury after ischemia myocardium was observed.Results:The best formulations for Ligustrazine ethosomes were 10 g/L phospholipids concentration,45%(v/v) ethanol content and 5 min sonication time, and Ligustrazine ethosomes prepared according to this formulations was with uniform size distribution, mean size (78.71±1.23) nm, mean encapsulating efficiency (86.42±1.50)%. The best formulations of Ligustrazine ethosomes patch were 0.4 g acrylic resin,0.23 g succinic acid and 0.054 g triethyl citrate,10% Ligustrazine ethosomes and 5% azone. The 24h drug accumulation permeation quantity of the Ligustrazine ethosomes patch was 183±18μg-cm-2, the release profile in vitro was in line with Higuchi formulation, and it had significant controlled release effect in 24h. AUC value on heart of group B was2.52 times of that of group A, AUC value on liver of group B was 1.57 times of that of group A, and the relative bioavailability was 209.45%. This revealed that Ligustrazine ethosomes enhanced the drug efficacy for heart and relatively relieved the liver toxicity. And AUC value of group C and A was not significantly different, the relative bioavailability was 98.63%, this revealed that transdermal effect was comparatively poor. The results of protection experiment showed that Ligustrazine ethosomes patch had protection effect for cells of myocardial ischemia by experimental coronarospasm because there were significant difference between the hemorheology index of Ligustrazine ethosomes patch group and control group (P<0.01). And in the Ligustrazine ethosomes patch group, it was not obviously improved for arrhythmia induced by myocardium reperfusion, but could diminish significantly the myocardial infarction range caused by following long time ischemia.Conclusions:Ligustrazine ethosomes patch has good transdermal effect, significant controlled release action, increased relative bioavailability, and protection effect for ischemia myocardium and reperfusion injury after ischemia myocardium.