The Application And Mechanism Of Small Molecule Organic Acids In The Transdermal Delivery Of Loxoprofen Sodium

Objective:This study aimed to investigate the potential effect of small molecule organic acids in promoting transdermal penetration of NSAIDs,explore the possible mechanism,and evaluate the feasibility and advantage of its application in topical preparations.Methods:1.The enhancing effects of lactic acid and fumaric acid on in vitro transdermal permeation of ibuprofen,naproxen,flurbiprofen,diclofenac sodium and loxoprofen sodium were compared;2.The drug distribution,skin structure and drug structure changes caused by organic acids were analyzed by tape stripping,Attenuated Total Reflection Fourier infrared spectroscopy,differential scanning calorimetry,~1H-NMR and so on;3.Loxoprofen sodium gel with organic acid was prepared and evaluated from the aspects of preparation’s appearance and stability,skin irritation and in vivo anti-inflammatory effect.Results:The transdermal enhancing effects of lactic acid and fumaric acid on the five non-steroidal anti-inflammatory drugs were different:1)Lactic acid and fumaric acid didn’t change the transdermal behavior of naproxen,diclofenac sodium and flurbiprofen under the condition of same p H value;2)Lactic acid and fumaric acid could significantly increase the transdermal permeation rate of ibuprofen and loxoprofen sodium as well as reducing time lag;3)Fumaric acid could more significantly promot the transdermal rate of loxoprofen sodium;4)Increasing the ratio of fumaric acid could further improve the cumulative penetration amount and transdermal rate of loxoprofen sodium.Exploring the possible mechanism of fumaric acid in promoting permeation rate of loxoprofen sodium,the results showed that:1)Pretreating skin with fumaric acid did not affect the transdermal rate of loxoprofen sodium;2)Fumaric acid would not influence the skin morphology or disturb strateum corneum’s lipid and protein structure,which suggested that fumaric acid might not directly act on the strateum corneum;3)The introduction of fumaric acid could change the complexation state of loxoprofen sodium and increase the drug retention in the strateum corneum,which might be one of the reasons for the increase of transdermal rate of loxoprofen sodium.The comparation results between loxoprofen sodium gels showed that:1)The gel with fumaric acid had good appearance and stability,and the introduction of fumaric acid did not lead to gel’s properties change or degradation products’increase;2)In vivo anti-inflammatory experiments showed that the gel with fumaric acid could quickly inhibit the rats’toe swelling.Conclusion:The in vitro transdermal enhancing effect of small molecule organic acids,lactic acid and fumaric acid,on aryl alkyl acid non-steroidal anti-inflammatory drugs were studied.It proved that fumaric acid had an exciting effect on promoting the transdermal rate of loxoprofen sodium associated with the changes of drug complexation and drug distribution in the skin.Fumaric acid could be applied to the preparation of loxoprofen sodium topical gel,which could lead to good preparation appearance,stable preparation property,rapid transdermal rate and fast anti-inflammation effect.