Construction And In Vitro/in Vivo Evaluation Of Glycyrrhetinic Acid-paeoniflorin And Triamcinolone Acetonide-econazole Nitrate (Trans) Dermal Therapeutic Systems

Systems for drug delivery pathing by skin include transdermal therapeutic system(TTS)and dermal therapeutic system(DTS),which could delivery drugs through or into skins.TTSs provide systemic delivery and skin is not the target.While DTSs delivery drug into skin locally and skin is the target.In the present study,glycyrrhetinic acid-paeoniflorin patch and econazole nitrate-triamcinolone acetonide tape were selected to represent for the two kinds of systems.Glycyrrhetinic acid(GA)and paeoniflorin(PF)are the main active ingredients in Chinese peony-Liquorice Decoction which shows analgesic effect and is a widely used Traditional Chinese Medicine.Triamcinolone acetonide(TA)is a glucocorticoid and econazole nitrate(ECN)is an anti-fungal,and they are often combined used to therapy various dermatoses such as eczema and dermatitis.Firstly,GA-PF patch could be constructed based on the previous work,thus pressure sensitive adhesive was selected by comparing the in vitro skin permeation of the two ingredients,and DURO-TAK(?)87-4098 was selected as matrix of the patches.Meanwhile the ECN-TA tape was optimized,that the effect of excipients on the permeation of ECN and TA was investigated.By drawing on the experience of developing GA-PF patch,orgic acid was added in the tape formulation and the cumulate permeation amount of ECN was on the equal level or more than the reference preparation.Then the key problems appeared during the construction of ECN-TA tapes were solved,which were the degradation of ingredients and control of impurities.It was defined that TA would degrade in PSAs containing self-crosslinkers.Besides during the stability test,unproductive degradation of ECN was observed.The impurity was separated and identified as a novel oxidative product of ECN.An amount of the oxidative product was synthesized and the qualitative and quantitative analysis methods have been developed.We determined mechanism of the pheneomenon,which was ECN in tapes was oxidized by oxygen in the air by a radical mechanism with the assistance of impurities in the excipients,including AIBN and metal ions.The metal ions in PEG 400 should be the major cause.The degradation of ECN in tapes can be inhibited by applying an antioxidant and a complexing agent.Lastly,the in vitro/in vivo evaluation of GA-PF patch and ECN-TA tape were performed.Dysmenorrhea model mice were produced to compare the analgesic effects of the patches with different proportions of GA-PF.Results showed in dysmenorrhea mice,GA-PF patches and meloxicam(the positive control drug)could relieve pain to equal degrees,and the two ingredients displayed a synergistic effect based on the Bliss Independence criterion.Applying the optimized GA-PF patch(10%GA-10%PF,wt)on dysmenorrhea model mice and the number of writhes exhibited by the dysmenorrhea mice was recorded at designated time points,and skin,muscle under skin and plasma samples were collected,for assessments of drug distribution,pharmacokinetics parameters and PK-PD relationgship characteristics.Specifically,a single dose of the patch exerted a steady analgesic effect for 48 h in dysmenorrhea mice,but this effect lagged behind the changes of GA concentration in plasma.The compound preparation GA-PF TTS patch might be suitable for topically analgesic therapy causing by spasm and inflammatory.For the ECN-TA tape,the permeation of the two ingredients through skins with different thickness shows that ECN might retention in the superficial layer of skin and TA could arrive at the deep layer.That is fit for the therapy aim.Additionally in the topical skin pharmacokinetic study,tmax of ECN indicats it would take effect rapidly,and the Cmax of TA was steady in 1?12 h shows that the anti-inflammatory effect could be maintained.The different profile of ECN and TA might be bentfit for the therapy of dermatitis caused by fungal.In conclusion,to construct compound preparations of TTS/DTS,the matrix and exicipients should be selected considering the differences of drug characteristics.Then the evaluation should be performed based on the therapy aim.GA-PF and ECN-TA were chosen for the present comparative study on TTS/DTS,the preliminary results about permeation,excipients,pharmacokinetics and pharmacodynamics might contribute to induction of common experience on degisn of compound preparations of TTS/DTS.