Double Regulation Of Drug Skin Permeating Amount By Combining Ion-pair Strategy With Chemical Enhancers In Patch Containing Bisoprolol And Indapamide

In the treatment of hypertension,combination therapy is an important strategy to achieve blood pressure target.The combination of bisoprolol(BSP)and indapamide(IND)adds considerable antihypertensive efficacies and avoids certain adverse effects.Therefore,designing a transdermal patch containing BSP and IND which can not only provide satisfactory antihypertensive effects but also improve patients' compliance is desirable.To date,the respective oral preparations of BSP and IND have been in market,and their daily doses and bioavailability are both quite close.It demonstrates that in order to exert expected therapeutic effects,their required amounts entering into body in 24 hours are comparable.Accordingly,their skin permeating amounts from their compound patch are also expected to be comparable,and it would be better to achieve synchronous skin permeation.However,according to our preliminary wok,the accumulated permeating amount of BSP was about 16 times that of IND.The two drugs with such remarkable disparity in their permeating amounts could not achieve synchronous permeation,and thus an effective regulating method was in great demand.Therefore,in this work an interesting double regulation strategy was initiated combining the technique of ion pair complexation with chemical enhancers for the synchronous skin permeation of drugs as well as the simultaneous up-regulation of drug kin permeating amounts as much as possible.Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation.Among them,bisoprolol tartrate(BSP-T)down-regulated skin permeating amount of BSP to the same extent as that of IND.Furthermore,the effects of ion-pair complexes on the process of BSP release from patches and its percutaneous absorption were studied.The mechanism of ion-pair complexes down-regulating BSP skin permeation can be attributed to the reduction of BSP release amount.Chemical enhancers were employed to simultaneously up-regulate the skin permeating amounts of the two drugs.The results showed that some chemical enhancers showed an excellent enhancing effect on the permeating amounts of IND or BSP-T.Similarly,the effects of chemical enhancers and their combinatons on the process of drug release from patches and their percutaneous absorption were investigated.In the latter process,the combination of Azone(AZ)and NMP(N-methyl pyrrolidone)achieved the highest synergy value,demonstrating a strong synergistic interaction between AZ and NMP on the ability of IND percutaneous ability.By constrast,no synergistic interaction was found between the investigated chemical enhancers on BSP-T percutaneous ability.In the former process,when different chemical enhancers or their combinations were employed,there was no significant difference in IND release profiles.Differently,BSP-T release amounts were greatly influenced with the variation of chemical enhancers or their combinations.To further explore the mechanism of chemical enhancers in BSP-T release from patches,their influence on BSP-T-adhesive interaction,free volume of adhesive and BSP-T saturation degree in adhesive were investigated.The results demonstrated that chemical enhancer Span80(SP)with strong hydrogen-bond forming ability can disturb the hydrogen bonds formed between adhesive and BSP-T.The decrease of interaction between adhesive and BSP-T led to the improvement of BSP-T release from adhesive of patches.The increase of chemical enhancer amount can also facilitate BSP-T release from adhesive via promoting the formation frequency of free volume of adhesive.Based on the above mechanism research of chemical enhancers on BSP-T and IND,we combined SP,AZ and NMP together in order to simultaneously up-regulate the permeating amounts of BSP-T and IND in patches.The concentrations of them were optimized by central composite design,in which their permeating amounts were expected to be maximized and comparable,and the total amount of enhancers was minimized.The effect of double regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies.The results demonstrated that BSP-T and IND achieved the synchronous skin permeation in their compound patch by the double regulation strategy of combining the technique of ion-pair complexation with chemical enhancers.