Iontophoretic Transdermal Delivery Of Cytisine

Objectives To explore the characteristics of cytisine（CTS）passive and iontophoresis transdermal delivery and investigate some of the influence conditions of iontophoresis technology to promote its transdermal delivery.To analyze the penetration mechanism of iontophoresis CTS,and judge the feasibility of transdermal delivery of CTS based on the transdermal delivery behavior of using iontophoresis technology in vivo and in vitro.Methods The in vitro analysis method of CTS was developed by HPLC,and the in vivo analysis method of CTS was developed by LC-MS technology,and related methodological verification were performed.The stability of CTS during iontophoretic delivery was evaluated.Vertical Franz diffusion cells were used to conduct in vitro transdermal experiments with pig ear skin as a barrier to explore the effects of different penetration enhancers on the passive transdermal delivery of CTS,and to investigate the effects of different current densities,different drug concentrations and matrix in the vehicles on iontophoretic transdermal delivery of CTS.The small neutral molecule acetaminophen（ACE）was used as a marker molecule to distinguish the mechanism of iontophoresis of CTS,and the mechanism of CTS iontophoresis was analyzed.To investigate the pharmacokinetic characteristics of CTS delivered by transdermal iontophoresis in rats,and the constant input model and the time-variant model were used to fit the average plasma concentration of iontophoresis CTS,and the pharmacokinetic parameters of transdermal delivery of CTS were estimated.Results According to the methodological investigation,the in vivo and in vitro analysis methods of CTS could satisfy the quantitative measurement of CTS.During the iontophoresis process,the stability of CTS was not affected by skin enzymolysis or current degradation.After 7 hours of passive transdermal delivery,the cumulative permeation of CTS was 42.73±6.54μg·cm^-2,and different penetration enhancers including 5%（w/v）propylene glycol（PG）,5%（w/v）PG and 2%（w/v）N-methylpyrrolidone（NMP）,5%（w/v）PG and 2%（w/v）Transcutol were added respectively into the vehicles,which resulted in all of them could slightly increase their cumulative permeation,and the 5%（w/v）PG and 2%（w/v）Transcutol group obtained the best effect,which resulted in cumulative permeation of76.21±11.61μg·cm^-2.However,under the condition of passive transdermal delivery,the cumulative permeation of CTS could not meet the effective therapeutic dose.Application of iontophoresis for 7 hours under a constant current density of 0.5 m A·cm^-2resulted in cumulative permeation of 1726.23±408.90μg·cm^-2,which was 39 times higher than that no current was applied.The steady-state flux of CTS showed a good correlation with current density（r=0.9983）,and was proportional to its concentration in the vehicles;when the matrix in the vehicle was 7%HEC gel,the cumulative permeation was not significantly different from the MES solution matrix（P>0.05）.The analysis of the iontophoresis mechanism found that electromigration EM played a dominant role in the iontophoresis of CTS,and its proportion in the total iontophoresis was more than 90%;the transport efficiency of CTS was between 6.6%and 8.9%,and delivery efficiency was between 16.2%and 40.2%.The in vivo transdermal experiments of rats,the plasma concentration of the passive transdermal group was not detected.The plasma concentration of the iontophoresis group increased with time within 5 hours of the application of current,and the CTS quickly reached a significant drug level within 30 minutes(215.35±79.33 ng·m L^-1),and the plasma concentration reached783.08±163.42 ng·m L^-1 after 5 hours.Through model fitting,it was found that the time-variant model and the average plasma concentration of CTS after iontophoresis was better than the constant input model.According to the model fitting results and the plasma concentration-time curve,the relevant pharmacokinetics of CTS in vivo transdermal delivery was estimated,which resulted in either in the constant input model or the time-variant model,the in vivo transdermal delivery rate was higher than the in vitro transdermal delivery rate.Conclusions These results showed that iontophoresis of CTS can achieve rapid,controllable and effective transdermal delivery.This strategy will provide a new idea for the development of new dosage forms of CTS for smoking cessation.Figure 14;Table 16;Reference 125...