| Zaltoprofen(ZAL)belongs to a propionic acid class of non-steroidal anti-inflammatory drugs(NSAIDs),with powerful anti-inflammatory and analgesic effect.Due to its weak acid structure,ZAL is prone to ionization under physiological conditions.Considering the leading role of lipoidal intercellular pathway across the stratum corneum,ionized drugs are generally not well absorbed by human skin.In the present study,an ion pair strategy was used to facilitate ZAL transdermal delivery,and the mechanism of action for ion pairs in modulating skin permeation of ZAL was investigated.The ion pair with the best skin permeability was then selected and designed into a transdermal patch.The practical application of ion pairs in the patch delivery system was further evaluated according to pharmacokinetic,pharmacodynamic and skin safety tests.Seven organic amines were chosen as counter ions and the mechanism of action for ion pairs was investigated in the system of isopropyl palmitate(IPP).The interaction between ZAL and organic amines was studied by FTIR and 1H-NMR spectroscopy,which confirmed the formation of hydrogen-bonded ion pairs.In vitro permeation studies showed that the permeation of ZAL was significantly promoted with alkylamines and cycloalkanolamines,while significantly retarded with alkanolamines.The results were further visualized by confocal laser scanning microscopy(CLSM)studies,which also revealed a lipoidal intercellular pathway of ion pairs across the stratum corneum.Investigations from the standpoint of dissolution,partition and diffusion indicated that the modulation mechanism of ion pairs was mainly attributed to an alteration of ZAL diffusion in the skin,which was accomplished by masking the carboxyl of ZAL and adding the hydrogen bonding groups of counter ions.A negative correlation was observed between the enhancement ratio of ion pairs and the polar surface area of counter ions(r=0.929),which provided a potential method for rapid screening of efficacious counter ions.Molecular modeling revealed that ion pairs acted with the nature of different affinity to ceramide,which would be responsible for the diffusion retardation(r=0.954).Based on the above results,various ZAL ion-pair complexes were synthesized and investigated for the practical application in the transdermal patch system to deliver ZAL.A drug-in-adhesive patch was developed with DURO-TAK? 87-4098 as the matrix.In vitro permeation studies showed that the enhancement effect of ion pairs in the patch system was in the similar tendency to that observed in the IPP system(r=0.981),with the cumulative amount of drug permeated in the following trend:ZAL and alkylamine complexes>ZAL and cycloalkanolamine complexes>ZAL>ZAL and alkanolamine complexes.Further insights revealed a negative correlation(r=0.926)between the enhancement effect of ion-pair complexes in the patch and the polar surface area of counter ions,which indicated the modulation mechanism of ion-pair complexes in the patch could also be attributed to an alteration of the permeant’s diffusion in the skin.In detail,upon the formation of ion pairs,the hydrogen bonding potential of ZAL was modulated by the different polar surface area of counter ions through the ion-pair interaction,which led to an alteration of drug diffusion within the stratum corneum and resulted in an inverse correlated skin permeation amounts.In the present study,the highest permeation rate was provided by the ZAL-triethylamine complex(ZAL-TEA),therefore,ZAL-TEA was chosen to further investigate the penetration enhancement potential of chemical enhancers on the skin permeation of ion pairs.The in vitro permeation results showed that,overall,highly lipophilic chemical enhancers were potent to ZAL-TEA permeation.A positive correlation(r=0.919)was observed between the enhancement ratio of chemical enhancers and their log Ko/w(octanol-water partition coefficient).Based on the single factor test,the formulation was designed in combination with the ion pair and chemical enhancer strategy,and defined as follows:10%(w/w)ZAL-TEA as the permeant,10%(w/w)isopropyl myristate(IPM)as the chemical enhancer,and DURO-TAK? 87-4098 as the pressure sensitive adhesive matrix.The in vivo pharmacokinetic performance of the developed ZAL-TEA patch was studied on rabbits.Results showed that the optimized patch system could deliver ZAL effectively into the systemic circulation with a longer duration.The mean residence time(MRT)was 9.28±0.55 h,which was more than four times longer than that from the intravenous administration.The absolute bioavailability was 42.53%.Furthermore,the in vivo absorption reflected a point-to-point Level A correlation with the in vitro permeation,and the correlation coefficient was 0.988.The analgesic effect of the optimized patch was evaluated by means of acetic acid induced writhing response on mice.Results showed that the optimized ZAL-TEA patch exhibited a potent analgesic effect,with a pain inhibition ratio(PIR)of 72.16%,which was comparable with the commercial Vantelin? indometacin plaster.According to the Draize method,the skin irritation test was conducted and the results revealed no occurrence of erythema and edema,which indicated that the developed ZAL-TEA patch was with good skin compatibility.The present study was conducted to investigate the mechanism of the ion pair strategy in modulating ZAL skin permeation,together with the practical application of ion pairs in the transdermal patch delivery system.As the mechanism studies indicated,the H-bonding property of the permeant was of great importance.In order to obtain the maximum enhancement effect via ion-pair strategy,one should consider the nature of the masked and the introduced H-bonding groups and determine whether the replacement contributes to a better diffusion.Furthermore,it was feasible for transdermal delivery of ZAL by the synergistic action of ion pair and chemical enhancer,and the developed ZAL-TEA patch was in good performance according to the pharmacokinetic,pharmacodynamic and skin safety evaluation. |
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