Effects of microneedle system on the skin permeation of drugs

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Microneedle systems have been paid attention as having many advantages overtransdermal patches and hypodermic needles． The procedure provides adequate skinpermeation rates without pain or severe infection． to obtain information for designing amicroneedle system， the pretreatment effect of microneedle puncture in the skin barrierstratum corneum on the in vitro skin permeatien of fluorescein isothiocyanate（FITC）一dextrans （4．3， 9．6 and 42．0 kDa） （FD－4， FD－10 and FD－40） was evaluated in hairlessrats． The effect of sandpaper abrasion was also investigated for comparison． Bothpretreatments on the skin barrier significantly increased the skin permeation of FDs． Lactatedehydrogenase （LDH） leaching was measured after the pretreatment of microneedle punctureand sandpaper abrasion on the skin barrier to evaluate the skin damage bythese pretreatments．Lower leaching of LDH was observed after the microneedle puncture than after sandpaperabrasion． Next， a parallel permeation－resistance model of the skin barrier was established tosee a relationship between number of rnicroneedle puncture and enhancement effect on theskin permeation of drugs． Skin permeation of FD－10 could be predicted by the model as afunction of the number of peres in the skin banier． Our results suggest that the needlepuncture may provide a safe， efficient and controllable alternative for increasing transdermaldrug delivery． Next， a combination of microneedle pretreatment and iontophoresis was evaluated forthe potential to further increase skin permeation of drugs． Two model compounds with lowartd high molecular， D20 and FDs （FD－4， FD－10， FD－40， FD－70 and FD－2000； averagemoiecular weight of 4．3， 9．6， 42．0， 71．2 and 2000 kDa）， respectively， were used and the effectof microneedle pretreatment and iontophoresis on their in vitro permeability was evaluatedusing excised hairless rat skin with a modified 2-chamber diffusion cell． Convective solventfiow through the skin was measured using a set of calibrated capillaries attached to thediffusion cell． The following results were obtained： （1） convective solvent flow（electroosmosis）during iontophoresis through microneedle-pretreated skin，2．62士0．32μL／cm2／h， was almost the same as through intact skin， 2．71 ± O．25 μL/cm2/h， and （2） the combination of microneedle pretreatment and subsequent iontophoresis significantlyenhanced FD flux compared with microneedle pretreatment alone or iontophoresis alone，whereas no synergistic eflfect was found en the flux of D20． These results suggest that thecombination of iontophoresis with microneedle pretreatment may be a usefu1 means to furtherincrease skin permeation of high molecular compounds． Finally， linear phenomenolegical equations were applied te analyze drug transportphenomena through the microneedle－pretreated skin． They enable us better understandingand explanation to each contribution of passive diffuision and electroosmosis to the skinpermeation of drugs． Applying the cenoept of refiection coeffricient， we obtained areasonable explenation to mechanism of the combined effects of microneedle pretreatmentand iontophoresis on the skin permeation of high molecular compounds． These resultssuggest that the linear phenomenological equations are useful to mechanistically analyzepermeability phenomena when a system contains mere than two driving forces．

学位授与機関：城西大学 学位記番号：博甲第35号，学位の種別：博士（薬学）， 学位授与年月日： 平成19年(2007年) 3月20日. 50p.

identifier:JOS-PhDK35

博士論文