對於大分子的藥物而言，經皮穿透常受限於表皮層內的角質層所形成之屏障，導致藥物穿透不易。根據文獻得知，不同粒徑之微氣泡對比劑與超音波作用後在於開啓血腦障蔽、基因治療皆有不同效益；而本研究即針對不同粒徑微氣泡對比劑用於加強大分子經皮穿透之不同效果進行驗證。

實驗參數分為: (1)控制組(C)、(2)單純施打超音波組(U)、(3)添加1.4 μm微氣泡對比劑組(U+1.4 μm)、(4)添加2.1 μm微氣泡對比劑組(U+2.1 μm)及(5)添加3.5 μm微氣泡對比劑組(U+3.5 μm)。根據實驗結果可得知，U+3.5 μm組在3 W/cm2能量作用下於仿體及豬皮穿透深度方面相較於1.4 μm組及2.1μm組分別增加了34%及14%; 37%及19%於經皮穿透濃度分析中，U+3.5 μm組穿透濃度相較1.4 μm組及2.1 μm組分別增加了23%及10%；於美白效果方面進行四週動物實驗(C57BL/6J老鼠)，第一週皮膚即有明顯亮度提升的效果(增加28%)，於第二週持續增加(34%)，治療於第三週後亮度雖趨於平緩但也高達(45%)，而添加3.5 μm微氣泡對比劑組相較於添加其他粒徑微氣泡對比劑組別在治療第一周時即有相當顯著的皮膚亮度，當治療時間一樣時，添加3.5 μm組相較於其他組別能夠達到顯著的美白成效。

由此實驗結果可以得知，超音波結合不同粒徑微氣泡對比劑之治療可以不同程度的加強穿透濃度及四異棕櫚酸酯維生素C之藥物釋放，進而使四異棕櫚酸酯維生素Ｃ在對老鼠皮膚沒有傷害的情形下更有效地到達基底層抑制黑色素生成。

The application of transdermal delivery to a wider range of high molecular weight drugs is limited due to the significant barrier to penetration across the skin which is associated with the stratum corneum layer of the epidermis. In previous study, both in opening Blood-Brain-Barrier and gene transfection that different size microbubble (MB) caused different effects. In this study, the different effects of the different size MBs and as the high molecular weight drugs delivery enhancers for transdermal delivery were firstly demonstrated. The effects of different size MBs and Ascorbyl Tetraisopalmitate (VC-IP) on skin transdermal efficiency were proved in vitro or for in vivo experiments. Experiment parameters were randomly divided into five groups: (1) only penetrating VC-IP (C); (2) ultrasound combines with penetrating VC-IP (U); (3) ultrasound combines with 1.4 μm MBs contrast agent and penetrating VC-IP (U+1.4 μm); (4) ultrasound combines with 2.1 μm MBs and penetrating VC-IP(U+2.1 μm); (5)ultrasound combines 3.5 μm contrast agent and penetrating VC-IP(U+3.5 μm). According to the results, at 3 W/cm2 energy the penetration depth of agarose phantom and pig skin of U+3.5 μm group compared with U+1.4 μm and U+2.1 μm group increase 34% and 14 %; 37% and 19%, respectively. In skin permeation of VC-IP, U+3.5 μm group has greater VC-IP concentration than U+1.4 μm and U+2.1 μm group is 23% and 10%, respectively. The whitening effect (luminosity index (L*)) of mice skin in U+3.5 μm group has significantly increase 28% in one week, 34% in two weeks and tends towards stability in three weeks (45%) in C57BL/6J mice over a 4-week experimental period.

Our results investigated that the treatments of ultrasound combined with different size MBs can different degree increase skin permeability, enhance VC-IP delivery to inhibit melanogenesis and not damage the skin in mice.

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