本研究開發出能同時釋放親疏水性雙重藥物於皮膚之鑲嵌式高分子微針，利用親脂性之聚草酸碳酸酯(polycarbonate-co-polyoxalate, PCOX)做為微針主體並包覆疏水性藥物，微針中所含的交聯型明膠微米粒子則包覆親水性藥物，後端再結合水溶性之高分子聚乙烯吡咯烷酮/聚乙烯醇[poly(N-vinylpyrrolidone)/poly(vinyl alcohol), PVP/PVA]做為支撐陣列貼片。PVP/PVA支撐陣列可提供皮膚穿刺時的機械強度，使微針完整的刺入皮膚，並在接觸到水份後溶解，僅留微針鑲嵌於皮膚中，持續的釋放藥物。當微針刺入皮膚時，明膠微粒可吸收皮膚中的組織液後快速膨潤並釋放親水性藥(尼羅藍，nile blue)，同時造成微針崩解，加速疏水性藥(羅丹明，rhodamine 6G)的釋出，達到同時釋放雙重藥物於皮膚的效果。本研究利用W/O乳化聚合方式製備出明膠微粒，再以天然的交聯劑genipin進行交聯，交聯六小時之明膠微粒能在接觸水份後90秒內，快速膨脹至其粒徑的2倍(n = 10)。將吸附nile blue的微粒，以離心灌模的方式包覆於微針中，並以兩段式灌模法製針。由穿刺實驗證實，所製備之聚草酸碳酸酯微針具有足夠之強度可刺穿角質層，並鑲嵌於皮膚中，穿刺豬皮的深度約為1000微米。明膠微粒確實能在吸水後快速膨潤，使微針在150秒內完全崩解。體外釋放實驗發現，微粒所包覆之nile blue在14天釋放約80 %，rhodamine 6G約在50天達到100%釋放；而未包覆微粒之微針在50天僅釋放約75 %的疏水性藥物，由此可證明微粒膨潤所造成的微針崩解，確實可加速藥物由微針釋放。體內釋放實驗證實，微針能於大鼠皮膚內能逐漸降解，nile blue的螢光大約在第14天僅剩下25%，第21天則完全消失，而rhodamine 6G的螢光則可持續至少28天以上，且包覆微粒組別的放藥速度確實較未含微粒組快。以上結果證實，所開發之鑲嵌式聚草酸碳酸酯微針可同時傳輸親疏水性雙重藥物於皮膚中，具有緩釋藥物的能力，有潛力開發為一長效且雙效型的新一代經皮藥物傳輸系統。

This study reports embeddable polycarbonate-co-polyoxalate (PCOX) microneedles (MNs) containing crosslinked gelatin microspheres (MPs) as a dual- drug transdermal delivery system for hydrophilic and hydrophobic drugs. In this system, hydrophobic model drugs, rhodamine 6G (Rh6G), was encapsulated within the MNs; whereas hydrophilic model drugs, nile blue, was loaded within the MPs. PCOX MNs were mounted to the top of a dissolvable poly(N- vinylpyrrolidone)/poly(vinyl alcohol) (PVP/PVA) supporting array, providing mechanical strength to fully insert the MNs into the skin. When inserted into the skin, the supporting array can be quickly dissolved by interstitial fluid, leaving the MNs within the skin for sustained drug delivery without requiring a transdermal patch. The gelatin MPs quickly swell to release nile blue because of contact with skin’s water. Such swelling will cause the MN disintegration, thus accelerating Rh6G release from the MNs. The gelatin MPs was prepared by utilizing W/O emulsion polymerization and then crosslinked with genipin solution for 6 h. When contact with water for 90 s, the diameter of the crosslinked MPs can swell to ~2 times their initial diameter (n = 10). The MNs were then prepared by filling a MN mold with nile blue-loaded MPs. These MNs have sufficient mechanical strength to be inserted into porcine and rat skins at a depth of 700~1000 μm. In vitro drug release study showed that nile blue can be quickly released from the MNs (~80% at Day 14). At Day 50, 100% of Rh6G was released from the group with MPs, whereas there is only 75% of Rh6G release from their counterpart. This indicated that MP swelling indeed enhances drug release from the MNs. Such release behavior can be also observed from the in vivo drug release study. These results demonstrated that the embeddable PCOX MNs with gelatin MPs, which enable to simultaneously release hydrophilic and hydrophobic drugs into the skin in a sustained manner, may be a new generation of transdermal delivery system.

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