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論文名稱(外文):Fully Embeddable Chitosan Microneedles for Transdermal Sustained Delivery of Macromolecules
指導教授(外文):Mei-Chin Chen
外文關鍵詞:Microneedle patchChitosanTransdermal drug delivery
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近年來,利用高分子微針貼片作為一種可自我施行且無痛之經皮藥物輸送裝置已廣為研究。然而,大多數的高分子微針皆在短時間內溶解,無法長效地釋放藥物,且由於高分子微針之機械強度較弱,微針往往無法完全刺進皮膚,降低藥物傳輸之效率。本研究將幾丁聚醣微針和機械強度較高的聚乳酸 [poly(L-lactide-co-DL-lactide), PLA] 支持軸陣列組合,製備出一具有生物可分解性且可將高分子微針完全刺入並鑲嵌於皮膚中的經皮微針貼片裝置。此鑲嵌式微針可於常溫常壓下,將幾丁聚醣溶液經離心灌模,並於半乾情形下與PLA支持軸組合而成。由體外豬皮穿刺結果證實,此鑲嵌式幾丁聚醣微針的穿刺比例可達100%,穿刺深度為550 ± 50 μm,可成功穿越皮膚角質層、到達有大量可引發免疫反應的抗原呈現細胞所存在的表皮層與真皮層。幾丁聚醣微針在穿刺後可與PLA支持軸分離,進而鑲嵌於皮膚中做為緩釋藥物的載體。由體外經皮藥物傳輸實驗證實,幾丁聚醣微針確實可長效釋放包覆的大分子藥物至少持續一週。進一步將幾丁聚醣微針刺入大鼠背部評估其體內降解特性,從組織切片結果可知,幾丁聚醣微針確實會在體內逐漸降解,植入後兩週仍可觀察到殘存的微針碎片。將包覆卵白蛋白 (model antigen) 之幾丁聚醣微針刺入大鼠中進行免疫測試,由分析血中特徵抗體IgG濃度發現,利用幾丁聚醣微針經皮傳輸相同劑量 (1 mg) 的卵白蛋白,可引發和傳統肌肉注射相當的抗體反應,證實由微針傳輸大分子活性物質之可行性。綜觀以上結果證實,此鑲嵌式幾丁聚醣微針裝置確實可有效突破角質層障礙,成功鑲嵌於皮膚中長效性傳輸生物巨分子藥物,可避免皮膚長期接觸貼片造成之不適,未來有潛力應用於疫苗與其他大分子藥物之經皮傳輸。
Recently, various polymeric microneedle devices have been developed for painless and self-administration transdermal delivery of biopharmaceuticals. However, most of polymer microneedles are rapidly dissolved and only for burst release. Additionally, these polymer materials are mechanically weaker than metal or silicon and thus result in incomplete insertion of microneedles and some waste of drugs. In this study, we developed a biodegradable transdermal microneedle device, which combined chitosan microneedles with a poly (L-lactide-co-DL-lactide) (PLA) supporting base, and it can be fully embedded inside the skin after insertion. To prevent damaging the integrity of encapsulated biomolecules, a gentle fabrication process for chitosan microneedle was developed. In vitro porcine skin insertion test showed that the insertion ratio and penetration depth of chitosan microneedle patch were 100% and 550 ± 50 μm, respectively. This penetration depth corresponded to insertion across the epidermis layer into the dermis layer where antigen-presenting cells are abundantly present. After insertion, the chitosan microneedle can be separated from the PLA supporting base and be left in the skin for sustained drug release. In vitro drug delivery study indicated that encapsulated model drugs can be released from chitosan microneedles for at least one week, indicating that the embeddable microneedle patch has potential for long-term drug treatment. In vivo degradability study showed that the embedded chitosan microneedle was gradually degraded within the rat skin over time for at least 2 weeks. In the rat immunization study, the model antigen—ovalbumin (OVA) released from the chitosan microneedles induced similar IgG antibody production with intramuscular injection at the same dosage (1 mg). This result indicated that the integrity of OVA still remained after the microneedle fabrication process. In conclusions, we believe that this embeddable and degradable microneedle patch can be an attractive alternative for transdermal delivery of vaccines or other macromolecular drugs.
摘要 II
Table of Contents IV
List of Tables VI
List of Figures VII
1.1 Transdermal Drug Delivery 1
1.1.1 Skin structure 3
1.1.2 Currently available transdermal drug delivery products 6
1.1.3 Other transdermal delivery systems 8
1.2 Microneedle for Transdermal Delivery 13
1.2.1 Definition of Microneedle 14
1.2.2 Polymeric Microneedles 19
1.2.3 Chitosan 20
1.2.4 Trehalose 22
1.2.5 Poly (L-lactide) (PLA) 23
1.2.6 Polyvinylpyrrolidone (PVP) 24
1.3 Sustained Delivery System for Vaccine Delivery 25
1.4 Objective 26
2.1 Materials 28
2.2 Equipment 30
2.3 Methods 31
2.3.1 Fabrication of chitosan-PLA microneedle patch 31
2.3.2 Skin insertion: in vitro and in vivo evaluation 42
2.3.3 In vitro drug release study 44
2.3.4 In vivo skin recovery study 47
2.3.5 In vivo degradability study 48
2.3.6 In vivo immunization study of OVA microneedles 49
3.1 Fabrication of Embeddable Chitosan-PLA Microneedles Patch 53
3.2 Skin Insertion Study: In Vitro and In Vivo 61
3.3 In Vitro Drug Release Study 67
3.4 Skin Recovery after Applying Microneedle Patch in Rats 70
3.5 In Vivo Degradability of embedded Microneedles 73
3.6 Antibodies Titers after Immunization 75
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