- 學位論文
微針陣列與具酸鹼敏感性PLGA-HMS微粒之兩階段經皮藥物釋放系統
A Two-Step Controlled Release System Based on The Microneedle array filled with pH-sensitive PLGA hollow microspheres (HMS) for transdermal drug delivery
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摘要
經由皮膚傳遞藥物(Transdermal Drug Deliveyr; TDD)是以控制適量劑型藥物傳送至皮膚而釋放到全身血液循環的方式，不會有注射般疼痛，且可在患部發揮最大藥效，也不會如口服藥物般經過腸胃道等被酵素分解而降低藥效等優點，但由於皮膚表皮的角質層為構成藥物傳輸的障礙，因此，本論文利用生醫微機電(Bio-MEMS)之技術應用，使之能在醫學上提供效能高和便利性佳的治療方法及減輕治療與診斷的不舒適感。 傳統皮膚癌之化學治療為使用抗癌藥物、局部麻醉藥及血管收縮劑，因抗癌藥物於癌細胞作用較慢，而局部麻醉藥及血管收縮劑半衰期較短，因此，本論文以治療皮膚癌為模擬應用，以生醫微機電製作微針陣列結合PLGA((Poly latic-co-glycotic acid)中空微粒(Hollow Microspheres, HMS)，製作可控制釋放(controlled-release)之二階段治療的皮膚貼片。 論文中主要分為兩主題，一、利用UV-lithography製程製做高深寬比微針陣列模具，使用生物相容性之材料製作大面積之微針貼片，做為第一階段釋放。二、以雙乳化方式(double emulsion)製作具有酸鹼敏感之中空微粒做第二階段釋放，結合此二主題，提出一新型兩階段經皮藥物控制釋放貼片，可經由控制高分子PVP(polyvinylpyrrolidone)微針濃度來控制第一階段快速釋放時間，以具酸鹼敏感性之中空微粒控制第二階段釋放時間，藉由此方式製作一具有時間差之兩階段釋放系統，並以此系統進行體外釋放 (in vitro)、活體外穿刺能力測試(ex vivo)以及活體內釋放實驗(in vivo)，以証實此兩階段微針貼片具有控制釋放之效果。
並列摘要
Transdermal delivery is an attractive alternative of drug delivery. Comparing to the conventional drug delivery techniques using pills or injections, this approach avoids degradation in the gastrointestinal tract and the pain of injections. But it is limited by the low permeability of skin because the stratum corneum (SC) in the upper skin (10-20 μm) is the main barrier. Hence, we used the Bio-MEMS technique to make microneedle array patch to inset into skin. This microneelde array patch could easily cross the SC but not so long that reach the deeper tissue and simulate nerves to developed a convenient, pain-free, and high efficient transdermal delivery patch. In this study, we present a novel approach to transdermal drug delivery that is two-step controlled-release system based on the skin cancer application. We used fluorescent dyes as model drugs to simulate the slow effect of anti-cancer drug and short half-time of anesthesia and vasoconstrictor. First, we used backside exposure technology of UV-lithography to fabricate microneedle array mold and bio-available PVP polymer with 1st model drug as the microneedle array materal. Second, we used double emulsion technology to fabricate pH-sensitive PLGA HMS (Hollow Micro-Spheres) with 2nd model drug. Sequentially, we combined these two techniques to fabricate the two-step controlled-release microneedle patch. This microneedle patch was shown two-step releasing profiles in vitro, the insertion capability ex vivo, and the transcutaneous delivery in vivo. As a consequence, we conclude that the two-step controlled-release can release two drugs with a time difference to the skin.
參考文獻
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