與傳統式的皮下注射途徑相比，微針貼片於經皮給藥領域上具有潛在優勢。微針的侵入性較小，可避免刺激神經帶給患者的不適性，同時可達到與注射相似的給藥效果。本研究主要為開發具有不同釋放行為模式之高分子微針，並應用於經皮傳遞胰島素。研究分為兩部份：第一部分為利用快溶型高分子微針傳遞胰島素，取代臨床針劑給藥；第二部分則為以快溶型微針貼片包覆含有胰島素之幾丁聚醣立方體，應用於經皮緩釋胰島素，達到長效控制血糖之目的。
在第一部份之研究中，我們利用澱粉及明膠製備可溶解型微針貼片，用於快速有效地經皮傳遞胰島素。此微針穿刺皮膚5分鐘後可完全溶解，並迅速地將所包覆之胰島素傳遞至皮膚中。組織切片結果顯示，微針具有足夠的機械強度，可刺入豬皮約200 μm之深度，而活體大鼠皮膚穿刺深度則約200～250 μm，此穿刺深度不會引起明顯的皮膚刺激及疼痛感。為了評估使用可溶性微針治療糖尿病的可行性，將含有胰島素之微針固定於自製敷貼器上，進行糖尿病大鼠治療。由藥物動力學結果可得知，含有胰島素之微針的相對生物可利用率及相對藥理有效性皆約為92 %，表示胰島素包覆於微針中及釋放後仍然保持其藥理活性，具有接近皮下注射相似之降血糖效果。儲存穩定性分析證實，於25 ℃及37 ℃儲存微針1個月後，胰島素依然保有90 %以上的生物活性。這些結果證實，所開發的澱粉/明膠微針能夠穩定地包覆生物活性分子，並且具有以相對無痛、快速和方便的方式透過經皮傳遞胰島素。
第二部分之研究主要為開發可緩釋胰島素之劑型，期望可長時間穩定糖尿病患者之血糖值。將胰島素以幾丁聚醣立方體包覆後，裝載於快溶型聚乙烯醇/聚乙烯吡咯烷酮(Polyvinyl alcohol, PVA / Polyvinylpyrrolidone, PVP)微針中。當微針穿刺皮膚3分鐘後，水溶性PVA/PVP針體可完全溶解，使幾丁聚醣立方體鑲嵌於皮膚中持續釋放胰島素。由組織切片結果顯示，幾丁聚醣立方體可鑲嵌於豬皮與活體鼠皮之深度約為500~550 μm及 450~500 μm，相當於真皮層中。穿刺後在皮膚產生之微通道能夠在9小時內癒合，避免傷口感染之疑慮。儲存穩定性分析證實，於25 ℃及37 ℃儲存3個月後，依然保有約90 %胰島素的生物活性，推測可能是帶正電幾丁聚醣與胰島素間之靜電作用力，能維持胰島素之結構穩定性。將包覆胰島素(6 IU/kg for 30 days)之微針應用於糖尿病老鼠身上，可在穿刺3小時後測得胰島素濃度約為160 μIU/ml，血糖值降至約初始值之45 %，與皮下注射0.2 IU/kg/day持續注射30天，所造成降至46 %血糖值相近，微針降血糖之效果可維持約30天，推測是幾丁聚醣及胰島素間之分子鏈糾纏，並隨著幾丁聚醣被緩釋降解而逐漸釋放胰島素，最後測得相對皮下注射之生物可利用率及藥理有效性分別為90.5 ± 11.2 % (n = 6)和91.8 ± 9.8 % (n = 6)。以上實驗證實，利用PVA/PVP微針可讓含有胰島素之幾丁聚醣立方體鑲嵌致皮膚真皮層，並於皮膚中持續釋放胰島素，達到長時間穩定血糖功能。
本研究成功開發出二款微針劑型，分別可快速及長效釋放胰島素。第一部份之澱粉/明膠快溶型微針，可在刺入皮膚後，5分鐘內溶解快速釋放胰島素，有機會取代臨床針劑注射，達到相對無痛、快速又有效的胰島素給藥。第二部份以快溶型PVA/PVP微針包覆含有胰島素之幾丁聚醣立方體，做為緩釋胰島素之劑型，能長時間釋放胰島素並穩定血糖數值，將可成為新一代的非注射式緩釋型胰島素給藥技術。

Compared with conventional subcutaneous injection, microneedle patch is potentially a more advantageous transdermal administration approach. The less invasive nature of microneedle patch enables it to achieve a comparable drug delivery effect as subcutaneous injection without the discomfort caused by stimulated nerves. In this study, polymeric microneedles of various drug release modes were developed for the transdermal administration of insulin. The study comprised two stages. In the first stage, rapid-dissolving polymeric microneedles were employed to clinically replace syringes in the delivery of insulin. In the second part, rapid-dissolving microneedle patches were used to administer insulin encapsulated in chitosan microcubes to provide durable blood sugar control through the sustained transdermal delivery of insulin.
The first part presents a dissolving microneedle patch, composed of starch and gelatin, for the rapid and efficient transdermal delivery of insulin. The microneedles completely dissolve after insertion into the skin for 5 min, quickly releasing their encapsulated payload into the skin. A histological examination shows that the microneedles have sufficient mechanical strength to be inserted in vitro into porcine skin to a depth of approximately 200 μm and in vivo into rat skin to 200-250 μm depth. This penetration depth does not induce notable skin irritation or pain sensation. To evaluate the feasibility of using these dissolving microneedles for diabetes treatment insulin-loaded microneedles were administered to diabetic rats using a homemade applicator. Pharmacodynamic and pharmacokinetic results show a similar hypoglycemic effect in rats receiving insulin-loaded microneedles and a subcutaneous injection of insulin. The relative pharmacological availability and relative bioavailability of insulin were both approximately 92 %, demonstrating that insulin retains its pharmacological activity after encapsulation and release from the microneedles. Storage stability analysis confirms that more than 90 % of the insulin remained in the microneedles even after storage at 25 or 37°C for 1 month. These results confirm that the proposed starch/gelatin microneedles enable stable encapsulation of bioactive molecules and have great potential for transdermal delivery of protein drugs in a relatively painless, rapid, and convenient manner.
The second part primarily involved the development of dosage forms for the sustained delivery of insulin, thereby stabilizing the blood sugar level of patients with diabetes for an extended duration of time. This was achieved by encapsulating insulin in chitosan microcubes, which were then loaded into a quick-dissolving microneedle made of polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP). The water-soluble PVA/PVP microneedle completely dissolved 3 minutes after penetrating the skin, enabling the chitosan microcubes, which were embedded in the skin as a result, to release insulin in a sustained manner. An examination of histological sections revealed that chitosan microcubes were successfully embedded 500-550 μm and 450-500 μm, respectively, in porcine skin and live rodent skin, equivalent to the depth of the dermis. The micro-passages created by microneedle penetration typically healed within 9 h, precluding the concern for wound infection. A storage stability analysis indicated that the insulin in microneedles retained approximately 90 % biological activity after being stored for 3 months at 25°C and 37°C. This may be attributed to the electrostatic force between positively charged chitosan and insulin, which helped insulin maintain its structural integrity. Microneedles carrying encapsulated insulin (6 IU/kg for 30 days) were applied to diabetic mice. Three hours after application, the mice had an insulin level of approximately 160 μIU/ml, and their blood sugar level lowered to approximately 45 % of the baseline value. These results were comparable to receiving subcutaneous injection of insulin (0.2 IU/kg/day) for 30 consecutive days, which reduced blood sugar level to approximately 46 % of the baseline value. The effect of the microneedles lasted for approximately 30 days, possibly because the entangled molecular chains of chitosan and insulin resulted in the sustained release of insulin as chitosan was gradually degraded. Compared with subcutaneous injection, the application of microneedles achieved 90.5 ± 11.2 % bioavailability (n = 6) and 91.8 ± 9.8 % pharmacological effectiveness (n = 6) in animal models. The results proved that PVA/PVP microneedles enabled insulin-carrying chitosan microcubes to be embedded in the dermis, where the microcubes released insulin in a sustained manner to stabilize blood sugar level for an extended duration of time.
Two dosage forms were successfully developed, one for rapid release and the other for sustained release of insulin. In the first part of this study, rapid-dissolving starch/gelatin microneedles were used. The microneedles dissolved in 5 minutes after penetrating into the skin, making them a clinically viable replacement for syringes to achieve relatively painless, quick, and effective insulin delivery. In the second part, rapid-dissolving PVA/PVP microneedles that contained insulin-carrying chitosan microcubes were used for the sustained release of insulin. With their ability to stabilize blood sugar level for an extended duration of time through sustained insulin release, this type of microneedles can be expected to become the next generation of injection-free sustained insulin delivery method.

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