TW201109043A

TW201109043A - Flexible drug delivery chip, its fabrication method and uses thereof

Info

Publication number: TW201109043A
Application number: TW98130097A
Authority: TW
Inventors: San-Yuan Chen; Wei-Chen Huang; Dean-Mo Liu
Original assignee: Univ Nat Chiao Tung
Priority date: 2009-09-07
Filing date: 2009-09-07
Publication date: 2011-03-16

Abstract

Disclosed herein is a flexible drug delivery chip. The flexible drug delivery chip comprises a drug-releasing chamber constructed on a flexible substrate. The chamber is characterized in having at least one layer of drug-containing nanoparticles deposited on the substrate and at least one layer of a metal deposited over the layer of the drug-containing nanoparticles. One side of the chamber remains unsealed and serves as an exit for releasing the drug from the layer of drug-containing nanoparticles by magnetic stimulation.

Description

201109043 - 六、發明說明： • 【發明所屬之技術領域】本發明大致屬於植入式藥物傳送裝置領域。詳言之，是有關一種可植入到體腔或空腔以進行藥物之控制釋放的裝置、其之製造方法與用途。【先前技術】傳送藥物到病患個體體内的途徑有許多種，包括口〇服、經鼻吸入、經皮膜擴散、皮下注射及肌肉注射、非經腸胃道方式和植入等。口服一直是最常見的方式。但是，目前的口服藥物，包括膠囊及藥錠都還有一些缺點，例如，藥效不彰、不具控制釋放效果致使藥物太快被吸收或是吸收不完全、腸胃道不適等其他副作用。此外，這些藥物可能無法提供局部治療效果，和/或無法即時監控藥物的釋出情形。目前也有多種藥物傳送裝置和/或方法被提出，希望能更有效地將藥物傳送至患者體内標的位置處。 ❹ 為了回應上述需求，目前已發展出可局部傳送藥物的醫療裝置，期望能解決前述系統性投藥的相關問題。可以被動地或主動地來控制藥物的釋放。可控制釋放藥物的裝置可參見揭示於美國專利6,808,522及6,875,208中的裝置。植入式裝置對某些不易以現行方式治療或是疾病部位不易接觸的疾病來說特別有用。最好的例子之一就是癌症。癌症治療涉及透過靜脈注射對患者施予高劑量的毒性化合物，例如拉巴黴素或治癌妥（irinotecan，CPT-11)，這 201109043 * 些毒性化合物會對標的位置處以外的細胞造成傷宝，進而 . 引發患者身上強烈的副作用。因此，需要一種改良的植入式藥物傳送系統和/或裝置’其具有較佳的活體内適應性且可更有效率地傳送藥物至活體内的標的位置，同時不會造成強烈的副作用。本發明設計、製造及採用一種新穎的植入式裝置傳送晶片’可透過適當地刺激個體身體之一特定部位，而能在不引起任何不欲求副作用的情況下，主動地、由遠端將藥 ❹物樺出。 ' 【發明内容】本揭示内容是有關於一種可撓式藥物傳送曰片，其之製造方法與用途。此可撓式藥物傳送晶片載有藥物的磁性核殼（亦即，Fe304@Si〇2)奈米顆*電泳沉積到可挽式導電基板上所製造而成的。此可挽式藥物傳送晶片可以活體植入方式植入到一個體之一身體部位上，且可透過 ❹磁性誘導，依據所施加之磁場強度與時間，以栌制釋放方式，將藥物從上述的磁性核-殼奈米顆粒中釋出:此種可撓式晶片可提供許多習知藥物傳送裝置所無法提供的優點，包括改善藥物傳送劑量的精確度、容易操作、更廣泛的藥物釋出模式以及順服性更佳。因此，本揭示内容第一態樣是提供一種藥槽室 _)，此槽室可用來建構出上述可撓式藥物傳送晶片。此藥槽室包括一可换式基板和一藥物儲存槽（a ' dmg-containing reServoir)。此藥物儲存槽是形成在可撓式 201109043 * 基板上且更包括：多個側壁，用以界定出一藥物儲存空 ‘ 間’其中該藥物儲存空間的至少一側並未被該些側壁所密封’一第一層含有藥物的奈米顆粒層，沉積在該可撓式基板,該藥物儲存空間内；一層金屬層，沉積在該第一層含有藥物的奈米顆粒層上；及一第二層含有藥物的奈米顆粒層’沉積在該金屬層上。在一實施方式中，此藥槽室包含兩層金屬層’且每一層金屬層都是夾設在兩層含有藥物的奈米顆粒層之間。 ❹ 在實例中’該多個側壁是由選自下列的生物可相容材料裝成’包括聚氯乙烯(PVC)、聚丙交酯(p〇iyiactide)、聚乙烯、乙烯-乙酸乙烯酯、聚醯亞胺、聚醯胺、聚乙二醇、聚己内醋多元醇（P〇lyCapr〇laet〇ne，PCL)、聚甘醇 (polycolide)、聚對二氧環己酮(p〇iydi〇xanone)及其之衍生物和共聚物。上述的可撓式藥物傳送晶片是由選自下列的材料製成’包括聚對苯二甲酸乙二酯（PET)、聚（氯乙烯)(PVC)、聚對萘二曱酸乙二酯（PEN)、聚醯亞胺(PI)和聚 ❹ 芳基醚酮(P〇lyaryletheretherketone，PEEK)。每一含有藥物的奈米顆粒是由一含有磁性氧化鐵的核心以及二氧化矽外殼所組成，且藥物是被包埋在含有磁性氧化鐵的核心中。在一實例中，所述藥物是一種抗癲癇藥物。至於金屬層中的金屬則是選自Au、Ag、Pt和Ta中。在一實例中，該金屬是Au。本揭示内容第二態樣是提供一種製造上述内含藥物 _ 之槽室的方法。此方法包括以下步驟：提供一可撓式基板；藉由在該可撓式基板上形成多個側壁以界定出一藥物 201109043 * 儲存空間而建構出一藥物儲存槽，其中該藥物儲存空間之 . 至少一侧並未被該多個側壁所密封；電泳沉積一第一層含有藥物的奈米顆粒層在該藥物儲存空間内之該可撓式基板上；濺鍍一層金屬層在該第一層含有藥物的奈米顆粒層上；及電泳沉積一第二層含有藥物的奈米顆粒層在該金屬層上。在一實例中，電泳沉積是以下列步驟來實施：（1)提供一電泳沉積槽，其包含：一膠體溶液，其中含有約 0 0.01 -30%(重量％)之含有藥物的奈米顆粒，和一對電極；（2) 將該可撓式基板浸潰在該電泳沉積槽中的該膠體溶液内，其中該可撓式基板上已建構有上述的藥物儲存槽；和 (3)施加約1-50伏特的電位到該對電極上約1-30分鐘或是直到該層含有藥物的奈米顆粒層的厚度已達至少0.1微米。上述的膠體溶液是藉由將該含有藥物的奈米顆粒懸浮在一稀釋用介質中所製備而成的，該稀釋用介質可以是水、Cw醇類、二醇、甘油、二曱亞砜或其之組合。該電 q 泳沉積槽中該對電極中的每一電極彼此間隔約0.5公分至約5公分的距離。此電泳沉積步驟可在約-10°C至約70°C 間的溫度下執行。在另一實例中，濺鍍沉積可以是以下任一種：離子束濺鍍、反應性濺鍍、離子輔助沉積、高功率脈衝式磁電管濺鍍(HPIMS)或氣流濺鍍。濺鍍反應中的金屬是選自Au、 Ag、Pt和Ta中。在一實例中，該金屬是Au。 .本揭示内容第三態樣是提供一種可撓式藥物傳送晶片，其是由兩個上述之藥槽室，以頭-對-頭方式組成，藉 201109043 * 以形成一藥物釋放腔室。每一上述藥槽室特徵是具有一層 . 夾設在兩層該含有藥物的奈米顆粒層之間的金屬層。此藥物釋放腔室的特徵則是腔室的一側是暴露在周圍環境下以便提供一出口，讓藥物流出。在一實例中，包埋在每一奈米顆粒中的藥物是利用施加一外部磁場來進行控制釋放，所施加的外部磁場功率在約0.05 kA/m至約2.5 kA/m 間，時間持續約10秒至約180秒。此可撓式藥物傳送晶片的厚度不超過0.5mm。 q 透過以下的詳細說明及附隨之請求範圍，可更了解本發明的這些及其他優點。在進一步說明以前，應瞭解在說明書及後附之申請專利範圍中的用語不應被解釋成限制在一般及字典上的意義，基於為了最佳釋明而允許發明人適當地定義用語之原則，應以對應本發明之技術觀點的意義與觀念而為解釋。因此，於此所提之敘述是僅為說明之目的之一較佳實施例，並非意圖限制本發明的範疇，所以應瞭解在不脫離本 ^ 發明之精神及範疇下，對本發明為其他均等意義及修改是可能的。【實施方式】下文中，將配合附圖詳細說明本發明之較佳實施例。以下描述用於活體内磁性誘發藥物釋放的可撓式藥物傳送晶片，其之製備方法與用途。此新穎的可撓式藥物 ..傳送晶片可植入至一個體之欲求的身體部位，以便能主動 201109043 * 地透過遠端控制而將所包埋的藥物釋出至該身體部位，例 , 如，一個體（如，人）的手臂或其他適當的身體部分。製造藥槽室參照第1(a)圖，其為一藥槽室100的示意圖。此藥槽室100可用來建構出本發明的可撓式藥物傳送晶片。藥槽室100的特徵是具有一個「门」形的藥物儲存槽110，其係由形成在可撓式基板130上之多個側壁120所共同界定出來的一藥物儲存空間140。此藥物儲存槽110的特徵是 0 該藥物儲存空間140的至少一側並未被該些側壁120所密封。參照第1(b)圖，其為第1(a)圖之藥物儲存槽110的截面前視圖，在該藥物儲存空間140中依序沉積了多層材料，由底部到頂部包括：一第一層之含有藥物的奈米顆粒層150、一金屬層160、和一第二層之含有藥物的奈米顆粒層150。在另一種實施方式中，上述藥物儲存槽110的兩側，而非一側，並未被該些側壁120所密封，因此其特徵是形 q 成一「L」形或其它形狀的藥物儲存槽110。當所形成的藥物儲存槽110為「L」形時，該儲存槽110的兩相鄰側邊是同時暴露在周圍環境中，因此形成兩個彼此成直角之可供藥物流出的出口。本揭示内容中的可撓式基板一般是由選自以下的材料製成：聚對苯二曱酸乙二酯(PET)、聚（氯乙烯)(PVC)、聚對萘二曱酸乙二酯（PEN)、聚醯亞胺（PI)和聚芳基醚酮 . (polyaryletheretherketone, PEEK)。在一實例中，可撓式基板130是由PET製成。該些側壁120是由生物可相容材料 9 201109043 • 製成，包括，但不限於，包括聚氣乙晞(pvc)、聚丙交酯 - (polylactlde)、聚乙烯、乙烯-乙酸乙烯酯、聚醯亞胺、聚蕴胺、聚乙一醇、聚己内i旨多元醇（polycaprolactone， PCL)、聚甘醇(p〇iyc〇iide)、聚對二氧環己酮(p〇iydioxanone) 及其之衍生物和共聚物。在一實例中，該些側壁是由pvc 製成。每一含有藥物的奈米顆粒是由一含有磁性氧化鐵的核心以及二氧化矽外殼所組成（亦即，Fe3〇4@Si02)，且藥 ❹ 物是被包埋在含有磁性氧化鐵的核心中。此含有藥物的奈米顆粒可依照公開文獻中所揭示的方法來製造，參見Hu et al” “Core/Single-Crystal-Shell Nanospheres for Conducting Drug Release via a Magnetically Triggered Rupturing Mechanism’’，Adv. Mater.，2008 20, 2690-2695，在此併入其全部揭示内容做為參考。一般來說，奈米顆粒的平均直徑在約 10 nm 至約 100 nm 間，例如約 10、15、20、30、40、 50、60、70、80、90 或 100 nm。 q 在本文中「藥物（drug)」或「生物活性物質（biological active substance)」兩名詞可交替使用，並係指可用來治療和/或預防疾病之活性有機物體，且可被施用在動物，如哺乳類動物，特別是人類身上的化合物或組合物。可用於本文中的藥物包括，但不限於：核酸，如DNA或小型干擾性RNA (siRNA);胜肽；蛋白質，如牛血清白蛋白、醣蛋白或膠原蛋白；抗生素；抗氧化劑’如維生素E或維生素C (即，抗壞血酸）；免疫原性製備物，例如疫苗；抗癲癇藥劑，例如乙醯唑磺胺（acetazolamide)、卡馬西平 201109043 (carbamazepine)、可洛巴寧（clobazam)、氯硝安定 (clonazepam)、寧神平（diazepam)、乙玻胺（ethosuximide)、乙苯妥因（ethotoin)、非氨酯（felbamate)、填苯妥因 (fosphenytoin)、加巴潘汀（gabapentin)、樂命達 (lamotrigine)、左乙拉西坦（levetiracetam)、美芬妥因 (mephenytoin)、美沙比妥（metharbital)、甲破胺 (methsuximide)、曱氮酿胺（methazolamide)、除癲達 (oxcarbazepine)、苯巴比妥（Phenobarbital)、苯妥因 (phenytoin)、苯琥胺（phensuximide)、普瑞巴林 (pregabalin)、去氧苯巴比妥(primidone)、丙戊酸鈉（sodium valproate)、司替物醇（stiripentol)、嗟加濱（tiagabine)、托 °比酯（topiramate)、三曱雙酮（trimethadione)、丙戊酸 (valproic acid)、氨己烯酸（vigabatrin)或唑尼沙胺 (zonisamide);抗腫瘤藥劑，例如紫杉醇（taxol)、喜樹鹼 (camptothecin，CPT)、抗癌妥（topotecan，TPT)或治癌妥 (irinotecan, CPT-11);抗菌劑，例如氧化鋅或四級胺化合物；抗病毒藥劑，例如無環鳥苷（acyclovir)、雷巴威林 (ribavirin)、扎那米爾（zanamivir)、奥嗟来爾（oseltamivir)、齊多夫錠(zidovudine)或拉脈優鍵(lamivudine);抗增生藥劑，例如放線菌素（actinomycin)、阿黴素(doxorubicin)、唐黴素（daunorubicin)、戊黴素（valrubicine)、泛達黴素 (idarubicin)、表阿黴素(epirubicin)、博來黴素（bleomycin)、光輝黴素(plicamycin)或絲裂黴素(mitomycin);抗發炎藥劑’例如類固醇（corticosteroids)、布洛芬（ibuprofen)、除癌錠(methotrexate)、阿思匹靈（aspirin)、水楊酸(saliCyClic 201109043 * acid)、二苯氫胺（diphenyhydramine)、人人百炎鍵 (naproxen)、保泰松（phenylbutazone)、吲哚美辛 (indomethacin)或酮基布洛芬（ketoprofen);抗糖尿病藥劑，包括續醯尿素（sulfonylureas)，例如甲苯續丁脲 (tolbutamide)、醋續己脲（acetohexamide)、妥拉續腺 (tolazamide)、氯確丙脲(chlorpropamide)、σ比續環己腺 (glipizide)、格列本腺(glyburide)、格列美脲(glimepiride) 或甲續比脲(gliclazide)，苯丙胺酸衍生物(meglitinides)，例如瑞格列奈(repaglinide)或那格列萘(nateglinide);雙脈類（biguanides)例如二曱双胍（metformin)、苯乙双胍 (phenformin)或丁双胍（buformin); 嗟唾烧二剩類似物 (thiazolidinediones)例如羅格列酮（rosiglitazone)、皮利酮 (pioglitazone)或曲格列酮(troglitazone); α-葡萄糖苷酶抑制劑（alpha_glucosidase inhibitors)例如米格列醇(miglitol)或阿卡波糖(acarbose);類胜肽(peptide analogs)，例如艾塞那肽（exenatide)、利拉鲁肽（liraglutide)、他司鲁肽 ◎ (taspoglutide)、维格列汀（vildagliptin)、佳糖維（sitagliptin) 或普蘭林肽(pramlintide);和荷爾蒙，例如胰島素、表皮生長因子（epidermal growth factor, EGF)和固醇類，例如黃體素、雌激素、腎上腺皮質類固醇和雄性激素。在一實施例中，此藥物為諸如乙琥胺之類的抗癲癇藥劑。依據本發明一實施方式’可包埋在奈米顆粒中的藥物量約在0.01〇/〇至80%(重量％)之間，例如約〇.(H、〇.〇5、〇.卜0.2、0.5、 1、2、5、8、10、12、15、18、20、22、25、28、30、32、 12 201109043 35、38、40、42、45、48、50、52、55、58、60、62、65、 68、70、72、75、78 或 80 %。至於金屬層170中的金屬通常是選自Au、Ag、pt和 Ta中。在一實例中，該金屬是Au。參照第2圖，其詳細繪出如何依據本發明一特定實施方式來形成第1圖之藥槽室100的流程圖200。所述方法是以步驟201開始，其中將一 PET基板剪成適當大小，約 20 mm X 50 mm X 0.02 mm。在步驟202中，將數條裁切成適當大小的PVC條黏在PET基板上，形成一「门」形儲存槽，其特徵是此「门」形儲存槽的一侧並未被該些PVC 條所密封。在步驟203至205中，依序沉積多層材料在「门」形儲存槽中，包括：一第一層之含有藥物的奈米顆粒層（步驟203)、一金屬層（步驟204)、和一第二層之含有藥物的奈米顆粒層（步驟205)。。在步驟203或205中之含有藥物的奈米顆粒層是利用電泳沉積（electrophoretie deposition，EPD)來形成，步驟204中的金屬層則是利用滅鑛沉積（sputter deposition，SD)來形成。電泳沉積一般是以如下步驟來進行：（1)提供一電泳沉積槽，其内包含：一膠體溶液，其中含有約0.01-30〇/〇(重量％)之含有藥物的奈米顆粒，和一對電極；（2)將該可挽式基板(例如’ PET板）浸潰在該電泳沉積槽中的該膠體溶液内’其中該可撓式基板上已建構有上述的藥物儲存槽；和（3)持續施加約1-50伏特的電位到該對電極上約丨_3〇分鐘或是直到該層含有藥物的奈米顆粒層的厚度已達至少0.1微米。上述的膠體溶液是藉由將該含有藥物的奈米 13 201109043 顆粒懸浮在一稀釋用介質中所製備而成的，該稀釋用介質可以是水、Cu醇類、二醇、甘油、二曱亞砜或其之組合。該Cu醇類可選自曱醇、乙醇、丙醇、異丙醇、丁醇、異丁醇、二級-丁醇、戊醇、異戊醇、己醇等類似物中。該電泳沉積槽中該對電極中的每一電極彼此間隔約0.5公分至約5公分的距離。在一實例中，該電泳沉積槽中該兩電極彼此間隔約2公分。此電泳沉積步驟可在約-10°C至約70 °C間的溫度下執行。濺鍍沉積是一種透過濺鍍來沉積材料的物理性沉積技術，也就是說從一靶材來源物（如，一塊金屬）將材料射出，然後將所濺射出來的材料沉積在一塊基板上（例如， PET板）。可用來沉積本發明金屬層的適當濺鍍沉積方法可以是以下任一種：電漿濺鍍、離子束濺鍍、反應性濺鍍、離子辅助沉積、高功率脈衝式磁電管濺鍍(HPIMS)或氣流濺鍍。在一實例中，是利用電漿濺鍍來沉積出一層Au層。一般來說，濺鍍形成的金屬層厚度約在5至10 μπι間。在一實例中，該Au層的厚度為6.5μπι。可視藥槽室中欲求的藥物儲存空間大小，而分別重複實施上述的電泳沉積與濺鍍沉積數次，例如約2、3或4 次。在一實例中，重覆實施兩次上述的電泳沉積，至於濺鍍沉積則僅施行1次。在其他實例中，則是重覆實施相同數目的電泳沉積與濺鍍沉積至少一次，例如約2、3或4 次。 201109043 •建構可於活體内利用磁性來控制釋放藥物的藥物傳送晶 • 片為了建構出藥物傳送晶片300’將兩個依照上述步驟所製成的藥槽室100’以頭·對-頭方式相揍在一起，如第 3(a)圖所示。詳言之’將一個藥槽室1〇〇反轉後放在另一個藥槽室1 〇〇的頂端並使多個侧壁120分別對齊，使得兩個藥槽室100可共同形成一個藥物釋放腔室310。此藥物釋放腔室310的特徵是此腔室有一側並未密封，而是暴露 ❹ 在周圍環境下’因而形成一可供藥物流出的出口。該腔室一般是透過將雨藥槽中該些側壁對齊，使得兩藥槽室上、下相連後所形成的該腔室310仍保持有一侧腔室暴露在周圍環境下。或I ’當以具有兩側未被該些側壁120密封之藥槽室100來建構藥物傳送晶片300時，則所形成的腔室 310會有兩側’而非一侧’暴露在周圍環境下，進而能提供兩個可供藥物洗出的出口。依所述方式建構出來的藥物傳送晶片300 ^般厚度不超過0.5 mm ° q 依上述方式建構出來的藥物傳送晶片300可被植入一個體之一適當的身體部位，例如手臂區域、腦部區域或腹膜腔或是人雜中任一空腔處，端視所需治療的疾病、狀況等而定。本揭示内容的藥物傳送晶片300也表現出良好的機械可撓性’因此在植入後更能順應體内周圍環境的變化。可受益於本揭示内容之藥物傳送晶片300的個體包括’但不限於’人類或非人類的動物。這類非人類的動物包括所有馴養威野生的動物，例如包括靈長類、狗、嚅齒類（如，小鼠或大鼠）、貓、羊、馬或豬等在内的哺乳動物； 15 201109043 ' 以及包括鳥、兩棲動物、渐蜴等在内的非哺乳類動物。在 ·-實例中’因植人本揭示内容之藥物傳送晶片細而受益的個體乃是患有癲癇症的人類。可透過施加功率約在0.05kA/m的外部磁場(magnetic field，MF)’來誘使藥物從每一層含有藥物之奈米顆粒層15〇之奈米顆粒中釋出。所施加^場的強度從約 0.05 kA/m 至約 2.5 kA/m ’ 例如約〇〇5、〇 i、〇 2、 0.3 >0.4 ^0.5>0.6^0.7>0.8^0.9>i.〇M1m；2m；3^ ◎ 1.4 、 1.5 、 1.6 、 1.7 、 1.8 、 1.9 、 2.0 、 2·ι 、 2 2 、 2 3 、 2 4 或2.5 kA/m。施加ΜΓ的期間從約10秒到約18〇秒，例如約 10、20、30、40、50、60、70、80、9〇、1〇〇、11〇 ^、^、^^、^⑺或⑽秒^於藥物釋放 Μ室3H)有-側是與周圍環境相通’因此可保持藥物被緩慢地從腔室中釋出’雖然在某些例子中，即# *，仍有極少量藥物自腔室中釋出。在：發所釋出的藥物量為未經磁性誘發所釋出的藥物量之至少、10倍。在另-實例中，透過重複在適當的間隔後啟動和/或關閉MF’可達成逐步釋出藥物的模式。舉例來說，啟動MF約1分鐘，接著關閉MF約1〇分鐘，然後重複此啟動和關閉的動作至少2、3、4或5次；或是直到累積釋放的藥物量已到達預定程度為止。因此’可透過控^所施加之MF的強度與持續時間，來控制該身體部位中的有效藥物量。換言之，透過適當地調整施加在該個體特定身體部位上之MF的強度與持續時間，可達成以控制釋放的方 201109043 式來控制釋放本發明藥物傳送晶片中包埋在奈米顆粒中的特定藥物。以下’將透過特定實施例及附隨圖示’進一步閣述本發明内容。需知’除非另做說明，否則圖示中相同元件符號代表相同元件。實施例以下實施例係為了闡述本發明特定態樣而提供，本發〇明範疇並不侷限於此。實施例1製造裝载有藥物的奈米顆粒 1.1製造核-殼卩63〇4@8丨〇2奈米顆粒可利用習知的微乳化法和溶凝膠法（sol-gel techniques) 來製造核-殼Fe304@Si02奈米顆粒（#lHuetal.，J· Nanosci· Nanotechnol. (2005) 8:1-5 ;以及 Santra et al” Adv. Mat. (2006) 17:2165-2169)。簡言之，經由高溫分解醋酸鐵 (Fe(acac)3)來合成分散的超順磁氧化鐵(Fe304)奈米顆粒， €) 其中必須執行兩個關鍵步驟。首先，在200°C下生長核，接著升高反應溫度到300°c使氧化鐵奈米顆粒成長到約相同大小。所長成的氧化鐵奈米顆粒平均直徑大約5奈米。為了設計這種核-殼結構’將少量（約0.5毫升）的Fe304懸浮液加到約7.7毫升的環己烷中，進而創造出油相，同時間水相則是由1.6毫升的己醇與0.34毫升的水所組成。接者’將兩相混合並加入2克辛基苯紛聚乙氧基化物（〇ctyl - Phenol ethoxylate)做為界面活性劑來形成水在油中之相溶 • 液。再加入2克TEOS ’使溶液老化約6小時，即可藉由 17 201109043 • 微乳化法和溶凝膠法製造出核-殼Fe304@Si02奈米顆粒。 - 上述方式使得水解和縮合反應得以進行，並經由溶凝膠而合成奈米顆粒。接著以穿透式電子顯微鏡(TEM，JEM_21〇〇, 曰本）檢查所合成的奈米顆粒，並使用電泳式光散射法 (electrophoretic light scattering，ELS)來決定 Zeta 電位。第3(a)至3(c)圖為所製備成的奈米顆粒之高解析度穿透式電子顯微鏡照片（high resolution transmission electron microscopy，HRTEM)。從第3(a)至3(c)圖的照片可確認奈〇米顆粒為平均直徑約300 nm的球形結構，且奈米級磁性粒子是隨機分散並包埋在核中。每一奈米顆粒具有Fe3〇4 結晶為核心和二氧化矽殼層。殼層的厚度大約5_1〇 nm。第4圖中的影像顯示二氧切外殼相當緊實，即使在高解析度的顯微鏡下也看不到孔隙。 1.2包埋有藥物之奈米顆粒的製造與特性分析為了將親水性抗癲癎藥物，乙琥胺(ESM)，包埋到具〇有核·殼結構的奈米難+，先將藥物完全溶解成濃度約 5°/❶的水溶液’接著使用上述合成Fe3〇4@Si〇2奈米顆粒（同上述Hu等人之文章）時所用的乳化製程，將藥物包埋到奈米顆粒中。待藥物被包入奈米顆粒的核心後，再沉積一層 -氧化梦到核心表©上’做為—層可調控藥物釋放模式的阻障材料層。以傅立葉轉換紅外光(FTIR)分析儀來確認此包埋有乙 - 琥胺的Fe3〇4@Sl〇2奈米顆粒，結果示於第5圖中。圖中位在1714 nm處的波峰代表含有乙號胺之奈米顆粒中的 201109043 二 = 用先前文獻(同上述Sa_等人 =!顆粒中釋出’藉此來決定出包埋在奈米顆 •立"、乙號胺篁。第6圖顯示有或無外加磁場誘導的情況下’，Fe304@Si〇2奈来顆粒中釋放出藥物的模式。完整的磁場強度為2.5kA/m。在完整磁場強度作用下，每隔1〇秒抽取少量緩衝液，然後以Ηριχ來對所釋出的乙玻胺 Ο (ESM)i^行定篁，並透過以下方程式⑴來決定出累積釋放出來的藥物量。累積釋放的藥物(％)= ⑽％201109043 - VI. Description of the invention: • Technical field to which the invention pertains The present invention generally pertains to the field of implantable drug delivery devices. In particular, it relates to a device that can be implanted into a body cavity or cavity for controlled release of a drug, a method of manufacture thereof, and a use thereof. [Prior Art] There are many ways to deliver drugs to patients, including oral sputum, nasal inhalation, transmucosal diffusion, subcutaneous and intramuscular injection, parenteral and implantation. Oral has always been the most common way. However, current oral medications, including capsules and ingots, have some disadvantages, such as poor efficacy and non-controlled release resulting in too fast absorption or incomplete absorption, gastrointestinal discomfort and other side effects. In addition, these drugs may not provide a local therapeutic effect and/or may not be able to monitor the release of the drug in real time. A variety of drug delivery devices and/or methods have also been proposed, and it is desirable to deliver the drug more efficiently to the target location within the patient. ❹ In response to these needs, medical devices that can deliver drugs locally have been developed, and it is expected to solve the aforementioned problems associated with systemic administration. The release of the drug can be controlled passively or actively. A device that can control the release of a drug can be found in the devices disclosed in U.S. Patent Nos. 6,808,522 and 6,875,208. Implantable devices are particularly useful for certain conditions that are not easily treated in the current manner or that are not easily accessible to the diseased area. One of the best examples is cancer. Cancer treatment involves administering high doses of toxic compounds such as rapamycin or irinotecan (CPT-11) to patients via intravenous injection. This 201109043 * some toxic compounds cause damage to cells outside the target location. Further, it causes strong side effects in the patient. Accordingly, there is a need for an improved implantable drug delivery system and/or device that has better in vivo compliance and that delivers the drug to the target site in vivo more efficiently without causing significant side effects. The present invention contemplates, manufactures, and employs a novel implantable device to transport a wafer that can actively and distally administer a drug without causing any undesirable side effects by appropriately stimulating a particular part of the individual's body. Animal birch. SUMMARY OF THE INVENTION The present disclosure is directed to a flexible drug delivery cymbal, a method of manufacture and use thereof. The flexible drug delivery wafer is fabricated by electrophoretic deposition of a magnetic core shell (i.e., Fe304@Si〇2) nanoparticle* of a drug onto a conductive substrate. The pullable drug delivery wafer can be implanted into one body part of a body by living body implantation, and can be induced by sputum magnetic force, according to the intensity and time of the applied magnetic field, and the drug is released from the above by means of tanning. Release in Magnetic Core-Shell Nanoparticles: This flexible wafer offers many advantages not offered by conventional drug delivery devices, including improved drug delivery dose accuracy, ease of handling, and broader drug release modes. And better obedience. Accordingly, a first aspect of the present disclosure is to provide a vat chamber _) that can be used to construct the above-described flexible drug delivery wafer. The cartridge chamber includes a replaceable substrate and a drug storage reservoir (a 'dmg-containing reServoir). The drug storage tank is formed on the flexible 201109043* substrate and further includes: a plurality of side walls for defining a drug storage space, wherein at least one side of the drug storage space is not sealed by the side walls a first layer of a drug-containing nanoparticle layer deposited on the flexible substrate in the drug storage space; a metal layer deposited on the first layer of the drug-containing nanoparticle layer; and a second A layer of nanoparticle containing the drug is deposited on the metal layer. In one embodiment, the chamber contains two layers of metal' and each layer of metal is sandwiched between two layers of nanoparticle containing the drug. ❹ In the example 'the plurality of side walls are made of biocompatible materials selected from the group consisting of polyvinyl chloride (PVC), polylactide (p〇iyiactide), polyethylene, ethylene-vinyl acetate, poly醯imine, polyamine, polyethylene glycol, polycaprolactone polyol (P〇lyCapr〇laet〇ne, PCL), polycolide, polydioxanone (p〇iydi〇) Xanone) and its derivatives and copolymers. The flexible drug delivery wafer described above is made of a material selected from the group consisting of polyethylene terephthalate (PET), poly(vinyl chloride) (PVC), and polyethylene naphthalate. PEN), polyimine (PI) and polyfluorene aryl ether ketone (PEEK). Each of the drug-containing nanoparticles is composed of a core containing magnetic iron oxide and a ceria shell, and the drug is embedded in a core containing magnetic iron oxide. In one example, the drug is an anti-epileptic drug. As for the metal in the metal layer, it is selected from the group consisting of Au, Ag, Pt and Ta. In one example, the metal is Au. A second aspect of the present disclosure is to provide a method of manufacturing the above-described tank containing the drug. The method comprises the steps of: providing a flexible substrate; constructing a drug storage tank by forming a plurality of sidewalls on the flexible substrate to define a drug 201109043* storage space, wherein the drug storage space. At least one side is not sealed by the plurality of sidewalls; a first layer of a drug-containing nanoparticle layer is electrophoretically deposited on the flexible substrate in the drug storage space; and a metal layer is sputtered on the first layer On the layer of nanoparticle containing the drug; and electrophoretically depositing a second layer of the nanoparticle containing the drug on the metal layer. In one example, electrophoretic deposition is performed in the following steps: (1) providing an electrophoretic deposition bath comprising: a colloidal solution containing from about 0.01% to about 30% by weight of the drug-containing nanoparticle, And a pair of electrodes; (2) immersing the flexible substrate in the colloidal solution in the electrophoretic deposition bath, wherein the flexible substrate has been constructed with the above-described drug storage tank; and (3) applying about A potential of 1-50 volts is applied to the pair of electrodes for about 1-30 minutes or until the thickness of the layer of nanoparticle containing the drug in the layer has reached at least 0.1 micron. The above colloidal solution is prepared by suspending the drug-containing nanoparticle in a dilution medium, which may be water, Cw alcohol, glycol, glycerin, disulfoxide or a combination of them. Each of the pair of electrodes in the electrophoretic deposition bath is spaced apart from each other by a distance of from about 0.5 cm to about 5 cm. This electrophoretic deposition step can be carried out at a temperature between about -10 ° C and about 70 ° C. In another example, the sputter deposition can be any of the following: ion beam sputtering, reactive sputtering, ion assisted deposition, high power pulsed magnetron sputtering (HPIMS), or gas flow sputtering. The metal in the sputtering reaction is selected from the group consisting of Au, Ag, Pt and Ta. In one example, the metal is Au. A third aspect of the present disclosure is to provide a flexible drug delivery wafer comprising two of the above-described drug chambers in a head-to-head manner, by means of 201109043* to form a drug release chamber. Each of the above chambers is characterized by a layer of metal sandwiched between two layers of the drug-containing nanoparticle layer. The drug release chamber is characterized in that one side of the chamber is exposed to the surrounding environment to provide an outlet for the drug to flow out. In one example, the drug embedded in each nanoparticle is controlled release by application of an external magnetic field, and the applied external magnetic field power is between about 0.05 kA/m and about 2.5 kA/m for a time duration of about 10 seconds to about 180 seconds. The flexible drug delivery wafer has a thickness of no more than 0.5 mm. These and other advantages of the present invention will become more apparent from the detailed description and appended claims. In the course of further explanation, it should be understood that the terms used in the specification and the appended claims should not be construed as limited to the general and lexical meanings, and the principles that allow the inventor to properly define the terms for optimal interpretation, It should be explained in terms of the meaning and concept of the technical point of view of the present invention. Therefore, the description of the present invention is intended to be a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. And modifications are possible. [Embodiment] Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The following describes a flexible drug delivery wafer for magnetically induced drug release in vivo, its preparation method and use. The novel flexible drug: the transfer wafer can be implanted into a body part of a body to actively release the embedded drug to the body part through remote control, such as, for example, , the body of a body (eg, person) or other appropriate body part. Manufacturing the tank chamber Referring to Fig. 1(a), it is a schematic view of a tank chamber 100. This cartridge chamber 100 can be used to construct a flexible drug delivery wafer of the present invention. The medicated chamber 100 is characterized by a "door" shaped drug storage reservoir 110 that is defined by a plurality of sidewalls 120 formed on the flexible substrate 130. The drug storage tank 110 is characterized by 0 that at least one side of the drug storage space 140 is not sealed by the side walls 120. Referring to FIG. 1(b), which is a cross-sectional front view of the drug storage tank 110 of FIG. 1(a), a plurality of layers of material are sequentially deposited in the drug storage space 140, including a first layer from bottom to top. The drug-containing nanoparticle layer 150, a metal layer 160, and a second layer of the drug-containing nanoparticle layer 150. In another embodiment, the two sides of the drug storage tank 110, rather than one side, are not sealed by the side walls 120, and thus are characterized by an "L" shape or other shape of the drug storage tank 110. . When the formed drug storage tank 110 is in the "L" shape, the two adjacent sides of the storage tank 110 are simultaneously exposed to the surrounding environment, thereby forming two outlets at right angles to each other for the drug to flow out. The flexible substrate in the present disclosure is generally made of a material selected from the group consisting of polyethylene terephthalate (PET), poly(vinyl chloride) (PVC), and poly(p-naphthalene diacetate). Ester (PEN), polyimine (PI) and polyaryletheretherketone (PEEK). In one example, the flexible substrate 130 is made of PET. The sidewalls 120 are made of biocompatible material 9 201109043 • including, but not limited to, polyoxyethylene (pvc), polylactide (polylactlde), polyethylene, ethylene vinyl acetate, poly醯imine, polyamine, polyethyl alcohol, polycaprolactone (PCL), polyglycerol (p〇iyc〇iide), polydioxanone (p〇iydioxanone) and Derivatives and copolymers. In one example, the sidewalls are made of pvc. Each of the drug-containing nanoparticles is composed of a core containing magnetic iron oxide and a ceria shell (i.e., Fe3〇4@Si02), and the drug is embedded in a core containing magnetic iron oxide. in. The drug-containing nanoparticle can be produced according to the method disclosed in the publication, see Hu et al ""Core/Single-Crystal-Shell Nanospheres for Conducting Drug Release via a Magnetically Triggered Rupturing Mechanism'', Adv. Mater. , 2008 20, 2690-2695, the entire disclosure of which is incorporated herein by reference. Generally, the nanoparticles have an average diameter of between about 10 nm and about 100 nm, such as about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 nm. q In this context, the terms "drug" or "biological active substance" are used interchangeably and refer to an active organic substance that can be used to treat and/or prevent a disease, and can be administered to an animal. A compound or composition such as a mammal, especially a human. Drugs useful herein include, but are not limited to, nucleic acids such as DNA or small interfering RNA (siRNA); peptides; proteins such as bovine serum albumin, glycoproteins or collagen; antibiotics; antioxidants such as vitamin E Or vitamin C (ie, ascorbic acid); immunogenic preparations, such as vaccines; anti-epileptic agents, such as acetazolamide, carbamazepine 201109043 (carbamazepine), clobazan, clonazepam (clonazepam), diazepam, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, le Lamotrigine, levetiracetam, mephenytoin, metharbital, methsuximide, methazolamide, oxcarbazepine ), Phenobarbital, phenytoin, phensuximide, pregabalin, primidone, sodium valproate, Division Stiripentol, tiagabine, topiramate, trimethadione, valproic acid, vigabatrin or zonisamide ( Zonisamide); anti-tumor agents such as taxol, camptothecin (CPT), topotecan (TPT) or irinotecan (CPT-11); antibacterial agents such as zinc oxide or tetra Amine compound; antiviral agent, such as acyclovir, ribavirin, zanamivir, oseltamivir, zidovudine or vein Lamivudine; anti-proliferative agents, such as actinomycin, doxorubicin, daunorubicin, valrubicine, idarubicin, epidermis Epirubicin, bleomycin, plicamycin or mitomycin; anti-inflammatory agents such as corticosteroids, ibuprofen, metorexate ), aspirin, salicylic acid (saliCyCl) Ic 201109043 * acid), diphenyhydramine, naproxen, phenylbutazone, indomethacin or ketoprofen; antidiabetic agents , including sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chlorpropamide, σ than continuous hexagram (glipizide) ), glyburide, glimepiride or gliclazide, meglitinides, such as repaglinide or nateglinide ; biguanides such as metformin, phenformin or buformin; thiazolidinediones such as rosiglitazone, derpirone (pioglitazone) or troglitazone; alpha-glucosidase inhibitors such as miglitol or acarbose; peptide analogs, such as AI Senatin (exenatid e), liraglutide, taspoglutide, vildagliptin, sitagliptin or pramlintide; and hormones such as insulin, epidermal growth Epidermal growth factor (EGF) and sterols such as lutein, estrogen, adrenocortical steroids and androgens. In one embodiment, the drug is an anti-epileptic agent such as ethosuxamine. According to an embodiment of the present invention, the amount of the drug that can be embedded in the nanoparticle is between about 0.01 〇/〇 and 80% (% by weight), for example, about 〇. (H, 〇.〇5, 〇. , 0.5, 1, 2, 5, 8, 10, 12, 15, 18, 20, 22, 25, 28, 30, 32, 12 201109043 35, 38, 40, 42, 45, 48, 50, 52, 55 , 58, 60, 62, 65, 68, 70, 72, 75, 78 or 80%. The metal in the metal layer 170 is typically selected from the group consisting of Au, Ag, pt and Ta. In one example, the metal is Au. Referring to Figure 2, a detailed flow chart 200 of how to form the drug chamber 100 of Figure 1 in accordance with a particular embodiment of the present invention is depicted. The method begins with step 201 in which a PET substrate is cut into Appropriate size, about 20 mm X 50 mm X 0.02 mm. In step 202, a plurality of PVC strips cut into appropriate sizes are adhered to the PET substrate to form a "door" shaped storage tank, which is characterized by the "door" One side of the shaped storage tank is not sealed by the PVC strips. In steps 203 to 205, a plurality of layers of material are sequentially deposited in the "door" shaped storage tank, including: a first layer of the drug-containing nai a particle layer (step 203), a metal layer (step 204), and a second layer of the drug-containing nanoparticle layer (step 205). The drug-containing nanoparticle layer in step 203 or 205 is utilized. Electrophoretic deposition (EPD) is formed, and the metal layer in step 204 is formed by using sputter deposition (SD). Electrophoretic deposition is generally carried out by the following steps: (1) providing an electrophoretic deposition bath And comprising: a colloidal solution containing about 0.01-30 〇/〇 (wt%) of the drug-containing nanoparticle, and a pair of electrodes; (2) the removable substrate (for example, 'PET board) Soaking in the colloidal solution in the electrophoretic deposition bath 'where the above-described drug storage tank has been constructed on the flexible substrate; and (3) continuously applying a potential of about 1-50 volts to the pair of electrodes _3〇 minutes or until the thickness of the nanoparticle layer containing the drug in the layer has reached at least 0.1 μm. The above colloidal solution is prepared by suspending the drug-containing nano 13 201109043 particles in a dilution medium. Made of The diluent medium may be water, Cu alcohol, glycol, glycerin, disulfoxide or a combination thereof. The Cu alcohol may be selected from the group consisting of decyl alcohol, ethanol, propanol, isopropanol, butanol, isobutanol. In the second-butanol, pentanol, isoamyl alcohol, hexanol, etc. Each of the pair of electrodes in the electrophoretic deposition bath is spaced apart from each other by a distance of from about 0.5 cm to about 5 cm. In an example The two electrodes in the electrophoretic deposition bath are spaced apart from each other by about 2 cm. This electrophoretic deposition step can be carried out at a temperature between about -10 ° C and about 70 ° C. Sputter deposition is a physical deposition technique that deposits material by sputtering, that is, ejecting material from a target source (eg, a piece of metal) and depositing the sputtered material on a substrate ( For example, PET board). Suitable sputtering deposition methods that can be used to deposit the metal layer of the present invention can be any of the following: plasma sputtering, ion beam sputtering, reactive sputtering, ion assisted deposition, high power pulsed magnetron sputtering (HPIMS), or Air flow sputtering. In one example, a layer of Au is deposited by plasma sputtering. Generally, the thickness of the metal layer formed by sputtering is about 5 to 10 μπι. In one example, the Au layer has a thickness of 6.5 μm. The above-mentioned electrophoretic deposition and sputtering deposition are repeated several times, for example, about 2, 3 or 4 times, depending on the size of the desired drug storage space in the drug chamber. In one example, the above electrophoretic deposition was repeated twice, and only one pass was performed for the sputter deposition. In other examples, the same number of electrophoretic deposition and sputter deposition are repeated at least once, for example about 2, 3 or 4 times. 201109043 • Constructing a drug delivery crystal that can utilize magnetic properties to control drug release in vivo. To construct a drug delivery wafer 300', two drug chambers 100' made in accordance with the above steps are in a head-to-head manner. Put together, as shown in Figure 3(a). In detail, 'turn one tank chamber 1 〇〇 and place it on the top of the other tank chamber 1 并使 and align the plurality of side walls 120 respectively, so that the two tank chambers 100 can together form a drug release. The chamber 310. The drug release chamber 310 is characterized in that one side of the chamber is not sealed, but is exposed to the surrounding environment, thereby forming an outlet for the drug to flow out. The chamber is generally aligned by aligning the side walls of the aerosol tank such that the chamber 310 formed by the upper and lower chambers of the two tank chambers remains exposed to the surrounding environment. Or I's when the drug delivery wafer 300 is constructed with the drug chambers 100 that are not sealed on both sides by the side walls 120, the chamber 310 is formed with two sides 'not one side' exposed to the surrounding environment. In turn, two outlets for drug washout can be provided. The drug delivery wafer 300 constructed in the above manner has a thickness of not more than 0.5 mm. The drug delivery wafer 300 constructed in the above manner can be implanted into a suitable body part of one body, such as an arm area and a brain area. Or in any of the peritoneal cavity or human cavity, depending on the disease, condition, etc., to be treated. The drug delivery wafer 300 of the present disclosure also exhibits good mechanical flexibility' so it is more compliant with changes in the surrounding environment of the body after implantation. Individuals of the drug delivery wafer 300 that may benefit from the present disclosure include, but are not limited to, 'human or non-human animals. Such non-human animals include all domesticated wild animals, such as mammals including primates, dogs, caries (eg, mice or rats), cats, sheep, horses, or pigs; 201109043 ' and non-mammals including birds, amphibians, and stag. In the "example", an individual who has benefited from the fineness of the drug delivery wafer implanted in the present disclosure is a human suffering from epilepsy. The drug can be induced to be released from each layer of nanoparticle containing the drug nanoparticle layer 15 by applying an external magnetic field (MF) of about 0.05 kA/m. The intensity of the applied field is from about 0.05 kA/m to about 2.5 kA/m', for example about 〇5, 〇i, 〇2, 0.3 >0.4^0.5>0.6^0.7>0.8^0.9>i.〇M1m;2m; 3^ ◎ 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2·ι, 2 2 , 2 3 , 2 4 or 2.5 kA/m. The period of application of ΜΓ is from about 10 seconds to about 18 sec seconds, for example, about 10, 20, 30, 40, 50, 60, 70, 80, 9 〇, 1 〇〇, 11 〇 ^, ^, ^^, ^ (7) Or (10) seconds in the drug release diverticulum 3H) the - side is in communication with the surrounding environment 'so it can keep the drug slowly released from the chamber' although in some cases, ie # *, there are still very few drugs Released from the chamber. In: The amount of drug released by the hair is at least 10 times the amount of drug released without magnetic induction. In another example, a mode of gradual release of the drug can be achieved by repeating the initiation and/or closure of the MF' after the appropriate interval. For example, the MF is activated for about 1 minute, then the MF is turned off for about 1 minute, and then the activation and shutdown actions are repeated for at least 2, 3, 4, or 5 times; or until the cumulative amount of drug released has reached a predetermined level. Therefore, the amount of effective drug in the body part can be controlled by controlling the intensity and duration of the MF applied. In other words, by appropriately adjusting the intensity and duration of the MF applied to a specific body part of the individual, it is possible to achieve a controlled release of the formula 201109043 to control the release of the specific drug embedded in the nanoparticle in the drug delivery wafer of the present invention. . The present invention will be further described in the following detailed description and the accompanying drawings. It is to be understood that the same element symbols in the drawings represent the same elements unless otherwise indicated. EXAMPLES The following examples are provided to illustrate certain aspects of the invention, and the scope of the invention is not limited thereto. Example 1 Production of Drug-Loaded Nanoparticles 1.1 Preparation of Core-Shells 63〇4@8丨〇2 Nanoparticles can be produced by conventional microemulsification and sol-gel techniques. Core-shell Fe304@Si02 nanoparticle (#lHuetal., J. Nanosci. Nanotechnol. (2005) 8:1-5; and Santra et al" Adv. Mat. (2006) 17:2165-2169). Synthesis of dispersed superparamagnetic iron oxide (Fe304) nanoparticles by pyrolysis of iron acetate (Fe(acac)3), €) where two critical steps must be performed. First, the core is grown at 200 ° C. Then, the reaction temperature is raised to 300 ° C to grow the iron oxide nanoparticles to about the same size. The average diameter of the iron oxide nanoparticles grown is about 5 nm. In order to design such a core-shell structure, a small amount (about 0.5) The milliliters of Fe304 suspension was added to about 7.7 ml of cyclohexane to create an oil phase, while the aqueous phase consisted of 1.6 ml of hexanol and 0.34 ml of water. And adding 2 grams of octyl benzene ethoxylate (〇ctyl - Phenol ethoxylate) as a surfactant to form water in oil The solution and the liquid are added. After adding 2 g of TEOS' to aging the solution for about 6 hours, the core-shell Fe304@Si02 nanoparticle can be produced by the method of 19 201109043 • microemulsification and sol gelation. Hydrolysis and condensation reactions are carried out, and nanoparticles are synthesized via sol gel. The synthesized nanoparticles are then examined by a transmission electron microscope (TEM, JEM_21〇〇, transcript) and electrophoretic light scattering method is used. (electrophoretic light scattering, ELS) to determine the zeta potential. Figures 3(a) to 3(c) show the high resolution transmission electron microscopy (HRTEM) of the prepared nanoparticles. From the photographs of Figures 3(a) to 3(c), it can be confirmed that the nanobe granules are spherical structures having an average diameter of about 300 nm, and the nano-sized magnetic particles are randomly dispersed and embedded in the nucleus. The rice grain has Fe3〇4 crystal as the core and the ceria shell layer. The thickness of the shell layer is about 5_1〇nm. The image in Fig. 4 shows that the dioxodes shell is quite compact, even under a high-resolution microscope. Less than pores. 1.2 packs In the manufacture and characterization of drug-containing nanoparticles, in order to embed the hydrophilic antiepileptic drug, ethylamine (ESM), into the nano-hard shell with a nucleus-shell structure, the drug is completely dissolved into a concentration. The aqueous solution of about 5°/❶ was then used to embed the drug into the nanoparticles using the emulsification process used in the synthesis of Fe3〇4@Si〇2 nanoparticles (the same as in the above-mentioned article by Hu et al.). After the drug is encapsulated in the core of the nanoparticle, a layer of barrier material is deposited as a layer-regulating drug release mode. The Fe3〇4@Sl〇2 nanoparticle embedded with ethyl succinamine was confirmed by a Fourier transform infrared light (FTIR) analyzer, and the results are shown in Fig. 5. The peak at 1714 nm in the figure represents 201109043 in the nanoparticle containing B. II. = Use the previous literature (same as Sa_ et al. = release in the particle above) to determine the embedding in the nanoparticle. •立立", B-amine 篁. Figure 6 shows the mode of release of the drug in the Fe304@Si〇2 Nailai particles with or without the application of an external magnetic field. The complete magnetic field strength is 2.5kA/m. Under the action of the complete magnetic field strength, a small amount of buffer is taken every 1 〇 second, then the released acetaminophen (ESM) is determined by Ηριχ, and the cumulative release is determined by the following equation (1). The amount of drug coming out. Cumulative release of drug (%) = (10)%

L 其中L和Rt分別代表一開始載入至奈米顆粒中的藥量以及在t時間所釋放並累積的藥量。當磁場不存在時’幾乎偵測不到被釋放的藥物，雖然在浸泡20秒後，仍可偵測到極少（約4—5%)但穩定的藥物〇釋出量’ 一般認為這是殘留在奈米顆粒表面上的藥物被洗出所造成的現象。但是，大部分的ESM(〜100%)仍是透過短時間（約30至40秒）的磁場誘導而釋出。此代表可輕易地達成一種爆發式的釋放模式（burst release profile)。此測試不僅顯示出藥物的包埋效率大約為10%左右，同時釋放模示的結果也顯示Fe304@Si02奈米顆粒可對磁場作用產生快速反應。 - Zeta電位分析結果顯示，奈米顆粒的等電位 . (isoelectric point，IEP)大概位在高酸性區域，如下表一所 201109043 示。因此，Fe304@Si02奈米顆粒在pH值約3至12的範圍内，其負電荷有逐漸增加的趨勢。與純Si02奈米顆粒的 Zeta電位比較可知，在純Si02中併入Fe3〇4可稍微中和二氧化矽殼層上的負電荷。此帶有高度負電荷的Fe304@Si02 奈米顆粒，在以乙醇重新分散後，可成為相當穩定的懸浮液，能保持懸浮至少24小時。L wherein L and Rt represent the amount of the drug initially loaded into the nanoparticles and the amount of drug released and accumulated at time t. When the magnetic field is not present, 'the drug that is released is almost not detected. Although it is detected after 20 seconds of immersion, very little (about 4-5%) but stable drug release amount is detected. A phenomenon caused by the washing of the drug on the surface of the nanoparticle. However, most of the ESM (~100%) is still released by magnetic field induction for a short period of time (about 30 to 40 seconds). This representative can easily achieve an explosive release profile. This test not only showed that the embedding efficiency of the drug was about 10%, but also the results of the release model showed that the Fe304@Si02 nanoparticle could react rapidly to the magnetic field. - Zeta potential analysis results show that the isoelectric point (IEP) of the nanoparticle is located in the highly acidic region, as shown in Table 01, 201109043. Therefore, the Fe304@Si02 nanoparticle has a tendency to gradually increase its negative charge in the range of pH about 3 to 12. Comparing with the Zeta potential of pure SiO 2 nanoparticles, it was found that the incorporation of Fe 3 〇 4 in pure SiO 2 slightly neutralized the negative charge on the ruthenium dioxide shell. This highly negatively charged Fe304@Si02 nanoparticle, after redispersing with ethanol, can be a fairly stable suspension that can remain suspended for at least 24 hours.

表一、Zeta電位分析顯示奈米顆粒的等電位大概位在pH 值約3至12的範圍内Table 1. Zeta potential analysis shows that the isopotential of the nanoparticles is approximately in the range of about 3 to 12 pH.

pH值 Si02 的Zeta電位 (mV) Si02@Fe3〇4 的Zeta電位 (mV) 2.85 -36 -11 5.48 -51.6 -41.3 9.06 -53.5 -42.9 11.82 -54.2 -47 實施例2 製造藥物傳送晶片 2.1 製造藥槽室以大小為20毫米X 50毫米x0.02毫米之鍍有ITO (摻雜有銦的氧化錫）的可撓導電板(PET基板，JoinWill Tech Co.，Ltd (台灣），電阻為sq/50Q)作為陽極，並以PVC膠帶在此可撓導電板的三侧作出侧壁，留下一侧是未被膠帶密封的（參見第1圖），用來當作藥物的出口。PET板上可 201109043 • 料進行後_層沉__大概為i平方公分。以大小 '為20毫米X 50毫米x 〇.02毫米之不鏽鋼鐵板(316L)當作陰極，並接續在至溫下於丙酮、乙醇和去離子水中進行超音波震堡清洗。清洗後，以氣氣將陰極風乾。在一燒杯中垂直放入上述之陰極與陽極，彼此相距2公分，此燒杯内同時裝有5/。(重量/〇)的實施例12之含有ESM的奈米顆粒懸浮液。在兩電極間施加約3〇伏特的直流電大約1〇分鐘。沉積完成後’小心地從燒杯中取出基板並在室溫下乾 ❹ 燥約1小時。在30伏特的電位下作用10分鐘，可於基板上沉積出厚度約22 μιη的奈米顆粒層，沉積速度相當於約 2’2 μιη/min。以掃描式電子顯微鏡觀察沉積膜層，可發現膜層呈現均勻多孔狀（第7圖），此表示奈米顆粒可成功地在可撓性基板上組裝成—有秩序的結構。待實施例1.2之包埋有ESM之奈米顆粒(做為第一層）的第一次沉積完成後，可進一步透過濺鍍在第一層上鍍上一層金膜。鍍上金膜的目的有兩個：首先，它可防止第一〇層之奈米顆粒膜層脫落；其次，它可使後續沉積具有導電性。依照所述操作，可接續沉積第二及三層之奈米顆粒膜層’藉以完成藥槽室的製作。經乾燥後，進行分析形成於藥槽室中的多層膜結構，可發現其厚度約70 μιη且具有極佳的結構完整性。此外，也沒有偵測到明顯的分層現象。以顯微鏡觀察發現膜層具有封裝完整之藥物的奈米載體，整個膜層中留下許多均勻 . 分佈、奈米尺寸的空隙。這種封裝完整的奈米結構可能是 ®為奈米顆粒本身具有高負電性，致使顆粒與顆粒間產生 21 201109043 * 排斥力後所造成的。在中性情況下，Zeta電位大概在_42 • mV，此可強力地調節撞擊在陰極板上之奈米顆粒的組裝過程。僅管如此，估計每分鐘每一平方微米的表面積上的奈米顆粒數目可達約350個。 2.2 建構藥物傳送晶片以第2圖所示方式，將兩個實施例21的藥槽室以頭對頭方式進行配置，使晶片的一侧維持開放形態，亦即，〇暴露在週圍職下，做為可供藥物流出的出口。建構的實際方式如第2(a)圖，所得的晶片總厚度約〇 5微米且具有機械可撓性(參見第2(b)圖）。、 2,3分析實施例2.2之藥物傳送晶片的特性以實施例2·2的藥物傳送晶片來進行體外藥物釋放測試°簡言之’以自行製造的交流電磁場產生器，在7〇 kHz 的恒·定頻率下產生磁場，藉以誘發藥物從可撓式藥物傳送 Ο 晶片中流出，並依此檢視此晶片釋放藥物的能力。以逆相高效液體層析法（RPHPLC) (AGILENT TECHNOLOGIES CO. LTD，台灣）來分析釋放測試前與釋放測試後的藥物濃度。取50μ1的藥物溶液注入到HPLC中，將二極陣列偵測器設定在217 nm，以便偵測ESM。HPLC中的移動相是由50%的水(稱為「A相」）以及50%的曱醇(稱為「B相」) 組成’流速為1毫升/分鐘，洗脫的濃度梯度為：〇到5分 : 鐘内’濃度線性增加速率為5-50%之B ; 5到10分鐘，濃度線性降低逮率為50_5%之B;最後則是一段約1〇分鐘的 22 201109043 。一般標準製造方式，將3%(體積比)之 Fe3^@Sl〇2奈米顆粒浸潰在水中，而製備出不包含藥物的 “顆粒懸净液。依照相同步驟製備出測試樣品，其中並使用包埋有ESM的3% (體積比）的Fe3〇4@si〇2奈米顆粒在各種磁性紐條件下，來崎藥物釋賴試。於第8圖中。第8圖顯示在不同強度的磁場(MF)作用下，包括0 A/m (亦即，沒有MF)、L0 kA/m和2 5 kA/m，從可撓式〇曰曰片中釋放出藥物的模式。沒有外加磁場下，所釋放出來的ESM董相當低’在全部60分鐘内，僅有約9_ 的藥物釋出。相反的，在全部60分鐘内，當磁場強度為1〇 kA/m 時，約有40%的ESM釋出，而當磁場強度提高到2 5〇kA/m 時，釋出的ESM量高達100%。這些與磁場強度明顯成比例的藥物釋放模式，顯示施加磁場可有效地誘使藥物從沉積膜層中釋出。透過不同時間的間隔、磁場的開啟或關閉，都可獲得 ❹ 階梯狀的藥物釋出模式，如第9圖所示。當有誘導磁場存在時，可觀察到爆發式的藥物釋放模式，如果沒有磁場誘導，藥物的釋放模式即呈現缓慢釋出模式。基本上，緩慢釋出模式是晶片内部的藥物持續往外流動所造成的結果，源自於外速移除前一階段誘導作用後所產生的直接結果，並#由於晶片釋放藥物所致。在此基礎上，本發明基板上可達成零釋放或接近零釋放的模式’做為晶片的另一種藥物釋放模式。 23 201109043 實施例3 實施例2之藥物傳送晶片的活體内藥物釋放研究在此實例中，使用Long-Evans雄鼠(n=8)，並將所有小鼠隨機分成4組，每組15隻老鼠。所有的小鼠均飼養在室溫、隔音且白天·黑夜各12小時（照光時間從早上7點到晚上7點）且可自由使用食物與水的環境中。整個實驗流程是經過動物照護與使用委員會的認可後實施。簡言之，以巴比妥酸鹽（6〇毫克/毫升，注射）將動物麻醉後，植入記〇錄用電極。接著，將小鼠放在標準的立體定位儀（stereotaxic) 中。在從頭骨内雙向覆蓋皮質層之額骨（相對於前囪，A +2·0, L 2.0)和枕骨區域(A-6.0, L 2.0)中總計鎖進6根不鏽鋼螺絲以記錄皮質的場電位。從尾部到第11節（lambda) 間約2mm處則植入接地電極。以牙科用接合劑將插座固定在頭骨表面。接著以手術線縫合，給予動物抗生素（氯四環黴素)並單獨飼養在籠中，待其復原。在本實驗中使用Long-Evans小鼠的原因，是這類小鼠 Q 經常表現出自發性的突波放電（spike-wave discharge, SWDs)，依據許多方面的證據，已知這種SWDs與癲癇有關係。為了媒認SWDs是經由皮質控制，使用了另一種藥學上的癲癇鼠模型，亦即在Wistar小鼠上注射低劑量戊烯四唑(20毫克/公斤，靜脈注射）。在此初步的動物試驗中，比較了生理食鹽水、乙琥胺(ESM)、内含ESM的奈米顆粒 (ESM-Fe3〇4@Si〇2)、和内含ESm的晶片（ESM_晶片）對、 Long-Evans小鼠之自發性SWDs的效果。將實施例2 3的晶片（大小為5笔米X 5毫米X 〇.〇2毫米）植入小鼠的腹腔 24 201109043 ' :，其它劑量則經由靜脈注射來施予。結果示於第ίο圖 τ 0 第1〇圖繪示出對實驗動物施用生理食鹽水、ESM、Zeta potential (mV) of pH SiO 2 Zeta potential (mV) of Si02@Fe3 〇 4 2.85 -36 -11 5.48 -51.6 -41.3 9.06 -53.5 -42.9 11.82 -54.2 -47 Example 2 Manufacturing drug delivery wafer 2.1 Manufacturing drug The chamber is a flexible conductive plate (PET substrate, JoinWill Tech Co., Ltd., Taiwan) with a size of 20 mm X 50 mm x 0.02 mm plated with ITO (tin oxide doped with indium), resistance is sq/ 50Q) As the anode, the side walls are made of PVC tape on the three sides of the flexible conductive plate, leaving one side unsealed (see Fig. 1) for use as an outlet for the drug. PET board can be 201109043 • After the material is processed, the layer __ is about i square centimeter. A stainless steel iron plate (316L) of size 20 mm x 50 mm x 〇.02 mm was used as the cathode, and ultrasonic cleaning was performed in acetone, ethanol and deionized water at a temperature. After washing, the cathode was air-dried with gas. The above cathode and anode were placed vertically in a beaker at a distance of 2 cm from each other, and the beaker was simultaneously filled with 5/. (Weight/〇) of the ESM-containing nanoparticle suspension of Example 12. A direct current of about 3 volts is applied between the two electrodes for about 1 minute. After the deposition was completed, the substrate was carefully taken out from the beaker and dried at room temperature for about 1 hour. At a potential of 30 volts for 10 minutes, a layer of nanoparticle having a thickness of about 22 μm was deposited on the substrate at a deposition rate equivalent to about 2'2 μm/min. Observation of the deposited film layer by a scanning electron microscope revealed that the film layer was uniformly porous (Fig. 7), which indicates that the nanoparticles can be successfully assembled into an orderly structure on the flexible substrate. After the first deposition of the ESM-coated nanoparticle (as the first layer) of Example 1.2 is completed, a gold film may be further plated on the first layer by sputtering. The gold film is plated for two purposes: first, it prevents the nanoparticle layer of the first layer from falling off; second, it allows the subsequent deposition to be electrically conductive. According to the operation, the second and third layers of the nanoparticle film layer can be successively deposited to complete the preparation of the chamber. After drying, the multilayer film structure formed in the chamber was analyzed and found to have a thickness of about 70 μm and excellent structural integrity. In addition, no significant stratification was detected. Microscopic observation revealed that the membrane layer had a nanocarrier with a packaged drug, leaving a lot of uniform, distributed, nanometer-sized voids throughout the membrane. This encapsulated intact nanostructure may be caused by the high negative charge of the nanoparticles themselves, resulting in a repulsive force between the particles and the particles. In the neutral case, the Zeta potential is approximately _42 • mV, which strongly adjusts the assembly process of the nanoparticles that impinge on the cathode plate. In this case, it is estimated that the number of nanoparticles per square micrometer of surface area per minute can be up to about 350. 2.2 Constructing a Drug Delivery Wafer The two chamber chambers of Example 21 are arranged in a head-to-head manner in the manner shown in Figure 2, so that one side of the wafer is maintained in an open configuration, that is, the crucible is exposed to the surrounding position, For the export of drugs available. The actual construction is as shown in Figure 2(a), and the resulting wafer has a total thickness of about 5 microns and is mechanically flexible (see Figure 2(b)). 2,3 Analysis of the characteristics of the drug delivery wafer of Example 2.2 The drug delivery wafer of Example 2.2 was used for in vitro drug release testing. Briefly, 'self-manufactured AC electromagnetic field generator, constant at 7 kHz A magnetic field is generated at a constant frequency to induce the drug to flow out of the flexible drug delivery wafer, and the ability of the wafer to release the drug is thereby examined. The concentration of the drug before and after the release test was analyzed by reverse phase high performance liquid chromatography (RPHPLC) (AGILENT TECHNOLOGIES CO. LTD, Taiwan). A 50 μl drug solution was injected into the HPLC, and the two-pole array detector was set at 217 nm to detect the ESM. The mobile phase in HPLC consists of 50% water (called "A phase") and 50% sterol (called "B phase"). The flow rate is 1 ml/min. The elution concentration gradient is: 〇 Up to 5 points: In the clock, the linear increase rate of concentration is 5-50% B; 5 to 10 minutes, the linear decrease in concentration is 50_5% B; the last is 22 201109043 for about 1 minute. In a standard manufacturing method, 3% (by volume) of Fe3^@Sl〇2 nanoparticle is immersed in water to prepare a "particle suspension" containing no drug. According to the same procedure, a test sample is prepared, wherein The 3% (by volume) Fe3〇4@si〇2 nanoparticle embedded with ESM was used under various magnetic conditions to solve the drug release test. In Figure 8, Figure 8 shows the different strengths. The magnetic field (MF), including 0 A / m (ie, no MF), L0 kA / m and 25 kA / m, the mode of drug release from the flexible sepal. No external magnetic field Next, the released ESM Dong is quite low', and only about 9% of the drug is released in all 60 minutes. On the contrary, in all 60 minutes, when the magnetic field strength is 1〇kA/m, about 40% The ESM is released, and when the magnetic field strength is increased to 25 〇kA/m, the amount of ESM released is as high as 100%. These drug release modes, which are significantly proportional to the magnetic field strength, show that the applied magnetic field can effectively induce the drug from Released in the deposited film. 阶梯 Stepped drugs can be obtained through different time intervals, magnetic field opening or closing The mode is shown in Figure 9. When there is an induced magnetic field, an explosive drug release mode can be observed. If there is no magnetic field induction, the drug release mode shows a slow release mode. Basically, the slow release mode It is the result of the continuous outward flow of the drug inside the wafer, which is derived from the direct result of the external phase removal before the induction of the previous stage, and # due to the release of the drug by the wafer. On the basis of the substrate of the present invention. A zero release or near zero release mode can be achieved as another drug release mode for the wafer. 23 201109043 Example 3 In vivo drug release study of the drug delivery wafer of Example 2 In this example, Long-Evans male rats were used. (n=8), and all mice were randomly divided into 4 groups of 15 mice each. All mice were housed at room temperature, soundproofed and 12 hours each day and night (lighting time from 7 am to 7 pm) Point) and free to use food and water in the environment. The entire experimental procedure was carried out after approval by the Animal Care and Use Committee. In short, with barbiturate (6〇) Kg/ml, injection) After anesthetizing the animal, implant the electrode for recording. Next, place the mouse in a standard stereotaxic instrument. The frontal bone of the cortical layer is covered in both directions from the skull (relative to the front) In the chimney, A +2·0, L 2.0) and the occipital region (A-6.0, L 2.0), a total of 6 stainless steel screws were locked to record the field potential of the cortex. From the tail to the 11 mm (lambda) about 2 mm The grounding electrode is implanted. The socket is fixed to the surface of the skull with a dental cement. The suture is then sutured, and the animal is given an antibiotic (chlorotetracycline) and housed separately in a cage until it is restored. The reason for the use of Long-Evans mice in this experiment is that these mice often exhibit spontaneous spoke-wave discharges (SWDs), which are known to be based on evidence in many respects. There are relationships. To mediate SWDs via cortical control, another medicinal epileptic mouse model was used, i.e., a low dose of penten-4-tetrazole (20 mg/kg, iv) was administered to Wistar mice. In this preliminary animal experiment, physiological saline, ethyl sulphate (ESM), ESM-containing nanoparticles (ESM-Fe3〇4@Si〇2), and ESm-containing wafers (ESM_chip) were compared. The effect of spontaneous, SWDs on Long-Evans mice. The wafer of Example 2 3 (size 5 x 5 mm X 〇. 〇 2 mm) was implanted into the abdominal cavity of the mouse 24 201109043 ' :, other doses were administered via intravenous injection. The results are shown in Figure τ 0. Figure 1 shows the application of physiological saline, ESM to experimental animals.

、Fe3〇4@Si〇2、和 ESM-晶片後對 SWDs 的影響。SWDs 變化。在此實驗中’分別紀錄了處理前^小時(基虚嬙、與處理後3〇分鐘後的腦波活動。將兩次1小時的基、’平均做為指數。在施用ESM-Fe3〇4@Si〇2與ESM-晶片時’小鼠是被固定在-塑膠箱中並放到線圈中心，然後以磁場刺激(2.5kA/m)使ESM能夠從奈米顆粒中被釋放出來。雖然很難量化釋出到小鼠體内的ESM含量，但可以確定的是，相較於單獨使用ESM (第11A圖）來說，蛊論是從ESM-Fe3〇4@si〇2 (第lm圖）或是從Ε__晶片（第爪)圖）釋出到小鼠體内的ESM量，明顯可減少出現自發性SWDs的數目與其持續期間。雖然植入晶片的實驗部位是腹腔，而非腦部，但從這些活體内收集到的ESM控制釋放數據，僅管仍屬非常初步的結果，已顯示具有ESM的奈米顆粒與晶片可透過外加磁場刺激成功地使藥物釋出，一如體外試驗的一般。同時，被釋出的ESM具有明顯可抑制swDs的治療性效果。如上所遂，本發明之較佳實施例已經參照附圖而詳細地敘述。然而，應瞭解當中所表示為本發明之較佳實施例者，其中詳㈣敘述以及特定的實驗例僅為說明之目的而已，對本發明所屬技術領域中之技術人士而言，由以上詳 25 201109043 - 細地說明，在本發明之範疇與精神内為各式變化與修改是 , 顯而易見的。【圖式簡單說明】為讓本發明之上述和其他目的、特徵、優點與實施例能更明顯易懂，所附圖式之說明如下：第1(a)圖為本發明一實施方式中所述之藥槽室的示意 rg*t · 圓，〇第1(b)圖為第1(a)圖之藥槽室的戴面示意圖；第2圖為本發明一特定實施方式用來製造第丨(&)圖之藥槽室的步驟流程圖；第3(a)圖依據為本發明一實施方式以兩個第i圖所示的藥槽室來建構藥物傳送晶片的示意圖；第3(b)圖示出第3(a)圖之藥物傳送晶片的機械可撓性；第4圖是依據為本發明一實施方式所成之 Fe3〇4@Si〇2奈米顆粒的高解析度電子顯微鏡(HRTEM)照片；第5圖為本發明一實施方式中Fe304@Si02奈米顆粒、ESM和包埋有ESM之奈米顆粒的傅立葉轉換紅外光譜數據；第6圖為依據為本發明一實施方式從包埋有ESM之奈米顆粒中釋放出藥物的模式； 26 201109043 第7圖為依據為本發明一實施方式中基板的掃描式電，子顯微鏡(SEM)照片’ SEM照片顯示基板上的鍍臈具有均一且非孔狀的結構；第8圖為依據為本發明一實施方式，以不同磁場連續刺激實施例2的可撓式晶片後，其釋放出ESM的模式；第9圖依據為本發明一實施方式，在各種磁場誘導情況的下，藥物從實施例2的可撓式晶片釋放的模式；第10圖示出依據本發明實施方式，對實驗動物腹腔〇施用生理食鹽水、乙琥胺(ESM) (28 mg/Kg，ip)、内含ESM 的奈米顆粒（ESM-Fe304@Si〇2) (4〇 mg/Kg，ip)、和内含 ESM的晶片（ESM-晶片）（40 mg/Kg，植入在腹腔)後對實驗動物所表現之SWDs的影響；第11圖示出以生理食鹽水及3種不同形式的ESM來處理Long-Evans小鼠(n=8)後，對其SWDs數目與SWD總持續時間的影響，其中（A)代表施用ESM (0.5 ml，28 mg/Kg, ip)明顯降低SWDs數目與SWD總持續時間，（B)代表施用〇内含 ESM 的奈米顆粒（ESM- Fe304@Si02) (40 mg/Kg，ip) 同樣明顯降低SWDs數目與SWD總持續時間，且(〇代表施用ESM晶片（40 mg/Kg，植入在腹腔），同樣明顯降低 SWDs 數目與 SWD 總持續時間，*p < 0.01，**p<〇.〇〇1。 140 【主要元件符號說明】 100 藥槽 120 側壁藥物儲存空間 110 藥物儲存槽 130可撓式基板 150 含有藥物的奈米顆粒層 27 201109043 方法 • 160 金屬層 200 201-205 步驟, Fe3〇4@Si〇2, and ESM-wafer effects on SWDs. SWDs change. In this experiment, 'the brain hours before treatment were recorded separately (base 嫱, and brain wave activity after 3 minutes after treatment. The base of one hour and 'average as the index. The application of ESM-Fe3〇4 @Si〇2 and ESM-wafer when the mouse was fixed in a plastic box and placed in the center of the coil, then stimulated by a magnetic field (2.5 kA/m) to allow the ESM to be released from the nanoparticle. It is difficult to quantify the ESM content released into mice, but it is certain that compared to ESM alone (Fig. 11A), the paradox is from ESM-Fe3〇4@si〇2 (lm map) Or the amount of ESM released from the Ε__ wafer (claw) map into the mouse significantly reduces the number of spontaneous SWDs and their duration. Although the experimental site of the implanted wafer is the abdominal cavity, not the brain, the ESM controlled release data collected from these organisms is still a very preliminary result. It has been shown that the nanoparticles with ESM and the wafer can be permeable. Magnetic field stimulation successfully releases the drug as in an in vitro test. At the same time, the released ESM has a therapeutic effect that significantly inhibits swDs. As described above, the preferred embodiments of the present invention have been described in detail with reference to the accompanying drawings. However, it is to be understood that the preferred embodiment of the invention is to be understood as the preferred embodiment of the invention, and the specific examples are only for the purpose of illustration. - It is obvious that various changes and modifications are apparent within the scope and spirit of the invention. BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects, features, advantages and embodiments of the present invention will become more <RTIgt; The schematic rg*t · circle of the drug chamber is described, and the first (b) is a schematic view of the wearing of the drug chamber of the first (a); FIG. 2 is a manufacturing embodiment of the present invention. FIG. 3(a) is a schematic view showing the construction of a drug delivery wafer by using two drug chambers shown in FIG. 1 according to an embodiment of the present invention; (b) illustrates the mechanical flexibility of the drug delivery wafer of FIG. 3(a); and FIG. 4 is a high resolution of the Fe3〇4@Si〇2 nanoparticle formed according to an embodiment of the present invention. Electron microscope (HRTEM) photograph; Fig. 5 is a Fourier transform infrared spectrum data of Fe304@Si02 nanoparticle, ESM and ESM-embedded nanoparticle in an embodiment of the present invention; Embodiments of a mode for releasing a drug from an ESM-embedded nanoparticle; 26 201109043 Figure 7 is a Scanning electric, sub-microscope (SEM) photographs of the substrate in the embodiment show that the rhodium plating on the substrate has a uniform and non-porous structure; FIG. 8 is an embodiment of the present invention, which is continuously stimulated by different magnetic fields. After the flexible wafer of Embodiment 2, it releases the mode of ESM; FIG. 9 is a mode of releasing the drug from the flexible wafer of Embodiment 2 under various magnetic field induction conditions according to an embodiment of the present invention; Figure 10 is a diagram showing the application of physiological saline, ethylamine (ESM) (28 mg/Kg, ip), and ESM-containing nanoparticles (ESM-Fe304@Si〇) to the abdominal cavity of experimental animals according to an embodiment of the present invention. 2) (4〇mg/Kg, ip), and the effect of the ESD-containing wafer (ESM-wafer) (40 mg/Kg, implanted in the abdominal cavity) on the SWDs exhibited by the experimental animals; Figure 11 shows The effect of the number of SWDs on the total duration of SWD after treatment of Long-Evans mice (n=8) with physiological saline and three different forms of ESM, wherein (A) represents the administration of ESM (0.5 ml, 28 mg) /Kg, ip) significantly reduces the number of SWDs and the total duration of SWD, and (B) represents the application of nanoparticles containing EMS in the sputum Particles (ESM-Fe304@Si02) (40 mg/Kg, ip) also significantly reduced the number of SWDs and the total duration of SWD, and (〇 represents the application of ESM wafers (40 mg/Kg, implanted in the abdominal cavity), also significantly reducing SWDs Number and total duration of SWD, *p < 0.01, **p<〇.〇〇1. 140 [Main component symbol description] 100 Pharmacy 120 Side wall drug storage space 110 Drug storage tank 130 Flexible substrate 150 Contains drugs Nanoparticle layer 27 201109043 Method • 160 Metal layer 200 201-205 Steps

〇 28〇 28

Claims

201109043 VII. Patent application scope: 1. A medicine chamber, comprising: a flexible substrate; and a drug storage tank formed on a money flexible substrate and comprising: a rate storage;疋出—Drug storage space, wherein the music storage space _ at least - the side is not sealed by the side walls. Ο formula (4) on the pullable layer. & layer metal layer, " in the - The layer contains the drug on the nanoparticle layer. a second layer of a layer of drug-containing nanoparticle deposited on the metal, 2. The chamber of claim 1 wherein the sidewalls are made of a selected biocompatible material, including Polyethylene (pvc), poly(lactide lactide), polyethylene, ethylene vinyl acetate, polyamidamine, polyethylene glycol, polycaprolactone (PCL) , p〇iyC〇iide, p〇iydioxanone, and derivatives and copolymers thereof. 3. The tank chamber of claim 1, wherein the flexible substrate is made of a material selected from the group consisting of: polyethylene terephthalate, (ΡΕτ), polyethylene (PVC) ), polyethylene naphthalate (PEN), poly 29 201109043 brewed imine (PI) and polyaryletherketone (PEEK) ° 4. The tank chamber according to claim 1, Each of the drug-containing nanoparticles comprises a magnetic iron oxide core and a layer of ruthenium dioxide, and the drug is embedded in the magnetic iron oxide core. 5. The chamber of claim 4, wherein the drug is ethosuxamine. 〇 6. The chamber of claim 1 wherein the metal is selected from the group consisting of Au, Ag, Pt and Ta. 7. The drug chamber of claim 1, wherein the drug storage tank comprises two metal layers, and each of the metal layers is a layer of two layers of drug-containing nanoparticle that are lost in the drug storage space. between. Ο 8. A method of manufacturing a drug chamber, comprising: providing a flexible substrate; constructing a drug storage tank for utilizing the definable drug storage space, wherein the drug storage = 芝至夕一The side is not sealed by the plurality of side walls; the neat (tetra) grain layer of the flexible material in the storage space is on the drug 201109043 a metal layer of the antimony ore layer on the first layer of the drug-containing nanoparticle layer; and electrophoretic deposition A second layer of drug-containing nanoparticle layer is on the metal layer. 9. The method according to claim 8, wherein the electrophoretic deposition is carried out according to the following steps: providing an electrophoretic deposition tank comprising: a colloidal solution containing about 0.01-30% by weight of a drug-containing solution therein a nanoparticle, and a pair of electrodes; the colloidal substrate in which the flexible substrate is immersed in the electrophoretic deposition bath; the drug storage tank has been constructed on the flexible substrate; and the addition of about 1_5 The potential of the volts is about i (10) minutes or = to the thickness of the layer of the nanoparticle containing the drug in the layer has reached at least 0.1 micro. . Drug == into, the dilute heart dimethyl sarcoplasm or a combination thereof. The method of claim 8, wherein each of the pair of electrodes in the electrophoretic deposition bath is spaced apart from each other by a distance of about 0.5 cm to about 5 cm. The method of claim 8, wherein the electrophoretic deposition step is performed at a temperature between about -10 ° C and about 70 ° C. The method of claim 8 wherein the metal is selected from the group consisting of Au, The method of claim 8, wherein the sidewalls are made of a biocompatible material selected from the group consisting of polyvinyl chloride (PVC) and polylactide. (polylactide), polyethylene, ethylene-vinyl acetate, poly-imine, polyamine, polyethylene glycol, polycaprolactone (PCL), polycolide, poly-pair The method of claim 8, wherein the flexible substrate is made of a material selected from the group consisting of poly(p-phenylene), and a copolymer thereof. Ethylene diacetate (PET), polyvinyl chloride (PVC), polyethylene naphthalate (PEN), poly brewing A method of claim 8, wherein each of the drug-containing nanoparticles comprises a magnetic iron oxide core and a layer of dioxide. The outer shell, and the drug is embedded in the magnetic iron oxide core. 17. The method of claim 8, wherein the drug is ethosylamine. 18. A flexible drug delivery wafer comprising: Two drug chambers according to claim 1, arranged in a head-to-head manner such that the drug storage spaces of each of the drug chambers are connected to each other to jointly define a drug release chamber, and the drug is released The chamber has one side that is not sealed by the side walls to become a magnetically induced release of the drug. 19. The flexible drug delivery wafer of claim 18, wherein each of the drug-containing wafers is embedded The drug in the nanoparticle is controlled release by application of an external magnetic field, and the applied external magnetic field power is between about 0.05 kA/m and about 2.5 kA/m for a period of time from about 10 seconds to about 180 seconds. As requested in item 19 The flexible wafer-described drug delivery, wherein the drug is to ethosuximide and the thickness of the flexible drug delivery of the wafer is not more than 0.5mm ° 33