TWI306869B - Amphiphilic block copolymers and nano particles comprising the same - Google Patents
Amphiphilic block copolymers and nano particles comprising the same Download PDFInfo
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- TWI306869B TWI306869B TW094147662A TW94147662A TWI306869B TW I306869 B TWI306869 B TW I306869B TW 094147662 A TW094147662 A TW 094147662A TW 94147662 A TW94147662 A TW 94147662A TW I306869 B TWI306869 B TW I306869B
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- Prior art keywords
- copolymerized polymer
- nanocarrier
- segment
- nanoparticle
- polymer
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Description
1306869 九、發明說明： 【發明所屬之技術領域】 本發明係有關於一種高分子，特 生物相容性與生物可分解性之團聯c-種具有 聚高分子之奈米微粒。 子及包含此共 【先前技術】 標的給藥是將治療的藥物送 果，並降低藥物副作用，此研發方向、—直=增加治療的效 最大的挑戰與夢想。利用—個且 樂物開發人員 λα - - ^ 、 &的将性的藥物傳輸載 虹杈冋癌細胞的受樂率，並在腫_ 物，以提高治療的效果’就成為值得研究‘的f J作為傳輸戴體的材料需要具備生物相容以生物;二 的循環性，當注射進人人體内後ί =要具備有長效 測而摧毀或被腎臟排除，進一步才能到達特俱 而將藥物慢慢釋放出來，達到治療致 ^ 1 材料為兩性高分子的二團聯（dibl〇ck 1冑常見的載體 聚合物，其主要是以載體尺寸大倾制=目聯(tdblock)共 識而摧毀，其中有些不具有生物分解體㈣免被辨 寸效應並無法具有穩定的錢性及生―㈣尺 Sugiyama 等人在 Journal of P0lyiner Science A: Polymer Chemistry (2003) 1992-2000 中揭露一種含有鱗酸 膽驗(phosphorylcholine)之兩性材料，此材料是以2_(甲基 0648-A21158TWF(N2)；P13940006TW；david 5 130686彡
* 丙細酰氧基）-乙基石粦酸膽驗（2-(methacryloyl〇xy)-ethyl phosphorylcholine(MPC：>)為親水鏈段，膽固醇（choksteryl) 為疏水鏈段，藉由共聚合方式形成一種兩性枋料，其CMC 、值為2.5xl(T4 wt%〜2.7xl0'5 wt°/〇，此種材料會與膽固醇分 子形成錯合的凝態層狀結構，層與層之間空隙為3.52奈 _ 米’此材料具有良好的血液相容性，並藉由高分子鏈上膽 固醇的疏水性質可包覆親油性藥物於其中。此種新穎性微 胞材料以丙烯酸酯（acrylate)系列MPC為主體，並加上膽固
I 醇鏈段，此種材料聲稱具有良好生物相容性但結構上並不 具有生物可分解特性。
Stenzel 等人在 Macromolecular Bioscience (2004) 445-453中揭露一種具有_酸膽驗(phosphorylcholine)的兩 性共聚合物，可作為具有生物相容性的奈米載體。此種兩 性材料是以聚丙烯酸丁酯（poly (butyl aery late))與聚（2 -丙烯 號氧基乙基鱗酸膽驗）(p〇ly(2-acryloyloxyethyl • phosphorylcholine))以 RAFT 聚合方式（reversible addition fragmentation transfer)產生共聚合物。此種材料其奈米顆粒 大小隨著分子鏈段不同而改變，介於40〜160奈米，此篇 新穎性奈米載體材料以丙烯酸酯（acrylate)系列反應物聚合 而成，並不具有生物可分解特性。
Nakabayashi 等人在 Journal of Biomedical Materials Research 65A (2003) 164-169中揭露一種含有鱗酸膽驗 (phosphorylcholine)之生物可分解性材料，此種生物可分解 性材料為聚乳酸(poly(L-lactide))，磷酸膽鹼為L-α·甘油磷 0648-A21158TWF(N2)；P13940006TW；david 6 1306869 » . • 酸膽驗(L-a-Glycerophosphorylcholine, LGPC)，此種生物可 分解性材料藉由LGPC為起始劑進行開環聚合，合成不同 分子量之聚乳酸。藉由血球細胞實驗發現，當此種生物可 、分解性材料中磷酸膽鹼含量比例越高，越可有效的減少血 • 球細胞的吸附。此材料只具有單一結構之生物可分解性材 料，並不具有微胞性赁，可用於組織工程支架所需之材料。
Oishi 等人在 Polymer (1997) 3109-31 15 中揭露一種含 有碗酸膽驗(phosphorylcholine)的 poly(fumaramate)。此種 新穎的poly(fumaramate)材料在水溶液中具有兩性微胞性 質，益且在fumaramat合成結構中導入異丙基及曱基，用 以改變不同之臨界微胞濃度，其臨界微胞濃度（CMC)為 1.7χ10·3Μ及1χ10·3Μ。將此種材料用於牛血清蛋白吸附實 驗發現，當材料中含有磷酸膽鹼可有效的降低牛i清蛋白 的吸附，可用於體内用之生醫材料應用。
Sommerdijk 等人在 Journal of Polymer Science Part A: _ Polymer Chemistry (2001) 468-474 中揭露一種具有生物相 容性之聚苯乙烯(polystyrenes)。在此種材料側鏈經由接枝 反應分別接上四乙二醇(tetra(ethylene glycol))或鱗酸膽驗 (phosphorylcholine)，經由蛋白質吸附實驗及人類皮膚纖維 母細胞(human dermal fibroblasts)生長實驗發現，若結構中 只單獨含有四乙二醇或磷酸膽鹼並無法減少蛋白質吸附及 纖維母細胞生長，但若同時具有四乙二醇及磷酸膽鹼可有 效降低蛋白質吸附及纖維母細胞生長。
Langer 等人在美國專利 US 5,543，158 及 US 6,007,845 0648-A21158TWF(N2)；P13940006TW；david 7 1306869 •中揭露-生物可分解性的注射式奈米微粒，此微粒為ab 或ABC，其中A為親水鏈段如咖⑷，B為 疏水鏈段如生物可分解的聚乳酸甘醇酸(pLGA)，c為生物 .活性分子如抗體，此微粒可降低在血液中流動時被聚嗟細 ,胞（maCr〇phage)清除之機率，並且可經由末端羥基鍵結生物 活性分子而能對細胞或臟器有iargei效果。在此篇專利中 並沒有提到AB或ABC具有生物辨識隱藏特性，且其c的 鍵結為抗體並非礙酸膽驗(口]：1〇5口11〇71〇11〇1丨1^)。
Kim荨人在美國專利US 6,322,805中揭示一生物可分 解性微胞的藥物包覆組成，此微胞結構為BA、ΑΒΑ或 ΒΑΒ，其中Α為生物可分解性疏水鏈段，Β為親水性聚乙 二醇(PEG)，利用物理包覆方式將紫杉醇(paclitaxel)包覆 於微胞中。共聚合物最佳分子量介於1,430〜6,000，親水 鏈段組成比例為50 wt%〜70 wt%。此專利中所提到三團鏈 為A或B分子鏈段重複，並非ABC。 . Marchant等人在美國專利US 5,741，852中揭露一種具 令抗血栓生成之二團聯共聚合物。此種材料疏水鍵段為生 物可分解性南分子’親水輕段為多醣體，如糊精（dextran) 或肝素(heparin) ’藉由三團聯聚合生成一種具有抗血拴形 成之新賴材料。
Ishihara等人在美國專利US 6,204,324中揭露一種在 水溶液中之高分子含有磷酸膽鹼官能基之製備方式。此種 製備方式為聚合材料結構中含有一填酸膽驗 (phosphorylcholine)的可聚合單體，在無金屬起始劑並且在 0648~A21158TWF(N2)；P13940006TW；david 1306869 水"貝的情況下產生聚合反應，聚合之原始產物以分離膜 之方式進行純化，藉由此種方式可得到一在水溶液中含有 碟酸膽驗官能基之材料，且不純物含量低於2,000ppin。 【發明内容】 本發明提供一種團聯共聚高分子，包括一或多個疏水 性鏈段以及一或多個兩性分子。該團聯共聚高分子更包括 一或多個與該疏水性鏈段鍵結之親水性鏈段。 本發明另提供一種奈米微粒，包括一或多個上述之團 聯共聚高分子。 本發明再提供一種奈米載體，包括上述之奈米微粒以 及一包覆於内之活性物質。 【實施方式】 本發明提供一種團聯共聚高分子，包括一或多個疏水 性高分子以及一或多個兩性分子。 上述共聚高分子可為一兩性團聯共聚高分子。此團聯 共聚高分子可包括CMC值介於0.1〜0.01 wt%的二團聯共聚 高分子，其疏水性鏈段的分子量大體介於1，〇〇〇~30,000， 組成分子可包括聚己内酯(polycaprolactone，PCL)、聚戊内 酯（polyvalerolactone， PVL)、聚乳酸-甘醇酸 (poly(lactide-co-glycolide)，PLGA)、聚乳酸(polylactic acid, PLA)、聚丁 内酉旨（polybutyrolactone, PBL)、聚甘醇酸 (polyglycolide)或聚丙内酯（polypropiolactone，PPL)的聚酯 類。而兩性分子可包括磷酸膽驗(phosphorylcholine，PC)、 石黃酸内錄鹽（sulfobetaine, NS)或胺基酸。 0648-A21158TWF(N2)；P13940006TW；david 9 1306869 % ， 此團聯共聚高分子更包括一或多個與疏水性鏈段鍵結 的親水性鏈段，以形成由親水性鏈段、疏水性鏈段與兩性 分子共同組成的三團聯共聚高分子。親水性鏈段的分子量 ' 大體介於550〜20,000，組成分子可包括聚乙二醇(methoxy ' P〇lyethylene glyc〇l，mPEG)、透明質酸(hyaiur〇nic acid，HA) 成聚麩胺酸(poly-Y-gliitamic acid, PGA)。本發明二或三團 &的共t向分子具有生物可分解性(bi〇_degradabie)及生物 鲁 相容性(bio-compatible)。 本發明另提供一種奈米微粒，包括一或多個上述的團 恥共聚尚分子。此奈米微粒的内部呈疏水性，外部呈親水 性，其粒徑大體介於20〜1，0〇〇奈米。 本發明開發一種新的共聚合物，此新材料同時具有生 物相容性、生物可分解性及生物辨識隱藏性。此類共聚合 物具有親水鏈段及疏水鏈段，其在低濃度時為完全溶解於 水中，當咼於其臨界濃度即形成微胞型態分散於水溶液。 • 此共聚合物同時具有仿細胞膜結構之兩性分子（zwitterions) 官能基，當進入人體内可使其避免體内免疫系統辨識。此 共聚合物的組成物之一可以被水解，水解後剩餘的部分可 溶解於水中，然後挑出體外。 本發明再提供一種奈米载體，包括上述奈米微粒以及 、 —包覆於内的活性物質。 活性物質可包括例如喜樹驗㈣狎加加也)或其衍生物 的脂溶性藥物、生長因子、基因或例如甩於皮膚保養的脂 溶性化妝品成分。此奈米載體可透過口服、經皮吸收、注 0648-A21158TWF(N2) ；P 13940006TW;david 10 1306869 « • 射或吸入等方式進行活性物質的傳輸。 本發明團聯共聚高分子可由下述方式合成。首先，製 備一包括一親水性鏈段與一疏水性鏈段的共聚高分子，例 . 如聚乙二醇-聚己内酯（mPEG-PCL)、聚乙二醇-聚戊内酯 (mPEG-PVL)或聚乙二醇-聚丙内酯（PEG-PPL)。接著，將此 % 共聚高分子溶解於例如二氯曱燒（dichloromethane)的溶劑 中 ，並使其末端連接 上例如 2-c]iloro-2-oxo-l，3,2，dioxapliospholane(COI>)、丁二酸野 ^ (succinic anhydride, SA)或 3-(二甲基胺基）丙基胺 (3-(dimethylamino)propylamine，DMAPA)的化學基團。之 後，將此修飾後的共聚高分子溶於例如乙腈（acetonitrile) 或三氯甲烧(chloroform)的溶劑中，並使其末端再與例如三 曱基胺(trimethylamine, TMA)、1，3-丙烧石黃内酯（l，3-propane sultone，PS)或笨组氨酸(benzyl histidine)的化學基團反應 形成一兩性分子，至此，即可獲得一包括一親水性鏈段、 k 一疏水性鏈段以及一兩性分子的共聚高分子。 Ψ 以下藉由實施例以更進一步說明本發明之特徵及優 點。 【實施例】 【實施例1】 聚乙二醇-聚己内酯-磷酸膽鹼(mPEG-PCL-PC)合成 0648-A21158TWF(N2)；P13940006TW；david 11 1306869 PEG-PCL-OH +
Me3N 60oC，24hr
X
Et3N 0°C; 3-51ir PEG-PCL-0 〇- I/O、 PEG-PCL-0
'N+^l (1)聚乙二醇-聚己内酯(PEG-PCL)聚合反應 dmPEG/Sn2+ r ,
-► mPEGr〇C〇-(CH2)5——OH 160°C Jn
首先，取60克的聚乙二醇(mPEG,分子量5,000)與12 克的己内酯（ε-caprolactone)加入體積250毫升的玻璃反應 器，缓慢升高溫度，直至完全溶解。溫度繼續升高至攝氏 160度後，加入0.38毫升作為觸媒的辛酸錫（stannous 2-ethyl hexanoate)進行聚合反應24小時。產物以二氯曱烷 (dichloromethane)溶解進行純化，再以乙醚（diethyl ether) 再沈;殿。重複上述純化步驟2〜3次，並在攝氏40度真空乾 無24小時’即獲得聚乙二醇-聚己内酯共聚高分子。
(2)聚乙二醇-聚己内酯-COP合成 首先’取5克的聚乙二醇聚己内酯（mpEG-PCL)共聚 合物、0.43克的三乙基胺(triethylamine)與70毫升的二氯 曱烷混合加入於體積250毫升的反應瓶中，溫度控制在攝 氏0度’以機械攪拌至完全溶解。同時，將3.5克的2-氯 -2- 氧代 -1，3,2- 二噁烷磷雜環戊烷 (2-chloro-2-oxo-l，3,2-dioxaphospholane, COP)溶於 30 毫升 的·一鼠甲烧以製備另一 ί谷液。接著，將此.COP溶液綠慢滴 0648-A21158TWF(N2)；P13940006TW;david 12 1306869 • 入反應瓶中。滴入時間約l小時，溫度控制在攝氏o度， 反應4小時。反應完成後，將反應液回溫至室溫，並以 0·45μπι的濾紙過濾，以移除副產物氯化三乙基胺 (triethylammonium chloride)，即獲得聚乙二醇-聚己内酯 -COP共聚高分子。 (3)聚乙二醇-聚己内酯-墙酸膽鹼(mpEG-PCL-PC)合成 首先，取聚乙二醇-聚己内酯-COP與70毫升的乙腈 (acetonitrile)在室溫下混合加入一反應瓶中。接著，將1〇 ’ 毫升的三乙基胺（trimethylamine, 33 wt% in ethanol)滴入反 應瓶中，在攝氏60度條件下攪拌反應24小時。反應完成 後，將溶劑抽乾，再以二氯曱烷/水的混合溶液萃取三次， 之後，將二氯曱烷抽乾並真空乾燥24小時，即得到白色固 體的聚乙二醇-聚己内酯-磷酸膽鹼共聚高分子，其NMR光 譜圖請參閱第1圖。 【實施例2】 聚乙二醇-聚戊内酯-磷酸膽鹼(mPEG-PVL-PC)合成
(1)聚乙二醇-聚戊内酯(PEG-PVL)聚合反應
0648-A21158TWF(N2)；P13940006TW；david 13 1306869 首先，取60克的聚乙二醇(mPEG，分子量5,000)與12 克的聚戊内酯（δ-valerolactone)加入體積250毫升的玻璃反 應器，缓慢升高溫度，直至完全溶解。溫度繼續升高至攝 氏100-160度之間，加入0_38亳升作為觸媒的辛酸錫 (stannous 2-ethyl hexanoate)進行聚合反應24小時。產物以 二氯曱娱：（dichloromethane)溶解並以乙醚（diethyl ether)再 沈澱，得到的白色沈殿物隨後清洗三次並在攝氏40度真空 乾燥24小時，即可獲得聚乙二醇-聚戊内酯共聚高分子。 (2) 聚乙二醇-聚戊内酯-COP合成 首先，取5克的聚乙二醇-聚戊内酯（mPEG-PVL)共聚 合物、0.43克的三乙基胺(triethylamine)與70毫升的二氯 曱烧混合加入於體積250毫升的反應瓶中，溫度控制在攝 氏0度，以機械攪拌至完全溶解。同時，將3.5克的2_氯 -2-氧代-1,3,2-二喔烧構雜環戊烧 (2-chloro-2-oxo-l，3,2-dioxaphospholane，COP)溶於 30 毫升 的二氯甲烷以製備另一溶液。接著，將此COP溶液缓慢滴 入反應瓶中。滴入時間約1小時，溫度控制在攝氏0度， 反應6小時。反應完成後，將反應液回溫至室溫，並以 0.45μπι的滤紙過濾，以移除副產物氯化三乙基胺 (triethylammonium chloride)，抽乾二氯曱烧溶劑後即可獲 得聚乙二醇-聚戊内酯-COP共聚高分子。 (3) 聚乙二醇-聚戊内酯-磷酸膽鹼(mPEG-PVL-PC)合成 首先，取聚乙二醇-聚戊内酯-COP與70毫升的乙腈 (acetonitrile)在室温下混合加入一反應瓶中。接著，將10 0648-A21158TWF(N2)；P13940006TW；david 14 1306869 %
宅升的二乙基fe(trimethylamine, 33 wt% in ethanol)滴入反 應瓶中，在攝氏60度條件下攪拌反應24小時。反應完成 後，將溶劑抽乾，再以二氯甲烷/水的混合溶液萃取三次， 之後，將二氯甲烷抽乾並真空乾燥24小時，即得到白色固 體的聚乙一醇-聚戊内酯-鱗酸膽驗共聚高分子。 【實施例3】 聚乙二醇-聚己内石黃酸内銨鹽（mpEG_pCL_NS)合成 CH3〇-h〇H2CH2〇i^C—(CH2)5—o^-H —. RT ) 〇 m anhydride || 0
CH3O^CH2CH2〇i^C—(CH2)5—〇^LCH2CH2C〇〇H DCC/NHS/ DMAPA χ dichloromethane II f\ (? ch3 CH3〇-hCH2CH2〇ij-C~(CH2)5—O^C—CH2CH2C—ΝΗ(ΟΗ2)3Νκ propane 、Ch3 sultone_ dichloromethane CH3O^CH2CH2〇i^C—(CH2)5~〇i^CHCH2CH2CNH(CH2)3NtcH2)3-S〇3- CH3 (1)聚乙二醇-聚己内酉旨-丁二酸酐(mpEG_pCL_SA)合成 首先，取3克的聚乙二醇-聚已内酯（pEG_pCL)共聚合 物、0.1 克的 4-二曱基胺吡啶（4_dimethylamin〇pyridine, DMAP)與60宅升的一氣甲烧混合加入於體積250毫升的 反應瓶中，溫度控制在攝氏0度，以機械攪拌至完全溶解。 同時，將0.1克的三甲基胺與0.5克的丁二酸酐（succinic anhydride，SA)溶於1〇毫升的二氣曱烷以製備另一溶液。 接著，將此丁二酸酐溶液緩慢滴入反應瓶中。滴入時間約 0648-A21158TWF(N2)；P13940006TW；david 15 1306869 * 1小時，溫度控制在攝氏25度，反應24小時。最後，溶 液以乙醚沈澱三次並真空乾燥24小時，即可獲得聚乙二醇 -聚己内酯-丁二酸酐共聚高分子。 _ (2)聚乙二醇-聚己内酯-TA合成 首先，取2克的聚乙二醇-聚己内酯-丁二酸酐 * (mPEG-PCL-SA)共聚合物、0.2克的1，3-二環己基碳二酸胺 (l，3-dicyclohexylcarbodiimide，DCC)、0.1 克的 N-經基號珀 硫亞氨(N-hydroxysuccinimide，NHS)舆40毫升的二氯甲炫 &混合加入於體積250毫升的反應瓶中，温度控制在攝氏〇 度’以機械攪拌至完全溶解。同時，將0.1克的3-(二甲基 胺基）丙基胺(3-(dimethylamino)propylamine, DMAPA)溶於
10毫升的二氯甲烷以製備另一溶液。接著，將此DMAPA 溶液缓慢滴入反應瓶中。滴入時間約1小時，温度控制在 攝氏25度，反應24小時。最後，溶液以乙醚沈澱三次並 真空乾燥24小時，即可獲得聚乙二醇_聚己内酯-TA共聚 k 高分子。 Ψ (3)聚乙二醇-聚己内酯-磺酸内銨鹽(mPEG-PCL-NS)合成 首先，取0.15克的聚乙二醇-聚己内酯·ΤΑ共聚合物與 60毫升的三氯甲燒混合加入一反應瓶中，溫度控制在攝氏 ’ 0度，以機械攪拌至完全溶解。同時，將0.36克的1，3-丙 烷石黃内酯（l，3-propane sultone，PS)溶於適當量的三氯甲烧 以製備濃度20%的混合溶液。接著，將此混合溶液缓慢滴 入反應瓶中並攪拌。溫度控制在攝氏30度，反應24小時。 最後，溶液以乙醚沈澱三次並真空乾燥24小時，即可獲得 0648-A21158TWF(N2)；P13940006TW；david 16 1306869 • 聚乙二醇-聚己内酯-磺酸内銨鹽共聚高分子，其NMR光譜 圖請參閱第2圖。 【實施例4】 聚乙二醇-聚己内醋-苯組氨酸(mPEG-PCL-benzyl histidine) 合成 t 聚乙二醇-聚己内酯·丁二酸酐（mPEG-PCL-SA)與苯組氨酸 之偶合反應 CH30—fCH2CH2〇-}^-CCH2〇H2CH2CH2CH2〇-)y*-I-
N 。 I jj . jj 丫00H
Ν^νΪ^〇Η DCC CH3〇—rCH2CH20^fCCH2CH2CH2CH3CH20-^CCH2CH2C—N—CHCH2--r—N + ch2 2 -► i \ ό NHS Ϊ CH, 首先，取2克的聚乙二醇-聚己内酯-丁二酸酐 • (mPEG-PCL-SA)共聚合物、0.1547克的1，3-二環己基碳二 酸胺（l，3-dicyclohexylcarbodiimide, DCC)、0.0863 克的 N-羥基珑珀硫亞氨(N-hydroxysuccinimide, NHS)與50毫升的 二氯曱烧混合加入於體積250毫升的反應瓶中，溫度控制 在攝氏40度，以機械攬拌至完全溶解。同時，將0.368克 • 的苯組氨酸溶於1〇〇毫升的f醇以製備另一溶液。接著， 將此苯組氨酸溶液緩慢滴入反應瓶中。溫度控制在攝氏60 度，反應24小時。反應完成後，將反應液回溫至室溫，並 0648-A21158TWF(N2)；P13940006TW；david 17 1306869 % 以〇.45μιη的濾紙過濾，以移除未反應物質，抽乾二氯甲烷 溶劑後，即可獲得聚乙二醇-聚己内酯-苯組氨酸共聚高分 子，其NMR光譜圖請參閱第3圖。 【實施例5】 高分子微胞CMC值測定 本實施例測定微胞CMC值的方法係參照Jeong於1999 年所揭示的方法。首先，將〇.4111]\/[的1，6-二苯基-1,3,5-己 三烯（l，6-diphenyl-l,3,5-liexatriene,· DPH)水溶液與濃度 > 2〜2χ10—4wt%的共聚高分子混合。之後，以一紫外光-可見 光光譜儀測定此混合溶液在波長356奈米位置的吸收值。 最後，將吸收值與高分子濃度對數值作圖，圖中兩不同斜 率的交會點即是此高分子微胞的CMC值。 本發明團鏈共聚高分子之CMC值係列於表1 編號 mPEG分子量 PCL分子量 CMC (g/mole) (g/mole) (χ 10'2wt%) mPEG-PCL-P 5000 1900 3.26 Cl mPEG-PCL-P 5000 1100 17.92 C2 mPEG-PCL- 2000 1000 1.46 NS1 mPEG-PCL- 2000 2000 4.47 NS2 0648-A21158TWF(N2)；P13940006TW；david 18 1306869 mPEG-PCL- 5000 2500 3.95 NS3 mPEG-PCL- 5000 3700 7.76 NS4 表1 【實施例6】 微胞製備與其粒徑分析 首先，取10毫克的兩性團聯高分子溶於1毫升的四氫 呋喃（THF)，以製備一溶液。接著，將此溶液藉由2.5毫升 的注射器緩慢注入30毫升的去離子水中並攪拌之。之後， 將混合溶液置於透析膜中透析24小時，以形成一微胞溶 液。最後，.將此微胞溶液置於透光容器中，以測量微胞粒 徑及利用光子相關光譜（photon correlation spectroscopy)(Malvern Instrument Zetasizer Nano ZS)分析 微胞之粒徑分布，結果如表2所示。 編號 mPEG分子 量 (g/mole) PCL分子量 (g/mole) 粒徑 (nm) mPEG-PCL-PCl 5000 1900 113.8 mPEG-PCL-PC2 5000 1100 mPEG-PCL-NSl 2000 1000 148.3 0648-A21158TWF(N2)；P13940006TW；david 19 1306869 mPEG-PCL-NS2 2000 2000 34.7 mPEG-PCL-NS3 5000 2500 27.2 mPEG-PCL-NS4 5000 3700 一 表2 【實施例7】 體外隱藏性試驗 在血液中，巨嗟細胞(macrophage)辨識外來物質後，會 被活化而產生活性氧物質，因此，藉由活性氧物質含量的 測定可進一步分析微胞對巨噬細胞的隱藏性。首先，將 2’，7’- 二氯二氫螢光素二乙酸酯 (2’,7’-dichlorodihydrofluorescein diacetate, DCFDA)力σ入巨 噬細胞培養液(RAW264.7)中。接著，加入濃度高於CMC 值的微胞溶液並一起培養24小時。過程中，若巨噬細胞備 被微胞活化，則DCFDA會因產生的活性氧而轉變成2’,7’-二氯螢光素(2’，7’-dichIorofluorescin, DCF)，其螢光強度與 活性氧含量成正比。最後，再由流式細胞儀（flow cytometer) 測定微胞的隱藏性。不同條件下DCF的螢光強度係揭露於 圖4〜6 〇 當培養液中無微胞時，平均螢光強度為9.39，如第4 圖所示。當加入mPEG-PCL-PC2微胞時，平均螢光強度為 10.8 ’如第5圖所示。而當加入1 pg的PMA時（正控制組）， 平均螢光強度為20.13，如第6圖所示。由於第4圖與第5 圖呈現的螢光強度相近，因此可知，微胞對巨噬細胞來說 0648-A21158TWF(N2)：P13940006TW；david 20 1306869 ’是具有隱藏性的。 【實施例8】 高分子奈米微粒製備 - 首先’取10毫克的mPEG-PCL-PC加入；[毫升的_甲 基亞楓（dimethyl sulfoxide, DMSO)並擾拌之。/士 ' 付冷康乾燥 移除二甲基亞楓後’加入1亳升，1〇%的蔗糖溶液進行水 合。之後，溶解冷凍乾燥的固體以形成一懸浮液。待超音 波震盪10分鐘後’即形成本發明之高分子奈采微粒 施例利用雷射粒徑分析儀（laser particle size analyzer! Coulter N4 plus)測定微粒尺寸的分布，介於12〇〜丨5〇齐米 【實施例9】 ' 含藥物奈米載體製備 喜樹鹼(camptothecin)為脂溶性藥物的一種，其溶解度 僅3fig/ml。首先，取1毫克的喜樹鹼與1〇毫克的 mPEG_PCL-PC加入1毫升的二曱基亞颯（沿瓜她^ φ sulfoxide，DMSO)並攪拌之。待冷凍乾燥移除二曱基亞楓 後，加入1毫升，10%的蔗糖溶液進行水合。之後，溶解 冷凍乾燥的固體以形成一懸浮液。再經超音波震盪丨〇分 鐘，即形成本發明包覆喜樹鹼的高分子奈米微粒。接著， 將懸浮液以〇·45μπι的濾紙過濾，以移除未包覆的喜樹驗晶 •體。本實施例利用雷射粒徑分析儀（laser particie size analyzer，Coulter N4 plus)測定微粒尺寸的分布，介於 130〜190奈米。本實施例以HPLC測定喜樹鹼在徵胞溶液 中的濃度為〇.9mg/ml。而喜樹鹼的溶解度在此處增加3〇 0648-A21158TWF(N2)；P13940006TW；david 21 1306869 ，倍。 【實施例10】 含藥物奈米載體溶血試驗 - 本實施例依據ASTM規範F756標準測試揭示的測試 方式定量分析高分子微胞包覆或未包覆喜樹鹼時對紅血球 的毒性。由表3的結果可看出，本發明奈来载體為盔溶血 性之載體。 ’奋 載體型式 溶血指數（〇/0) "------- 溶血等級 mPEG-PCL-PCl (不含 喜樹驗） -0.07 ^~-- 無溶血性 mPEG-PCL-PCl(喜樹 驗） 0.44 -~~~—1—-----一 Γ一--——_, 热溶血性 表3 —~~~~ 雖然本發明。，于又，揭露如上，鈇 限定本發明，任何熟習此技藝者，在 、士 4，、亚非, 和範圍内，當可作各種之更動與潤飾不：：本發明之彡 範圍當視後附之申請專利範圍所界定者為.準 I月之^ 0648-A21158TWF(N2)；P13940006TW；david 1306869 ， 【圖式簡早說明】 第1圖係為本發明聚乙二醇-聚己内酯-磷酸膽鹼共聚 高分子之NMR光譜圖。 _ 第2圖係為本發明聚乙二醇-聚己内醋-磺酸内銨鹽共 聚高分子之NMR光譜圖。 第3圖係為本發明聚乙二醇-聚己内酯-苯組氨酸共聚 高分子之NMR光譜圖。 第4〜6圖係為本發明於不同條件下DCF之平均螢光強 ® 度。 【主要元件符號說明】 無。 參 0648-A21158TWF(N2)；P13940006TW；david 23
Claims (1)
1306869 • 十、申請專利範圍： 1· 一種團聯共聚高分子，包括一或多個疏水性鏈段以 及一或多個兩性分子。 . 2·如申請專利範圍第1項所述之團聯共聚高分子，其 中該共聚高分子係為一兩性團聯共聚高分子。 3. 如申請專利範圍第1項所述之團聯共聚高分子，其 中該團聯共聚高分子係包括二團聯共聚高分子。 4. 如申請專利範圍第1項所述之團聯共聚高分子，其 > 中該疏水性鏈段之分子量大體介於1,000〜30,000。 5. 如申請專利範圍第1項所述之團聯共聚高分子，其 中該疏水性鏈段係包括聚酯。 6. 如申請專利範圍第1項所述之團聯共聚高分子，其 中該疏水性鏈段係包括聚己内酯(polycaprolactone，PCL)、 聚戊内醋（polyvalerolactone，PVL)、聚乳酸-甘醇酸 (poly(lactide-co-glycolide)，PLGA)、聚乳酸(polylactic acid, PLA)、聚 丁内醋（polybutyrolactone, PBL)、聚甘醇酸 Ψ (polyglycolide)或聚丙内酉旨（polypropiolactone，PPL)。 7. 如申請專利範圍第1項所述之團聯共聚高分子，其 中該兩性分子係包括罐酸膽驗(phosphorylcholine, PC)、石黃 酸内録鹽（sulfobetaine, NS)或胺基酸。 8. 如申請專利範圍第1項所述之團聯共聚高分子，更 包括一或多個與該疏水性鏈段鍵結之親水性鏈段。 9. 如申請專利範圍第1項所述之團聯共聚高分子，其 中該團聯共聚向分子係包括由親水性鍵段、疏水性鏈段與 0648-A21158TWF(N2)；P13940006TW；david 24 1306869 * • 兩性分子組成之三團聯共聚高分子。 10·如申請專利範圍第8項所述之團聯共聚高分子，其 中該親水性鏈段之分子量大體介於550〜20,000。 - η·如申請專利範圍第8項所述之團聯共聚高分子，其 .中該親水性鏈段係包括聚乙二醇（meih〇Xy p〇iyethylene glycol，mPEG)、透明質酸(hyaluronic acid, HA)或聚麩胺酸 (polyfglutamic acid, PGA)。 > 12·如申請專利範圍第丨項所述之團聯共聚高分子，其 中該共t而分子係具有生物可分解性(bio-degradable)。 ί3_如申請專利範圍第1項所述之團聯共聚高分子，其 中該共聚向分子係具有生物相容性(bi〇_c〇mpatible)。 14. 一種奈米微粒，包括一或多個如申請專利範圍第i 項所述之團聯共聚高分子。 15. 如申凊寻利範圍.弟14項所述之奈来微粒，其中該 奈米微粒之内部疏水性，外部為親水性。 _ 16·如申請專利範圍第14項所述之奈米微粒，其中該 奈米微粒之粒徑大體介於20〜1，〇〇〇奈米。 17. —種奈米載體，包括： 一如申請專利範圍第14項所述之奈米微粒；以及 一活性物質’包覆於該微粒内部。 18·如申請專利範圍第17項所述之奈米載體，其中該 活性物質係包括脂溶性藥物、生長因子、基因或脂溶性化 妝品。 19·如申請專利範圍第17項所述之奈米載體，其中該 0648-A21158TWF(N2)-P13940006TW.david 1306869 Λ • 活性物質係包括喜樹驗(camptothecin)或其衍生物。 20.如申請專利範圍第17項所述之奈米載體，其中該 活性物質係包括用於皮膚保養之脂溶性成分。 . 21.如申請專利範圍第17項所述之奈米載體，其中該 奈米載體係透過口服、經皮吸收、注射或吸入之方式進行 傳輸。
0648-A21158TWF(N2)；P13940006TW；david 26
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| CN110628004B (zh) * | 2019-09-09 | 2021-08-31 | 浙江恒澜科技有限公司 | 一种两亲性大分子抗静电剂及其制备方法 |
| CN110564123B (zh) * | 2019-10-29 | 2021-07-20 | 吉林大学 | 一种聚乳酸/生物玻璃复合材料及制备方法 |
| CN111234143B (zh) * | 2020-03-11 | 2022-08-23 | 河北工业大学 | pH响应性的嵌段共聚物和纳米粒子、制备方法和药物 |
| JP2024507947A (ja) * | 2021-02-26 | 2024-02-21 | ノボマー， インコーポレイテッド | 生分解性ポリエステルの製造方法 |
| CN116004728B (zh) * | 2021-10-21 | 2025-02-28 | 深圳大学总医院 | 一种聚合物包裹的脂质纳米粒及其制备方法、药物制剂 |
| CN114146021A (zh) * | 2021-12-31 | 2022-03-08 | 北京清美联创干细胞科技有限公司 | 一种含表皮生长因子的化妆品组合物及其制备方法 |
| GB2624638A (en) * | 2022-11-22 | 2024-05-29 | Landa Labs 2012 Ltd | Nano-Carriers for Drug Delivery and Methods of Preparing the Same |
| CN115403750B (zh) * | 2022-09-29 | 2023-04-18 | 山东宝斯泰医用材料有限公司 | 一种含羧酸甜菜碱端基的聚乙二醇-聚酯嵌段共聚物及其制备方法 |
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| CA2154166A1 (en) * | 1992-11-19 | 1994-05-26 | Roger E. Marchant | Nonthrombogenic implant surfaces |
| US5543158A (en) * | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
| US6007845A (en) * | 1994-07-22 | 1999-12-28 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
| JP3532692B2 (ja) * | 1995-04-03 | 2004-05-31 | 日本油脂株式会社 | ホスホリルコリン基含有重合体水性溶液および製造方法 |
| KR0180334B1 (ko) * | 1995-09-21 | 1999-03-20 | 김윤 | 블럭 공중합체 미셀을 이용한 약물전달체 및 이에 약물을 봉입하는 방법 |
| US6201072B1 (en) * | 1997-10-03 | 2001-03-13 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| EP1480619B1 (en) * | 2002-03-07 | 2013-08-07 | Biocompatibles UK Limited | Drug carriers comprising amphiphilic block copolymers |
| SE0202619D0 (sv) | 2002-09-05 | 2002-09-05 | Fredrik Nederberg | New Polymers and Applications |
| US20060183863A1 (en) * | 2005-02-14 | 2006-08-17 | Ciphergen Biosystems, Inc. | Zwitterionic polymers |
| US8124128B2 (en) * | 2005-11-08 | 2012-02-28 | Industrial Technology Research Institute | Amphiphilic block copolymers and nano particles comprising the same |
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| US20070104654A1 (en) | 2007-05-10 |
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| US8940333B2 (en) | 2015-01-27 |
| TW200727912A (en) | 2007-08-01 |
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