跳到主要內容

臺灣博碩士論文加值系統

(34.204.169.230) 您好!臺灣時間:2024/02/28 08:04
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:紀政嫻
研究生(外文):Chen Hsien Chi
論文名稱:抗帕金森氏症藥物之傳輸劑型設計研究:以奈米注射及經皮吸收劑型為例
論文名稱(外文):The development and evaluation on drug delivery systems for anti-Parkinson drugs: nano-carriers for injection and transdermal delivery formulation
指導教授:方嘉佑
指導教授(外文):J. Y. Fang
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:138
中文關鍵詞:Apomorphine帕金森氏症Lipid-coated microbubbles超聲波SelegilineSolupor水性凝膠
外文關鍵詞:ApomorphineParkinson’s diseaseLipid-coated microbubblesUltrasoundSelegilineSoluporHydrogel
相關次數:
  • 被引用被引用:1
  • 點閱點閱:541
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
Apomorphine 為專一性之多巴胺促動劑 (dopamine agonist) 主要作用在 D1/D2 受器 (D1/D2 receptor)。本研究試圖發展出適當的藥物載體系統包覆抗帕金森氏症之藥物 apomorphine,本研究的藥物載體 lipid-coated microbubbles 粒徑大小落在 大約 150~380 nm 之間。利用原子力顯微鏡 (AFM) 與超聲波診斷儀觀察 lipid-coated microbubbles 形貌與聲波性質,證實超聲波的導入確實能將 lipid-coated microbubbles 中內相 perfluoropentane 由液體狀態轉變為氣體狀態,而由原子粒顯微鏡顯示出 lipid-coated microbubbles 之形狀爲卵形或葡萄乾形。由安定性實驗證明 lipid-coated microbubbles 確時可以保護 apomorphine 的藥物分解。利用 Franz diffusion cell 試驗證實,apomorphine 經由 lipid-coated microbubbles 包覆後,確實會延緩藥物釋放之時間,達到緩慢釋放之目的,而 lipid-coated microbubbles 具有聲波活性,因此導入 1 MHz 超聲波確實可促進 apomorphine hydrochloride 的藥物釋放含量增加。藥物 apomorphine 藉由 lipid-coated microbubbles 作為藥物載體證實具有相當的安全性與穩定性,因此本研究成功的發展出對於抗帕金森藥物 apomorphine 之藥物傳遞系統。
Selegiline 為治療帕金森氏症之具有選擇性且為不可逆的單胺氧化抑制劑 (MAO-B inhibitor)。帕金森患者多半伴隨吞嚥困難的症狀,對於口服藥物具有一定限制,本研究擬以不同的水性凝膠 (AVC、CMCNa、CU 20、HEC、HPC) 作為藥物載體包覆模式藥物 selegiline 且利用市售之 Solupor® 為藥物釋放控制薄膜,建立完整之系統評估模式,期望能提高藥物治療效果,減少刺激性與皮膚過敏反應,增加病患服藥之依順性。本研究利用直立式體外穿透試驗裝置藉不同種類之動物皮膚對親水性藥物 selegiline 做ㄧ系列機轉探討。由電子顯微鏡可得知不論是藥物釋放控制薄膜或是水性凝膠皆具有多孔特性與交聯結構。水性凝膠與藥物釋放控制薄膜兩者互相比較,則藥物釋放控制薄膜的孔徑較水性凝膠小了許多,而實驗結果也顯示出藥物釋放控制薄膜可作為 selegiline 的藥物傳遞的速率調控者,並且會使得經皮藥物穿透減少,且不同種類之藥物釋放控制薄膜導致模式藥物 selegiline 的藥物穿透速率減少是可以被相互比較的。除此之外,對於水性凝膠而言雖然不會減少藥物的經皮傳遞,但卻與藥物釋放控制薄膜顯示出能有效的降低個體間差異,因為皮膚為個體差異性大的器官,因此這對於經皮輸藥系統而言是十分重要的。藥物經皮傳遞系統中同時使用藥物釋放控制薄膜與水性凝膠作為之實驗結果可證明藥物傳遞的速率決定步驟為藥物釋放控制薄膜,而不是水性凝膠。由實驗結果證實利用不同水性凝膠作為藥物載體,並配合藥物釋放控制薄膜確實可以延長藥物的釋放,達到緩釋的目的,並可克服皮膚間個體差異大的問題,對於日後臨床上之應用有很大的助益。
Apomorphine is a non-selective agonist of D1 and D2 dopamine receptors. Apomorphine is a very effective drug in the management of ‘on-off’ motor response fluctuations in the treatment of Parkinson’s disease. The aim of this present work was to develop acoustically active lipid-coated microbubbles for encapsulation of both apomorphine hydrochloride and apomorphine base to circumvent these delivery problems. The lipid-coated microbubbles were prepared using coconut oil and perfluoropentane as the inner phase, which was emulsified by phospholipids and cholesterol. The lipid-coated microbubbles were characterized in terms of their morphology, size, zeta potential, and drug release. The lipid-coated microbubbles particle size ranged about from 150 to 380 nm, with the differences in changing the coconut oil or perfluoropentane ratio in the formulations. The atomic force microscopy confirmed an oval- or raisin-shaped particle and narrow size-distribution of these systems. Ultrasound imaging confirmed the echogenic activity of lipid-coated microbubbles developed in this study. The stability experiment results indicated that lipid-coated microbubbles could protect apomorphine from degradation in the circulation. The evaporation of lipid-coated microbubbles at 37 °C was also limited. apomorphine hydrochloride and apomorphine base in lipid-coated microbubbles showed retarded and sustained release. Using a 1 MHz ultrasound, an increased release of apomorphine hydrochloride in the presence of plasma could be established, illustrating a possible drug-targeting effect. On the contrary, apomorphine base showed a decreased release by ultrasound application. The lipid-coated microbubbles loading with apomorphine showed promised stability and safety. They were successful in sustaining apomorphine delivery.
Selegiline, also commonly referred to in the clinical and pharmacological literature as L-deprenyl, is an acetylenic derivative of phenethylamine. It acts as an irreversible inhibitor of monoamine oxidase type B (MAO-B), an intracellular enzyme associated with the outer membrane of mitochondria. The present work was aimed to design a transdermal systems of selegiline using hydrogel-based drug reservoir and rate controlling membrane (Solupor polyethylene membrane). Both Solupor membrane and hydrogel showed a cross-linking structure with micropores. Various skin membrance, including nude mice skin, porcine skin, stratum corneum (SC)-stripped skin, delipidized skin and cellulose membrane, were used as permeation barrier to elucidate the mechanisms and pathyway. Drug transfer through Solupor but not hydrogel has been demonstrated to be the rate-limiting step when incorporating the membrane and hydrogel together as the delivery system. The inter-subject variation from the skin was greatly reduced by both Solupor membrane and hydrogel. The results of this study encourage the further investigation of hydrogel-membrane delivery systems for transdermal selegiline administration.
總目錄
頁次
指導教授推薦書
論文口試委員審定書
授權書
誌謝 iv
中文摘要 vi
Abstract ix
總目錄 xi
圖目錄 xvi
表目錄 xix
第一章、緒論 1
第一節、帕金森氏症 1
第二節、模式藥物 5
1. Apomorphine 5
2. Selegiline 8
第三節、奈米級/次微米級藥物載體 12
第四節、Lipid-coated microbubbles 15
第五節、水性凝膠 26
1. Ammonium acryloydimethyltaurate/vinylpyrrolidone copolymer 27
2. Carbopol® Ultrez 20 27
3. Sodium carboxymethyl cellulose 28
4. Hydroxyethyl cellulose 28
5. Hydroxypropyl cellulose 29
第六節、研究動機 30
第二章、材料與方法 34
第一節、試劑、醫材與儀器設備 34
一、試劑與醫材 34
二、儀器 36
第二節、實驗方法 39
第一部份:Lipid-coated microbubbles 實驗方法 39
1. 模式藥物 apomorphine base 製備 39
2. Lipid-coated microbubbles 的製備 39
3. Lipid-coated microbubbles 物理化學性質分析 41
3-1 粒徑 41
3-2 表面電位 41
4. 以原子力顯微鏡顯示 lipid-coated microbubbles 之形態 42
5. 應用超聲波診斷儀觀察 lipid-coated microbubbles 之氣穴現象 42
6. Lipid-coated microbubbles 之安定性實驗 43
7. 在人體血漿環境下不同處方之 lipid-coated microbubbles 包覆 apomorphine 之安定性實驗 43
8. Lipid-coated microbubbles 體外藥物釋放實驗 43
9. Lipid-coated microbubbles 於血漿中體外藥物釋放實驗 45
10. 在超聲波條件下 lipid-coated microbubbles 體外藥物釋放實驗 45
11. Lipid-coated microbubbles 的溶血實驗 45
11-1 紅血球混合懸浮液製備 45
11-2 溶血試驗 46
12. Apomorphine hydrochloride/apomorphine base之 HPLC 分析條件 47
13.統計方法 47
第二部份:水性凝膠實驗方法 48
1. 模式藥物 selegiline 熔點測定 48
2. 模式藥物 selegiline 之油水分布係數 48
3. 模式藥物 selegiline 之皮膚/溶媒分配係數 48
4. 以掃描式顯微鏡顯示藥物釋放控制薄膜之形態 49
5. 以原子力顯微鏡顯示藥物釋放控制薄膜之形態 50
6. 水性凝膠製備 50
7. 以掃描式顯微鏡觀察水性凝膠之形態 50
8. 動物皮膚之皮膚製備 50
8.1正常狀態裸鼠皮、豬皮處理 50
8.2正常狀態小白鼠皮、大白鼠皮處理 51
8.3物理性皮膚處理 51
8.4化學性皮膚處理 51
9. Selegiline之體外藥物釋放實驗 51
10. 藥物釋放控制薄膜之體外藥物釋放實驗 52
11. 水性凝膠之體外藥物釋放實驗 52
12. 結合藥物釋放控制薄膜與水性凝膠之體外藥物釋放實驗 52
13. Selegiline 之 HPLC 分析條件 52
14. 統計方法 53
第三章、實驗結果 54
第一部份:lipid-coated microbubbles 實驗結果 54
1. 模式藥物 apomorphine base 製備 54
2. Lipid-coated microbubbles 的處方設計 59
3. Lipid-coated microbubbles 的物理化學性質評估 60
4. 原子力電子顯微鏡觀察 lipid-coated microbubbles 之形態 64
5. 應用超聲波診斷儀觀察 lipid-coated microbubbles 之氣穴現象 67
6. Lipid-coated microbubbles 之安定性實驗評估 68
7. 在人體血漿環境下不同處方之 lipid-coated microbubbles 包覆 apomorphine 之安定性實驗評估 72
8. Apomorphine hydrochloride 與 apomorphine base 自 lipid-coated microbubbles釋放速率的評估 74
9. 在超音波條件下 lipid-coated microbubbles 對 apomorphine 釋放之評估 77
10. Lipid-coated microbubbles 的溶血實驗評估 84
第四章、實驗相關討論 85
第一部份:lipid-coated microbubbles 之相關討論 85
第二部份:水性凝膠之相關討論 92
第五章、結論 98
參考文獻 101

圖目錄
圖一 不同的抗帕金森藥物之作用位置 6
圖二 Apomorphine、dopamine、levodopa 結構圖 6
圖三 Morphine 製備 apomorphine 示意圖 7
圖四 Selegiline 與其代謝產物 7
圖五 奈米級微粒劑型在肝細胞中躲避 Kupffer cell 示意圖 18
圖六 Microbubbles 及與藥物結合示意圖 16
圖七 Microbubbles 導入超聲波機轉圖 17
圖五 奈米級微粒劑型在肝細胞中躲避 Kupffer cell 示意圖 18
圖八 藥物在 microbubbles 內分布的情形 21
圖九 氣穴現象之能量閥值與超聲波頻率及 microbubbles 粒徑相對關係圖 22
圖十 超聲波誘導 microbubbles 氣穴現象 23
圖十一 本研究所使用之惰性氣體 perfluoropentane 化學結構圖 24
圖十二 超聲波誘導 microbubbles 至標的部位 25
圖十三 Franz diffusion cell 44
圖十四 IR 光譜圖 42
圖十八 Lipid-coated microbubbles 處方有無添加 CH 之粒徑大小差異 (EPC system) 62
圖十九 Lipid-coated microbubbles 處方調高油相與氣體比例之粒徑大小差異 63
圖二十 利用原子力電子顯微鏡觀察 lipid-coated microbubbles 之形態 50
圖二十三 助乳劑 PE 之 lipid-coated microbubble安定性比較 69
圖二十四 助乳劑 DSPE 之 lipid-coated microbubble安定性比較 70
圖二十五 高油相與氣體之 lipid-coated microbubble 安定性比較 71
圖二十七 Apomorphine base 經由 lipid-coated microbubbles 處於人體血漿環境下之安定性比較 73
圖三十一 Lipid-coated microbubbles 處方 (M1) 在血漿中有無導入超聲波之藥物 apomorphine hydrochloride 釋放速率比較 78
圖三十二 Lipid-coated microbubbles 處方 (M9) 在血漿中有無導入超聲波之藥物 apomorphine hydrochloride 釋放速率 79
圖三十三 Lipid-coated microbubbles 處方 (M10) 在血漿中有無導入超聲波之藥物 apomorphine hydrochloride 釋放速率 80
圖三十四 控制組在血漿中有無導入超聲波之藥物 apomorphine base 釋放速率 81
圖三十五 Lipid-coated microbubbles 處方 (M1) 在血漿中有無導入超聲波之藥物 apomorphine base 釋放速率 81
圖三十六 Lipid-coated microbubbles 處方 (M9) 在血漿中有無導入超聲波之藥物 apomorphine base 釋放速率 82
圖三十七 Lipid-coated microbubbles 處方 (M10) 在血漿中有無導入超聲波之藥物 apomorphine base 釋放速率 82
圖三十八 Lipid-coated microbubbles 的溶血率試驗 64
圖三十九 不同角度 Solupor® 經原子力顯微鏡顯影 69

表目錄
表一 帕金森氏症之症狀分期 2
表二 帕金森氏症常見之治療方式 2
表三 現今市面上常見的單胺氧化抑制劑 9
表四 口服與經皮吸收系統之 selegiline 比較 8
表五 磷脂質的結構 18
表六 具有不同取代基的磷脂質 19
表七 Perfluorocarbon 的物化性質 19
表八 Lipid-coated microbubbles 的治療應用 20
表九 本研究之模式藥物 33
表十 溶血試驗不同測試溶液配置 46
Adden, R., Müller, R., Brinkmalm, G, Ehrler, R, Mischnick, Petra, 2006. Comprehensive analysis of the substituent distribution in hydroxyethyl celluloses by quantitative MALDI-ToF-MS. Macromol. Biosci. 6, 435-444.
Apfel, R.E., Holland, C.K., 1991. Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound. Ultrasound Med. Biol. 17, 179-185.
Baert, B., Deconinck, E., Van Gele, M., Slodicka, M., Stoppie, P., Bodé, S., Slegers, G., Vander Heyden, Y., Lambert, J., Beetens, J., De Spiegeleer, B., 2007. Transdermal penetration behavior of drugs: CART-clustering, QSPR and selection of model compounds. Bioorg. Med. Chem. 15, 6943-6955.
Baldessarmni, R.J., Arana, G.W., Kula, N.S., Campbell, A., Harding, M., 1981. Preclinical studies of the pharmacology of aporphines, in: G.L. Gessa, G.U. Corsini (Eds.), apomorphine and other dopamimetics, Raven Press, New York, 219-228.
Bekeredjian, R., Chen, S., Grayburn, P.A., Shohet, R.V., 2005. Augmentation of cardic protein delivery using ultrasound targeted microbubble destruction. Ultrasound Med. Biol. 31, 687-691.
Borden, M.A., Pu, G., Runner, G.J., Longo, M.L., 2004. Surface phase behavior and microstructure of lipid/PEG-emulsifier monolayer-coated microbubbles. Colloid. Surf. B: Biointerface 35, 209-223.
Buhse, L., Kolinski, R., Westenberger, B., Wokovich, A., Spencer, J., Chen, C.W.,Turujman, S., Gautam-Basak, M., Kang, G.J., Kibbe, A., Heintzelman, B., Wolfgang, E., 2005. Topical drug classification. Int. J. Pharm. 295, 101-112.
Buszello, K., Harnisch, S., Müller, R.H., Müller, B.W., 2000. The influence of alkali fatty acids on the properties and the stability of parenteral O/W emulsions modified with Solutol HS151. Eur. J. Pharm. Biopharm. 49, 143-149.
Byrappa, K., Ohara, S., Adschiri, T., 2008. Nanoparticles synthesis using supercritical fluid technology-towards biomedical applications. Adv. Drug Deliv. Rev 60, 299-327.
Castro-Puyana, M., Lomsadze, K., Crego, A.L., Marina, M.L., Chankvetadze, B., 2007. Separation of enantiomers of deprenyl with various CDs in CE and the effect of enantiomer migration order on enantiomeric impurity determination of selegiline in active ingredients and tablets. Electrophoresis 28, 388-394.
Chen, H., Chang, X., Du, D., Liu, W., Liu, J., Weng, T., Yang, Y., Xu, H., Yang, X., 2006. Podophyllotoxinloaded solid lipid nanoparticles for epidermal targeting. J. Control. Release 110, 296-306.
Chen, J.J., Obering, C., 2005. A review of intermittent subcutaneous apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson’s disease. Clin. Ther. 27, 1710-1724.
Chen, R.C., Chang, S.F., Su, C.L., 2001. Prevalence, incidence, and mortality of PD: a door-to-door survey in Ilan country, Taiwen. Neurology 57, 1670-1686.
Chen, R.H., Chen, W.Y., 2003. Skin hydration effects, film formation time, and physicochemical properties of a moisture mask containing Monostroma nitidium water-soluble mucilage. J. Cosmet. Sci. 54, 9-20.
Chin, Y.W., Balunas, M.J., Chai, H.B., Kinghorn, A.D., 2006. Drug discovery from natural sources. AAPS J. 8, 239-253.
Chiumiento, A., Dominguez, A., Lamponi, S., Villalonga, R., Barbucci, R., 2006. Anti-inflammatory properties of superoxide dismutase modified with carboxymetil-cellulose polymer and hydrogel. J. Mater. Sci. Mater. Med. 17, 427-435.
Chung, H., Kim, T.W., Kwon, M., Kwon, I.C., Jeong, S.Y., 2001. Oil components modulate physical characteristics and function of the natural oil emulsions as drug or gene delivery system. J. Control. Release 71, 339-350.
Clarke, A., Brewer, F., Johnson, E.S., Mallard, N., Hartig, F., Taylor, S., Corn, T.H., 2003. A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J. Neural. Transm. 110, 1241-1255.
Constandinides, P.P., Lambert, K.J., Tustian, A.K., Schneider, B., Lalji, S., Ma, W., Wentzel, B., Kessler, D., Worah, D., Quay, S.C., 2000. Formulation development and antitumor activity of a filter-sterilizable emulsion of paclitaxel. Pharm. Res. 17, 175-182.
Costa, P., Lobo, J.M.S., 2001. Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci. 13, 123-133.
Crum, L.A., Roy, R.A., Dinno, M.A., Church, C.C., Apfel, R.E., Holland, C.K., Madanshetty, S.I., 1992. Acoustic cavitation produced by microsecond pulses of ultrasound: a discussion of some selected results. J. Acoust. Soc. Am. 91, 1113-1119.
Danhof, M., Van der Geest, R., Laar, T., Bodde, H.E., 1998. An integrated pharmacokinetic-pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson’s disease. Adv. Drug Deliv. Rev. 33, 253-263.
Doh, H.J., Cho, W.J., Yong, C.S., Choi, H.G., Kim, J.S., Lee, C.H., Kim, D.D., 2003. Synthesis and evaluation of Ketorolac ester prodrugs for transdermal delivery. J. Pharm. Sci. 92, 1008-1017.
Elkashef, A., Fudala, P.J., Gorgon, L., Li, S.H., Kahn, R., Chiang, N., Vocci, F., Collins, J., Jones, K., Boardman, K., Sather, M., 2006. Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence. Drug Alcohol Depend. 85, 191-197.
Fang, J.Y., Chen, J.P., Leu, Y.L., Hu, J.W., 2008. The delivery of platinum drugs from thermosensitive hydrogels containing different ratios of chitosan. Drug Deliv. 15, 235-243.
Fang, J.Y., Chen, J.P., Leu, Y.L., Wang, H.Y., 2006. Characterization and evaluation of silk protein hydrogels for drug delivery. Chem. Pharm. Bull., 54, 156-162.
Fang, J.Y., Huang, Y.B., Wang, H.Y., Tsai, Y.H., 2005. Electrically-assisted skin permeation of two synthetic capsaicin derivatives, sodium nonivamide acetate and sodium nonivamide propionate, via rate-controlling polyethylene membranes. Biol. Pharm. Bull., 28, 1695-1701.
Fang, J.Y., Hung, C.F., Liao, M.H., Chien, C.C., 2007. A study of the formulation design of acoustically active lipospheres as carriers for drug delivery. Eur. J. Pharm. Biopharm. 67, 67-75.
Fang, J.Y., Hwang, T.L., Huang, Y.L., Fang, C.L., 2006. Enhancement of the transdermal delivery of catechins by liposomes incorporating anionic surfactants and ethanol. Int. J. Pharm. 310, 131-138.
Fang, J.Y., Lee, W.R., Shen, S.C., Huang, Y.L., 2006. Effect of liposome encapsulation of tea catechins on their accumulation in basal cell carcinomas. J. Dermatol. Sci. 42, 101-109.
Farinha, A., Toscano, C., Campos, R., Bica, A., Hadgraft, J., 2003. Permeation of naproxen from saturated solutions and commercial formulations through synthetic membranes. Drug Dev. Ind. Pharm. 29, 489-494.
Feiger, A.D., Rickels, K., Rynn, M.A., Zimbroff, D.L., Robinson, D.S., 2006. Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial. J. Clin. Psychiatry 67, 1354-1361.
Fernandez, H.H., Chen, J.J., 2007. Monoamine oxidase inhibitors: current and emerging agents for Parkinson disease. Clin. Neuropharmacol. 30, 150-168.
Foley, P., Gerlach, M., Youdim, M.B.H., Riederer, P., 2000. MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders? Parkinsonism Relat. Disord. 6, 25-47.
Frampton, J.E., Plosker, G.L., 2007. Selegiline transdermal system in the treatment of major depressive disorder. Drugs 67, 257-265.
Gancher, S.T., Nutt, J.G., Woodward, W.R., 1991. Absorption of apomorphine by various routes in Parkinsonism. Mov. Disord. 6, 212-216
Goldin, B., Touitou, E., 2007. Transdermal skin drlivery: predicitions for humans from in vivo, ex in vivo and animal models. Adv.Drug Deliv. Rev. 59, 1152-1161.
Heal, D.J., Pierce, D.M., 2006. Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system. CNS Drugs 20, 713-738.
Hernot, S., Klibanov, A.L., 2008. Microbubbles in ultrasound-triggered drug and gene delivery. Adv. Drug Deliv. Rev. 60, 1153-1166.
Hoehn, M.M., Yeahr, M.D., 1967. Parkinsonsonism: onset progression, and mortality. Neurology 17, 427-427.
Holtzheimer, P.E., Nemeroff, C.B., 2006. Advances in the treatment of depression. NeuroRx 3, 42-56.
Howland, R.H., 2006. Transdermal selegiline: a novel MAOI formulation for depression. J. Psychosoc. Nurs. 44, 9-12.
Huang, Z.R., Hung, C.F., Lin, Y.K., Fang, J.Y., 2008. In vitro and in vivo evaluation of topical delivery and potential dermal use of soy isoflavones genistein and daidzein. Int. J. Pharm., 364, 36-44.
Hung, C.H., Lin, Y.K., Huang, Z.R., Fang, J.Y., 2008. Delivery of resveratrol, a red wine polyphenol, from solutions and hydrogels via the skin. Biol. Pharm. Bull. 31, 955-962.
Ingram, W.M., Priston, M.J., Sewell, G.J., 2006. Improved assay for R (-)-apomorphine with application to clinical pharmacokinetic studies in Parkinson’s disease. J. Chromatogr. B 831, 1-7.
Ishii, F., Nagasaka, Y., 2004. Interaction between erythrocytes and free phospholipids as an emulsifying agent in fat emulsions or drug carrier emulsions for intravenous injections. Colloid. Surf. B: Biointerface 37, 43-47.
Ishii, F., Saski, I., Ogata, H., 1990. Effect of phospholipids emulsifiers on physicochemical properties of intravenous fat emulsions and/or drug carrier emulsions. J. Pharm. Pharmacol. 42, 513-515.
Jumaa, M., Müller, B.W., 1998. The effect of oil components and homogenization condition on the physicochemical properties and stability of parenteral fat emulsions. Int. J. Pharm. 163, 81-89.
Katzhendler, I., Hoffman, A., Goldberger, A., Friedman, M., 1997. Modeling of drug release from erodible tablets. J. Pharm. Sci. 86, 110-115.
Kawakami, S., Yamashita, F., Hashida, M., 2000. Deposition characteristics of emulsions and incorporated drugs after systemic or local injection. Adv. Drug Deliv. Rev. 45, 77-88.
Kim, S.W., Bae, Y.H., Okno, T., 1992. Hydrogels: swelling, drug loading, and release, Pharm. Res. 9, 283-290.
Kleirolomoom, A., Dayton, P.A., Lum, A.F.H., Little, E., Paoli, E.E., Zheng, H., Ferrara, K.W., 2007. Acoustically-active microbubbles conjugated to liposomes: characterization of a proposed drug delivery vehicle. J. Control. Release 118, 275-284.
Kleirolomoom, A., Dayton, P.A., Lum, A.F.H., Little, E., Paoli, E.E., Zheng, H., Ferrara, K.W., 2007. Acousticallyactive microbubbles conjugated to liposomes: Characterization of a proposed drug delivery vehicle. J. Control. Release 118, 275-284.
Klibanov, A., 1999. Targeted delivey of gas-filled microsphere, contrast agents for ultrasound imaging. Adv. Drug Deliv. Rev. 37, 139-157.
Korpanty, G., Chen, S., Shohet, R.V., Ding, J., Yang, B., Frenkel, P.A., Grayburn, P.A., 2005. Targeting of the VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles. Gene Ther. 121, 305-312.
Kreuter, J., 2007. Nanoparticles-a historical perspective. Int. J. Pharm. 331, 1-10.
Kyosuke, Y., Fuminori, M., Takeo, M., Miyata, Y., Hiroko, I., 2007. Phagocytosis of ultrasound contrast agent microbubble by Kupffer cells. Ultrasound. Med. Biol. 33, 318-325.
Lanza, G.M., Wallace, K.D., Scott, M.J., Cacheris, W.P., Abendschein, D.R., Christy, D.H., Sharkey, A.M., Miller, J.G., Gaffney, P.J., Wickline, S.A., 1996. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation 94, 3334-3340.
Li, G.L., Danhof, M., Bouwstra, J.A., 2001. Iontophoretic delivery of apomorphine in vitro: physicochemic considerations. Pharm. Res. 18, 1509-1513.
Li, G.L., de Vries, J.J., van Steeg, T.J., van den Bussche, H., Maas, H.J., Reeuwijk, H.J.E.M., Danhof, M., Bouwstra, J.A., van Laar, T., 2005. Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment. J. Control. Release 101, 199-208.
Liu, Y., Miyoshi, H., Nakamura, M., 2006. Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. J. Control. Release 114, 89-99.
Lombardi Borgia, S., Regehly, M., Sivaramakrishnan, R., Mehnert, W., Korting, H.C., Danker, K., Röder, B., Kramer, K.D., Schäfer-Korting, M., 2005. Lipid nanoparticles for skin penetration enhancement - correlation to drug localization within the particle matrix as determined by fluorescence and parelectric spectroscopy. J. Control. Release 110, 151-163.
Löscher, W., Hönack, D., 1995. Anticonvulsant and antiepileptogenic effect of L-deprenyl (selegiline) in the kindling model of epilepsy. J. Pharmacol. Exp. Ther. 274, 307-314.
Lu, W., Jiang, W., Chen, J., Yin, M., Wang, Z, Jiang, X., 2008. Modulation of brain delivery and copulation by intranasal apomorphine hydrochloride. Int. J. Pharm. 349, 196-205.
Lum, A.F.H., Borden, M.A., Dayton, P.A., Kruse, D.E., Simon, S.I., Ferrara, K.W., 2006. Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles. J. Control. Release 111, 128-134.
McDannold, N., Vykhodtseva, N., Hynynen, K., 2008. Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med. Biol. 34, 834-840.
Mi, F.L., 2005. Synthesis and characterization of a novel chitosan-gelatin bioconjugate with fluorescence emission. Biomacromol. 6, 975-987.
Montenegro, L., Carbone, C., Maniscalco, C., Lambusta, D., Nicolosi, G., Ventura, C.A., Puglisi, G., 2007. In vitro evaluation of quercetin-3-O-acyl esters as topical prodrugs. Int. J. Pharm. 336, 257-262.
Müller, R.H., Mäder, K., Gohla, S., 2000. Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur. J. Pharm. Biopharm. 50, 161-177.
Nagayasu, A., Uchiyama, K., Kiwada, H., 1999. The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv. Drug Deliv. Rev. 40, 75-87.
Narasimhan, B., Peppas, N.A., 1997. Molecular analysis of drug delivery systems controlled by dissolution of the polymer carrier. J. Pharm. Sci. 86, 297-304.
Ooms, F.G.B., Kedlder, E.M., Schoonman, J., Gerritis, N., Smedinga, J., Calis, G., 2001.Performance of Solupor® separator materials in lithium ion batteries. J. Power Sources. 97-98, 598-601.
Pae, C.U., Lim, H.K., Han, C, Neena, A, Lee, C, Patkar, A.A., 2007. Selegiline transdermal system: Current awareness and promise. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1153-1163.
Pancholi, K.P., Farook, U., Moaleji, R., Stride, E., Edirisinghe, M.J., 2007. Novel methods for preparing phospholipid coated microbubbles. Eur. Biophys. J. 37, 515-520.
Patkar, A.A., Pae, C.U., Masand, P.S., 2006. Transdermal selegiline: the new generation of monoamine oxidase inhibitors. CNS Spectr. 11, 363-375.
Peira, E., Scolari, P., Gasco, M.R., 2001. An integrated pharmacokinetic- pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson’s disease. Int. J. Pharm. 226, 47-51.
Pfeiffer, R.F., Gutmann, L., Hull Jr, L.K., Bottini, P.B., Sherry, J.H., 2007. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinsonism Relat. Disord. 13, 93-100.
Piras, A.M., Chiellini, F., Chiara, F., Bartoli, C., Chiellini, E., Fiorentino, B., Farina, C., 2008. A new biocompatible nanoparticle delivery system for the release of fibrinolytic drugs. Int. J. Pharm. 357, 260-271.
Pisani, E., Tsapis, N., Paris, J., Nicolas, V., Cattel, L., Fattal, E., 2006. Polymeric nano/microcapsules of liquid perfluorocarbons for ultrasonic imaging: physical characterization. Langmuir 22, 4397-4402.
Porter, T.R., LeVeen, R.F., Fox, R., Kricsfeld, A., Xie, F., 1996. Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles. Am. Heart J. 132, 964-968.
Riviere, J.E., Papich, M.K., 2001. Potential and problems of developing transdermal patches for veterinary application. Adv. Drug Deliv. Rev. 50, 175-203.
Roberts, M.S., 1997. Targeted drug delivery to the skin and deeper tissues: roles of physiology, solute structure and disease. Int. J. Pharm. 24, 874-879.
Robinson, D.S., Amsterdam, J.D., 2008. The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability. J. Affect. Disord. 105, 15-23.
Rohatagi, S., Barrett, J.S., McDonald, L.J., Morris, E.M., Darnow, J., DiSanto, A.R., 1997. Selegiline percutaneous absorption in various species and metabolism by human skin. Pharm. Res. 14, 50-55.
Sam, E., Jeanjean, A.P., Maloteaux, J.M., Verbeke, N., 1995. Apomorphine pharmacokinetics after intranasal and subcutaneous application. Eur. J. Drug Metab. Pharmacokinet. 20, 27-33.
Samsioe, G., 2004. Transdermal hormone therapy: gels and patches. Climacteric 7, 347-356.
Schöler, N., Olbrich, C., Tabatt, K., Müller, R.H., Hahn, H., Liesenfeld, O., 2001. Surfactant, but not the size of solid lipid nanoparticles (SLN) influences viability and cytokine production of macrophages. Int. J. Pharm. 221, 57-67.
Seki, J., Sonoke, S., Saheki, A., Fukui, H., Sasaki, H., Mayumi, T., 2004. A nanometer lipid emulsion, lipid nano-sphere (LNS®), as a parenteral drug carrier for passive drug targeting. Int. J. Pharm. 273, 75-83.
Shin, S.C., Kim, H.J., Oh, I.J., Cho, C.W., Yang, K.H., 2005. Development of tretinion gels for enhanced transdermal delivery. Eur. J. Pharm. Biopharm. 60, 67-71.
Shin, S.C., Kim, J., Yoon, M.K., Oh, I.J., Choi, J.S., 2002. Transdermal delivery of triprolidine using TPX polymer membrane. Int. J. Pharm. 235, 141-147.
Singh, S., Singh, J., 1993. Transdermal drug delivery by passive diffusion and iontophoresis. Med. Res. Rev. 13, 569-621.
Sloan, K.B., Wasdo, S., 2003. Designing for topical delivery: prodrugs can make the difference. Med. Res. Rev. 23, 763-793.
Small, G., Dubois, B., 2007. A review of compliance to treatment in Alzheimer’s disease: potential benefits of a transdermal patch. Curr. Med. Res. Opin. 23, 2705-2713.
Souchkova, V.N., Baggs, R.B., Francis, C.W., 2000. Effect of 40-kHz ultrasound on acute thrombotic ischemia in a rabbit femoral artery thrombosis model. Circulation 101, 2296-2301.
Stacy, M., Silver, D., 2008. Apomorphine for the acute treatment of ‘‘off’’ episodes in Parkinson’s disease. Parkinsonism Relat. Disord. 14, 85-92.
Stibe, C.M., Kempster, P.A., Lees, A.J., Stern, G.M., 1988. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1, 403-406.
Stride, E., Saffari, N., 2003. Microbubble ultrasound contrast agent: a review. Proc. Inst. Mech. Eng. Part H 217, 429-447.
Subramony, J.A., 2006. Apomorphine in Dopaminergic Therapy. Mol. Pharm. 3, 380-385.
Suedee, R., Bodhibukkana, C., Tangthong, N., Amnuaikit, C., Kaewnopparat, S., Srichana, T., 2008. Development of a reservoir-type transdermal enantioselective-controlled delivery system for racemic propranolol using a molecularly imprinted polymer composite membrane. J. Control. Release 129, 170-178.
Sung, K.C., Fang, J.Y., Wang, J.J., Hu, O.Y.P., 2003. Transdermal delivery of nalbuphine and its prodrugs by electroporation. Eur. J. Pharm. Sci. 18, 63-70.
Suzuki, R., Takizawa, T., Negishi, Y., Hagisawa, K., Tanaka, K., Sawamura, K., Utoguchi, N., Nishioka, T., Maruyama, K., 2007. Gene delivery by combination of novel liposomal bubbles with perfluoropropane and ultrasound. J. Control. Release 117, 130-136.
Takalkar, A.M., Klibanov, A.L., Rychak, J.J., Lindner, J.R., Ley, K., 2004. Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow. J. Control. Release 96, 473-482.
Talu, E., Lozano, M.M., Powell, R.L., Dayton, P.A., Longo, M.L., 2006. Long term stability by lipid coating monodisperse microbubbles formed by a xow-focusing device. Langmuir 22, 9487-9490.
Thase, M.E., 2006. Novel transdermal delivery formulation of the monoamine oxidase inhibitor selegiline nearing release for treatment of depression. J. Clin. Psychiatry 67, 671-672.
Torchilin, V.P., 2005. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4,145-160.
Tosi G, Costantino L, Ruozi B, Forni F, Vandelli MA. 2008. Polymeric nanoparticles for the drug delivery to the central nervous system. Expert Opin. Drug Deliv. 5, 155-174.
Treat, L.H., McDannold, N., Zhang, Y., Vykhodtseva, N., Hynynen, K., 2007. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int. J. Cancer 121, 901-907.
Tsutsui, J.M., Xie, F., Porter, R.T., 2004. The use of microbubbles to target drug delivery. Cardiovasc. Ultrasound 2, 23.
Ugwoke, M.I., Kaufmann, G., Verbeke, N., Kinget, R., 2000. Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems. Int. J. Pharm. 202, 125-131.
Unger, E.C., Hersh, E., Vannan, M., Matsunaga, T.O., McCreery, T., 2001. Local Drug and Gene Delivery Through Microbubbles. Prog. Cardiovasc. Dis. 44, 45-54.
Unger, E.C., Matsunaga T.O., McCreery T., Schumann P., Sweitzer R., Quigley R., 2002. Therapeutic applications of microbubbles. Eur. J. Radiol. 42, 160-168.
Unger, E.C., Porter, T., Culp, W., Labell, R., Matsunaga, T., Zutshi, R., 2004. Therapeutic applications of lipid-coated microbubbles. Adv. Drug Deliv. Rev. 56, 1291-1314.
Van der Geest, R., Kruger, P., Gubbens-Stibbe, J.M., van Laar, T., Bodde, H.E., Danhof, M., 1997. Assay of R-apomorphine, S-apomorphine, apocodeine, isoapocodeine and their glucuronide and sulfate conjugates in plasma and urine of patients with Parkinson’s disease. J. Chromatogr. B 702, 131-141.
van Wamel, A., Bouakaz, A., Versluis, M., de Jong, N., 2004. Micromanipulation of endothelial cells: ultrasound -microbubble-cell interaction. Ultrasound Med. Biol. 30, 1255-1258.
Vance, D.E., Vance, J., 2002. Biochemistry of lipids, Lipoproteins and membranes (4th). Elservier Publisher, Amsterdam.
Wang, J.J., Sung, K.C., Yeh, C.H., Fang, J.Y., 2008. The delivery and antinociceptive effects of morphine and its ester prodrugs from lipid emulsions. Int. J. Pharm. 353, 95-104.
Wcker, L., James S., Copeland, N., Pacheco, M.A., 2003. Transdermal selegiline effect on manoamine oxidase in the brain. Biol. Psychiatry 54, 1099-1104.
Wissing, S.A., Kayser, O., Müller, R.H., 2004. Solid lipid nanoparticles for parenteral drug delivery. Adv. Drug Deliv. Rev. 56, 1257-1272.
Wu, W.R., Zhu, X.Z., 1999. The amphetamine-like reinforcing effect and mechanism of L-deprenyl on conditioned place preference in mice. Eur. J. Pharmacol. 364, 1-6.
Yang, B., Yu, Y., Deng, C., Duan, G., 2006. Determination of apomorphine in canine plasma by liquid chromatography-electrospray ionization mass spectrometry and its application to a pharmacokinetic study. J. Sep. Sci. 29, 2173-2178.
Yoshioka, T., Florence, A.T., 1994. Vesicle (noisome)-in-water-in-oil (v/w/o) emulsions: an in vitro study. Int. J. Pharm. 108, 117-123.
Yu, Y.B., 2006. Fluorocarbon nanoparticles as multifunctional drug delivery vehicles. J. Drug Target 14, 663-669.
Zhan, X., Tang, G., Chen, S., Mao, Z., 2006. A new copolymer membrane controlling clonidine linear release in a transdermal drug delivery system. Int. J. Pharm. 322, 1-5.
Zhao, K., Singh, J., 2000. Mechanisms of in vitro percutaneous absorption enhancement of tamoxifen by enhancer. J. Pharm. Sci. 89, 771-780.
Zhao, Y.Z., Luo, Y.K., Liang, H.D., Mei, X.G., Tang, J., Lu, C.T., Zhang, Y., Lin, Q., 2006. Comparing transfection efficiency and safety for antisense oligodeoxyribonucleotide between phospholipids-based microbubbles and liposomes. J. Drug Target 14, 687-693.
Zobrist, R.H., Schmid, B., Feick, A., Quan, D., Sanders, S.W., 2001. Pharmacokinetics of the R- and S-enantiomers of oxybutynin and N-desethyloxybutynin following oral and transdermal administration of the racemate in healthy volunteers. Pharm. Res. 18, 1029-1034.
王新元,2005,以物理性經皮吸收促進方法提升親水性大分子及小分子藥物之皮膚穿透能力,長庚大學碩士論文
花淑秋,2007,抗癌藥物順氯氨鉑及喜樹鹼之微奈米級劑型開發與研究,長庚大學碩士論文
黃妍菱,2005,微脂粒包覆ㄧ系列茶多酚其物理化學性質及體內藥物動力學研究,長庚大學碩士論文
黃梓柔,2008,天然抗氧化物白藜蘆醇及大豆異黃酮之經皮膚投與傳輸系統研究,長庚大學碩士論文
葉智惠,2007,一系列麻醉止痛劑之前驅藥物傳輸劑型設計研究,長庚大學碩士論文
廖美惠,2006,白藜蘆醇於奈米/次微米級微粒劑型之藥物傳遞及生體內有效性研究,長庚大學碩士論文
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊