研究生: |
李思賢 Si-Xian Li |
---|---|
論文名稱: |
PLLA-PEG-PLLA三團聯共聚物微胞內藥物分配係數與尺寸關係及其藥物釋放實驗 The Relationships between Partition Coefficient and Size in Micelles of PLLA-PEG-PLLA Triblock Copolymers and Their Drug Release Experiments |
指導教授: |
胡孝光
Shiaw-Guang Hu |
口試委員: |
徐治平
Jyh-Ping Hsu 朱一民 I-Ming Chu 王夢菊 Meng-Jiy Wang |
學位類別: |
碩士 Master |
系所名稱: |
工程學院 - 材料科學與工程系 Department of Materials Science and Engineering |
論文出版年: | 2009 |
畢業學年度: | 97 |
語文別: | 中文 |
論文頁數: | 98 |
中文關鍵詞: | 藥物擴散係數 、尺寸 、藥物分配係數 、微胞 、聚乳酸-聚乙二醇三團聮共聚物 、藥物釋放模型 、無因次化分析 |
外文關鍵詞: | Diffusion coefficient, Size, Partition coefficient, micelle, PLLA-PEG-PLLA triblok copolymers, Drug release model, The method of dimension analysis |
相關次數: | 點閱:221 下載:2 |
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本研究合成不同疏水鏈段聚合度的聚乳酸(PLLA,聚合度=149~478)-聚乙二醇(PEG , The number average of molecular weight = 4000 g/mol) (PLLA-PEG-PLLA)三團聯共聚物製備微胞溶液,使用螢光光譜儀及焦油腦探針測定臨界微胞濃度,以動態光散射儀測量微胞粒徑,隨疏水鏈段聚合度越高,臨界微胞濃度越低,微胞半徑越大。微胞半徑與疏水鏈段聚合度的標度指數,符合Halperin的理論預測。以紫外光/可見光分光光度計測量三團聯共聚物微胞中包覆藥物Vitamin K3的濃度,計算藥物分配係數,隨疏水鏈段聚合度提高而增加。
三(PLLA-PEG-PLLA)與雙團聯共聚物(PLLA-MePEG)中,分配係數的對數對微胞半徑的標度關係,三團聯微胞化焓絕對值較低,得到標度指數較小,另可能受親水鏈段(PEG)的迴路效應(looping effect)影響微胞核亂度,使三團聯界面能較低,標度指數變小。在分配係數的對數與疏水鏈段聚合度倒數的關係中,斜率則受到交互作用參數(χPLLA-water)的影響,亦可能與三與雙團聯共聚物的界面能有關。我們利用上述分析方式估計文獻中不同情況和藥物的標度指數及斜率,除上述原因使微胞半徑的標度指數及疏水鏈段倒數中的斜率有差異,可能受藥物由水相進入微胞的界面自由能影響,標度指數甚至有一到兩個數量級的差別。
以紫外光/可見光分光光度計在相同間隔時間測量三團聯共聚物微胞中釋放Vitamin K3濃度。釋放初期隨藥物分配係數越高,釋放率對時間作圖斜率越小。釋放初期的釋放率(1-F)對無因次時間(π1)的指數,無因次溶離常數(π2)增加,指數越大,而Fickian球釋放模型、Higuchi藥物溶出模型的結果以及文獻Poly(caprolactone)-Methoxy Poly(ethylene glycol)(PCL-PEO)作微胞載荷釋放不同含量的17β-estradiol(E2)實驗, (1-F)對π1的指數受π2影響,皆與本實驗有相同趨勢;在初期釋放時π2越大,釋放機制越接近恆速釋放。在相同π1時,本實驗π2較文獻π2小很多,造成實驗釋放率對π2的指數絕對值比文獻大。
當實驗藥物分配係數越高,飽和藥物釋放率越低。但藥物釋放模型結果,在任意無因次溶離常數,飽和釋放率均達到1,不符合實驗結果。
Poly(ethylene glycol)-Poly(L-lactide) (PEG-PLLA-PEG) triblock copolymers with PEG(The number average of molecular weight =4000 g/mol)and various PLLA length(monomer number from 149 to 478)were synthesized, and the critical micelle concentrations(CMC’s), micellar radius and concentration of Vitamin K3 in the micelles for various copolymers were determined with fluorescence spectroscopy with pyrene probe, dynamic light scattering, and UV/Vis spectroscopy, respectively. It is found that CMC’s decrease with PLLA block length. The micellar radius and partition coefficient from the water phase to micelle increases with the PLLA length and micellar radius is proportional to the 0.46th power of PLLA block length, which fits the prediction by Halperin.
We plot of the double logarithm of partition coefficient versus the logarithm of micellar radius, show that the scaling exponent is smaller for PLLA-PEG-PLLA than PLLA-MePEG diblock copolymers, due to the smaller enthalpy of micellization of PLLA-PEG-PLLA is smaller then PLLA-MePEG. The looping effect of PEG segment maybe affect the entropy of the micelle core, and the interfacial energy of triblock copolymer is smaller than diblock copolymer, making the scaling exponent of PLLA-PEG-PLLA triblock copolymer smaller. In the relationship between the logarithm of partition coefficient and the reciprocal of hydrophobic length, the slopes are related to the core-water interaction parameters and the interfacial energy between triblock or diblok copolymers and water phase. We use the same methods of analysis to evaluate exponents and slopes in various conductions and drugs in literature, and relate them to the interfacial free energy of the drugs from water to micelle phase as the extra factor.
The concentrations of Vitamin K3 releasing from the micelles of PLLA-PEG-PLLA triblock copolymer were determined by UV/Visible spectroscopy in a time interval of one hour. In the initial stage, the slopes of plots of the fractional release (1-F) versus the time decrease with increasing the partition coefficient. The exponents between fractional release and dimensionless release time (π1) increases with dimensionless drug partition constant (π2). The exponents between (1-F) and π1 of Fick’s sphere model, Higuchi model, and the literature data dealing with the release of the 17β-estradiol from the micelles of PCL-PEO diblock copolymers, are affected by π2, and the same trend was also found in our experiments. When π2 is bigger, the release mechanism approaches closer to the constant rate release. The absolute value of exponent between (1-F) and π2 of our experiment is bigger than the absolute value of exponent in the literature, as a result that the π2 of our experiment is smaller than that in the literature.
The saturated fractional release decrease with increasing the partition coefficient in our experiment, which can not fitted with the drug release model predicting the saturated fractional release of drug approaching to 1 at any dimensionless drug partition constant.
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