臺灣博碩士論文加值系統

第一部分是以NIPAAm及可分解之交聯劑Polycaprolactone diacrylate 製備一系列溫度感應性水膠，其中Polycaprolactone diacrylate的合成是以acryloyl chloride將polycaprolactone diol乙烯化。研究中以改變交聯劑的種類及含量和膠化的方法來測量對膠體膨潤度和物理性質的影響。結果顯示，膨潤度隨PCL含量越多而越低。比較以NMBA及PCLdA此兩種交聯劑製備出的膠體，由PCLdA所製備之膠體具有較低的CGTT、較強的機械強度、交聯密度和分解性。另一方面，相較於無孔膠體，多孔膠體具有較高的膨潤度且其CGTT轉變平緩。製備的多孔膠體還具有溫度快速應答能力和較快分解速率。
第二部份是以NIPAAm、AA 及可分解之交聯劑Polycaprolactone diacrylate 製備一系列溫度/酸鹼感應性水膠。研究主要以改變單體組成的比例來測量膠體在水中及緩衝液中之膨潤度和物理性質的影響。結果顯示，隨著AA含量的增加，膠體的膨潤度上升。此系列膠體由於是以PCLdA交聯而得，故其CGTT低於以NMBA製備的水膠。另外，膠體的機械強度隨著AA含量增加而降低。此系列膠體展現良好的溫度及酸鹼敏感度。與NMBA製備之膠體相比以PCLdA製備之水膠具有較高的交聯密度和機械強度。在藥物釋放方面，此高分子膠體對水溶性藥物咖啡因及維他命B12的吸藥量受到膠體膨潤度及藥物分子大小影響。膠體對帶電性藥物CV的吸藥量及釋放率隨著AA含量增加而增加，反之，負電性藥物phenol red則減少。針對非親水性藥物sulfanilamide，其吸藥量隨著AA含量增加而減少，而釋放量受到膠體在緩衝液中的膨潤度影響。膠體對indomethacin的吸藥量受到膠體和乙醇水溶液間親和力的影響，釋放量則是受到膠體膨潤度影響。
第三部分為合成ABA 兩性三團塊共聚物，由疏水性的PCL diol及不同鏈長的親水性寡聚物PEO diacid聚縮合而成，其中PEO diacid是由PEG與succinic anhydride反應獲得。將此共聚物(PCL-PEO-PCL diol) 乙烯化做為PCL-PEO-PCL三團塊交聯劑(PCEdA)，以FT-IR, 1H-NMR, XRD and GPC分析共聚物的結構。此研究以低溫照光聚合此共聚物(PCEdA)製備出可分解的多孔網目，並量測此高分子網目的熱性質、膨潤度和分解性。結果顯示，當此三團聯共聚物有較長的PEO鏈段，其膨潤度較大。DSC結果顯示，此三團聯共聚物乙烯化和交聯成網目後可使其ΔH and Tm降低，而當PEO鏈段增長時網目的ΔH and Tm增加。將共聚物交聯成網目後擁有較好的熱性質。單體濃度越高所形成的網目孔洞越小，分解速率也隨之降低。在藥物釋放方面，膠體對indomethacin載藥量與釋放率與膠體膨潤度有關。咖啡因及維他命B12之吸藥量與膠體組成有關，而釋放量跟膨潤度相關。

A series of Biodegradable functional hydrogels based on thermo-sensitive N-isopropylacrylamide (NIPAAm) through crosslinked with the bioresorbable ester crosslinker-polycaprolactone diacrylate (PCLdA) that was synthesized from polycaprolactone diol with acryloyl chloride. The effect of the content of crosslinker and gelation method on the swelling behaviors and physical properties for the poly(NIPAAm-PCL) hydrogels was investigated. The results showed that the swelling ratio of the gel in deionized water decreased with an increase of the content of PCL segment in the poly(NIPAAm) hydrogels. The gels crosslinked with PCLdA were compared with those crosslinked with NMBA. The results showed that the critical gel transition temperature (CGTT) of the PCL gels was lower than the gels crosslinked with NMBA due to the hydrophobicity and crystallinity of PCL segment but the compressive modulus increased with increase of PCL segment content. The results also showed that the gel crosslinked with PCLdA had not only a higher mechanical strength but also a higher crosslinking density (ρx) than the gel crosslinked with NMBA. On the other hand, the porous gels were compared with non-porous gels. The results showed that the swelling ratio of the porous was higher and the CGTT of the porous was higher and the transition temperature curve observed was smooth. The porous gels also had rapid response thermally sensitivity and faster degradation rates.
In order to improve the hydrophilicity of (PNIPAAm-PCL) hydrogels, a series of biodegradable functional hydrogels were prepared from N-isopropylacrylamide (NIPAAm), acrylic acid (AA), and a biodegradable crosslinker, polycaprolactone diacrylate (PCLdA), which was synthesized from polycaprolactone diol with acryloyl chloride. The effect of the different monomer ratios of the poly(NIPAAm-co-AA) copolymeric hydrogel on the swelling behaviors and physical properties were investigated. The results showed that the swelling ratio in deionized water and in phosphate buffer solution increased with an increase of the content of AA in the copolymeric hydrogel, and the critical gel transition temperature (CGTT) of the copolymeric hydrogel crosslinked with PCLdA was lower than the gel crosslinked with N,N’-methylenebisacrylamide (NMBA). The compressive modulus decreased with AA content in the copolymeric hydrogels. The gels show good pH/ temperature sensitive behavior. The results also showed that the gel crosslinked with PCLdA has a higher crosslinking density (ρx) and a higher mechanical strength than the gel crosslinked with NMBA. The influence of the copolymeric composition on the drug release behavior in the poly(NIPAAm-co-AA) hydrogels was also investigated in this study.
ABA amphiphilic triblock copolymers was synthesized by the condensation reaction of hydrophobic polycaprolactone diol (PCL diol) (A) with hydrophilic dicarboxypolyethylene oxide (PEO diacid) (B) obtained by the reaction of PEG with succinic anhydride. Then, the triblock copolymers were modification with acryloyl chloride to form PCL-PEO-PCL diacrylate (PCEdA), and then characterized by FT-IR, 1H-NMR, and GPC. The porous biodegradable gels were prepared through photopolymerization of the PCEdA dissolved in DMSO at low temperature. Thermal behavior, swelling ratio, and morphological characteristics as well as degradability of the gels were investigated. The results showed that the swelling ratio in deionized water increased with an increase of the PEO chain length in the copolymeric gel. DSC showed that the acrylation and gelation decreased the ΔH and Tm of copolymeric gels, and the value of copolymeric gels increased with the length of the PEO segment increased. Thermal stability of PCE gels was higher than that of PCE copolymers. The pore size of the PCE gels was influenced by the concentration of PCE copolymer. In vitro release behavior of drugs from PCE gels was also investigated, the results showed that the loading amount and release ratio of indomethacin increased with an increase of the swelling ratio in ethanol and deionized water. The loading amount of caffeine and B12 was related to the composition of gels, but the release ratio was related to the swelling ratio of the PCE gels.

ACKNOWLEDGEMENT --------------------------------------------------- i
ENGLISH ABSTRACT ---------------------------------------------------- ii
CHINESE ABSTRACT ---------------------------------------------------- v
TABLE OF CONTENT ---------------------------------------------------- vii
LIST OF SCHEMES --------------------------------------------------------- xi
LIST OF TABLES ------------------------------------------------------------- xi
LIST OF FIGURES ---------------------------------------------------------- xii
CHAPTER 1 INTRODUCTION -------------------------------------------- 1
CHAPTER 2 EXPERIMENTAL -------------------------------------------- 6
2.1 Materials --------------------------------------------------------------- 6
2.2 Preparation of Polycaprolatone diacrylate as a crosslinker------ 7
2.3 Preparation of poly(NIPAAm) hydrogels-------------------------- 7
2.4 Preparation of porous poly(NIPAAm-PCL) copolymeric hydrogels---------------------------------------------------------------
8
2.5 Preparation of poly(NIPAAm-AA-PCL) copolymeric hydrogels--------------------------------------------------------------
9
2.6 Preparation of PCL-PEO-PCL amphiphilic triblock copolymers ------------------------------------------------------------
15
2.7 Preparation of PCL-PEO-PCL diacrylate copolymers---------- 16
2.8 Preparation of porous PCL-PEO-PCL copolymeric gels-------- 16
2.9 Instrumental Analysis ---------------------------------------------- 19
2.10 Measurement of Swelling Ratio ---------------------------------- 20
2.11 Measurement of Dynamic Swelling ------------------------------ 20
2.12 Measurement of deswelling kinetics ------------------------------ 21
2.13 Fast swelling-deswelling behavior of the copolymeric hydrogels---------------------------------------------------------------
21
2.14 Measurement of Equilibrium Swelling Ratio at Various
Temperatures-----------------------------------------------------------
22
2.15 Measurement of Physical Properties measurement ------------- 22
2.16 Measurement of Equilibrium Swelling Ratio at Various pH buffer Solutions-------------------------------------------------------
23
2.17 Drug release experiment -------------------------------------------- 23
2.18 Morphologies -------------------------------------------------------- 24
2.19 Biodegradability of gels -------------------------------------------- 24
CHAPTER 3 RESULTS AND DISCUSSION ---------------------------- 25
3.1 Studies on Preparation and Properties of Porous Biodegradable Poly(NIPAAm-PCL) Copolymeric Hydrogels--
25
3.1.1 Charecterization of PCL diacrylate ----------------------- 25
3.1.2 Characterization of the Poly(NIPAAm) hydrogels----- 30
3.1.3 Swelling Kinetics for the Poly(NIPAAm-PCL) Copolymeric Gels in Deionized Water --------------------
30
3.1.4 The Mechanical Properties of Poly(NIPAAm) Copolymeric Hydrogel ---------------------------------------
31
3.1.5 Deswelling Behaviors for the porous Poly(NIPAAm-PCL) Copolymeric Gels--------------------
34
3.1.6 Fast Swelling-Deswelling Behavior for the porous Poly(NIPAAm-PCL) Copolymeric Hydrogels------------
34
3.1.7 Effect of Temperature on Swelling Ratio------------------- 37
3.1.8 Biodegradability------------------------------------------------ 40
3.1.9 Morphologies--------------------------------------------------- 42
3.2 Studies on Preparation, Properties and Drug Release of Biodegradable Functional Poly(NIPAAm-AA-PCL) Copolymeric Hydrogels ---------------------------------------------

44
3.2.1 Characterization of the Poly(NIPAAm-AA-PCL) Copolymeric Gels---------------------------------------------
44
3.2.2 Swelling Kinetics of the Poly(NIPAAm-AA-PCL) Copolymeric Hydrogels in Deionized Water and Phosphate Buffer Solution------------------------------------

36
3.2.3 Mechanical Properties of the Poly(NIPAAm-AA-PCL)
Copolymeric Hydrogels---------------------------------------
45
3.2.4 Effect of Temperature on Swelling Ratio------------------- 51
3.2.5 Effect of pH on Swelling Ratio------------------------------- 53
3.2.6 Effect of Alcohol Aqueous Solution on Swelling Ratio--- 53
3.2.7 Morphologies--------------------------------------------------- 56
3.2.8 Biodegradability------------------------------------------------ 56
3.2.9 Drug Release of poly(NIPAAm-AA-PCL) Copolymeric Hydrogel---------------------------------------------------------
59
3.3 Synthesis and Drug Release Behavior of Porous Biodegradable Amphiphilic Triblock Copolymeric Hydrogel--
70
3.3.1 Measurement of PCL-PEO-PCL triblock copolymers and gels----------------------------------------------------------
70
3.3.2 Characterization of the PCE gels-------------------------- 78
3.3.3 Morphologies --------------------------------------------------- 79
3.3.4 Biodegradability ----------------------------------------------- 79
3.3.5 Drug release of the PCE gels ------------------------------- 82
CHAPTER 4 CONCLUSION ----------------------------------------------- 88
CHAPTER 5 REFERENCES ----------------------------------------------- 90

1.Wichterle O, Lim D. Nature 1960, 185, 117
2.Lim F, Sun AM. Science 1980,210, 908-910.
3.Yannas IV, Lee E, Orgill DP. Acad. Sci. USA 1989, 86, 933-937.
4.Hoffman AS, Afrassiabi A, Dong LC. J Control Release 1986, 4, 213.
5.Dong LC, Hoffman AS. J Controlled Release 1991, 5, 141.
6.Wu XS, Hoffman AS, Yager P. J Intelligent Material Systems and Structures 1993, 4, 202
7.Yoshida R, Sakai K, Okano T, Sakurai Y. Polym J 1991, 23, 1111.
8.Okayama Y, Yoshida R, Sakai K, Okano T, Sakurai Y. J Biometry Sci Polym Ed 1993, 4, 545.
9.Bea YH, Okano T, Kim SW. Makromol Chem Rapid Commun 1987, 8, 481.
10.Freltas RFS, Cussler EL. Sep Sci Technol 1987, 22, 911.
11.Dong LC, Hoffman AS. J Control Release 1986, 4, 223.
12.Heskins M, Guillet JE. J Macromol Sci Chem 1968, A2, 1441.
13.Hirokawa Y, Tanaka T.J Phys Chem 1984, 81, 6379.
14.Zhang XZ, Sun GM, Chu CC. Eur Polym J 2004, 40, 2251-2257.
15.Zhang XZ, Wu DQ , Chu CC. Biomaterials 2004, 25, 4719–4730.
16.Kuo PYP, Saltzman WM. Crit Rev Eukar Gene Express1996, 6, 59.
17.Philippe D, Mohan K, Ramani N. Polymer 1999, 40, 3091–3100.
18.Hideto T, Takeharu I. Int J Biological Macro.2001, 29, 83–89.
19.Kissel T, Li YX, Volland C, Gorich S, Koneberg R. J Controlled Rel 1996, 39, 315-326.
20.Bezwada RS, Jamiolkowski DD, Lee I, Vishvaroop A, PersivaleJ,Treka-Benthi n S, Erneta M, Suryadevara J, Yang A, Liu S.
Biomaterials 1995, 16, 1141–8.
21.Darney PD, Monroe SE, Klaisle CM, Alvarado A. Am J Obstet Gynecol 1989, 160, 1292–5.
22.Woodward SC, Brewer PS, Moatamed F. J Biomed Mater Res1985, 44, 437–44.
23.Pitt CG, Gratzei MM, Kimmei GL, Surles J, Schindler A. Biomaterials1981, 2, 215–20.
24.Kweon HY, Yoo MK, Park IK, Kim TH, Lee HC, Lee HS, Oh JS, Akaike T, Cho CS. Biomaterials 2003, 24, 801-808.
25.Lee Y.M., Kim S.S., Polymer Vol. 38 No. 10, 1997, p.2415-2420.
26.Zhang Y., Zhuo R., Biomaterials 26, 2005, p.6736-6742.
27.Am Ende MT, Hariharan D, Peppas NA. Reactive Polymers 1995, 25, 127.
28.Lee WF, Chiu RJ. Materials Science and Engineering C 2002, 20, 161.
29.Sawahata K, Hara M, Yasunaga H, Osada Y, Journal of Controlled Release 1990, 9, 283.
30.Kabra G, Gehrke SH, Hwang ST. J Appl Polym Sci 1991, 2409, 42.
31.Franson M, Peppas NA. J Appl Polym Sci 1983, 1299, 28.
32.Korsemeyer M, Merrwall EW, Peppas NA. J Polym Sci Polym Phys Ed 1986, 409, 24.
33.Peppas NA, Barr-Howell BD. Hydrogels in Medicine and Pharmacy, CRC Press, Boca Raton 1986, 1, 27.
34.Treloar LRG. The Physics of Rubber Elasticity, Clarendon Press: Oxford, 1975.
35.Crescenze V, Manzini G, Calzolari G, Borri C. Eur Polym J 1972, 8, 449–63.
36.Alfrey T, Gurnee EF, Lloyd WG. J Polym Sci 1966, C12, 249.
37.Pitt CG, Gratzei MM, Kimmei GL, Surles J, Schindler A. Biomaterials1981, 2, 215–20.
38.Lee WF, Shieh CH. J Appl Polym Sci 1999, 73, 1955