多孔纤维素水凝胶微球的制备与性能研究
摘要
本文以反相悬浮聚合法,以羟丙基甲基纤维素(HPMC)为原料,二乙烯基砜(DVS)为交联剂,聚甘油单硬脂酸酯为分散剂,环己烷为连续相,合成了水凝胶微球。另外,分别通过以碳酸钙纳米粉末和封端的聚乙二醇为制孔剂,制备了多孔纤维素水凝胶微球。
本文分为三个部分:反相悬浮工艺条件、碳酸钙制孔、封端聚乙二醇制孔。在第一部分研究了反相悬浮工艺如温度、纤维素水相浓度及交联剂等对水凝胶微球性能的影响,并探讨了反相悬浮的稳定因素及工艺条件对微球粒径变化的影响。在制孔部分研究了制孔剂对多孔水凝胶微球表面及内部孔络结构、吸水速率、吸水倍率、溶涨行为等微球性能的影响。对制孔机理进行探讨,制孔剂用量只有达到一定程度后才可制备出具有贯穿孔结构的多孔微球。
通过对溶胀动力学的研究,更好的理解了水凝胶微球吸水溶胀的过程,理解了微球表面及内部结构对溶胀行为的影响,比表面积的增大使得微球具有更高的吸水速率。
采用红外光谱(IR)、扫描电镜(SEM)、差示扫描量热法(DSC)等方法对产物的内部结构及表面结构、微球形态、比表面积进行了表征。
The HPMC hydrogel beads were prepared by inverse suspension polymerization, in which divinylsulfone(DVS) was used as crosslinker. The amphiphilic copolymer of tripolyglycerol monostearate was used as dispersant and cyclohaxane was used as the organic phase. In addition, the porous hydrogels were prepared, in which calcium carbonate and polyethylene glycol were used as porosigen.
There are three parts in this paper: The technics of inverse suspension polymerization, porous hydrogels prepared by calcium carbonate and porous hydrogels prepared by polyethylene glycol. In the first part, the factors influencing the water absorption capacities of the hydrogels such as temperature, solution concentration, the amount of crosslinker were characterized. The factors which affect the stability of the polymerization and the factors which affect the particle size were also investigated. In the part of preparing porous hydrogels, the effect of porosigen on the surface and structures of the beads, swelling velocity, swelling degree and swelling kinetics were investigated. The porous structure was made when the porosigen dosage reach the enough quantity.
The swelling kinetics was well investigated. The effect of structure and aspect area on swelling behavior was well characterized. As aspect area increased, the swelling velocity was increased.
The surface structures, morphology of hydrogels beads and aspect area were characterized by IR, SEM and DSC. etc.
本文分为三个部分:反相悬浮工艺条件、碳酸钙制孔、封端聚乙二醇制孔。在第一部分研究了反相悬浮工艺如温度、纤维素水相浓度及交联剂等对水凝胶微球性能的影响,并探讨了反相悬浮的稳定因素及工艺条件对微球粒径变化的影响。在制孔部分研究了制孔剂对多孔水凝胶微球表面及内部孔络结构、吸水速率、吸水倍率、溶涨行为等微球性能的影响。对制孔机理进行探讨,制孔剂用量只有达到一定程度后才可制备出具有贯穿孔结构的多孔微球。
通过对溶胀动力学的研究,更好的理解了水凝胶微球吸水溶胀的过程,理解了微球表面及内部结构对溶胀行为的影响,比表面积的增大使得微球具有更高的吸水速率。
采用红外光谱(IR)、扫描电镜(SEM)、差示扫描量热法(DSC)等方法对产物的内部结构及表面结构、微球形态、比表面积进行了表征。
The HPMC hydrogel beads were prepared by inverse suspension polymerization, in which divinylsulfone(DVS) was used as crosslinker. The amphiphilic copolymer of tripolyglycerol monostearate was used as dispersant and cyclohaxane was used as the organic phase. In addition, the porous hydrogels were prepared, in which calcium carbonate and polyethylene glycol were used as porosigen.
There are three parts in this paper: The technics of inverse suspension polymerization, porous hydrogels prepared by calcium carbonate and porous hydrogels prepared by polyethylene glycol. In the first part, the factors influencing the water absorption capacities of the hydrogels such as temperature, solution concentration, the amount of crosslinker were characterized. The factors which affect the stability of the polymerization and the factors which affect the particle size were also investigated. In the part of preparing porous hydrogels, the effect of porosigen on the surface and structures of the beads, swelling velocity, swelling degree and swelling kinetics were investigated. The porous structure was made when the porosigen dosage reach the enough quantity.
The swelling kinetics was well investigated. The effect of structure and aspect area on swelling behavior was well characterized. As aspect area increased, the swelling velocity was increased.
The surface structures, morphology of hydrogels beads and aspect area were characterized by IR, SEM and DSC. etc.
引文
[1]胡玉洁.天然高分子材料改性与应用,北京:化学工业出版社,2003.1
[2]刘锋,卓仁禧,[J].高分子通报,1995,( 4):205~216
[3]邹新禧,超强吸水剂,北京:化学工业出版社,2002, 1~2
[4] Allan S. Hoffman, Hydrogels for biomedical applications, [J] Advanced Drug Delivery Reviews 43(2002)3~12
[5] S.H. Gehrke, L.H. Uhden, J.F. McBride, Enhanced loading and activity retention of bioactive proteins in hydrogel delivery systems, Journal of Controlled Release 55 (1998)21~33
[6]高瑞昶,李凭力,颗粒单分散聚丙烯酰胺凝胶微球的制备,化工学报,2000, 51(4): 527~530
[7] O. Wichterle, D. Lim, Hydrophilic gels in biologic use, Nature 185(1960)117
[8] J.M. Harris, S. Zalipsky, Eds. Poly(ethylene glycol) chemistry and biological applications, ACS Symposium Series, American Chemical Society, Washington, DC, 1997
[9] Sasa Baumgartner, Julijana Kristl, Nicholas A. Peppas, Network structure of cellulose ethers used in pharmaceutical applications during swelling and at equilibrium, Pharmaceutical Research, Vol. 19, No. 8, August 2002
[10] Derya Gulsen, Anuj Chauhan, Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle, International Journal of Pharmaceutics 292(2005)95~117
[11] Abdel Wahab M. El-Naggar, Safaa G. Abd Alla, Hossam M. Said, Temperature and pH responsive behaviours of CMC/AAc hydrogels prepared by electron beam irradiation, Materials Chemistry and Physics 95(2006)158~163
[12] Lene Simonsen, Lars hovgaard, Per Brobech Mortensen, Eds, Dextran hydrogels for colon-specific drug delivery. V. degradation in human intestinal incubation models, European Journal of Pharmaceutical Sciences 3(1995)329~337
[13] Jia Kui Lia, Nuo Wanga, Xue Shen Wu, Poly(vinyl alcohol) nanoparticles prepared by freezing–thawing process for protein / peptide drug delivery, Journal of Controlled Release 56(1998)117~126
[14] Beom-Jin Lee, Seung-Goo Ryu, Jing-Hao Cui, Controlled release of dual drug-loaded hydroxypropyl methycellulose matrix tablet using drug-containing polymeric coatings, International Journal of Pharmaceutics 188(1999)71~80
[15] F. Lim, A.M. Sun, Microencapsulated islets as bioartificial pancreas, Science 210(1980)908~910
[16] J. O. Karlsson, P. Gatenholm, Cellulose fibre-supported pH-sensitive hydrogels, Polymer 40(1999)379~387
[17] Annaclaudia Espositoa, Alessandro Sanninob, Anna Cozzolinoc, Eds. Response of intestinal cells and macrophages to an orally administered cellulose-PEG based polymer as a potential treatment for intractable edemas, Biomaterials 26(2005) 4101~4110
[18] Omidian H, Hashemi S A, Sammes P. G. Eds. Journal of Polymer, 1998, 39(15): 3459~3466
[19] Chen J. W, Zhao Y. M, Journal of Applied Polymer Science, 1999, 74(1): 119~124
[20]李贤真,李彦锋,朱晓夏等,高分子水凝胶材料研究进展,功能材料,2003年第4期(34)卷
[21]房喻,胡道道,崔亚丽,智能型高分子水凝胶的应用研究现状,高技术通讯,2001年11卷3期
[22]陈建海,科学出版社,北京,2003:194
[23]石艳丽,李珍,张高奇等,CMC/PNIPAAm半互穿网络水凝胶的溶涨动力学研究,功能高分子学报,2005年3月,Vol. 18
[24] Xian-Zheng Zhang, Yi-Yan Yang, Tai-Shung chung, Effect of mixed solvents on characteristics of poly(N-isopropylacrylamide) gels, Langmuir, 2002, 18, 2538~2542
[25] Ping Gao, Richard H. Meury, Swelling of hydroxypropyl methylcellulose matrix tablets. 1. Characterization of Swelling Using a Novel Optical Imaging Method, Journal of Pharmaceutical Sciences, Vol. 85, No. 7, July 1996
[26] J. Siepmann, K. Podual, M. Sriwongjanya, Eds. A New Model Describing the Swelling and Drug Release Kinetics from Hydroxypropyl Methylcellulose Tablets, Journal of Pharmaceutical Sciences, Vol. 88, No. 1, January 1999
[27] Sasa Baumgartner, Gojmir Lahajnar, Ana Sepe, Eds. Investigation of the State and Dynamics of Water in Hydrogels of Cellulose Ethers by HNMR Spectroscopy, AAPS PharmSciTech 2002, 3(4)article 36
[28] Flory P J, Principles of Polymer Chemistry, New York: Cornell University Press, Ithace, 1953: 589
[29] O. Dufaud, E. Favre, V. Sadtler, Porous Elastomeric Beads from Crosslinked Emulsions, Journal of Applied Polymer Science, Vol. 83, 967~971(2002)
[30]杨新林,白锋,黄文强,单分散功能性聚合物,高分子科学前言与进展,772~778
[31] Li K, Stover H.D.H, Journal of Polymer Science Part A: Polymer Chemical, 1993, 31: 9746~9752
[32] Stephen M. O’Connor, Stevin H. Gehrke,Synthesis and characterization of thermally-responsive hydroxypropyl methylcellulose gel beads, Journal of Applied Polymer Science, Vol. 66, 1279~1290(1997)
[33] Alois Jungbauer, Rainer Hahn, Karin Deinhofer, Eds. Performance and characterization of a nanophased porous hydroxyapatite for protein chromatography, Biotechnology and Bioengineering, Vol, 87, NO. 3, August 5, 2004
[34] H. Omidian, S.A. Hashemi, P.G. Sammes, Eds. A model for the swelling of superabsorbent polymers, Polymer, 1998, 39(26): 6697~6703
[35]制铁化学工业株式会社,生产一种吸水树脂的方法,中国专利,CN 1004550B, 1989-6-21
[36]路建美,朱秀林等,高吸水性树脂的合成及性能研究,应用化学,1992, 16(1): 89~91
[37] K. Moana Raju, M. Padmanabha Raju, Synthesis and Swellling Properties of Superabsorbent Copolymers, Advances in Polymer Technology, 2001, 20(2): 146~154
[38] R. A. Grinsted, L. Clark, J.L. Koenig, Study of cyclic sorption-desorption into poly(methlmethacrylate) rods using NMR imaging, Macromolecules 1992, 25, 1235
[39] F. Rouquerol, J. Rouquerol, K. Sing, Adsorption by powders and porous solids, London: Academic Press, 1999, 165~179
[40] K.S.W. Sing, Adsorption metheds for the characterization of porous materials, J. Coll. Int. Sci. 1998, 76~77(1): 3~11
[41] N.A. Peppas, Eds. Hydrogels in medicine and pharmacy, CRC Press: Boca Raton, FL, 1987
[42] F. Esposito, M. A. Del. Nobile, G. Mensitieri, Eds. Water sorption in cellulose-based hydrogels, Journal of Applied Polymer Science, 1996, 60: 2043
[43] A. Sannino, A. Cozzolino, L. Nicolais, Eds. A system of body water elimination based on cellulose derivatives superabsorbent hydrogels, J Biomed Mater Res 2003, 67A: 1016~24
[44] Anil Dube, Iwao Teraoka, Infusion of Polymer into a Porous Glass Bead As Studied by Space-Resolved Jamin Interferometry, Macromolecules, 1997, 30, 5352~5360
[45] Hyun Goo Kang, Sang Bong Lee, Young Moo Lee, Novel preparative method for porous hydrogels using overrun process, Polymer International, 54:537~543 (2005)
[46] Schulz M B, Daniels R. Hydroxypropyl methylcellulose (HPMC) as emulsifier for submicron emulsions: influence of molecular weight and substitution type on the droplet size after high-pressure homogenization, Europe Journal of Pharmaceutics and Biopharmaceutics, 2000, 49(3): 231~236
[47] A.J. Paine, Y. Deslandes, G. Paul, Eds. Dispersion polymerization of styrene in polar solventsⅡV isualization of surface layers of steric stabilizer on dispersion- polymerized and precipitated polystyrene latex particles by transmission electron microscopy, Journal of Colloid and Interface Science, 1990, 138(1): 170~181
[48] E. Melzer, J. Kreuter, D. Rolf, Ethylcellulose: a new type of emulsion stabilizer, European Journal of Pharmaceutics and Biopharmaceutics, 2003, 56(1): 23~27
[49] H. Yoshiyuki, Eds. Nippon Shokuai Kagaku Kogyo Co, JP 04-15286, 14 Aug 1992
[50] M.M. Doeff, Eds. Characteristics of laminated electrochromic devices using polyorganodisulfide electrodes , Journal of Electrochem Soc, 1992, 139(8): 2077
[51] J.H. Burgert, Eds. Antibiotic resistance: Will infection control meet the challenge , Dow Chemical Co, WO 94 20547, 15 Sep, 1994
[52] T. Yanaki, Eds. Lymphocytic adenohypophysitis: An immunohistochemical study , Shiseido Co, WO 91 5376, 02 May 1991
[53] M. Yamato, Eds. Dynamic magnetic resonance imaging of shoulder joint disorders, Journal of Biochem, 1995, 117: 940
[54] A. Delbruck, Eds. Changes in the extracellular matrix of the autogenous patellar tendon graft after posterior cruciate ligament reconstruction: a biochemical study in sheep Connect Tissue Res, 1986, 15: 155
[55] M.B. Aydelotte, K.E. Kuettner, Biochemical and morphological studies of bovine articular chondrocytes cultured in agarose gel, Connect Tissue Res, 1988, 18: 205
[56] A. Jason, Matthew Ward, Ellen Liang, Eds, Stimulation of neurite outgrowth byneurotrophins delivered from degradable hydrogels, Biomaterials, 2006, 27: 452~459
[2]刘锋,卓仁禧,[J].高分子通报,1995,( 4):205~216
[3]邹新禧,超强吸水剂,北京:化学工业出版社,2002, 1~2
[4] Allan S. Hoffman, Hydrogels for biomedical applications, [J] Advanced Drug Delivery Reviews 43(2002)3~12
[5] S.H. Gehrke, L.H. Uhden, J.F. McBride, Enhanced loading and activity retention of bioactive proteins in hydrogel delivery systems, Journal of Controlled Release 55 (1998)21~33
[6]高瑞昶,李凭力,颗粒单分散聚丙烯酰胺凝胶微球的制备,化工学报,2000, 51(4): 527~530
[7] O. Wichterle, D. Lim, Hydrophilic gels in biologic use, Nature 185(1960)117
[8] J.M. Harris, S. Zalipsky, Eds. Poly(ethylene glycol) chemistry and biological applications, ACS Symposium Series, American Chemical Society, Washington, DC, 1997
[9] Sasa Baumgartner, Julijana Kristl, Nicholas A. Peppas, Network structure of cellulose ethers used in pharmaceutical applications during swelling and at equilibrium, Pharmaceutical Research, Vol. 19, No. 8, August 2002
[10] Derya Gulsen, Anuj Chauhan, Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle, International Journal of Pharmaceutics 292(2005)95~117
[11] Abdel Wahab M. El-Naggar, Safaa G. Abd Alla, Hossam M. Said, Temperature and pH responsive behaviours of CMC/AAc hydrogels prepared by electron beam irradiation, Materials Chemistry and Physics 95(2006)158~163
[12] Lene Simonsen, Lars hovgaard, Per Brobech Mortensen, Eds, Dextran hydrogels for colon-specific drug delivery. V. degradation in human intestinal incubation models, European Journal of Pharmaceutical Sciences 3(1995)329~337
[13] Jia Kui Lia, Nuo Wanga, Xue Shen Wu, Poly(vinyl alcohol) nanoparticles prepared by freezing–thawing process for protein / peptide drug delivery, Journal of Controlled Release 56(1998)117~126
[14] Beom-Jin Lee, Seung-Goo Ryu, Jing-Hao Cui, Controlled release of dual drug-loaded hydroxypropyl methycellulose matrix tablet using drug-containing polymeric coatings, International Journal of Pharmaceutics 188(1999)71~80
[15] F. Lim, A.M. Sun, Microencapsulated islets as bioartificial pancreas, Science 210(1980)908~910
[16] J. O. Karlsson, P. Gatenholm, Cellulose fibre-supported pH-sensitive hydrogels, Polymer 40(1999)379~387
[17] Annaclaudia Espositoa, Alessandro Sanninob, Anna Cozzolinoc, Eds. Response of intestinal cells and macrophages to an orally administered cellulose-PEG based polymer as a potential treatment for intractable edemas, Biomaterials 26(2005) 4101~4110
[18] Omidian H, Hashemi S A, Sammes P. G. Eds. Journal of Polymer, 1998, 39(15): 3459~3466
[19] Chen J. W, Zhao Y. M, Journal of Applied Polymer Science, 1999, 74(1): 119~124
[20]李贤真,李彦锋,朱晓夏等,高分子水凝胶材料研究进展,功能材料,2003年第4期(34)卷
[21]房喻,胡道道,崔亚丽,智能型高分子水凝胶的应用研究现状,高技术通讯,2001年11卷3期
[22]陈建海,科学出版社,北京,2003:194
[23]石艳丽,李珍,张高奇等,CMC/PNIPAAm半互穿网络水凝胶的溶涨动力学研究,功能高分子学报,2005年3月,Vol. 18
[24] Xian-Zheng Zhang, Yi-Yan Yang, Tai-Shung chung, Effect of mixed solvents on characteristics of poly(N-isopropylacrylamide) gels, Langmuir, 2002, 18, 2538~2542
[25] Ping Gao, Richard H. Meury, Swelling of hydroxypropyl methylcellulose matrix tablets. 1. Characterization of Swelling Using a Novel Optical Imaging Method, Journal of Pharmaceutical Sciences, Vol. 85, No. 7, July 1996
[26] J. Siepmann, K. Podual, M. Sriwongjanya, Eds. A New Model Describing the Swelling and Drug Release Kinetics from Hydroxypropyl Methylcellulose Tablets, Journal of Pharmaceutical Sciences, Vol. 88, No. 1, January 1999
[27] Sasa Baumgartner, Gojmir Lahajnar, Ana Sepe, Eds. Investigation of the State and Dynamics of Water in Hydrogels of Cellulose Ethers by HNMR Spectroscopy, AAPS PharmSciTech 2002, 3(4)article 36
[28] Flory P J, Principles of Polymer Chemistry, New York: Cornell University Press, Ithace, 1953: 589
[29] O. Dufaud, E. Favre, V. Sadtler, Porous Elastomeric Beads from Crosslinked Emulsions, Journal of Applied Polymer Science, Vol. 83, 967~971(2002)
[30]杨新林,白锋,黄文强,单分散功能性聚合物,高分子科学前言与进展,772~778
[31] Li K, Stover H.D.H, Journal of Polymer Science Part A: Polymer Chemical, 1993, 31: 9746~9752
[32] Stephen M. O’Connor, Stevin H. Gehrke,Synthesis and characterization of thermally-responsive hydroxypropyl methylcellulose gel beads, Journal of Applied Polymer Science, Vol. 66, 1279~1290(1997)
[33] Alois Jungbauer, Rainer Hahn, Karin Deinhofer, Eds. Performance and characterization of a nanophased porous hydroxyapatite for protein chromatography, Biotechnology and Bioengineering, Vol, 87, NO. 3, August 5, 2004
[34] H. Omidian, S.A. Hashemi, P.G. Sammes, Eds. A model for the swelling of superabsorbent polymers, Polymer, 1998, 39(26): 6697~6703
[35]制铁化学工业株式会社,生产一种吸水树脂的方法,中国专利,CN 1004550B, 1989-6-21
[36]路建美,朱秀林等,高吸水性树脂的合成及性能研究,应用化学,1992, 16(1): 89~91
[37] K. Moana Raju, M. Padmanabha Raju, Synthesis and Swellling Properties of Superabsorbent Copolymers, Advances in Polymer Technology, 2001, 20(2): 146~154
[38] R. A. Grinsted, L. Clark, J.L. Koenig, Study of cyclic sorption-desorption into poly(methlmethacrylate) rods using NMR imaging, Macromolecules 1992, 25, 1235
[39] F. Rouquerol, J. Rouquerol, K. Sing, Adsorption by powders and porous solids, London: Academic Press, 1999, 165~179
[40] K.S.W. Sing, Adsorption metheds for the characterization of porous materials, J. Coll. Int. Sci. 1998, 76~77(1): 3~11
[41] N.A. Peppas, Eds. Hydrogels in medicine and pharmacy, CRC Press: Boca Raton, FL, 1987
[42] F. Esposito, M. A. Del. Nobile, G. Mensitieri, Eds. Water sorption in cellulose-based hydrogels, Journal of Applied Polymer Science, 1996, 60: 2043
[43] A. Sannino, A. Cozzolino, L. Nicolais, Eds. A system of body water elimination based on cellulose derivatives superabsorbent hydrogels, J Biomed Mater Res 2003, 67A: 1016~24
[44] Anil Dube, Iwao Teraoka, Infusion of Polymer into a Porous Glass Bead As Studied by Space-Resolved Jamin Interferometry, Macromolecules, 1997, 30, 5352~5360
[45] Hyun Goo Kang, Sang Bong Lee, Young Moo Lee, Novel preparative method for porous hydrogels using overrun process, Polymer International, 54:537~543 (2005)
[46] Schulz M B, Daniels R. Hydroxypropyl methylcellulose (HPMC) as emulsifier for submicron emulsions: influence of molecular weight and substitution type on the droplet size after high-pressure homogenization, Europe Journal of Pharmaceutics and Biopharmaceutics, 2000, 49(3): 231~236
[47] A.J. Paine, Y. Deslandes, G. Paul, Eds. Dispersion polymerization of styrene in polar solventsⅡV isualization of surface layers of steric stabilizer on dispersion- polymerized and precipitated polystyrene latex particles by transmission electron microscopy, Journal of Colloid and Interface Science, 1990, 138(1): 170~181
[48] E. Melzer, J. Kreuter, D. Rolf, Ethylcellulose: a new type of emulsion stabilizer, European Journal of Pharmaceutics and Biopharmaceutics, 2003, 56(1): 23~27
[49] H. Yoshiyuki, Eds. Nippon Shokuai Kagaku Kogyo Co, JP 04-15286, 14 Aug 1992
[50] M.M. Doeff, Eds. Characteristics of laminated electrochromic devices using polyorganodisulfide electrodes , Journal of Electrochem Soc, 1992, 139(8): 2077
[51] J.H. Burgert, Eds. Antibiotic resistance: Will infection control meet the challenge , Dow Chemical Co, WO 94 20547, 15 Sep, 1994
[52] T. Yanaki, Eds. Lymphocytic adenohypophysitis: An immunohistochemical study , Shiseido Co, WO 91 5376, 02 May 1991
[53] M. Yamato, Eds. Dynamic magnetic resonance imaging of shoulder joint disorders, Journal of Biochem, 1995, 117: 940
[54] A. Delbruck, Eds. Changes in the extracellular matrix of the autogenous patellar tendon graft after posterior cruciate ligament reconstruction: a biochemical study in sheep Connect Tissue Res, 1986, 15: 155
[55] M.B. Aydelotte, K.E. Kuettner, Biochemical and morphological studies of bovine articular chondrocytes cultured in agarose gel, Connect Tissue Res, 1988, 18: 205
[56] A. Jason, Matthew Ward, Ellen Liang, Eds, Stimulation of neurite outgrowth byneurotrophins delivered from degradable hydrogels, Biomaterials, 2006, 27: 452~459