聚酸酐的合成及其在静电纺丝中的应用研究
|
摘要
近年来,生物可降解高分子材料被广泛应用于药物控释体系、可吸收缝合线、外科矫形器件、细胞组织工程等生物医用领域。聚酸酐作为一类具有良好生物相容性、表面溶蚀特性及降解速度可调的生物降解性高分子材料,倍受人们关注。到目前为止,人们合成了各种类型的聚酸酐,然而在药物控释领域应用最多的实际上是由不同单体按照一定比例聚合而成的各种酸酐共聚物。这主要是因为:一方面随着聚酸酐在药物控释领域应用的不断扩展,单独的聚酸酐均聚物很难满足药物控释要求,仅靠其分子量和分子量分布调节降解速度具有很大的局限性;另一方面为了进一步改进冲击强度、渗透性及亲水性,人们开始对聚酸酐骨架进行修饰,引入其它聚酸酐或其它可降解高分子材料形成各类共聚物,改进聚酸酐的性能,以更好地满足药物控释的要求。本文也在这方面做了研究,包括以下主要内容:
1.以癸二酸(SA)和合成单体1,3-双对羧基苯氧基丙烷(CPP)为起始原料,采用熔融缩聚法合成了一系列具有不同共聚组成比的脂肪族—芳香族共聚酸酐P(CPP-SA)。考察了反应温度和反应时间等对聚酸酐分子量的影响。研究结果表明,在实验室条件下,最佳的聚合条件为:真空度55mmHg,反应温度为180℃下聚合2h,合成的聚酸酐粘均分子量最高可达60,000左右。所得的聚酸酐用FT-IR、~1H NMR、粘度法、DSC及XRD进行了表征,实验结果表明合成的聚酸酐具有分子量高,熔点低,热稳定性好等特点。利用变温红外研究了聚酸酐P(CPP-SA)(20:80)的热稳定性及其结晶相关谱带,结果发现:PSA链段的稳定性比PCPP链段的稳定性差;1471,1412,1359cm~(-1)三个谱带在变温过程中表现得很特别,推测其与聚酸酐的结晶相关联,可能是其结晶相关谱带。
2.采用了熔融缩聚法合成了SA、CPP、PEG三元醚酐共聚物及SA、F127二元醚酐共聚物。~1H NMR和FTIR证实了单体、预聚物及无规共聚物的结构。理化性质表征结果显示:合成的醚酐共聚物具有分子量高,熔点较低,热稳定性较好等作为药物缓释材料必备的性能。同时研究发现PEG的引入对聚酸酐的分子量、结晶度及亲水性有较大影响。
3.以P(CPP-SA)共聚酸酐为载体材料,采用静电纺丝技术制备了未载药的及载有模型药物对乙酰氨基酚的纤维膜,体外降解研究表明,聚酸酐P(CPP-SA)在前期的降解速度特别快,一天内重量损失就达到了50%左右,而后期是一个比较缓慢的降解。且随着聚酸酐中疏水性单体CPP含量的增加,降解速度减慢,这些结果表明了聚酸酐的降解与聚酸酐的组成及基质的几何形状大小密切相关。体外释放研究表明,聚酸酐的溶蚀是控释的机理。药物释放初期产生了一个明显的突释过程,突释量达到了45%左右,而后是一个缓释过程。
In recent years, biodegradable polymeric materials have been found to be useful in drug delivery, absorbable suture, surgical orthopedic device and cell tissue engineering applications. In these materials, polyanhydride was a kind of biodegradable polymer, which attracted the interest of many researchers, because it was biocompatible, surface-eroding behavior and the rate of degradation was adjustable. Up to now, many types of polyanhydrides have been synthesized, but in the controlled drug delivery systems, the most wide use of application is the copolymers which are synthesized by different monomer ratios. The main cause include two parts. On the one hand, with the increasing application of controlled drug delivery systems, polyanhydride homopolymer can not meet requirement for drug delivery. To adjust the rate of degradation only depend on molecular weight and molecular weight distribution of copolymers have limitation. On another hand, in order to improve impact strength, permeability and hydrophilicity, other polyanhydrides or biodegradable polymeric materials are incorporated into the polymer backbone, which improve the performance of polyanhydride to meet requirement for drug delivery. This paper also research in this respect, the main results are as follows:
1. The biodegradable polyanhydride copolymers composed of p-carboxyhenoxy propane (CPP) and sebacic acid (SA) in different weight ratios were polymerized by a melt polycondensation process. Additionally, several factors which affected the molecular weight had been studied, such as reaction time, reaction temperature and so on. The optimized conditions under laboratory conditions were vacuum degree 55mmHg, reaction temperature 180℃and reaction time 2h. The copolymers were characterized by FT-IR, ~1H NMR, Ubbelohde viscometer, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) etc. It show that all the prepared polyanhydrides possesses high molecular weights, low melting points, and desired thermal stability. It was found that PCPP chain segment exhibit more stable than PSA after being investigated by FTIR spectra between 24-300℃. The peaks of 1471, 1412, 1359 cm~(-1) changed sharply after 70℃in this process. It was deduced that these three peaks are linked to the crystalline of P(CPP-SA).
2. A series of biodegradable poly(ether-anhydrides) composed of poly(ethyleneglycol)(PEG), and 1,3-bis(carboxyphenoxy)propane(CPP), sebacic acid(SA), or PluronicF127 and sebacic acid(SA) were synthesized by a melt polycondensation process. Characterization of the copolymers by FTIR and ~1H NMR confirms their structures. The physical and chemical properties showed that all the prepared poly(ether-anhydrides) meet the essential requirement for polyanhydrides as drug delivery material including high molecular weights, low melting points, and desired thermal stability. Meanwhile, the research shows that PEG blocks existed has great influence on molecular weight, crystallinity and hydrophilicity of polyanhydride.
3. Copolymer ultrafine fibers, which contain paracetamol as a model drug and P(CPP-SA) were prepared by electrostatic spinning. The experimental results showed that degradation rate was fast in the fist day and slowed in the following period, furthermore the degradation rate decreased with the increase of the content of CPP in copolymers. These results reveal the degradation is closely related to copolymer composition and geometry of matrice. In vitro release study showed that polyanhydride erosion is the mechanism of drug controlled release. There was an initial burst release about 45% and sustained released in the following period.
1.以癸二酸(SA)和合成单体1,3-双对羧基苯氧基丙烷(CPP)为起始原料,采用熔融缩聚法合成了一系列具有不同共聚组成比的脂肪族—芳香族共聚酸酐P(CPP-SA)。考察了反应温度和反应时间等对聚酸酐分子量的影响。研究结果表明,在实验室条件下,最佳的聚合条件为:真空度55mmHg,反应温度为180℃下聚合2h,合成的聚酸酐粘均分子量最高可达60,000左右。所得的聚酸酐用FT-IR、~1H NMR、粘度法、DSC及XRD进行了表征,实验结果表明合成的聚酸酐具有分子量高,熔点低,热稳定性好等特点。利用变温红外研究了聚酸酐P(CPP-SA)(20:80)的热稳定性及其结晶相关谱带,结果发现:PSA链段的稳定性比PCPP链段的稳定性差;1471,1412,1359cm~(-1)三个谱带在变温过程中表现得很特别,推测其与聚酸酐的结晶相关联,可能是其结晶相关谱带。
2.采用了熔融缩聚法合成了SA、CPP、PEG三元醚酐共聚物及SA、F127二元醚酐共聚物。~1H NMR和FTIR证实了单体、预聚物及无规共聚物的结构。理化性质表征结果显示:合成的醚酐共聚物具有分子量高,熔点较低,热稳定性较好等作为药物缓释材料必备的性能。同时研究发现PEG的引入对聚酸酐的分子量、结晶度及亲水性有较大影响。
3.以P(CPP-SA)共聚酸酐为载体材料,采用静电纺丝技术制备了未载药的及载有模型药物对乙酰氨基酚的纤维膜,体外降解研究表明,聚酸酐P(CPP-SA)在前期的降解速度特别快,一天内重量损失就达到了50%左右,而后期是一个比较缓慢的降解。且随着聚酸酐中疏水性单体CPP含量的增加,降解速度减慢,这些结果表明了聚酸酐的降解与聚酸酐的组成及基质的几何形状大小密切相关。体外释放研究表明,聚酸酐的溶蚀是控释的机理。药物释放初期产生了一个明显的突释过程,突释量达到了45%左右,而后是一个缓释过程。
In recent years, biodegradable polymeric materials have been found to be useful in drug delivery, absorbable suture, surgical orthopedic device and cell tissue engineering applications. In these materials, polyanhydride was a kind of biodegradable polymer, which attracted the interest of many researchers, because it was biocompatible, surface-eroding behavior and the rate of degradation was adjustable. Up to now, many types of polyanhydrides have been synthesized, but in the controlled drug delivery systems, the most wide use of application is the copolymers which are synthesized by different monomer ratios. The main cause include two parts. On the one hand, with the increasing application of controlled drug delivery systems, polyanhydride homopolymer can not meet requirement for drug delivery. To adjust the rate of degradation only depend on molecular weight and molecular weight distribution of copolymers have limitation. On another hand, in order to improve impact strength, permeability and hydrophilicity, other polyanhydrides or biodegradable polymeric materials are incorporated into the polymer backbone, which improve the performance of polyanhydride to meet requirement for drug delivery. This paper also research in this respect, the main results are as follows:
1. The biodegradable polyanhydride copolymers composed of p-carboxyhenoxy propane (CPP) and sebacic acid (SA) in different weight ratios were polymerized by a melt polycondensation process. Additionally, several factors which affected the molecular weight had been studied, such as reaction time, reaction temperature and so on. The optimized conditions under laboratory conditions were vacuum degree 55mmHg, reaction temperature 180℃and reaction time 2h. The copolymers were characterized by FT-IR, ~1H NMR, Ubbelohde viscometer, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) etc. It show that all the prepared polyanhydrides possesses high molecular weights, low melting points, and desired thermal stability. It was found that PCPP chain segment exhibit more stable than PSA after being investigated by FTIR spectra between 24-300℃. The peaks of 1471, 1412, 1359 cm~(-1) changed sharply after 70℃in this process. It was deduced that these three peaks are linked to the crystalline of P(CPP-SA).
2. A series of biodegradable poly(ether-anhydrides) composed of poly(ethyleneglycol)(PEG), and 1,3-bis(carboxyphenoxy)propane(CPP), sebacic acid(SA), or PluronicF127 and sebacic acid(SA) were synthesized by a melt polycondensation process. Characterization of the copolymers by FTIR and ~1H NMR confirms their structures. The physical and chemical properties showed that all the prepared poly(ether-anhydrides) meet the essential requirement for polyanhydrides as drug delivery material including high molecular weights, low melting points, and desired thermal stability. Meanwhile, the research shows that PEG blocks existed has great influence on molecular weight, crystallinity and hydrophilicity of polyanhydride.
3. Copolymer ultrafine fibers, which contain paracetamol as a model drug and P(CPP-SA) were prepared by electrostatic spinning. The experimental results showed that degradation rate was fast in the fist day and slowed in the following period, furthermore the degradation rate decreased with the increase of the content of CPP in copolymers. These results reveal the degradation is closely related to copolymer composition and geometry of matrice. In vitro release study showed that polyanhydride erosion is the mechanism of drug controlled release. There was an initial burst release about 45% and sustained released in the following period.
引文
[1] VJ. Chen, P.X. Ma. Nano-fibrous poly(L-lactic acid) scaffolds with interconnected spherical macropores. Biomaterials, 2004,25(11): 2065-2073.
[2] N.D. Miller, D.F. Williams, D. F. The in vivo and in vitro degradation of PGA suture material as a function of applied strain, Biomaterials, 1984,5: 365-368.
[3] K.A. Athanasiou, C.M. Agrawal, et al. Orthopaedic applications for PLA-PGA biodegradable polymers. Arthroscopy, 1998,14(7): 726-37.
[4] C.M. Agrawal, K.F. Haas, D.A. Leopold, H.G. Clark. Evaluation of poly(L-lactic acid) as material for intravascular polymeric stents, Biomaterials, 1992,13:176-782.
[5] A.J. Domb, I. Ringel. Polymeric drug carrier systems in the brain. Methods Neurosci, 1994, 21:169-183.
[6] D. Stephens, L Li, D. Robinson, et al. Investigation of the in vitro release of gentamicin from a polyanhydride matrix, J. Controlled Release, 2000,63: 305-317
[7] W.B. Dang, T. Daviau, D. Nowotnik. In vitro erosion kinetics of implantable polyanhydride GliadelTM. Proc. Int. Symp. Control. Rel. Bioact. Mater, 1996, 23: 731-732.
[8] K.E. Uhrich, T.T. Thomas, C.T. Laurencin, R.Langer. In vitro degradation characteristics of poly(anhydride-co-imides) containing trimellityimidoglycine. J. Appl. Polym. Sci, 1997, 63:1401-1411.
[9] Cheng-Kuang Chan, I-Ming Chu. Phase behavior and miscibility in blends of poly(sebacic anhydride)/poly(ethylene glycol). Biomaterials, 2002, 23:2353-2358.
[10] J.M. Gao, L. Niklason, X.M. Zhao, R. Langer. Surface modification of polyanhydride microspheres. J. Pharm. Sci, 1998, 87: 246-248.
[11] M.S. Kim, K.S. Seo et al. Synthesis and characterization of polyanhydride for local BCNU delivery carriers. Bio-Medical Materials and Engineering 2005,15:229-238.
[12] D. Stephens, L. Li, D. Robinson. Investigation of the in vitro release of gentamicin from a polyanhydride matrix. J Control Release, 2000,63(3): 305-317.
[13] D.B. Masters, C.B. Berde, S. Dutta et al. Sustained local-anesthetic release from bioerodible polymer matrices-a potential method for prolonged regional anesthesia. Pharm. Res 1993,10:1527-1532.
[14] A.S. Determan AS, J.H.Wilson, M.J. Kipper. Protein stability in the presence of polymer degradation products: Consequences for controlled release formulations. Biomaterials 2006,27: 3312-3320.
[15] M.P. Torres, A.S. Determan, G.L. Anderson. Amphiphilic polyanhydrides for protein stabilization and release. Biomaterials 2007, 28:108-116.
[16] E. Mathiowitz, M.D. Cohen, R. Langer. Novel microcapsules for delivery systems. React. Polym., Ion Exch., Sorbents, 1987,6: 275-283.
[17] Bucher JB, Slade W C. The anhydrides of isophthatic and terephthalic acids. J Am Chem Soc, 1909: 32: 1319
[18] J.W. Hill, W.H. Carothers. Studies of Polymerization and Ring Formation XIV: a Linear Superpolyanhydride and a Cyclic Dimeric Anhydride from Sedacic Acid. J Am Chem Soc, 1932,54:1969.
[19] A. Conix. New high-melting fibre-forming polymers. Makromol Chem, 1957,24: 74.
[20] N. Yoda, A. Miyake. Crystalline and high melting poly(amide) poly(anhydride) of methylene bis(p-carboxyphenyl) amide. J. Polym. Sci., Part A, 1962,1:1323-1338.
[21] A.J. Domb, C.F. Gallardo, R. Langer. Poly(anhydrides). 3. Poly(anhydrides) Based on Aliphatic-Aromatic Diacids. Macromolecules, 1989, 22(8): 3200-3204
[22] W.X. Guo, Z.L. Shi, et al. Polyanhydride modified unsaturated polyesters as injectable drug carriers: Synthesis and antitumor efficacy in Sarcoma-180 mice bearing tumor. Polymer Degradation and Stability, 2006,91: 2924-2930
[23] J. Fu, R.X. Zhuo, C.L. Fan. Studies on the syntheses and drug release properties of polyanhydrides containing phosphonoformic(or acetic)and ethyl ester in the main chain. Chem J Chinese U, 1997,18(10): 1706-1710.
[24] J. Fu, R.X. Zhuo, C.L. Fan. Studies on the syntheses and properties of phosphorus-containing polyanhydrides for DDS. Chem J Chinese U, 1997,18(5): 813-817.
[25] H. L. Jiang, K. J. Zhu. Synthesis, characterization and in vitro degradation of a new family of alternate poly(ester-anhydrides) based on aliphatic and aromatic diacids. Biomaterials, 2001,22:211-218.
[26] B. APfeifer, J.A. Burdick, R. Langer. Formulation and surface modification of poly(ester-anhydride) micro- and nanospheres. Biomaterials, 2005,26:117-124.
[27] M.Y. Krasko, A. Shikanov, A. Ezra, AJ. Domb. Poly(ester anhydride)s Prepared by the Insertion of Ricinoleic Acid into Poly(sebacic acid). J Poly Sci, Part A: Polym Chem, 2003, 41:1059-1069.
[28] J. Fu, J. Fiegel, J. Hanes. Synthesis and Characterization of PEG-Based Ether-Anhydride Terpolymers: Novel Polymers for Controlled Drug Delivery. Macromolecules, 2004, 37: 7174-7180.
[29] H. L. Jiang, K. J. Zhu. Preparation, characterization and degradation characteristics of polyanhydrides containing polyethylene glycol. Polym Int, 1999,48: 47-52.
[30] C.K. Chan, I.M. Chu. Crystalline and dynamic mechanical behaviors of synthesized poly(sebacic anhydride-co-ethylene glycol). Biomaterials, 2003,24: 47~54.
[31] J. Fiegel, J. Fu, J. Hanes. Poly(ether-anhydride) dry powder aerosols for sustained drug delivery in the lungs. J Controlled Release, 2004,96: 411.
[32] H. L. Jiang, K. J. Zhu. Pulsatile protein release from a laminated device comprising of polyanhydrides and pH-sensitive complexes. Int J pharm, 2000,194(1): 51-60
[33] M. Hartmann, V. Schulz. Synthesis and characterization of polyanhydrides containing amino groups. Macromol. Chem, 1989,190: 2133
[34] A. Staubli, E. Mathiowitz, R. Langer. Sequence distribution and its effect on glass transition temperatures of poly(anhydride-co-imides) containing asymmetric monomers. Macromolecules, 1991,24: 2291-2298
[35] U. Edlund, A.C. Albertsson. Copolymerization and polymer blending of trimethylene carbonate and adipic anhydride for tailored drug delivery. J. Appl. Polym. Sci, 1999, 72(2): 227-239.
[36] M. Maniar, X. Xie, A.J. Domb. Polyanhydrides: V. Branched Polyanhydrides. Biomaterials, 1990,11(9): 690-694
[37] D.S. Muggli, A.K. Burkoth, K.S. Anseth. Crosslinked Polyanhydrides for Use in Orthopedic Applications: Degradation Behavior and Mechanics. J. Biomed. Mater. Res, 1999, 46: 271-278.
[38] A. J. Domb, R. Langer. Polyanhydrides. I. Preparation of High Molecular Weight Polyanhydrides. J Poly Sci, Part A: Polym Chem, 1987,25(11): 3373-3386.
[39] K.W. Leong, B.C. Bortt, R. Langer. Bioerodible polyanhydrides as drug carrier matricesI: characterization, degradation and release characteristics. J Biomed Mater Res, 1985, 19 : 941-955.
[40] A.J. Domb. Biodegradable polymers derived from amino acids. Biomaterials, 1990,11(9): 686-689.
[41] A.C. Albertsson, S. Lundmsrk. Synthesis of poly(adipic) anhydride by use of ketene. J. Macromol. Sci. Chem.A, 1990,27: 397-412.
[42] S. Lundmark, M. Sjoling, A.C. Albertsson. Polymerization of oxipane-2,7-dione in solution and synthesis of block copolymer of oxipane-2,7-dione and 2-oxipanone. J. Macromol. Sci. Chem.A, 1991, 28:15-29.
[43] N. Ropson, Ph. Dubois, R. Jerome, et al. Living (co)polymerization of adipic anhydride and selective end functionalization of the parent polymer. Macromolecules, 1992, 25: 3820-3824.
[44]J.S.Young,K.D.Gonzales,K.S.Anseth.Photopolymers in orthopedics:characterization of novel crosslinked polyanhydrides.Biomaterials,2000,21(11):1181-1188
[45]A.Gopferich,J.Tessmar.Polyanhydride degradation and erosion.Advanced Drag Delivery Reviews,2002,54:911-931.
[46]A.Gopferich,R.Langer,The influence of microstructure and monomer properties on the erosion mechanism of a class polyanhydrides.J.Polym.Sci,1993,31:1445-1458.
[47]A.Gopferich.Polymer degradation and erosion:mechanism and applications.Eur.J.Pharm.Biopharm,1996,42:1-11.
[48]A.J.Domb,M.Rock,J.Schwartz.Metabolic disposition and elimination studies of a radiolabelled biodegradable polymeric implant in the rat brain.Biomaterials,1994,15(9):681-688.
[49]A.J.Domb,M.Rock,C.Perkin.Excretion of a radiolabeled anticancer biodegradable polymeric implant from the rabbit brain.Biomaterials,1995,16(14):1069-1072.
[50]国生物材料评价标准ASTMF-748-87和ASTMF-981-87.
[51]中华人民共和国国家国家技术监督局,中华人民共和国国家标准医疗器械生物学评价(1997:GB/T 16886).中国计量出版社,1997.
[52]C.Laurencin,A.Domb,C.Morris.Poly(anhydride)administration in high doses in vivo:studies of biocompatibility and toxicology.J Biomed Mater Res,1990,24(11):1463-1481
[53]A.J.Domb,L.Turovsky,R.Nudelman.Chemical interactions between drugs containing reactive amines with hydrolysable insoluble biopolymers in aqueous solutions.Pharm Res,1994,11(6):865-868.
[54]M.Krishnan,D.R.Flanagan.FFIR-ATR spectroscopy for monitoring polyanhydride/anhydride-amine reactions.J Control Release,2000,69(2):273-281.
[55]C.T.Laurencin,T.Gerhart,P.Witschger,et al.Bioerodible polyanhydrides for antibiotic drug delivery:in vivoosteomyelitis treatment in arat model system.J Orthop Res,1993,11(2):256-262.
[56]J.S.Deng,L.Li,D.Stephens et al.Effect of γ-radiation on a polyanhydride implant containing gentamicin sulfate.International Journal of Pharmaceutics,2002,232(1-2):1-10.
[57]A.J.Domb,Z.H.Israel,O.Elmalak,et al.Preparation and characterization of carmustine loaded polyanhydride wafers for treating brain tumors.Pharm Res,1999,16(5):762-765.
[58]M.Sandor,N.A.Bailey,E.Mathiowitz.Characterization of polyanhydride microsphere degradation by DSC.Polymer,2002,3(2):279-288.
[59]E.Mathiowitz,J.S.Jacob,et al.Biologically erodible potential microspheres as oral drug delivery systems.Nature,1997,386:410.
[60]H.Brem,M.S.Mahalty,A.V.Nicholas.Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas.J.Neurosurg,1991,74:441-446.
[61]C.T.Laurencin,T.Garhart,P.Witschger P,et al.Bioerodible polyanhydrides for antibiotic drug delivery:in vivo osteomyelitis treatment in a rat model system.J Orthop Res,1993,11(2):256-262
[62]A.J.Domb,R.Langer.Polyanhydrides.Ⅳ.Unsaturated and Cross-linked Polyanhydrides.Journal of Polymer Science:Part A:Polymer Chemistry,1991,29:571-579.
[63]D.B.Mastors,C.B.Berde,S.Dutta,et al.Sustained local anesthetic release from bioerodible polymer matrices:a potential method for prolonged regional anesthesia,Pharm.Res,1993,10(10):1527
[64]M.Deitzel,J.Kleinmeuer,J.K.Hirvonen,T.N.C.Beck.Controlled deposition of electrospun poly(ethylene oxide)fibers.Polymer,2001,42:8163-8170.
[65]S.A.Riboldi,M.Sampaolesi,P.Neuenschwander,et al.Electrospun degradable polyester urethane membranes,Potential scaffolds for skeletal muscle tissue engineering.Biomaterials,2005,26(22):4606-4615.
[66]《阿霉素的超细纤维剂型及其制备方法[P]》,专利申请号CN200310115823.0,发明人:景遐斌,曾敬,陈学思,徐效义,边新超,徐秀玲公开日:2004.11.10中国
[67]J.Zhang,X.Y.Xu,X.S.Chen,et al.Biodegradable electrospun fibers for drag delivery.Journal of Controlled Release,2003,92(3):227-231.
[68]E.R.Kenawy,G.L.Bowlin,K.Mansfield,et al.Release of tetracycline hydrochloride from electrospun poly(lactic acid)and a blend.J Control Release:2002,81:57-64.
[69]W.Kataphinan,S.Dahney,D.Smith,D.Reneker.Fabrication of electrospun and encapsulation into polymer nanofibers.J Textile Apparel,Technol Manage.Special issue:The Fiber Society Spring 2001 Conference,Raleigh NC.2001,1.
[70]W.J.Li,C.T.Laurencin,E.J.Caterson,et al.Electrospun nanofibers structure:A novel scaffold for tissue engineering.Journal of Biomedical Materials Research,2002,60(4):613-621.
[71]A.Pedicini,R.J.Farfis.Thermally induced color change in electrosptm fiber mats.J Polym Sci Part B:Polym Phys 2004,42:752-757.
[72]尹桂波,张幼珠.电子纺丝及其制备的纳米纤维的应用.合成纤维,2004,33(1):13-15.
[72]H.Seong,D.Moon,G.Khang,H.B.Lee.Preparation and characterization of BCNU-loaded PLGA wafer.Polymer,2002,26:128-138.
[73]H.Gollwitzer,K.Ibrahim,H.Meyer,et al.Antibacterial poly(D,L-lactic acid)coating of medical implants using a biodegradable drug delivery technology.J.Antimicrob.Chemother 2003,51:585-591.
[74]于美丽,王勇等.聚酸酐的合成及在生物上的应用.生物医学工程学杂志,2003,20(1):135-138.
[75]莫志深,张宏放.晶态聚合物结构和X射线衍射.2003,10:198-200.
[76]周玉,武高辉.材料分析测试技术—材料X射线衍射与电子显微分析.哈尔滨工业大学.1998.
[77]K.Nakamura,Y.Maitani,A.M.Lowman,K.Takayama.Uptake and release of budesonide from mucoadhesive,pH-sensitive copolymers and their application to nasal delivery.J. Control. Rel, 1999,61:329-335.
[78] K.J. Zhu, X.Z. Lin, S.L. Yang. Preparation, characterization and properties of polylactide (PLA)-poly(ethylene glycol) (PEG) copolymers: a potential drug carrier. J. Appl. Polym. Sci, 1990,39:1-9.
[79] J. Fu, J. Fiegel, E. Krauland, et al. New polymeric carriers for controlled drug delivery following inhalation or injection. Biomaterials, 2002,23:4425-4433.
[80] E. Mathiowitz, H. Bernstein, et al. Polyanhydride microspheres. IV. Morphology and characterization of systems made by spray drying,. J. Appl. Polym. Sci, 1992,45:125-134.
[2] N.D. Miller, D.F. Williams, D. F. The in vivo and in vitro degradation of PGA suture material as a function of applied strain, Biomaterials, 1984,5: 365-368.
[3] K.A. Athanasiou, C.M. Agrawal, et al. Orthopaedic applications for PLA-PGA biodegradable polymers. Arthroscopy, 1998,14(7): 726-37.
[4] C.M. Agrawal, K.F. Haas, D.A. Leopold, H.G. Clark. Evaluation of poly(L-lactic acid) as material for intravascular polymeric stents, Biomaterials, 1992,13:176-782.
[5] A.J. Domb, I. Ringel. Polymeric drug carrier systems in the brain. Methods Neurosci, 1994, 21:169-183.
[6] D. Stephens, L Li, D. Robinson, et al. Investigation of the in vitro release of gentamicin from a polyanhydride matrix, J. Controlled Release, 2000,63: 305-317
[7] W.B. Dang, T. Daviau, D. Nowotnik. In vitro erosion kinetics of implantable polyanhydride GliadelTM. Proc. Int. Symp. Control. Rel. Bioact. Mater, 1996, 23: 731-732.
[8] K.E. Uhrich, T.T. Thomas, C.T. Laurencin, R.Langer. In vitro degradation characteristics of poly(anhydride-co-imides) containing trimellityimidoglycine. J. Appl. Polym. Sci, 1997, 63:1401-1411.
[9] Cheng-Kuang Chan, I-Ming Chu. Phase behavior and miscibility in blends of poly(sebacic anhydride)/poly(ethylene glycol). Biomaterials, 2002, 23:2353-2358.
[10] J.M. Gao, L. Niklason, X.M. Zhao, R. Langer. Surface modification of polyanhydride microspheres. J. Pharm. Sci, 1998, 87: 246-248.
[11] M.S. Kim, K.S. Seo et al. Synthesis and characterization of polyanhydride for local BCNU delivery carriers. Bio-Medical Materials and Engineering 2005,15:229-238.
[12] D. Stephens, L. Li, D. Robinson. Investigation of the in vitro release of gentamicin from a polyanhydride matrix. J Control Release, 2000,63(3): 305-317.
[13] D.B. Masters, C.B. Berde, S. Dutta et al. Sustained local-anesthetic release from bioerodible polymer matrices-a potential method for prolonged regional anesthesia. Pharm. Res 1993,10:1527-1532.
[14] A.S. Determan AS, J.H.Wilson, M.J. Kipper. Protein stability in the presence of polymer degradation products: Consequences for controlled release formulations. Biomaterials 2006,27: 3312-3320.
[15] M.P. Torres, A.S. Determan, G.L. Anderson. Amphiphilic polyanhydrides for protein stabilization and release. Biomaterials 2007, 28:108-116.
[16] E. Mathiowitz, M.D. Cohen, R. Langer. Novel microcapsules for delivery systems. React. Polym., Ion Exch., Sorbents, 1987,6: 275-283.
[17] Bucher JB, Slade W C. The anhydrides of isophthatic and terephthalic acids. J Am Chem Soc, 1909: 32: 1319
[18] J.W. Hill, W.H. Carothers. Studies of Polymerization and Ring Formation XIV: a Linear Superpolyanhydride and a Cyclic Dimeric Anhydride from Sedacic Acid. J Am Chem Soc, 1932,54:1969.
[19] A. Conix. New high-melting fibre-forming polymers. Makromol Chem, 1957,24: 74.
[20] N. Yoda, A. Miyake. Crystalline and high melting poly(amide) poly(anhydride) of methylene bis(p-carboxyphenyl) amide. J. Polym. Sci., Part A, 1962,1:1323-1338.
[21] A.J. Domb, C.F. Gallardo, R. Langer. Poly(anhydrides). 3. Poly(anhydrides) Based on Aliphatic-Aromatic Diacids. Macromolecules, 1989, 22(8): 3200-3204
[22] W.X. Guo, Z.L. Shi, et al. Polyanhydride modified unsaturated polyesters as injectable drug carriers: Synthesis and antitumor efficacy in Sarcoma-180 mice bearing tumor. Polymer Degradation and Stability, 2006,91: 2924-2930
[23] J. Fu, R.X. Zhuo, C.L. Fan. Studies on the syntheses and drug release properties of polyanhydrides containing phosphonoformic(or acetic)and ethyl ester in the main chain. Chem J Chinese U, 1997,18(10): 1706-1710.
[24] J. Fu, R.X. Zhuo, C.L. Fan. Studies on the syntheses and properties of phosphorus-containing polyanhydrides for DDS. Chem J Chinese U, 1997,18(5): 813-817.
[25] H. L. Jiang, K. J. Zhu. Synthesis, characterization and in vitro degradation of a new family of alternate poly(ester-anhydrides) based on aliphatic and aromatic diacids. Biomaterials, 2001,22:211-218.
[26] B. APfeifer, J.A. Burdick, R. Langer. Formulation and surface modification of poly(ester-anhydride) micro- and nanospheres. Biomaterials, 2005,26:117-124.
[27] M.Y. Krasko, A. Shikanov, A. Ezra, AJ. Domb. Poly(ester anhydride)s Prepared by the Insertion of Ricinoleic Acid into Poly(sebacic acid). J Poly Sci, Part A: Polym Chem, 2003, 41:1059-1069.
[28] J. Fu, J. Fiegel, J. Hanes. Synthesis and Characterization of PEG-Based Ether-Anhydride Terpolymers: Novel Polymers for Controlled Drug Delivery. Macromolecules, 2004, 37: 7174-7180.
[29] H. L. Jiang, K. J. Zhu. Preparation, characterization and degradation characteristics of polyanhydrides containing polyethylene glycol. Polym Int, 1999,48: 47-52.
[30] C.K. Chan, I.M. Chu. Crystalline and dynamic mechanical behaviors of synthesized poly(sebacic anhydride-co-ethylene glycol). Biomaterials, 2003,24: 47~54.
[31] J. Fiegel, J. Fu, J. Hanes. Poly(ether-anhydride) dry powder aerosols for sustained drug delivery in the lungs. J Controlled Release, 2004,96: 411.
[32] H. L. Jiang, K. J. Zhu. Pulsatile protein release from a laminated device comprising of polyanhydrides and pH-sensitive complexes. Int J pharm, 2000,194(1): 51-60
[33] M. Hartmann, V. Schulz. Synthesis and characterization of polyanhydrides containing amino groups. Macromol. Chem, 1989,190: 2133
[34] A. Staubli, E. Mathiowitz, R. Langer. Sequence distribution and its effect on glass transition temperatures of poly(anhydride-co-imides) containing asymmetric monomers. Macromolecules, 1991,24: 2291-2298
[35] U. Edlund, A.C. Albertsson. Copolymerization and polymer blending of trimethylene carbonate and adipic anhydride for tailored drug delivery. J. Appl. Polym. Sci, 1999, 72(2): 227-239.
[36] M. Maniar, X. Xie, A.J. Domb. Polyanhydrides: V. Branched Polyanhydrides. Biomaterials, 1990,11(9): 690-694
[37] D.S. Muggli, A.K. Burkoth, K.S. Anseth. Crosslinked Polyanhydrides for Use in Orthopedic Applications: Degradation Behavior and Mechanics. J. Biomed. Mater. Res, 1999, 46: 271-278.
[38] A. J. Domb, R. Langer. Polyanhydrides. I. Preparation of High Molecular Weight Polyanhydrides. J Poly Sci, Part A: Polym Chem, 1987,25(11): 3373-3386.
[39] K.W. Leong, B.C. Bortt, R. Langer. Bioerodible polyanhydrides as drug carrier matricesI: characterization, degradation and release characteristics. J Biomed Mater Res, 1985, 19 : 941-955.
[40] A.J. Domb. Biodegradable polymers derived from amino acids. Biomaterials, 1990,11(9): 686-689.
[41] A.C. Albertsson, S. Lundmsrk. Synthesis of poly(adipic) anhydride by use of ketene. J. Macromol. Sci. Chem.A, 1990,27: 397-412.
[42] S. Lundmark, M. Sjoling, A.C. Albertsson. Polymerization of oxipane-2,7-dione in solution and synthesis of block copolymer of oxipane-2,7-dione and 2-oxipanone. J. Macromol. Sci. Chem.A, 1991, 28:15-29.
[43] N. Ropson, Ph. Dubois, R. Jerome, et al. Living (co)polymerization of adipic anhydride and selective end functionalization of the parent polymer. Macromolecules, 1992, 25: 3820-3824.
[44]J.S.Young,K.D.Gonzales,K.S.Anseth.Photopolymers in orthopedics:characterization of novel crosslinked polyanhydrides.Biomaterials,2000,21(11):1181-1188
[45]A.Gopferich,J.Tessmar.Polyanhydride degradation and erosion.Advanced Drag Delivery Reviews,2002,54:911-931.
[46]A.Gopferich,R.Langer,The influence of microstructure and monomer properties on the erosion mechanism of a class polyanhydrides.J.Polym.Sci,1993,31:1445-1458.
[47]A.Gopferich.Polymer degradation and erosion:mechanism and applications.Eur.J.Pharm.Biopharm,1996,42:1-11.
[48]A.J.Domb,M.Rock,J.Schwartz.Metabolic disposition and elimination studies of a radiolabelled biodegradable polymeric implant in the rat brain.Biomaterials,1994,15(9):681-688.
[49]A.J.Domb,M.Rock,C.Perkin.Excretion of a radiolabeled anticancer biodegradable polymeric implant from the rabbit brain.Biomaterials,1995,16(14):1069-1072.
[50]国生物材料评价标准ASTMF-748-87和ASTMF-981-87.
[51]中华人民共和国国家国家技术监督局,中华人民共和国国家标准医疗器械生物学评价(1997:GB/T 16886).中国计量出版社,1997.
[52]C.Laurencin,A.Domb,C.Morris.Poly(anhydride)administration in high doses in vivo:studies of biocompatibility and toxicology.J Biomed Mater Res,1990,24(11):1463-1481
[53]A.J.Domb,L.Turovsky,R.Nudelman.Chemical interactions between drugs containing reactive amines with hydrolysable insoluble biopolymers in aqueous solutions.Pharm Res,1994,11(6):865-868.
[54]M.Krishnan,D.R.Flanagan.FFIR-ATR spectroscopy for monitoring polyanhydride/anhydride-amine reactions.J Control Release,2000,69(2):273-281.
[55]C.T.Laurencin,T.Gerhart,P.Witschger,et al.Bioerodible polyanhydrides for antibiotic drug delivery:in vivoosteomyelitis treatment in arat model system.J Orthop Res,1993,11(2):256-262.
[56]J.S.Deng,L.Li,D.Stephens et al.Effect of γ-radiation on a polyanhydride implant containing gentamicin sulfate.International Journal of Pharmaceutics,2002,232(1-2):1-10.
[57]A.J.Domb,Z.H.Israel,O.Elmalak,et al.Preparation and characterization of carmustine loaded polyanhydride wafers for treating brain tumors.Pharm Res,1999,16(5):762-765.
[58]M.Sandor,N.A.Bailey,E.Mathiowitz.Characterization of polyanhydride microsphere degradation by DSC.Polymer,2002,3(2):279-288.
[59]E.Mathiowitz,J.S.Jacob,et al.Biologically erodible potential microspheres as oral drug delivery systems.Nature,1997,386:410.
[60]H.Brem,M.S.Mahalty,A.V.Nicholas.Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas.J.Neurosurg,1991,74:441-446.
[61]C.T.Laurencin,T.Garhart,P.Witschger P,et al.Bioerodible polyanhydrides for antibiotic drug delivery:in vivo osteomyelitis treatment in a rat model system.J Orthop Res,1993,11(2):256-262
[62]A.J.Domb,R.Langer.Polyanhydrides.Ⅳ.Unsaturated and Cross-linked Polyanhydrides.Journal of Polymer Science:Part A:Polymer Chemistry,1991,29:571-579.
[63]D.B.Mastors,C.B.Berde,S.Dutta,et al.Sustained local anesthetic release from bioerodible polymer matrices:a potential method for prolonged regional anesthesia,Pharm.Res,1993,10(10):1527
[64]M.Deitzel,J.Kleinmeuer,J.K.Hirvonen,T.N.C.Beck.Controlled deposition of electrospun poly(ethylene oxide)fibers.Polymer,2001,42:8163-8170.
[65]S.A.Riboldi,M.Sampaolesi,P.Neuenschwander,et al.Electrospun degradable polyester urethane membranes,Potential scaffolds for skeletal muscle tissue engineering.Biomaterials,2005,26(22):4606-4615.
[66]《阿霉素的超细纤维剂型及其制备方法[P]》,专利申请号CN200310115823.0,发明人:景遐斌,曾敬,陈学思,徐效义,边新超,徐秀玲公开日:2004.11.10中国
[67]J.Zhang,X.Y.Xu,X.S.Chen,et al.Biodegradable electrospun fibers for drag delivery.Journal of Controlled Release,2003,92(3):227-231.
[68]E.R.Kenawy,G.L.Bowlin,K.Mansfield,et al.Release of tetracycline hydrochloride from electrospun poly(lactic acid)and a blend.J Control Release:2002,81:57-64.
[69]W.Kataphinan,S.Dahney,D.Smith,D.Reneker.Fabrication of electrospun and encapsulation into polymer nanofibers.J Textile Apparel,Technol Manage.Special issue:The Fiber Society Spring 2001 Conference,Raleigh NC.2001,1.
[70]W.J.Li,C.T.Laurencin,E.J.Caterson,et al.Electrospun nanofibers structure:A novel scaffold for tissue engineering.Journal of Biomedical Materials Research,2002,60(4):613-621.
[71]A.Pedicini,R.J.Farfis.Thermally induced color change in electrosptm fiber mats.J Polym Sci Part B:Polym Phys 2004,42:752-757.
[72]尹桂波,张幼珠.电子纺丝及其制备的纳米纤维的应用.合成纤维,2004,33(1):13-15.
[72]H.Seong,D.Moon,G.Khang,H.B.Lee.Preparation and characterization of BCNU-loaded PLGA wafer.Polymer,2002,26:128-138.
[73]H.Gollwitzer,K.Ibrahim,H.Meyer,et al.Antibacterial poly(D,L-lactic acid)coating of medical implants using a biodegradable drug delivery technology.J.Antimicrob.Chemother 2003,51:585-591.
[74]于美丽,王勇等.聚酸酐的合成及在生物上的应用.生物医学工程学杂志,2003,20(1):135-138.
[75]莫志深,张宏放.晶态聚合物结构和X射线衍射.2003,10:198-200.
[76]周玉,武高辉.材料分析测试技术—材料X射线衍射与电子显微分析.哈尔滨工业大学.1998.
[77]K.Nakamura,Y.Maitani,A.M.Lowman,K.Takayama.Uptake and release of budesonide from mucoadhesive,pH-sensitive copolymers and their application to nasal delivery.J. Control. Rel, 1999,61:329-335.
[78] K.J. Zhu, X.Z. Lin, S.L. Yang. Preparation, characterization and properties of polylactide (PLA)-poly(ethylene glycol) (PEG) copolymers: a potential drug carrier. J. Appl. Polym. Sci, 1990,39:1-9.
[79] J. Fu, J. Fiegel, E. Krauland, et al. New polymeric carriers for controlled drug delivery following inhalation or injection. Biomaterials, 2002,23:4425-4433.
[80] E. Mathiowitz, H. Bernstein, et al. Polyanhydride microspheres. IV. Morphology and characterization of systems made by spray drying,. J. Appl. Polym. Sci, 1992,45:125-134.