可生物降解聚酰胺酸酐和聚酯酸酐的合成及性能研究
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摘要
近年来，生物可降解高分子材料被广泛应用于药物控制释放，手术缝合线，人造皮肤，骨固定和修复以及细胞组织工程等领域。与非生物降解型高分子材料相比，生物降解型具有更大的优点，它不需要二次手术，是生物医用高分子材料发展的主流方向，本文概述了生物可降解高分子材料的研究进展。其中聚酸酐类可降解性高分子材料是80年代初发展起来的一类新型可生物降解材料。由于其具有良好的生物相容性、表面溶释降解性、降解速度可调及易加工性等优异性能，很快在医学前沿领域得到应用。本文概述了聚酸酐的合成进展以及其临床应用概况。
聚酰胺酸酐是一类新型的聚酸酐材料。高分子主链上交替的酰胺键不但降低了聚合物的降解速度，还改善了聚合物的物理和机械性能。文章合成了化合物N，N’双(L-丙氨酸)癸二酰胺(BASM)，并聚合得到了PBASM，还将它与1，6-双(对羧基苯氧基)己烷(CPH)共聚得到了共聚物P(CPH-BASM)。另外文章还制备了不同重量比的共混物P(CPH-BASM)／PLA，研究了聚合物的体外降解性能(PBS，pH=7.4，37℃)并用DSC研究了它们的热学性质。
为了制备这类性能良好的聚酰胺酸酐的单体，论文还将丁二酸酐、戊二酸酐以及己二酸酐分别与甘氨酸和L-丙氨酸制备了N-羧甲基琥珀酰胺酸、N-(1-羧乙基)琥珀酰胺酸、4-羧甲基氨基甲酰丁酸、4-(1-羧乙基)氨基甲酰丁酸、5-羧甲基氨基甲酰戊酸、5-(1-羧乙基)氨基甲酰戊酸。将得到的目标化合物用IR，~1H NMR进行了表征。
高分子前药和共轭前药最近得到了广泛的研究，与单独给药的药物相比，这类高分子药物可以延长药物的血液浓度。它们有以下几个优点：一是可以使药物以一定的规律释放；二是可以减少由药物的突然释放而引起的副作用。本文首次以己二酸酐和水杨酸为原料，制备了己二酸单(2-羧苯酚)酯，并以它为单体聚合得到了相应得聚酯酸酐。另外还讨论了聚合温度、真空度等对分子量的影响。另外本文还对聚合物在不同的pH值条件下的体外降解行为进行了研究。
In recent years, biodegradable polymeric materials have been used for drug delivery, bone and cartilage repairing, cell issue engineering application. Compared to non-biodegradable polymers, they have favorable advantages. That is, they do not need to be taken out and can degrade into small molecules in body. Biodegradable polymers are the most potential materials for biomedical applications. In this paper, recent developments of biopolymers were reviewed. Novel biodegradable polymers-poly anhydrides have been developed since 1980s' by the group of Langer. These materials are highly biocompatible, demonstrated by tissue response and toxicological study. In addition, they show surface-eroding behavior, thus provide a sustained release rate over a long period of time, and the rate is adjustable. So these materials are very promising in biomedical applications. This paper presented an outline of recent researches and clinical applications of this kind of polymers.
Amide containing polyanhydrides based on natural amino acids are novel materials which have lots of superior properties. One advantage is that the alternate amide groups in the main chains slow down the rate of degradation. Another important advantage is that the physical and mechanical properties are raised as the result of the incorporation of hydrogen bonds which reinforce the polymer by intermolecular attractive forces. In this paper we synthesized N,N'-bis(L-alanine)sebacoylamide(BASM) and PBASM, a novel amide-containing polyanhydride. BASM was then copolymerized with CPH which increased the hydrophobic property and slowed down the release rate. Then the blends of copolymers and PLA with different weight ratios were prepared. The thermal properties and in vitro degradation(PBS, pH=7.4, 37C) of these polymers were studied in this research.
In order to prepare monomers of this kind of poly(amide-anhydrides), N-Carboxymeth yl-succinamic acid, N-(1-Carboxy-ethyl)- succinamic acid, 4-(Carboxymethyl- carbamo- yl)- butyric acid, 4-(1-Carboxy-ethyl carbamoyl)-butyric acid, 5 -(Carboxym- ethylcarb- amoyl)- pentanoic acid, 5-(1-Carboxy-ethylcarb amoyl)-pentanoic acid were synthesized by the react of adipic anhydride with glycine and L-alanine respectively. The intermediates and objective products were identified by spectrum of IR, 1HNMR.
Recently, many polymeric and conjugated prodrugs have been developed which prolong the blood concentration of the drug as compared to the free drug given alone.
This phenomenon is indicative of the prodrug's ability to release the drug in a controlled manner and reduced the site effects which may be incurred if the drug is released immediately. In this paper, o-Carboxy phenyl adipic monoester was synthesized for the first time from adipic anhydride and salicylic acid, from which the related polymers were prepared. Additionally, several factors which affected the molecular weight had also been studied, such as vacuum, temperature and so on. The degradation under PBS with different pH was also estimated.
聚酰胺酸酐是一类新型的聚酸酐材料。高分子主链上交替的酰胺键不但降低了聚合物的降解速度，还改善了聚合物的物理和机械性能。文章合成了化合物N，N’双(L-丙氨酸)癸二酰胺(BASM)，并聚合得到了PBASM，还将它与1，6-双(对羧基苯氧基)己烷(CPH)共聚得到了共聚物P(CPH-BASM)。另外文章还制备了不同重量比的共混物P(CPH-BASM)／PLA，研究了聚合物的体外降解性能(PBS，pH=7.4，37℃)并用DSC研究了它们的热学性质。
为了制备这类性能良好的聚酰胺酸酐的单体，论文还将丁二酸酐、戊二酸酐以及己二酸酐分别与甘氨酸和L-丙氨酸制备了N-羧甲基琥珀酰胺酸、N-(1-羧乙基)琥珀酰胺酸、4-羧甲基氨基甲酰丁酸、4-(1-羧乙基)氨基甲酰丁酸、5-羧甲基氨基甲酰戊酸、5-(1-羧乙基)氨基甲酰戊酸。将得到的目标化合物用IR，~1H NMR进行了表征。
高分子前药和共轭前药最近得到了广泛的研究，与单独给药的药物相比，这类高分子药物可以延长药物的血液浓度。它们有以下几个优点：一是可以使药物以一定的规律释放；二是可以减少由药物的突然释放而引起的副作用。本文首次以己二酸酐和水杨酸为原料，制备了己二酸单(2-羧苯酚)酯，并以它为单体聚合得到了相应得聚酯酸酐。另外还讨论了聚合温度、真空度等对分子量的影响。另外本文还对聚合物在不同的pH值条件下的体外降解行为进行了研究。
In recent years, biodegradable polymeric materials have been used for drug delivery, bone and cartilage repairing, cell issue engineering application. Compared to non-biodegradable polymers, they have favorable advantages. That is, they do not need to be taken out and can degrade into small molecules in body. Biodegradable polymers are the most potential materials for biomedical applications. In this paper, recent developments of biopolymers were reviewed. Novel biodegradable polymers-poly anhydrides have been developed since 1980s' by the group of Langer. These materials are highly biocompatible, demonstrated by tissue response and toxicological study. In addition, they show surface-eroding behavior, thus provide a sustained release rate over a long period of time, and the rate is adjustable. So these materials are very promising in biomedical applications. This paper presented an outline of recent researches and clinical applications of this kind of polymers.
Amide containing polyanhydrides based on natural amino acids are novel materials which have lots of superior properties. One advantage is that the alternate amide groups in the main chains slow down the rate of degradation. Another important advantage is that the physical and mechanical properties are raised as the result of the incorporation of hydrogen bonds which reinforce the polymer by intermolecular attractive forces. In this paper we synthesized N,N'-bis(L-alanine)sebacoylamide(BASM) and PBASM, a novel amide-containing polyanhydride. BASM was then copolymerized with CPH which increased the hydrophobic property and slowed down the release rate. Then the blends of copolymers and PLA with different weight ratios were prepared. The thermal properties and in vitro degradation(PBS, pH=7.4, 37C) of these polymers were studied in this research.
In order to prepare monomers of this kind of poly(amide-anhydrides), N-Carboxymeth yl-succinamic acid, N-(1-Carboxy-ethyl)- succinamic acid, 4-(Carboxymethyl- carbamo- yl)- butyric acid, 4-(1-Carboxy-ethyl carbamoyl)-butyric acid, 5 -(Carboxym- ethylcarb- amoyl)- pentanoic acid, 5-(1-Carboxy-ethylcarb amoyl)-pentanoic acid were synthesized by the react of adipic anhydride with glycine and L-alanine respectively. The intermediates and objective products were identified by spectrum of IR, 1HNMR.
Recently, many polymeric and conjugated prodrugs have been developed which prolong the blood concentration of the drug as compared to the free drug given alone.
This phenomenon is indicative of the prodrug's ability to release the drug in a controlled manner and reduced the site effects which may be incurred if the drug is released immediately. In this paper, o-Carboxy phenyl adipic monoester was synthesized for the first time from adipic anhydride and salicylic acid, from which the related polymers were prepared. Additionally, several factors which affected the molecular weight had also been studied, such as vacuum, temperature and so on. The degradation under PBS with different pH was also estimated.
引文
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2. Kato Y P, Christiansen D, Hahn R, et al. Mechanical Properties of Collegan Fibers: Evaluation of Biocompatibility, Biomaterials, 1989, 10: 38.
3. Majeti N V, Kumar R. Nano and Mieropartieals as Controlled Drag Delivery Devices and Mechanical Properties. Bull Mater Sci, 1999, 22: 905.
4. Francis J K, Matthew W T. Application of Chitosan-based Polysaccharide Biomaterials in Cartilage Tissue Engineering: a Review, Biomaterials, 2000, 21: 2589.
5．赵中丹等，替加氟白蛋白微球的制备，广东医学，2000，10(30)：19．
6. Tabata Y, et al. Synthesis of Gelatin Microspheres Containing Interferon, J Pharm Res, 1989, 6: 422.
7. Yan C, Zhang X, Zhou C, et al. Synthesis of Polymeric Latexes for Diagnosis Reagent Carders, Biomaterials, 1991, 12: 640.
8. Tabata Y, Yoshito I. Targeting of Muramyl Dipeptide to Macrophaes by Gelatin Conjugation to Enhanced their in vivo Antitumor Activity, J Controlled Release, 1993, 27: 79.
9. Tabata Y, et al. Suppressive Efevt of Recombinat THF-gelatin Conjugate on Murine Tumor Growth in vivo, J Pharm Pharmacol, 1993, 45: 303.
10．赖凌燕，艾长荣，壳聚糖制剂研究及应用，广西医学，1999，21(5)：878．
11．梁桂媛，方华丰等，5-氟尿嘧啶壳聚糖微球的制备，广东药学院学报，2000，6(1)：7．
12．梁佩红，李芳，马福广等，以Ⅰ型胶原为基底的表皮细胞培养法，实用医学杂志，1999，11(3)：149．
13. Watanabe K, Saiki I, Uraki Y, et al. 6-O-Carboxymethyl-Chitin(CM-Citin) as a Drug Carder, Chem Pharm Bull, 1990, 38(2): 506.
14. Allcock H R. Macromolecular and Materials Design Using Polyphosphazenes, Poymer Prepr, 1993, 34(1): 261.
15. Allcock H R, Fuller T J, et al. Polyphosphazenes as Carrier Molecules for
Controlled Release Systems, Polym Prepr, 1980, 21(1): 111.
16. Allcock H R, Kown S R. Bioerodible Polymers with a Phosphorus-Nitrogen Backbone, Polym Prepr, 1990, 31(2): 180.
17. Allcock H R. Fuller T J, et al. Synthesis of Poly[(amino acid alkyl ester) phosphazene], Macromolecules, 1977, 10(4): 824.
18. Allcock H R, Shawn R Pucher. Synthesis of Poly(organophosphazenes) with Glycoic Acid Ester and Lactic Acid Ester Side Group: Prototypes for New Biodegradable Polymers, Macromolecules, 1994, 27(1): 1.
19. Hideki H, Makiya N, Yoshinobu T. Development and Pharmacokinetics of Galactosylated Poly(L-glutamic acid) as a Biodegradable Carriers for Liver Specific Drug Delivery, Pharmaceutical Research, 1996, 13(6): 880.
20. Hoste K, Schacht E, Seymour L. New Derivatives of Poly(glutamic acid) as Drug Carrier Systems. Journal of Controlled Release, 2000, 64: 53.
21. Yasuyosi M, Kazuyuki J, Masahito O, et al. Preparation and Properties of Biodegradable Copoly(N-hydroxyalklyl-D, L-glutamine) membranes, European Polymer Journal, 1999, 35: 767.
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