葡聚糖—多巴胺和壳聚糖—美他沙酮大分子前药的合成及药控释放研究
摘要
设计合成了多巴胺和美他沙酮的大分子前药,采用多种手段表征了所合成的大分子前药,并模拟人体环境,对合成的大分子前药进行了药物控制释放研究。
采用琥珀酸酐作为连接基与葡聚糖反应,生成中间体葡聚糖琥珀酸酯,再利用中间体的端羧基与多巴胺的氨基反应,合成出了两种葡聚糖-多巴胺大分子前药:D20000-DA和D40000-DA,并使用红外光谱及差示扫描量热仪对其进行了分析和表征。研究了两种葡聚糖-多巴胺前药在pH=1.1、pH=7.4和pH=9.0缓冲溶液中的释药速率。实验表明:合成的两种D-DA大分子前药均能缓慢释放出母药多巴胺;在相同的pH缓冲溶液及释放条件下,两种大分子前药随着葡聚糖分子量的增大,释放出多巴胺的速率变慢。
用琥珀酸酐和聚乙二醇单甲醚对壳聚糖改性,生成水溶性较好的N-琥珀酰壳聚糖-聚乙二醇单甲醚。然后以改性后的壳聚糖为载体,与N-氯乙酰基美他沙酮连接,合成了壳聚糖-聚乙二醇单甲醚-美他沙酮大分子前药,采用IR及DSC对目标化合物进行了分析与表征。研究了壳聚糖-聚乙二醇单甲醚-美他沙酮(SC-mPEG-Met)大分子前药在pH=1.1、pH=7.4和pH=10.0缓冲溶液中的释药速率。结果表明:合成的SC-mPEG-Met大分子前药能缓慢释放出小分子母药美他沙酮;随着pH值的增大,合成的SC-mPEG-Met前药释放出母药速率加快。
研究了所合成的三种大分子前药在胰蛋白酶和α-糜蛋白酶存在下,pH=8.0的缓冲溶液中的释药速率,并与酶不存在时的释药速率相比较。结果表明:胰蛋白酶和α-糜蛋白酶存在时,均能加快前药释放出母药的速率,但差别不是很大。
Macromolecular prodrugs of metaxalone and dopamine were prepared and characterized through various technologies.The controlled release studies were performed in various media.
Dopamine(DA) was covalently linked to dextran via succinic anhydride spacer. The average molecular weight used for dextran are 20000 and 40000,respectively, and the procedure of chemical modification for dextrans was conducted by a twostep: (1) preparation of dextran having carboxylic end groups;(2) synthesis of D20000-DA and D40000-DA.The two prodrugs were characterized by DSC and IR analysis.The release studies were performed in pH 1.1,7.4 and 9.0 buffer solutions, The results demonstrated that,under the same condition,the release rate of dopamine for D40000-DA is slower than that of D20000-DA.
Methoxy poly(ethylene glycol) was covalently linked to chitosan via succinic anhydride spacer.The procedure of chemical modification for chitosan was conducted by a four-step protocol:(1) synthesis of N-succinyl-chitosan;(2) synthesis of N-succinyl-chitosan-mPEG;(3) synthesis of N-chloroacetyl-metaxalone; (4) synthesis of CS-mPEG-Met.The controlled drug release studies were performed in buffer solutions with pH values equal to 1.1,7.4 and 10.0.
In the present of parenzyme andα-chymotrypsin,the release studies were performed in pH=8.0 buffer solutions.More amounts of metaxalone and dopamine can be detected releasing from polymer-drug conjugate at the presence ofα-chymotrypsin and parenzyme compared with its absence.The three novel macromolecular prodrugs can improve the pharmacokinetics of dopamine and metaxalone, particularly by increasing its half-life period.
采用琥珀酸酐作为连接基与葡聚糖反应,生成中间体葡聚糖琥珀酸酯,再利用中间体的端羧基与多巴胺的氨基反应,合成出了两种葡聚糖-多巴胺大分子前药:D20000-DA和D40000-DA,并使用红外光谱及差示扫描量热仪对其进行了分析和表征。研究了两种葡聚糖-多巴胺前药在pH=1.1、pH=7.4和pH=9.0缓冲溶液中的释药速率。实验表明:合成的两种D-DA大分子前药均能缓慢释放出母药多巴胺;在相同的pH缓冲溶液及释放条件下,两种大分子前药随着葡聚糖分子量的增大,释放出多巴胺的速率变慢。
用琥珀酸酐和聚乙二醇单甲醚对壳聚糖改性,生成水溶性较好的N-琥珀酰壳聚糖-聚乙二醇单甲醚。然后以改性后的壳聚糖为载体,与N-氯乙酰基美他沙酮连接,合成了壳聚糖-聚乙二醇单甲醚-美他沙酮大分子前药,采用IR及DSC对目标化合物进行了分析与表征。研究了壳聚糖-聚乙二醇单甲醚-美他沙酮(SC-mPEG-Met)大分子前药在pH=1.1、pH=7.4和pH=10.0缓冲溶液中的释药速率。结果表明:合成的SC-mPEG-Met大分子前药能缓慢释放出小分子母药美他沙酮;随着pH值的增大,合成的SC-mPEG-Met前药释放出母药速率加快。
研究了所合成的三种大分子前药在胰蛋白酶和α-糜蛋白酶存在下,pH=8.0的缓冲溶液中的释药速率,并与酶不存在时的释药速率相比较。结果表明:胰蛋白酶和α-糜蛋白酶存在时,均能加快前药释放出母药的速率,但差别不是很大。
Macromolecular prodrugs of metaxalone and dopamine were prepared and characterized through various technologies.The controlled release studies were performed in various media.
Dopamine(DA) was covalently linked to dextran via succinic anhydride spacer. The average molecular weight used for dextran are 20000 and 40000,respectively, and the procedure of chemical modification for dextrans was conducted by a twostep: (1) preparation of dextran having carboxylic end groups;(2) synthesis of D20000-DA and D40000-DA.The two prodrugs were characterized by DSC and IR analysis.The release studies were performed in pH 1.1,7.4 and 9.0 buffer solutions, The results demonstrated that,under the same condition,the release rate of dopamine for D40000-DA is slower than that of D20000-DA.
Methoxy poly(ethylene glycol) was covalently linked to chitosan via succinic anhydride spacer.The procedure of chemical modification for chitosan was conducted by a four-step protocol:(1) synthesis of N-succinyl-chitosan;(2) synthesis of N-succinyl-chitosan-mPEG;(3) synthesis of N-chloroacetyl-metaxalone; (4) synthesis of CS-mPEG-Met.The controlled drug release studies were performed in buffer solutions with pH values equal to 1.1,7.4 and 10.0.
In the present of parenzyme andα-chymotrypsin,the release studies were performed in pH=8.0 buffer solutions.More amounts of metaxalone and dopamine can be detected releasing from polymer-drug conjugate at the presence ofα-chymotrypsin and parenzyme compared with its absence.The three novel macromolecular prodrugs can improve the pharmacokinetics of dopamine and metaxalone, particularly by increasing its half-life period.
引文
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