缓释性能丝素蛋白的制备及效果评价
发布时间：2019-04-02 00:35
【摘要】：药物缓释给药系统具有减少给药次数、维持血药浓度，以及提高生物利用度，提高药物疗效，降低药物毒副作用的作用，在减轻病人多次用药痛苦，提高病人用药依从性等提高临床用药水平方面具有重大意义，成为了近年来国内外新型药物制剂研发领域的热点之一[1]。药物缓释给药系统一般由药物缓释材料或辅料、主体药物组成，药物缓释载体材料起着调节药物缓控释的作用，极为重要。研究人员筛选了大量天然、合成材料，获得了如聚乳酸、环糊精、羟基乙基纤维素等缓释材料。作为天然蛋白质的丝素蛋白，，也被发现可以成为缓控释用药用高分子材料。丝素蛋白具有优良的生物相容性、生物降解性和营养保健功能，是一种可持续获得的蛋白质资源。本文即采用水相共混法制备了小分子量丝素蛋白（silk fibroin peptide，SFP）/聚乙烯醇(PolyvinylAlcohol，PVA)/聚乙二醇（Polyethylene glycol，PEG）药用缓释载体材料，并对其释药效果进行了研究。 课题首先使用了中性蛋白酶将大分子量丝素蛋白质酶解，得到分子量在6KD以下、β-折叠结构有所减少，活性反应侧基有所增加的小分子量丝素蛋白肽。然后采用水相共混的方法制备了SFP/PVA/PEG药物缓释复合材料，对三者的配比进行了筛选性研究。通过机械性能测定及扫描电镜观察结果显示，(SFP/PVA)/PEG比例为90/10的比例（其中SFP/PVA=30/70）性能最佳；红外光谱、X-射线衍射、差示扫描量热分析结果显示，聚乙二醇的加入提高了小分子量丝素蛋白肽和聚乙烯醇的相容性及材料机械性能。采用人工胃液对SFP/PVA/PEG药物缓释载体材料进行了体外溶蚀机制研究，推测该材料的溶蚀首先是从丝素蛋白开始，在其溶蚀后随着液体侵蚀，聚乙二醇和聚乙烯醇逐渐溶蚀。细胞毒性试验是采用了MTT法、使用了小鼠成纤维细胞进行，结果表明该载体材料细胞毒性指数为0级或1级，且还有促细胞生长效果。体外释药实验以吸光度值变化明显的水溶性药物硫酸羟基氯喹作为模型药物，将其均匀混合在本载体材料中，制备了SFP/PVA/PEG载药片，然后在pH=1.2和pH=6.8两种不同释放介质中进行了药物释放试验，结果显示SFP/PVA/PEG载药片在两种介质中药物释放都比较缓慢，都符合缓释制剂的基本动力学方程（一级释放动力学）；通过Peppas、Higuchi药物释放动力学方程对SFP/PVA/PEG载药片释药数据的拟合结果分析，该缓释载体对水溶性药物的释放主要是通过扩散机制完成的；并且以上数据显示，该载药片在pH=6.8的释放介质中缓释效果明显优于pH=1.2的酸性释放介质。本缓释载体材料具有开发为肠溶缓释制剂的前景。
[Abstract]:The sustained-release drug delivery system can reduce the times of drug administration, maintain the blood concentration, improve the bioavailability, improve the efficacy of drugs, reduce the side effects of drugs, and alleviate the pain of repeated administration of drugs. It is of great significance to improve the compliance of patients in drug use and to improve the level of clinical drug use. It has become one of the hot spots in the research and development of new drug preparations at home and abroad in recent years [1]. Drug sustained-release delivery system is usually composed of drug sustained-release material or adjunct and main drug. Drug sustained-release carrier material plays an important role in regulating drug slow-release and controlled-release. Researchers screened a large number of natural, synthetic materials, such as polylactic acid, cyclodextrin, hydroxyethyl cellulose and other sustained-release materials. Silk fibroin, as a natural protein, has also been found to be a controlled-release medicinal polymer material. Silk fibroin has good biocompatibility, biodegradability and nutritional health function. It is a kind of sustainable protein resource. In this paper, small molecular weight silk fibroin (silk fibroin peptide,SFP) / polyvinyl alcohol (PolyvinylAlcohol,PVA) / polyethylene glycol (Polyethylene glycol,PEG) sustained-release drug carrier materials were prepared by water-phase blending method, and the drug release effect was studied. First of all, neutral protease was used to hydrolyze large molecular weight silk fibroin protein to obtain small molecular weight silk fibroin peptide, whose molecular weight was below 6KD, 尾-fold structure was reduced, and active side group was increased. Then the SFP/PVA/PEG drug sustained-release composites were prepared by means of water-phase blending, and the screening properties of the three composites were studied. The results of mechanical properties and scanning electron microscopy (SEM) showed that the ratio of (SFP/PVA) to PEG (90 / 10) was the best, in which SFP/PVA=30/70 was the best. The results of infrared spectrum, X-ray diffraction and differential scanning calorimetry showed that the addition of polyethylene glycol improved the compatibility and mechanical properties of small molecular weight silk fibroin peptide and polyvinyl alcohol. The dissolution mechanism of SFP/PVA/PEG drug delivery carrier material in vitro was studied by using artificial gastric juice. It was speculated that the dissolution of the material began with silk fibroin protein. After the dissolution, polyethylene glycol (PEG) and polyvinyl alcohol (PVA) gradually dissolved with the erosion of liquid. The cytotoxicity test was carried out by using MTT method and mouse fibroblasts. The results showed that the cytotoxicity index of the carrier material was grade 0 or grade 1, and the cytotoxicity index of the carrier material was 0 or 1, and it had the effect of promoting cell growth. Hydroxychloroquine sulfate, a water-soluble drug with obvious change in absorbance value, was used as model drug in vitro release test. The drug-loaded tablets of SFP/PVA/PEG were prepared by mixing them uniformly in this carrier material. Then the drug release test was carried out in two different release mediums: pH=1.2 and pH=6.8. The results showed that the drug release of SFP/PVA/PEG tablets was slow in both media. All accord with the basic kinetic equation of sustained-release preparation (first-order release kinetics); The drug release data of SFP/PVA/PEG loaded tablets were fitted by Peppas,Higuchi drug release kinetics equation. The release of the drug by the sustained release carrier to water-soluble drugs was mainly accomplished by diffusion mechanism. The above data show that the sustained release effect of the tablet in the release medium of pH=6.8 is obviously better than that of the acid release medium of pH=1.2. This sustained-release carrier material has the prospect of developing into intestinal-soluble sustained-release preparation.
【学位授予单位】：重庆理工大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R318.08
本文编号：2452057
[Abstract]:The sustained-release drug delivery system can reduce the times of drug administration, maintain the blood concentration, improve the bioavailability, improve the efficacy of drugs, reduce the side effects of drugs, and alleviate the pain of repeated administration of drugs. It is of great significance to improve the compliance of patients in drug use and to improve the level of clinical drug use. It has become one of the hot spots in the research and development of new drug preparations at home and abroad in recent years [1]. Drug sustained-release delivery system is usually composed of drug sustained-release material or adjunct and main drug. Drug sustained-release carrier material plays an important role in regulating drug slow-release and controlled-release. Researchers screened a large number of natural, synthetic materials, such as polylactic acid, cyclodextrin, hydroxyethyl cellulose and other sustained-release materials. Silk fibroin, as a natural protein, has also been found to be a controlled-release medicinal polymer material. Silk fibroin has good biocompatibility, biodegradability and nutritional health function. It is a kind of sustainable protein resource. In this paper, small molecular weight silk fibroin (silk fibroin peptide,SFP) / polyvinyl alcohol (PolyvinylAlcohol,PVA) / polyethylene glycol (Polyethylene glycol,PEG) sustained-release drug carrier materials were prepared by water-phase blending method, and the drug release effect was studied. First of all, neutral protease was used to hydrolyze large molecular weight silk fibroin protein to obtain small molecular weight silk fibroin peptide, whose molecular weight was below 6KD, 尾-fold structure was reduced, and active side group was increased. Then the SFP/PVA/PEG drug sustained-release composites were prepared by means of water-phase blending, and the screening properties of the three composites were studied. The results of mechanical properties and scanning electron microscopy (SEM) showed that the ratio of (SFP/PVA) to PEG (90 / 10) was the best, in which SFP/PVA=30/70 was the best. The results of infrared spectrum, X-ray diffraction and differential scanning calorimetry showed that the addition of polyethylene glycol improved the compatibility and mechanical properties of small molecular weight silk fibroin peptide and polyvinyl alcohol. The dissolution mechanism of SFP/PVA/PEG drug delivery carrier material in vitro was studied by using artificial gastric juice. It was speculated that the dissolution of the material began with silk fibroin protein. After the dissolution, polyethylene glycol (PEG) and polyvinyl alcohol (PVA) gradually dissolved with the erosion of liquid. The cytotoxicity test was carried out by using MTT method and mouse fibroblasts. The results showed that the cytotoxicity index of the carrier material was grade 0 or grade 1, and the cytotoxicity index of the carrier material was 0 or 1, and it had the effect of promoting cell growth. Hydroxychloroquine sulfate, a water-soluble drug with obvious change in absorbance value, was used as model drug in vitro release test. The drug-loaded tablets of SFP/PVA/PEG were prepared by mixing them uniformly in this carrier material. Then the drug release test was carried out in two different release mediums: pH=1.2 and pH=6.8. The results showed that the drug release of SFP/PVA/PEG tablets was slow in both media. All accord with the basic kinetic equation of sustained-release preparation (first-order release kinetics); The drug release data of SFP/PVA/PEG loaded tablets were fitted by Peppas,Higuchi drug release kinetics equation. The release of the drug by the sustained release carrier to water-soluble drugs was mainly accomplished by diffusion mechanism. The above data show that the sustained release effect of the tablet in the release medium of pH=6.8 is obviously better than that of the acid release medium of pH=1.2. This sustained-release carrier material has the prospect of developing into intestinal-soluble sustained-release preparation.
【学位授予单位】：重庆理工大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R318.08
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