緩釋性能絲素蛋白的制備及效果評價
發(fā)布時間：2019-04-02 00:35
【摘要】：藥物緩釋給藥系統(tǒng)具有減少給藥次數(shù)、維持血藥濃度，以及提高生物利用度，提高藥物療效，降低藥物毒副作用的作用，在減輕病人多次用藥痛苦，提高病人用藥依從性等提高臨床用藥水平方面具有重大意義，成為了近年來國內(nèi)外新型藥物制劑研發(fā)領(lǐng)域的熱點之一[1]。藥物緩釋給藥系統(tǒng)一般由藥物緩釋材料或輔料、主體藥物組成，藥物緩釋載體材料起著調(diào)節(jié)藥物緩控釋的作用，極為重要。研究人員篩選了大量天然、合成材料，獲得了如聚乳酸、環(huán)糊精、羥基乙基纖維素等緩釋材料。作為天然蛋白質(zhì)的絲素蛋白，，也被發(fā)現(xiàn)可以成為緩控釋用藥用高分子材料。絲素蛋白具有優(yōu)良的生物相容性、生物降解性和營養(yǎng)保健功能，是一種可持續(xù)獲得的蛋白質(zhì)資源。本文即采用水相共混法制備了小分子量絲素蛋白（silk fibroin peptide，SFP）/聚乙烯醇(PolyvinylAlcohol，PVA)/聚乙二醇（Polyethylene glycol，PEG）藥用緩釋載體材料，并對其釋藥效果進(jìn)行了研究。 課題首先使用了中性蛋白酶將大分子量絲素蛋白質(zhì)酶解，得到分子量在6KD以下、β-折疊結(jié)構(gòu)有所減少，活性反應(yīng)側(cè)基有所增加的小分子量絲素蛋白肽。然后采用水相共混的方法制備了SFP/PVA/PEG藥物緩釋復(fù)合材料，對三者的配比進(jìn)行了篩選性研究。通過機械性能測定及掃描電鏡觀察結(jié)果顯示，(SFP/PVA)/PEG比例為90/10的比例（其中SFP/PVA=30/70）性能最佳；紅外光譜、X-射線衍射、差示掃描量熱分析結(jié)果顯示，聚乙二醇的加入提高了小分子量絲素蛋白肽和聚乙烯醇的相容性及材料機械性能。采用人工胃液對SFP/PVA/PEG藥物緩釋載體材料進(jìn)行了體外溶蝕機制研究，推測該材料的溶蝕首先是從絲素蛋白開始，在其溶蝕后隨著液體侵蝕，聚乙二醇和聚乙烯醇逐漸溶蝕。細(xì)胞毒性試驗是采用了MTT法、使用了小鼠成纖維細(xì)胞進(jìn)行，結(jié)果表明該載體材料細(xì)胞毒性指數(shù)為0級或1級，且還有促細(xì)胞生長效果。體外釋藥實驗以吸光度值變化明顯的水溶性藥物硫酸羥基氯喹作為模型藥物，將其均勻混合在本載體材料中，制備了SFP/PVA/PEG載藥片，然后在pH=1.2和pH=6.8兩種不同釋放介質(zhì)中進(jìn)行了藥物釋放試驗，結(jié)果顯示SFP/PVA/PEG載藥片在兩種介質(zhì)中藥物釋放都比較緩慢，都符合緩釋制劑的基本動力學(xué)方程（一級釋放動力學(xué)）；通過Peppas、Higuchi藥物釋放動力學(xué)方程對SFP/PVA/PEG載藥片釋藥數(shù)據(jù)的擬合結(jié)果分析，該緩釋載體對水溶性藥物的釋放主要是通過擴(kuò)散機制完成的；并且以上數(shù)據(jù)顯示，該載藥片在pH=6.8的釋放介質(zhì)中緩釋效果明顯優(yōu)于pH=1.2的酸性釋放介質(zhì)。本緩釋載體材料具有開發(fā)為腸溶緩釋制劑的前景。
[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.
【學(xué)位授予單位】：重慶理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R318.08
本文編號：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.
【學(xué)位授予單位】：重慶理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R318.08
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