【摘要】：聚乳酸(Polylactic acid,PLA)具有良好的生物可降解性、生物相容性以及良好的力學(xué)性能和加工性能,是生物降解醫(yī)用材料領(lǐng)域中最受重視的材料之一,在緩釋藥物體系中具有重要的應(yīng)用價(jià)值。但是,聚乳酸表面的疏水性基團(tuán)使其的親水性較低,導(dǎo)致細(xì)胞相容性降低,不利于藥物被細(xì)胞吸收從而降低了藥效。為了改善聚乳酸的性能缺陷,提高其親水性和降解性能,增加聚乳酸在緩釋藥物體系中的使用性能,本文對(duì)聚乳酸進(jìn)行了改性,并以改性聚乳酸為囊材制備了聚乳酸載藥微球,研究了聚乳酸載藥微球的釋藥性能。(1)采用五氯化磷(PCl5)為酰氯化試劑聚乳酸進(jìn)行酰氯化反應(yīng),然后與己二胺反應(yīng)從而制備得到己二胺改性的聚乳酸(EPLA)。隨后對(duì)產(chǎn)物的結(jié)構(gòu)進(jìn)行了傅里葉紅外光譜以及核磁共振氫譜的測(cè)試表征,從而證明了己二胺被接枝到聚乳酸上。(2)使用上一步制備的己二胺改性聚乳酸(EPLA)為原料,先與戊二醛反應(yīng)再與膠原蛋白反應(yīng)得到膠原蛋白改性聚乳酸。通過(guò)傅里葉紅外以及異硫氰酸熒光素標(biāo)記熒光光譜測(cè)試對(duì)改性后的聚乳酸進(jìn)行了表征,結(jié)果表明戊二醛以及膠原蛋白被成功的接枝到到己二胺改性的聚乳酸上。并且通測(cè)得改性的聚乳酸中,膠原蛋白的接枝率為8.7%。(3)對(duì)材料進(jìn)行了性能測(cè)定。測(cè)試表明:膠原蛋白、戊二醛與己二胺共同改性作用下的聚乳酸的親水性最好,己二胺改性聚乳酸次之,而PLA的親水性相對(duì)最差。從材料的失重率以及降解介質(zhì)的pH變化方面,考察材料的降解性能。測(cè)定結(jié)果表明:降解的初期,改性聚乳酸的失重率高于聚乳酸,PLA在之后降解過(guò)程中的失重率始終高于EPLA、CPLA。在降解過(guò)程中,未改性聚乳酸的降解介質(zhì)的pH發(fā)生明顯的下降,而EPLA和CPLA的降解介質(zhì)的pH也出現(xiàn)了下降的現(xiàn)象,但是其下降幅度較小。(4)以膠原蛋白改性聚乳酸為囊材,胰蛋白酶為芯材,采用水包油包水(W1/O/W2)型溶劑揮發(fā)法制備得到載胰蛋白酶改性聚乳酸微球。研究得到了載藥微球的最佳工藝條件:水油相比為1:6,CPLA與胰蛋白酶的質(zhì)量比為1:6,初乳的攪拌速率為14000 r/min,聚乙烯醇濃度為0.75%,復(fù)乳的攪拌速率為800 r/min,聚乳酸的濃度為5.0%。利用環(huán)境掃描電鏡對(duì)制備的載藥微球的形貌進(jìn)行表征,結(jié)果表明載藥微球的成球效果比較好,表面比較光滑且形貌圓整,分散性良好,微球大小比較均勻。在最佳工藝條件下制備的載藥微球的平均粒徑為:PLA載藥微球?yàn)?.75μm,EPLA載藥微球?yàn)?.22μm,CPLA載藥微球?yàn)?.09μm。研究測(cè)定了三種載藥微球的包封率和載藥量,結(jié)果為CPLA(29)EPLA(29)PLA。研究測(cè)定了胰蛋白酶載藥微球的體外釋藥性能,結(jié)果表明:與PLA載藥微球相比,EPLA載藥微球和CPLA載藥微球具有更好的長(zhǎng)效緩釋效果。
[Abstract]:Polylactic acid (Polylactic) has good biodegradability, biocompatibility, good mechanical properties and processability. It is one of the most important materials in the field of biodegradable medical materials, and has important application value in slow-release drug system. However, the hydrophobic group on the surface of polylactic acid makes its hydrophilicity lower, leading to the decrease of the cell compatibility, which is not conducive to the absorption of the drug by the cell and thus reduces its efficacy. In order to improve the performance defects of polylactic acid, improve its hydrophilicity and degradation performance, and increase the performance of polylactic acid in slow-release drug system, the polylactic acid microspheres were prepared with modified PLA as capsule material in this paper. The release properties of poly (lactic acid) loaded microspheres were studied. (1) Polylactic acid (EPLA).) modified by hexanediamine was prepared by acylation of poly (lactic acid) with phosphorous pentachloride (PCl5) as acylated reagent and then reaction with hexanediamine. The structure of the product was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). It was proved that hexane diamine was grafted onto polylactic acid. (2) Hexanediamine modified polylactic acid (EPLA) was used as raw material. Collagen modified polylactic acid was obtained by first reacting with glutaraldehyde and then with collagen. The modified poly (lactic acid) was characterized by FTIR and fluorescein isothiocyanate labeling. The results showed that glutaraldehyde and collagen were successfully grafted onto the polylactic acid modified by hexanediamine. The graft rate of collagen in modified PLA was 8.7%. (3) the properties of the modified PLA were determined. The results showed that the hydrophilicity of poly (lactic acid) modified by collagen glutaraldehyde and hexanediamine was the best and that of hexanediamine was the second while the hydrophilicity of PLA was the worst. The degradation performance of the material was investigated from the aspects of the weight loss rate and pH change of the degradation medium. The results showed that in the early stage of degradation, the weight loss rate of modified PLA was higher than that of PLA after degradation. In the process of degradation, the pH of the degradation medium of unmodified polylactic acid decreased obviously, while the pH of the degradation medium of EPLA and CPLA also decreased, but the decrease was relatively small. (4) the collagen modified polylactic acid was used as the capsule material. Polylactic acid microspheres modified by trypsin were prepared by water in oil in water (W1/O/W2) solvent volatilization method with trypsin as core material. The optimum technological conditions were obtained as follows: the mass ratio of water-oil ratio 1: 6 CPLA to trypsin was 1: 6, the mixing rate of colostrum was 14000 r / min, the concentration of polyvinyl alcohol was 0.75%, the mixing rate of composite emulsion was 800 r / min, and the concentration of polylactic acid was 5.0%. The morphology of the drug-loaded microspheres was characterized by environmental scanning electron microscope. The results showed that the drug-loaded microspheres had a good effect of forming, the surface was smooth, the morphology was round, the dispersity was good, and the size of the microspheres was uniform. The average particle size of the drug-loaded microspheres prepared under the optimum conditions was 2.75 渭 m EPLA-loaded microspheres, 4.22 渭 m CPLA microspheres and 4.09 渭 m CPLA microspheres. The encapsulation efficiency and drug loading capacity of three kinds of drug-loaded microspheres were determined. The results were as follows: CPLA (29) EPLA (29) PLA. The in vitro release properties of trypsin loaded microspheres were studied. The results showed that PLA microspheres and CPLA loaded microspheres had better long-term sustained release effects than those of PLA loaded microspheres.
【學(xué)位授予單位】：齊魯工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：O633.14;TQ460.1

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