光交联聚醚酐凝胶纳米粒的制备及包载疏水性药物研究
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摘要
本研究通过制备一种具有交联疏水内核-亲水外壳结构的可降解性聚醚酐凝胶纳米粒(gel nanoparticles, GNP),以克服聚合物胶束在大量体液稀释下会解缔合等不稳定性问题,并将其用于增溶疏水性药物。文中通过改变PEG链段长度和加入疏水性单体来调节凝胶纳米粒的结构与亲水疏水性,并最终影响凝胶纳米粒的降解和载药性能。
本研究首先成功合成了两亲性可光交联醚酐大分子单体和两种疏水性可光交联单体,分别用红外和核磁进行了结构表征;然后采用乳液光聚合制备了聚醚酐凝胶纳米粒,观察其形态基本为圆球或椭圆球状,而加入疏水性单体硬脂酸单丙烯酸酐(monoacrylic stearic acid, MSA)后凝胶纳米粒具有了较明显的核-壳结构,激光粒度仪测定其粒径为340-670 nm,X-射线衍射显示凝胶纳米粒中PEG链段结晶度降低,MSA以无定形态接枝于内核网络中,凝胶纳米粒能在较短时间内完全降解,并可通过PEG链段长短调节其降解速率。
通过原位或后包合的方法将模型药物吲哚美辛(indomethacin, IND)包载于凝胶纳米粒中,通过红外验证了吲哚美辛在原位包载过程中未发现化学变化,激光粒度仪测定出载药凝胶纳米粒的粒径比空白凝胶纳米粒有所增加,X-射线衍射结果验证了原位载药可使吲哚美辛以无定形态高度分散于内核网络中,而后包载药则仍有部分药物以结晶态存在。载药量和包封率受醚酐单体种类和内核疏水性等因素影响,本文中最高可达65%左右。体外溶出结果显示,纯醚酐单体制得载药凝胶纳米粒的溶出速率和溶出量比原料药有明显增加,且随着PEG链段增长而更明显;但加入MSA后,释药速率明显减缓,且出现释药不完全现象;这表明药物的溶出与凝胶纳米粒亲水外壳厚度和内核交联度及疏水性密切相关。而溶解度结果显示六种凝胶纳米粒都能不同程度的增溶吲哚美辛,提高其溶解度。
综上结果,此具有疏水交联内核-亲水外壳的聚醚酐凝胶纳米粒在增溶和输送难溶性药物上具有一定的潜力。
Biodegradable poly(ether-anhydride) gel nanoparticles (GNP) with hydrophobic crosslinked core-hyphophilic shell sturcture were prepared, which could overcome the instable problems of polymer micelles, such as disintegration by dilution in the body, and could be used to solubilize hydrophobic drugs. The structure and hydrophilicity/hydrophobicity of GNP was modified by changing PEG chain length and adding hydrophobic monomers, which could finally affect the degradability and the drug loading capacity GNP.
Amphiphilic photocrosslinkable ether-anhydride macromers and two hydrophobic photocrosslinkable monomers were synthesized initially and characterized by FT-IR and 1H NMR spectrum, then poly(ether-anhydride) gel nanoparticles were prepared by emulsion photopolymerization method, which were found to be spherical or elliptoid in shape and with obvious core-shell structure when stearic monoacrylic anhydride (MSA) was added. The particle size measured by laser particle analyzer (LPA) was 340-670 nm. The X-ray diffraction of GNP showed that the crystality of PEG chain decreased and MSA was grafted to core networks in amorphous state. GNP could degrade in a few hours in vitro, and the degradation rate could be tailored by regulating the length of PEG chain.
Indomethacin (IND) was chosed to be the model hydrophobic drugs, which was entrapped in the hydrophobic crosslinked core by in situ or post embedding method. The FT-IR of IND in situ loaded GNP showed that there was no chemical change of IND structure during the preparation indicating that IND kept stable during the entrapment. The particle size of IND loaded GNP measured by LPA became slightly larger than that of blank GNP. The X-ray diffraction showed that IND was highly dispersed in the hydrophobic crosslinked core and stayed in amorphous or molecular state when in situ loaded in GNP, while some of the loaded IND stayed in crystal state when it was post embedded in GNP. The drug loading and encapsulation efficacy of IND by in situ method was affected by many factors, such as the different ether-anhydride macromers and the hydrophobicity of the core, which could be as high as 65% in this thesis. The in vitro release behavior of IND loaded GNP showed that GNP prepared by ether-anhydride macromers could improve the dissolution rate greatly, especially the GNP prepared by larger weight macromers. But the dissolution rate decreased obviously and IND could not be released completely after MSA added. The dissolution results implied that drug dissolution rate is closely related to the hydrophilic shell thickness and crosslinking density and hydrophobicity of the core. Six drugs loaded GNP could solubilize IND in different levels by measuring dissolution in water.
The results indicate that these novel poly(ether-anhydride) gel nanoparticles with hydrophobic crosslinked core-hyphophilic shell are potential in solubilizing and deliverying hydrophobic drugs.
本研究首先成功合成了两亲性可光交联醚酐大分子单体和两种疏水性可光交联单体,分别用红外和核磁进行了结构表征;然后采用乳液光聚合制备了聚醚酐凝胶纳米粒,观察其形态基本为圆球或椭圆球状,而加入疏水性单体硬脂酸单丙烯酸酐(monoacrylic stearic acid, MSA)后凝胶纳米粒具有了较明显的核-壳结构,激光粒度仪测定其粒径为340-670 nm,X-射线衍射显示凝胶纳米粒中PEG链段结晶度降低,MSA以无定形态接枝于内核网络中,凝胶纳米粒能在较短时间内完全降解,并可通过PEG链段长短调节其降解速率。
通过原位或后包合的方法将模型药物吲哚美辛(indomethacin, IND)包载于凝胶纳米粒中,通过红外验证了吲哚美辛在原位包载过程中未发现化学变化,激光粒度仪测定出载药凝胶纳米粒的粒径比空白凝胶纳米粒有所增加,X-射线衍射结果验证了原位载药可使吲哚美辛以无定形态高度分散于内核网络中,而后包载药则仍有部分药物以结晶态存在。载药量和包封率受醚酐单体种类和内核疏水性等因素影响,本文中最高可达65%左右。体外溶出结果显示,纯醚酐单体制得载药凝胶纳米粒的溶出速率和溶出量比原料药有明显增加,且随着PEG链段增长而更明显;但加入MSA后,释药速率明显减缓,且出现释药不完全现象;这表明药物的溶出与凝胶纳米粒亲水外壳厚度和内核交联度及疏水性密切相关。而溶解度结果显示六种凝胶纳米粒都能不同程度的增溶吲哚美辛,提高其溶解度。
综上结果,此具有疏水交联内核-亲水外壳的聚醚酐凝胶纳米粒在增溶和输送难溶性药物上具有一定的潜力。
Biodegradable poly(ether-anhydride) gel nanoparticles (GNP) with hydrophobic crosslinked core-hyphophilic shell sturcture were prepared, which could overcome the instable problems of polymer micelles, such as disintegration by dilution in the body, and could be used to solubilize hydrophobic drugs. The structure and hydrophilicity/hydrophobicity of GNP was modified by changing PEG chain length and adding hydrophobic monomers, which could finally affect the degradability and the drug loading capacity GNP.
Amphiphilic photocrosslinkable ether-anhydride macromers and two hydrophobic photocrosslinkable monomers were synthesized initially and characterized by FT-IR and 1H NMR spectrum, then poly(ether-anhydride) gel nanoparticles were prepared by emulsion photopolymerization method, which were found to be spherical or elliptoid in shape and with obvious core-shell structure when stearic monoacrylic anhydride (MSA) was added. The particle size measured by laser particle analyzer (LPA) was 340-670 nm. The X-ray diffraction of GNP showed that the crystality of PEG chain decreased and MSA was grafted to core networks in amorphous state. GNP could degrade in a few hours in vitro, and the degradation rate could be tailored by regulating the length of PEG chain.
Indomethacin (IND) was chosed to be the model hydrophobic drugs, which was entrapped in the hydrophobic crosslinked core by in situ or post embedding method. The FT-IR of IND in situ loaded GNP showed that there was no chemical change of IND structure during the preparation indicating that IND kept stable during the entrapment. The particle size of IND loaded GNP measured by LPA became slightly larger than that of blank GNP. The X-ray diffraction showed that IND was highly dispersed in the hydrophobic crosslinked core and stayed in amorphous or molecular state when in situ loaded in GNP, while some of the loaded IND stayed in crystal state when it was post embedded in GNP. The drug loading and encapsulation efficacy of IND by in situ method was affected by many factors, such as the different ether-anhydride macromers and the hydrophobicity of the core, which could be as high as 65% in this thesis. The in vitro release behavior of IND loaded GNP showed that GNP prepared by ether-anhydride macromers could improve the dissolution rate greatly, especially the GNP prepared by larger weight macromers. But the dissolution rate decreased obviously and IND could not be released completely after MSA added. The dissolution results implied that drug dissolution rate is closely related to the hydrophilic shell thickness and crosslinking density and hydrophobicity of the core. Six drugs loaded GNP could solubilize IND in different levels by measuring dissolution in water.
The results indicate that these novel poly(ether-anhydride) gel nanoparticles with hydrophobic crosslinked core-hyphophilic shell are potential in solubilizing and deliverying hydrophobic drugs.
引文
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