去甲斑蝥酸钠聚己内酯微球的制备、表征和释药机制
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摘要
聚合物微球广泛用于各种水溶性和脂溶性药物的包封和输送,但很少见其用于可离子化水溶性药物的包封和输送。由于自身理化性质的原因,可离子化水溶性药物很难成功包封。因此,关于可离子化水溶性药物包封及释放等基础研究的文献报道很少,这不利于此类药物的微球制剂研究与开发。
本文分别以去甲斑蝥酸钠(DSNC)和聚己内酯(PCL)为模型药物和包囊材料,较深入探讨了微球的制备、表征和释药机制等基础性研究,为包封其它水溶性药物(尤其是可离子化药物)奠定了重要理论基础。
首先采用S/O/W溶剂挥发法制备微球,并对主要工艺参数进行了筛选和优化。结果发现,聚合物浓度对去甲斑蝥酸钠包封率高低起着至关重要的作用。聚合物浓度越高,则S/O分散相的粘度越高,药物粒子朝水相泄漏的程度就相对降低,从而得到较高的包封率。
对载药微球的形态、结晶性和体外释药行为进行了表征。SEM结果显示载药微球表面粗糙内部多孔,进一步研究表明载药微球的多孔性是药物本身性质决定的。XRD结果表明,去甲斑蝥酸钠在微球中以结晶形式存在;聚己内酯保持着半结晶性,但其结晶度随着投药量的增加而明显降低。此外,药物和材料之间不存在相互作用力。体外药物释放结果表明药物很快就释放完全,这主要是由药物的高水溶性和微球的多孔性决定。
针对载药微球的多孔性和释药快的问题,采用往连续相中加氯化钠来修饰微球形态和释药行为。结果发现,微球制备时连续相中加氯化钠有利于降低连续相和分散相的渗透压差,即能降低连续相中的水朝分散相内部迁移的程度,因而导致微球孔隙率的降低、包封率增加、粒径减小、密度增加。同时,加入氯化钠所制得的微球具有较慢的药物释放行为。
根据以上研究结果提出了独特的微球形成过程和释药机制。在微球制备过程中,连续相的水朝乳滴内部扩散溶解部分的药物粒子,溶解后药物使乳滴内部表现出高渗透压,从而驱使连续相中的水继续朝乳滴内部迁移。随着水不断朝内迁移,乳滴内部形成内水相,乳液状态由S/O/W转变成W/O/W,这种乳液状态的转变导致微球干燥后呈现疏松多孔的内部结构。体外药物释放结果表明DSNC聚己内酯微球的药物释放由渗透压和扩散共同控制:在突释阶段,渗透压和扩散共同参与药物的释放;但在突释之后,药物释放主要由扩散控制。
Polymeric microspheres have been widely-used to encapsulate hydrophilic and hydrophobic drugs, however, there are only a few literatures about their application for the encapsulation and delivery of the ionic water-soluble drugs. Because of their particular physicochemical characteristics, the ionic water-soluble drugs are difficult to encapsulate successfully. Thus, there are few literatures about such basic investigations as the encapsulation and release mechanism of the ionic water-soluble drugs, which is unfavorable for their pharmaceutical research and development.
In this study, disodium norcantharidate (DSNC) and poly(ε-caprolactone) (PCL) microspheres were chosen as model drug and encapsulation material respectively, and the preparation, characterization and drug release mechanism of the microspheres were investigated systematically. This study paid basic foundation for the investigations in the encapsulation and release of water-soluble drugs.
First, DSNC-loaded PCL microspheres were prepared by s/o/w solvent evaporation method and several preparation parameters were investigated and optimized. The results implied that the polymer concentration was crucial to the successful encapsulation of DSNC. A higher concentration of the polymer resulted in a higher viscosity of the s/o dispersion, which decreased the leakage of the drug into the continuous phase thus increasing the encapsulation efficiency of DSNC.
DSNC-loaded PCL microspheres were characterized by terms of microspehre morphology, crystallinity and in vitro drug release. SEM results indicated that the drug-loaded microspheres were of porosity which was a result of the physicochemical property of DSNC itself. XRD study indicated that the drug and the polymer maintained crystallinity and semi-crystallinity in the microspheres, respectively. However, the degree of crystallinity of the polymer decreased with the introduction of the model drug. Besides, there was no interaction between the drug and the polymer. In vitro release tests indicated that DSNC was rapidly released, which was attributed to the high water-solubility of the drug and the porosity of the microspheres.
With regards to the porosity and rapid drug release of DSNC-loaded PCL microspheres, the morphology and release behavior were modified by adding sodium chloride in the continuous phase during the microsphere preparation. The results indicated that the addition of NaCl resulted into the decrease in porosity and particle size as well as the increase in density and encapsulation efficiency. In addition, the drug release was much slower from the microspheres prepared with the addition of NaCl than from those prepared without the addition of NaCl.
Finally, the mechanism of particle formation and drug release were put forward according to the investigations conducted. During the microsphere preparation, the water in the continuous phase can diffuse into the emulsion droplets and dissolve drug particle, which generated high osmotic pressure driving the water flow in continuously. As the water influx proceeded, the state of the emulsion was transferred from s/o/w to w/o/w which was responsible for the porosity of the microspheres. The in vitro release tests indicated that the drug release from the microspheres was a result of a combination of osmotic effect and diffusion. The initial release was controlled by the two factors, but the release after the initial was mainly controlled by diffusion.
本文分别以去甲斑蝥酸钠(DSNC)和聚己内酯(PCL)为模型药物和包囊材料,较深入探讨了微球的制备、表征和释药机制等基础性研究,为包封其它水溶性药物(尤其是可离子化药物)奠定了重要理论基础。
首先采用S/O/W溶剂挥发法制备微球,并对主要工艺参数进行了筛选和优化。结果发现,聚合物浓度对去甲斑蝥酸钠包封率高低起着至关重要的作用。聚合物浓度越高,则S/O分散相的粘度越高,药物粒子朝水相泄漏的程度就相对降低,从而得到较高的包封率。
对载药微球的形态、结晶性和体外释药行为进行了表征。SEM结果显示载药微球表面粗糙内部多孔,进一步研究表明载药微球的多孔性是药物本身性质决定的。XRD结果表明,去甲斑蝥酸钠在微球中以结晶形式存在;聚己内酯保持着半结晶性,但其结晶度随着投药量的增加而明显降低。此外,药物和材料之间不存在相互作用力。体外药物释放结果表明药物很快就释放完全,这主要是由药物的高水溶性和微球的多孔性决定。
针对载药微球的多孔性和释药快的问题,采用往连续相中加氯化钠来修饰微球形态和释药行为。结果发现,微球制备时连续相中加氯化钠有利于降低连续相和分散相的渗透压差,即能降低连续相中的水朝分散相内部迁移的程度,因而导致微球孔隙率的降低、包封率增加、粒径减小、密度增加。同时,加入氯化钠所制得的微球具有较慢的药物释放行为。
根据以上研究结果提出了独特的微球形成过程和释药机制。在微球制备过程中,连续相的水朝乳滴内部扩散溶解部分的药物粒子,溶解后药物使乳滴内部表现出高渗透压,从而驱使连续相中的水继续朝乳滴内部迁移。随着水不断朝内迁移,乳滴内部形成内水相,乳液状态由S/O/W转变成W/O/W,这种乳液状态的转变导致微球干燥后呈现疏松多孔的内部结构。体外药物释放结果表明DSNC聚己内酯微球的药物释放由渗透压和扩散共同控制:在突释阶段,渗透压和扩散共同参与药物的释放;但在突释之后,药物释放主要由扩散控制。
Polymeric microspheres have been widely-used to encapsulate hydrophilic and hydrophobic drugs, however, there are only a few literatures about their application for the encapsulation and delivery of the ionic water-soluble drugs. Because of their particular physicochemical characteristics, the ionic water-soluble drugs are difficult to encapsulate successfully. Thus, there are few literatures about such basic investigations as the encapsulation and release mechanism of the ionic water-soluble drugs, which is unfavorable for their pharmaceutical research and development.
In this study, disodium norcantharidate (DSNC) and poly(ε-caprolactone) (PCL) microspheres were chosen as model drug and encapsulation material respectively, and the preparation, characterization and drug release mechanism of the microspheres were investigated systematically. This study paid basic foundation for the investigations in the encapsulation and release of water-soluble drugs.
First, DSNC-loaded PCL microspheres were prepared by s/o/w solvent evaporation method and several preparation parameters were investigated and optimized. The results implied that the polymer concentration was crucial to the successful encapsulation of DSNC. A higher concentration of the polymer resulted in a higher viscosity of the s/o dispersion, which decreased the leakage of the drug into the continuous phase thus increasing the encapsulation efficiency of DSNC.
DSNC-loaded PCL microspheres were characterized by terms of microspehre morphology, crystallinity and in vitro drug release. SEM results indicated that the drug-loaded microspheres were of porosity which was a result of the physicochemical property of DSNC itself. XRD study indicated that the drug and the polymer maintained crystallinity and semi-crystallinity in the microspheres, respectively. However, the degree of crystallinity of the polymer decreased with the introduction of the model drug. Besides, there was no interaction between the drug and the polymer. In vitro release tests indicated that DSNC was rapidly released, which was attributed to the high water-solubility of the drug and the porosity of the microspheres.
With regards to the porosity and rapid drug release of DSNC-loaded PCL microspheres, the morphology and release behavior were modified by adding sodium chloride in the continuous phase during the microsphere preparation. The results indicated that the addition of NaCl resulted into the decrease in porosity and particle size as well as the increase in density and encapsulation efficiency. In addition, the drug release was much slower from the microspheres prepared with the addition of NaCl than from those prepared without the addition of NaCl.
Finally, the mechanism of particle formation and drug release were put forward according to the investigations conducted. During the microsphere preparation, the water in the continuous phase can diffuse into the emulsion droplets and dissolve drug particle, which generated high osmotic pressure driving the water flow in continuously. As the water influx proceeded, the state of the emulsion was transferred from s/o/w to w/o/w which was responsible for the porosity of the microspheres. The in vitro release tests indicated that the drug release from the microspheres was a result of a combination of osmotic effect and diffusion. The initial release was controlled by the two factors, but the release after the initial was mainly controlled by diffusion.
引文
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[9] Pistel K.-F., Kissel T., Effects of salt addition on the microencapsulation of proteins using W/O/W double emulsion technique [J]. J. Microencapsul. 2000, 17 (4): 467–483.
[10] Jiang G., Thanoo B.C., Deluca P.P., Effect of osmotic pressure in the solvent extraction phase on BSA release profile from PLGA microspheres [J]. Pharm. Dev. Tech. 2002, 7 (4): 391–399.
[11] Takada S., Kurokawa T., Miyazaki K., et al., Utilization of an amorphous form of a water-soluble PGIIb/IIIa antagonist for controlled release from biodegradable microspheres [J]. Pharm. Res. 1997, 14 (9): 1146–1150.
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