静电喷射法制备生物可降解聚膦腈/聚酯微球及不同形态微球形成机理的研究
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摘要
聚合物微球制剂作为一种新型的控释给药体系,具有能控制制剂微粒粒径、控制药物释放速率、延长药物作用时间、减少药物不良反应、降低用药剂量等优点,还可用于特定组织和器官的药物靶向释放等。微囊化的具体制备方法有乳液法、相分离法、喷雾干燥法、静电喷射法等。已有的研究表明,静电喷射技术是一种可制备具有可控粒径(从几十纳米到几十微米)、可控表面形态(光滑或多孔)的高分子微粒的一种技术,是目前所知的唯一能得到具有高度单分散性微粒的成型方法。由于粒子的流动性或在特定部位的聚集性,都和粒径大小相关,而且在药物控制释放体系中,单分散微粒往往释放行为能得到更为准确的控制和匀速释放,因此在微粒的制备过程中,对粒径的控制显得尤为重要,而这正是静电喷射所具有的最突出的优势。由于静电喷射技术在微球粒径控制上的特殊优势以及其他的诸多优点,采用该技术制备聚膦腈载药微球可以将聚膦腈的特殊性能和静电喷射的技术优势相结合而制备出更优异的聚合物药物控释微球,已有的关于静电喷射技术的研究多集中于微球粒径大小以及微球粒径分布的控制上,本研究中合成了两种氨基酸酯取代聚膦腈,并研究了它们在静电喷射过程中溶剂对其微球形貌的影响规律,力图实现氨基酸酯取代聚膦腈静电喷射微球的形貌可控,并通过调整静电喷射过程中各种工艺参数实现了氨基酸酯取代聚膦腈静电喷射微球的粒径控制；在此基础上合成了聚乳酸-羟基乙酸共聚物以及聚己内酯两种可生物降解聚酯,用这两种聚合物进行静电喷射研究,来丰富和印证在聚膦腈静电喷射过程中总结的形貌和粒径控制规律,发现溶剂对聚酯类聚合物的形貌影响与对聚膦腈的影响并不一致,聚酯类聚合物的静电喷射中溶剂对微球形貌影响规律丰富了聚合物溶液在静电喷射过程中形成微球的机理；在粒径控制方面各种工艺参数对微球粒径的影响规律与聚膦腈中得到的规律一致。
1.在甘／苯丙氨酸乙酯混合取代聚膦腈(PGPP)静电喷射过程中,由于聚合物结构和性质的特殊性在所选用溶剂四氢呋喃中改变各种工艺参数都只得到圆盘状形貌的微球；通过选取不同的溶剂进行静电喷射,碗状、塌球状等形状饱满接近圆球状的微球被制得,此外通过降低聚合物的分子量可以进一步制备更加接近圆球状的微球。总结所选用的溶剂对最终微球形貌的影响,我们发现溶剂具有的不同的性质是造成不同形貌微球产生的原因。通过比较各种溶剂中的静电喷射上限浓度和最终微球的形貌,我们发现在溶剂所具有的各种性质中,对聚合物的溶解性和溶剂的挥发速率是调节微球形貌的重要参数,在挥发速率接近的溶剂中选用对聚合物溶解较差的溶剂进行静电喷射可以使得静电喷射的上限浓度提高,从而提高液滴的固含量而使微球变得丰满。分子量对微球形貌的影响是小分子量聚合物溶液由于缠结浓度较高可以有更高的静电喷射浓度,而分子量较低的高分子运动能力较强也利于制备圆球状微球,因此在PGPP静电喷射过程中选取对聚合物具有不同溶解性的溶剂和不同的分子量是制备不同形貌PGPP微球的关键。
在微球粒径调控方面可以通过流速、电压、接收距离等操作参数来控制微球的粒径大小,其中流速对微球粒径影响较大,通过改变流速可以使微球的平均粒径从2.2μm增加到3.2μm。此外溶液电导率和表面张力也可以影响微球粒径,而且通过增加溶液电导率和降低溶液表面张力可以使小粒径微球数量明显增多,使得微球平均粒径降低到1.5μm。
2.合成了甘／丙氨酸乙酯混合取代聚膦腈(PAGP),由于PAGP分子中的丙氨酸乙酯取代基空间位阻与PGPP分子中的苯丙氨酸乙酯取代基相比较小,两种聚膦腈性质有一定的差别,采用静电喷射技术制备了甘／丙氨酸乙酯混合取代聚膦腈(PAGP)微球,在静电喷射过程中PAGP分子的扩散运动能力更强,在所选用的溶剂中进行静电喷射所制备的微球都为圆球状,但是在不同溶剂中进行静电喷射的上限浓度有着明显的不同,在良溶剂中同样具有较小的静电喷射上限浓度。通过流速、电压和接收距离等操作参数的改变可以制备平均粒径不同的微球,通过参数的调整可以使得平均粒径大小在2μm到3μm之间可控。
3.采用静电喷射技术制备了氨基酸酯取代聚膦腈载有蛋白质颗粒的微球。在制备过程中我们发现微球中的蛋白质颗粒对微球的形貌没有造成影响,研究了蛋白质颗粒在两种氨基酸酯取代聚膦腈微球中的药物释放行为,发现聚合物的不同结构与性质对最终微球的药物释放行为有着重要的影响。
4.研究了不同溶剂和分子量对PLGA静电喷射过程的影响,通过选用不同的溶剂可以制备形貌不同的PLGA微球,溶剂的改变使得PLGA微球的形貌发生了从圆球状到塌球状明显的变化,微球从圆球状到塌球状的变化与溶剂对聚合物的溶解性有着对应关系,随着所选溶剂中聚合物特性粘度的下降亦即溶剂对聚合物的溶解性降低而出现塌球状,同时在各种溶剂中静电喷射的上限浓度不再随特性粘度的降低而升高,而是随着特性粘度的降低而降低,通过对各种溶剂中实验结果的比较发现PLGA静电喷射过程中聚合物与溶剂之间的相互作用影响了溶剂的挥发造成了微球形貌的差异。良溶剂与聚合物的相互作用很强,因此可以使得溶剂从溶液中脱除受阻,而劣溶剂与聚合物之间的相互作用较弱,聚合物对溶剂的脱除影响较小,因此在良溶剂中聚合物分子有更多的时间向内部扩散,同时在下落过程中溶剂挥发缓慢而使液滴的浓度上升较小而可以继续分裂,劣溶剂的存在下溶剂快速的脱除使得射流表面的溶液浓度达到缠结浓度而出现拉丝。因此在PLGA的静电喷射过程中选取良溶剂可以制备圆球状微球,选取劣溶剂可以制备塌球状微球。在粒径控制方面通过调节流速、电压和接收距离可以制备平均粒径在5μm到8μm之间的微球,通过参数的调节可以控制平均粒径的大小。
5.采用静电喷射技术制备了PCL微球,通过溶剂的改变可以制备不同形貌的微球,文献中报道的圆球状PCL微球在这里通过溶剂的调整可以得到碗状形貌的微球,影响微球形貌的原因同样在于聚合物和溶剂的相互作用。通过改变流速、电压和接收距离同样可以调控微球平均粒径的大下,可以使得微球的平均粒径在9μm到14μm范围内可控。
6.基于氨基酸酯取代聚膦腈和生物可降解脂肪族聚酯的静电喷射的实验结果以及所总结的形貌、粒径控制规律提出了总结了高分子溶液静电喷射的形貌、粒径控制规律,并提出了高分子溶液静电喷射的模型假设。V
The Research on the Preparation of Biodegradable Phosphazene/Polyester Drug-Loaded Microparticles by Electrohydrodynamic Atomization and the Formation Mechanism of Different Microparticles Morphologies
Polymeric microspheres are regarded as a promising controlled drug release delivery system with a good number of advantages such as fine controlled sphere size, controlled release rate, prolonged function time, reduced adverse biological reaction and relatively low dose, and can be applied in target drug delivery of tissues and organs. The common processing methods of microspheres incorporate emulsion, phase separation, spray drying, electrospraying and so on. Previous studies showed electrospraying, as a microsphere processing technique which can achieve controllable sphere diameter (from tens of nanometers to a few micrometers) and controllable morphologies (smooth or porous), is the only method capable of obtaining highly monodispersed particles. Besides, electrospray outweighs other preparing methods in that it can exercise a good control of particle diameters, which is of vital importance because of two reasons. On the one hand, the particle's mobility and aggregation in specific area are closely dependent on its size; on the other hand, monodispersed particles' release behavior is in a uniform rate, and can be better controlled.
In the light of the merits of electrospraying in terms of controlling microsphere size as well as other advantages, and the special properties of polyphosphazene, the application of this technique to preparing polyphosphazene drug delivery microspheres can yield better performed polymer drug-control microspheres. Prior researches on electrospraying mostly focused on the control of size and size distribution of microspheres. In the present study, two types of amino acid ester substituted polyphosphazene were synthesized, and the solvent's influence law on their electrosprayed morphologies was presented. Efforts were made to achieve morphology control of eletrosprayed amino acid ester substituted polyphosphazene microsphere, and to achieve size control by controlling various processing parameters. Furthermore, two biodegradable polyesters PLGA and PCL were synthesized and studied to verify and extend the law which was derived from the electrospraying of polyphosphazene microsphere. It is found that the solvent's influences on morphology of polyester polymers and on that of polyphosphazene are different while the influence of processing parameter on the size of both types of polymers is identical.
1. Due to the special structure and properties of polymer, the products of glycin/phenylalanine ethyl ester substituted PGPP by electrospraying in tetrahydrofuran solvent were plate shaped microparticles. With different solvent, we can obtain particles with different morphologies, such as bowl-shaped and wrinkled sphere, which were close to spherical spheres. Besides, the decreasing of molecular weight can further produced microspheres much closer to spherical ones. After analyzing the morphologies of particles in relation to solvents, we get that it is the different properties of solvents that lead to different morphologies of microparticles. By comparing the upper limit condensation of polymer in different solvents and the ultimate morphologies of microparticles, it is discovered that among all the properties of the solvent the key parameters determining the shape of microparticles are the volatilization rate of solvent and the solubility of polymer. With the similar volatilization rate, the solvent which has poor dissolving capability will raise the upper limit concentration of polymer in electrospraying, and hence will increase the solid content and make the microparticles closer to spheres. Additionally, the solution of the polymer with smaller macromolecular weight has a higher concentration for electrospray owing to the higher entanglement concentration, and spherical microspheres tend to be obtained out of these polymers due to the motion ability of macromolecules. Thus, the solvent and the macromolecular weight are key factors in determining the morphologies of electrosprayed PGPP microparticles.
The diameter of particles can be controlled by such processing parameters as liquid flow rate, applied voltage and nozzle-plate distance, among which liquid flow is the key factor influencing the diameter. The size of particles ranges from 2.2μm to 3.2μm as the flow rate increasing. Furthermore, the electrical conductivity and surface tension of solution also play roles in the formation of particles. Higher electrical conductivity and lower surface tension of solution will produce an increasing number of small microparticles, with the average diameter decreasing to 1.5μm.
2. The glycin/phenylalanine ethyl ester mixed substituted polyphosphazene (PAGP) has different properties from PGPP, since PAGP has smaller steric hindrance with lactamine ethyl ester in comparison with phenylalanine ethyl ester in PGPP. PAGP has higher diffusion capability in the solution, so it can produce spherical microparticles by electrospray in various solvents. However, there are significant differences in terms of upper limit concentration in different solvents. In good solvent the upper limit concentration is lower. The size can be adjusted by changing liquid flow rate, voltage, and nozzle-plate distance, and the particle diameter can be controlled in a size range between 2μm and 3μm.
3. Amino acid ester substituted polyphosphazene microspheres carrying protein particles were prepared by means of electrospray technique. In the preparation process, it was found that the protein particles within the microspheres did not exert influence on microsphere morphology. Besides, the drug release behavior of protein particles within two different types of amino acid ester substituted polyphosphazenes were also probed into, and the finding was that different structures and properties of polymers have greatly influenced the final drug release behavior of microspheres.
4. The influence of the solvent and molecular weight on the electrospray process of PLGA was examined. The adoption of different solvent led to different morphologies of microspheres varying from spherical ones to collapsed ones. The corresponding relation between the morphology of microspheres and the solubility of the solvent was observed, and it is found that as the intrinsic viscosity of polymers decreased, i.e. the decreasing of the solubility of the polymer in the solvent, the collapsed microspheres occurred. On the basis of the comparison among different solvents, it is obtained that in the electrospray of PLGA, the interaction between the polymer and the solvent influenced the volatilization, which led to differences in microsphere morphologies. Since the interaction between the good solvent and the polymer is strong, the solvent is kept from removing from the solution. On the contrary, because the interaction between the solvent and polymer is weak, the removal of polymer solvent has been less affected. Therefore, the polymer molecules in good solvent have more time to diffuse toward the core, and in the process of falling down, continuous splitting is achieved due to the less increase of the droplet concentration caused by slow volatilization. However, in the poor solvent, the swift removal of solvent makes the solution concentration of the exterior jet increase to the entanglement concentration to yield fibers. Therefore, in the PLGA electrospray process, good solvent can be adopted when producing the spherical microspheres, and the poor solvent can be utilized to obtain the collapsed microspheres. As for the size control, the average diameter of particles can be controlled by means of adjusting parameters such as the flow rate, voltage, and nozzle-plate distance. By controlling these parameters, the microspheres with the controllable average diameter ranging from 5μm to 8μm can be obtained.
5. The preparation of PCL by electrospray. Different morphologies of microspheres can be prepared by changing the solvent. Previous literature has reported on the spherical PCL microspheres, while in the present study, the bowl shaped PCL microspheres were yielded by utilizing a different solvent. The factor influencing the morphologies of microspheres lies also in the interaction between the polymer and the solvent. By adjusting the flow rate, voltage, and nozzle-plate distance, the diameters of microspheres, were within the controllable spectrum between 9μm and 14μm.
6. Based on the results of the experiments on electrospray of amino acid ester substituted polyphosphazene and biodegradable aliphatic polyester and the rules of morphology and diameter control derived from the results, this paper analyzed the mechanism of electrospray of polymer solution from the perspective of interactions among macromolecules in polymer solution and different solubility of polymers in different solvents, and finally established an explanatory model of electrospray of polymer solution.
1.在甘／苯丙氨酸乙酯混合取代聚膦腈(PGPP)静电喷射过程中,由于聚合物结构和性质的特殊性在所选用溶剂四氢呋喃中改变各种工艺参数都只得到圆盘状形貌的微球；通过选取不同的溶剂进行静电喷射,碗状、塌球状等形状饱满接近圆球状的微球被制得,此外通过降低聚合物的分子量可以进一步制备更加接近圆球状的微球。总结所选用的溶剂对最终微球形貌的影响,我们发现溶剂具有的不同的性质是造成不同形貌微球产生的原因。通过比较各种溶剂中的静电喷射上限浓度和最终微球的形貌,我们发现在溶剂所具有的各种性质中,对聚合物的溶解性和溶剂的挥发速率是调节微球形貌的重要参数,在挥发速率接近的溶剂中选用对聚合物溶解较差的溶剂进行静电喷射可以使得静电喷射的上限浓度提高,从而提高液滴的固含量而使微球变得丰满。分子量对微球形貌的影响是小分子量聚合物溶液由于缠结浓度较高可以有更高的静电喷射浓度,而分子量较低的高分子运动能力较强也利于制备圆球状微球,因此在PGPP静电喷射过程中选取对聚合物具有不同溶解性的溶剂和不同的分子量是制备不同形貌PGPP微球的关键。
在微球粒径调控方面可以通过流速、电压、接收距离等操作参数来控制微球的粒径大小,其中流速对微球粒径影响较大,通过改变流速可以使微球的平均粒径从2.2μm增加到3.2μm。此外溶液电导率和表面张力也可以影响微球粒径,而且通过增加溶液电导率和降低溶液表面张力可以使小粒径微球数量明显增多,使得微球平均粒径降低到1.5μm。
2.合成了甘／丙氨酸乙酯混合取代聚膦腈(PAGP),由于PAGP分子中的丙氨酸乙酯取代基空间位阻与PGPP分子中的苯丙氨酸乙酯取代基相比较小,两种聚膦腈性质有一定的差别,采用静电喷射技术制备了甘／丙氨酸乙酯混合取代聚膦腈(PAGP)微球,在静电喷射过程中PAGP分子的扩散运动能力更强,在所选用的溶剂中进行静电喷射所制备的微球都为圆球状,但是在不同溶剂中进行静电喷射的上限浓度有着明显的不同,在良溶剂中同样具有较小的静电喷射上限浓度。通过流速、电压和接收距离等操作参数的改变可以制备平均粒径不同的微球,通过参数的调整可以使得平均粒径大小在2μm到3μm之间可控。
3.采用静电喷射技术制备了氨基酸酯取代聚膦腈载有蛋白质颗粒的微球。在制备过程中我们发现微球中的蛋白质颗粒对微球的形貌没有造成影响,研究了蛋白质颗粒在两种氨基酸酯取代聚膦腈微球中的药物释放行为,发现聚合物的不同结构与性质对最终微球的药物释放行为有着重要的影响。
4.研究了不同溶剂和分子量对PLGA静电喷射过程的影响,通过选用不同的溶剂可以制备形貌不同的PLGA微球,溶剂的改变使得PLGA微球的形貌发生了从圆球状到塌球状明显的变化,微球从圆球状到塌球状的变化与溶剂对聚合物的溶解性有着对应关系,随着所选溶剂中聚合物特性粘度的下降亦即溶剂对聚合物的溶解性降低而出现塌球状,同时在各种溶剂中静电喷射的上限浓度不再随特性粘度的降低而升高,而是随着特性粘度的降低而降低,通过对各种溶剂中实验结果的比较发现PLGA静电喷射过程中聚合物与溶剂之间的相互作用影响了溶剂的挥发造成了微球形貌的差异。良溶剂与聚合物的相互作用很强,因此可以使得溶剂从溶液中脱除受阻,而劣溶剂与聚合物之间的相互作用较弱,聚合物对溶剂的脱除影响较小,因此在良溶剂中聚合物分子有更多的时间向内部扩散,同时在下落过程中溶剂挥发缓慢而使液滴的浓度上升较小而可以继续分裂,劣溶剂的存在下溶剂快速的脱除使得射流表面的溶液浓度达到缠结浓度而出现拉丝。因此在PLGA的静电喷射过程中选取良溶剂可以制备圆球状微球,选取劣溶剂可以制备塌球状微球。在粒径控制方面通过调节流速、电压和接收距离可以制备平均粒径在5μm到8μm之间的微球,通过参数的调节可以控制平均粒径的大小。
5.采用静电喷射技术制备了PCL微球,通过溶剂的改变可以制备不同形貌的微球,文献中报道的圆球状PCL微球在这里通过溶剂的调整可以得到碗状形貌的微球,影响微球形貌的原因同样在于聚合物和溶剂的相互作用。通过改变流速、电压和接收距离同样可以调控微球平均粒径的大下,可以使得微球的平均粒径在9μm到14μm范围内可控。
6.基于氨基酸酯取代聚膦腈和生物可降解脂肪族聚酯的静电喷射的实验结果以及所总结的形貌、粒径控制规律提出了总结了高分子溶液静电喷射的形貌、粒径控制规律,并提出了高分子溶液静电喷射的模型假设。V
The Research on the Preparation of Biodegradable Phosphazene/Polyester Drug-Loaded Microparticles by Electrohydrodynamic Atomization and the Formation Mechanism of Different Microparticles Morphologies
Polymeric microspheres are regarded as a promising controlled drug release delivery system with a good number of advantages such as fine controlled sphere size, controlled release rate, prolonged function time, reduced adverse biological reaction and relatively low dose, and can be applied in target drug delivery of tissues and organs. The common processing methods of microspheres incorporate emulsion, phase separation, spray drying, electrospraying and so on. Previous studies showed electrospraying, as a microsphere processing technique which can achieve controllable sphere diameter (from tens of nanometers to a few micrometers) and controllable morphologies (smooth or porous), is the only method capable of obtaining highly monodispersed particles. Besides, electrospray outweighs other preparing methods in that it can exercise a good control of particle diameters, which is of vital importance because of two reasons. On the one hand, the particle's mobility and aggregation in specific area are closely dependent on its size; on the other hand, monodispersed particles' release behavior is in a uniform rate, and can be better controlled.
In the light of the merits of electrospraying in terms of controlling microsphere size as well as other advantages, and the special properties of polyphosphazene, the application of this technique to preparing polyphosphazene drug delivery microspheres can yield better performed polymer drug-control microspheres. Prior researches on electrospraying mostly focused on the control of size and size distribution of microspheres. In the present study, two types of amino acid ester substituted polyphosphazene were synthesized, and the solvent's influence law on their electrosprayed morphologies was presented. Efforts were made to achieve morphology control of eletrosprayed amino acid ester substituted polyphosphazene microsphere, and to achieve size control by controlling various processing parameters. Furthermore, two biodegradable polyesters PLGA and PCL were synthesized and studied to verify and extend the law which was derived from the electrospraying of polyphosphazene microsphere. It is found that the solvent's influences on morphology of polyester polymers and on that of polyphosphazene are different while the influence of processing parameter on the size of both types of polymers is identical.
1. Due to the special structure and properties of polymer, the products of glycin/phenylalanine ethyl ester substituted PGPP by electrospraying in tetrahydrofuran solvent were plate shaped microparticles. With different solvent, we can obtain particles with different morphologies, such as bowl-shaped and wrinkled sphere, which were close to spherical spheres. Besides, the decreasing of molecular weight can further produced microspheres much closer to spherical ones. After analyzing the morphologies of particles in relation to solvents, we get that it is the different properties of solvents that lead to different morphologies of microparticles. By comparing the upper limit condensation of polymer in different solvents and the ultimate morphologies of microparticles, it is discovered that among all the properties of the solvent the key parameters determining the shape of microparticles are the volatilization rate of solvent and the solubility of polymer. With the similar volatilization rate, the solvent which has poor dissolving capability will raise the upper limit concentration of polymer in electrospraying, and hence will increase the solid content and make the microparticles closer to spheres. Additionally, the solution of the polymer with smaller macromolecular weight has a higher concentration for electrospray owing to the higher entanglement concentration, and spherical microspheres tend to be obtained out of these polymers due to the motion ability of macromolecules. Thus, the solvent and the macromolecular weight are key factors in determining the morphologies of electrosprayed PGPP microparticles.
The diameter of particles can be controlled by such processing parameters as liquid flow rate, applied voltage and nozzle-plate distance, among which liquid flow is the key factor influencing the diameter. The size of particles ranges from 2.2μm to 3.2μm as the flow rate increasing. Furthermore, the electrical conductivity and surface tension of solution also play roles in the formation of particles. Higher electrical conductivity and lower surface tension of solution will produce an increasing number of small microparticles, with the average diameter decreasing to 1.5μm.
2. The glycin/phenylalanine ethyl ester mixed substituted polyphosphazene (PAGP) has different properties from PGPP, since PAGP has smaller steric hindrance with lactamine ethyl ester in comparison with phenylalanine ethyl ester in PGPP. PAGP has higher diffusion capability in the solution, so it can produce spherical microparticles by electrospray in various solvents. However, there are significant differences in terms of upper limit concentration in different solvents. In good solvent the upper limit concentration is lower. The size can be adjusted by changing liquid flow rate, voltage, and nozzle-plate distance, and the particle diameter can be controlled in a size range between 2μm and 3μm.
3. Amino acid ester substituted polyphosphazene microspheres carrying protein particles were prepared by means of electrospray technique. In the preparation process, it was found that the protein particles within the microspheres did not exert influence on microsphere morphology. Besides, the drug release behavior of protein particles within two different types of amino acid ester substituted polyphosphazenes were also probed into, and the finding was that different structures and properties of polymers have greatly influenced the final drug release behavior of microspheres.
4. The influence of the solvent and molecular weight on the electrospray process of PLGA was examined. The adoption of different solvent led to different morphologies of microspheres varying from spherical ones to collapsed ones. The corresponding relation between the morphology of microspheres and the solubility of the solvent was observed, and it is found that as the intrinsic viscosity of polymers decreased, i.e. the decreasing of the solubility of the polymer in the solvent, the collapsed microspheres occurred. On the basis of the comparison among different solvents, it is obtained that in the electrospray of PLGA, the interaction between the polymer and the solvent influenced the volatilization, which led to differences in microsphere morphologies. Since the interaction between the good solvent and the polymer is strong, the solvent is kept from removing from the solution. On the contrary, because the interaction between the solvent and polymer is weak, the removal of polymer solvent has been less affected. Therefore, the polymer molecules in good solvent have more time to diffuse toward the core, and in the process of falling down, continuous splitting is achieved due to the less increase of the droplet concentration caused by slow volatilization. However, in the poor solvent, the swift removal of solvent makes the solution concentration of the exterior jet increase to the entanglement concentration to yield fibers. Therefore, in the PLGA electrospray process, good solvent can be adopted when producing the spherical microspheres, and the poor solvent can be utilized to obtain the collapsed microspheres. As for the size control, the average diameter of particles can be controlled by means of adjusting parameters such as the flow rate, voltage, and nozzle-plate distance. By controlling these parameters, the microspheres with the controllable average diameter ranging from 5μm to 8μm can be obtained.
5. The preparation of PCL by electrospray. Different morphologies of microspheres can be prepared by changing the solvent. Previous literature has reported on the spherical PCL microspheres, while in the present study, the bowl shaped PCL microspheres were yielded by utilizing a different solvent. The factor influencing the morphologies of microspheres lies also in the interaction between the polymer and the solvent. By adjusting the flow rate, voltage, and nozzle-plate distance, the diameters of microspheres, were within the controllable spectrum between 9μm and 14μm.
6. Based on the results of the experiments on electrospray of amino acid ester substituted polyphosphazene and biodegradable aliphatic polyester and the rules of morphology and diameter control derived from the results, this paper analyzed the mechanism of electrospray of polymer solution from the perspective of interactions among macromolecules in polymer solution and different solubility of polymers in different solvents, and finally established an explanatory model of electrospray of polymer solution.
引文
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[13]. Grado'n, L.,& Marijnissen, J. C. M., Optimization of Aerosol Drug Delivery, The Netherlands:Kluwer Academic Publishers,2003.
[14]. Hong, S. H., Moon, J. H., Lim, J. M., Kim, S. H.,& Yang, S. M., Fabrication of spherical colloidal crystals using electrospray, Langmuir, 2005,21:10416-10421
[15]. Jingwei Xie, Liang Kuang Lim, Yiyong Phua, Jinsong Hua, Chi-Hwa Wang,Electrohydrodynamic atomization for biodegradable polymeric particle production, Journal of Colloid and Interface Science,2006,302:
103-112
[16]. J W Xie, CM Jan, CH Wang, Microparticles developed by electro-hydrodynamic atomization for the local delivery of anticancer drug to treat C6 glioma in vitro, Biomaterials,2006,27:3321-3332.
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