微通道内固体脂质纳米粒的成形与传质机理研究
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摘要
固体脂质纳米粒(solid lipid nanoparticles,SLN)是20世纪90年代初发展起来的一种新型纳米粒载药系统,与传统的微乳、脂质体及聚合物纳米粒相比,SLN因具有良好生理相容性、靶向性、可缓控释性及适合多种给药途径等优点而备受关注。目前已发展起来的SLN制备方法通常存在制备条件苛刻、溶剂残留、过程复杂等问题,且SLN的粒径及分布也是影响其性能的重要因素,因此,研究开发具有粒径小、分布均匀的SLN的新型制备方法具有重要意义。
论文提出利用抗溶剂法原理在微通道内制备SLN,首先采用同心管微通道法制备了SLN,并与常规大空间间歇成粒法制备结果进行了对比,结果表明采用同心管微通道可制备获得粒径更小的颗粒,说明微通道在SLN制备方面的可行性。而且与传统制备方法相比,微通道法制备具有操作简单、条件温和、易于控制等优点,是一种制备SLN的有效方法。
论文分别在同心管微通道、T形微通道及“十”字形微通道内考察了脂相流速、水相流速、脂相中脂质体浓度、水相中表面活性剂浓度、脂相溶剂种类及通道尺寸等因数对SLN成粒规律的影响。结果表明：保持水相流速不变,SLN粒径随着脂相流速的增大而增大；对同心管微通道和“十”字形微通道来说,保持脂相流速不变,SLN粒径随水相流速的增大而减小,但在T形微通道内,SLN粒径随水相流速的增大而略有增长；水相中表面活性剂浓度增大时,SLN粒径增大；以乙醇作为酯相溶剂时可得到比丙酮作为溶剂时更小粒径的SLN；微通道尺寸越小,所得到的颗粒粒径也越小。因此,合理控制操作条件,可以使SLN在一定粒径范围内可控。
论文还考察了向微通道内引入弹状流后对颗粒制备结果的影响,及其在解决微通道堵塞问题上的有效性。结果表明：向微通道的主道内引入气相后所得到的SLN平均粒径与无气相注入时无明显差异,在同心管微通道和“十”形微通道内甚至略有减小趋势,表明气相的引入对制备过程无不良影响,却可有效防止微通道堵塞、实现SLN的长周期连续化制备。
通过显微技术与高速摄像相结合的方法,对微通道内流体的流动特点进行了可视化研究,在此基础上对微通道内成粒机理进行了分析,并对传质过程建立了相应的数学模型。将弹状流条件下“十”字型微通道内成粒过程分为弹状气泡形成前的对流传质区、弹状气泡进入后的液膜传质区及液塞传质区三个区域,建立了成粒过程的“三区传质模型”。求解结果表明：液膜内的传质速率明显大于液塞内的传质,这一结果与文献报道结果相一致,说明建立的成粒过程模型具有一定的可靠性；另外,增大气量有利于加强液塞内流体的湍动程度及液膜内的液速,从而强化传质,使纳米粒以更快的速度析出。传质模型的建立为微通道内SLN的制备及微通道设计提供了依据。
Solid lipid nanoparticles (SLN) is a new drug delivery system developed in 1990s. It has attracted increasing attention for its advantages of excellent biocompatibility, controlled release, targeted therapy and suitability for different kinds of medication routes comparing to the traditional delivery systems, such as emulsions, liposomes and polymeric nanoparticles. In the traditional preparing methods of SLN, the preparing processes are generally conducted complexly under overcritical operation conditions like high speed, high temperature or pressure, and toxicological solvents were always employed. Furthermore the size and distribution of SLN are important factors for the property of SLN. Therefore, it is important to develop a novel method for preparing SLN with small size and narrow size distribution.
Microchannels are applied to prepare SLN based on the anti-solvent precipitation in this thesis. The SLN samples were prepared by using a co-flowing microchannel and were compared with the samples prepared by ordinary batch method. The results show that the SLN prepared by co-flowing microchannels had smaller diameter, and that microchannels are suitable for SLN preparation. Compared with the traditional prepartion methods, the prepartion process by using microchannals is a very simple one, with moderate condition and easy to control. Therefore, it could be expected to be an efficient method for SLN preparation.
The influences of lipid phase velocity, liquid phase velocity, the concentration of surfactant in liquid phase, the concentration of lipid, the solvent kinds and the dimension of microchannels on the formation of SLN were investigated in co-flowing microchannels, T junction microchannels and microchannels with cross-junction, respectively. It was found that the diameter of SLN increases with the increase of the lipid phase velocity at a certain aqueous phase velocity. For co-flowing microchannels and microchannels with cross-junction, the diameter of SLN decreases with the increase of the aqueous phase velocity at a certain lipid phase velocity, on the contrary, the diameter of SLN increases with the increase of the aqueous phase velocity for T junction microchannels. Moreover, the diameter of SLN increases with the increase of surfacent concentration in the aqueous phase, smaller SLN can be prepared when ethanol is used as lipid phase solvent instead of acetone, and the diameter of SLN decreased as the microchannel dimension decreased. Therefore, SLN with expected properties like small diameter and narrow size distribution can be prepared by controlling these operation conditions.
The effect of slug flow on the formation of SLN was studied by inputing gas flow in microchannels. No blockage is observed in the mirochannels when slug flow is employed. The experiments also display that the slug flow has no negative influence on the size of SLN and its distribution, but smaller diameter SLN could be prepared for co-flowing microchannels and microchannels with cross-junction. This may indicate that slug flow can eliminate blockage and is good to the continueous production of SLN in microchannels.
The flow patterns in the microchannels were inspected by digital inversion microscope and electron eyepiece or CCD. The mechanisms of mass transfer and the formation of SLN were analysed, and mathematical models were established. For the cross-junction microchannels, the process of SLN formation under slug flow was divided into three zones, such as convectional zone before bubble formation, liquid film zone and slug zone after bubble formation. The corresponding mathematical models for these zones were developed respectively. The solution of the models indicated that the velocity of mass transfer in the film is higher than that in the slug, which is similar to the reports in references, indicating that the model established is credible. On the other hand, the solution of the models also indicated that the increase of gas velocity resulted in the increase of slug turbulence, the film flow velocity and the mass transfer, so SLN was precipited faster. The mechanisms of mass transfer provide a reference for the the preparation of SLN and the design of microchannel apparatus.
论文提出利用抗溶剂法原理在微通道内制备SLN,首先采用同心管微通道法制备了SLN,并与常规大空间间歇成粒法制备结果进行了对比,结果表明采用同心管微通道可制备获得粒径更小的颗粒,说明微通道在SLN制备方面的可行性。而且与传统制备方法相比,微通道法制备具有操作简单、条件温和、易于控制等优点,是一种制备SLN的有效方法。
论文分别在同心管微通道、T形微通道及“十”字形微通道内考察了脂相流速、水相流速、脂相中脂质体浓度、水相中表面活性剂浓度、脂相溶剂种类及通道尺寸等因数对SLN成粒规律的影响。结果表明：保持水相流速不变,SLN粒径随着脂相流速的增大而增大；对同心管微通道和“十”字形微通道来说,保持脂相流速不变,SLN粒径随水相流速的增大而减小,但在T形微通道内,SLN粒径随水相流速的增大而略有增长；水相中表面活性剂浓度增大时,SLN粒径增大；以乙醇作为酯相溶剂时可得到比丙酮作为溶剂时更小粒径的SLN；微通道尺寸越小,所得到的颗粒粒径也越小。因此,合理控制操作条件,可以使SLN在一定粒径范围内可控。
论文还考察了向微通道内引入弹状流后对颗粒制备结果的影响,及其在解决微通道堵塞问题上的有效性。结果表明：向微通道的主道内引入气相后所得到的SLN平均粒径与无气相注入时无明显差异,在同心管微通道和“十”形微通道内甚至略有减小趋势,表明气相的引入对制备过程无不良影响,却可有效防止微通道堵塞、实现SLN的长周期连续化制备。
通过显微技术与高速摄像相结合的方法,对微通道内流体的流动特点进行了可视化研究,在此基础上对微通道内成粒机理进行了分析,并对传质过程建立了相应的数学模型。将弹状流条件下“十”字型微通道内成粒过程分为弹状气泡形成前的对流传质区、弹状气泡进入后的液膜传质区及液塞传质区三个区域,建立了成粒过程的“三区传质模型”。求解结果表明：液膜内的传质速率明显大于液塞内的传质,这一结果与文献报道结果相一致,说明建立的成粒过程模型具有一定的可靠性；另外,增大气量有利于加强液塞内流体的湍动程度及液膜内的液速,从而强化传质,使纳米粒以更快的速度析出。传质模型的建立为微通道内SLN的制备及微通道设计提供了依据。
Solid lipid nanoparticles (SLN) is a new drug delivery system developed in 1990s. It has attracted increasing attention for its advantages of excellent biocompatibility, controlled release, targeted therapy and suitability for different kinds of medication routes comparing to the traditional delivery systems, such as emulsions, liposomes and polymeric nanoparticles. In the traditional preparing methods of SLN, the preparing processes are generally conducted complexly under overcritical operation conditions like high speed, high temperature or pressure, and toxicological solvents were always employed. Furthermore the size and distribution of SLN are important factors for the property of SLN. Therefore, it is important to develop a novel method for preparing SLN with small size and narrow size distribution.
Microchannels are applied to prepare SLN based on the anti-solvent precipitation in this thesis. The SLN samples were prepared by using a co-flowing microchannel and were compared with the samples prepared by ordinary batch method. The results show that the SLN prepared by co-flowing microchannels had smaller diameter, and that microchannels are suitable for SLN preparation. Compared with the traditional prepartion methods, the prepartion process by using microchannals is a very simple one, with moderate condition and easy to control. Therefore, it could be expected to be an efficient method for SLN preparation.
The influences of lipid phase velocity, liquid phase velocity, the concentration of surfactant in liquid phase, the concentration of lipid, the solvent kinds and the dimension of microchannels on the formation of SLN were investigated in co-flowing microchannels, T junction microchannels and microchannels with cross-junction, respectively. It was found that the diameter of SLN increases with the increase of the lipid phase velocity at a certain aqueous phase velocity. For co-flowing microchannels and microchannels with cross-junction, the diameter of SLN decreases with the increase of the aqueous phase velocity at a certain lipid phase velocity, on the contrary, the diameter of SLN increases with the increase of the aqueous phase velocity for T junction microchannels. Moreover, the diameter of SLN increases with the increase of surfacent concentration in the aqueous phase, smaller SLN can be prepared when ethanol is used as lipid phase solvent instead of acetone, and the diameter of SLN decreased as the microchannel dimension decreased. Therefore, SLN with expected properties like small diameter and narrow size distribution can be prepared by controlling these operation conditions.
The effect of slug flow on the formation of SLN was studied by inputing gas flow in microchannels. No blockage is observed in the mirochannels when slug flow is employed. The experiments also display that the slug flow has no negative influence on the size of SLN and its distribution, but smaller diameter SLN could be prepared for co-flowing microchannels and microchannels with cross-junction. This may indicate that slug flow can eliminate blockage and is good to the continueous production of SLN in microchannels.
The flow patterns in the microchannels were inspected by digital inversion microscope and electron eyepiece or CCD. The mechanisms of mass transfer and the formation of SLN were analysed, and mathematical models were established. For the cross-junction microchannels, the process of SLN formation under slug flow was divided into three zones, such as convectional zone before bubble formation, liquid film zone and slug zone after bubble formation. The corresponding mathematical models for these zones were developed respectively. The solution of the models indicated that the velocity of mass transfer in the film is higher than that in the slug, which is similar to the reports in references, indicating that the model established is credible. On the other hand, the solution of the models also indicated that the increase of gas velocity resulted in the increase of slug turbulence, the film flow velocity and the mass transfer, so SLN was precipited faster. The mechanisms of mass transfer provide a reference for the the preparation of SLN and the design of microchannel apparatus.
引文
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