超临界撞击流微粒包覆工艺基础研究
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摘要
微胶囊的制备技术是影响其应用的关键,其中超临界快速膨胀(RESS)法和超临界反溶剂(SAS)法是目前超临界流体过程在制备药物微胶囊领域中应用较为广泛的方法。这两种方法虽然能够克服传统方法的粒径偏大、分布范围较宽、制备过程温度较高、有机溶剂残留、团聚现象严重等缺点；但也存在着RESS法包覆不均匀、SAS法对微胶囊的壁材和芯材从有机溶剂中析出顺序要求严格等问题。
在总结前人研究的基础上,本论文将超临界流体过程、撞击流和流化床技术相结合,提出了一种新的制备微胶囊技术—超临界撞击流技术(SFIT)。该技术既弥补了RESS法和SAS法制备药物微胶囊的不足,又承接了RESS结合流化床技术制备微胶囊过程的优点,解决了芯材在超临界流体中受溶解度限制的问题,强化了流场中相间的传递过程,使得微胶囊的包覆效率得到了显著提高,药物的适用范围得到了扩大。
根据超临界撞击流技术原理,本论文建立了实验装置、实验程序与步骤以及分析测试手段,形成了一整套超临界撞击流实验技术。以玻璃微珠为包覆芯材、石蜡为包覆壁材,利用SFIT进行了制备微胶囊的模型实验研究,并对制得的微胶囊进行了表征和评价。结果表明,论文设计建立的实验装置完全满足SFIT实验要求,并且制备出的微胶囊具有良好的完整性,同时确定了主要操作参数(如混合器内压力、混合器内温度、撞击距离和膨胀前温度等)对微胶囊包覆效果(如微胶囊表面形态、粒径及粒径分布、表观包覆率等)的影响规律,并得到了较为适宜的操作参数。
研究选用半衰期较短的抗生素类药物阿莫西林和生物利用度较低的降血压类药物尼群地平为包覆芯材,选用药品辅材中较为常用的聚乙二醇4000(PEG4000)为包覆壁材,利用SFIT进行包覆实验研究。应用DSC技术或XRD技术对阿莫西林/PEG和尼群地平/PEG微胶囊进行完整性和晶型的检测,并根据国家药典规定,对这两种药物微胶囊进行药物释放实验研究,进一步确定了包覆完整性和释放效果。从微胶囊表面形态、粒径及粒径分布、载药量等方面对这两种药物微胶囊进行了分析和评价；同时考察了混合器内压力、混合器内温度、撞击距离和膨胀前温度等操作参数对微胶囊包覆效果(如表面形态、粒径及粒径分布和载药量等)的影响规律,得到了较为适宜的操作参数。
选用释放速度快、化学性质不稳定、易于分解的维生素类药物维生素C(Vc)为包覆芯材,可完全生物降解、医药制药领域中应用较为广泛的左旋聚乳酸(PLLA)为包覆壁材,利用SFIT进行包覆实验研究。选用XRD技术对Vc/PLLA微胶囊进行了晶体结构检测,并配置缓释溶液对Vc/PLLA微胶囊进行了释放实验,采用紫外-可见分光光度计分析,得到释放曲线；通过考察混合器内压力、混合器内温度、撞击距离和膨胀前温度等操作参数对微胶囊包覆效果(如表面形态、粒径及粒径分布和载药量等)的影响,得到了Vc/PLLA微胶囊制备过程较为适宜的操作参数。
利用PIV测试技术对SFIT流场进行测试实验研究。选择喷嘴出口到撞击区为研究对象,考察了混合器内压力、混合器内温度和撞击距离对轴向速度的影响规律,得到了撞击流流场的速度矢量图。进而描述了SFIT两喷嘴间流场的整体形貌,揭示了各操作参数对撞击流流场的影响规律。
Preparation technology of microcapsules plays a key role in their application. At present, the supercritical fluid technology is usually used to produce the pharmaceutical microcapsules. The representative rapid expansion of supercritical solution (RESS) and supercritical anti-solvent (SAS) methods are able to overcome the drawbacks of the traditional preparation technologies, such as large particle diameters, wide size distributions and serious agglomerations. However, RESS fails in obtaining a uniformly coating, while SAS requires that core material must deposit before wall material.
Herein, we presente a new technology called supercritical fluid impinging technology (SFIT) for the preparation of microcapsule base on previous studies, which involve supercritical fluid process, impinging streams technology and fluidized-bed coating technology. SFIT overcomes the disadvantages of RESS and SAS methods for microcapsule production when taking advantage of combines RESS and fluidized-bed technology. Besides, this method also avoids the restriction of core material's solubility in supercritical fluid, and strengthened the inter-phase mass transfer, which resultes in improving encapsulation efficiency and expanding the scope of micro-particles.
According to the theory of supercritical fluid and impinging stream, we have developed an experimental facility, the corresponding experimental procedure and analysis method, and finally propose a whole set of SFIT. SFIT is investigated by using glass beads as the core material and paraffin as the wall material. The results indicate that the experimental facility satisfies the requirement of SFIT experiment completely, and the microcapsules are produced with good integrity. Furthermore, the effects of main operating parameters, such as pressure of the mixing vessel, temperature of the mixing vessel and impinging distances on the encapsulation like surface morphology, average particle size and apparent encapsulation efficiency are investigated, and thereby the optimize operating parameters are obtained.
SFIT is further investigated by using pharmaceutical microcapsules. Amoxicillin as antibiotic medicine with a short half—life period and nitrendipine as hypotensive drug are chosen as the core materials, and PEG4000is chosen as the wall material. The integrity and crystal morphology of the amoxicillin/PEG4000and nitrendipine/PEG4000microcapsules obtaine by SFIT is tested with DSC and XRD. According to the requirements of the China Pharmacopoeia committee, the experimental study on drug release is also conducted to examine the coating integrity and drug releasing ability. In addition, this study dealt with the influence of different parameters such as pressure of the mixing vessel, temperature of the mixing vessel, impinging distance and pre-temperature on the morphology, particle size and size distribution, and drug loading capacity. The optimized operating parameters are thereby obtained.
SFIT is also investigated using another pharmaceutical microcapsule. Vitamin C which is fast releasing, chemically unstable and easy to degrade is selected as the core material, and PLLA which is biodegradable and popular in pharmaceutical field is selected as the wall material. The Vc/PLLA microcapsule obtains by SFIT is valuated with XRD. The sustained-release experiment is conducted using a buffer solution, and the corresponding drug release rate is obtained by UV-visible spectrophotometer. In addition, the effects of different parameters such as pressure of the mixing vessel, temperature of the mixing vessel, impinging distance and pre-temperature on the characteristics such as the morphology, particle size and size distribution, and drug loading capacity of microcapsules are investigated, and thereby the optimized operating parameters for VC/PLLA microcapsule producing process are obtained.
The flow field in SFIT process is studied with PIV. The area from the jet outlet to the impinging surface is selected to be the research zone.The effects of operating parameters such as pressure of the mixing vessel, temperature in the mixing vessel and impinging distance on the axial velocity are studied. Thus, the velocity vector diagram and the regular pattern how the parameters affect the flow fields are obtained.
在总结前人研究的基础上,本论文将超临界流体过程、撞击流和流化床技术相结合,提出了一种新的制备微胶囊技术—超临界撞击流技术(SFIT)。该技术既弥补了RESS法和SAS法制备药物微胶囊的不足,又承接了RESS结合流化床技术制备微胶囊过程的优点,解决了芯材在超临界流体中受溶解度限制的问题,强化了流场中相间的传递过程,使得微胶囊的包覆效率得到了显著提高,药物的适用范围得到了扩大。
根据超临界撞击流技术原理,本论文建立了实验装置、实验程序与步骤以及分析测试手段,形成了一整套超临界撞击流实验技术。以玻璃微珠为包覆芯材、石蜡为包覆壁材,利用SFIT进行了制备微胶囊的模型实验研究,并对制得的微胶囊进行了表征和评价。结果表明,论文设计建立的实验装置完全满足SFIT实验要求,并且制备出的微胶囊具有良好的完整性,同时确定了主要操作参数(如混合器内压力、混合器内温度、撞击距离和膨胀前温度等)对微胶囊包覆效果(如微胶囊表面形态、粒径及粒径分布、表观包覆率等)的影响规律,并得到了较为适宜的操作参数。
研究选用半衰期较短的抗生素类药物阿莫西林和生物利用度较低的降血压类药物尼群地平为包覆芯材,选用药品辅材中较为常用的聚乙二醇4000(PEG4000)为包覆壁材,利用SFIT进行包覆实验研究。应用DSC技术或XRD技术对阿莫西林/PEG和尼群地平/PEG微胶囊进行完整性和晶型的检测,并根据国家药典规定,对这两种药物微胶囊进行药物释放实验研究,进一步确定了包覆完整性和释放效果。从微胶囊表面形态、粒径及粒径分布、载药量等方面对这两种药物微胶囊进行了分析和评价；同时考察了混合器内压力、混合器内温度、撞击距离和膨胀前温度等操作参数对微胶囊包覆效果(如表面形态、粒径及粒径分布和载药量等)的影响规律,得到了较为适宜的操作参数。
选用释放速度快、化学性质不稳定、易于分解的维生素类药物维生素C(Vc)为包覆芯材,可完全生物降解、医药制药领域中应用较为广泛的左旋聚乳酸(PLLA)为包覆壁材,利用SFIT进行包覆实验研究。选用XRD技术对Vc/PLLA微胶囊进行了晶体结构检测,并配置缓释溶液对Vc/PLLA微胶囊进行了释放实验,采用紫外-可见分光光度计分析,得到释放曲线；通过考察混合器内压力、混合器内温度、撞击距离和膨胀前温度等操作参数对微胶囊包覆效果(如表面形态、粒径及粒径分布和载药量等)的影响,得到了Vc/PLLA微胶囊制备过程较为适宜的操作参数。
利用PIV测试技术对SFIT流场进行测试实验研究。选择喷嘴出口到撞击区为研究对象,考察了混合器内压力、混合器内温度和撞击距离对轴向速度的影响规律,得到了撞击流流场的速度矢量图。进而描述了SFIT两喷嘴间流场的整体形貌,揭示了各操作参数对撞击流流场的影响规律。
Preparation technology of microcapsules plays a key role in their application. At present, the supercritical fluid technology is usually used to produce the pharmaceutical microcapsules. The representative rapid expansion of supercritical solution (RESS) and supercritical anti-solvent (SAS) methods are able to overcome the drawbacks of the traditional preparation technologies, such as large particle diameters, wide size distributions and serious agglomerations. However, RESS fails in obtaining a uniformly coating, while SAS requires that core material must deposit before wall material.
Herein, we presente a new technology called supercritical fluid impinging technology (SFIT) for the preparation of microcapsule base on previous studies, which involve supercritical fluid process, impinging streams technology and fluidized-bed coating technology. SFIT overcomes the disadvantages of RESS and SAS methods for microcapsule production when taking advantage of combines RESS and fluidized-bed technology. Besides, this method also avoids the restriction of core material's solubility in supercritical fluid, and strengthened the inter-phase mass transfer, which resultes in improving encapsulation efficiency and expanding the scope of micro-particles.
According to the theory of supercritical fluid and impinging stream, we have developed an experimental facility, the corresponding experimental procedure and analysis method, and finally propose a whole set of SFIT. SFIT is investigated by using glass beads as the core material and paraffin as the wall material. The results indicate that the experimental facility satisfies the requirement of SFIT experiment completely, and the microcapsules are produced with good integrity. Furthermore, the effects of main operating parameters, such as pressure of the mixing vessel, temperature of the mixing vessel and impinging distances on the encapsulation like surface morphology, average particle size and apparent encapsulation efficiency are investigated, and thereby the optimize operating parameters are obtained.
SFIT is further investigated by using pharmaceutical microcapsules. Amoxicillin as antibiotic medicine with a short half—life period and nitrendipine as hypotensive drug are chosen as the core materials, and PEG4000is chosen as the wall material. The integrity and crystal morphology of the amoxicillin/PEG4000and nitrendipine/PEG4000microcapsules obtaine by SFIT is tested with DSC and XRD. According to the requirements of the China Pharmacopoeia committee, the experimental study on drug release is also conducted to examine the coating integrity and drug releasing ability. In addition, this study dealt with the influence of different parameters such as pressure of the mixing vessel, temperature of the mixing vessel, impinging distance and pre-temperature on the morphology, particle size and size distribution, and drug loading capacity. The optimized operating parameters are thereby obtained.
SFIT is also investigated using another pharmaceutical microcapsule. Vitamin C which is fast releasing, chemically unstable and easy to degrade is selected as the core material, and PLLA which is biodegradable and popular in pharmaceutical field is selected as the wall material. The Vc/PLLA microcapsule obtains by SFIT is valuated with XRD. The sustained-release experiment is conducted using a buffer solution, and the corresponding drug release rate is obtained by UV-visible spectrophotometer. In addition, the effects of different parameters such as pressure of the mixing vessel, temperature of the mixing vessel, impinging distance and pre-temperature on the characteristics such as the morphology, particle size and size distribution, and drug loading capacity of microcapsules are investigated, and thereby the optimized operating parameters for VC/PLLA microcapsule producing process are obtained.
The flow field in SFIT process is studied with PIV. The area from the jet outlet to the impinging surface is selected to be the research zone.The effects of operating parameters such as pressure of the mixing vessel, temperature in the mixing vessel and impinging distance on the axial velocity are studied. Thus, the velocity vector diagram and the regular pattern how the parameters affect the flow fields are obtained.
引文
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