【作者】 蒋茂星；

【导师】 李军；

【作者基本信息】 厦门大学 ， 化学工程， 2008， 硕士

【摘要】 超临界流体（SCF）技术已经在许多领域获得了重要的进展。利用SCF的高膨胀能力、对有机溶剂的萃取能力,SCF技术可应用于对各种物质进行微粒化及其微囊化（或复合微粒化）;利用其性质对温度和压力的敏感性,可以调节这些操作条件来控制所得微粒的形貌、粒径大小和分布;另外,SCF技术尤其对热敏感、结构不稳定和具有生物活性的物系的微粒化或微囊化具有明显优势。课题组和国外合作提出了超临界流体抗溶剂-雾化SAS-A（supercritical anti-solvent atomization）技术,该技术以SEDS（solution enhanccd dispersion by supcrcdtical fluids）和PGSS（particle formation fromgas-saturated solution）为基础,能处理含水体系。首先计算了实验体系所涉及的二元和三元系统高压下液相体积膨胀率。用t-mPR状态方程（EoS）对CO₂+丙酮、CO₂+乙醇二元体系和CO₂+乙醇+水三元体系的高压汽液平衡（VLE）进行计算,并与课题组之前采用PR-EoS得到的结果进行比较。结果表明t-mPR EoS可以对这些体系的VLE取得较好的计算效果。进一步对上述体系的液相体积膨胀率进行预测,t-mPR EoS对二元体系预测结果比PR-EoS的预测结果的精度有所提高,对三元体系的预测表明其在7.8MPa左右能更好地反映实验现象。另外,计算还表明:CO₂+丙酮体系的体积膨胀率要远远大于CO₂+乙醇体系;对CO₂+乙醇+水三元体系的体积膨胀率在7.8MPa左右有一个最大值,提高乙醇在乙醇/水溶液中的摩尔分数,可以提高该溶液的最大体积膨胀率。以SAS-A技术研究从乙醇、丙酮及乙醇/水中制备聚乙二醇（PEG）微粒。探讨预膨胀压力、溶液浓度和溶液流量等工艺参数对所制备的PEG微粒形态及粒径的影响;重点讨论不同溶剂对颗粒形态和粒径分布的影响。结果表明,制备得到的PEG微粒基本上为球形,利用丙酮和乙醇,粒径分布分别可以控制在1-5μm和2-15μm之间;增大预膨胀压力容易得到分散的球形微粒,并能减小其粒径,粒径分布也随之变窄;对应PEG/丙酮体系,溶液浓度升高,所得到的微粒粒径增大;对应PEG/乙醇体系,溶液浓度对粒径大小影响不大,但溶液浓度增大会使粒径分布变宽;采用乙醇水溶液为溶剂时,初始乙醇浓度越低,移出水的效果越差,易形成结块的不规则微粒。以SAS-A技术研究从胰岛素/乙醇/水溶液中制备胰岛素微粒。探讨各种操作参数对微粒形态、平均粒径和胰岛素活性的影响。在各种操作条件下制备的胰岛素产品均为球形微粒,粒径分布主要在0.1-1.5μm之间。操作压力在8MPa左右有良好的水移除能力,进一步增大压力会使所得微粒倾向于团聚。通过改变操作条件可以有效地控制微粒的形态和大小:降低溶液流量会使微粒变小,粒径分布变窄,但是流量低于2ml/min时,倾向于生成不规则颗粒;在所选的胰岛素浓度范围内,增大浓度可以使微粒粒径变小,粒径分布也随之变窄;乙醇浓度对微粒形态和大小影响不大,但是对胰岛素活性的起主要影响作用,乙醇浓度越高,胰岛素活性损失越大;其它操作条件的改变对胰岛素活性的影响不明显,活性均保持在90%以上。FTIR与DTA的测试结果表明,胰岛素活性丧失与其二级结构的变化有关,即β-折叠的增强和α螺旋的减小。以SAS-A技术研究制备PEG/胰岛素复合微粒;改进的SAS-A技术流程研究制备三棕榈酸甘油酯/胰岛素复合微粒。探讨工艺参数和操作条件对微粒形貌、粒径大小、分布的影响。进行复合微粒的胰岛素的溶出（控释）实验,研究复合微粒中蛋白质和载体的结合情况、控释情况。研究表明,不同条件下所得PEG/胰岛素复合微粒为近球形,该复合微粒的控释实验说明其中PEG和胰岛素的结合良好。研究表明,不同温度条件下得到的三棕榈酸甘油酯/胰岛素复合微粒形态不同:45℃时得到块状附着有小球颗粒,50℃时得到较为特殊的菊花状颗粒;该复合微粒的控释实验表明:45℃时得到的复合微粒仍然存在突释,前一分钟的胰岛素释放量达到了36%,50℃时得到的复合微粒有很好的控释效果,完全没有突释现象。更多还原

【Abstract】 Supercritical fluid（SCF） technology has been widely applied to various areas,and very important progress has been achieved.Among the applications,particle formation or encapsulation with assistance of SCF by using its high solvency power and expansion ability to lots of solvents is a hot research topic in recent decades.It is possible to control the morphology,particle size（PS）,and particle size distribution（PSD） for the produced products due to the sensitivity of SCF to the operating temperature and pressure. Furthermore,it is also available for the formulation of those materials such as active substances,thermosensitive substances,which usually cannot be processed by conventional methods.In this thesis,supercritical anti-solvent atomization（SAS-A）,which is a combination of SEDS（solution enhanced dispersion by supercritical fluids） and PGSS （particle formation from gas-saturated solution）,was employed to study the precipitation of polyethylene glycol 6000（PEG） and insulin microparticles,as well as PEG/insulin and tripalmitin/insulin composite mieroparticles.Prior to the particle formation study,the volume expansion of the liquid phases for the CO₂/acetone and CO₂/ethanol binary systems and the CO₂/ethanol/water ternary system was investigated using the t-mPR equations of state（t-mPR EoS） and the PR equations of state（PR-EoS）.The correlations for the published vapor-liquid equilibrium（VLE） data of the above systems show that both the EoS can provide fairly good VLE calculations for the binary systems,but t-mPR EoS gives slightly better results.The volume expansion prediction for the above systems and the comparison with the published data show that, compared to PR-EoS,t-mPR EoS gives better results for the binary systems but worse results for the ternary system,but provides more reasonable results around 7.8MPa. Moreover,the calculations indicate that the volume expansion of the CO₂/acetone system is always larger than that of the CO₂/ethanol system.The volume expansion of the ternary system shows a maximum point corresponding to about the CO₂/ethanol mixture’s critical pressure（about 7.8MPa）;increase in the content of ethanol can improve the maximun volume expansion and therefore help to enhance the removal of water.The SAS-A process was applied to the generation of PEG microparticles from different solvents（acetone,ethanol,and ethanol/water）.The effect of the processing conditions,including operating pressure,PEG concentration,and solution flow rate,on the morphology and size of the produced PEG particles was investigated,especially,the influence of using different solvents was evaluated.The PEG particles produced by using acetone and ethanol are generally spherical with sizes of 1-5μm and 2-15μm,respectively. A high pre-expansion pressure can produce spherical and discrete particles with relatively small size and narrow size distribution.Increasing the PEG concentration in acetone can evidently increase the PEG particle sizes and widen the PSD for the PEG/acetone system, while increasing the PEG concentration can slightly widen the PSD,but has little effect on the PEG particle sizes for the PEG/ethanol system in the studied concentration range. Decreasing the content of ethanol in the ethanol/water solution can generate irregular and agglomerated particles due to the difficulty of water removal.The SAS-A process was employed to produce insulin particles from its ethanol/water solutions at 45℃.The effect of the operating conditions on the morphology,size and bioactivity of the produced insulin particles was evaluated.The formed primary particles are spherical and discrete with sizes of 0.1-1.5μm.The loss of the activity of the insulin particles depends on the ethanol content in the solution;other operating conditions show little effect on the insulin particles’ activity.It is possible to produce insulin microparticles with almost no loss of its bioactivity by the SAS-A process at low ethanol content（less than 40%in mass）.The FTIR and DTA analyses compared to that of the unprocessed insulin confirm that the changes in the content ofα-helix andβ-sheet decrease the protein activity.Finally,the SAS-A process was employed to produce PEG/insulin composite microparticles,and a modified SAS-A process was employed to produce tripalmitin/insulin composite microparticles.The effects of different cartier materials,different ratios of carrier/insulin on the particle morphology and PSD and the insulin release from the produced composites were examined.Good combination of insulin to PEG in spherical composites is indicated on the basis of the insulin release from the PEG/insulin composite. Initial burst completely disappears for the insulin release from the tripalmitin/insulin composite particles（particles like flowers） produced at 50℃by the modified SAS-A process,while the intial burst is still high（36%in 1 min） for the tripalmitin/insulin composite particles（large particles attached with spheres） obtained at 45℃.更多还原