摘要
本论文选用CO_2作为超临界流体，首先采用气体抗溶剂(GAS)技术对难溶性药物尼莫地平进行微粒化制备，然后将GAS技术与共沉析技术相结合，一步制备得到尼莫地平—聚乙二醇药物载体复合粒子，并对得到的产物粒子分别进行了形貌、粒径及溶出度的考察。
在较宽的温度压力范围内测定了尼莫地平在超临界CO_2中的溶解度，结果表明：在实验考察的范围内，尼莫地平的溶解度较小，摩尔分率在10~(-5)—10~(-6)之间。压力超过一定值时，其溶解度随着压力的增加而增加，在9～12Mpa下，溶解度随温度的变化存在“反向区”。
GAS技术可得到球形度较好的尼莫地平药物微粒。在实验范围内，粒子平均粒径随料液浓度、升压速率的增加而减小，粒子球形度提高，粒径分布变均匀。产物粒子的大小对沉降室压力、沉降室温度的变化均不敏感。
采用GAS共沉析技术制备得到尼莫地平—聚乙二醇6000药物载体复合粒子。实验发现在不同的制备条件下产物粒子出现球形包覆、方形包覆、片状薄膜粘附及不规则粘附等不同形态结构。考察操作参数对粒子大小的影响发现：选用不同溶剂，操作参数对产物粒径的影响不同。乙醇作为溶剂时，药物载体之比的影响较大，产物随载体比例的增长而变大，形态由均匀微球趋于不规则态。沉降室温度升高，产物粒径明显减小。但采用丙酮作为溶剂时粒径对温度变化并不敏感。乙醇或丙酮为溶剂时，产物粒径均随升压速率的增大而明显减小。
对微粒化药物及药物载体复合粒子进行溶出度实验，并与原料药物相对比，结果表明：细化后的药物微粒较原料药物，溶出度有了很大提高。在药物粒子中直接添加载体，可进一步改善药物溶出效果。而GAS共沉析法制备得到的药物载体复合粒子具有最佳的溶出速率，且根据药物与载体的比例不同，溶出速率有差异，在考察的三种药物载体比例(1∶1、1∶5、1∶9)下，药物溶出度随着载体的比例增大而增大。
This work is to prepare the ultrafme particles of Nimodipine (NMD) by GAS (Gas Antisolvent) technique and to prepare the Nimodipine (NMD)-Polyethylene Glycol(PEG6000) particles by GAS copercipition technique.
The solubility of NMD in supercritical CO2 was first measured within a large range of pressure and temperature. The effects of temperature and pressure on the solubility were investigated. It was found that NMD has poor solubility in SC-CO2 and its solubility increases with the increasing of pressure and temperature in certain range. The retrograde area as reported in some literatures was found when pressure was low enough.
In GAS process, NMD particles prepared are generally smaller, more uniform and better morphology than the starting material. Size of particles was found to decrease with the increasing of the solution concentration and the rising rate of pressure. Temperature and pressure of precipitator have no obvious effect on the size of the particles.
NMD-PEG6000 copercipitates could be prepared by GAS process. The change in particles size and morphology of the drug crystals were studied. The copercipatates with different shapes could be obtained under different experiment conditions. When ethanol was selected as solvent, higher PEG-NMD ratio led to more anomalistic particle shape and bigger particle size, and increasing temperature could bring smaller products. However, when acetone was used as solvent, temperature and drug-carrier ratio had little effect on the products. Furthermore, the size of particles decreases obviously when the rising rate of pressure increases with acetone or ethanol.
The dissolution rate of NMD ultrafme particles and NMD-PEG6000 copercipitates prepared were measured. The microparticle products had a better dissolution rate compared to the starting material, and the supporting of drug on a hydrophilic carrier of PEG 6000 enhanced release dosage form farther. NMD-PEG6000 coprecipitates show a remarkable enhancement in drug dissolution rate. It was found that the increasing the amount of carrier can enhance the drug dissolution rate.
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