| Objective:To discover the emulsification application in microparticle drug delivery system using SPG elmusification in preparing tetrandrine microspheres targeting toward lungs. Tetrandrine(Tet), known as tetrandine, was extracted from radix stephaniae Tetrandrae, which was one of two segments base isopropyl kinds alkaloid, and its pharmacology was very widespread. Nowadays, it becomes a hot topic of research on lung cancer treatment. But the Tet was insoluble in fulid in vivo, which resulted in its bioavailability low orally, and its unstable effect. The normal Tet caused its distribution untargeting in vivo after injection, which lead to its widespread of pharmacology, difficult to reach the safe and effect of drugs requirements, therefore, its side effects were large. In order to deal with these problems, the Tet was prepared in microspheres, that had targeting and controlled-releasing characteristics, which can target towards the specific organ. However, the particles diameter of the microspheres were all controllable and the preparations batches of its repeatability all were inter-related with bioavailability, thus, the traditional preparations such as homogenization emulsification, ultrasonic emulsification etc. on particles diameter sizes of the microspheres and that of their distributions were all uncontrollable. In order to solve these problems, we have used SPG emulsifications to control emulsion particles diameter sizes and its uniformity, and it can enhance the repeatability of the preparations microspheres, in vitro drug releasing, and in vivo efficacy batches of among its repeatability, which can control the particles diameter sizes between the range of2μm～10μm targeting towards the lungs. SPG membrane is vitreous with a small phase separation made from glassy volcanic ash after sintering by southern kyushu, Japan. The chemical ingredients are CaO-Al2O3-SiO2, then acid is used to remove the soluble CaO and B2O3. Finally it can be formatted the uniform microporous structure of materials of Al2O3-SiO2skeleton, and processed into certain thickness and shape. The materials at last can be known as SPG membrane.Methods: The SPG emulsification was used to prepare the blank microspheres, the elmusification pressure, the peristaltic pumping flow rate and the HLB etc. were selected as single factor to be discovered. Upon the single factor discovered and pre-experiment basis, the polylactic acid (PLA) was used as capsule-loading materials, the orthogonal test was prepared. Tet-PLA microspheres targeting toward lungs with various of characterization techniques that were used to screen the formulation and the preparation process, lightning-microscope, scan-electro microscope etc were used to discover the microspheres morphology; grain size-analyzer was used to analysis the particles diameter sizes ant its distribution; UV was used to analysis the microspheres encapsulation efficiency and drugs loading dosage. From the best preparation process to prepare the Tet-PLA microspheres to do the first investigation of the stability, dialysis method was being used to discover the microspheres in vitro drugs-releasing. The Tet solution was performed as control-group to do the organ distribution of research and targeting evaluation.Results:The factors influenced of preparation Tet-PLA microspheres were large, the factors of emulsification pressure, peristalsis pump flow and HLB value of emulsifier were investigated by single factor analysis. The result showed that average particle diameters, distribution and membrane flux were influenced by emulsification pressure mainly. The particle diameters increased as the emulsification pressure enhanced; the droplet size decreased as the flow of continuous phase increased when the pressure was0.06Mpa, but the particle diameters was changed little, and the membrane flux was influenced by the flow of continuous phase little; the average particle diameters decreased as the HLB value increased, but membrane flux changed little; the microsphere surface changed rounder as the concentration of PLA increased, and the membrane flux decreased meanwhile. The particle diameters and distribution was changed little; Morphology of microspheres was influenced by the oil-water phase proportion little, and the microsphere was so round. The average particle diameters increased and the distribution of particle diameters was broadened as the volume of continuous phase increased.SPG membrane was used to prepare the Tet-PLA microsphere, and orthogonal experiment was done to optimize the best condition. The results showed that the average of drug load rate was12.2%, entrapment efficiency was81%, the span value was0.67, MV was3.16μm, all that indicated that the distribution was very average and had no difference. The average of microsphere of Tet-PLA was3.16μm, which was accordance with lung intake. Therefore, intravenous injection was done to make the Tet-PLA microsphere targeting toward lung.The preliminary stability of freeze-dried powder of microsphere was investigated, and found that the best storage condition of Tet-PLA was in-20℃or4℃. On that condition, Drug load rate, entrapment efficiency and appearance characters had changed little-appearance of Tet-PLA was white and pine appearance solid powers which had the good characteristics of dispersion.The in vitro release profiles expressed by the model of zero order, one order, Higuchi and Ritger-Peppas, and found that the release profiles was followed by the model of one order and Higuchi better. The results above illustrated that the in vitro release profiles of microspheres were mixed. The mechanism of release was resulted from the combination of PLA polymers degradation dissolution and diffusion.Compared with distribution of Tet between solution and microsphere, it was shown that the concentration Tet microsphere was higher than that in other organs, but the concentration of Tet solution was no significance in different organs. The targeting evaluation TQe value was shown that the lung distribution concentration Tet solution was6.97%of totally, but the concentration of Tet microsphere was89.69%of totally.Conclusion:SPG membrane emulsification is the new technology to prepare microspheres, and can be used to prepare the microspheres targeting toward lung owning characteristics of equal and regulative diameter, controllable, high entrapment efficiency and character stability meanwhile. The microspheres could increase the concentration of Tet in lung and maintain it sustained release in lung. It could improve the efficacy of Tet in lung cancer treatment. Up to now, the research is new, without any report at home and abroad. The results also provide a more efficiency drug delivery system of Tet, and a new example and method for applying TDDS technology to traditional Chinese medicine. |
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