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Optimization of solid structural properties of freeze-dried pharmaceutics by freezing process control with ultrasound devices.

通过超声装置冷冻过程控制优化冻干药物的固体结构特性。

基本信息

批准号：
19780102
负责人：
NAKAGAWA Kyuya
金额：
$ 2.43万
依托单位：
University of Hyogo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

项目摘要

This research work on optimization of pharmaceutical freeze-drying process was to investigate solid structural properties that form in the cryo-concentrated phase during freezing. The results from mannitol freeze-drying test concluded that the crystalline structures (polymorphs) were heterogeneously distributed in the dried bulk dependent to its freezing condition. When we add a model protein (enzyme, lactic acid dehydrogenase was employed) in the starting formulation, the enzymatic activity in the freeze-dried bulk was also heterogeneously distributed. It was clearly suggested that the activity variances were due to the structural property variances of the lyoprotectant. We thus had an attempt to stabilize the freeze-dried enzyme activity simply by the process operation, that is, freezing process. It was found that the ultrasound device that can control the ice nucleation event was useful to control thermal history of the solution during freezing, and to control the solid structure of crystalline substances. However, it was not so much effective to control the solid structure in the solution with lyoprotectant. Nevertheless, kinetics of the structural change (such as sol-gel transition) of the lyoprotectant was supposed to be a crucial factor to stabilize protein. A substance that exhibits gelling feature was thus employed as a lyoprotectant. As a matter of fact, we found that the cooling protocol and the sol-gel transition kinetics were strongly correlated to the protein activities. These results indicate that the stability (or activity) of freeze-dried protein pharmaceutics is to be controlled simply by thermal protocols that controls structural characteristics of solid substances during freezing.

本研究的目的是研究药物冷冻干燥过程中在冷冻浓缩阶段形成的固体结构特性。甘露醇冷冻干燥试验结果表明，甘露醇的晶体结构（多晶）在干燥体中呈非均匀分布，这取决于其冷冻条件。当我们在起始配方中添加模型蛋白（酶，乳酸脱氢酶）时，冻干散装中的酶活性也呈非均匀分布。结果表明，活性差异是由lyo保护剂的结构性质差异引起的。因此，我们试图通过简单的工艺操作，即冷冻过程来稳定冻干酶的活性。研究发现，控制冰核事件的超声装置可用于控制溶液在冻结过程中的热历史，以及控制结晶物质的固体结构。而lyo保护剂对溶液中固相结构的控制效果不明显。然而，lyoprotectant的结构变化动力学（如溶胶-凝胶转变）被认为是稳定蛋白质的关键因素。因此，一种具有胶凝特性的物质被用作冻干保护剂。事实上，我们发现冷却方案和溶胶-凝胶转变动力学与蛋白质活性密切相关。这些结果表明，冻干蛋白质制剂的稳定性（或活性）可以通过控制固体物质在冷冻过程中的结构特征的热协议来控制。