Dokument

Summary:
In the present work, the NC of three poorly water-soluble antioxidants, BI-6C9, hesperetin and rutin, were prepared, characterized, and tested in suitable cell culture models. In addition, the production was optimized to obtain tailor-made NC for the treatment of oxidative stress-related diseases. These should be formulated to increase the solubility and thus bioavailability of the antioxidants used, while meeting the requirements of different administration routes regarding particle size, physical stability, and the final formulation. The synthesized compound, BI-6C9, was aimed to be converted into a formulation suitable for i.v. application in a resource-saving manner. This was successfully realized by using a small scale BM process in a batch size of 2 mL. A time and resource-saving pre-screening of four stabilizers (SDS, PLC, Tween 80, Span 20) was performed by microscopy, where SDS was identified to be the most suitable stabilizer. Then, BI-6C9 was successfully converted to NC with an average particle size of about 600 nm applying a milling time of 24 h. However, only the stabilizer Tween 80 is approved as save for intracortical or intracerebral application. By optimizing the milling time to 90 h, a Tween 80-stabilized nanosuspension was successfully produced and comparable to the SDS formulation regarding particle size and stability over seven days of storage. Also, in a cell culture model of oxidative stress-induced neuronal cell death, both nanosuspensions showed the same protective dose-response curve as a BI-6C9 solution in DMSO. This means that both NC formulations have reached their highest pharmacological efficacy because a formulation cannot become more effective than its solution. In addition, as an advantage, no harmful solvents were used for the cell culture studies and, especially, for a possible in-vivo application. By optimizing the preparation and stabilization with Tween 80 and SDS, tailor-made i.v. or orally applicable NC formulations were successfully developed for the treatment of neuronal oxidative stress.

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