Potential Transdermal Cancer Treatment Through Blood Brain Barrier with a Crystalline Neratinib Salt
The tyrosine kinase inhibitor Neratinib has demonstrated its efficacy against HER2+ breast cancer metastases as the maleate salt. It has, however, had only a limited success as the maleate acid salt to cross the blood-brain barrier (BBB) due in part to its low oral absorption rate. At high oral doses severe diarrhea occurs. The potential to treat metastasized HER2+ cancer in the cerebellum and spinal cord that effects 30-50% of patients with this condition with a new crystalline salt and a topical application of a dimethyl sulfoxide (DMSO) solution has been investigated. This work proposes to use different Neratinib salts to improve solubility and BBB transport by a transdermal rather than an oral administration protocol. The preparation of the salts is described, and analytical methods developed for LC and LC/MS. The log P coefficient utilizing octanol/buffered water, shake flask method, will be used as a predictor of potential improvement in BBB transfer due to increased lipophilicity. Solubility data is supplied. An extensive review of DMSO and BBB experiments was undertaken leading to the establishment of rules to make this methodology work. First, a log P in the range of 2-4 is essential. Second, amine functions have to be blocked with suitable salts. If an amine function is present, it will be trapped by the endothelial membrane. DMSO has a well-documented favorable toxicological profile and can be sterilized making it safe for oral and parenteral routes. A transdermal protocol using Neratinib succinate in 20/20/60: H2O/EtOH/DMSO is described with all the safety measures presented.
DOI: 10.29245/2578-2967/2022/1.1197 View / Download Pdf