Effect of Nonionic Surfactants and HPMC F4M On the Development of Formulations of Neuro-epo As A Neuroprotective Agent - Effect of Nonionic Surfactants and HPMC F4M On the Development of Formulations of Neuro-epo As A Neuroprotective Agent - Open Access Pub

The purpose of this study was to investigate the effect of cremophor RH-40 and polysorbate 80 with hydroxypropyl methylcellulose (HPMC) F4M on the development of formulations of intranasal erythropoietin with low sialic acid content (Neuro-EPO) as a neuroprotective agent. Parameters such as pH, osmolality, apparent viscosity, and protein concentration were controlled for minimizing the differences between formulations. All Neuro-EPO formulations showed similar behaviour in the physicochemistry quality control. However significant differences between formulations were observed in the permanent unilateral ischemia model. The formulations and the vehicles containing cremophor RH-40 showed higher neurotoxicity levels than those containing polysorbate 80 as a nonionic surfactant. Formulations containing HPMC F4M at 0.6% as a bioadhesive polymer showed higher levels of survival and better neurological status than those without the polymer. The formulations with polysorbate 80 and HPMC F4M showed a higher index of survival, smaller incidence of clinical signs of stroke, and similar behavior in the learning and the memory to the false injured animals used as control. These findings suggest that the intranasal pathway constitutes a safe and alternative route of access of the Neuro-EPO to the brain. DOI10.14302/issn.2328-0182.japst-13-206 The neuroprotective effect of recombinant human erythropoietin (rHu-EPO) administered intravenously (IV) in many preclinical studies showed reduction of injury caused by ischemic stroke 1, 2, 3. Similar effect occurs in humans 4, 5. However, clinical and experimental results show a high risk of cardiovascular complications by induction of erythropoiesis 6. When sialic acid content is less than 9 sialic acid molecules per molecule protein, is considered a low sialic acid erythropoietin, and is identified like Neuro-EPO, is normally eliminated, since it is not biologically active by the systemic route7, 8. Surprisingly, it has been found that intranasal (IN) administration of Neuro-EPO has higher therapeutic values than the traditional rHu-EPO 9, 10. The non-hematopoietic derivatives of rHu-EPO and the intranasal route are the most promising perspectives for the treatment of acute and chronic neurological diseases 11, 12. The rate and capacity of drug transport from the nasal cavity to the brain depends primarily on its physicochemical properties. For high-molecular-weight drugs such as rHu-EPO, IN pharmacokinetics exhibit relatively low bioavailability (less of 1%) and relatively high variability compared to IV 13, 14. This can