Nose to brain delivery of melatonin lipidic nanocapsules as a promising post-ischemic neuroprotective therapeutic modality.

Ischemic stroke accounts for about 87% of all strokes, causing long-term disability in adults, and is the second leading cause of death worldwide. In search of new therapeutic modalities, the use of neuroprotective agents loaded in nanocarriers to be delivered by noninvasive means (i.e. via intranasal route) became a popular approach. In the current study, melatonin (MEL) was loaded in lipidic nanocapsules (LNCs) prepared using the phase inversion method, and characterized in terms of size, polydispersity, zeta potential, in vitro drug release, viscosity, storage stability, and ex vivo permeation across sheep nasal mucosa. Moreover, MEL-LNCs were tested for efficacy in cerebral ischemia/reperfusion (I/R/) injury model through histopathological assessment, and analysis of oxidative stress markers, pro-inflammatory cytokines, and apoptotic markers. Results showed that LNCs exhibited particle size ranging from 18.26 to 109.8 nm, negative zeta potential, good storage stability, spherical morphology, and a burst release followed by a sustained release pattern. LNCs exhibited 10.35 folds higher permeation of MEL than the drug solution across sheep nasal mucosa. Post-ischemic intranasal administration of MEL-LNCs revealed lowering of oxidative stress manifested by a decrease in malondialdehyde levels, and elevation of glutathione and superoxide dismutase levels, lowering of the inflammatory markers tumor necrosis factor-α, NO, myeloperoxidase, and significant inhibition of Caspase-3 activity as an apoptotic marker. Western blot analysis delineated a recovery of protein expression Nrf-2 and HO-1 with downregulation in the parent inflammatory markers nuclear factor kappa B p65, inducible nitric oxide synthase, Bax, and Cytochrome C expressions, and upregulation of B-cell lymphoma-2 Bcl-2, hence promoting neuronal survival. This was supported by histological evidence, revealing significant restoration of hippocampal neurons. In light of the above, it can be concluded that MEL-LNCs could be a promising delivery system for nose to brain delivery for treatment of cerebral ischemia.

Intranasally administered melatonin core-shell polymeric nanocapsules: A promising treatment modality for cerebral ischemia.

AIMS: The neurohormone melatonin (MEL) has been reported as a promising neuroprotective molecule, however it suffers pharmaceutical limitations such as poor solubility and low bioavailability, which hinder its pharmacological and clinical potential. In the current work, MEL was loaded in core-shell nanocarrier system; polymeric nanocapsules (PNCs), and assessed for its potential in cerebral ischemia reperfusion injury rat model when administered intranasally. KEY FINDINGS: Adopting a D-optimal factorial design, MEL-PNCs were successfully formulated using the nanoprecipitation technique. MEL-PNCs exhibited a particle size ranging from 143.5 to 444 nm, negative zeta potential values ranging from -24.2 to -38.7 mV, cumulative release % for MEL ranging from 36.79 to 41.31 % over 8 h period, with overall good storage properties. The selected MEL-PNCs formulation displayed 8-fold higher permeation than the drug solution across sheep nasal mucosa. MEL-PNCs administered intranasally decreased oxidative stress and hippocampal inflammation, and the histological examination revealed the significant restoration of hippocampal neurons. SIGNIFICANCE: MEL-PNCs administered intranasally could be a promising treatment modality in brain ischemia.

Novel nail penetration enhancer containing vesicles "nPEVs" for treatment of onychomycosis.

CONTEXT: The systemic treatment of onychomycosis has been hampered by the reported side effects of antifungals in addition to the limited blood circulation to the affected nails. Topical ungual treatment would circumvent the limitations of systemic onychomycosis treatment. OBJECTIVE: Preparation and characterization of nail penetration enhancer containing nanovesicles (nPEVs) loaded with sertaconazole for topical treatment of onychomycosis. MATERIALS AND METHODS: nPEVs were prepared using different nail penetration enhancers (N-acetyl-L-cysteine, thioglycolic acid, thiourea and ethanol) by the thin film hydration method, and characterized for their particle size, zeta potential, entrapment efficiency (EE%), elasticity, viscosity, physical stability and morphology. The selected nPEVs formula and the marketed Dermofix® cream were compared in terms of nail hydration, transungual drug uptake and antifungal activity against Trichophyton rubrum. RESULTS: N-acetyl-l-cysteine was the optimum nail penetration enhancer for incorporation within vesicles. nPEVs showed high EE% of sertaconazole ranging from 77 to 95%, a size ranging from 38-538 nm and a zeta potential ranging from +48 to +72 mV. The selected nPEVs formula displayed spherical morphology and good storage stability. Compared to the conventional marketed cream, the selected nPEVs formula showed 1.4-folds higher hydration and drug uptake enhancement into nail clippings. Furthermore, it showed significantly higher zone of inhibition for Trichophyton rubrum (20.9 ± 0.25 mm) than the marketed cream (11.6 ± 0.44 mm). CONCLUSION: Nail penetration enhancer containing nanovesicles (nPEVs) present a very promising option, worthy of clinical experimentation on onychomycotic patients.