The Potential Synergistic Activity of Zolmitriptan Combined in New Self-Nanoemulsifying Drug Delivery Systems: ATR-FTIR Real-Time Fast Dissolution Monitoring and Pharmacodynamic Assessment

Abstract

Purpose The current work aimed to overcome the poor permeability and undesirable adverse effects of Zolmitriptan (ZMT) and to increase its efficacy in the treatment of acute migraine by exploiting the synergistic effect of the essential oil, lavender, to fabricate ZMT self-nanoemulsifying drug delivery systems (ZMT-SNEDDS). Methods ZMT-SNEDDS were fabricated based on full factorial design (3 2 ) to statistically assess the impact of oil and surfactant concentrations on the nanoemulsion globule size, zeta potential and percentage drug dissolution efficiency. An ATR-FTIR method was developed and validated for continuous real-time monitoring of ZMT dissolution and permeation. The dose of the optimized ZMT-SNEDDS used in the efficacy study was selected according to the acute toxicity study. The efficacy study was performed on migraineous rats induced by nitroglycerin and was evaluated by the activity cage and thermal tests, electroencephalogram, electroconvulsive stimulation, and biochemical analysis of brain tissue. Finally, histopathological and immunohistochemical examinations of the cerebra were carried out. Results Upon dilution, the optimized ZMT-SNEDDS (F5) exhibited nanosized spherical droplets of 19.59±0.17 nm with narrow size distribution, zeta potential (−23.5±1.17mV) and rapid emulsification characteristics. ATR-FTIR spectra elucidated the complete time course of dissolution and permeation, confirming F5 superior performance. Moreover, ZMT-SNEDDS (F5) showed safety in an acute toxicity study. ZMT concentration in rat brain tissues derived from F5 was lower compared to that of ZMT solution, yet its effect was better on the psychological state, algesia, as well as maintaining normal brain electrical activity and delayed convulsions. It counteracted the cerebral biochemical alternations induced by nitroglycerin, which was confirmed by histopathological examination. Conclusion In a nutshell, these findings corroborated the remarkable synergistic efficacy and the high potency of lavender oil-based ZMT-SNEDDS in migraine management compared to the traditional zolmitriptan solution.

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration

“…A small number of SEDDS-based products have already been successfully introduced into the pharmaceutical market, with none of them loading drugs for the treatment of neurological disorders. Until now, several in vivo assays using oral SEDDS have been carried out for neuropharmaceuticals brain targeting [ 4 , 6 , 23 , 24 , 25 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 70 ], but only a few in vivo pre-clinical studies have been reported for IN administration of neurotherapeutics loaded in SEDDS. In fact, only six studies were found that investigated the IN administration of neurotherapeutics loaded in SEDDS: clonazepam [ 45 ], diazepam [ 44 ], and perampanel [ 28 ] for epilepsy treatment; Bdph for glioblastoma treatment [ 4 ]; huperzine A [ 30 ] for Alzheimer’s disease; and naringin [ 5 ] as a neuroprotective for Alzheimer’s and Parkinson’s disease.…”

“…In Table 2 , it can also be observed that the majority of the here-reviewed compounds belong to BCS class II or IV, similar to most chemical entities investigated to treat neurological disorders [ 6 , 7 ]. Only zolmitriptan [ 46 ], ginsenoside Rg1 [ 47 ], and chlorogenic acid [ 48 ] are reported to belong to BCS class III.…”

“…Still, the same efficacy in treating status epilepticus could be achieved, since AUC brain /AUC plasma ratios after nasal and IV administrations to rats were similar ( Table 2 ) [ 44 ]. Abd El-Halim et al [ 46 ] also reported lower zolmitriptan brain concentrations using a SNEDDS when compared with an oral solution. Still, physiological state and algesia, maintaining normal brain activity, were attained after oral administration of SNEDDS, reaching the same therapeutic efficacy with lower brain concentrations [ 46 ].…”

“…Abd El-Halim et al [ 46 ] also reported lower zolmitriptan brain concentrations using a SNEDDS when compared with an oral solution. Still, physiological state and algesia, maintaining normal brain activity, were attained after oral administration of SNEDDS, reaching the same therapeutic efficacy with lower brain concentrations [ 46 ]. After IN administration, Meirinho et al [ 28 ] and Nagaraja et al [ 5 ] demonstrated, respectively, an increase in perampanel and naringin plasmatic and brain C max and AUC 0-t , compared with the corresponding suspensions.…”

Design and optimization of cranberry extract loaded bile salt augmented liposomes for targeting of MCP-1/STAT3/VEGF signaling pathway in DMN-intoxicated liver in rats

“…The mean VS, PDI, and ZP of the various fabricated CBE loaded BSALs were examined using Malvern Zetasizer (Abd El-Halim et al., 2021 ).…”