Abstract
This study aimed at delivering intranasal zolmitriptan directly to the brain through preparation of bilosomes incorporated into a mucoadhesive in situ gel with extended nasal mucociliary transit time. Zolmitriptan-loaded bilosomes were constructed through a thin film hydration method applying Box–Behnken design. The independent variables were amount of sodium deoxycholate and the amount and molar ratio of cholesterol/Span® 40 mixture. Bilosomes were assessed for their entrapment efficiency, particle size and in vitro release. The optimal bilosomes were loaded into mucoadhesive in situ gel consisting of poloxamer 407 and hydroxypropyl methylcellulose. The systemic and brain kinetics of Zolmitriptan were evaluated in rats by comparing intranasal administration of prepared gel to an IV solution. Statistical analysis suggested an optimized bilosomal formulation composition of sodium deoxycholate (5 mg) with an amount and molar ratio of cholesterol/Span® 40 mixture of 255 mg and 1:7.7, respectively. The mucoadhesive in situ gel containing bilosomal formulation had a sol-gel temperature of 34.03 °C and an extended mucociliary transit time of 22.36 min. The gelling system possessed enhanced brain bioavailability compared to bilosomal dispersion (1176.98 vs. 835.77%, respectively) following intranasal administration. The gel revealed successful brain targeting with improved drug targeting efficiency and direct transport percentage indices. The intranasal delivery of mucoadhesive in situ gel containing zolmitriptan-loaded bilosomes offered direct nose-to-brain drug targeting with enhanced brain bioavailability.
Highlights
Migraine is the most abundant type of neurological disorder; coupled with atypical serotonergic activity [1,2], it is considered the second major cause of disability, especially among young people [3]
In order to choose a suitable surfactant for the preparation of zolmitriptan-loaded niosomes, eight non-ionic surfactants with different HLB values were used under fixed conditions to inspect the effect of surfactant type on the EE of the formed vesicles
That from IN mucoadhesive in situ gelling system (Treatment B) is 1173.64%. These results indicated that nasal application of the prepared bilosomes resulted in brain targeting of the incorporated zolmitriptan
Summary
Migraine is the most abundant type of neurological disorder; coupled with atypical serotonergic activity [1,2], it is considered the second major cause of disability, especially among young people [3]. Migraine can be associated with aura or not, with the latter being the most common type. Zolmitriptan is a potent second generation triptan which acts as a selective serotonin receptor agonist [2]. It is used as pain terminator in migraine and cluster headache treatment and is given to patients with migraine attacks, with or without an aura. The oral administration of zolmitriptan is the most common route of administration, it is associated with poor bioavailability (≈40%) owing to severe hepatic first pass effect, slow onset of action [7,8] and systemic side effects such as nausea, dizziness, paraesthesia, neck pain and tightness [9]. The oral administration of anti-migraine drugs can be inconvenient, especially in patients with associated with nausea and vomiting
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