Migraine attack is a troublesome physiological condition associated with throbbing, intense headache, in one half of the head. Zolmitriptan is a potent second-generation triptan, prescribed for patients with migraine attacks, with or without an aura, and cluster headaches. The absolute bioavailability of zolmitriptan is about 40% for oral administration; due to hepatic first metabolism. Nasal administration would circumvent the pre-systemic metabolism thus increasing the bioavailability of zolmitriptan. In addition, due to the presence of microvilli and high vasculature, the absorption is expected to be faster compared to oral route. However, the bioavailability of nasal administered drugs is particularly restricted by poor membrane penetration. Thus, the aim of this work is to explore the potential of novel nanovesicular fatty acid enriched structures (novasomes) for effective and enhanced nasal delivery of zolmitriptan and investigate their nose to brain targeting potential. Novasomes were prepared using nonionic surfactant, cholesterol in addition to a free fatty acid. A 2 3 full factorial design was adopted to study the influence of the type of surfactant, type of free fatty acid and ratio between the free fatty acid and the surfactant on novasomes properties. The particle size, entrapment efficiency, polydispersity index, zeta potential and % zolmitriptan released after 2 h were selected as dependent variables. Novasomes were further optimized using Design Expert Õ software (version 7; Stat-Ease Inc., Minneapolis, MN), and an optimized formulation composed of Span Õ 80:Cholesterol:stearic acid (in the ratio 1:1:1) was selected. This formulation showed zolmitriptan entrapment of 92.94%, particle size of 149.9 nm, zeta potential of À55.57 mV, and released 48.43% zolmitriptan after 2 h. The optimized formulation was further examined using transmission electron microscope, which revealed non-aggregating multi-lamellar nanovesicles with narrow size distribution. DSC, XRD examination of the optimized formulation confirmed that the drug have been homogeneously dispersed throughout the novasomes in an amorphous state. In-vivo bio-distribution studies of 99m Tc radio-labeled intranasal zolmitriptan loaded novasomes were done on mice, the pharmacokinetic parameters were compared with those following administration of intravenous 99m Tc-zolmitriptan solution. Results revealed the great enhancement in zolmitriptan targeting to the brain, with drug targeting potential of about 99% following intranasal administration of novasomes compared with the intravenous drug solution. Zolmitriptan loaded novasomes administered via the nasal route may therefore constitute an advance in the management of acute migraine attacks.

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99m Tc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic Õ P123:Pluronic Õ L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE ¼ 242.3%), drug targeting index (DTI ¼ 144.25), and nose-to-brain direct transport percentage (DTP ¼ 99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

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Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5-13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NMloaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with 99m Tc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NMloaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/ g) in the heart of mice following administration of 99m Tc-NM loaded LPM were lower compared with that following administration of 99m Tc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of 99m Tc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of 99m Tc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.