Abstract: The opposing effect of the blood-brain barrier against the delivery of most drugs warrants the
need for an efficient brain targeted drug delivery system for the successful management of neurological
disorders. Temazepam-loaded nanostructured lipid carriers (NLCs) have shown possibilities for
enhancing bioavailability and brain targeting affinity after oral administration. This study aimed to
investigate these properties for insomnia treatment. Temazepam-NLCs were prepared by the solvent
injection method and optimized using a 42 full factorial design. The optimum formulation (NLC-1)
consisted of; Compritol® 888 ATO (75 mg), oleic acid (25 mg), and Poloxamer® 407 (0.3 g), with an
entrapment efficiency of 75.2 ± 0.1%. The average size, zeta potential, and polydispersity index were
determined to be 306.6 ± 49.6 nm, -10.2 ± 0.3 mV, and 0.09 ± 0.10, respectively. Moreover, an in vitro
release study showed that the optimized temazepam NLC-1 formulation had a sustained release profile.
Scintigraphy images showed evident improvement in brain uptake for the oral 99mTc-temazepam
NLC-1 formulation versus the 99mTc-temazepam suspension. Pharmacokinetic data revealed a
significant increase in the relative bioavailability of 99mTc-temazepam NLC-1 formulation (292.7%),
compared to that of oral 99mTc-temazepam suspension. Besides, the NLC formulation exhibited
a distinct targeting affinity to rat brain. In conclusion, our results indicate that the developed
temazepam NLC formulation can be considered as a potential nanocarrier for brain-mediated drug
delivery in the out-patient management of insomnia.