Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 2³ full-factorial design and in vivo determination of GABA neurotransmitter

Abstract

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 2 full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1 h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.

Prolonged Zaleplon Treatment Increases the Expression of Proteins Involved in GABAergic and Glutamatergic Signaling in the Rat Hippocampus

“…Consistent with the sedative-hypnotic mechanism of zaleplon action, the results of our study suggest increased GABA synthesis and its packaging into vesicles, as evidenced by higher levels of the GAD67 protein and GABA immunostaining and VGAT proteins, respectively. Previous studies reported increased levels of GABA in the whole brain and plasma of healthy rabbits after administration of both low and high doses of zaleplon [30], whereas the same effect was observed in the whole brain of rats at the high dose of zaleplon (4 mg/kg, p. o.)…”

Rapid oral transmucosal delivery of zaleplon–lavender oil utilizing self-nanoemulsifying lyophilized tablets technology: development, optimization and pharmacokinetic evaluation

“…This is due to ZP’s interaction with the receptor of gamma-aminobutyric acid type A (GABA A ), preferentially at the α 1 β 2 γ 2 subunit binding site, which is the benzodiazepine binding site in the central nervous system. Thus, it is also used as a strong anticonvulsant medication in pentylenetetrazole and electroshock-induced convulsions (Hosny et al., 2006 ; Abd-Elrasheed et al., 2018 ).…”