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 2³ 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.

Keywords:

• Zaleplon
• intranasal
• solid dispersion
• brain targeting
• GABA measurement

Acknowledgements

The authors acknowledge Al Andalous for Pharmaceutical Industries (6th of October city, Egypt), October Pharma S.A.E (6th of October city, Egypt), and BASF SE (Carl-Bosch-str. 0.3867056, Ludwigshafen, Germany) for gifting medical materials supporting the research.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.