Nefopam HCl in situ mucoadhesive liquid suppository, a potential drug delivery system to enhance bioavailability

Abstract

Background Nefopam hydrochloride (NPH) is a non-narcotic analgesic that is severely affected by its extensive hepatic metabolism resulting in low oral bioavailability. This study aimed to develop NPH thermosensitive in situ gel to enhance its bioavailability by avoidance of first pass effect through rectal administration. Methods A cold method was employed to develop NPH thermosensitive rectal in situ gel utilizing various concentrations of poloxamer 407 (P 407) and poloxamer 188 (P188) alone or in mixture as thermosensitive polymers and hydroxypropyl methylcellulose K4M (HPMCK4M) as well as carboxymethyl cellulose (CMC) as mucoadhesive polymers. The achieved formulas were assessed for various in vitro constraints including: solution-gel temperature, gelation time, appearance, pH, gel strength, viscosity, in vitro drug release study. Furthermore, the optimized formula was evaluated for in vivo localization and permeability. Results The obtained outcomes demonstrated a direct correlation between solution-gelation temperatures and poloxamer 188 concentration as well as an inverse correlation with the concentration of both P407 and HPMCK4M. A direct correlation was perceived between the mucoadhesive forces and viscosity with HPMCK4M concentration. Additionally, an inverse correlation was observed between NPH released with HPMCK4M concentration. The optimal NPH gel formula (F8) (18% P407/2% P188 and 0.6%) presented a compatible pH value (7.2±0.35), an acceptable sol-gel T (35.4 °C), gel strength (39.54 ± 0.803), a mucoadhesion force of 6340.6 dyne/cm 2 and sustained drug release of 85% at 8 hrs. Additionally it showed sufficient localization and a permeation flux of 0.0398 mg/cm 2 /h, and apparent permeability (Papp) of 1.99*10 −3 . Conclusions It was concluded that this drug delivery system may serve as a promising alternative to other dosage forms containing NPH, owing to avoidance of first-pass metabolism, enhanced bioavailability, non-invasiveness, and reduced adverse effects associated with other forms.