Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability

Abstract

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl β cyclodextrin inclusion complex (AM-HPβCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29–34 °c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120 min (99.1 ± 0.44%w/v). Dissolution in simulated nasal fluid was 92.33 ± 0.15%w/v at the end of 120 min. Locomotor activity was improved with nasal gel containing AM-HPβCD as compared to AM and AM-HPβCD oral solution in rats. C_max for nasal gel was found to be more (9 ng/ml) as compared to AM-HPβCD (5.5 ng/mL) and oral standard solution (2 ng/ml). T_max was found to be 1.5 h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.

Keywords:

• Asenapine maleate
• hydroxy propyl
• cyclodextrin
• solubility enhancement
• thermo-responsive
• rheology
• bioavailability

Acknowledgements

We are grateful to Dr. Kapil Joshi and Mr. Anant Kukkar, Anton Paar, Mumbai, India, for helping us to carry out rheological studies for this research work.

Disclosure statement

Authors declare no conflicts of interests.