Pharmacokinetic Study of Mucoadhesive Itopride Hydrochloride In Situ Nasal Gel Formulations in a Comparative In Vivo Study and Histopathological Safety Evaluation

Abstract

Hepatic first-pass metabolism has been a major cause of reduced bioavailability for many drugs. Using the nasal route as an alternative route to deliver drugs to the systemic circulation provided the solution to this problem. One of the drugs which are highly affected by first-pass metabolism is itopride hydrochloride (ITO HCl). It is a prokinetic agent used for the treatment of various gastrointestinal motility disorders, mainly gastroesophageal reflux. The objective of this study was to determine the pharmacokinetic parameters of selected mucoadhesive in situ nasal gel formulations (F1 and F17) of itopride hydrochloride (ITO HCl) and to evaluate their safety after topical application on the nasal mucosa. The tested formulations contained 18% w/v poloxamer 407 with 0.5% w/v of HPMC K4M (F1), or with 0.5% w/v MC (F17). A randomized cross-over study was done on six rabbits after administration of F1, F17, and commercial oral tablets (Ganaton®). Plasma levels were assessed using high-performance liquid chromatography (HPLC) to compare the nasal gel formulations with the conventional oral tablets. Histopathological study of the nasal mucosa was performed in rats after nasal application of both in situ gel formulas. The in vivo pharmacokinetic profiles of in situ nasal gel formulas F1 and F17 provided showed improvement in Cmax, Ke, t1/2, AUC0–24, AUC24–inf, AUC0–inf, AUMC24–inf, AUMC0–inf, MRT, Vd, and Cmax/AUC0–24 values over commercial tablets (p < 0.05). No statistically significant difference was found between both nasal gel formulas (F1 and F17). The percentage relative bioavailability of ITO HCl nasal in situ gel F1 and F17 was found to be 171.22% and 178.91%, respectively, in comparison with the commercial tablet. Histopathological study of the nasal mucosa revealed the safety of nasal in situ gel formulations to the nasal mucosa after 14 days of application. The study showed that the formulation of itopride hydrochloride as a mucoadhesive in situ nasal gel has enhanced the drug bioavailability due to avoidance of first-pass metabolism. The study points to the potential of mucoadhesive nasal in situ gel in terms of safety and efficiency.

Keywords

• itopride hydrochloride
• nasal drug delivery
• in situ gel
• animal study
• bioavailability
• histopathology