FORMULATION AND EVALUATION OF NANO FORMULATION OF BTK INHIBITOR BY BOX-BEHNKEN DESIGN AND HIGH-PRESSURE HOMOGENIZATION FOR ENHANCED BIOAVAILABILITY AND REDUCING THE EFFECTS OF FOOD

Abstract

Objective: The study aims to enhance the solubility and oral bioavailability of the poorly soluble drug Ibrutinib (IBR), a type IV irreversible kinase inhibitor, using Nanosuspension (NS) as a formulation strategy. The study also evaluates the ability of NS to minimize fasted-fed variability and improve drug absorption.

Methods: NS was prepared using High-Pressure Homogenization (HPH) and optimized with a Box-Behnken design. Poloxamer 188 and Hydroxypropyl Methylcellulose (HPMC E-15) were used as stabilizers to prevent particle aggregation. A comprehensive evaluation of the formulation was conducted, including particle size analysis, zeta potential measurement, Scanning Electron Microscopy (SEM) for shape determination, drug-excipient interactions, in vitro dissolution studies, and in vivo pharmacokinetic assessments in both fed and fasting conditions.

Results: The particle size of the optimized NS ranged from 134.6 to 214.0 nm, with polydispersity indices between 0.189 and 0.56, indicating a uniform size distribution. SEM confirmed the nanosized particles with a stable morphology. IBR-NS exhibited an 18.45-fold increase in solubility compared to pure IBR, reducing precipitation and enhancing intestinal absorption. Pharmacokinetic studies demonstrated a 3.05-fold increase in concentration max and a 3.97-fold increase in area under the curve_0–t under both fed and fasting conditions. Notable differences in pharmacokinetics between the fed and fasted states were observed, supporting improved drug absorption.

Conclusion: The study confirms that NS is a promising approach for improving IBR solubility and bioavailability. The NS formulation effectively reduces fasted-fed variability, enhances intestinal absorption, and holds potential for better therapeutic outcomes.