Raloxifene HCl - Naringin co-amorphous system: Preparation, characterization and pharmacokinetic studies

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Physical Chemistry

Background:

• Poor water-solubility affects approximately 90% of NCEs and 40% of approved drugs, limiting oral bioavailability.
• Raloxifene HCl (RLX), a BCS class II drug, exhibits low oral bioavailability (2%) due to poor solubility (0.5 μg/mL) and extensive pre-systemic metabolism via CYP3A4 and P-glycoprotein (P-gp).
• Naringin (NRG), a natural compound, acts as an inhibitor of both CYP3A4 and P-gp, presenting a potential synergistic approach for drug formulation.

Purpose of the Study:

• To explore the co-amorphization of Raloxifene HCl (RLX) with Naringin (NRG) to improve RLX's solubility and bioavailability.
• To investigate the molecular interactions and solid-state properties of the resulting co-amorphous systems (CAMs).
• To evaluate the enhanced solubility, drug release, and in vivo pharmacokinetic profile of RLX-NRG CAMs.

Main Methods:

• Co-amorphous systems (CAMs) of RLX and NRG were prepared using the solvent evaporation technique.
• Solid-state characterization was performed to analyze molecular-level changes.
• Solubility, drug release, ex vivo permeation, and in vivo pharmacokinetic studies were conducted.

Main Results:

• The RLX-NRG CAMs demonstrated a 3.5-fold increase in solubility compared to RLX alone.
• Ex vivo permeation studies showed a 10-fold enhancement, while in vivo studies revealed an 8.1-fold increase in Cmax and a 2.8-fold increase in AUC.
• These improvements indicate significantly enhanced oral bioavailability of RLX when formulated as a CAM with NRG.

Conclusions:

• Co-amorphization using Naringin is a viable strategy to overcome the poor solubility and bioavailability challenges of Raloxifene HCl.
• The developed RLX-NRG CAMs exhibit superior pharmacokinetic properties, suggesting potential as a platform technology for improving drug performance at the molecular level.