Preparation and evaluation of stable amorphous flurbiprofen complexes using two different cyclodextrins.

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Drug Delivery Systems

Background:

• Poorly water-soluble drugs often exhibit low oral bioavailability.
• Amorphous solid dispersions are a strategy to enhance drug solubility and absorption.
• Cyclodextrins (CDs) are widely used to form inclusion complexes with drugs.

Purpose of the Study:

• To develop stable amorphous inclusion complexes of flurbiprofen (FP) with cyclodextrins (CDs).
• To investigate the stabilizing effect of different cyclodextrins, particularly gamma-cyclodextrin (γ-CD), on amorphous drug-CD systems.
• To evaluate the impact of these complexes on drug dissolution and in vivo oral absorption.

Main Methods:

• Co-grinding of crystalline flurbiprofen/beta-cyclodextrin (β-CD) complexes with alpha-cyclodextrin (α-CD) or gamma-cyclodextrin (γ-CD) to form ternary amorphous systems.
• Assessment of physical stability under accelerated humid conditions.
• In vitro dissolution studies to evaluate supersaturation.
• In vivo pharmacokinetic studies in rats to determine oral absorption parameters (Cmax, AUC).

Main Results:

• The ternary amorphous FP/β-CD/γ-CD system demonstrated superior physical stability compared to binary amorphous FP/β-CD.
• A small molar ratio of γ-CD (1:0.1) was sufficient to inhibit crystallization of the FP/β-CD complex.
• The FP/β-CD/γ-CD complex maintained a supersaturated state longer in vitro.
• In vivo studies showed a significant enhancement in FP oral absorption (2.4-fold Cmax, 2.1-fold AUC) with the ternary complex.

Conclusions:

• Gamma-cyclodextrin (γ-CD) is an effective stabilizer for amorphous cyclodextrin-based drug complexes.
• Combining two different cyclodextrins can enhance both physical stability and oral bioavailability of poorly water-soluble drugs.
• Ternary amorphous systems offer a promising strategy for improving drug delivery.