Co-amorphous Approach for Enhancing Rilpivirine Oral Bioavailability using CYP3A4 Inhibitor as a Co-former

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Materials Science

Background:

• Rilpivirine, a BCS class II drug, exhibits poor water solubility and limited oral bioavailability, hindering effective HIV treatment.
• Developing advanced drug delivery systems is crucial for enhancing the therapeutic efficacy of poorly soluble drugs.

Purpose of the Study:

• To improve the solubility and oral bioavailability of rilpivirine by creating a co-amorphous system (CAMS).
• To utilize nicotinamide as a co-former, selected through knowledge-based methods including Hansen solubility and Flory-Huggins parameters, and molecular modeling.

Main Methods:

• Co-amorphous systems (CAMS) were prepared using solvent evaporation and quench cooling at various molar ratios (1:1, 1:2, 2:1).
• Characterization involved phase solubility studies, Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and field-emission scanning electron microscopy (FE-SEM).
• In vitro dissolution, ex vivo permeation, and pharmacokinetic studies in Wistar rats were conducted to assess drug performance and bioavailability.

Main Results:

• The 1:1 molar ratio of rilpivirine-nicotinamide CAMS demonstrated optimal complex formation.
• CAMS exhibited a 38-fold increase in saturation solubility compared to pure rilpivirine.
• Significant enhancements were observed in in vitro drug release (2.86-fold) and ex vivo permeation (2.87-fold).
• Pharmacokinetic studies revealed a 2.49-fold improvement in oral bioavailability, attributed to enhanced dissolution and potential CYP3A4 inhibition by nicotinamide.

Conclusions:

• The developed rilpivirine-nicotinamide CAMS effectively enhances solubility, dissolution, permeation, and oral bioavailability.
• This co-amorphous formulation represents a promising strategy for improving the delivery of rilpivirine in antiretroviral therapy.
• The CAMS demonstrated good physical stability, maintaining its amorphous state for over three months.