Isosorbide-5-nitrate sustained-release pellets - an example of computer-supported drug development.

Area of Science:

• Pharmacology
• Pharmaceutical Technology
• Drug Delivery Systems

Background:

• Angina pectoris requires long-term treatment with drugs offering fast onset and sustained action.
• Developing a once-daily dosage form for isosorbide-5-nitrate (IS-5-N) is crucial to manage therapeutic levels and avoid tolerance.
• Membrane-controlled release pellets minimize physiological variability, ensuring consistent drug delivery.

Purpose of the Study:

• To develop and evaluate a composite dosage form of IS-5-N for angina pectoris.
• To investigate the in vitro-in vivo correlation of drug release from the novel formulation.
• To predict plasma drug concentration profiles based on pharmacokinetic and dissolution data.

Main Methods:

• Preparation of three composite dosage form variants with varying initial dose (Di) and maintenance dose (Dm) ratios.
• In vitro dissolution testing to determine mean dissolution time (TDiss).
• In vivo pharmacokinetic studies in humans to assess bioavailability (ba) and mean residence time (MRT).

Main Results:

• Strong linear correlations were observed between in vitro dissolution (TDiss) and in vivo performance (MRT, ba).
• MRT showed a significant positive correlation with TDiss (r=0.949, p<0.001).
• Bioavailability (ba) demonstrated significant negative correlations with both MRT (r=-0.845, p<0.01) and TDiss (r=-0.886, p<0.05).

Conclusions:

• The developed composite dosage form enables predictable drug release and pharmacokinetic behavior.
• In vitro dissolution parameters effectively predict in vivo performance, facilitating formulation optimization.
• This approach supports the development of effective, once-daily IS-5-N formulations for angina pectoris management.