Stability and bioavailability of diltiazem/polyethylene oxide matrix tablets

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Materials Science

Background:

• Sustained-release formulations are crucial for maintaining therapeutic drug levels.
• Polyethylene oxide (PEO) is a common polymer used in sustained-release matrix tablets.
• Understanding drug stability and in vivo performance is essential for formulation development.

Purpose of the Study:

• To prepare and evaluate in vitro and in vivo Diltiazem-Hydrochloride (DTZ) sustained-release matrix tablets.
• To assess the stability of DTZ tablets formulated with different molecular weights of PEO and electrolytes under accelerated storage conditions.
• To compare the in vivo pharmacokinetic profiles and therapeutic equivalence of a selected DTZ formulation against a reference product.

Main Methods:

• Preparation of DTZ sustained-release matrix tablets using PEO (900K, 4000K, 8000K) with/without electrolytes.
• Short-term stability testing (1 month at 40°C/75% RH) evaluating DTZ content, Differential Scanning Calorimetry (DSC), and drug release via Flow-Through Cell (USP Apparatus IV).
• In vivo pharmacokinetic study in healthy volunteers comparing a selected formula against a reference product, analyzing Cmax, AUC0-48, and AUC0-∞.

Main Results:

• Most stored DTZ tablets maintained their DTZ content and drug release profiles after 1 month of accelerated storage.
• DSC analysis revealed a new exothermic peak in stored samples, not observed after long-term room temperature storage.
• In vivo studies showed different DTZ-plasma profiles, but no statistically significant differences in Cmax, AUC0-48, or AUC0-∞; however, therapeutic inequivalence was determined based on 90% confidence intervals.

Conclusions:

• DTZ tablets formulated with PEO exhibited stability under short-term accelerated storage regarding drug content and release.
• Accelerated stability testing revealed potential changes (new exothermic peak) not seen with long-term room temperature storage.
• Despite similar pharmacokinetic parameters, the tested DTZ formulation was found to be therapeutically inequivalent to the reference product, highlighting potential discrepancies between stability testing regimes.