Development of a multi particulate extended release formulation for ZK 811 752, a weakly basic drug

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems

Background:

• ZK 811 752, a candidate for autoimmune disease treatment, exhibits pH-dependent solubility.
• Conventional mini matrix tablets show decreased drug release at higher pH values.
• This pH dependency poses a challenge for consistent therapeutic efficacy.

Purpose of the Study:

• To develop pH-independent mini matrix tablets for ZK 811 752.
• To overcome the pH-dependent solubility and release characteristics of the drug.
• To achieve consistent drug release profiles regardless of the dissolution medium's pH.

Main Methods:

• Mini matrix tablets were formulated using direct compression with ZK 811 752, polyvinylacetate/polyvinylpyrrolidone (Kollidon SR), and various excipients (lactose, calcium phosphate, maize starch).
• Fumaric acid was incorporated into the drug-polymer-excipient system to modulate the micro-environmental pH.
• Drug release studies were conducted in phosphate buffer at pH 6.8, and tablet stability was assessed under various storage conditions.

Main Results:

• The addition of fumaric acid successfully maintained a low micro-environmental pH within the tablets during drug release.
• This resulted in pH-independent release of ZK 811 752 from the mini matrix tablets.
• Water-soluble and highly swellable excipients (lactose, maize starch) accelerated drug release more than water-insoluble excipients (calcium phosphate).
• Stability studies confirmed no drug degradation and reproducible release profiles after 6 months of storage.

Conclusions:

• The incorporation of fumaric acid effectively overcomes the pH-dependent release of ZK 811 752.
• The developed mini matrix tablets offer a promising approach for achieving consistent drug delivery in autoimmune disease treatment.
• The formulation strategy provides a robust and stable drug product with predictable release characteristics.