Design and development of an ethyl cellulose bulk-engineered spherule-based capsule system

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Chronopharmaceutics

Background:

• Angina attacks often occur in the early morning, linked to the body's circadian rhythm.
• Effective drug delivery is crucial to manage circadian-related cardiovascular events.
• Isosorbide dinitrate (ISDN) is a key medication for angina, but its release profile needs optimization.

Purpose of the Study:

• To formulate and optimize Isosorbide dinitrate (ISDN)-loaded spherules for delayed and sustained release (DR/SR).
• To achieve drug release aligned with the body's natural circadian rhythm for early morning angina prevention.
• To engineer a novel drug delivery system for enhanced therapeutic efficacy.

Main Methods:

• Formulation of ISDN-loaded spherules using ethyl cellulose via spheronization.
• Optimization using Design of Experiments (DOE) to define the design space (DOS).
• In vitro drug release studies at gastric (pH 1.2) and colonic (pH 7.4) conditions.
• Evaluation of spherule flow characteristics (Angle of repose, Carr's index, Hausner's Ratio).

Main Results:

• Optimized DR-coated spherules showed improved flow properties compared to granules and SR spherules.
• Negligible ISDN release (<4.8%) at pH 1.2 confirmed gastric resistance.
• At pH 7.4, a 40% burst release followed by ~60% release over 24h demonstrated controlled release.
• Ethyl cellulose and Eudragit S-100 coated spherules exhibited strong gastric resistance.
• DOE optimization and validation showed results within 5% deviation, confirming targeted performance.

Conclusions:

• Engineered ISDN spherules successfully modulated drug release profiles.
• The developed DR/SR system is suitable for targeting early morning angina by aligning with circadian rhythms.
• This novel formulation offers a promising approach for chronotherapeutic management of cardiovascular conditions.