Modified-Release Ryanodine Receptor Compositions for Calcium Control
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Solution Overview
Problem
Existing treatments for conditions associated with ryanodine receptors (RyRs) such as cardiac disorders, musculoskeletal disorders, cancer-associated muscle weakness, and diabetes are inadequate due to issues with the release and regulation of calcium ions, leading to inappropriate channel opening and reduced muscle contractions.
Innovation Solution
A modified-release pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or its pharmaceutically-acceptable salt, formulated as a gastro-resistant tablet with a core, sub-coating, and enteric coating, designed to release the active ingredient in the small intestine, providing prolonged and controlled release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If immediate release formulation is used, then rapid onset of action is achieved, but inappropriate channel opening and calcium ion regulation issues occur
Solution Approach 1:
The patent employs a modified-release formulation that releases the active ingredient in a controlled, periodic manner rather than immediately. The gastro-resistant coating system (enteric coating + sub-coating + core) ensures the drug is released in stages as the tablet moves through different pH environments in the gastrointestinal tract, providing periodic action that prevents inappropriate channel opening while maintaining therapeutic effectiveness
Solution Approach 2:
The patent applies preliminary protective action by coating the tablet core with multiple layers (enteric coating and sub-coating) before administration. These pre-applied coatings prevent premature drug release in the stomach and ensure the active ingredient is only released in the appropriate location (small intestine), thereby preventing inappropriate channel opening while ensuring reliable calcium ion regulation
2Reliability
If gastro-resistant formulation with multiple coating layers is used, then controlled release in small intestine is achieved, but device complexity increases
Solution Approach 1:
The patent utilizes parameter changes in the gastrointestinal environment (pH changes) to control drug release. The enteric coating is designed to dissolve at specific pH levels (higher pH in the small intestine), automatically triggering drug release without complex mechanical or electronic controls. This pH-dependent parameter change simplifies the overall device complexity while maintaining reliable controlled release
Solution Approach 2:
The patent introduces intermediary coating layers (enteric coating and sub-coating) that mediate between the active ingredient and the gastrointestinal environment. These intermediary layers protect the drug from premature release and control its dissolution timing, achieving reliable controlled release through a relatively simple multi-layer structure that leverages natural physiological gradients
Data Source
AI summary
The present disclosure provides a modified-release pharmaceutical composition comprising 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, and a pharmaceutically-acceptable excipient. The present disclosure methods of treating conditions associated with RyRs, including, for example, cardiac disorder or disease, a musculoskeletal disorder or disease, cancer associated muscle weakness, malignant hyperthermia, and diabetes.