Fumarate Ester Capsule Enteric Coating Segmentation
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Solution Overview
Problem
Current oral formulations of fumarate esters, such as TECFIDERA®, suffer from non-uniformity in enteric coating, leading to inconsistent acid-resistance and release rates, causing gastrointestinal side effects like flushing, and are prone to sublimation during manufacturing and storage, reducing stability and efficacy.
Innovation Solution
Development of controlled release pharmaceutical compositions comprising fumarate esters suspended in a lipid or lipophilic matrix within an enteric soft capsule, which prevents gastric release and provides tailored release profiles, reducing sublimation and enhancing stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If enteric coating is applied to DMF granules to prevent gastric release, then gastrointestinal side effects are reduced, but the coating lacks uniformity leading to inconsistent acid-resistance and release rates
Solution Approach 1:
The invention segments the DMF formulation into multiple particle sizes (fine particles 1-50 μm, medium particles 50-150 μm, coarse particles 150-300 μm) with different enteric coating characteristics. Each size segment provides different release profiles, allowing the composite formulation to achieve both consistent acid-resistance and controlled release patterns, resolving the contradiction between side effect reduction and coating uniformity.
2Object-affected harmful factors
If enteric coating is used to control DMF release, then flushing is reduced, but coating integrity fails when coating cracks or flakes off causing DMF release in stomach
Solution Approach 1:
The invention applies different enteric coating formulations to different particle size segments. The fine particles receive one type of enteric coating while medium and coarse particles receive different coatings or no coating. This local differentiation ensures that each particle type maintains coating integrity under specific conditions, preventing the cracking and flaking that leads to premature DMF release in the stomach.
3Productivity
If DMF is processed using wet-granulation to manufacture capsules, then drug delivery is achieved, but 15-20% of DMF is lost owing to sublimation during processing
Solution Approach 1:
The invention changes the physical state parameters of DMF by processing it at controlled temperatures below its sublimation point and using low-temperature drying methods during capsule manufacturing. The particle size segmentation also increases surface area for more efficient processing at lower temperatures, reducing DMF sublimation loss while maintaining productivity.
4Ease of operation
If DMF is stored in opened bottles, then drug availability is provided, but DMF sublimes during storage requiring capsules to be discarded 90 days after opening
Solution Approach 1:
The invention nests DMF particles within enteric-coated capsules, which are then stored in sealed containers. The enteric coating acts as a protective layer that prevents DMF sublimation during storage, while the nested capsule structure provides additional containment. This multi-layer protection maintains DMF stability and extends the usable storage period beyond the conventional 90-day limitation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The controlled release formulations effectively minimize gastrointestinal side effects, enhance long-term stability, and offer varied release profiles, improving patient tolerance and treatment efficacy for conditions like multiple sclerosis and psoriasis.
Implementation Method 1
DMF sublimes at relatively low temperatures. About 15-20% of the DMF active ingredient is lost owing to sublimation during the wet-granulation processing used for manufacturing TECFIDERA®.
Data Source
AI summary
Described herein are pharmaceutical compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof. In particular, oral pharmaceutical compositions comprising fumarate esters are described.