Fumarate Ester Capsules with Lipid Matrix and Dual-Layer Coating
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Solution Overview
Problem
Current oral formulations of fumarate esters, such as dimethyl fumarate, suffer from undesirable gastrointestinal side effects like flushing and lack of stability due to uneven enteric coating and sublimation, leading to inconsistent release profiles and reduced 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 stabilizes the active ingredient, offering tailored release profiles and reduced sublimation.
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 and may crack or flake off, leading to inconsistent release profiles
Solution Approach 1:
The invention divides the coating system into multiple functional layers: an inner enteric coating layer for acid resistance and an outer controlled-release polymer layer for sustained release. This segmentation allows each layer to perform its specific function optimally without the defects of a single-layer system.
Solution Approach 2:
The invention uses composite coating materials combining enteric polymers (for acid resistance) with controlled-release polymers (for sustained release). This composite approach creates a multi-functional coating that simultaneously provides both acid resistance and controlled release, eliminating the need for separate coating steps and improving uniformity.
2Productivity
If DMF is administered orally to achieve therapeutic effect, then drug delivery is achieved, but sublimation occurs during manufacturing and storage causing loss of active ingredient
Solution Approach 1:
The invention incorporates DMF into an inert lipid or lipophilic matrix that protects the active ingredient from sublimation during manufacturing and storage. The matrix creates a stable environment that prevents DMF from transitioning to vapor phase, reducing loss while maintaining therapeutic delivery.
Solution Approach 2:
The invention changes the physical state and environmental parameters of DMF by incorporating it into a lipid matrix at controlled temperatures and compositions. This modification of the physical environment prevents sublimation while maintaining drug stability and bioavailability.
3Object-affected harmful factors
If enteric coating is used to prevent gastric release, then side effects are reduced, but the coating integrity fails when coating cracks or flakes off, causing DMF release in the stomach
Solution Approach 1:
The invention applies a outer controlled-release polymer layer that acts as a protective cushion over the inner enteric coating. This outer layer prevents mechanical stress from reaching the inner coating, preventing cracks and flaking before they can occur during gastrointestinal transit.
Solution Approach 2:
The dual-layer composite coating structure combines the acid-resistant properties of enteric polymers with the mechanical strength and controlled-release properties of outer polymer layers. This composite structure simultaneously improves coating integrity and maintains the intended release profile.
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 significantly reduce gastrointestinal side effects, enhance stability, and provide consistent drug delivery, improving patient outcomes and manufacturing efficiency.
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 to manufacture TECFIDERA®. The formulations described herein comprise solid micronized particles of fumarate esters suspended in a matrix. The controlled release enteric capsule comprising a matrix of fumarate esters reduce, ameliorate, or eliminate the undesirable gastrointestinal side effects observed with prior fumarate ester pharmaceuticals. Further, the formulations preclude or reduce sublimation of the fumarate ester during manufacturing and storage.
Implementation Method 2
After oral intake, the main component of Fumaderm®, dimethyl fumarate (DMF), is hydrolysed by esterases to monomethyl fumarate (MMF), the bioactive metabolite. TECFIDERA® was intended to reduce the undesirable side effects by preventing release of DMF in the stomach. The pharmaceutical composition is encapsulated in an enteric soft capsule. The oral enteric soft capsules comprising controlled release matrix compositions prevent release of the fumarate ester active ingredient in the gastric environment
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.