Fumarate Ester Liquid Suspension Capsules
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Solution Overview
Problem
Current oral formulations of fumarate esters, such as TECFIDERA, suffer from issues like non-uniformity in shape and size, uneven enteric coating, leading to gastrointestinal side effects and reduced bioavailability, along with sublimation during manufacturing and storage, which affects the stability and efficacy of the drug.
Innovation Solution
Development of an oral pharmaceutical composition comprising a liquid suspension of fumarate esters in a lipid or lipophilic matrix, encapsulated in a soft capsule with a controlled release profile, using solubility enhancing agents like polyvinylpyrrolidone and polyoxyl 40 hydrogenated castor oil, to enhance bioavailability and reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enterically coated DMF granules are used in TECFIDERA, then release of DMF in the stomach is prevented, but the enteric coating lacks uniformity in shape and size and may not be evenly distributed, leading to diminished enteric properties and affecting acid-resistance, dissolution, and release rates
Solution Approach 1:
The patent changes the physical state of DMF from solid granules to liquid form, and modifies the dosage form from hard gelatin capsules to soft gelatin capsules. This parameter change eliminates the need for enteric coating on granules, as the liquid DMF can be directly encapsulated with consistent properties, ensuring uniform distribution and reliable enteric release without the manufacturing precision issues of coating solid granules
Solution Approach 2:
The patent uses a composite approach by combining liquid DMF with a lipid or lipophilic liquid carrier system within the soft gelatin capsule. This composite formulation allows the active ingredient to be delivered in a liquid state with improved solubility and bioavailability, while the soft capsule shell provides the enteric barrier function, achieving both uniformity and reliable gastric protection
2Object-affected harmful factors
If enteric coating is applied to DMF granules, then gastric release is prevented, but the integrity of the coating fails when the coating cracks or flakes off, leading to DMF release in the stomach and causing flushing and negative gastrointestinal side effects
Solution Approach 1:
The patent changes DMF from solid granule form to liquid form and transitions from hard gelatin to soft gelatin capsules. This eliminates the enteric coating layer that is prone to cracking and flaking, as the liquid DMF is directly encapsulated in the soft gelatin shell which provides flexible, crack-resistant enteric protection, ensuring coating integrity and preventing premature gastric release
Solution Approach 2:
The patent employs soft gelatin capsules with flexible shells that can accommodate the liquid DMF content without cracking or flaking. The flexible nature of the soft gelatin shell maintains integrity during handling and digestion, preventing the coating failure modes seen in hard gelatin capsules with brittle enteric coatings, thus eliminating the harmful effect of unintended gastric release
3Ease of manufacture
If wet-granulation processing is used to manufacture TECFIDERA, then DMF can be formulated into capsules, but about 15-20% of the DMF active ingredient is lost owing to sublimation during processing
Solution Approach 1:
The patent changes DMF from solid to liquid state and eliminates the wet-granulation process by directly encapsulating liquid DMF in soft gelatin capsules. This parameter change removes the heating and drying steps that cause sublimation, thereby eliminating the 15-20% active ingredient loss while still achieving capsule formulation capability through a simpler liquid-filled encapsulation process
Solution Approach 2:
The patent extracts the problematic wet-granulation processing steps from the manufacturing process by using liquid DMF that can be directly filled into soft gelatin capsules. This eliminates the need for granulation, drying, and extensive heating operations, thereby removing the source of DMF sublimation loss while maintaining the ability to produce capsule dosage forms
4Duration of action of stationary object
If DMF is stored in TECFIDERA capsules, then the drug remains stable for use, but sublimation also causes loss of DMF during storage and unused capsules must be discarded 90 days after opening
Solution Approach 1:
The patent changes DMF from solid to liquid form and uses soft gelatin capsules instead of hard gelatin capsules. This parameter change improves storage stability by eliminating the air space and sublimation pathways present in hard gelatin capsules, as the liquid DMF is in direct contact with the capsule shell which provides a tighter seal, thereby reducing sublimation loss during storage and extending the usable shelf life beyond 90 days
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 composition provides enhanced bioavailability, reduced gastrointestinal side effects, and increased stability, allowing for a consistent release profile and extended shelf life, while maintaining therapeutic efficacy with lower doses.
Implementation Method 1
fumarate esters suspended in a lipid or lipophilic liquid with enhanced bioavailability
Implementation Method 2
oral controlled release pharmaceutical compositions comprising fumarate esters suspended in liquid matrices
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 controlled release pharmaceutical compositions comprising fumarate esters suspended in liquid matrices are described. One embodiment described herein is a pharmaceutical composition comprising fumarate esters suspended in a lipid or lipophilic liquid with enhanced bioavailability.