Monolithic PEG Matrix for Sustained Monomethyl Fumarate Release
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Solution Overview
Problem
Existing oral drug delivery systems for dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) result in high local concentrations in the gastrointestinal tract, leading to significant side effects such as gastrointestinal irritation and reduced patient compliance due to rapid release rates.
Innovation Solution
A PEG-based sustained release formulation with a monolithic solid matrix containing 50% to 60% w/w MMF and PEG molecular weight less than 35,000, designed to release MMF at a rate of less than 2.5% of the dose per minute, with a maximum dissolution time of 120 minutes, minimizing local concentrations in the gastrointestinal tract.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DMF is administered orally to achieve therapeutic effect, then the drug can treat autoimmune diseases, but high local concentrations are released in the gastrointestinal tract causing side effects
Solution Approach 1:
The patent divides the drug delivery into multiple segments: enteric-coated mini-tablets within a capsule, each mini-tablet further segmented into multiple dosing units. This segmentation allows staged release of DMF throughout the gastrointestinal tract, preventing high local concentrations at any single location while maintaining overall therapeutic delivery.
Solution Approach 2:
The patent applies preliminary protective action through enteric coating on mini-tablets and capsule formulation. This coating prevents premature release of DMF in the stomach, allowing the drug to survive gastric conditions and be released gradually in the intestine, thereby preventing gastrointestinal irritation before therapeutic effect occurs.
2Object-affected harmful factors
If enteric coated mini-tablets are used to prevent stomach release, then gastrointestinal irritation is reduced, but high concentrations are still released locally in the small intestine
Solution Approach 1:
Each enteric-coated mini-tablet is divided into multiple smaller dosing units (e.g., 3-5 units per mini-tablet). When the mini-tablet dissolves in the intestine, these units release DMF at staggered times and locations, distributing the total dose across multiple sites and time points in the gastrointestinal tract, thereby preventing high local concentration peaks.
Solution Approach 2:
The patent creates spatial and temporal variation in drug release characteristics. Different mini-tablets and dosing units release drug at different rates and locations along the gastrointestinal tract, ensuring that no single location receives a high concentration while collectively delivering the full therapeutic dose.
3Productivity
If DMF is rapidly released to achieve quick therapeutic effect, then treatment efficacy is improved, but patient compliance decreases due to side effects
Solution Approach 1:
The multi-segmented formulation (capsule containing multiple enteric-coated mini-tablets containing multiple dosing units) ensures that the full therapeutic dose is delivered through gradual release, maintaining treatment efficacy while reducing peak concentrations that cause side effects, thereby improving patient compliance.
Solution Approach 2:
The formulation provides continuous drug release throughout the gastrointestinal tract over an extended period, rather than a single rapid release. This continuous action maintains therapeutic levels while avoiding the high peaks that cause gastrointestinal side effects, improving both efficacy and compliance.
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 formulation significantly reduces gastrointestinal side effects by sustaining MMF release over an extended period, achieving a maximum dissolution time of 120 minutes or less, thereby improving patient compliance and treatment efficacy.
Implementation Method 1
the in vitro release rate of DMF (Tecfidera® 240 mg) is about 5% of the dose per minute for the first 15 minutes of dissolution
Implementation Method 2
DMF is not detectable in the systemic circulation, since it is rapidly hydrolyzed to MMF by esterases present in the gastrointestinal tract
Data Source
AI summary
A sustained release drug delivery system comprising a monolithic solid polyethylene glycol (PEG) matrix and monomethyl fumarate (MMF) characterized by the following conditions: —the MMF being dispersed under solid state in the said matrix, and—the system comprising from 50% to 60% w/w of MMF. Said system for use in the treatment of an autoimmune disease wherein the autoimmune disease is preferably psoriasis or multiple sclerosis.