Monomethyl Fumarate Enteric Capsule Gastrointestinal Tolerability
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Solution Overview
Problem
Current treatments for multiple sclerosis using dimethyl fumarate, such as TECFIDERA, often result in undesirable gastrointestinal side effects due to high concentrations in the stomach, necessitating the development of oral formulations with enhanced bioavailability and lower doses that minimize these side effects.
Innovation Solution
Pharmaceutical compositions comprising monomethyl fumarate in an immediate releasing single-phase non-aqueous liquid vehicle, encapsulated in an enterically coated soft capsule, which provides a lower incidence of gastrointestinal side effects and improved bioavailability compared to dimethyl fumarate formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dimethyl fumarate is administered in high doses to treat multiple sclerosis, then therapeutic efficacy is improved, but gastrointestinal side effects increase
Solution Approach 1:
The patent changes the chemical parameter from dimethyl fumarate to monomethyl fumarate, which has different pharmacokinetic properties. This parameter change allows achieving therapeutic efficacy at lower doses while reducing gastrointestinal side effects, as monomethyl fumarate is better tolerated by the gastrointestinal tract
Solution Approach 2:
The patent uses an enteric coating as an intermediary layer that prevents direct contact between the fumarate ester and the stomach lining. The enteric coating dissolves in the alkaline environment of the intestine rather than the acidic stomach environment, thereby mediating the delivery of the drug to avoid gastrointestinal irritation while maintaining therapeutic effect
2Object-affected harmful factors
If enteric coating is applied to delay release in the intestine, then gastrointestinal side effects are reduced, but absorption efficiency may be compromised
Solution Approach 1:
The patent changes the chemical structure from dimethyl fumarate to monomethyl fumarate, which has improved solubility and absorption characteristics. This parameter change ensures that when the enteric coating dissolves in the intestine, the drug is more efficiently absorbed, thereby maintaining or improving bioavailability while still benefiting from the protective enteric coating
Solution Approach 2:
The patent creates a composite dosage form combining monomethyl fumarate with an enteric coating material. This composite structure allows the drug to be protected in the stomach and then released in the intestine where both the coating dissolves and the drug is efficiently absorbed, achieving both protection and bioavailability
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 monomethyl fumarate compositions reduce the frequency and severity of gastrointestinal adverse events, including vomiting and diarrhea, while maintaining therapeutic efficacy for multiple sclerosis and psoriasis treatment, with a Modified Overall Gastrointestinal Symptom Scale (MOGISS) score of ≤4, and enhanced bioavailability.
Implementation Method 1
encapsulated in an enterically coated soft capsule
Implementation Method 2
Both dimethyl fumarate (DMF) and monomethyl fumarate (MMF) activate the nuclear factor erythroid-derived 2-like (Nrf2) pathway in vitro and in vivo in humans. The Nrf2 pathway is involved in the cellular response to oxidative stress.
Implementation Method 3
Upon oral ingestion, one methyl moiety of DMF is hydrolysed by esterases to form MMF, the bioactive metabolite.
Data Source
AI summary
Described herein are pharmaceutical compositions comprising one or more fumarate esters and methods for treating multiple sclerosis subjects with the compositions where the incidence of gastrointestinal side effects is reduced compared to treatments comprising dimethyl fumarate (e.g., TECFIDERA®). In particular, described herein are oral pharmaceutical compositions comprising monomethyl fumarate in a liquid vehicle that have reduced gastrointestinal side effects.