Polymer-Conjugated MMF Injections for Stable RRMS Drug Release
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Solution Overview
Problem
Existing oral formulations of dimethyl fumarate (DMF) for treating relapsing-remitting multiple sclerosis (RRMS) and psoriasis suffer from adverse side effects and highly variable pharmacokinetics, including gastrointestinal issues and inconsistent drug absorption.
Innovation Solution
Development of polymer-conjugated monomethyl fumarate (MMF) derivatives, such as PEGylated MMF, to create stable injectable compositions that provide controlled release and improved pharmacokinetic properties, reducing gastrointestinal side effects and enhancing bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oral dimethyl fumarate (DMF) is used to treat RRMS and psoriasis, then therapeutic effects are achieved through Nrf2 pathway activation, but gastrointestinal side effects and highly variable pharmacokinetics occur due to rapid hydrolysis to monomethyl fumarate (MMF)
Solution Approach 1:
The patent changes the chemical structure parameter by conjugating MMF with polymer chains (PEG, polyacrylic acid, polyvinylpyrrolidone) to create prodrugs with modified pharmacokinetic properties. This conjugation alters the molecular weight, solubility, and metabolic stability parameters, enabling controlled release and reduced gastrointestinal irritation while maintaining therapeutic efficacy through Nrf2 pathway activation
Solution Approach 2:
The patent introduces polymer conjugates as intermediary carriers that protect MMF from rapid hydrolysis by esterases in the gastrointestinal tract. These polymer-MMF conjugates serve as mediators that control the release rate of active MMF, reducing peak concentrations that cause gastrointestinal side effects while ensuring sustained therapeutic levels
2Duration of action of moving object
If DMF is rapidly hydrolyzed by esterase in the gastrointestinal tract to MMF, then MMF becomes the active metabolite with 36-hour half-life, but the rapid hydrolysis causes inconsistent absorption and variable plasma concentrations
Solution Approach 1:
The patent applies preliminary protection by pre-conjugating MMF with polymer chains before administration. This preliminary action prevents rapid hydrolysis in the gastrointestinal tract, ensuring consistent absorption and predictable plasma concentration-time profiles while maintaining the desired 36-hour half-life of the active MMF metabolite
3Productivity
If polymer-conjugated MMF derivatives are developed for controlled release, then bioavailability and pharmacokinetic predictability improve, but formulation complexity increases
Solution Approach 1:
The patent creates composite prodrug molecules by chemically conjugating MMF with biocompatible polymer chains (PEG, polyacrylic acid, polyvinylpyrrolidone). These composite structures combine the pharmacological activity of MMF with the beneficial properties of polymers (controlled release, improved solubility, extended circulation), achieving enhanced bioavailability through a single molecular design rather than complex delivery devices
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 polymer-conjugated MMF derivatives offer improved bioavailability, predictable drug release, reduced side effects, and consistent pharmacokinetics, achieving therapeutic plasma concentrations with fewer injections and lower dosing frequency.
Implementation Method 1
DMF is rapidly hydrolyzed by esterase in the gastrointestinal tract to monomethyl fumarate (MMF) prior to entering systemic circulation
Data Source
Figure 1A~1B
Figure 2A~2B
Figure 3A
AI summary
The present invention comprises compounds of formula (I): where R1 may be PEG or other polymeric moieties. For example, R1 may be repeating PEG units - (CHs-CH2-O)n-, wherein n = 1 - 455. R1 may also be other polymeric moieties of varying sizes and structures, for example, R1 may be poly(glycolide), poly(lactic acid), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactideco-glycolide), or poly(lactic acid)-butanol. One or more embodiments of the invention may also relate to injectable pharmaceutical compositions comprising polymer conjugated monomethyl fumarate, and methods for treating relapsing-remitting multiple sclerosis and psoriasis.