Enterically-Coated DMF Particles for Once-Daily Dosing
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Solution Overview
Problem
Current dimethyl fumarate (DMF) formulations face challenges with poor processability, safety risks due to handling issues, and lack of a once-a-day dosing regimen, along with gastrointestinal side effects from rapid DMF release in the stomach.
Innovation Solution
Development of enterically-coated DMF particles with controlled release profiles, suitable for once-a-day dosing, using wet-milling to achieve desirable particle size and morphology, minimizing exposure and improving absorption by reducing immediate release in the stomach.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If jet-milling process is used to reduce particle size, then particle size is reduced, but processability deteriorates due to particle to particle cohesiveness
Solution Approach 1:
The patent changes the physical-chemical parameters of DMF particles through controlled crystallization from solvent, producing particles with specific size ranges (D10: 5-20 μm, D50: 20-40 μm, D90: 40-60 μm) and controlled morphology that improve flow properties and processability while maintaining therapeutic efficacy
Solution Approach 2:
The patent creates particles with non-uniform size distribution and specific morphological characteristics, where the polydisperse nature and controlled shape provide optimal balance between dissolution rate and processability, avoiding the cohesiveness issues of monodisperse jet-milled particles
2Speed
If DMF is released rapidly in the stomach, then immediate dose is provided, but gastrointestinal side effects increase
Solution Approach 1:
The patent uses enteric coating as an intermediary layer that prevents DMF release in the acidic stomach environment (pH 1.2-3.0) and enables release in the more neutral intestinal environment (pH 6.8), thereby eliminating GI side effects while maintaining drug delivery
Solution Approach 2:
The patent changes the release conditions by using pH-sensitive enteric coatings that remain intact at gastric pH but dissolve at intestinal pH, controlling where and when the drug is released to avoid harmful interactions in the stomach
3Ease of operation
If handling procedures are simplified, then ease of operation is improved, but safety risks increase due to sublimation and dust explosion potential
Solution Approach 1:
The patent changes the physical state parameters by controlling crystallization from solvent to produce particles with reduced sublimation tendency and improved dust characteristics, making the material safer to handle while maintaining effectiveness
Solution Approach 2:
The patent converts the potential harm of fine particulate matter (which can cause dust explosions) into a benefit by controlling particle morphology and size distribution to improve flow properties and reduce static charge accumulation, thereby reducing explosion risk
4Loss of time
If once-a-day dosing is implemented, then convenience is improved, but maintaining pharmacokinetic profile becomes challenging
Solution Approach 1:
The patent segments the dosing regimen into two components: an immediate-release component for rapid initial dosing and an enteric-coated controlled-release component for sustained delivery, allowing once-daily administration while maintaining therapeutic levels
Solution Approach 2:
The patent uses enteric coating as a preliminary protective action that ensures the drug survives stomach conditions and is released at the optimal location (intestine), enabling simplified once-daily dosing while maintaining reliable pharmacokinetics
Data Source
AI summary
The present invention provides dimethyl fumarate (DMF) particles and methods of preparing the DMF particles. Also provided is DMF coated particles comprising DMF particles coated with an enteric coating. The invention also provides various dosage forms and methods of treating a disease or disorder (e.g., multiple sclerosis).