Fumarate Ester Soft Capsule with Enteric Minitablets
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Solution Overview
Problem
Current oral formulations of fumarate esters, such as dimethyl fumarate, for treating multiple sclerosis and other disorders, suffer from high side effects like flushing, headaches, and gastrointestinal issues due to high concentrations in the stomach, and there is a need for formulations with enhanced bioavailability and lower doses that are equally effective.
Innovation Solution
Development of oral pharmaceutical compositions containing fumarate esters in an immediate releasing single-phase non-aqueous liquid vehicle, encapsulated in soft capsules, using a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid, which provides bioequivalent pharmacokinetic parameters to higher doses of dimethyl fumarate, reducing side effects and improving bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high concentrations of fumarate esters are released in the stomach, then therapeutic effect is achieved, but side effects like flushing, headaches, and gastrointestinal issues increase
Solution Approach 1:
The patent divides the single high-dose release into multiple lower-dose releases over time using enteric-coated minitablets contained within a delayed-release capsule. This segmentation reduces peak concentration in the stomach while maintaining cumulative therapeutic effect, thereby reducing side effects like flushing and gastrointestinal issues.
Solution Approach 2:
The patent employs enteric coating on minitablets before encapsulation in the delayed-release capsule. This preliminary protective action prevents premature release in the stomach, allowing the drug to survive gastric conditions and release gradually in the intestine, thus avoiding stomach-related side effects while achieving therapeutic goals.
2Reliability
If higher doses of dimethyl fumarate are administered, then treatment efficacy is improved, but side effects increase
Solution Approach 1:
The patent segments the total daily dose into multiple smaller doses delivered through enteric-coated minitablets within a delayed-release capsule. This approach maintains cumulative efficacy equivalent to higher single doses while distributing the load over time, thereby reducing peak-related side effects.
Solution Approach 2:
The patent introduces an enteric coating as an intermediary layer between the fumarate ester and the gastric environment. This coating acts as a mediator that protects the drug from premature degradation and controlled release, enabling higher cumulative doses to be administered without proportionally increasing side effects.
3Ease of operation
If conventional oral formulations are used, then ease of administration is maintained, but bioavailability is insufficient
Solution Approach 1:
The patent creates a composite formulation combining enteric-coated minitablets within a delayed-release capsule containing liquid fill. This composite structure leverages the advantages of both solid and liquid dosage forms, improving bioavailability through enhanced dissolution while maintaining oral ease of administration.
Solution Approach 2:
The patent changes the physical and chemical parameters of the formulation by using enteric coating materials and delayed-release capsule components that optimize drug dissolution and absorption. These parameter changes enhance bioavailability without complicating the administration process, as the final product remains an orally ingestible capsule.
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 described compositions achieve enhanced bioavailability and reduced side effects by providing bioequivalent pharmacokinetic parameters to higher doses of dimethyl fumarate, effectively treating multiple sclerosis with lower doses, thereby improving treatment efficacy and patient tolerance.
Implementation Method 1
an immediate releasing single-phase non-aqueous liquid vehicle comprises a mixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lactic acid
Implementation Method 2
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, processes for making the same, and compositions and methods for treating multiple sclerosis subjects with the compositions. In particular, oral pharmaceutical compositions comprising fumarate esters in liquid vehicles are described. One embodiment is an oral delayed release pharmaceutical dosage form comprising a soft capsule encapsulating an immediate releasing liquid comprising one or more fumarate esters.