Modified Release RPPX Formulations for Neuroprotection

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Solution Overview

Problem

Current treatments for neurodegenerative disorders using pramipexole enantiomers face limitations due to dose titration requirements and side effects related to dopamine receptor agonist activity, restricting the therapeutic potential of the R(+) enantiomer (RPPX) despite its neuroprotective potency.

Innovation Solution

Development of modified release formulations of RPPX with high chiral purity, allowing for administration of higher doses without dose titration and minimizing dopamine receptor agonist-related side effects, thereby maximizing neuroprotective benefits.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If RPPX is administered at high doses to achieve neuroprotective effects, then neuroprotective potency is improved, but dopamine receptor agonist-related side effects increase

Engineering Contradiction:

Improveneuroprotective effectVSAvoiddopamine receptor agonist-related side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the release parameters of the formulation to achieve controlled, sustained release of RPPX over extended periods (12-24 hours or longer), allowing higher total doses to be administered while maintaining safe plasma levels through controlled release kinetics rather than immediate high-concentration exposure

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The formulation dynamically adjusts the release rate of RPPX over time, initially releasing at a controlled rate and then maintaining lower steady-state levels, which allows the system to tolerate higher total doses while minimizing peak-related side effects through time-dependent release control

Inventive Principle:

Principle #15Dynamics

2Object-affected harmful factors

If dose titration is performed to minimize side effects, then safety is improved, but treatment time is extended

Engineering Contradiction:

Improveside effectsVSAvoiddose titration duration

Core Design Contradiction:

Object-affected harmful factorsVSLoss of time

Solution Approach 1:

The formulation is designed to pre-establish safe plasma concentration profiles through controlled release mechanisms, eliminating the need for gradual dose titration by directly achieving therapeutic levels with minimized side effects from the first dose through sustained release over 12-24 hours or longer

Inventive Principle:

Principle #10Preliminary action

3Productivity

If maximum tolerated dose is increased to exploit neuroprotective potential, then therapeutic effectiveness is improved, but safety margin is reduced

Engineering Contradiction:

Improveneuroprotective therapeutic effectivenessVSAvoidsafety margin

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The formulation maintains continuous, sustained release of RPPX over extended periods (12-24 hours or longer), allowing the maximum tolerated dose to be administered continuously while the controlled release mechanism prevents harmful peak concentrations, thereby maintaining both high therapeutic effectiveness and safety margin through continuous controlled action rather than intermittent high-dose exposure

Inventive Principle:

Principle #20Continuity of useful action

Data Source

PatentUS8524695B2Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same

Publication Date: 2013.09.03 ARETEIA THERAPEUTICS INC

AI summary

Modified release pharmaceutical compositions (controlled release, sustained release, and/or extended release) of the R-(+) enantiomer of pramipexole (RPPX) and methods of using such compositions for the treatment of neurodegenerative diseases, or those related to mitochondrial dysfunction or increased oxidative stress are disclosed.