Controlled-Release Levodopa Dosing for Stable Plasma Levels

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Solution Overview

Problem

Current oral levodopa (LD) dosage forms experience rapid metabolism, leading to unpredictable plasma levels and motor fluctuations in Parkinson's disease patients, making it difficult to achieve steady plasma concentrations and effective dosing frequencies, particularly with absorption issues in the gastrointestinal tract.

Innovation Solution

A dosing regimen using controlled release pharmaceutical compositions of LD, allowing twice or thrice daily dosing with a combination of immediate and modified release components, such as beads or pellets, to maintain steady plasma levels and minimize fluctuations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oral levodopa is administered without controlled release formulation, then immediate therapeutic effect is achieved, but plasma levels fluctuate unpredictably and duration of action is short

Engineering Contradiction:

Improveplasma level stabilityVSAvoidduration of therapeutic effect

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The levodopa dosage form is segmented into multiple beads or pellets, each with different release characteristics. This segmentation allows simultaneous presence of immediate-release and controlled-release components in the same dosage form, achieving both rapid onset and sustained effect without requiring multiple separate administrations.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention merges immediate-release and controlled-release levodopa components into a single combined dosage form. This merging allows the patient to receive both rapid therapeutic effect and sustained plasma level maintenance from one administration, resolving the contradiction between immediate effect and duration of action.

Inventive Principle:

Principle #5Merging (Combining)

2Duration of action of moving object

If levodopa is released from dosage form in lower gastrointestinal tract, then extended duration is achieved, but absorption is minimal due to narrow absorption window

Engineering Contradiction:

Improveduration of levodopa releaseVSAvoidamount of levodopa absorbed

Core Design Contradiction:

Duration of action of moving objectVSQuantity of substance

Solution Approach 1:

Different beads or pellets within the dosage form have different release properties tailored to specific gastrointestinal locations. Some beads are designed to release levodopa in the upper GI tract where absorption is optimal, while others release later in the lower GI tract to extend duration. This local quality differentiation ensures that levodopa is released at the right place and time for maximum absorption and sustained effect.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The dosage form implements periodic release of levodopa through different bead populations releasing at different times and locations along the GI tract. This periodic action ensures continuous presence of levodopa in the absorption window, maintaining steady plasma levels while extending overall duration of action.

Inventive Principle:

Principle #19Periodic action

3Reliability

If levodopa is administered frequently to maintain steady plasma levels, then motor fluctuations are reduced, but patient compliance and ease of operation deteriorate

Engineering Contradiction:

Improvemotor symptom controlVSAvoiddosing frequency

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The invention combines immediate-release and controlled-release levodopa in a single dosage form, allowing the patient to achieve steady plasma levels and reduced motor fluctuations from once or twice daily administration rather than requiring multiple doses throughout the day. This merging improves ease of operation while maintaining reliable motor symptom control.

Inventive Principle:

Principle #5Merging (Combining)

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 regimen provides stable plasma concentrations of LD, reducing 'Off' time and increasing 'On' time, with minimal fluctuations, and therapeutic benefits throughout the day, including during sleep, while minimizing adverse reactions.

Implementation Method 1

controlled release pharmaceutical compositions of LD

Methodology Applied

Scientific EffectControlled release:

Implementation Method 2

Combinations of LD and a decarboxylase inhibitor (typically carbidopa (hereinafter 'CD')) to treat PD

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Data Source

PatentUS12447139B2Levodopa dosing regimen

Publication Date: 2025.10.21 AMNEAL PHARMACEUTICALS LLC

AI summary

The invention is a method for treating patients with Parkinson's disease by orally administering a controlled release levodopa formulation and the method provides an improvement of a patient's total post-dose “Off” time, total post dose “On” time and total post dose “Good On” time compared to post-dose of treatment regimens with oral immediate release levodopa tablets.