Amorphous Dispersion Sustained Release Formulation for A2A Antagonists

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Solution Overview

Problem

Current formulations of A2A receptor antagonists, such as those for Parkinson's disease, face challenges with poor solubility and bioavailability, particularly when co-administered with proton-pump inhibitors, leading to variable therapeutic serum levels and adverse effects due to frequent dosing requirements.

Innovation Solution

An amorphous dispersion comprising an A2A antagonist, a polymer matrix, and a plasticizer, specifically formulated through hot-melt extrusion to create a stable supersaturated solution that maintains therapeutic serum levels for extended periods, potentially up to 24 hours, using a combination of methacrylic acid-based copolymers and triethylcitrate as a plasticizer.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional formulations of A2A receptor antagonists are used, then the drug can be administered, but solubility and bioavailability are poor leading to variable therapeutic serum levels

Engineering Contradiction:

ImprovebioavailabilityVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent transforms the crystalline API into an amorphous state and incorporates it into a polymer matrix with plasticizers, fundamentally changing the physical and chemical parameters of the drug formulation. This parameter change enables the poorly soluble API to achieve enhanced solubility and bioavailability while maintaining compositional stability during storage and administration.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite material system consisting of the A2A antagonist API dispersed within a polymer matrix (such as HPMC or Eudragit) combined with plasticizers. This composite structure leverages the properties of each component: the polymer provides structural stability and controlled release, while the plasticizer enhances flexibility and solubility, collectively resolving the contradiction between solubility and stability.

Inventive Principle:

Principle #40Composite materials

2Reliability

If frequent dosing is administered to maintain therapeutic levels, then therapeutic effect is maintained, but adverse effects increase due to frequent administration

Engineering Contradiction:

Improvetherapeutic effectVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent designs a sustained-release formulation that transforms frequent periodic dosing into less frequent periodic administration. The amorphous dispersion in polymer matrix releases the API continuously over extended periods (e.g., 12-24 hours), maintaining therapeutic serum levels while reducing dosing frequency from multiple times daily to once or twice daily, thereby reducing adverse effects associated with frequent administration.

Inventive Principle:

Principle #19Periodic action

Solution Approach 2:

The formulation ensures continuous release of the A2A antagonist at therapeutic levels over an extended period through the controlled dissolution and diffusion mechanisms of the amorphous dispersion system. This continuous action maintains stable plasma concentrations, avoiding the peaks and troughs associated with frequent dosing, and thereby reduces adverse effects while preserving therapeutic efficacy.

Inventive Principle:

Principle #20Continuity of useful action

3Speed

If immediate release formulation is used, then rapid onset of action is achieved, but therapeutic serum levels cannot be maintained for extended periods

Engineering Contradiction:

Improveonset of actionVSAvoidduration of therapeutic effect

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The patent creates a dynamic release system where the amorphous dispersion in polymer matrix provides both rapid initial release for quick onset of action and sustained release for extended duration. The system adapts its release rate based on gastrointestinal conditions, providing fast dissolution when needed while maintaining therapeutic levels over 12-24 hours, thus resolving the contradiction between speed and duration.

Inventive Principle:

Principle #15Dynamics

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 formulation provides consistent bioavailability and sustained therapeutic serum levels for 12 to 24 hours, reducing the frequency of administration and minimizing adverse effects, while maintaining effective treatment of Parkinson's disease symptoms.

Implementation Method 1

An amorphous dispersion comprising an A2A antagonist, a polymer matrix, and a plasticizer, specifically formulated through hot-melt extrusion to create a stable supersaturated solution

Methodology Applied

Scientific EffectAmorphous dispersion:

Implementation Method 2

specifically formulated through hot-melt extrusion to create a stable supersaturated solution

Methodology Applied

Scientific EffectHot-melt extrusion: Extrusion

Data Source

PatentUS10207002B2Sustained release formulation and tablets prepared therefrom

Publication Date: 2019.02.19 MERCK SHARP & DOHME LLC

AI summary

Disclosed are formulations and tablets made therefrom comprising the compound of Formula IA or Formula IB which have sustained-release properties, and the dispersion containing the compounds of Formula IA or IB which facilitates such sustained release: Formula IA, Formula IB.