Factor Xa Inhibitor and Clopidogrel Fixed-Dose Combination

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Solution Overview

Problem

Current anticoagulant and antiplatelet therapies for thrombotic diseases often require dose titration and have limitations in combination therapies, leading to inadequate therapeutic benefits and safety concerns, particularly with existing anticoagulants like warfarin and fondaparinux, which are not suitable for fixed-dose combinations with antiplatelet agents.

Innovation Solution

A pharmaceutical composition combining a factor Xa inhibitor, specifically [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide (Compound A), with clopidogrel, allowing for predictable anticoagulation levels and a synergistic effect, enabling a fixed, non-dose-titrated combination therapy for treating thrombotic conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If warfarin is used as an anticoagulant for chronic use, then anticoagulation effect is achieved, but dose titration is required using INR clotting assays to avoid excessive blood thinning and bleeding risk, making it unsuitable for fixed-dose combination with antiplatelet agents

Engineering Contradiction:

Improveanticoagulation effectVSAvoiddose titration requirement

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent changes the pharmacological parameter by selecting a factor Xa inhibitor (Compound A) with a different mechanism of action compared to warfarin. This new compound achieves predictable anticoagulation at fixed doses without requiring INR monitoring, thereby resolving the contradiction between reliability of anticoagulation and ease of operation regarding dose titration

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs a fixed-dose regimen that does not require ongoing monitoring or adjustment, effectively replacing the need for continuous INR testing and dose adjustment with a simple fixed-dose administration strategy, improving ease of operation while maintaining therapeutic effectiveness

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Adaptability or versatility

If fondaparinux is combined with antiplatelet agents, then combination therapy is provided, but the combination does not provide sufficient therapeutic benefit as patients continue to experience thrombotic events

Engineering Contradiction:

Improvecombination therapy capabilityVSAvoidtherapeutic benefit

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent creates a composite therapeutic regimen by combining Compound A (a factor Xa inhibitor with specific chemical structure) and clopidogrel (a P2Y12 inhibitor). This composite combination provides synergistic antithrombotic effects that are superior to fondaparinux plus antiplatelet agents, as evidenced by reduced thrombotic events in clinical studies

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent introduces Compound A as an intermediary agent that bridges the gap between anticoagulation and antiplatelet therapy. By inhibiting factor Xa specifically, it provides a mechanism that complements P2Y12 inhibition by clopidogrel, creating a more effective dual mechanism approach compared to fondaparinux

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If combination therapy with anticoagulant and antiplatelet agents is implemented, then efficacy is increased and patient compliance is improved, but safety concerns arise regarding excessive blood thinning and bleeding risk

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidbleeding risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent eliminates the need for feedback-based dose adjustment (INR monitoring) by using a fixed-dose regimen of Compound A combined with clopidogrel. The predictable pharmacokinetics and pharmacodynamics of this combination allow for pre-determined dosing that maintains therapeutic efficacy while minimizing bleeding risk through optimized dose selection

Inventive Principle:

Principle #23Feedback

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 combination of Compound A with clopidogrel provides a superior efficacy and safety profile by achieving predictable anticoagulation levels and enhanced antithrombotic activity, with a wider safety margin and reduced risk of bleeding, compared to existing therapies, while allowing for lower dosages and improved patient compliance.

Implementation Method 1

Factor Xa, a serine protease, is the sole enzyme responsible for sustained thrombin formation in the vasculature. Thus, inhibition of factor Xa is considered to be an efficient anticoagulant strategy.

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Implementation Method 2

In another embodiment, the other therapeutic agent is an antiplatelet agent. In a further embodiment, the other therapeutic agent is clopidogrel.

Methodology Applied

Scientific EffectReceptor antagonism:

Data Source

PatentEP2155195B1Combination anticoagulant therapy with a compound that acts as a factor Xa inhibitor

Publication Date: 2014.07.16 MILLENNIUM PHARMACEUTICALS INC

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AI summary

The present invention is directed to methods of using combination therapies containing [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide for the treatment of thrombotic disease(s) and pharmaceutical compositions thereof.