Thermoreversible Hydrogel Plasminogen Activator Formulation

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Solution Overview

Problem

Current treatments for intracerebral hemorrhage (ICH) using tissue plasminogen activator (tPA) face limitations such as slow and inefficient haematoma evacuation, risk of rebleeding, and neuromodulatory side effects, with existing formulations struggling to maintain protein activity and achieve substantial haematoma reduction.

Innovation Solution

A slow-release composition of plasminogen activator nanoparticles combined with a thermoreversible polymer, specifically using poloxamer 407, allows for high concentration loading and controlled release of plasminogen activator over 24 hours, reducing the need for repeated injections and enhancing thrombolytic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If repeated injections of tPA are used to evacuate haematoma, then haematoma reduction is achieved, but treatment time is extended and patient exposure to side effects increases

Engineering Contradiction:

Improvehaematoma evacuation efficiencyVSAvoidtotal treatment time

Core Design Contradiction:

ProductivityVSLoss of time

Solution Approach 1:

The patent employs a sustained-release formulation of tPA embedded in a hydrogel matrix that continuously releases the thrombolytic agent over 24-48 hours, eliminating the need for repeated injections and maintaining continuous therapeutic action at the haematoma site

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The tPA is pre-loaded into the hydrogel matrix before administration, allowing the drug to be delivered in a controlled manner over an extended period, thereby achieving the therapeutic effect without requiring multiple separate administration events

Inventive Principle:

Principle #10Preliminary action

2Productivity

If high concentration of tPA is administered to accelerate clot lysis, then thrombolytic efficacy is improved, but risk of rebleeding and harmful side effects increases

Engineering Contradiction:

Improvethrombolytic efficacyVSAvoidrebleeding risk and neuromodulatory side effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The hydrogel formulation enables high local concentration of tPA at the haematoma site while the sustained-release mechanism prevents systemic circulation of excessive drug levels, thereby achieving effective local clot lysis without proportionally increasing systemic side effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The continuous low-dose release profile maintains therapeutic efficacy while avoiding peak concentration spikes that would trigger rebleeding and neuromodulatory side effects

Inventive Principle:

Principle #20Continuity of useful action

3Reliability

If standard tPA formulation is used, then clot lysis is achieved, but protein activity is lost due to degradation and repeated injections are required

Engineering Contradiction:

Improveplasminogen activator activityVSAvoidduration of therapeutic effect

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The hydrogel matrix serves as an intermediary carrier that protects tPA from degradation enzymes in the bloodstream and interstitial fluid, maintaining protein integrity and activity throughout the sustained-release period

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The sustained-release mechanism ensures continuous therapeutic action over 24-48 hours from a single administration, eliminating treatment gaps that would otherwise require repeated injections

Inventive Principle:

Principle #20Continuity of useful action

4Productivity

If multiple injections are administered to achieve substantial haematoma reduction, then treatment efficacy is improved, but treatment complexity and patient burden increase

Engineering Contradiction:

Improvehaematoma reduction achievementVSAvoidtreatment protocol complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The tPA is pre-loaded into the hydrogel matrix at optimized concentrations during manufacturing, allowing a single injection to deliver the complete therapeutic dose that would otherwise require multiple separate administrations

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The formulation combines the drug delivery system and sustained-release mechanism into a single injectable hydrogel product, simplifying the treatment protocol while achieving the cumulative effect of multiple injections

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 composition achieves better thrombolytic efficacy with reduced side effects, allowing for substantial haematoma reduction and improved patient outcomes by maintaining plasminogen activator activity and facilitating safer, more efficient clot lysis.

Implementation Method 1

a slow-release composition of plasminogen activator nanoparticles combined with a thermoreversible polymer, specifically using poloxamer 407, allows for high concentration loading and controlled release of plasminogen activator over 24 hours

Methodology Applied

Scientific EffectThermoreversible gelation: Gel

Implementation Method 2

Tissue plasminogen activator (tPA) is the only medicine (recombinant Thrombolytic agent) approved for the treatment of Ischemic Stroke. This 527 amino-acids glycoprotein is composed of five domains from the N-terminal end to the C-terminal end: finger domain, EGF-like domain, two kringle domains and the proteolytic domain

Methodology Applied

Scientific EffectEnzymatic catalysis: Enzyme

Data Source

PatentUS20230263870A1Slow release plasminogen activator formulation for use in the treatment of thrombotic or haemorrhagic disease

Publication Date: 2023.08.24 OP2LYSIS

AI summary

The present invention relates to slow release plasminogen activator composition. The present invention also relates to the therapeutic use of said composition, in particular in thrombotic or haemorrhagic disease.