Liquid Factor VIII Stabilization via Protease Removal

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Solution Overview

Problem

Current Factor VIII products are unstable in liquid form, requiring lyophilization and reconstitution, which is cumbersome for patients, and existing liquid formulations have limited stability, retaining less than 80% potency for only hours or days.

Innovation Solution

A liquid composition of Factor VIII or Factor VIII/von Willebrand Factor complex is developed using stabilizers such as glycerol, sorbitol, sucrose, trehalose, betaine, antithrombin III, and heparin, combined with affinity chromatography to remove proteases, achieving stability for at least 100 days.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If Factor VIII is formulated in liquid state for patient convenience, then ease of operation is improved, but stability deteriorates with potency retention below 80% after only hours or days

Engineering Contradiction:

Improveease of useVSAvoidstability

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary action by performing affinity chromatography treatment during manufacturing to remove proteases before the product is stored and used. This pre-removal of degrading enzymes ensures that the Factor VIII remains stable throughout storage and administration, eliminating the need for lyophilization while maintaining potency for extended periods

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent changes the compositional parameters by formulating the liquid product with specific stabilizing excipients and controlling protease content through affinity chromatography. This parameter optimization allows the liquid formulation to maintain >80% potency for at least 100 days, resolving the stability issue while preserving the convenience of liquid administration

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If lyophilization is used to preserve Factor VIII stability, then stability is improved, but device complexity increases due to reconstitution requirements

Engineering Contradiction:

ImprovestabilityVSAvoidcomplexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent extracts and removes the harmful proteases from the Factor VIII formulation through affinity chromatography treatment. By eliminating these degrading enzymes during manufacturing, the product achieves sufficient stability in liquid form without requiring lyophilization, thereby simplifying the administration process and reducing device complexity

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent creates a disposable-like convenience by providing a pre-stabilized liquid formulation that can be directly administered without reconstitution. The affinity chromatography treatment during manufacturing creates a product that is stable enough for direct use, eliminating the need for complex reconstitution procedures and making the treatment simpler and more patient-friendly

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Manufacturing precision

If proteases are present in the formulation, then manufacturing precision is maintained, but stability deteriorates due to proteolytic degradation

Engineering Contradiction:

Improvemanufacturing precisionVSAvoidstability

Core Design Contradiction:

Manufacturing precisionVSStability of the object's composition

Solution Approach 1:

The patent converts the harmful effect of proteases into a benefit by using their specific binding properties during affinity chromatography. The proteases are selectively captured by the affinity resin through their unique molecular recognition, allowing for their efficient removal while preserving the Factor VIII activity. This transforms the protease presence from a stability problem into a selective purification opportunity

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent introduces an intermediary substance - the affinity chromatography resin - that mediates between the proteases and the Factor VIII. This intermediary selectively binds the proteases, allowing their removal from the formulation while leaving the Factor VIII intact. The affinity resin acts as a mediator that separates the harmful proteases from the therapeutic Factor VIII, resolving the stability issue

Inventive Principle:

Principle #24Intermediary (Mediator)

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 maintains >80% of initial Factor VIII:C activity for extended periods, exceeding previous stability limits, allowing for stable storage and use of liquid Factor VIII products.

Implementation Method 1

affinity chromatography to remove proteases

Methodology Applied

Scientific EffectAffinity chromatography: Chromatography

Implementation Method 2

stabilizers such as glycerol, sorbitol, sucrose, trehalose, betaine

Methodology Applied

Scientific EffectOsmotic pressure: Osmotic Pressure

Data Source

PatentUS20240189398A1Liquid composition comprising factor viii or factor viii/von willebrand factor complex

Publication Date: 2024.06.13 GRIFOLS WORLDWIDE OPERATIONS

AI summary

A liquid composition comprising Factor VIII or Factor VIII/von Willebrand Factor complex comprising one or more stabilizers selected from glycerol, sorbitol, sucrose, trehalose, betaine, proline, arginine, histidine, NaCl, calcium, surfactants, antithrombin III, heparin, and albumin, wherein the content of proteases is 30 ng/1,000 FVIII IU or less, wherein osmolality of said composition is between 350 and 800 mOsmol/kg.