Heat-sterilized Chitosan-Glycerol Solution for Ophthalmic Use

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Solution Overview

Problem

Current chitosan compositions are not stable, clear, and viscous at neutral pH after heat sterilization, making them unsuitable for pharmaceutical use, particularly for ophthalmic applications.

Innovation Solution

A process involving solubilizing water-insoluble chitosan in an aqueous solution of a weak acid, adding glycerol, adjusting the pH with a weak base, and steam sterilizing to create a clear and viscous solution at a pH between 6 and 7.5, preventing aggregate formation and ensuring stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chitosan is heat-sterilized in aqueous solution, then sterilization is achieved, but aggregates form and solution clarity is lost

Engineering Contradiction:
ImprovesterilizationVSAvoidsolution clarity
Core Design Contradiction:
ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary action by adjusting the pH to acidic conditions (pH 2-4) before heat sterilization. This pre-adjustment prevents aggregate formation during sterilization by ensuring chitosan remains in its soluble protonated form, thereby maintaining solution clarity while achieving sterilization.

Inventive Principle:
Principle #10Preliminary action

2Adaptability or versatility

If pH is adjusted to neutral range (6-7.5), then physiological compatibility is improved, but chitosan precipitation occurs

Engineering Contradiction:
Improvephysiological compatibilityVSAvoidsolution stability
Core Design Contradiction:
Adaptability or versatilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by carefully controlling the final pH within the specific range of 6-7.5 after sterilization. This optimized pH range allows the solution to achieve physiological compatibility while maintaining chitosan solubility and preventing precipitation, thus ensuring both adaptability and compositional stability.

Inventive Principle:
Principle #35Parameter changes

3Productivity

If chitosan concentration is increased for desired viscosity, then therapeutic efficacy is improved, but aggregate formation increases

Engineering Contradiction:
ImproveviscosityVSAvoidaggregate formation
Core Design Contradiction:
ProductivityVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary action by adjusting pH to acidic conditions before heat sterilization and maintaining this control throughout the process. This pre-established acidic environment prevents aggregate formation even at higher chitosan concentrations required for therapeutic viscosity, thereby achieving both productivity and compositional stability.

Inventive Principle:
Principle #10Preliminary action

4Reliability

If heat sterilization is applied to existing chitosan formulations, then sterility is achieved, but solution stability and clarity are compromised

Engineering Contradiction:
ImprovesterilityVSAvoidsolution stability
Core Design Contradiction:
ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary action by adjusting the pH to acidic conditions (pH 2-4) before heat sterilization. This pre-adjustment ensures chitosan remains in its soluble form during the sterilization process, preventing aggregate formation and maintaining solution stability and clarity while achieving sterility.

Inventive Principle:
Principle #10Preliminary action

Solution Approach 2:

The patent applies parameter changes by optimizing the pH range after sterilization to 6-7.5. This controlled parameter adjustment ensures the final formulation achieves both sterility and long-term solution stability, preventing precipitation while maintaining therapeutic efficacy.

Inventive Principle:
Principle #35Parameter changes

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 process results in a stable, clear, and viscous chitosan-glycerol solution suitable for pharmaceutical use, particularly for ophthalmic applications, effectively addressing the challenges of aggregate formation and stability issues in existing compositions.

Implementation Method 1

Solubilizing chitosan having an average molecular weight ranging from 10 kDa to 250 kDa and a degree of deacetylation higher than 60% in an aqueous solution of weak acid comprising a carboxylic group

Methodology Applied
Scientific EffectProtonation:

Implementation Method 2

Steam sterilizing; thereby forming a heat-sterilized composition comprising solubilized chitosan and glycerol that is a clear and viscous solution

Methodology Applied
Scientific EffectHeat sterilization: Heating

Data Source

PatentEP3212166B1Heat-sterilized formulation comprising chitosan and process of preparation thereof
Publication Date: 2020.12.02 LABE MEDIDOM
  • EP3212166B1 patent drawingFigure 1~2
  • EP3212166B1 patent drawingFigure 3A~4
  • EP3212166B1 patent drawingFigure 5

AI summary

The present invention relates to a heat-sterilized aqueous composition comprising a solubilized chitosan and glycerol. It also relates to a process of preparation of the same, as well as the use thereof, including compositions useful for the prevention and treatment of dry eye syndrome and arthritic diseases or disorders.