GSNO Stabilization via Alkaline pH and Polymers

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Solution Overview

Problem

Current NO-donor compounds for treating microcirculatory disturbances, such as diabetic ulcers, have stability issues due to rapid degradation and systemic effects, limiting their efficacy and safety for local vasodilation without significant systemic impact.

Innovation Solution

A pharmaceutical composition with S-nitrosoglutathione (GSNO) at an alkaline pH of 8-9, stabilized by polymers like PVA and PEG, which enhances stability and maintains local vasodilatory effects, preventing rapid decomposition and systemic absorption.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional NO-donor compounds (nitroglycerine, nitroprusside, nitrate) are used for local vasodilation, then NO can be released to improve microcirculation, but rapid degradation occurs leading to loss of stability and predictable local effect

Engineering Contradiction:

Improvestability of NO-donor compoundVSAvoidduration of local vasodilator effect

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent changes the chemical state of the NO-donor by using S-nitrosoglutathione (GSNO) instead of conventional nitrate/nitroprusside compounds. This parameter change in molecular structure fundamentally alters the degradation kinetics, providing both stability and sustained local action without rapid decomposition

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces polysaccharide-type polymers as intermediary substances that stabilize GSNO in the formulation. These polymers act as mediators that prevent rapid degradation of the NO-donor while maintaining its vasodilator activity, thereby extending the duration of local effect

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If NO-donor compounds are administered to achieve local vasodilation, then microcirculatory disturbance can be treated, but systemic circulation is affected causing unwanted systemic effects

Engineering Contradiction:

Improvesystemic effects of NO-donorVSAvoidlocal specificity of vasodilation

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent achieves local specificity by formulating GSNO in a topical composition with polysaccharide-type polymers that remain largely in the local tissue environment. This local quality approach ensures that the NO is released primarily at the application site rather than entering systemic circulation, thereby treating local microcirculatory disturbances without causing widespread systemic effects

Inventive Principle:

Principle #3Local quality

3Productivity

If GSNO is produced under acidic condition to obtain maximum yield, then good production efficiency is achieved, but stability under alkaline condition deteriorates

Engineering Contradiction:

Improveyield of GSNO productionVSAvoidstability of GSNO under alkaline condition

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The patent resolves this contradiction by changing the pH parameter of the formulation to alkaline conditions (pH 8-9) after production. This parameter change creates a stable environment for GSNO that prevents degradation while maintaining the high yield achieved during acidic production. The polysaccharide-type polymers further enhance this stability in alkaline conditions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies preliminary action by producing GSNO under acidic conditions to achieve maximum yield, then immediately adjusting the pH to alkaline conditions and adding stabilizing polymers before application. This preliminary production step followed by stabilization ensures both high yield and long-term stability in the final formulation

Inventive Principle:

Principle #10Preliminary action

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 provides sustained local vasodilation and increased blood flow, effectively treating and preventing conditions like diabetic ulcers and neuropathy with enhanced stability for storage and application.

Implementation Method 1

GSNO is a quickly reacting gaseous compound... the decomposition of GSNO... NO is released

Methodology Applied

Scientific EffectDecomposition: Decomposition (biological)

Implementation Method 2

GSNO produced in good yield under acidic condition is more stabile under alkaline condition, especially in the presence of stabilizing polymers... the stabilizing effect of polymers can be significantly enhanced when the pH value of the composition is within the alkaline range

Methodology Applied

Scientific EffectStabilization:

Implementation Method 3

NO can beneficially affect the microcirculatory disturbance... smooth muscle relaxing effect... local vasodilation

Methodology Applied

Scientific EffectVasodilation:

Data Source

PatentEP2252260B1Method for stabilization of s-nitrosoglutathione and composition prepared by the same

Publication Date: 2015.03.04 PHARMAGENIX

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AI summary

The invention relates to pharmaceutical compositions having alkaline pH comprising S-nitrosoglutathione (GSNO) as active ingredient together with usual additives, optionally with one or more polysaccharide-type polymer(s). Another subject of the invention is a method for stabilizing a solution or non-solid composition containing GSNO wherein the pH of the solution or composition is adjusted to an alkaline value.