Ketoprofen Patch Zinc Complex Stabilization

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Solution Overview

Problem

Nonsteroidal anti-inflammatory analgesics like ketoprofen, when combined with L-menthol in patches, face stability issues due to the formation of menthol esters and crystal precipitation, and existing solutions that add metal compounds hinder drug release.

Innovation Solution

A patch comprising ketoprofen, L-menthol, zinc oxide, and a fatty acid ester, which suppresses menthol ester production and crystal precipitation while maintaining excellent skin permeability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If metal compounds (metal oxides, metal hydroxides, metal carbonates) are added to suppress menthol ester formation, then stability is improved, but drug release from patches is suppressed

Engineering Contradiction:
ImprovestabilityVSAvoiddrug release
Core Design Contradiction:
Stability of the object's compositionVSProductivity

Solution Approach 1:

The patent changes the type of metal compound from conventional metal oxides/hydroxides/carbonates to a specific complex compound containing zinc ion and organic acid (where the organic acid is a hydroxy acid or amino acid). This parameter change in chemical composition allows the zinc complex to suppress menthol ester formation while maintaining drug release capability, resolving the contradiction between stability and productivity

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The invention uses a composite material approach by forming a complex compound between zinc ion and organic acid (hydroxy acid or amino acid). This composite structure provides both the stability function of metal compounds and the compatibility needed for drug release, overcoming the limitations of simple metal oxides/hydroxides/carbonates

Inventive Principle:
Principle #40Composite materials

2Ease of operation

If L-menthol is blended in patches with ketoprofen, then refreshing effect is improved, but menthol ester formation occurs reducing drug stability

Engineering Contradiction:
Improverefreshing effectVSAvoiddrug stability
Core Design Contradiction:
Ease of operationVSStability of the object's composition

Solution Approach 1:

The zinc complex compound acts as an intermediary substance between ketoprofen and L-menthol. It suppresses the direct reaction between ketoprofen's carboxylic acid group and L-menthol that would form menthol esters, thereby preventing drug degradation while allowing L-menthol to maintain its refreshing effect on the skin

Inventive Principle:
Principle #24Intermediary (Mediator)

3Duration of action of stationary object

If ketoprofen is stored over time in patches, then cumulative effect is improved, but crystal precipitation occurs reducing efficacy

Engineering Contradiction:
Improvecumulative effectVSAvoidcrystal precipitation
Core Design Contradiction:
Duration of action of stationary objectVSStability of the object's composition

Solution Approach 1:

The zinc complex compound serves as a stabilizing intermediary that prevents crystal precipitation of ketoprofen during long-term storage. By coordinating with ketoprofen molecules, it maintains them in a stable state and prevents crystallization, allowing the drug to maintain its amorphous state and efficacy over extended storage periods

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 patch effectively prevents menthol ester formation and crystal precipitation, ensuring stability and efficient drug release over time, while maintaining skin permeability.

Implementation Method 1

ketoprofen and L-menthol react to produce menthol esters, and it has long been known that problems occur in the stability of the drug... the addition of the above metal compounds suppresses drug release from the patches

Methodology Applied
Scientific EffectComplex formation:

Implementation Method 2

when a patch comprising ketoprofen and L-menthol also comprises zinc oxide as well as a fatty acid ester, such patch can suppress the production of a menthol ester of ketoprofen and yet shows excellent skin permeability

Methodology Applied
Scientific EffectPermeation enhancement:

Implementation Method 3

the present inventor has also found that the present invention can also suppress crystal precipitation of ketoprofen with time

Methodology Applied
Scientific EffectCrystal precipitation suppression:

Data Source

PatentUS20230398083A1Ketoprofen-containing patch
Publication Date: 2023.12.14 TEIKOKU SEIYAKU CO LTD

AI summary

The present invention provides a patch which prevents ketoprofen from forming a menthol ester, suppresses crystal precipitation, and yet shows excellent skin permeability. Specifically, the present invention provides a patch comprising ketoprofen, L-menthol, zinc oxide, and a fatty acid ester in a pasty preparation.