Topical Diaminophenothiazine Formulation for Ocular Peripheral Neuropathy

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Solution Overview

Problem

Current treatments for diabetic peripheral neuropathy, particularly affecting the corneal nerves, are inadequate, and methylthioninium chloride (MTC) is toxic and unsuitable for ocular use due to solubility issues and potential harm.

Innovation Solution

A topical preparation using a low concentration of 3,7-bis(dimethylamino) phenothiazin-5-ium chloride, buffered to physiological pH and formulated with a carrier-medium, is applied to prevent and treat peripheral nerve damage, including corneal nerve issues, with controlled release and increased viscosity to enhance bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If methylthioninium chloride (MTC) is used to treat peripheral neuropathy, then nerve damage is reduced, but toxicity and unsuitability for ocular use occur

Engineering Contradiction:

Improveeffectiveness in reducing nerve damageVSAvoidtoxicity and harm to ocular tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the concentration parameter of MTC from typical therapeutic levels to a low concentration range (0.001-150 μM), and modifies the formulation parameters by buffering to physiological pH and adding carrier media. This resolves the contradiction by maintaining neuroprotective effectiveness while reducing toxicity and improving ocular compatibility.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces carrier media (such as hydrogels, cyclodextrins, or lipid-based carriers) as intermediaries to deliver MTC to peripheral nerves. This mediator approach allows the active compound to exert its neuroprotective effect while the carrier system reduces direct toxicity and improves ocular tolerance by controlling release and reducing peak concentrations.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If MTC is formulated for ocular use, then corneal nerve damage is prevented, but solubility issues and staining occur

Engineering Contradiction:

Improveprotection of corneal nervesVSAvoidsolubility and formulation stability

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent formulates MTC as a composite preparation combining the active compound with carrier media such as hydrogels, cyclodextrins, or lipid-based systems. This composite approach resolves solubility issues by incorporating MTC into a compatible matrix, improves formulation stability, and reduces staining by controlling the release and distribution of the compound.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

Carrier media act as intermediaries that improve the solubility of MTC in aqueous ocular environments. These carriers (hydrogels, cyclodextrins, lipids) form stable complexes with MTC, enhancing its solubility and formulation stability while preventing direct contact that would cause staining.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If high concentration of MTC is used, then neuroprotective effect is enhanced, but toxicity and staining increase

Engineering Contradiction:

Improveneuroprotective effectVSAvoidtoxicity and unsightly stains

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent employs sustained-release formulations that deliver MTC in periodic or prolonged low-dose regimens rather than single high-dose applications. This periodic delivery maintains neuroprotective effectiveness over time while keeping peak concentrations low enough to avoid toxicity and staining.

Inventive Principle:

Principle #19Periodic action

Solution Approach 2:

The patent uses low concentrations of MTC (0.001-150 μM) that are partially sufficient for immediate effect but are delivered continuously through sustained-release mechanisms. This partial action approach maintains effectiveness while avoiding the excessive concentrations that cause toxicity and staining.

Inventive Principle:

Principle #16Partial or excessive 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 formulation effectively reduces nerve damage by minimizing glucose-induced mitochondrial stress and toxin effects, providing sustained protection and reducing unsightly stains, suitable for ocular and peripheral nerve applications.

Implementation Method 1

Methylthioninium Chloride (MTC) (also known as Methylene blue (MB)... has been used as an oxidizing/reducing ( redox) agent

Methodology Applied

Scientific EffectRedox reactions: Redox Reactions

Data Source

PatentEP4017496B1Formulations for use in the prevention and/or treatment of peripheral neuropathy and its associated diseases

Publication Date: 2026.01.07 LOH YIN SZE

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AI summary

The invention relates to formulations and methods of using formulations of topical preparation of diaminophenothiazine compounds such as 3,7-bis(dimethylamino)phenothiazin-5-ium chloride in the prevention and/or treatment of peripheral neuropathy and its associated conditions, particularly in the eye. In a preferred embodiment, a topical formulation comprising 3,7-bis(dimethylamino)phenothiazin-5-ium chloride encapsulate in poly(lactic-co-glycolic acid (PLGA) microparticles is prepared, wherein the microparticles are coated with a mucoadhesive agent such as chitosan.