Tropicamide Ophthalmic Formulation Neutral pH Stability

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Solution Overview

Problem

Current ophthalmic formulations of tropicamide are poorly tolerated due to acidic pH, leading to discomfort and reduced bioavailability, as they require repeated administration and have instability issues, especially when using high temperatures and long processing times for solubilization.

Innovation Solution

An ophthalmic composition combining HP-β-CD at concentrations from 0.8 to 2.0% with polyethylene glycol (15)-hydroxystearate (Solutol HS 15) at similar concentrations, formulated at neutral pH using phosphate, citrate, or borate buffers, along with osmotizing agents and viscous polymers, to enhance solubility and stability without requiring high temperatures or long processing times.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If tropicamide is formulated at acidic pH (4.0-5.8) to improve solubility, then solubility is improved, but ocular tolerability deteriorates causing discomfort and lacrimation

Engineering Contradiction:

ImprovesolubilityVSAvoidocular tolerability

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent changes the pH parameter from acidic (4.0-5.8) to neutral (6.5-7.6), and simultaneously modifies the solubilization mechanism by introducing HP-β-CD and surfactants. This allows maintaining adequate solubility while eliminating the harmful acidic effect on the ocular surface.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

HP-β-CD acts as an intermediary substance that forms inclusion complexes with tropicamide, enabling solubilization at neutral pH. The surfactant serves as another intermediary that facilitates solubility through micelle formation, both allowing pH adjustment to tolerable levels.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If repeated doses are administered to maintain therapeutic effect, then bioavailability is maintained, but treatment duration and patient discomfort increase

Engineering Contradiction:

ImprovebioavailabilityVSAvoidtreatment duration

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The formulation provides continuous therapeutic action through extended pre-corneal residence time (at least 4 hours), reducing the frequency of administration from 3-4 times to once or twice daily, thereby maintaining bioavailability while reducing treatment duration and patient burden.

Inventive Principle:

Principle #20Continuity of useful action

3Stability of the object's composition

If high concentration of HP-β-CD (4%) is used to ensure physical stability, then physical stability is improved, but cost and toxicity increase

Engineering Contradiction:

Improvephysical stabilityVSAvoidtoxicity and cost

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent combines HP-β-CD with a surfactant in synergistic association, where the surfactant enhances the solubilizing effect. This allows reducing HP-β-CD concentration from 4% to 0.8-2.0% while maintaining physical stability, thereby reducing toxicity and cost.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The formulation uses a composite system of HP-β-CD and surfactant working together, where each component contributes to solubilization and stability. This composite approach achieves enhanced stability at lower individual component concentrations, reducing overall toxicity and manufacturing cost.

Inventive Principle:

Principle #40Composite materials

4Quantity of substance

If high concentration of surfactant (15% pluronic P85) is used to solubilize tropicamide at neutral pH, then solubility is improved, but ocular tolerability deteriorates

Engineering Contradiction:

ImprovesolubilityVSAvoidocular tolerability

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent merges HP-β-CD with a surfactant (polyethylene glycol (15)-hydroxystearate) in optimal proportions, where the cyclodextrin provides the primary solubilization mechanism through inclusion complexes, and the surfactant provides secondary solubilization through micelle formation. This synergistic combination achieves adequate solubility at much lower surfactant concentrations (0.8-2.0%) compared to pluronic P85 (15%), thereby improving ocular tolerability.

Inventive Principle:

Principle #5Merging (Combining)

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 achieves physical stability for 24 months, is well-tolerated, and exhibits a synergistic solubilizing effect, reducing the overall excipient content needed to maintain tropicamide in solution at neutral pH, thereby increasing bioavailability and pre-corneal residence time.

Implementation Method 1

The solubilization effect is ascribed to the association between TRP and HP-β-CD, as well as to the surfactant

Methodology Applied

Scientific EffectInclusion complexation: Absorption (physical)

Implementation Method 2

said at least one surfactant is polyethylene glycol (15)-hydroxystearate

Methodology Applied

Scientific EffectSurfactant action: Surfactant

Data Source

PatentEP3641764B1Tropicamide-based ophthalmic formulations

Publication Date: 2025.01.01 MEDIVIS SRL

AI summary

The present invention relates to an ophthalmic composition comprising tropicamide, at least one cyclodextrin at concentrations of less than 2.5%, at least one surfactant at concentrations of less than 2.5%. Said composition is physically stable at neutral pH.