Voriconazole Hydrogel Synthesis via Schiff Base Condensation

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Solution Overview

Problem

Conventional voriconazole eye drops suffer from poor solubility, low bioavailability, and short retention time on the ocular surface, necessitating frequent administration and potential side effects due to low osmolality and poor permeability.

Innovation Solution

A method is developed to synthesize voriconazole hydrogel using polyaldehyde oligomer and amino-functionalized hyaluronic acid through a Schiff base condensation reaction, enhancing solubility, penetration, and ocular surface retention, incorporating a nano-enzymatic composite hydrogel with thixotropic properties for improved drug distribution.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If voriconazole is used in conventional eye drops, then the drug can be administered topically, but the solubility is poor and bioavailability is low

Engineering Contradiction:

ImprovesolubilityVSAvoidbioavailability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent combines voriconazole with cyclodextrin to form an inclusion complex, creating a composite material system where the cyclodextrin cavity encapsulates the voriconazole molecule. This composite structure dramatically improves water solubility while maintaining drug stability and bioavailability, directly resolving the contradiction between solubility and bioavailability

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

Cyclodextrin acts as an intermediary substance that mediates between the hydrophobic voriconazole molecule and the aqueous environment. The cyclodextrin cavity provides a hydrophobic interior space for voriconazole while the exterior remains hydrophilic, enabling the drug to dissolve in water without compromising its molecular integrity or bioavailability

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If voriconazole eye drops are administered frequently to maintain effective concentration, then therapeutic effect is improved, but side effects increase and antifungal resistance is promoted

Engineering Contradiction:

Improvetherapeutic effectVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The cyclodextrin-inclusion complex formulation provides sustained and stable drug release, maintaining effective voriconazole concentrations continuously at the ocular surface. This continuous therapeutic action eliminates the need for frequent dosing while preventing the development of resistance and reducing side effects associated with repeated administration

Inventive Principle:

Principle #20Continuity of useful action

3Reliability

If osmolality regulators are added to voriconazole eye drops, then osmolality is regulated, but the formulation becomes more complex

Engineering Contradiction:

ImproveosmolalityVSAvoidformulation complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Cyclodextrin serves multiple functions simultaneously: it acts as a solubilizing agent to improve voriconazole solubility, a stabilizer to maintain drug integrity, and an osmolality regulator to ensure physiological compatibility. This multi-functionality eliminates the need for separate osmolality regulators, reducing formulation complexity while maintaining reliable osmolality control

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 method significantly increases drug permeability and retention time, allowing for reduced dosing frequency from 12 times a day to 2 times a day, while providing an electrostatic repulsion antifungal effect and scavenging reactive oxygen species, effectively treating fungal keratitis.

Implementation Method 1

A method is developed to synthesize voriconazole hydrogel using polyaldehyde oligomer and amino-functionalized hyaluronic acid through a Schiff base condensation reaction

Methodology Applied

Scientific EffectSchiff base condensation reaction: Chemical Bonding

Implementation Method 2

incorporating a nano-enzymatic composite hydrogel with thixotropic properties for improved drug distribution

Methodology Applied

Scientific EffectThixotropy: Thixotropy

Implementation Method 3

providing an electrostatic repulsion antifungal effect and scavenging reactive oxygen species

Methodology Applied

Scientific EffectElectrostatic repulsion: Electrostatics

Data Source

PatentUS20240415766A1Preparation method of voriconazole hydrogel and eye drops using the same

Publication Date: 2024.12.19 EYE INSTITUTE OF SHANDONG FIRST MEDICAL UNIVERSITY (SHANDONG EYE INSTITUTE QINGDAO EYE HOSPITAL

AI summary

In response to poor solubility and permeability of conventional voriconazole eye drops and short retention time thereof at the ocular surface, a preparation method of voriconazole hydrogel and eye drops using the same are provided. The preparation method includes steps of: adding DAPA and sodium hydroxide to deionized water, stirring until completely dissolved to produce a DAPA solution; dropping the DAPA solution into triformylbenzene ethanol solution, and reacting at room temperature; then centrifugating, washing precipitation with ethanol, and freeze-drying in vacuum, so as to obtain a polyaldehyde oligomer; and reacting the polyaldehyde oligomer with AHA to synthesize the voriconazole hydrogel. A preparation method of a topical ocular drug includes: applying a therapeutically effective amount the voriconazole hydrogel, wherein the topical ocular drug is for mechanical injury or fungal keratitis. The present invention improves aqueous solubility, penetration, and ocular surface retention time of VCZ.