ETV Prodrug Sustained Release Formulation for HBV

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Solution Overview

Problem

Current treatments for chronic hepatitis B virus (HBV) infection, such as Entecavir (ETV), require daily dosing, which can lead to patient compliance challenges, and existing formulations do not provide sustained release, necessitating the development of a bioactive prodrug that offers prolonged therapeutic levels and improved administration methods.

Innovation Solution

A bioactive prodrug of ETV is formulated with specific functional groups and derivatives, including phosphate residues, which provides a sustained release mechanism when administered in aqueous solutions or oil solutions, allowing for long-acting antiviral activity against HBV, and is combined with water-soluble cellulose-based polymers and non-ionic surfactants for enhanced delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If daily dosing of ETV is used, then antiviral activity is maintained, but patient compliance deteriorates

Engineering Contradiction:

Improveantiviral activityVSAvoidpatient compliance

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent applies preliminary action by converting ETV into a prodrug form (ETV-palmitate) that is prepared in advance to provide sustained release. This prodrug is designed to release active ETV over an extended period (up to 1 month), eliminating the need for daily dosing while maintaining antiviral activity, thus resolving the compliance issue

Inventive Principle:

Principle #10Preliminary action

2Duration of action of moving object

If ETV-palmitate prodrug is used, then sustained release is achieved, but plasma levels above therapeutic level are not maintained for sufficient duration

Engineering Contradiction:

Improvesustained release durationVSAvoidtherapeutic plasma levels

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of ETV through prodrug conversion with different fatty acid esters (C12-C22). This structural modification changes the pharmacokinetic parameters, specifically extending the half-life and maintaining therapeutic plasma levels for prolonged periods (up to 1 month), thereby resolving the insufficient duration issue

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If conventional formulations are used, then administration is simple, but sustained release is not provided

Engineering Contradiction:

Improveadministration simplicityVSAvoidrelease duration

Core Design Contradiction:

Ease of operationVSDuration of action of moving object

Solution Approach 1:

The patent applies local quality by creating formulations with specific local characteristics - using water-soluble cellulose-based polymers and non-ionic surfactants in the formulation matrix. These localized functional components provide sustained release properties while maintaining ease of administration, resolving the contradiction between simple administration and prolonged release duration

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20240190878A1Antiviral prodrugs of ETV and formulations thereof

Publication Date: 2024.06.13 THE SCRIPPS RES INST

AI summary

Provided herein are compounds, compositions, and their methods of use for treatment and/or prevention of infections of HBV in a subject by administering a compound of structural formula (I) or a pharmaceutically acceptable salt thereof: wherein R1 and R2 are defined herein.