Dipeptide Prodrug Linkers for Controlled Drug Release

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Solution Overview

Problem

Current drug delivery methods face challenges with non-covalent polymer mixtures and permanent covalent attachments, such as uncontrolled drug release, loss of bioactivity, and interpatient variability, particularly for peptides and proteins, due to the need for efficient encapsulation and enzymatic dependence.

Innovation Solution

Development of carrier-linked prodrugs with temporary amide linkages between dipeptide moieties and aliphatic amine groups, allowing for controlled release of unmodified biologically active entities through autohydrolysis, utilizing a dipeptide linker with a permanent bond to a polymer carrier, enabling therapeutically useful hydrolysis rates without generating reactive intermediates.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If non-covalent polymer mixtures are used for drug encapsulation, then extended release profiles can be achieved, but uncontrolled burst-type release occurs and conformationally sensitive drugs become dysfunctional

Engineering Contradiction:

Improverelease durationVSAvoidrelease control

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The invention segments the drug delivery system into distinct functional components: a polymer carrier and a drug molecule connected through a specific linker architecture. The linker contains a polymer-conjugating group and a drug-conjugating group separated by a spacer, creating discrete functional zones that control drug release independently rather than relying on bulk polymer degradation

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The linker acts as an intermediary component between the polymer carrier and the drug molecule. It mediates the connection through temporary covalent bonds that can be cleaved to release the drug, providing controlled release without requiring bulk polymer degradation or physical encapsulation

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of manufacture

If non-covalent encapsulation is used, then drug release can occur through carrier degradation, but interpatient variability increases due to enzyme dependence

Engineering Contradiction:

Improveformulation simplicityVSAvoidrelease predictability

Core Design Contradiction:

Ease of manufactureVSAdaptability or versatility

Solution Approach 1:

The invention changes the chemical parameters of the drug-carrier connection by using temporary covalent bonds with specific cleavable linkages instead of relying on physical encapsulation or permanent covalent bonds. The linker design allows control of release kinetics through chemical structure modification rather than depending on variable enzymatic environments

Inventive Principle:

Principle #35Parameter changes

3Duration of action of stationary object

If permanent covalent attachment is used to extend half-life, then solubility and circulation time improve, but biological activity is lost due to inactivation

Engineering Contradiction:

Improvecirculation half-lifeVSAvoidbiological activity

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The invention introduces dynamic reversibility to the drug-carrier connection. The temporary covalent bonds in the linker can be cleaved to release the active drug molecule while allowing the carrier to remain in circulation. This dynamic system enables the drug to be activated when needed while maintaining extended circulation through carrier association

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The system allows for discarding the temporary covalent connection to release the active drug molecule when therapeutic effect is needed, while the polymer carrier can be recovered and remain in circulation to continue providing extended half-life for subsequent drug releases

Inventive Principle:

Principle #34Discarding and recovering

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

This approach provides a controlled and sustained release of active drugs with reduced bioactivity loss and interpatient variability, ensuring stable conjugates with a strong in vivo/in vitro correlation, and avoids the generation of potentially toxic side products.

Implementation Method 1

allowing for controlled release of unmodified biologically active entities through autohydrolysis

Methodology Applied

Scientific EffectAutohydrolysis: Hydrolysis

Data Source

PatentEP2525830B1Dipeptide-based prodrug linkers for aliphatic amine-containing drugs

Publication Date: 2016.05.11 ASCENDIS PHARM AS

AI summary

The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof, comprising a drug linker conjugate D-L, wherein D being a biologically active moiety containing an aliphatic amine group is conjugated to one or more polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeutically useful half-lives. The invention also relates to pharmaceutical compositions comprising said prodrugs and their use as medicaments.