PROTAC Amorphous Solid Dispersion for Bioavailability and Food Effects

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Solution Overview

Problem

PROTAC compounds face challenges with poor cellular permeability due to high molecular weight and large exposed polar surface area, leading to poor water solubility and low oral bioavailability, with significant variations in absorption affected by food intake.

Innovation Solution

A pharmaceutical composition comprising an amorphous solid dispersion (ASD) of PROTAC compounds with a surfactant, hydrophilic polymer, and optionally an acid, which enhances bioavailability and reduces food-effect variability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PROTAC compounds are used to target proteins, then protein degradation is achieved, but water solubility deteriorates due to high molecular weight and large exposed polar surface area

Engineering Contradiction:

Improveprotein degradation capabilityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent introduces an amorphous solid dispersion (ASD) formulation containing a PROTAC compound, surfactant, and hydrophilic polymer as intermediaries to improve solubility. The ASD matrix acts as a mediator that enhances the water solubility of the PROTAC compound while maintaining its protein degradation capability, directly resolving the contradiction between efficacy and solubility.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates a composite material system consisting of the PROTAC compound combined with surfactant and hydrophilic polymer in an amorphous solid dispersion. This composite formulation improves water solubility through the synergistic effects of the components while preserving the PROTAC's biological activity, thus resolving the solubility-activity contradiction.

Inventive Principle:

Principle #40Composite materials

2Reliability

If PROTAC compounds are administered orally, then protein degradation is achieved, but oral bioavailability deteriorates due to poor water solubility and high molecular weight

Engineering Contradiction:

Improveprotein degradation capabilityVSAvoidoral bioavailability

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The ASD formulation with surfactant and hydrophilic polymer acts as an intermediary system that enhances oral bioavailability. The surfactant improves membrane permeability while the hydrophilic polymer enhances solubility, together enabling better oral absorption of the PROTAC compound without compromising its protein degradation function.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the physical state parameters of the PROTAC compound by formulating it in an amorphous solid dispersion rather than crystalline form. This parameter change (amorphous vs crystalline) improves dissolution rate and bioavailability while maintaining the compound's biological activity, directly addressing the oral bioavailability issue.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If PROTAC compounds are administered with food, then absorption is improved, but absorption variability increases due to food effects

Engineering Contradiction:

ImproveabsorptionVSAvoidabsorption consistency

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The ASD formulation with surfactant and hydrophilic polymer serves as a protective intermediary that reduces the impact of food on absorption. The formulation design mitigates food effects by maintaining consistent dissolution and permeability characteristics regardless of dietary conditions, thereby reducing absorption variability while maintaining adequate absorption levels.

Inventive Principle:

Principle #24Intermediary (Mediator)

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 ASD formulation achieves at least 2-fold to 10-fold improvement in bioavailability compared to conventional compositions, with stable plasma concentrations and reduced absorption variations, allowing for effective oral administration.

Implementation Method 1

a pharmaceutical composition, wherein the pharmaceutical composition comprises a) an amorphous solid dispersion (ASD) that comprises: i) a proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof

Methodology Applied

Scientific EffectAmorphous solid dispersion:

Implementation Method 2

ii) a surfactant; iii) a hydrophilic polymer

Methodology Applied

Scientific EffectSurfactant action: Surfactant

Implementation Method 3

iii) a hydrophilic polymer

Methodology Applied

Scientific EffectHydrophilic interaction: Hydrophile

Data Source

PatentUS12350268B2Pharmaceutical compositions of PROTAC compounds and uses thereof

Publication Date: 2025.07.08 SHENZHEN PHARMACIN CO LTD

AI summary

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). Provided are pharmaceutical compositions which include a mixture of a PROTAC, a hydrophilic polymer, a surfactant, and optionally an acid and an adsorbent. Also described are methods for preparing and using such pharmaceutical compositions. In one aspect, disclosed herein is an amorphous solid dispersion comprising PROTAC.