CFTR Modulator Solid Forms for Stability and Bioavailability

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Solution Overview

Problem

Current CFTR modulators, particularly CFTR correctors, are not effective enough as monotherapy for treating cystic fibrosis, necessitating combination therapy with potentiators to enhance CFTR activity, and there is a need for new and better modulators to manage disease progression and severity.

Innovation Solution

Development of solid forms of the CFTR-modulating compound (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I) and its pharmaceutically acceptable salts, including crystalline and amorphous forms, to improve bioavailability and stability, which can be used in combination with other CFTR modulating agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If CFTR correctors are used as monotherapy, then the treatment approach is simplified, but the treatment efficacy is insufficient

Engineering Contradiction:

Improvetreatment simplicityVSAvoidtreatment efficacy

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent combines CFTR corrector and potentiator into a single dual-function compound (Compound I), merging two separate therapeutic mechanisms into one molecule. This resolves the contradiction by maintaining treatment simplicity (single compound administration) while achieving combined efficacy (both correction and potentiation functions)

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If new CFTR modulators are developed to improve treatment efficacy, then the treatment effectiveness increases, but the development complexity and time increase

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddevelopment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Compound I is designed with multi-functionality, acting as both a CFTR corrector and potentiator simultaneously. This universal design approach improves treatment effectiveness by addressing multiple disease mechanisms with a single compound, while avoiding the complexity of developing and coordinating multiple separate agents

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Stability of the object's composition

If solid forms of Compound I are developed, then the stability and bioavailability are improved, but the manufacturing process complexity increases

Engineering Contradiction:

Improvecompound stabilityVSAvoidmanufacturing ease

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent develops multiple crystalline forms (Polymorph I, Polymorph II, solvates) and amorphous forms of Compound I by changing physical parameters such as crystal structure, solvent content, and molecular arrangement. These parameter changes improve stability and bioavailability while providing options optimized for different manufacturing and formulation requirements

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250340568A1Solid forms of a macrocyclic compounds as CFTR modulators and their preparation

Publication Date: 2025.11.06 VERTEX PHARMACEUTICALS INC

AI summary

Processes and methods of preparing Compound I are disclosed. Crystalline forms of Compound I, pharmaceutically acceptable salts, solvates, hydrates, and cocrystals thereof, pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.