CFTR Potentiator Solid Forms for Cystic Fibrosis Treatment
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the CFTR protein, face challenges in effectively modulating the activity of mutant forms like ΔF508, leading to inadequate ion and fluid transport in epithelial tissues, resulting in severe respiratory and digestive issues.
Innovation Solution
Development of stable solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) that act as potent and selective CFTR potentiators, capable of enhancing the activity of both wild-type and mutant CFTR forms, including ΔF508, to improve ion and fluid transport.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments targeting CFTR protein are used, then some CFTR activity is maintained, but they fail to effectively modulate mutant forms like ΔF508, resulting in inadequate ion and fluid transport
Solution Approach 1:
The patent modifies the chemical structure of CFTR potentiators by changing parameters such as the R1 substituent (e.g., from hydrogen to methyl groups) and R2-R5 positions on the phenyl ring. These structural parameter changes enable the compound to effectively potentiate mutant CFTR forms like ΔF508 that previous treatments could not address, while maintaining efficacy for wild-type CFTR.
2Stability of the object's composition
If stable solid forms of Compound 1 are developed, then pharmaceutical stability and bioavailability are improved, but the complexity of isolating and characterizing specific crystal forms increases
Solution Approach 1:
The patent segments the solid form characterization into distinct crystal forms (Form A, Form B, Form C, etc.), each with specific X-ray diffraction patterns and stability characteristics. This segmentation allows systematic isolation, characterization, and selection of the most pharmaceutically appropriate polymorph, reducing the overall complexity by breaking down the problem into manageable discrete forms.
Solution Approach 2:
The patent uses X-ray diffraction patterns as characteristic 'fingerprints' to identify and differentiate between various crystal forms of Compound 1. Each polymorph exhibits distinct diffraction peak patterns at specific 2-theta angles, enabling rapid identification and characterization without complex analytical procedures.
Data Source
AI summary
The present invention relates to solid state forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1), pharmaceutical compositions thereof and methods therewith.