Crystalline CFTR Modulator Forms for Stable Cystic Fibrosis Therapy
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation in CFTR, are inadequate in addressing the severe forms of the disease, as they fail to correct protein folding and trafficking issues, leading to reduced anion and fluid transport across epithelia.
Innovation Solution
Development of crystalline forms of the CFTR modulator (14S)-8-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, which may exhibit higher purity, stability, and lower hygroscopicity, potentially improving drug efficacy and handling during manufacturing, storage, and administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If amorphous forms of CFTR modulators are used, then flexibility in formulation is improved, but stability and purity are worsened
Solution Approach 1:
The patent applies parameter changes by transitioning the CFTR modulator from an amorphous state to specific crystalline forms (Forms I-IV), each with defined XRPD patterns, melting points, and solubility characteristics. This phase change from amorphous to crystalline state resolves the contradiction by providing enhanced stability and purity while maintaining formulation flexibility through selection among multiple crystalline polymorphs and salt forms.
Solution Approach 2:
The invention utilizes phase transitions by establishing specific crystalline structures from the amorphous modulator compound. Each crystalline form (I, II, III, IV) represents a distinct phase with unique properties including characteristic XRPD diffraction patterns, melting ranges, and solubility profiles. This phase transition approach allows the patent to achieve improved stability and purity while preserving formulation adaptability through selection of appropriate crystalline forms.
2Reliability
If higher doses of CFTR modulators are administered to address severe disease forms, then therapeutic efficacy is improved, but off-target effects and toxicity are worsened
Solution Approach 1:
The patent applies local quality by developing specific crystalline forms with distinct solubility and bioavailability characteristics tailored to different therapeutic needs. Forms I-IV exhibit different dissolution rates and bioavailability profiles, allowing optimization of drug delivery to CFTR targets while minimizing systemic exposure and off-target effects. This localized optimization of drug properties enables effective treatment at appropriate doses without excessive toxicity.
Solution Approach 2:
The invention implements preliminary action through the development of stable crystalline forms that prevent degradation and maintain potency throughout storage and administration. By establishing predetermined stable crystalline structures with defined storage conditions, the patent ensures the modulator reaches the target in its intended dosage form, reducing the need for dose escalation and minimizing off-target effects from degraded or unstable compound.
3Adaptability or versatility
If multiple CFTR modulators are used in combination, then coverage of different mutations is improved, but treatment complexity is worsened
Solution Approach 1:
The patent applies universality by developing a single CFTR modulator compound capable of addressing multiple mutation types through its specific molecular structure and mechanism of action. The compound can correct defects in various CFTR mutations including F508del and other classes of mutations, eliminating the need for multiple different drugs. This multi-functional approach maintains broad mutation coverage while simplifying the treatment regimen to a single agent or standardized combination.
Data Source
AI summary
Crystalline forms of Compound I:pharmaceutically acceptable salts thereof, and solvates and hydrates thereof are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.