CFTR Modulator Composition Combining Corrector and Potentiator
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Solution Overview
Problem
There is no cure for cystic fibrosis (CF) and existing treatments do not effectively address the ion and fluid transport imbalances caused by CFTR mutations, leading to severe health issues such as respiratory disease, gastrointestinal problems, and infertility.
Innovation Solution
A pharmaceutical composition comprising a mixture of spray dried dispersions of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1) and N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 2), with optional polymers like hydroxypropyl methylcellulose, formulated into tablets for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for CFTR mediated diseases, then treatment options are limited, but the effectiveness in addressing ion and fluid transport imbalances is insufficient
Solution Approach 1:
The patent combines two distinct CFTR modulator compounds (Compound 1 and Compound 2) into a single pharmaceutical composition. Compound 1 acts as a corrector to improve CFTR protein folding and trafficking, while Compound 2 acts as a potentiator to enhance channel function. This combination approach addresses multiple defects in CFTR-mediated diseases simultaneously, providing both correction of misfolding and enhancement of channel activity, thereby improving overall treatment effectiveness while maintaining versatile therapeutic options
2Reliability
If CFTR mutations are present, then ion and fluid transport is impaired, but no effective cure exists
Solution Approach 1:
The patent employs pharmacological compounds that change the functional parameters of mutant CFTR proteins. Compound 1 alters the folding kinetics and trafficking efficiency of ΔF508-CFTR, increasing the number of functional channels reaching the apical membrane. Compound 2 modifies the gating parameters of CFTR channels, increasing open probability and chloride conductance. These parameter changes restore ion and fluid transport function despite the presence of disease-causing mutations, thereby reducing disease severity without requiring gene correction
3Quantity of substance
If ΔF508-CFTR channels are present in the membrane, then some anion transport occurs, but the number of functional channels is far less than wild-type CFTR
Solution Approach 1:
The patent uses Compound 1 to perform preliminary action by correcting the folding defects of ΔF508-CFTR proteins before they are degraded by the quality control system. This corrector compound binds to misfolded CFTR in the endoplasmic reticulum, stabilizing its structure and enabling proper trafficking to the cell surface. By acting preliminarily on the folding process, the compound increases the number of CFTR channels that reach the membrane, thereby improving anion transport capacity before the transport function is even attempted
Data Source
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AI summary
The present invention features compositions comprising a plurality of therapeutic agents wherein the presence of one therapeutic agent enhances the properties of at least one other therapeutic agent. In one embodiment, the therapeutic agents are cystic fibrosis transmembrane conductance regulators (CFTR) such as a CFTR corrector or CFTR potentiator for the treatment of CFTR mediated diseases such as cystic fibrosis. Methods and kits thereof are also disclosed.