Amorphous AKR1C3 KARS Inhibitor Composition for Oral Stability
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Solution Overview
Problem
There is a need for stable and bioavailable pharmaceutical compositions of AKR1C3 reductase-dependent KARS inhibitors to treat cancers with genetic alterations in the NRF2/KEAP1 pathway, particularly NRF2/KEAP1 mutated cancers, which currently lack selective therapeutic options.
Innovation Solution
Development of pharmaceutical compositions comprising 6′-fluoro-N-(4-fluorobenzyl)-4′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinoline]-1-carboxamide, formulated as amorphous or nano spray granules, stabilized with polymers, to provide improved stability, oral bioavailability, and low toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the AKR1C3 inhibitor is formulated as conventional solid dosage forms, then manufacturing is simple, but oral bioavailability is poor and stability is insufficient
Solution Approach 1:
The patent changes the physical state parameter of the inhibitor from crystalline to amorphous form, which improves bioavailability and stability. The amorphous formulation is achieved through specific processing methods that maintain the high-energy state of the molecule, preventing crystallization and enhancing drug performance.
Solution Approach 2:
The patent creates a composite formulation by combining the amorphous inhibitor with specific excipients and using spray-dried granule technology. This composite approach encapsulates the amorphous material in a stable granule structure that maintains bioavailability while improving manufacturability and storage stability.
2Reliability
If the AKR1C3 inhibitor is administered at high doses to achieve therapeutic effect, then therapeutic efficacy is improved, but toxicity increases
Solution Approach 1:
The patent changes the delivery parameter by using amorphous formulation with controlled release characteristics. This allows for lower doses to achieve the same therapeutic effect by improving absorption efficiency and reducing peak concentration toxicity, thereby maintaining efficacy while reducing harmful effects.
3Reliability
If the inhibitor is formulated to improve bioavailability, then oral absorption is enhanced, but formulation complexity increases
Solution Approach 1:
The patent uses spray-dried granule technology, which employs pneumatic principles to atomize the inhibitor solution and deposit it as fine droplets that form stable granules. This pneumatic process improves bioavailability through enhanced dispersion and absorption while maintaining a relatively simple formulation structure that can be manufactured using established equipment.
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 compositions effectively inhibit AKR1C3, offering a selective treatment approach for cancers overexpressing AKR1C3, enhancing therapeutic efficacy and safety.
Implementation Method 1
tricyclic ketone compounds that get converted to lysine t-RNA synthetase (KARS) inhibitors by AKR1C3 in the presence of NADPH
Data Source
AI summary
The present invention relates to solid phase pharmaceutical compositions of 6′-fluoro-N-(4-fluorobenzyl)-4′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinoline]-1-carboxamide that is useful as a AKR1C3 dependent KARS inhibitor. The present invention also relates to processes for the preparation of said pharmaceutical compositions of said compound, methods of using said pharmaceutical compositions in the treatment of various diseases and disorders, and their use in diseases and disorders mediated by an AKR1C3 dependent KARS inhibitor.