IDH1/2 Inhibitor Cocrystals for Oral Bioavailability and Low Hygroscopicity
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Solution Overview
Problem
Mutant IDH1 and IDH2 enzymes in cancer cells catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), contributing to cancer formation and progression, and existing inhibitors like 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine have limitations.
Innovation Solution
Development of solid forms, including cocrystals and crystalline forms of a compound of formula (I) with citric acid and maleic acid, which act as inhibitors of mutant IDH1 and IDH2 proteins, offering improved therapeutic potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If conventional solid oral dosage forms (tablets, capsules) are used, then ease of administration is maintained, but patient compliance deteriorates due to unpleasant tastes and gastrointestinal side effects
Solution Approach 1:
The patent changes the physical and chemical parameters of the drug by forming cocrystals with specific coformers (e.g., oxalic acid, tartaric acid). This modifies the dissolution rate, bioavailability, and gastrointestinal stability of the drug substance, thereby reducing GI side effects and improving patient compliance while maintaining tablet or capsule dosage forms for ease of administration
Solution Approach 2:
The patent creates composite crystalline structures (cocrystals) combining the active pharmaceutical ingredient with coformers in specific stoichiometric ratios. These composite materials exhibit improved physicochemical properties including enhanced solubility, controlled dissolution profiles, and reduced gastrointestinal irritation, thus improving patient compliance without compromising ease of administration
2Reliability
If intravenous administration is used, then bioavailability is improved, but ease of administration deteriorates due to requiring medical professionals and clinical settings
Solution Approach 1:
The patent modifies the dissolution rate and bioavailability parameters through cocrystal formation, enabling oral dosage forms to achieve bioavailability levels comparable to intravenous administration. The controlled dissolution profiles and enhanced solubility of the cocrystals allow for reliable drug absorption via the oral route, eliminating the need for intravenous administration while maintaining ease of administration
Solution Approach 2:
The patent substitutes the mechanical injection process (intravenous administration) with an oral dosage system. By engineering the cocrystal properties to ensure rapid and complete dissolution and absorption, the invention replaces the need for needle injection with simple oral ingestion, thereby maintaining high bioavailability while dramatically improving ease of administration
3Object-affected harmful factors
If amifostine is administered to reduce cisplatin toxicity, then patient safety is improved, but device complexity increases due to requiring separate administration systems and protocols
Solution Approach 1:
The patent merges the therapeutic agent (cisplatin) with the protective agent (amifostine or analogous compounds) into a single cocrystal structure. This combined formulation allows simultaneous delivery of both drugs in the correct stoichiometric ratio, reducing cisplatin toxicity while simplifying the administration system to a single dosage form rather than requiring separate administration protocols and systems
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 solid forms of the compound effectively inhibit mutant IDH1 and IDH2 enzymes, potentially halting cancer progression by reducing 2HG production, with favorable physicochemical properties such as high crystallinity and low hygroscopicity.
Implementation Method 1
cocrystals of formula (I) having the composition cisplatin:coformer in a molar ratio of 1:1
Data Source
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AI summary
Provided are solid forms of a compound useful for treating cancer, pharmaceutical compositions thereof, and methods of treating cancer comprising administering the solid forms described herein to a patient in need thereof.