Multiple Myeloma Solid Forms for Stability and Lower Toxicity
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Solution Overview
Problem
Current multiple myeloma therapies pose significant drawbacks, including toxicities and side effects, and there is a need for effective compounds to treat and manage the disease, particularly in patients with persistent residual disease or refractory cases, while minimizing these adverse effects.
Innovation Solution
Development of various solid forms, including crystalline and amorphous forms, of the compound (S)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, and their salts, which are used in pharmaceutical compositions for treating, preventing, and managing multiple myeloma, with improved properties such as stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional multiple myeloma therapies are used, then disease treatment is achieved, but toxicities and side effects occur
Solution Approach 1:
The patent applies parameter changes by developing multiple solid forms (crystalline polymorphs, amorphous forms, solvates, hydrates) and salt forms of the compound, each with different physical and chemical properties. These parameter variations in the drug substance enable optimization of therapeutic efficacy while reducing toxicity and side effects, as different solid forms can exhibit different solubility, stability, and bioavailability characteristics that influence the drug's safety and effectiveness profile
2Reliability
If novel therapeutic agents are used to increase response rates, then progression free survival is prolonged, but persistent residual disease remains below detection sensitivity
Solution Approach 1:
The patent employs preliminary action by establishing highly sensitive detection methods for minimal residual disease (MRD) at thresholds of 10^-4 to 10^-6 before relapse occurs. This preliminary detection capability allows for early identification of persistent residual disease that exists below the sensitivity of conventional methods, enabling timely intervention and maintenance of progression-free survival while monitoring for relapse
3Stability of the object's composition
If solid forms of the compound are developed, then stability and bioavailability are improved, but formulation complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the compound into multiple distinct solid forms (Forms A through L including polymorphs, amorphous forms, solvates, hydrates, and salt forms). Each solid form is characterized and isolated as a separate entity with specific stability and bioavailability properties. This segmentation allows selection of the most appropriate solid form for the intended application, improving drug stability and bioavailability while enabling systematic formulation development
Data Source
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AI summary
Provided herein are formulations, processes, solid forms and methods of use relating to salts of and solid forms comprising free base or salts of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile.