Amorphous Kinase Inhibitor Formulation for Fast Dissolution Stability
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Solution Overview
Problem
There is a need for stable oral formulations of broad-spectrum c-KIT and PDGFRα inhibitors to treat refractory gastrointestinal stromal tumors and other disorders, as well as other solid and hematological cancers, with improved pharmacokinetic profiles and fast dissolution rates.
Innovation Solution
Development of amorphous forms of compounds represented by Formula (I) in solid dispersions and pharmaceutical compositions, including a solid spray-dried dispersion with a pharmaceutically acceptable polymer, and specific blends for tablets that ensure minimal crystalline form presence, enhancing pharmacokinetic profiles and providing fast release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline forms of kinase inhibitors are used, then manufacturing and storage stability are improved, but dissolution rate and bioavailability are reduced
Solution Approach 1:
The patent changes the physical state parameter of the kinase inhibitor from crystalline to amorphous form. This parameter change enables the compound to achieve both enhanced dissolution rate and acceptable stability through controlled amorphous formulation, resolving the contradiction between stability and dissolution rate.
Solution Approach 2:
The patent creates a composite material system by combining the amorphous kinase inhibitor with specific excipients and formulation components. This composite approach maintains the amorphous state while providing manufacturing and storage stability, thus resolving the contradiction between stability and dissolution rate.
2Speed
If amorphous forms are used to enhance dissolution rate, then bioavailability is improved, but formulation stability is reduced
Solution Approach 1:
The patent introduces intermediary substances (excipients and formulation components) that act as stabilizing agents for the amorphous form. These intermediaries prevent crystallization and maintain formulation stability while preserving the enhanced dissolution rate characteristics of the amorphous state.
Solution Approach 2:
The patent develops a composite formulation system where the amorphous kinase inhibitor is combined with specific excipients that provide stabilizing effects. This composite material approach enables the amorphous form to maintain both high dissolution rate and formulation stability.
3Adaptability or versatility
If broad-spectrum inhibitors are developed to treat multiple cancer types, then therapeutic versatility is improved, but specificity and side effects are worsened
Solution Approach 1:
The patent applies local quality by designing the inhibitor to have specific binding characteristics that allow selective interaction with different kinase receptors expressed in various cancer types. This enables broad-spectrum activity while maintaining sufficient specificity to minimize off-target effects and side effects.
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 amorphous formulations provide enhanced pharmacokinetic profiles with fast dissolution and stability, ensuring effective treatment of various cancers by maintaining the amorphous form under controlled humidity conditions.
Implementation Method 1
maintaining the amorphous form under controlled humidity conditions
Data Source
AI summary
Provided herein is an amorphous compound represented by Formula (I):and compositions thereof, which are useful in the treatment of disorders related to the activity of the c-KIT and PDGFRα kinases, and oncogenic forms thereof.