Amorphous TYK2 Inhibitor Formulation for Stable Colon Release
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Solution Overview
Problem
Existing formulations of BMS-986165, a Tyk2 inhibitor, face challenges in providing sufficient bioavailability and stability, especially when co-administered with agents that raise gastric pH, and require extended release in low-water regions of the gastrointestinal tract.
Innovation Solution
Formulations comprising a dispersion of amorphous BMS-986165 in a polymer matrix, particularly hydroxypropyl methylcellulose acetate succinate (HPMCAS), with specific weight ratios, ensuring physical and chemical stability and bioavailability, including extended release in the colon.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline forms of BMS-986165 are used, then stability is improved, but bioavailability is reduced
Solution Approach 1:
The patent changes the physical form of BMS-986165 from crystalline to amorphous state, which fundamentally alters its dissolution and absorption characteristics. The amorphous form provides higher bioavailability while maintaining stability through specific formulation techniques, directly resolving the contradiction between stability and bioavailability.
Solution Approach 2:
The patent creates composite formulations by combining amorphous BMS-986165 with specific excipients and polymer matrices. This composite approach enables the drug to achieve both stability through the protective formulation environment and enhanced bioavailability through the amorphous state, resolving the traditional trade-off between these two properties.
2Duration of action of moving object
If formulations are designed for extended release, then duration of action is improved, but solubility in low-water regions is reduced
Solution Approach 1:
The patent applies different formulation strategies to different regions of the gastrointestinal tract. The extended release formulation is designed to release drug in the small intestine where water is available for dissolution, while the amorphous form maintains stability. This local differentiation allows extended duration of action without compromising solubility in the colon where water is limited.
Solution Approach 2:
The patent utilizes the different physical and chemical properties of the amorphous form compared to crystalline forms, enabling controlled release kinetics. The amorphous state provides higher solubility and faster dissolution rates in the small intestine, facilitating extended release while maintaining adequate solubility even in lower-water environments of the colon.
3Reliability
If amorphous form is used, then bioavailability is improved, but physical stability is reduced
Solution Approach 1:
The patent introduces specific excipients and polymer matrices as intermediary substances that stabilize the amorphous form of BMS-986165. These intermediaries prevent crystallization and maintain the amorphous state during storage and administration, thereby preserving the bioavailability benefits while achieving physical stability.
Solution Approach 2:
The patent develops composite formulation systems where amorphous BMS-986165 is combined with stabilizing excipients and polymer matrices. This composite structure provides both the enhanced bioavailability of the amorphous form and the physical stability needed for storage and handling, resolving the contradiction between these two properties.
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 formulations maintain bioavailability and stability, comparable to crystalline forms, even under elevated gastric pH conditions, and provide extended release in low-water regions, enhancing treatment efficacy for autoimmune diseases.
Implementation Method 1
formulations comprising a dispersion of amorphous BMS-986165 in a polymer matrix
Implementation Method 2
provide extended release in low-water regions, enhancing treatment efficacy
Data Source
Figure 1A
Figure 1B
Figure 2A~2C
AI summary
Stable and bioavailable formulations and dosage forms comprising a dispersion (e.g., spray-dried dispersion) of solid amorphous 6-(cyclopropaneamido)-4-((2-methoxy- 3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3- carboxamide (Formula (I); BMS-986165) in a solid polymer matrix are provided for the treatment of auto-immune and auto-inflammatory diseases such as an inflammatory bowel disease (IBD) and psoriasis.