Amorphous TYK2 Inhibitor Dosage Forms for pH-Robust Bioavailability
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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 gastric pH-raising medications and in regions like the colon where water availability is low, and in regions where solubility is low, such as the colon.
Innovation Solution
The formulations include amorphous BMS-986165 and one or more polymers, which provide improved bioavailability and stability, and dosage forms, specifically for the treatment of auto-inflammatory diseases such as psoriasis, lupus, and lupus, and auto-inflammatory diseases such as ulcerative and ulcerative colitis, and ulcerative ulcerative colitis, and Crohn's disease, and psoriasis.
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 deteriorates under elevated gastric pH conditions
Solution Approach 1:
The patent changes the physical state of BMS-986165 from crystalline to amorphous form, which fundamentally alters its dissolution and absorption characteristics. The amorphous form maintains stability while improving bioavailability under elevated gastric pH conditions by eliminating crystal lattice energy barriers to dissolution.
Solution Approach 2:
The patent creates composite formulations combining amorphous BMS-986165 with specific excipients and polymers that stabilize the amorphous state and enhance solubility. This composite approach allows the amorphous drug to maintain both stability and improved bioavailability that crystalline forms cannot achieve.
2Reliability
If amorphous formulations are used, then bioavailability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent introduces excipients and polymers as intermediary substances that facilitate the creation and stabilization of amorphous formulations. These intermediaries simplify the manufacturing process by providing a matrix that naturally maintains the amorphous state during processing and storage, reducing the need for complex manufacturing controls.
3Ease of manufacture
If conventional formulations are used, then manufacturing simplicity is maintained, but performance in low-water regions deteriorates
Solution Approach 1:
The patent changes the formulation parameters to create amorphous solid dispersions that are inherently more soluble and stable in low-water environments. This parameter change allows the formulation to maintain manufacturing simplicity while achieving superior performance in the colon and other low-water regions of the GI tract.
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 of BMS-986165 maintain bioavailability and stability, even under elevated gastric pH conditions, and in low-water regions of the GI tract, with extended-release profiles comparable to or better than crystalline forms, improving patient compliance and convenience.
Implementation Method 1
The present invention provides oral dosage forms of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165) made from dispersions of amorphous BMS-986165
Data Source
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: