Compound A Solid Forms for Thyroid Receptor Beta Selectivity
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Solution Overview
Problem
Existing thyroid hormone analogs lack thyroid hormone receptor beta selectivity and tissue-specific action, leading to undesirable effects such as hyperthyroidism and hypothyroidism, while failing to address metabolic disorders effectively.
Innovation Solution
Development of morphic forms, co-crystals, salts, and amorphous solid dispersions of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Compound A) with specific counter-ions and polymers to enhance receptor selectivity and tissue-specific action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing thyroid hormone analogs are used, then general thyroid hormone effects are achieved, but receptor beta selectivity and tissue-specific action are lacking, leading to undesirable hyperthyroidism and hypothyroidism effects
Solution Approach 1:
The patent develops specific morphic forms (crystalline salts with counter-ions like sodium, potassium, calcium, magnesium, and amorphous solid dispersions with polymers such as hydroxypropyl methylcellulose and polyvinylpyrrolidone) of Compound A to achieve localized enhancement of thyroid hormone receptor beta selectivity and tissue-specific action, thereby producing beneficial metabolic effects while avoiding unwanted systemic thyroid effects
Solution Approach 2:
The patent employs parameter changes by creating different solid state forms (crystalline and amorphous) of Compound A with specific physical and chemical properties. These parameter changes in the drug's physical form enhance its solubility, stability, and bioavailability, leading to improved receptor selectivity and reduced harmful effects
2Reliability
If thyroid hormone analogs are developed for metabolic disorders, then effects on body weight, lipids, and cholesterol are achieved, but cardiovascular function and HPT axis function are adversely impacted
Solution Approach 1:
The patent uses specific morphic forms of Compound A as intermediaries that selectively mediate metabolic effects through thyroid hormone receptor beta in peripheral tissues. These forms act as targeted delivery systems that facilitate beneficial metabolic changes while preventing adverse effects on cardiovascular function and the hypothalamus-pituitary-thyroid axis through enhanced tissue specificity
3Reliability
If crystalline salts and amorphous solid dispersions of Compound A are developed, then therapeutic effects on metabolic disorders are enhanced, but formulation complexity increases
Solution Approach 1:
The patent segments the formulation development into distinct categories: crystalline salts with specific counter-ions (sodium, potassium, calcium, magnesium, aluminum, ammonium, zinc, iron, manganese, lithium) and amorphous solid dispersions with specific polymers (hydroxypropyl methylcellulose, polyvinylpyrrolidone, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, polyethylene glycol). This segmentation allows systematic optimization of each form's properties to enhance therapeutic effects while managing formulation complexity through structured approaches
Data Source
AI summary
The present invention is directed to morphic forms, co-crystals, salts, and amorphous solid dispersions of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.