Spray-Dried FXR Agonist Formulation for Sustained Receptor Engagement
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Solution Overview
Problem
Existing treatments for conditions associated with farnesoid X receptor (FXR) activity, such as metabolic disorders and liver diseases, face challenges in achieving effective and sustained FXR activation with minimal adverse effects, particularly with bile acid-derived FXR agonists like obeticholic acid (OCA).
Innovation Solution
Development of a spray-dried solid dispersion of a structurally distinct FXR agonist, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, dispersed in a polymer matrix, which provides sustained FXR engagement and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bile acid-derived FXR agonists like obeticholic acid (OCA) are used, then FXR activation is achieved, but adverse effects increase and therapeutic window narrows
Solution Approach 1:
The patent applies parameter changes by developing a novel FXR agonist with a structurally distinct molecular framework that is not derived from bile acids. This structural parameter change fundamentally alters the drug's interaction with FXR, achieving effective activation while reducing adverse effects associated with bile acid-derived agonists like OCA.
Solution Approach 2:
The patent employs a spray-dried solid dispersion formulation that composite the FXR agonist with a polymer matrix. This composite material approach enhances the drug's solubility, stability, and bioavailability, while the spray-drying process creates a amorphous or fine crystalline state that improves dissolution rate and therapeutic efficacy.
2Duration of action of stationary object
If structurally distinct FXR agonist is dispersed in polymer matrix, then sustained FXR engagement is achieved, but formulation complexity increases
Solution Approach 1:
The patent utilizes phase transitions by employing spray-drying to transform the FXR agonist from a crystalline state to an amorphous or fine crystalline state within the polymer matrix. This phase change enhances solubility and dissolution rate, enabling sustained drug release and prolonged FXR engagement. The rapid solvent evaporation during spray-drying creates a homogeneous dispersion that maintains drug stability while controlling release kinetics.
Solution Approach 2:
The polymer matrix serves as an intermediary between the FXR agonist and the biological system. It controls drug release, maintains solubility, and protects the drug from degradation, thereby achieving sustained FXR engagement without requiring complex delivery systems or administration protocols.
3Reliability
If spray-dried solid dispersion is used, then potency and therapeutic window are enhanced, but manufacturing process complexity increases
Solution Approach 1:
The patent replaces traditional mechanical mixing and granulation processes with spray-drying technology. This substitution creates a more homogeneous dispersion of the drug in the polymer matrix, ensures consistent amorphous or fine crystalline state, and improves scalability. The spray-drying process occurs in a single step, reducing the number of manufacturing operations while enhancing product quality and therapeutic window.
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 spray-dried solid dispersion achieves enhanced potency and wider therapeutic window compared to OCA, allowing for once-daily dosing with improved safety and efficacy in treating conditions like non-alcoholic steatohepatitis (NASH) and metabolic disorders.
Implementation Method 1
spray-dried solid dispersion comprising: (a) 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, and (b) a pharmaceutically acceptable polymer; wherein 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer
Implementation Method 2
spray-dried solid dispersion
Implementation Method 3
In some embodiments of the spray-dried solid dispersion, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate is substantially amorphous
Data Source
AI summary
Described herein are pharmaceutical formulations of a farnesoid X receptor agonist, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, and methods of using such pharmaceutical formulations in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity.