Coated Oral Solid Formulation for Stable Blood Concentrations
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Solution Overview
Problem
Existing formulations of 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea (compound (I)) lead to rapid blood concentration increases and elimination, posing a risk of toxicity due to large fluctuations, necessitating a formulation that stabilizes blood concentration and reduces adverse effects.
Innovation Solution
A coated oral solid formulation with a specific coating agent that dissolves at a controlled pH, maintaining a sustained blood concentration of compound (I) for extended periods, allowing for administration once or twice a day.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If compound (I) is orally administered in a conventional formulation, then rapid absorption and onset of action is achieved, but rapid elimination occurs leading to large fluctuations in blood concentration and potential toxicity
Solution Approach 1:
The formulation is segmented into multiple components: compound (I) as active ingredient, excipients for bulk and flow, disintegrants for rapid breakdown, and lubricants for manufacturing. This segmentation allows each component to perform its specific function optimally, achieving both rapid disintegration and sustained release
Solution Approach 2:
The formulation uses a composite approach by combining multiple excipients with specific properties: hydrophilic excipients (lactose, mannitol, starch) for rapid wettability and disintegration, combined with hydrophobic excipients (microcrystalline cellulose, silicon dioxide) for controlled release. This composite material strategy balances rapid absorption with sustained blood concentration
2Stability of the object's composition
If compound (I) is administered frequently to maintain stable blood concentration, then toxicity from rapid fluctuations is reduced, but patient compliance and treatment convenience deteriorate
Solution Approach 1:
The formulation design ensures continuous release of compound (I) over an extended period (12-24 hours or longer) through the use of sustained-release excipients. This continuous action maintains stable blood concentration without requiring frequent dosing, allowing once-daily or twice-daily administration and improving patient compliance
Solution Approach 2:
The formulation dynamically adapts to the gastrointestinal environment by using excipients that respond to pH changes and moisture conditions. The disintegrants activate upon contact with gastric fluids, while hydrophobic excipients gradually release the drug, creating a dynamic release profile that maintains stability over time
3Stability of the object's composition
If a coating agent dissolving at pH 5.0-7.0 is used, then sustained blood concentration is achieved, but dissolution in acidic stomach conditions is delayed
Solution Approach 1:
The formulation uses an intermediary approach by incorporating both acid-soluble excipients (starch, gelatin, certain sugars) and pH-independent excipients that can dissolve or become porous in acidic conditions. These intermediaries facilitate initial drug release in the stomach while the pH-dependent coating provides sustained release in the intestine, bridging the gap between rapid and controlled release
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 formulation achieves a stable and prolonged blood concentration of compound (I), reducing the risk of toxicity and enabling effective treatment of TrkA-related conditions with minimal adverse effects.
Implementation Method 1
a coating layer covering the core, the coating layer containing at least one coating agent in which the coating layer of the formulation begins to dissolve in a solution within a range of pH=about 5.0 to about 7.0
Data Source
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AI summary
The present invention provides an oral solid formulation comprising 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. The present invention relates to an oral solid formulation comprising 1-((1R,2R)-2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-phenylpyridin-3-yl)urea, or a pharmaceutically acceptable salt thereof, or a solvate thereof.