Trametinib Powder for Oral Solution Pediatric Formulation
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Solution Overview
Problem
Formulating a stable and effective pediatric dosage form of trametinib, which is sensitive to light and humidity, and has poor solubility and bitter taste, posing challenges for oral administration, especially in pediatric populations where solid tablets are not preferred.
Innovation Solution
A powder for oral solution (POS) formulation of trametinib is developed, mixed with excipients and an aqueous vehicle, providing a stable and effective treatment option that is reconstituted to a clear solution, with controlled particle size and solubilizer ratios to maintain stability and bioavailability, and flavored to mask bitterness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If trametinib is formulated as a solid tablet, then it provides stable dosage form, but it is not preferred for pediatric populations who have difficulty swallowing tablets
Solution Approach 1:
The patent divides the solid tablet into a powder for oral solution that can be reconstituted with water, creating smaller, more manageable particles suitable for pediatric administration while maintaining the therapeutic dose
Solution Approach 2:
The patent introduces an aqueous vehicle as an intermediary medium to convert the solid powder into a liquid solution, facilitating easier administration to children who cannot swallow tablets
2Reliability
If trametinib is administered in solvate form, then it provides improved solubility, but desolvation releases unsolvated compound that exhibits poor pharmacodynamic properties
Solution Approach 1:
The patent modifies the physical-chemical parameters of the solvate by selecting specific solvents (dimethyl sulfoxide, ethanol, acetonitrile) and controlling crystallization conditions to produce stable solvates that maintain their structure during storage and administration
Solution Approach 2:
The patent creates composite pharmaceutical formulations that combine the trametinib solvate with excipients and aqueous vehicles, designing a multi-component system that preserves the solvate structure while enabling proper dissolution and absorption
3Reliability
If trametinib is formulated with low solubility, then it maintains compound integrity, but it provides insufficient and inconsistent exposure upon in vivo administration
Solution Approach 1:
The patent changes the solubility parameters by forming solvates with specific solvents and controlling particle size through milling processes, thereby increasing the apparent solubility and dissolution rate while maintaining adequate bioavailability
Solution Approach 2:
The patent transitions from solid tablet form to powder for oral solution, adding the liquid dimension to enhance dissolution and absorption, thereby improving in vivo exposure without compromising compound integrity
4Ease of operation
If trametinib is administered to pediatric populations, then it provides targeted treatment, but the bitter taste and light sensitivity pose additional challenges
Solution Approach 1:
The patent introduces flavoring agents and packaging materials as intermediaries to mask the bitter taste and protect from light, respectively, thereby improving pediatric acceptability without affecting the therapeutic action
Solution Approach 2:
The patent employs light-protective packaging and potentially inert atmosphere storage to create a protected environment that prevents degradation from light exposure, maintaining compound stability during pediatric administration
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 POS formulation ensures improved physical and chemical stability, increased bioavailability, and a consistent pharmacokinetic profile, addressing the challenges of light sensitivity, solubility, and taste issues, making it suitable for pediatric use.
Implementation Method 1
A powder for oral solution (POS) formulation of trametinib is developed, mixed with excipients and an aqueous vehicle, providing a stable and effective treatment option that is reconstituted to a clear solution
Data Source
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AI summary
Disclosed are novel pharmaceutical formulations containing N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxide solvate, methods of using the compositions in therapy and processes for preparing the same.