AXL/MER Inhibitor Formulation Using Acid-Surfactant Bioavailability Boost
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Solution Overview
Problem
Existing pharmaceutical formulations of AXL/MER inhibitors face challenges in achieving optimal bioavailability, which hinders their effectiveness in treating AXL/MER-mediated diseases such as cancer.
Innovation Solution
A pharmaceutical formulation comprising N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I) or its pharmaceutically acceptable salts, solvates, or hydrates, combined with an organic acid like citric acid and a surfactant such as poloxamer 407, to enhance bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pharmaceutical formulations of AXL/MER inhibitors are used, then the formulation is simple and easy to manufacture, but the bioavailability is insufficient
Solution Approach 1:
The patent applies composite materials by combining Compound I with multiple excipients including mannitol (filler), crospovidone (disintegrant), magnesium stearate (lubricant), and gelatin (capsule material). This composite formulation approach resolves the contradiction by creating a complex multi-component system that significantly improves bioavailability while maintaining manufacturability through standard pharmaceutical processing techniques.
Solution Approach 2:
The patent employs parameter changes by optimizing the ratios of different excipients in the formulation. Specifically, it uses mannitol at 50-80 wt%, crospovidone at 2-10 wt%, magnesium stearate at 0.5-5 wt%, and gelatin at 5-20 wt%. These optimized parameters enable the formulation to achieve enhanced bioavailability while remaining compatible with conventional manufacturing processes.
2Reliability
If the formulation includes multiple excipients to improve bioavailability, then the therapeutic efficacy is enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent applies segmentation by dividing the formulation into distinct functional components with specific roles: mannitol as filler (50-80 wt%), crospovidone as disintegrant (2-10 wt%), magnesium stearate as lubricant (0.5-5 wt%), and gelatin as capsule material (5-20 wt%). This segmentation allows each component to be optimized independently for its specific function while maintaining overall manufacturing simplicity through standard pharmaceutical processes.
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 significantly increases the bioavailability of Compound I, thereby improving its therapeutic efficacy in treating AXL/MER-mediated diseases.
Implementation Method 1
A pharmaceutical formulation comprising N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, an organic acid, and a surfactant
Data Source
AI summary
The present application relates to pharmaceutical formulations and dosage forms of an AXL/MER inhibitor, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, including methods of preparation thereof, which are useful in the treatment of AXL/MER mediated diseases such as cancer.