Eltrombopag Olamine Tablets With Stable Dissolution and Bioavailability
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Solution Overview
Problem
Formulating eltrombopag olamine into a solid oral pharmaceutical dosage form on a commercial scale is challenging due to its tendency to form insoluble metal complexes with coordinating metals and undergo a Maillard reaction with reducing sugars, affecting dissolution and stability.
Innovation Solution
A pharmaceutical tablet formulation of eltrombopag olamine with a defined particle size range (20-90 micrometers) using a wet granulation process, incorporating a high percentage of disintegrant (4-12%) and avoiding coordinating metals and reducing sugars, with a film coat containing minimal metal, ensuring improved stability and dissolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If eltrombopag olamine is formulated with coordinating metals or reducing sugars in conventional tablet formulations, then the manufacturing process is simplified, but the drug forms insoluble metal complexes or undergoes Maillard reaction, reducing dissolution and stability
Solution Approach 1:
The patent removes coordinating metals and reducing sugars from the tablet formulation, extracting the harmful components that cause insoluble complex formation and Maillard reactions. This is achieved by selecting specific excipients that do not contain these problematic substances, thereby eliminating the chemical incompatibilities while maintaining formulation simplicity
Solution Approach 2:
The patent introduces a specific excipient combination as an intermediary between the drug and potential harmful substances. By using excipients with defined chemical properties that do not coordinate metals or reduce sugars, the formulation creates a protective chemical environment that prevents unwanted reactions while allowing straightforward manufacturing
2Ease of manufacture
If eltrombopag olamine is formulated without controlling particle size, then the formulation process is simpler, but the dissolution rate and bioavailability are reduced
Solution Approach 1:
The patent changes the physical parameter of particle size by specifying that eltrombopag olamine be milled to a particle size distribution with D10 of 5-20 µm, D50 of 20-40 µm, and D90 of 40-90 µm. This controlled particle size enhancement increases the surface area available for dissolution, thereby improving oral bioavailability while maintaining a relatively simple milling and formulation process
3Productivity
If high disintegrant content (4-12%) is used to improve dissolution, then the dissolution rate increases, but the tablet structural integrity during manufacturing becomes more challenging
Solution Approach 1:
The patent changes the functional parameter of disintegrant content by specifying a range of 4-12% in the formulation. This optimized disintegrant level provides sufficient tablet disintegration and dissolution enhancement while maintaining adequate structural integrity during manufacturing, achieving a balance between dissolution performance and manufacturability
Solution Approach 2:
The patent uses a composite excipient system combining specific disintegrants with binders and fillers in defined proportions. This composite approach creates a synergistic formulation where the disintegrant works effectively at moderate levels (4-12%) while the accompanying excipients provide structural support, resolving the contradiction between dissolution enhancement and tablet strength
Data Source
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AI summary
Disclosed are novel pharmaceutical compositions containing 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine) (eltrombopag olamine) and processes for preparing the same.