Eltrombopag Bis(Monoethanolamine) Tablets with Calcium Silicate
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Solution Overview
Problem
Existing eltrombopag bis(monoethanolamine) formulations exhibit low solubility and permeability, and existing tablet compositions do not provide adequate dissolution, disintegration, stability, and are not dose proportional, making them unsuitable for commercial production and bioequivalence to Revolade®/Promacta®.
Innovation Solution
A film-coated swallowable tablet formulation using calcium silicate as a diluent, combined with isomalt and other pharmaceutically acceptable excipients, prepared via wet granulation, ensuring excellent disintegration properties and stability, and allowing for dose proportional strengths without precipitation issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If reducing sugars or coordinating metals are used as diluents, then the tablet composition can be formulated, but the eltrombopag bis(monoethanolamine) may undergo Maillard reaction or form insoluble metal complexes, reducing stability
Solution Approach 1:
The patent removes problematic reducing sugars and coordinating metals from the tablet formulation. By selecting calcium silicate as a diluent that lacks both reducing sugar properties and coordinating metal characteristics, the formulation avoids Maillard reactions and insoluble complex formation, thereby maintaining drug stability while enabling tablet manufacture.
Solution Approach 2:
Calcium silicate serves as an intermediary substance that fulfills the functional role of a diluent without introducing harmful chemical interactions. It provides the necessary physical properties for tablet formulation (flow, compression) while being chemically inert toward eltrombopag bis(monoethanolamine), thus mediating between manufacturing requirements and stability needs.
2Ease of manufacture
If the tablet formulation uses conventional diluents, then manufacturing is simplified, but dissolution and disintegration properties are inadequate
Solution Approach 1:
The patent changes the chemical and physical parameters of the diluent from conventional options (microcrystalline cellulose, mannitol) to calcium silicate. This parameter change introduces superior dissolution and disintegration properties while maintaining ease of manufacture, as calcium silicate can be processed using standard tablet manufacturing techniques.
Solution Approach 2:
The tablet formulation creates a composite material system where calcium silicate works synergistically with the active pharmaceutical ingredient and other excipients. This composite approach leverages the unique properties of calcium silicate to achieve both manufacturing feasibility and enhanced dissolution performance.
3Manufacturing precision
If different tablet strengths are formulated separately, then each strength can be optimized, but the formulation process becomes complex and non-dose proportional
Solution Approach 1:
The patent creates a universal base formulation using calcium silicate as diluent that can serve multiple dose strengths proportionally. By establishing a core blend of active ingredient and excipients that maintains consistent composition ratios, the formulation can be scaled to produce different tablet strengths (25mg, 50mg, 75mg, 100mg) from the same proportional mixture, simplifying manufacturing while maintaining dose optimization.
Data Source
AI summary
The present invention relates to a film-coated swallowable tablet comprising eltrombopag bis(monoethanolamine) and pharmaceutically acceptable excipients comprising calcium silicate as diluent. The invention further relates to the use of said tablet as a medicament, particularly in the treatment of immune thrombocytopenia (ITP), thrombocytopenia in patients with chronic hepatitis C virus (HCV) and severe aplastic anaemia (SAA).