Hydrogen Sulphate Composition for Solubility and Bioavailability
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Solution Overview
Problem
The free-base form of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide exhibits poor solubility and dissolution rates, leading to low bioavailability and instability during formulation processing and storage, which affects the efficacy of pharmaceutical compositions.
Innovation Solution
A pharmaceutical composition comprising the hydrogen sulphate salt of the compound dispersed in a carrier matrix consisting of d-alpha-tocopheryl polyethylene glycol 1000 succinate, polyglycolised glycerides, polyethylene glycols, or hard fats maintains the stability of the Agent during processing and storage, ensuring high solubility and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the free-base form of the Agent is used, then the compound can be formulated, but it exhibits poor solubility, low dissolution rate, and low bioavailability
Solution Approach 1:
The patent changes the chemical form of the Agent from free-base to hydrogen sulphate salt, which fundamentally alters its solubility and dissolution characteristics. This parameter change transforms the compound from BCS Class 4 (low solubility, low permeability) to a form with improved pharmaceutical properties, achieving both high solubility and high bioavailability simultaneously
Solution Approach 2:
The patent creates a composite pharmaceutical composition by combining the hydrogen sulphate salt of the Agent with specific carrier matrices (TPGS, polyglycolised glycerides, PEG, or hard fats). This composite formulation synergistically improves both solubility and bioavailability while maintaining stability during processing and storage
2Ease of manufacture
If the free-base form of the Agent is used, then the compound can be handled, but it shows instability during formulation processing and storage
Solution Approach 1:
The patent changes the chemical form from free-base to hydrogen sulphate salt, which fundamentally alters the stability profile. The salt form remains stable during formulation processing and storage, preventing degradation and ensuring consistent pharmaceutical properties throughout the product lifecycle
Solution Approach 2:
The hydrogen sulphate salt acts as an intermediary form that bridges the gap between handling convenience and stability requirements. During formulation processing, the salt form provides stability, and upon administration, it dissociates to release the active Agent, ensuring both ease of manufacture and compositional stability
3Ease of operation
If conventional tablet formulation is used, then the Agent can be delivered, but bioavailability is poor (approximately 18% in dogs)
Solution Approach 1:
The patent changes the physical and chemical parameters of the Agent by using the hydrogen sulphate salt form with specific carrier matrices. This transforms the delivery system from conventional tablets to a formulation with superior bioavailability, achieving high absorption and consistent pharmacokinetic profile
Solution Approach 2:
The patent develops a composite formulation system combining the hydrogen sulphate salt with optimized carrier matrices (TPGS, polyglycolised glycerides, PEG, or hard fats). This composite approach enhances bioavailability by improving dissolution kinetics, permeability, and absorption, while maintaining ease of oral delivery
Data Source
AI summary
The invention concerns pharmaceutical compositions containing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and solvates, crystalline forms and amorphous forms thereof, to the use of said compositions as a medicament, and to processes for the preparation of said compositions.