Rigosertib Formulation Stability via Basic PEG 400
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Solution Overview
Problem
Rigosertib formulations with water-soluble polymers like PEG 400 suffer from stability issues, impurity formation, and urothelial toxicity, requiring improved stability and bioavailability for effective cancer treatment.
Innovation Solution
Pharmaceutical compositions of Rigosertib with basic pre-treated low molecular weight polyethylene glycol at a pH of 11.0 to 14.0 and less than 5% water or aqueous solution, reducing impurities and enhancing oral bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If Rigosertib is formulated with water-soluble polymers like PEG 400 and aqueous buffers, then solubility and administration feasibility are improved, but stability deteriorates and impurity levels increase
Solution Approach 1:
The patent applies parameter changes by adjusting the pH to a highly basic range (11.0-14.0) and controlling water content to less than 5%. This transforms the formulation from an aqueous-based system to a non-aqueous basic system, fundamentally changing the chemical environment to prevent degradation while maintaining solubility through the basic PEG 400 medium.
Solution Approach 2:
The invention uses a composite formulation system combining basic pre-treated PEG 400 with Rigosertib and minimal water or aqueous solution. This composite approach creates a synergistic system where the basic PEG 400 provides both solubility enhancement and stability, while the limited water content prevents hydrolysis and impurity formation.
2Ease of operation
If Rigosertib is stored in formulations with PEG 400 and phosphate buffer at high pH, then solubility is maintained, but crystal formation occurs
Solution Approach 1:
The patent resolves crystal formation by changing the pH parameter to a highly basic range (11.0-14.0) and controlling water content to less than 5%. This parameter transformation prevents the drug from reaching its crystallization point while maintaining solubility through the basic PEG 400 environment.
Solution Approach 2:
The invention applies local quality by creating a highly basic microenvironment specifically around the Rigosertib molecules within the PEG 400 matrix. This localized basic condition prevents crystallization at the molecular level while maintaining overall formulation homogeneity and solubility.
3Ease of operation
If Rigosertib is administered orally, then treatment accessibility is improved, but urothelial toxicity increases
Solution Approach 1:
The patent applies parameter changes by formulating Rigosertib in a highly basic PEG 400 system with controlled water content. This formulation modification alters the drug's physicochemical properties, including solubility and stability characteristics, which in turn affects its metabolic profile and reduces urothelial toxicity while maintaining oral administrability.
Data Source
AI summary
Pharmaceutical compositions of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof are described as well as methods of their use, and a dose regimen of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt to reduce the incidence of urothelial toxicity.