Thiotepa Injection Formulation for Liquid Storage Stability
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Solution Overview
Problem
Thiotepa is unstable in aqueous solutions, leading to impurity generation and degradation during storage, making ready-to-use liquid dosage forms difficult to manage.
Innovation Solution
Formulations comprising thiotepa with PEG or DMSO, optionally with water or aqueous saline, are developed to enhance stability, minimizing impurities and maintaining effectiveness over extended periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If thiotepa is formulated in aqueous solutions for ready-to-use liquid dosage forms, then ease of operation is improved, but stability of the composition deteriorates due to degradation and impurity generation during storage
Solution Approach 1:
The patent changes the physical-chemical parameters of the formulation by incorporating specific excipients (PEG 300-600, DMSO, ethanol, benzyl alcohol) and adjusting their concentrations to achieve optimal stability. This resolves the contradiction by modifying the composition parameters to prevent aqueous degradation while maintaining liquid dosage form readiness.
Solution Approach 2:
The patent creates a composite formulation system combining thiotepa with multiple stabilizing excipients (PEG, DMSO, ethanol, benzyl alcohol) that work synergistically. This composite approach provides enhanced stability against hydrolysis and oxidation while preserving the liquid dosage form characteristics for ease of administration.
2Stability of the object's composition
If thiotepa is stored as a freeze-dried product requiring reconstitution, then stability of the composition is improved, but ease of operation deteriorates due to additional preparation steps
Solution Approach 1:
The patent modifies the formulation parameters by incorporating stabilizing excipients that enable long-term stability in liquid form without requiring freeze-drying. This eliminates the reconstitution step while maintaining compositional stability through careful selection of PEG, DMSO, and other stabilizers.
Solution Approach 2:
The patent extracts the stability function from the freeze-dried state and transfers it to the liquid formulation by incorporating specific stabilizing excipients. This allows the active ingredient to maintain stability in the liquid phase without requiring removal of water through freeze-drying, thereby simplifying the administration process.
3Stability of the object's composition
If thiotepa is formulated with ethanol as a solvent, then stability of the composition is improved, but object-generated harmful factors increase due to potential toxicity concerns
Solution Approach 1:
The patent creates a multi-component composite formulation where ethanol is combined with PEG, DMSO, and benzyl alcohol in specific ratios. This composite system distributes the stabilizing function across multiple excipients, allowing ethanol to be used at lower, safer concentrations while maintaining formulation stability and reducing overall toxicity concerns.
Solution Approach 2:
The patent optimizes the concentration parameters of ethanol and other excipients to achieve the minimum effective levels required for stability. By carefully controlling the ethanol content and balancing it with other stabilizers, the formulation maintains adequate stability while minimizing harmful effects.
Data Source
AI summary
The present disclosure provides pharmaceutical compositions comprising thiotepa and one selected from PEG, such as PEG400 or PEG600, and DMSO, and optionally water or an aqueous saline solution and thiosulfate. The composition is free or substantially free of impurities. Also provided is a method for treating cancer in a subject, or myeloablation prior to bone marrow transplantation using the composition. A method for enhancing the stability of a thiotepa formulation is also contemplated.