Tumor Peptide Formulation with Mannitol and Surfactant for Stable Reconstitution
Solution Overview
Problem
Existing cancer vaccine formulations, particularly for renal and glioblastoma, face challenges with poor solubility and stability, requiring vigorous shaking and ultrasound for dissolution and having limited shelf life, making them difficult to use effectively in clinical settings.
Innovation Solution
Pharmaceutical compositions comprising tumor-associated peptides with specific ratios of mannitol and poloxamer 188 or TWEEN 80, which enhance solubility and stability, allowing for easy reconstitution without ultrasound and maintaining effectiveness over time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If peptides are formulated with sodium hydrogen carbonate as disclosed in WO 2007/028573, then the composition can be prepared for injection, but the solubility is poor requiring vigorous shaking and ultrasound for dissolution
Solution Approach 1:
The patent changes the chemical composition parameters by replacing sodium hydrogen carbonate with a formulation containing mannitol and poloxamer 188 (or TWEEN 80). This parameter change fundamentally alters the dissolution behavior, allowing the peptide formulation to dissolve easily without requiring vigorous shaking or ultrasound treatment, thus resolving the contradiction between ease of manufacture and ease of operation.
Solution Approach 2:
The patent uses a composite formulation system combining mannitol (a sugar alcohol) with poloxamer 188 (a nonionic surfactant) or TWEEN 80 (another surfactant). This composite material approach creates synergistic effects where the surfactant reduces surface tension and promotes wetting, while mannitol provides solubility enhancement, together eliminating the dissolution difficulties associated with sodium hydrogen carbonate formulations.
2Productivity
If the composition uses sodium hydrogen carbonate, then dissolution can be achieved, but the resulting solution can only be used for about 30 minutes
Solution Approach 1:
The patent changes the formulation parameters by substituting the buffer system and excipients, replacing sodium hydrogen carbonate with mannitol and poloxamer 188/TWEEN 80. This parameter change stabilizes the peptide formulation, extending the usable duration from 30 minutes to at least 24 hours, thereby resolving the contradiction between dissolution speed and shelf life.
Solution Approach 2:
The patent eliminates the need for disposable short-lived solutions by creating a stable formulation that maintains its properties over extended periods. The new formulation with mannitol and surfactant provides long-term stability, removing the constraint of 30-minute usability and allowing the solution to be stored and used over much longer periods.
3Duration of action of stationary object
If the formulation is stored for 12 months at different temperatures, then the characteristics change over time, but no clear solution could be produced even after ultrasound homogenation
Solution Approach 1:
The patent employs a composite material system of mannitol combined with poloxamer 188 or TWEEN 80 that provides superior stability during long-term storage. The surfactant component prevents aggregation and maintains homogeneity, while mannitol acts as a stabilizing excipient. This composite formulation remains stable and produces clear solutions even after 12 months of storage at various temperatures, resolving the contradiction between storage duration and formulation stability.
Solution Approach 2:
The formulation includes stabilizing excipients (mannitol and surfactant) that provide protective cushioning against degradation during storage. These components preemptively prevent aggregation, precipitation, or other instability issues that would otherwise develop during long-term storage, ensuring the formulation remains stable and easily reconstitutable after extended periods.
4Ease of operation
If vigorous shaking and ultrasound homogenation are applied, then dissolution can be achieved, but the treatment cannot be applied by all physicians in their practices
Solution Approach 1:
The patent changes the formulation parameters to eliminate the need for complex dissolution procedures. By using mannitol and surfactant instead of sodium hydrogen carbonate, the formulation becomes inherently easy to reconstitute with simple mixing, removing the requirement for ultrasound homogenators and other specialized equipment, thus resolving the contradiction between dissolution achievement and device complexity.
Solution Approach 2:
The new formulation is designed to be self-dissolving, requiring only simple mixing without the need for external energy input from ultrasound or vigorous shaking. The surfactant and mannitol combination enables the peptides to dissolve automatically upon contact with the diluent, making the preparation process accessible to any physician without specialized equipment.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulations provide enhanced solubility and stability, enabling easy reconstitution and prolonged shelf life, ensuring effective and safe use in cancer immunotherapy.
Implementation Method 1
mannitol and poloxamer 188, wherein the ratio by weight of said peptide(s) to mannitol to poloxamer 188 is in the range including and between 1:5:1.5 to 1:8:2.2; or mannitol and TWEEN 80®, wherein the ratio by weight of peptides to mannitol to TWEEN 80® is in the range including and between 1:2:1.5 to 1:8:2.2
Data Source
AI summary
The present invention relates to novel formulations of tumor-associated peptides binding to human leukocyte antigen (HLA) class I or II molecules as vaccines for the use in immunotherapeutic methods. In particular, the present invention relates to formulations for the immunotherapy of cancer, in particular renal and brain cancer, in particular glioma, especially glioblastoma cancer. The present invention furthermore relates to vaccine compositions for eliciting anti-tumor immune responses.