High-Concentration G-CSF Formulation With Low Osmolality Stability
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Solution Overview
Problem
High-concentration G-CSF protein formulations face challenges with protein aggregation, osmolality, and stability issues, leading to potential injection pain and formulation instability.
Innovation Solution
A pharmaceutical composition comprising G-CSF dimer, buffering agent, stabilizing agent, tonicity agent, and surfactant, formulated to maintain stability and osmolality, with specific concentrations and pH levels, enhancing storage stability and in vivo tolerability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If high-concentration G-CSF protein formulations are used, then convenience for healthcare providers and patients is improved, but protein aggregation and instability increase
Solution Approach 1:
The patent applies parameter changes by carefully controlling the concentration of G-CSF protein within a specific range (0.1-10 mg/mL) and adjusting formulation parameters such as pH (4.0-7.0), ionic strength, and temperature to maintain protein stability while achieving high concentration. This resolves the contradiction by finding the optimal parameter set that simultaneously ensures convenience and stability.
Solution Approach 2:
The patent uses intermediary substances including stabilizing agents (e.g., polysorbates, poloxamers), buffering agents, and tonicity agents that mediate between the high protein concentration requirement and the stability requirement. These intermediaries prevent protein aggregation and maintain formulation stability without compromising the high concentration needed for convenience.
2Ease of operation
If high protein concentration is achieved, then formulation convenience is improved, but osmolality increases causing injection pain
Solution Approach 1:
The patent introduces tonicity agents (e.g., mannitol, sorbitol, sucrose) as intermediary substances that adjust the osmolality of the formulation. These agents compensate for the high protein concentration by balancing the overall osmotic pressure, ensuring the formulation remains isotonic or hypotonic to body fluids, thereby preventing injection pain while maintaining high protein concentration for convenience.
Solution Approach 2:
The patent changes the osmolality parameter by adding specific concentrations of tonicity agents (0.1-5% w/v) to counterbalance the osmotic effect of high protein concentration. This parameter adjustment ensures the formulation is tolerable for subcutaneous administration without causing tissue damage or injection pain.
3Ease of operation
If high protein concentration is used, then dosing convenience is improved, but stabilizer concentration must increase leading to osmolality issues
Solution Approach 1:
The patent employs multiple intermediary substances including stabilizing agents (polysorbates, poloxamers), buffering agents, and tonicity agents that work together to manage the osmolality burden. These intermediaries distribute the stabilizing function across multiple components rather than relying on single high-concentration stabilizers, thereby reducing the osmolality impact while maintaining formulation stability and dosing convenience.
Solution Approach 2:
The patent uses a composite formulation system combining multiple functional components: protein, stabilizing agents, buffering agents, tonicity agents, and surfactants. This composite approach allows the formulation to achieve high protein concentration for dosing convenience while the synergistic interaction of multiple components manages osmolality and stability requirements effectively.
Data Source
AI summary
Provided herein are methods of treating chemotherapy-induced neutropenia in a patient in need thereof by administering to the patient an effective amount of Eflapegrastim. Also provided herein are methods of treating radiation-induced neutropenia in a patient in need thereof by administering to the patient an effective amount of Eflapegrastim.