Lactate Anion Stabilization of High-Concentration hGH
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Solution Overview
Problem
High-concentration human growth hormone (hGH) aqueous compositions face challenges in stability, particularly at higher concentrations, due to rapid aggregation and deamidation, which limits their storage at room temperature and requires stringent regulatory approval for stability at elevated temperatures.
Innovation Solution
The formulation of hGH compositions at a pH of 6.1 with displaced buffers having pKa values 1-3 units from the pH, and osmolarity between 150-500 mOsm/L, in the absence of conventional buffers, along with the use of surfactants and preservatives, to minimize aggregation and deamidation, achieving stability across a range of concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high concentration of hGH is used in aqueous compositions, then productivity and dosing flexibility are improved, but aggregation rate increases significantly
Solution Approach 1:
The patent introduces lactate anion as an intermediary substance that mediates between high hGH concentration and aggregation prevention. The lactate anion specifically interacts with hGH at high concentrations to stabilize the protein and prevent aggregation, allowing the formulation to achieve both high productivity and reliability
Solution Approach 2:
The patent changes the chemical environment parameters by introducing lactate anion and adjusting pH to 6.1, which fundamentally alters the stability characteristics of hGH at high concentrations. This parameter change enables the system to maintain low aggregation rates even at concentrations exceeding 10 mg/mL
2Stability of the object's composition
If pH is adjusted to minimize deamidation rate, then chemical stability is improved, but aggregation may be affected
Solution Approach 1:
The patent merges two stabilization mechanisms by simultaneously optimizing pH to 6.1 (which minimizes deamidation) and introducing lactate anion (which prevents aggregation). The combination of these two approaches achieves both chemical stability and physical stability without compromise
3Stability of the object's composition
If conventional buffers are used in hGH formulations, then pH stability is maintained, but aggregation is promoted
Solution Approach 1:
The patent extracts or removes conventional buffer components from the formulation and replaces them with lactate anion. This extraction eliminates the aggregation-promoting effects of conventional buffers while maintaining adequate pH stability through the lactate buffer system
Solution Approach 2:
The patent uses a simple lactate buffer system instead of complex conventional buffer formulations. The lactate anion provides sufficient pH stability for therapeutic storage conditions without the destabilizing effects of traditional buffers, offering a simpler and more effective solution
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 approach results in <1% aggregation and no visible precipitation after incubation at 40°C for 8 weeks, and <3% after 18 weeks at 25°C, enhancing storage stability and regulatory acceptance for high-concentration hGH compositions.
Implementation Method 1
Stable formulations of growth hormone comprising lactate anion
Implementation Method 2
aqueous liquid compositions of hGH
Data Source
AI summary
An aqueous composition comprising a therapeutic protein further characterized in that(i) the pH of the composition is adjusted to be between about 5.9 and 6.3, preferably about 6.1;(ii) the composition comprises at least one displaced buffer having a pKa within 1 to 3 pH units of the pH of the composition;(iv) the osmolarity of the composition is between 150-500 mOsm/L.