rHDL Formulation Stabilizer Amino Acid Proline
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Solution Overview
Problem
Existing reconstituted high-density lipoprotein (rHDL) formulations face challenges in stability during lyophilization and may cause renal toxicity due to high sugar concentrations, which is particularly concerning for renally impaired patients.
Innovation Solution
The development of an rHDL formulation with a reduced concentration of lyophilization stabilizers, specifically using amino acids like proline, which provides good stability and reduces renal toxicity risks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If high concentrations of sugar stabilizers (e.g., 10% sucrose) are used to maintain rHDL stability during lyophilization, then the formulation shows good long-term stability, but the formulation causes or exacerbates renal problems in renally impaired patients
Solution Approach 1:
The patent changes the chemical nature of the stabilizer from sugar-based (sucrose, mannitol) to amino acid-based (proline, glycine, alanine). This parameter change maintains the stabilizing function during lyophilization while eliminating the renal toxicity associated with high sugar concentrations in renally impaired patients
Solution Approach 2:
The patent uses amino acids as stabilizers which are metabolically compatible and can be readily processed by the body, particularly in renal patients. Amino acids serve as effective stabilizers during lyophilization but do not accumulate to toxic levels in renal impairment the way sugar stabilizers do
2Stability of the object's composition
If conventional sugar and sugar alcohol stabilizers are used in rHDL formulations, then lyophilization stability is improved, but the functional performance of rHDL in biological assays is compromised
Solution Approach 1:
The patent changes the stabilizer type from sugars to amino acids, which do not interfere with the biological functionality of rHDL particles. This parameter change allows the formulation to maintain stability during lyophilization while preserving full functional activity in cholesterol efflux assays and other biological tests
3Reliability
If high concentrations of stabilizers are used to protect protein during freezing and drying, then protein denaturation is prevented, but the formulation complexity and manufacturing cost increase
Solution Approach 1:
The patent simplifies the formulation by using amino acids at lower concentrations (1-10% w/v) compared to conventional sugar stabilizers. This parameter change reduces formulation complexity while maintaining adequate protein protection during lyophilization, as amino acids provide effective stabilization at lower levels
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 formulation achieves long-term stability with reduced renal toxicity, allowing for better performance in functional assays and suitability for patients with renal impairments.
Implementation Method 1
stabilizers are often required in a protein formulation to protect protein stability both during freezing and drying processes
Implementation Method 2
amino acids, particularly proline, are useful lyophilization stabilizers for rHDL formulations
Data Source
AI summary
The present invention relates to reconstituted high density lipoprotein (rHDL) formulations comprising an apolipoprotein, a lipid and a lyophilization stabilizer. Said formulations have reduced renal toxicity and good long-term stability, especially in lyophilized form.