Preservative-Free Liquid Insulin Formulation Stability
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Solution Overview
Problem
Commercial insulin formulations face challenges with chemical and physical instability during storage and shipment, leading to degradation issues such as fibril formation and loss of potency, particularly due to the absence of preservatives and stabilizers like phenolic compounds which can be irritating.
Innovation Solution
Development of liquid insulin formulations containing 1-13 mM insulin, 50-150 mM salt, 3-24 mM pH buffering agent (citrate), and 1.9-2.7 zinc ions per insulin hexamer, without preservatives or stabilizers, optimized for pH 7.2-8.0 to maintain solubility and stability, allowing for extended shelf life and resistance to shear forces.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If phenolic preservatives and stabilizers are added to promote hexamer stability, then insulin chemical stability is improved, but patient safety and tolerability deteriorate due to mucosal irritation and malodorous effects
Solution Approach 1:
The invention removes phenolic preservatives and stabilizers from the insulin formulation, extracting the harmful components while maintaining insulin stability through alternative means (pH control at 7.2-8.0, zinc ions at 1.9-2.7 per hexamer, and specific ionic strength conditions). This eliminates mucosal irritation while preserving hexamer stability.
Solution Approach 2:
The invention changes the formulation parameters by controlling pH within a specific range (7.2-8.0) and adjusting zinc ion concentration (1.9-2.7 per hexamer), which stabilizes insulin through conformational changes in the B1-B8 region without requiring phenolic compounds. This parameter optimization resolves the contradiction between stability and safety.
2Productivity
If insulin concentration is increased to reduce formulation volume, then productivity is improved, but physical stability deteriorates due to increased susceptibility to fibril formation during shipment
Solution Approach 1:
The invention optimizes multiple parameters simultaneously: pH (7.2-8.0), zinc ion concentration (1.9-2.7 per hexamer), and ionic strength (50-150 mM salt). This combination stabilizes the hexameric form even at high insulin concentrations (up to 1000 U/mL or higher), preventing fibril formation during shipment while maintaining high productivity.
Solution Approach 2:
The invention creates a composite formulation system where zinc ions, pH buffering agents, and salt components work synergistically to stabilize insulin. This composite approach allows high concentration formulations to maintain physical stability by promoting hexamer formation and preventing monomer aggregation into fibrils.
3Quantity of substance
If pH is adjusted to optimize solubility, then insulin solubility is improved, but chemical stability deteriorates due to increased deamidation reactions at higher pH
Solution Approach 1:
The invention identifies an optimal pH window (7.2-8.0) that balances solubility and chemical stability. Within this range, insulin maintains adequate solubility while deamidation rates are controlled. The specific zinc ion concentration (1.9-2.7 per hexamer) further modulates this balance by stabilizing the hexameric form, which protects against pH-dependent degradation.
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 demonstrate enhanced chemical and physical stability, maintaining insulin potency and solubility for at least 24 months, with reduced degradation products and improved resistance to shear forces, making them suitable for both injection and inhalation delivery.
Implementation Method 1
The binding of two zinc molecules facilitates 3 dimers (In 2 ) assembling into the hexameric form. Hexameric insulin can transition between two primary states: T 6 and R 6 .
Implementation Method 2
phenolic preservatives and stabilizers bind to hydrophobic pockets located near the surfaces of insulin to promote the R 6 state
Implementation Method 3
The hydrophobic surfaces of the insulin molecule bind together, irreversibly forming an insulin fiber. Insulin monomers continue to bind, and the fiber elongates until it becomes insoluble in aqueous solution.
Implementation Method 4
The fiber elongates until it becomes insoluble in aqueous solution. The formation of these inactive insulin fibers, results in visible cloudiness and loss of potency
Implementation Method 5
a pH in the range of 7.2 to 8.0
Data Source
Figure 1
Figure 2
Figure 3~4
AI summary
Liquid formulations of insulin that contain physically and chemically stable insulin but do not contain preservatives or stabilizers are provided. The formulations also lack surfactants. The formulations are useful for various modes of delivery including pulmonary delivery.