Rapid-acting insulin compositions with citrate and treprostinil
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Solution Overview
Problem
Current insulin compositions have delayed uptake and action, leading to inadequate control of postprandial blood glucose levels and increased risk of hyperglycemia or hypoglycemia, despite efforts to develop rapid-acting analogs and formulations with additional excipients.
Innovation Solution
A pharmaceutical composition combining insulin with citrate, treprostinil, zinc, and stabilizing agents like magnesium chloride or sodium chloride, optimizing concentrations to enhance rapid uptake and stability, with specific formulations including insulin lispro, citrate, treprostinil, zinc, and preservatives like m-cresol, to achieve faster and more controlled insulin action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If rapid-acting insulin analogs are used, then the onset of action is faster than regular insulin, but the maximum plasma insulin level is not reached until 50-90 minutes following injection, which is still slower than endogenous insulin release
Solution Approach 1:
The patent changes the chemical parameters of the insulin formulation by adding specific excipients (arginine 1-10 mM, nicotinamide 1-20 mM, glutamic acid 1-10 mM) to modify the pharmacokinetic parameters of insulin, achieving a faster onset of action that better matches endogenous insulin release and glucose absorption profiles
Solution Approach 2:
The patent creates a composite insulin formulation by combining insulin with multiple excipients (arginine, nicotinamide, glutamic acid, and optionally oligosaccharides or polyanionic compounds) to achieve synergistic effects that accelerate insulin absorption and improve the time-action profile
2Speed
If administered insulin enters blood slowly from the subcutaneous space, then the composition is stable for storage, but the onset of action is too slow to control postprandial blood glucose levels
Solution Approach 1:
The patent modifies the formulation parameters by incorporating specific concentrations of excipients (arginine 1-10 mM, nicotinamide 1-20 mM, glutamic acid 1-10 mM) that accelerate insulin uptake from the subcutaneous space while maintaining chemical and physical stability during storage and use
Solution Approach 2:
The patent creates different local properties within the formulation by using excipients that specifically enhance absorption at the injection site (improving uptake speed) while the overall formulation maintains stability characteristics suitable for storage, effectively separating the local absorption enhancement from global stability requirements
3Duration of action of moving object
If a protracted duration of action from the subcutaneous space is used, then the composition provides extended insulin coverage, but excessive insulin between meals causes postprandial hypoglycemia
Solution Approach 1:
The patent creates a more physiological periodic action pattern by accelerating the initial uptake phase of insulin (matching the natural spike in endogenous insulin after meals) while allowing a more gradual decline, thereby avoiding the prolonged excessive insulin levels that cause postprandial hypoglycemia
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 composition provides a more rapid onset and offset of insulin action, improving pharmacokinetic and pharmacodynamic parameters by at least 20-50% compared to existing formulations, while maintaining chemical and physical stability for extended storage and use.
Implementation Method 1
a dissolution/stabilization agent, such as citric acid or sodium citrate
Implementation Method 2
zinc, in a concentration sufficient to provide at least 2 zinc ions per six molecules of insulin
Implementation Method 3
one or more additional stabilizing agents selected from magnesium-containing compounds and sodium chloride
Implementation Method 4
treprostinil, in a concentration from 0.04 to 20 μg/mL
Data Source
AI summary
The invention is a pharmaceutical composition of human insulin or insulin analog that includes citrate, treprostinil and stabilizing agents, that has faster pharmacokinetic and/or pharmacodynamic action than commercial formulations of existing insulin analog products and that is stable for commercial use.