Soluble High-Concentration Insulin Formulation for Predictable Release
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Solution Overview
Problem
Current long-acting insulin compositions face challenges such as potential immunogenic reactions, tissue irritation, and unpredictable release profiles due to particle size distribution variations upon injection.
Innovation Solution
A soluble insulin preparation comprising NεB29-hexadecandioyl-γ-Glu-(desB30) human insulin in concentrations from 1800 nmol/ml to 4200 nmol/ml, with specific ratios of zinc ions, niacinamide, treprostinil, citrate, and a pH range of 7.0 to 8.0, which maintains a pharmacokinetic profile similar to a U200 product while ensuring stability during storage and use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If crystallized insulin is used in long-acting formulations, then the duration of action is extended, but immunogenic reactions and tissue irritation occur
Solution Approach 1:
The patent changes the physical state parameter from crystallized to soluble form, and adjusts pH parameter to physiological range (7.0-8.0), eliminating crystallization-related harmful effects while maintaining extended duration of action through controlled insulin solubility and release characteristics
Solution Approach 2:
The patent employs a soluble insulin formulation that dissolves completely in body tissues, avoiding the need for persistent crystalline structures, thereby eliminating long-term immunogenic reactions and tissue irritation associated with crystallized insulin deposits
2Duration of action of moving object
If pH-adjusted insulin solutions are used to achieve protracted release, then the duration of action is extended, but particle size distribution becomes unpredictable and tissue irritation occurs
Solution Approach 1:
The patent changes the pH parameter to physiological range (7.0-8.0) rather than using acidic pH solutions, which eliminates unpredictable particle formation and ensures consistent, predictable release profile while maintaining extended duration of action through controlled insulin solubility
Solution Approach 2:
Instead of using low pH to control release (conventional approach), the patent uses physiological pH with controlled insulin solubility parameters to achieve protracted release, inverting the conventional wisdom and eliminating particle size unpredictability
3Quantity of substance
If high-concentration insulin formulations are used, then the quantity of substance per dose is increased, but stability during storage and use deteriorates
Solution Approach 1:
The patent changes the concentration parameter to achieve high concentration (U500 equivalent to 500 units/ml) while simultaneously adjusting solubility parameters and pH to physiological range, maintaining stability during storage and use through controlled insulin solubility and formulation chemistry
Solution Approach 2:
The patent creates a composite formulation system combining insulin with specific excipients and additives that maintain stability at high concentrations, using formulation chemistry to preserve insulin integrity and prevent degradation during storage and administration
4Stability of the object's composition
If hexamers are used to protect insulin from degradation, then the stability is improved, but the speed of action is delayed
Solution Approach 1:
The patent changes the insulin aggregate state parameter from hexamers to monomers through controlled solubility and pH conditions, which eliminates the delay in action while maintaining stability through formulation chemistry that prevents degradation without requiring hexamer formation
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 soluble insulin preparation achieves a pharmacokinetic profile substantially similar to a U200 product, ensuring stability and bioequivalence, allowing for less frequent device replacements and enabling high-dose basal insulin administration with a single daily dose.
Implementation Method 1
Zinc and phenolic additives are regularly used in therapeutic insulin preparations to promote hexamer formation as a precaution against degradation during storage
Implementation Method 2
A soluble insulin preparation comprising NεB29-hexadecandioyl-γ-Glu-(desB30) human insulin in concentrations from 1800 nmol/ml to 4200 nmol/ml
Implementation Method 3
When human insulin is injected into the subcutis in the form of a high-concentration pharmaceutical formulation it is self-associated, and here dissociation into monomers is relatively slow. Hexamers and dimers of insulin are slower to penetrate capillary wall than monomers
Data Source
AI summary
The invention concerns a soluble insulin preparation comprising NϵB29-hexadecandioyl-γ-Glu-(desB30) human insulin in a concentration from 1800 nmol/ml to 4200 nmol/ml, Zinc ions in a concentration from 4.0 Zn/6Ins to 7.0 Zn/6Ins, Niacinamide in a concentration from 110 mM to 220 mM or treprostinil in a concentration from 0.02 μg/ml to 1 μg/ml, Citrate in a concentration from 6 mM to 40 mM, and pH in the range from 7.0 to 8.0. The invention further comprises a method for using the soluble insulin preparation for reducing the blood glucose level in a mammal and a process for preparing the soluble insulin preparations.