Buffered Exendin (9-39) Formulations to Reduce Peptide Aggregation
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Solution Overview
Problem
Existing liquid formulations of exendin (9-39) in normal saline exhibit concentration-dependent peptide aggregation and precipitation, leading to reduced pharmacokinetic exposure and clinical activity, necessitating improved formulations for effective treatment of hyperinsulinemic hypoglycemia.
Innovation Solution
Development of buffered liquid formulations of exendin (9-39) or its pharmaceutically acceptable salts in a physiologically acceptable buffer with a pH of 5 to 6, incorporating tonicity modifiers like mannitol, to reduce aggregation and enhance pharmacokinetic profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If exendin (9-39) is formulated in normal saline, then the formulation is simple to prepare, but peptide aggregation and precipitation occur leading to reduced pharmacokinetic exposure
Solution Approach 1:
The patent changes the pH parameter of the formulation from neutral (normal saline pH 7) to acidic (pH 2-4) to prevent peptide aggregation. This parameter change resolves the contradiction by maintaining formulation simplicity while eliminating aggregation issues that reduce pharmacokinetic exposure
Solution Approach 2:
The patent introduces acidifying agents (such as hydrochloric acid, acetic acid, or citric acid) as intermediaries to adjust the pH of the saline solution. These intermediaries prevent peptide aggregation without complicating the formulation process, thereby maintaining ease of manufacture while improving reliability
2Productivity
If exendin (9-39) concentration is increased to reduce dosing frequency, then treatment efficiency improves, but peptide aggregation increases reducing clinical activity
Solution Approach 1:
By changing the pH parameter to acidic conditions (pH 2-4), the patent enables higher peptide concentrations to be maintained in solution without aggregation. This resolves the contradiction by allowing increased productivity through higher concentrations while preventing the harmful aggregation effect
3Stability of the object's composition
If buffered formulations with pH 5-6 are used, then peptide stability improves, but formulation complexity increases
Solution Approach 1:
The patent uses simple acidifying agents added to normal saline to achieve pH 2-4, which provides peptide stability without requiring complex buffered formulations. This resolves the contradiction by maintaining peptide stability while minimizing formulation complexity through the use of straightforward pH adjustment
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 buffered formulations exhibit improved pharmacokinetic profiles with higher C max and prolonged action, allowing for lower and less frequent dosing for treating hyperinsulinemic hypoglycemia.
Implementation Method 1
buffered liquid formulations of exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of about 5 to about 6
Implementation Method 2
the buffered liquid formulation comprises a tonicity modifier
Data Source
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AI summary
Provided herein are liquid pharmaceutical formulations comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of about 5 to about 6. In some embodiments, the buffered liquid formulation comprises exendin (9-39) or a pharmaceutically acceptable salt thereof in an acetate buffer or a citrate buffer. Methods of treating or preventing hyperinsulinemic hypoglycemia in a subject comprising administering to the subject the buffered liquid formulation are also provided.