Buffered Exendin (9-39) Formulation for Low-Aggregation Dosing
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Solution Overview
Problem
Current liquid pharmaceutical formulations of exendin (9-39) for treating hyperinsulinemic hypoglycemia, particularly post-bariatric hypoglycemia, suffer from issues of aggregation and reduced pharmacokinetic profiles, especially at higher concentrations, necessitating improved stability and potency.
Innovation Solution
Formulations of exendin (9-39) or its pharmaceutically acceptable salts in a physiologically acceptable buffer with a pH of 5 to 6, combined with a tonicity modifier, to reduce aggregation and enhance pharmacokinetic properties.
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 aggregation occurs and pharmacokinetic profiles are reduced
Solution Approach 1:
The patent changes the pH parameter of the formulation from neutral (normal saline pH 7.4) to acidic (pH 3.0-5.0). This parameter change prevents aggregation of exendin (9-39) while maintaining formulation simplicity. The acidic pH keeps the peptide in a monomeric state, improving stability without complicating the manufacturing process.
Solution Approach 2:
The patent introduces an intermediary substance (excipient) that mediates between the peptide and the aqueous environment. This intermediary prevents direct interaction between peptide molecules that would lead to aggregation, while still allowing the formulation to remain simple and easy to manufacture.
2Productivity
If exendin (9-39) concentration is increased to reduce dosing frequency, then treatment efficacy improves, but aggregation increases and stability decreases
Solution Approach 1:
By changing the pH parameter to acidic conditions (pH 3.0-5.0), the patent enables formulation of exendin (9-39) at high concentrations (up to 100 mg/mL or higher) without aggregation. The acidic pH maintains the peptide in a stable monomeric state even at these elevated concentrations, allowing reduced dosing frequency while preventing stability issues.
Solution Approach 2:
The patent creates a composite formulation system combining exendin (9-39) with specific excipients designed to work synergistically at high concentrations. This composite approach allows the peptide to maintain stability and solubility at concentrations that would otherwise cause aggregation, enabling more effective and less frequent dosing.
3Productivity
If exendin (9-39) is formulated at high concentration for lower dosing, then treatment efficiency improves, but pharmacokinetic profiles are reduced due to aggregation
Solution Approach 1:
The patent changes the pH parameter to acidic conditions, which prevents aggregation and ensures reliable pharmacokinetic profiles even at high concentrations. This parameter change allows the formulation to achieve both high treatment efficiency (through concentrated dosing) and reliable pharmacokinetics (through prevented aggregation).
Solution Approach 2:
The patent employs excipients that are optimized for single-use formulations at high concentrations. These excipients maintain peptide stability during the short time frame of administration and immediate post-administration, ensuring reliable pharmacokinetic profiles without requiring complex long-term stabilization strategies.
Data Source
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.