GLP-2 Analogue Formulation pH Adjustment and Propylene Glycol Stabilization
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Solution Overview
Problem
Current formulations of GLP-2 analogues face challenges in achieving stable liquid formulations capable of long-term storage without physical degradation, particularly when including preservatives, which tend to destabilize peptide drugs unpredictably.
Innovation Solution
The development of stable liquid pharmaceutical formulations for GLP-2 analogues involves reducing the pH to between 5.0 and 6.8 and/or adding propylene glycol to offset the destabilizing effects of preservatives like meta-cresol, enabling multi-dose formulations and improved chemical stability, allowing for the creation of ready-to-use delivery devices such as pre-filled syringes and auto-injectors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If preservatives are added to liquid formulations of GLP-2 analogues, then microbial stability is improved, but physical stability deteriorates due to unpredictable destabilization of peptide drugs
Solution Approach 1:
The patent introduces pH adjustment (to range 3-7) and excipients (mannitol, histidine, phenol red) as intermediary substances that mediate between the preservative and the peptide drug. These intermediaries create a buffered environment that protects the peptide from preservative-induced destabilization while allowing the preservative to maintain its antimicrobial function.
Solution Approach 2:
The patent changes the pH parameter of the formulation to a specific range (3-7) and adjusts other formulation parameters including the concentration of excipients. This parameter optimization allows the formulation to tolerate preservatives without physical destabilization, resolving the contradiction between microbial stability and physical stability.
2Stability of the object's composition
If pH is reduced to between 5.0 and 6.8, then chemical stability is improved, but formulation composition changes
Solution Approach 1:
The patent deliberately changes the pH parameter to a specific range (5.0-6.8) to improve chemical stability of the GLP-2 analogue. This parameter change is compensated by adjusting other formulation components to maintain overall formulation integrity and therapeutic efficacy.
Solution Approach 2:
The patent uses histidine buffer which serves multiple functions: it maintains pH within the stabilizing range, provides buffering capacity, and acts as an excipient that does not interfere with peptide stability. This multi-functional approach manages formulation complexity while achieving chemical stability.
3Stability of the object's composition
If propylene glycol is added, then physical stability is improved by offsetting preservative effects, but formulation complexity increases
Solution Approach 1:
Propylene glycol is introduced as an intermediary excipient that mediates between the preservative and the peptide drug. It protects the peptide from preservative-induced physical destabilization through its solvent and stabilizing properties, while being compatible with other formulation components.
Solution Approach 2:
The patent creates a composite formulation system combining multiple excipients (propylene glycol, mannitol, histidine, phenol red) that work synergistically. This composite approach manages the complexity by having each component serve specific stabilizing functions that collectively protect the peptide drug.
4Ease of operation
If GLP-2 analogues are formulated as liquid preparations, then ease of administration is improved, but long-term storage stability without degradation is compromised
Solution Approach 1:
The patent optimizes multiple formulation parameters including pH (3-7), excipient concentrations, and ionic strength to create a liquid formulation that remains stable during long-term storage. These parameter changes enable the liquid form to resist degradation pathways while maintaining ease of administration.
Solution Approach 2:
The patent incorporates stabilizing excipients and pH buffers in advance during formulation preparation, creating a pre-stabilized liquid formulation. This preliminary stabilization prevents degradation during storage, allowing the liquid form to maintain both ease of administration and long-term stability.
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 maintain at least 90% of the GLP-2 analogue in active form with less than 10% chemical degradation products for 18 months at 2-8°C, providing a stable and patient-friendly multi-dose delivery system without significant adverse effects on chemical stability.
Implementation Method 1
reducing the pH to between 5.0 and 6.8 to offset the destabilizing effects of preservatives
Implementation Method 2
adding propylene glycol to offset the destabilizing effects of preservatives like meta-cresol, enabling multi-dose formulations and improved chemical stability
Implementation Method 3
maintain at least 90% of the GLP-2 analogue in active form with less than 10% chemical degradation products for 18 months at 2-8°C
Data Source
AI summary
Liquid formulations of GLP-2 analogues are described that make it possible to include a preservative while allowing the formulation to be stabilised for long term storage as liquids and/or as multi-dose liquid formulations. The development of these formulations is base on the finding that that reducing the pH of the formulation to below 7.0, e.g. to a pH between about pH 5.0 and about 6.8, was able to offset the effect that the addition of a preservative such as meta-cresol has on the physical stability of the formulation. Additionally, the addition of an excipient such as propylene glycol was shown to be able to offset the effect that the addition of a preservative, such as meta-cresol, has on the physical stability of the formulation. This opens up the possibility of being able to deliver the GLP-2 analogues as multi-dose formulations, for example allowing the use of the formulations in a drug delivery device.