GLP-1 Agonist Solid Compositions with Histidine for Storage Stability
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Solution Overview
Problem
Human GLP-1 and its analogues have low oral bioavailability and stability issues, necessitating improved formulations to enhance absorption and maintain efficacy during storage.
Innovation Solution
A solid pharmaceutical composition comprising a GLP-1 agonist, such as semaglutide, combined with a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) and histidine, where the moles of histidine are at least equal to half the moles of the GLP-1 agonist, to enhance stability and absorption.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 agonist is formulated with absorption enhancers for oral administration, then oral bioavailability is improved, but stability during storage deteriorates
Solution Approach 1:
Histidine acts as an intermediary substance that mediates between the GLP-1 agonist and the absorption enhancer SNAC. It reduces the harmful interaction between SNAC and the peptide while maintaining the absorption-enhancing effect, thereby improving both stability and bioavailability simultaneously
Solution Approach 2:
The invention converts the potentially harmful effect of SNAC (which can cause degradation of the peptide) into a beneficial outcome by adding histidine. The histidine protects the peptide from SNAC-induced degradation while allowing SNAC to continue enhancing absorption, thus turning a harmful interaction into a beneficial formulation strategy
2Ease of operation
If GLP-1 agonist is stored at ambient temperature, then ease of storage is improved, but shelf-life deteriorates
Solution Approach 1:
The invention changes the chemical environment parameters by introducing histidine, which alters the pH and chemical stability profile of the formulation. This enables the product to maintain stability at ambient temperature conditions without requiring refrigeration, thereby extending shelf-life while improving ease of storage
3Reliability
If higher amount of absorption enhancer is used, then oral bioavailability is improved, but formulation complexity increases
Solution Approach 1:
Histidine serves as a mediator that allows the use of SNAC at optimized concentrations without requiring excessive amounts. It facilitates effective interaction between the enhancer and the peptide, achieving high bioavailability with a balanced formulation rather than requiring large excesses of any single component
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 achieves increased stability and improved oral bioavailability of GLP-1 agonists, allowing for therapeutically relevant plasma concentrations and extended shelf-life.
Implementation Method 1
The inventors have surprisingly found that an increased stability of GLP-1 agonists is observed when compositions are prepared with a relatively small amount of histidine
Implementation Method 2
Human GLP-1 and analogues thereof have a low oral bioavailability. Exposure and bioavailability of human GLP-1 and analogues thereof is very low following oral administration
Data Source
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AI summary
The invention relates to stabilised solid pharmaceutical compositions comprising a GLP-1 agonist. The invention further relates to processes for the preparation of such compositions, and their use in medicine.