GLP-1 Analogue Liquid Crystalline Depot Formulation
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Solution Overview
Problem
Current GLP-1 therapies for type 2 diabetes require frequent injections due to short plasma half-life and rapid degradation, leading to inconvenient self-administration, potential irritation at injection sites, and undesirable 'burst' release profiles that can cause hypoglycemia.
Innovation Solution
A pre-formulation comprising a low viscosity mixture of neutral diacyl lipids, phospholipids, biocompatible organic solvents, and GLP-1 analogues that forms a liquid crystalline phase upon contact with aqueous fluids, allowing for controlled and sustained release without significant 'burst' effects, suitable for self-administration through a narrow needle.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If frequent injections are used to maintain therapeutic levels, then the biological effect is maintained, but the convenience and compliance are reduced
Solution Approach 1:
The patent applies preliminary action by pre-formulating GLP-1 analogues in a depot formulation that is prepared in advance but activated only upon injection. The pre-formulation contains amphiphilic components and solvents that are ready to form liquid crystalline structures in the body, allowing the therapeutic agent to be loaded into a reservoir that will gradually release it over time, eliminating the need for frequent repeated injections.
Solution Approach 2:
The patent utilizes dynamics by creating a formulation that undergoes phase transition from a low-viscosity pre-formulation state to a high-viscosity liquid crystalline depot state upon contact with aqueous body fluids. This dynamic transformation allows the formulation to be easily injected as a low-viscosity solution but then forms a stable, slow-release depot structure in the tissue, controlling the release rate over extended periods.
2Productivity
If conventional formulations are used, then the active agent is delivered, but injection site irritation occurs
Solution Approach 1:
The patent applies parameter changes by modifying the physical and chemical parameters of the formulation, specifically using amphiphilic components with controlled hydrophobicity and incorporating specific solvents that form liquid crystalline phases. These parameter changes result in a depot formulation that releases GLP-1 analogues slowly and controllably, preventing the burst release that causes irritation, while the amphiphilic structure ensures biocompatibility and reduces local tissue reactions.
3Speed
If rapid release formulations are used, then the active agent is delivered quickly, but burst release causes hypoglycemia
Solution Approach 1:
The patent exploits phase transitions by designing a pre-formulation that exists in a low-viscosity state for easy injection but transitions to a high-viscosity liquid crystalline phase upon contact with body fluids. This phase transition mechanism controls the release rate, preventing rapid burst release that would cause hypoglycemia, while still allowing adequate initial delivery of the active agent through the liquid crystalline structure formation.
4Duration of action of moving object
If complex depot formulations are used, then controlled release is achieved, but manufacturing and administration become difficult
Solution Approach 1:
The patent uses an intermediary approach by introducing amphiphilic components and specific solvents as mediators that facilitate the formation of liquid crystalline structures. These intermediary substances enable the controlled release mechanism without requiring complex manufacturing processes, as they simply need to be mixed with the GLP-1 analogue and injected, allowing the liquid crystalline phase to form automatically in the body.
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 pre-formulation provides a stable, non-lamellar depot composition with controlled release, reducing the frequency of injections, minimizing irritation, and maintaining therapeutic levels with reduced risk of hypoglycemia, while being easy to manufacture and administer.
Implementation Method 1
which undergo phase transition upon exposure to aqueous fluids, such as body fluids, thereby forming a controlled release matrix
Implementation Method 2
forms a liquid crystalline phase upon contact with aqueous fluids
Data Source
AI summary
The present invention relates to compositions forming a low viscosity mixture of: a) at least one neutral diacyl lipid, such as a diacyl glycerol; b) at least one phospholipid, such as a phosphatidyl choline; c) at least one biotolerable solvent, such as an oxygen containing solvent; d) at least one GLP-1 analogue; wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, especially in treating diabetes, and to pre-filled administration devices and kits containing the formulations.