PEG Solvent Biodegradable Polymer Depot Formulation
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Solution Overview
Problem
Injectable in-situ forming depot formulations face challenges with storage stability, tolerability, and acute toxicity, particularly due to the need for chemical compatibility and ease of application, which existing technologies have not adequately addressed.
Innovation Solution
The use of a biodegradable polymer combined with a biocompatible water-miscible polyethylene glycol (PEG) solvent with a solidification point between 8° to 20°C, and optionally an additive, to create a stable, ready-to-use depot formulation that is free from sedimentation and has low viscosity, allowing for easy injection without the need for re-suspending.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If PLGA is dissolved in NMP (water miscible solvent) to create injectable in-situ forming depot, then ease of application and manufacturing is improved, but storage stability as liquid and tolerability deteriorate
Solution Approach 1:
The patent changes the solvent parameter from NMP to PEG with specific molecular weights (450-650), which fundamentally alters the formulation's storage stability while maintaining its liquid state and injectability. This parameter change resolves the contradiction by selecting a solvent that provides both ease of application and improved storage stability.
Solution Approach 2:
The patent creates a composite formulation combining PLGA polymer with PEG solvent in specific ratios (10-40% w/w polymer). This composite approach optimizes both the ease of application (through proper solubility and viscosity control) and storage stability (through compatible material selection and ratio optimization).
2Ease of operation
If PEG with low molecular weight is used to maintain liquid state at storage temperature, then injectability is improved, but sedimentation of drug substance particles occurs
Solution Approach 1:
The patent specifies PEG molecular weights between 450-650, which is a precise parameter range that balances liquid state maintenance at storage temperature with sufficient viscosity to prevent particle sedimentation. This targeted parameter selection resolves the contradiction between injectability and storage stability.
Solution Approach 2:
The patent references and builds upon existing Atrigel technology (WO 2005/120453, WO 2006/017852) but copies only the essential PLGA-NMP formulation approach, then modifies it by replacing NMP with PEG. This selective copying and modification allows optimization of both injectability and storage stability.
3Duration of action of moving object
If higher polymer concentration is used to achieve desired depot strength, then duration of action is improved, but viscosity increases making injection difficult
Solution Approach 1:
The patent optimizes polymer concentration within 10-40% w/w range and selects specific PEG molecular weights to maintain viscosity at injectable levels even at higher polymer concentrations. This parameter optimization allows achieving desired depot strength and duration of action while maintaining ease of injection.
Solution Approach 2:
The PEG solvent acts as an intermediary that enables higher polymer concentrations to be achieved without proportionally increasing viscosity. The PEG polymer chain structure provides steric stabilization and maintains fluidity, allowing the formulation to achieve both high duration of action (through higher polymer load) and good injectability.
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 formulation provides improved storage stability, tolerability, and reduced toxicity, enabling a convenient, ready-to-use injectable depot that maintains stability at refrigerator temperatures and remains liquid at room temperature, facilitating easy injection with minimal hemolysis and toxicity, and offering a controlled release profile for extended periods.
Implementation Method 1
the polymer solidifies after application by phase separation
Implementation Method 2
the depot degrades over the time. Currently, there are two injectable in-situ forming depots on the market: Atridox® and Eligard®. Both products were developed on Atrigel's technology
Data Source
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AI summary
A liquid pharmaceutical composition comprising a biodegradable polymer, polyethylene glycol having a molecular weight of less than 600 Daltons, a pharmaceutically active agent and less than 0.5 % of an biologically acceptable organic solvent.