Non-Aqueous Protein Microparticles for Sustained Release Stability
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Solution Overview
Problem
Existing aqueous emulsion systems for drug delivery face challenges such as protein degradation, aggregation, and leakage during encapsulation, limiting the stability and efficacy of therapeutic proteins in extended release formulations.
Innovation Solution
The use of non-aqueous emulsion systems, specifically hydrocarbon-fluorocarbon emulsions, to encapsulate proteins within biodegradable polymers, where hydrocarbon solvents are combined with fluorocarbon liquids and fluorosurfactants to form emulsion droplets, followed by solvent removal to create stable microparticles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If aqueous emulsion systems are used to encapsulate therapeutic proteins, then the encapsulation process is straightforward and proteins can be directly suspended in aqueous phase, but protein degradation, aggregation and precipitation occur at the aqueous organic interface reducing immunoreactivity
Solution Approach 1:
The patent replaces the aqueous environment with a non-aqueous fluorocarbon environment that is inert to protein degradation. The fluorocarbon continuous phase eliminates water-protein interactions that cause hydrolysis, while the hydrocarbon dispersed phase provides a non-polar environment that prevents protein aggregation at interfaces, thereby maintaining protein stability throughout the encapsulation process
Solution Approach 2:
The patent introduces fluorosurfactants as intermediary substances that stabilize the hydrocarbon-fluorocarbon interface without causing protein degradation. These fluorosurfactants act as mediators that reduce interfacial tension and prevent protein aggregation, allowing straightforward encapsulation while maintaining protein integrity
2Ease of manufacture
If aqueous emulsion systems are used, then proteins can be encapsulated in biodegradable polymers, but water diffuses into the organic phase causing protein hydrolysis and droplet merging leading to aggregation and precipitation
Solution Approach 1:
The patent creates an inert non-aqueous environment using fluorocarbon as the continuous phase, which prevents water diffusion into the organic phase. This eliminates the source of protein hydrolysis while maintaining the ability to encapsulate proteins in biodegradable polymers through the hydrocarbon-fluorocarbon emulsion system
Solution Approach 2:
The patent fundamentally changes the environmental parameters from aqueous to non-aqueous by using fluorocarbon continuous phase and hydrocarbon dispersed phase. This parameter change eliminates water-protein interactions that cause hydrolysis, while the fluorosurfactant stabilization prevents droplet merging and aggregation
3Reliability
If non-aqueous emulsion systems are used to prevent protein degradation, then protein stability is improved, but the system complexity increases and fewer reports exist in literature
Solution Approach 1:
The patent uses fluorosurfactants as intermediary substances that simplify the non-aqueous emulsion system by providing stable hydrocarbon-fluorocarbon interfaces. These fluorosurfactants reduce interfacial tension and prevent droplet coalescence, making the complex non-aqueous system easier to manufacture and more reproducible
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
This method enhances protein stability and encapsulation efficiency, maintaining the integrity of therapeutic proteins and preventing leakage, resulting in smooth-surfaced microparticles with controlled release properties.
Implementation Method 1
adding the first solution to a second solution, wherein the second solution comprises a fluorocarbon liquid and a fluorosurfactant to form a non-aqueous emulsion containing multiple emulsion hydrocarbon droplets in the fluorocarbon liquid
Implementation Method 2
removing the hydrocarbon solvent and removing the fluorocarbon liquid to isolate the sustained release or controlled release microparticles
Data Source
Figure 1A~1C
Figure 2A~4
Figure 5~7C
AI summary
Non-aqueous emulsion methods for producing polymeric or polymer-coated microparticles are provided. One method produces a sustained release microparticle composition by combining protein powder and a polymer into a hydrocarbon solvent to form a non-aqueous first solution and adding the first solution to a second solution, wherein the second solution comprises a fluorocarbon liquid and a fluorosurfactant to form a non-aqueous emulsion comprising multiple emulsion hydrocarbon droplets in the fluorocarbon liquid. The subsequent microparticle hardening process includes the steps of removing the hydrocarbon solvent from the formed emulsion droplets, which can be achieved through evaporation the hydrocarbon at ambient condition under stirring, or accelerated hardening through vacuum, or through adding hydrofluoroester into the fluorocarbon as a cosolvent. Removing the fluorocarbon liquid and washing with extra fluorocarbon liquid to isolate the sustained release microparticles, wherein the sustained release microparticles comprise one or more cores of protein and a cortex of polymer.