Phase-Separated Multi-Block Copolymers for Protein Delivery
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Solution Overview
Problem
Current biodegradable polymers, such as PLGA, are inadequate for the delivery of proteins due to their hydrophobic nature, leading to incomplete release, protein aggregation, and acidic micro-environments that can degrade therapeutic efficacy, while existing multi-block copolymers have limitations in controlling release and degradation properties.
Innovation Solution
Development of semi-crystalline, phase-separated, thermoplastic multi-block copolymers with a hydrolysable amorphous segment and a crystalline segment, linked by a multifunctional chain-extender, providing a hydrophilic environment for protein delivery and controlled release through swelling and diffusion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PLGA copolymers are used for protein delivery, then biodegradability and clinical biocompatibility are improved, but protein release completeness and protein stability are worsened due to hydrophobicity causing aggregation and acidic micro-environment formation
Solution Approach 1:
The patent uses PLGA-PEG block copolymers that combine the biodegradable and biocompatible PLGA segment with the hydrophilic PEG segment. This composite material structure allows the system to maintain the advantages of PLGA (biodegradability, clinical approval) while introducing PEG's hydrophilic properties to create a more favorable micro-environment for protein stability and release, preventing aggregation and reducing acidic micro-environment formation.
Solution Approach 2:
The patent creates a heterogeneous polymer matrix with distinct PLGA and PEG phases. The PLGA regions provide structural integrity and controlled degradation, while the PEG regions provide hydrophilic pathways for protein diffusion and release. This local differentiation of material properties within the same delivery system allows simultaneous achievement of biocompatibility and protein stability.
2Duration of action of moving object
If PLGA matrices are used for sustained release, then degradation-dependent release control is improved, but diffusion-controlled release of larger polypeptides is worsened due to rigid and non-swellable matrix structure
Solution Approach 1:
The PLGA-PEG block copolymer creates a composite matrix where PEG segments provide hydrophilic channels that facilitate diffusion of larger polypeptide molecules. Meanwhile, PLGA segments maintain the structural framework for sustained degradation-dependent release. This composite structure enables both diffusion-controlled and degradation-controlled release mechanisms to operate simultaneously.
Solution Approach 2:
The phase-separated structure of PLGA-PEG block copolymers creates nanoscale porous or channel-like structures through the hydrophilic PEG domains. These pores provide pathways for protein and polypeptide diffusion through the matrix, enabling size-dependent release where smaller molecules diffuse faster while larger molecules are retained longer, achieving sustained release without requiring complete matrix degradation.
3Object-generated harmful factors
If PEG content is increased in ABA triblock copolymers to improve protein compatibility, then hydrophilicity and protein stability are improved, but renal clearance issues worsen due to high molecular weight PEG
Solution Approach 1:
The patent segments the PEG component into controlled blocks within the ABA triblock structure, where each PEG block has a specific molecular weight below the renal clearance threshold. By dividing the total PEG content into multiple smaller segments rather than using a single high molecular weight PEG chain, the system maintains high hydrophilicity and protein stability while avoiding rapid renal clearance.
Solution Approach 2:
The patent optimizes the molecular weight parameter of the PEG blocks to be below 5000 Da (the renal clearance threshold) while adjusting the number and distribution of PEG blocks to achieve the desired total PEG content and hydrophilicity. This parameter optimization allows the system to maximize protein compatibility without triggering renal clearance mechanisms.
4Object-affected harmful factors
If short block lengths are used in ABA triblock copolymers to maintain low PEG molecular weight, then renal clearance issues are avoided, but glass transition temperature decreases below room temperature causing sticky materials and fast release
Solution Approach 1:
The patent creates a composite block copolymer structure where short PEG blocks (maintaining low Tg and avoiding renal clearance) are combined with biodegradable polyester blocks (PLA or PGA). The polyester blocks contribute higher Tg and crystalline regions that provide structural rigidity and prevent the material from being too sticky, while the short PEG blocks maintain hydrophilicity and prevent renal clearance. This composite approach balances opposing thermal and physiological requirements.
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 new multi-block copolymers offer improved compatibility and controlled release of proteins, avoiding acidic micro-environments and aggregation, with tunable degradation and release properties, enhancing therapeutic efficacy and patient compliance.
Implementation Method 1
The semi-crystalline, phase-separated, thermoplastic multi-block copolymers provide a hydrophilic environment for protein delivery and controlled release through swelling and diffusion
Implementation Method 2
controlled release through swelling and diffusion
Implementation Method 3
comprising a hydrolysable amorphous segment (A) and a semi-crystalline segment (B)
Data Source
Figure 1A~1B
Figure 1C~2
Figure 3~4
AI summary
This invention is directed to a biodegradable, semi-crystalline, phase separated thermoplastic multi-block copolymer, a process for preparing said multi-block copolymer, a composition for the delivery of at least one biological active compound, and to a method for delivering a biologically active compound to a subject in need thereof. A multi-block copolymer of the invention is characterised in that: a) it comprises at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment, b) said multi-block copolymer having a Tg of 37 °C or less and a Tm of 110-250 °C under physiological conditions; c) the segments are linked by a multifunctional chain-extender; d) the segments are randomly distributed over the polymer chain; e) at least part of the pre-polymer (A) segment is derived from a water-soluble polymer.