Block Copolymer Stabilizers for Protein Drying Stability
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Solution Overview
Problem
Existing methods for stabilizing proteins during the drying and extrusion steps in pharmaceutical compositions face challenges, particularly in maintaining protein stability and preventing rapid release of biopharmaceutical actives due to the use of traditional stabilizers like low molecular weight hydrosoluble compounds.
Innovation Solution
The use of di-block or multi-block copolymers, specifically formed from combinations of PEG and polymers such as polyurethane, polyvinylpyrrolidone, and poly(lactic acid), as stabilizers in protein-containing compositions. These copolymers act as water replacements, promote intimate mixing of proteins with hydrophobic polymers, and function as plasticizers to reduce processing temperatures, thereby enhancing protein stability and processing efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional stabilizers (low molecular weight hydrosoluble compounds) are used to stabilize proteins during drying and extrusion, then protein stability is improved, but rapid release of biopharmaceutical actives occurs due to phase separation and porous matrix formation
Solution Approach 1:
The patent employs block copolymers with amphiphilic structures (hydrophobic blocks and hydrophilic blocks) as composite materials. The hydrophobic blocks interact with the protein to stabilize it during drying, while the hydrophilic blocks ensure compatibility with the aqueous environment and prevent phase separation. This composite structure eliminates the need for separate stabilizers and inert ingredients, thereby preventing porous matrix formation and burst release while maintaining protein stability throughout processing and storage.
2Reliability
If high amounts of inert ingredients (stabilizers and hydrosoluble polymers) are added to stabilize proteins, then protein stability is improved, but blending with hydrophobic degradable matrices is hindered leading to phase separation
Solution Approach 1:
The block copolymer stabilizer acts as a molecular bridge between hydrophobic degradable matrices and hydrophilic protein drugs. The hydrophobic segments of the copolymer are miscible with the hydrophobic matrix, while the hydrophilic segments interact with the protein, creating a homogeneous mixture at the molecular level. This eliminates macroscopic phase separation while maintaining protein stability, allowing for uniform distribution of the active ingredient throughout the delivery device.
3Quantity of substance
If high drug loading is achieved in the formulation, then therapeutic efficacy is improved, but burst release effect is intensified due to phase separation
Solution Approach 1:
The amphiphilic block copolymer forms a homogeneous molecular-level dispersion that can accommodate high concentrations of drug (e.g., 20-80 wt% or more) without phase separation. The hydrophobic blocks embed within the hydrophobic matrix while the hydrophilic blocks solvate the drug molecules, creating a uniform composite structure. This molecular-level homogeneity ensures that even at high drug loadings, the release profile remains controlled and sustained rather than exhibiting burst release.
4Duration of action of moving object
If hydrophobic degradable matrices are used for controlled release, then sustained release profile is achieved, but protein stability during processing is compromised
Solution Approach 1:
The block copolymer stabilizer serves as an intermediary between the hydrophobic degradable matrix and the protein drug. During hot melt extrusion and other thermal processing steps, the stabilizer forms a protective interface around the protein, shielding it from direct contact with the hydrophobic matrix and preventing denaturation. The stabilizer's amphiphilic structure allows it to remain compatible with both phases while maintaining protein structure and activity, enabling the use of hydrophobic matrices for sustained release without compromising protein stability during processing.
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 described approach effectively stabilizes therapeutic proteins during drying and processing, maintaining their stability and biological potency, and allows for high protein loading in filaments and implantable drug delivery devices, with controlled release profiles and reduced burst effects.
Implementation Method 1
These copolymers act as water replacements, promote intimate mixing of proteins with hydrophobic polymers
Implementation Method 2
The di-block or multi-block copolymer, used as a stabilizer... promote intimate mixing of proteins with hydrophobic polymers
Implementation Method 3
function as plasticizers to reduce processing temperatures, thereby enhancing protein stability
Data Source
AI summary
The invention relates to the field of pharmaceutical compositions comprising proteins as therapeutic active ingredient. More particularly it is directed to di-block or multi-block copolymers used as excipients, and in particular as stabilizer, in protein-containing dried compositions, filaments obtained from these dried compositions, implantable drug delivery device formed from these filaments and to methods of producing such compositions, filaments and devices.