Reversible Protein Complexes for High-Concentration Formulations
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Solution Overview
Problem
Current biologic formulations face challenges with particle formation, immunogenicity, and high viscosity, which complicates storage and administration, particularly for highly concentrated protein solutions needed for subcutaneous delivery, and there is a need for compositions that efficiently dissociate under physiological conditions to maintain therapeutic efficacy.
Innovation Solution
The method involves forming reversible protein complexes using dextran sulfate or chondroitin sulfate as complexing agents, adjusting pH and ionic strength to achieve efficient complexation and dissociation, and incorporating excipients to stabilize the complexes, allowing for high concentration formulations that can be administered subcutaneously without immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If highly concentrated protein formulations (>100 mg/mL) are developed to enable single-injection subcutaneous delivery, then the therapeutic dose can be delivered via a single injection improving patient compliance, but the viscosity becomes excessively high complicating administration
Solution Approach 1:
The patent introduces a hydrophobic ion pairing agent as an intermediary substance that mediates between the protein and water molecules. This agent forms reversible complexes with the protein, allowing high concentration formulations to maintain lower viscosity by altering the solvation shell and reducing protein-protein interactions that lead to aggregation and viscosity increase.
Solution Approach 2:
The patent utilizes changes in pH and ionic strength as parameters to control the formation and dissociation of hydrophobic ion pairs. By adjusting these parameters, the formulation can transition between different states (complexed vs. dissociated), enabling control over viscosity and protein concentration without compromising stability or deliverability.
2Stability of the object's composition
If standard biologic formulations are stored at 5±3°C to maintain stability, then protein stability is ensured, but a complicated and costly cold chain supply chain is required decreasing drug accessibility
Solution Approach 1:
The patent employs lyophilization (freeze-drying) as a disposable-like approach where the formulation is converted to a stable solid state that can be stored at ambient temperatures. The lyophilized formulation acts as a stable precursor that is reconstituted immediately before use, eliminating the need for long-term cold chain storage while maintaining protein stability through the protective matrix formed during freeze-drying.
3Duration of action of stationary object
If lyophilization is used to increase stability and shelf-life of the drug product, then easier transportation and storage is enabled, but additional excipients such as cryoprotectants are required to protect the protein during the freeze-drying cycle
Solution Approach 1:
The patent merges the function of the hydrophobic ion pairing agent with the cryoprotectant function. The same agent that enables high concentration formulations through hydrophobic ion pairing also serves to protect the protein during freeze-drying by maintaining structural integrity and preventing aggregation in the dehydrated state, thereby reducing the need for additional separate excipients.
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 approach results in stable, high-concentration protein formulations that efficiently dissociate at physiological conditions, reducing viscosity and immunogenicity, enabling effective subcutaneous administration and improving patient compliance.
Implementation Method 1
the complexing agent is dextran sulfate or chondroitin sulfate, and wherein the protein and the complexing agent have opposite net charges when comprised in the buffer solution
Implementation Method 2
adjusting pH and ionic strength to achieve efficient complexation and dissociation
Implementation Method 3
adjusting pH and ionic strength to achieve efficient complexation and dissociation
Data Source
AI summary
The invention relates to a method for producing a composition comprising reversible protein complexes (RPCs), the method comprising the steps of contacting a protein and a complexing agent in a buffer solution, wherein the complexing agent is dextran sulphate or chondroitin sulphate, and wherein the protein and the complexing agent have opposite net charges when comprised in the buffer solution; formation of RPCs between the protein and the complexing agent in the buffer solution; and obtaining a suspension comprising the RPCs. Provided herein are also compositions, including pharmaceutical compositions/ formulations comprising the reversible protein complexes (RPCs) of the invention, in particular as obtained by the method provided herein.