Oligonucleotide Concentration via Salt-Stabilized Diafiltration
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Solution Overview
Problem
Current manufacturing processes for oligonucleotide drug products are inefficient due to the energy-intensive and time-consuming process of lyophilization, which also increases complexity and costs.
Innovation Solution
A method for preparing high concentration, liquid compositions of oligonucleotide compounds by ultrafiltration, using a diafiltration solution with salts to stabilize the oligonucleotide and increase its hydrodynamic diameter, thereby achieving concentrations greater than 150 mg/mL without the need for lyophilization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If lyophilization is used to prepare oligonucleotide drug substance, then stability and ease of transport are improved, but process time and energy consumption increase significantly
Solution Approach 1:
The invention changes the physical state parameter of the drug substance from solid (lyophilized powder) to liquid form, and modifies the solution parameters by adding specific salts (sodium chloride, sodium citrate, EDTA) to achieve high concentration (≥150 mg/mL) while maintaining stability without requiring lyophilization
Solution Approach 2:
Salts are introduced as intermediary substances to stabilize the oligonucleotide in high concentration liquid form, preventing aggregation and degradation, thereby enabling the liquid state to achieve the stability previously only obtainable through lyophilization
2Stability of the object's composition
If lyophilization is used to prepare oligonucleotide drug substance, then stability is improved, but manufacturing complexity and cost increase
Solution Approach 1:
The invention simplifies the manufacturing process by changing the final state parameter to liquid form and optimizing concentration and salt composition parameters, thereby eliminating the need for complex lyophilization equipment and multi-step reconstitution procedures
Solution Approach 2:
The invention extracts and removes the lyophilization step from the manufacturing process, replacing it with a simpler ultrafiltration concentration process that directly produces the desired high concentration liquid product without requiring freeze-drying equipment
3Quantity of substance
If ultrafiltration is used to concentrate oligonucleotide solution, then liquid form is achieved, but membrane fouling occurs at high concentrations
Solution Approach 1:
Salts serve as intermediary substances that modify the solution environment, reducing oligonucleotide-membrane interactions and preventing aggregation at the membrane surface, thereby minimizing fouling during ultrafiltration concentration to high levels
Solution Approach 2:
The invention changes the solution composition parameters by adding specific salts that alter the electrostatic and steric environment, reducing adhesion forces between oligonucleotides and membrane, enabling sustained ultrafiltration flux even at high concentrations
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 allows for the efficient production of high concentration oligonucleotide solutions, reducing process time and costs, while maintaining stability and minimizing membrane fouling.
Implementation Method 1
the diafiltration solution used for diafiltration comprises one or more salts which stabilize the oligonucleotide compound and/or increase its hydrodynamic diameter
Implementation Method 2
the salt(s) of the solution, e.g., DF solution, interact(s) with the oxygen atoms and/or sulfur atoms of the oligonucleotide compound via, e.g., hydrogen bonds, metal coordination, electrostatic interactions
Implementation Method 3
concentrating by ultrafiltration the first solution to obtain a high concentration, liquid composition comprising the oligonucleotide compound at a concentration of about 150 mg/mL or greater
Data Source
AI summary
Provided herein are methods of preparing a high concentration, liquid composition comprising an oligonucleotide compound. In exemplary embodiments, the method comprises exchanging by diafiltration an oligonucleotide compound in a starting solution into a diafiltration (DF) solution to obtain an intermediate solution, wherein the concentration of the oligonucleotide compound in the starting solution is 140 mg/mL or less and the DF solution comprises one or more salts, and concentrating by ultrafiltration the oligonucleotide compound in the intermediate solution to obtain a high concentration, liquid composition, wherein the concentration of the oligonucleotide compound in the high concentration, liquid composition is greater than about 150 mg/mL.