Aptamer Solubility via Salt Formation with Organic Bases
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Solution Overview
Problem
There is a need for improved pharmaceutical compositions that allow aptamers to be dissolved in a pharmaceutically acceptable solvent at a sufficient concentration for clinical use, as existing compositions struggle to achieve this due to the high molecular weight and stability issues of aptamers, particularly those that have been derivatized through PEGylation.
Innovation Solution
The development of pharmaceutical compositions comprising a salt formed between a protonated aptamer and a pharmaceutically acceptable organic base, or an amino acid ester/amide, along with a pharmaceutically acceptable organic solvent, which facilitates the formation of a solution that can be administered effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If aptamers are derivatized through PEGylation to improve stability and pharmacokinetic properties, then the half-life and target affinity are improved, but the molecular weight increases and solubility in pharmaceutically acceptable solvents deteriorates
Solution Approach 1:
The patent changes the chemical parameters of the aptamer by incorporating modified nucleotides (2'-fluoropyrimidine, 2'-O-methylpurine) and forming salts with organic bases, which alters the solubility and pharmacokinetic properties while maintaining stability
Solution Approach 2:
The patent uses salts formed between protonated aptamers and pharmaceutically acceptable organic bases as intermediaries to improve solubility and enable effective concentration in pharmaceutically acceptable solvents
2Productivity
If aptamers are used at higher concentrations to improve clinical utility, then the therapeutic efficacy is enhanced, but the solubility in pharmaceutically acceptable solvents becomes insufficient
Solution Approach 1:
The patent modifies the chemical parameters of the aptamer through nucleotide modifications and salt formation to enable dissolution at higher concentrations in pharmaceutically acceptable solvents, thereby improving clinical utility
3Ease of manufacture
If unmodified oligonucleotides are used to maintain simplicity, then the manufacturing is easier, but the stability against nuclease digestion deteriorates
Solution Approach 1:
The patent changes the chemical structure of the oligonucleotide by incorporating modified nucleotides (2'-fluoropyrimidine, 2'-O-methylpurine) that provide nuclease resistance while maintaining compatibility with standard synthesis methods
Solution Approach 2:
The patent uses temporary chemical modifications (salts with organic bases) that can be easily removed or degraded, providing stability during administration without long-term structural changes
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
These compositions enable the aptamers to be dissolved at higher concentrations, enhancing their clinical utility by improving solubility and stability, thereby allowing for more effective administration and prolonged action.
Implementation Method 1
a salt formed between a protonated aptamer and a pharmaceutically acceptable organic base
Implementation Method 2
an amino acid ester or amide
Implementation Method 3
a divalent metal cation
Implementation Method 4
a phospholipid, a phosphatidyl choline, or a sphingomyelin
Data Source
AI summary
Pharmaceutical compositions comprising an aptamer and an amino acid ester or amide or an aptamer; a divalent metal cation; and a carboxylic acid, a phospholipid, a phosphatidyl choline, or a sphingomyelin. Methods of treating or preventing a condition in an animal comprising administering to the animal the pharmaceutical compositions.