Low Substituted Polymyxins for Consistent Therapeutic Levels
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Solution Overview
Problem
Current commercial polymyxin products, such as Colistin, have toxicity issues and are not well-defined in terms of molecular weight and charge, leading to inconsistent therapeutic levels and stability, which complicates their use against antibiotic-resistant pathogens.
Innovation Solution
Development of polymyxins with two sulfomethyl groups attached to the γ-amino groups on DAB or DAP residues, enhancing water solubility, stability, and uniformity, and providing improved dosing and therapy compared to existing compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If commercial polymyxin mixtures (Polymyxin B and Polymyxin E) are used, then antibiotic activity against Gram-negative pathogens is achieved, but toxicity increases and therapeutic levels become inconsistent
Solution Approach 1:
The patent applies parameter changes by modifying the degree of sulfomethylation from the typical 3-5 substituents to exactly two sulfomethyl groups per molecule. This specific parameter change (number of substituents) results in more consistent molecular weight and charge characteristics, leading to more predictable therapeutic levels and reduced toxicity compared to commercial mixtures
Solution Approach 2:
The invention applies local quality by creating a more homogeneous product where each molecule has the same defined structure (two sulfomethyl groups at specific positions on the polymyxin backbone). This uniformity in local molecular structure ensures consistent pharmacological behavior and reduces the variability seen in commercial polymyxin mixtures
2Reliability
If sulfomethylated Colistin (CMS) is used to reduce toxicity, then therapeutic index improves, but product uniformity decreases due to complex mixture of derivatives
Solution Approach 1:
The patent applies the extraction principle by isolating and selecting only those polymyxin derivatives that have exactly two sulfomethyl groups, excluding all other sulfomethylated variants (one, three, four, or five substituents). This extraction of the specific uniform component from the complex CMS mixture resolves the uniformity issue while maintaining the beneficial toxicity profile of sulfomethylated compounds
Solution Approach 2:
The invention directly addresses homogeneity by defining a specific polymyxin structure with exactly two sulfomethyl groups, creating a more homogeneous product compared to the heterogeneous CMS mixture. This homogeneity ensures consistent molecular weight, charge, and pharmacological activity across all molecules in the formulation
3Quantity of substance
If polymyxins with multiple sulfomethyl groups are used, then water solubility increases, but molecular weight variability increases
Solution Approach 1:
The patent applies parameter changes by optimizing the number of sulfomethyl groups to exactly two, which provides sufficient water solubility for parenteral administration while maintaining well-defined molecular weight characteristics. This specific parameter value balances solubility requirements with molecular uniformity, avoiding the variability introduced by having zero, one, three, or more substituents
Data Source
AI summary
The present invention relates to novel low substituted polymyxins and compositions thereof.