Pentaaza Macrocyclic Metal Complexes for Oral Bioavailability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing transition metal pentaaza 15-membered macrocyclic ring complexes exhibit limited oral bioavailability, with less than 5% absorption when dosed as an aqueous solution and insufficient bioavailability in oil-based formulations, due to their ionized form in water, which impairs their ability to cross the intestinal barrier.
Innovation Solution
Development of transition metal complexes with pentaaza 15-membered macrocyclic ring systems coordinated by axial ligands such as —OC(O)X1, where X1 can be substituted or unsubstituted phenyl or —C(—X2)(—X3)(—X4), enhancing their oral bioavailability by maintaining a neutral, non-ionized form and improving solubility in both water and oil-based formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the complexes are administered as aqueous solutions, then water solubility is improved, but oral bioavailability deteriorates (less than 5% absorption)
Solution Approach 1:
The patent changes the ionization state parameter of the complexes by introducing axial ligands that maintain a neutral, non-ionized form. This parameter change allows the complexes to maintain water solubility while acquiring the ability to cross the intestinal barrier, thereby improving oral bioavailability without sacrificing solubility
Solution Approach 2:
The patent creates composite coordination complexes by combining the pentaaza macrocyclic ring system with specific axial ligands (such as —OC(O)X1 where X1 is phenyl or alkyl groups). This composite structure integrates both hydrophilic characteristics for water solubility and lipophilic characteristics for membrane permeability, resolving the contradiction between solubility and bioavailability
2Stability of the object's composition
If the complexes are formulated in oil-based formulations, then lipophilicity is improved, but oral bioavailability remains insufficient
Solution Approach 1:
The patent modifies the ionization parameter to a neutral, non-ionized state, which enhances lipophilic character and membrane permeability. This parameter change enables the complexes to effectively cross the intestinal barrier even in oil-based formulations, improving oral bioavailability while maintaining lipophilicity
3Quantity of substance
If the complexes are in ionized form, then water solubility is improved, but ability to cross intestinal barrier deteriorates
Solution Approach 1:
The patent changes the ionization parameter from ionized to neutral/non-ionized form through the introduction of specific axial ligands. This parameter change enables the complexes to maintain water solubility while acquiring the ability to cross the intestinal barrier, as the neutral form can penetrate lipid membranes more effectively
Solution Approach 2:
The axial ligands act as intermediaries that mediate between the hydrophilic macrocyclic ring system and the lipophilic intestinal barrier. These ligands (such as —OC(O)X1 groups) provide a bridge that allows the complex to maintain water solubility while enabling membrane permeability
Data Source
AI summary
Aspects of the present disclosure relate to compounds which have enhanced oral bioavailability. A transition metal complex includes a transition metal coordinated by a macrocycle comprising the pentaaza 15-membered macrocyclic ring corresponding to Formula A and two axial ligands having the formula —OC(O)X1.each of the two axial ligands has the formula —OC(═O)X1 wherein each X1 is independently substituted or unsubstituted phenyl or —C(—X2)(—X3)(—X4);each X2 is independently substituted or unsubstituted phenyl, or substituted or unsubstituted alkyl;each X3 is independently hydrogen, hydroxyl, alkyl, amino, —X5C(═O)R13 where X5 is NH or O, and R13 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or —OR14, where R14 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or together with X4 is (=O); andeach X4 is independently hydrogen or together with X3 is (=O).