Metformin-TGR5 Ligand Complexes for Enhanced Oral Bioavailability
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Solution Overview
Problem
Current treatments for diabetes, particularly type 2, have limitations such as poor bioavailability, side effects like hypoglycemic episodes, weight gain, gastrointestinal issues, and loss of responsiveness over time, necessitating the development of new therapies with improved bioavailability for effective management of diabetes and associated diseases.
Innovation Solution
The development of complexes comprising metformin or metformin analogues non-covalently bound to TGR5 ligands, which are administered in combination to enhance therapeutic efficacy for treating diabetes, polycystic ovary syndrome, cardiovascular disease, and cancer, with improved bioavailability and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If metformin HCl is administered alone or in combination with sulfonylurea and insulin, then hyperglycemia is reduced through decreased hepatic glucose output and enhanced glucose uptake, but oral bioavailability is poor (only about 50%) due to poor absorption from lower gastrointestinal tract
Solution Approach 1:
The patent forms a composite material by non-covalently binding metformin with a TGR5 ligand (such as a bile acid or derivative). This composite structure combines the glucose-lowering effects of metformin with the metabolic benefits of TGR5 activation, while the TGR5 ligand component improves the absorption and bioavailability of the complex in the gastrointestinal tract.
Solution Approach 2:
The TGR5 ligand acts as an intermediary that facilitates the absorption and delivery of metformin to target tissues. By binding to metformin, the TGR5 ligand enhances the complex's solubility and uptake in the lower gastrointestinal tract, thereby improving overall bioavailability while the TGR5 activation pathway provides additional therapeutic benefits.
2Reliability
If current oral hypoglycemic agents are administered long term, then glucose control is achieved, but responsiveness is lost over time and side effects occur including hypoglycemic episodes, weight gain, gastrointestinal problems, and edema
Solution Approach 1:
The patent merges two therapeutic mechanisms into a single complex: the glucose-lowering effect of metformin and the metabolic regulation effect of TGR5 activation. This combination allows for reduced dosing of individual components, thereby minimizing side effects such as hypoglycemia and weight gain while maintaining effective glucose control through dual pathways.
Solution Approach 2:
The patent changes the pharmacological parameters by introducing TGR5 activation alongside metformin's AMPK activation. This dual mechanism alters the dose-response relationship and therapeutic window, enabling effective glucose control at lower individual drug doses, thus reducing the occurrence of side effects like gastrointestinal problems, edema, and hypoglycemic episodes.
Data Source
AI summary
Provided herein are complexes of metformin or metformin analogues and a TGR5 ligand that are useful in treating diseases including diabetes, cardiovascular disease, and cancer.