Tris-ODAAD1 Salt Formulation for Oral GLP1R Agonist Bioavailability
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Solution Overview
Problem
Current therapies for type 1 and type 2 diabetes lack effective oral GLP1 receptor agonists with sufficient oral bioavailability due to rapid proteolysis of GLP1 into inactive metabolites, limiting their therapeutic potential.
Innovation Solution
Development of tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1R agonist, such as tris-ODAAD1, which forms solid compositions suitable for oral administration, enhancing bioavailability and stability, and providing therapeutic benefits for diabetes and obesity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP1 is used as a therapeutic agent, then it can activate GLP1R to improve glycemic control and insulin secretion, but it undergoes rapid proteolysis into inactive metabolites, resulting in poor oral bioavailability
Solution Approach 1:
The patent changes the chemical form of GLP1 from free base to salt form (tris(hydroxymethyl)aminomethane salt), which fundamentally alters the stability and bioavailability parameters. This parameter change allows the compound to resist proteolysis while maintaining therapeutic efficacy at the GLP1R target
Solution Approach 2:
The invention creates a composite chemical structure by combining GLP1 with tris(hydroxymethyl)aminomethane to form a salt. This composite material exhibits both the therapeutic properties of GLP1 and the stability characteristics of the salt form, resolving the contradiction between efficacy and bioavailability
2Stability of the object's composition
If small-molecule GLP1R agonists are developed for oral administration, then oral bioavailability is improved, but the ability to effectively activate class B GPCRs like GLP1R is compromised
Solution Approach 1:
The patent modifies the molecular parameters of the small-molecule agonist by forming a salt with tris(hydroxymethyl)aminomethane. This parameter change enhances the compound's stability in the gastrointestinal environment while preserving its ability to bind and activate the GLP1R receptor, thus resolving the contradiction between oral bioavailability and receptor activation efficacy
3Reliability
If peptide-based GLP1 agonists are used, then they can effectively activate GLP1R, but they lack sufficient oral bioavailability for consideration as oral drug agents
Solution Approach 1:
The invention extracts the essential pharmacophore elements of the peptide GLP1 and incorporates them into a small-molecule structure that forms a stable salt. This extraction approach retains the receptor-binding capability while eliminating the peptide backbone that is susceptible to proteolysis, thereby improving oral bioavailability without sacrificing efficacy
Solution Approach 2:
The tris(hydroxymethyl)aminomethane salt form acts as an intermediary that protects the active compound from degradation in the gastrointestinal tract. This intermediary form facilitates oral absorption while delivering the active agent to the target receptor, resolving the contradiction between peptide efficacy and oral bioavailability
Data Source
AI summary
The disclosure provides tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1 R agonist. The disclosure further provides solid compositions comprising tris(hydroxymethyl)aminomethane salts of the small-molecule GLP1R agonist. The disclosure further provides uses of tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1R agonist, e.g., for treating type 1 diabetes, type 2 diabetes, or obesity. Solid formulations further comprising an evaporation residue and a binder, such as hydroxy propyl methyl cellulose acetate succinate (HPMCAS), are also provided.