ELP Fusion Proteins for Controlled Peptide and Small-Molecule Release
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Solution Overview
Problem
The short half-life of peptide and small molecule drugs in circulation due to rapid renal clearance and enzymatic degradation limits their effectiveness, necessitating high doses and causing issues like nausea, and existing strategies fail to provide sustained release formulations.
Innovation Solution
Pharmaceutical formulations utilizing Elastin-Like-Protein (ELP) sequences that form reversible matrices at body temperature, combining hydrogen bonds and hydrophobic interactions to achieve slow absorption and long half-life, allowing for a sustained release of therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If peptide drugs are administered at high doses to counter short half-life, then the half-life is extended, but nausea and other side effects occur
Solution Approach 1:
The peptide drug is conjugated to an amino acid sequence capable of forming a reversible matrix at body temperature before administration. This preliminary structural modification enables the drug to be retained at the injection site and released slowly over time, extending half-life without requiring high doses that cause nausea.
Solution Approach 2:
The invention changes the physical state of the peptide drug by forming a reversible matrix through hydrogen bonds and hydrophobic contributions at body temperature. This parameter change from soluble to matrix-formed state enables controlled release and extended circulation half-life at therapeutic doses.
2Stability of the object's composition
If peptide drugs are administered frequently to maintain plasma levels, then plasma levels are maintained, but patient compliance decreases
Solution Approach 1:
The reversible matrix provides continuous slow absorption of the peptide drug into circulation over an extended period. This continuous release mechanism maintains stable plasma levels without requiring frequent administrations, thereby improving patient compliance while maintaining therapeutic efficacy.
3Object-affected harmful factors
If peptide drugs are administered at standard doses, then side effects are minimized, but the short half-life limits effectiveness
Solution Approach 1:
The amino acid sequence capable of forming a reversible matrix acts as an intermediary between the peptide drug and the circulation system. This intermediary structure retains the drug at the injection site and releases it slowly, extending half-life without requiring dose increases that would cause side effects.
4Speed
If rapid absorption is achieved for quick onset, then onset speed is improved, but peak-to-trough ratio increases and stability decreases
Solution Approach 1:
The reversible matrix provides dynamic control over drug release. The matrix forms and dissolves based on local concentration and temperature conditions, enabling slow absorption initially and then maintaining stable plasma levels, thereby reducing peak-to-trough ratio while providing sustained therapeutic effect.
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
The formulations provide a desirable pharmacokinetic profile with a shallow peak-to-trough ratio and long Tmax, enhancing bioavailability and stability of peptides and small molecules with reduced administration frequency.
Implementation Method 1
The reversible matrix is formed from hydrogen bonds (e.g., intra- and/or intermolecular hydrogen bonds) as well as from hydrophobic contributions
Implementation Method 2
The reversible matrix is formed from hydrogen bonds (e.g., intra- and/or intermolecular hydrogen bonds) as well as from hydrophobic contributions
Implementation Method 3
The amino acid sequence may exhibit a visible and reversible inverse phase transition with the selected formulation. That is, the amino acid sequence may be structurally disordered and highly soluble in the formulation below a transition temperature (Tt), but exhibit a sharp (2-3° C. range) disorder-to-order phase transition when the temperature of the formulation is raised above the Tt
Data Source
AI summary
The present disclosure provides pharmaceutical formulations for sustained release, and methods for delivering a treat-ment regimen with a combination of sustained release and long half-life formulations. The disclosure provides improved pharma-cokinetics for peptide and small molecule drugs.