Cyclic Peptide Composition With Surfactant for Oral Bioavailability
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Solution Overview
Problem
There are no reports of cyclic peptide compounds with selective KRAS inhibitory action on HRAS and NRAS being combined with a surfactant to enhance their membrane permeability and/or bioavailability (BA).
Innovation Solution
A composition comprising a cyclic peptide compound represented by a specific general formula and a surfactant, such as lauroyl-L-carnitine, sodium caprylate, or sodium lauryl sulfate, is used to enhance membrane permeability and/or BA, with the surfactant improving absorption through formulations like capsules or tablets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a cyclic peptide compound is used to achieve selective KRAS inhibitory action, then pharmacological activity is improved, but membrane permeability and bioavailability deteriorate due to medium molecular weight (500-2000 g/mol)
Solution Approach 1:
A surfactant is introduced as an intermediary substance to facilitate the interaction between the cyclic peptide compound and the intestinal membrane. The surfactant forms a complex with the peptide compound, enabling it to traverse the membrane more effectively while maintaining its pharmacological activity. This resolves the contradiction by using a mediator to bridge the gap between the peptide's therapeutic function and its poor permeability.
Solution Approach 2:
The invention creates a composite formulation consisting of the cyclic peptide compound combined with a surfactant. This composite material leverages the pharmacological properties of the peptide and the membrane-permeating capabilities of the surfactant, achieving both high pharmacological activity and improved membrane permeability simultaneously.
2Reliability
If the molecular weight of the peptide compound is increased to 500-2000 g/mol to achieve better pharmacological activity, then drug efficacy is improved, but absorption and distribution properties deteriorate
Solution Approach 1:
The surfactant acts as a mediator that temporarily associates with the medium molecular weight peptide compound, facilitating its absorption across the intestinal barrier. This intermediary relationship allows the peptide to achieve systemic circulation and distribute to target tissues despite its size, thereby improving absorption rate without compromising drug efficacy.
Solution Approach 2:
The invention changes the physical-chemical parameters of the peptide compound by forming a complex with the surfactant. This complexation alters the apparent molecular size, hydrophobicity, and other parameters that influence absorption, enabling the peptide to be absorbed efficiently while maintaining its pharmacological properties.
3Reliability
If a peptide compound is designed to migrate into cells for superior performance against protein-protein interactions, then therapeutic effectiveness is improved, but membrane permeability deteriorates
Solution Approach 1:
The surfactant serves as a mediator that enables the peptide compound to cross the cell membrane and reach intracellular targets. By forming a permeable complex, the surfactant allows the peptide to access protein-protein interaction sites within cells, thereby achieving therapeutic effectiveness against such targets while overcoming the natural barrier of poor membrane permeability.
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 combination significantly enhances the bioavailability of the cyclic peptide compound, with bioavailability values increasing by 1.1-fold or more, and Caco-2 Papp values increasing by 1.1-fold or more, demonstrating improved absorption.
Implementation Method 1
a combination of a peptide compound with a surfactant has been attempted to improve BA
Data Source
AI summary
The present invention relates to a composition comprising a compound represented by general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a surfactant. [wherein R1, P1, R2, P3, P4, R5, P6, R10, P10 and P11 are C1 to C6 alkyl or the like; R3 and P9 are hydrogen or the like; R7 is phenethyl optionally substituted by halogen or the like; R8 forms a 4-to 7-membered saturated heterocyclic ring together with a carbon atom bonded to P8 and R8 and a nitrogen atom bonded to P8; R9 forms a 3- to 8-membered alicyclic ring together with Q9 and a carbon atom bonded to R9 and Q9; and R11 is di-C1 to C6 alkylaminocarbonyl or the like].