Macrocyclic Peptide Formulations Using Salcaprozate for Oral Absorption
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Solution Overview
Problem
Poor oral bioavailability of large, hydrophilic biologically active molecules such as macrocyclic peptides, particularly those inhibiting the PD-L1 interaction with PD-1 or CD80, due to pH and enzyme interactions in the gastrointestinal tract, low membrane permeability, and restricted transport, hinders their widespread use in oral delivery for conditions like cancer and septic shock.
Innovation Solution
A pharmaceutical composition comprising a biologically active compound, salcaprozate sodium, nicotinamide, and optionally protease inhibitors, which enhances oral bioavailability by stabilizing the peptide in the acidic environment and improving intestinal absorption.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If macrocyclic peptides are administered orally, then convenience and patient compliance improve, but bioavailability deteriorates due to poor intestinal absorption and degradation
Solution Approach 1:
The patent employs a specialized oral formulation system comprising permeation enhancers, protease inhibitors, and pH buffering agents that act as intermediaries to facilitate peptide absorption and protect against degradation. This formulation mediates between the peptide's poor inherent permeability and the gastrointestinal environment's barriers, enabling sufficient oral bioavailability without parenteral administration
Solution Approach 2:
The invention creates a composite pharmaceutical formulation integrating multiple functional components: permeation enhancers (e.g., bile salts, fatty acids), protease inhibitors (e.g., aprotinin, soybean trypsin inhibitor), pH buffers, and the macrocyclic peptide. This composite approach addresses multiple failure modes simultaneously - permeability, stability, and absorption - to achieve reliable oral delivery
2Stability of the object's composition
If the peptide is stabilized in acidic environment, then gastrointestinal stability improves, but absorption efficiency may deteriorate due to reduced membrane permeability at lower pH
Solution Approach 1:
The formulation dynamically manages pH parameters throughout the gastrointestinal tract using buffer systems and pH-dependent release mechanisms. The composition maintains optimal pH in the stomach to prevent degradation, then facilitates pH transition in the intestine to enhance permeability and absorption, thereby resolving the contradiction between stability and absorption efficiency
Solution Approach 2:
The oral formulation pre-protects the peptide against acidic degradation through encapsulation and pH buffering before the peptide encounters harsh gastrointestinal conditions. This preliminary protection allows the peptide to survive gastric transit intact, then become available for absorption in the more favorable intestinal environment
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 composition significantly improves the oral bioavailability of macrocyclic peptides by 10-800%, enabling effective oral administration for treating cancer and septic shock, with enhanced immune response and cancer cell inhibition.
Implementation Method 1
enhances oral bioavailability by stabilizing the peptide in the acidic environment
Implementation Method 2
improving intestinal absorption
Implementation Method 3
the composition further comprises one or more protease inhibitors
Data Source
AI summary
In accordance with the present disclosure, pharmaceutical formulations that improve the oral bioavailability of biologically active compounds, including macrocyclic compounds, have been discovered.