Anhydrous Lipid Oral Formulation for Poorly Permeable CGRP Inhibitors
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Solution Overview
Problem
Poorly permeable molecules, classified as BCS Class III and Class IV compounds, face challenges in oral absorption due to intestinal membrane barriers, requiring frequent intravenous or subcutaneous administration and are susceptible to chemical instability and enzymatic degradation in the gastrointestinal tract.
Innovation Solution
Development of lipid-based, water-free formulations with a lipophilic phase, lipophilic and hydrophilic surfactants, and optional chemical stabilization agents, which form a single-phase suspension for oral delivery, enhancing bioavailability through delayed release in the intestine using permeation enhancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If water is included in the formulation to solubilize the API, then the API can be dissolved, but the poorly permeable molecules aggregate together reducing bioavailability
Solution Approach 1:
The patent uses a lipid-based formulation system as an intermediary medium to carry and deliver the poorly permeable API. The lipid excipients act as a mediator that prevents direct contact between water and the API, thereby preventing aggregation while still enabling transport across the intestinal membrane through lipid-like mechanisms.
Solution Approach 2:
The patent changes the physical-chemical parameters of the formulation by removing water and using anhydrous lipid-based excipients. This parameter change from aqueous to non-aqueous environment fundamentally alters how the API behaves, preventing aggregation and improving permeation through the lipid bilayer of the intestinal membrane.
2Reliability
If the formulation is designed for oral delivery of poorly permeable molecules, then bioavailability can be improved, but the molecules still face poor absorption through the intestinal membrane
Solution Approach 1:
The patent changes the physical state and chemical properties of the API by formulating it in an anhydrous lipid-based system. This parameter change makes the API more lipophilic, enabling it to pass through the lipid bilayer of the intestinal membrane more effectively and overcome the permeability barrier.
Solution Approach 2:
The lipid excipients serve as intermediaries that facilitate the transport of the API across the intestinal membrane. The formulation system acts as a carrier that enhances permeation by providing a lipid-compatible environment that matches the membrane structure.
3Reliability
If water is removed from the formulation to prevent aggregation, then bioavailability improves, but the formulation becomes more complex and may require additional stabilizing agents
Solution Approach 1:
The patent employs lipid-based excipients that perform multiple functions simultaneously: they serve as the formulation medium, provide structural stability, enable permeation enhancement, and prevent aggregation. This multi-functionality reduces the need for additional separate components, thereby simplifying the overall formulation despite the anhydrous nature.
4Quantity of substance
If the API is dispersed as powder in the formulation, then the drug load can be increased, but the physical stability may be compromised
Solution Approach 1:
The lipid excipients act as a stabilizing intermediary that surrounds and stabilizes the dispersed API powder particles. The lipid medium provides a compatible environment that maintains physical stability even at high API concentrations, preventing aggregation and phase separation while allowing increased drug load.
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 achieve higher bioavailability and stability for poorly permeable molecules like CGRP inhibitors by avoiding aggregation and enzymatic degradation, allowing for less frequent dosing and improved therapeutic efficacy.
Implementation Method 1
a lipophilic phase comprising triglycerides of fatty acids... and at least one lipophilic surfactant... which enhances bioavailability by avoiding aggregation and enzymatic degradation
Implementation Method 2
at least one lipophilic surfactant comprising partial esters of polyol and fatty acids... to improve permeation
Implementation Method 3
at least one hydrophilic surfactant with a hydrophilic lipophilic balance ('HLB') above 10... to improve permeation
Data Source
AI summary
The present disclosure is directed to a pharmaceutical formulation intended for oral delivery of synthetic or natural poorly permeable calcitonin gene-related peptide (CGRP) inhibitors or salts/solvates thereof having a therapeutic activity. The pharmaceutical formulation can include a synthetic or natural poorly permeable CGRP inhibitors or salt or solvate thereof in an amount 0.01-10 wt. % of the total weight of the formulation; a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt. % of the total weight of the formulation; and at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of about 10-50 wt. % of the total weight of the formulation.