Nanoparticle Trans-Epithelial Drug Delivery
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Solution Overview
Problem
Current methods for delivering macromolecules, such as proteins and nucleic acids, across epithelial tissues, like the intestinal lining, are hindered by low permeability, and existing permeation enhancers often come with toxicity or immunogenicity issues.
Innovation Solution
The use of negatively-charged nanoparticles with diameters less than 1 μm, specifically 50 nm or 20 nm, in conjunction with active ingredients of less than 40 kDa, to enhance trans-epithelial drug delivery by increasing permeability through modulation of tight junctions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chemical permeation enhancers (detergents, acids, salts, nitrogenous small molecules) are used to increase epithelial permeability, then macromolecular absorption is improved, but toxicity and immunogenicity occur
Solution Approach 1:
The invention changes the physical-chemical parameters of the delivery system by using nanoparticles with specific size ranges (20-200 nm) and surface charge characteristics instead of traditional chemical enhancers. This parameter change enables permeability enhancement through a different mechanism that does not involve the toxic effects of detergents, acids, salts, or nitrogenous compounds.
Solution Approach 2:
The nanoparticle acts as an intermediary carrier that facilitates macromolecule transport across the epithelial barrier. Rather than using chemical enhancers that directly interact with and damage the epithelium, the nanoparticle serves as a mediator that can be internalized by epithelial cells and transport the macromolecule payload through the barrier without causing toxicity or immunogenicity.
2Productivity
If macromolecules are loaded into or covalently bonded onto nanoparticles for trans-epithelial delivery, then delivery efficiency is improved, but effective delivery approaches are still lacking
Solution Approach 1:
The invention optimizes critical parameters including nanoparticle size (20-200 nm diameter), surface charge (negative charge), and macromolecule payload size (less than 40 kDa, 25 kDa, or 10 kDa). These parameter specifications transform the nanoparticle delivery approach from experimental to clinically viable, enabling reliable trans-epithelial delivery of macromolecules.
3Productivity
If the intestinal lining permeability is increased to allow oral delivery of macromolecules, then non-parenteral dosage forms become feasible, but the epithelial cellular barrier and mucus prevent absorption
Solution Approach 1:
The nanoparticle functions as a flexible nanoscale carrier that can navigate through the mucus layer and interact with the epithelial cellular barrier. The small size (20-200 nm) and surface properties of the nanoparticle allow it to penetrate or be internalized by the epithelial barrier, delivering the macromolecule payload through the protective layers that normally prevent oral absorption.
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
This approach effectively increases the permeability of epithelial barriers, allowing for improved absorption of macromolecular drugs, such as insulin and exenatide, without inducing cytotoxicity or immunogenicity, and demonstrates reversible and selective permeability enhancement.
Implementation Method 1
macromolecular permeability can be enhanced through modulation of the tight junctions, which are dynamic protein structures that connect epithelial cells and form a diffusion barrier between them
Data Source
AI summary
Provided herein are devices and dosage forms useful in delivering macromolecular active ingredients or drugs, such as proteins, peptides and nucleic acids, through epithelial membranes, such as intestinal epithelium. Also provided are trans-epithelial drug delivery methods and methods of treatment of diabetes or insulin resistance, or to induce weight loss.