Ternary Non-Lamellar Lipid Compositions for Stable Colloidal Delivery
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Solution Overview
Problem
Current non-lamellar compositions for pharmaceutical and neutraceutical applications often rely on lipids with high toxicity, leading to dose-limiting side effects and restricted indications, and struggle with achieving stable, colloidal-sized particles with narrow particle size distributions for effective active agent delivery.
Innovation Solution
A ternary amphiphilic composition comprising at least 50% structure forming amphiphile, 0-40% structure swelling amphiphile, and 2-20% dispersion stabilizing polymeric amphiphile, which forms stable non-lamellar particles with reduced toxicity and controlled particle size distribution, suitable for colloidal dispersions and enhanced active agent delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-lamellar compositions use traditional lipids to form stable particles, then particle stability is improved, but toxicity increases leading to dose-limiting side effects
Solution Approach 1:
The patent uses a composite lipid system combining structure-forming lipids (cubic phase formers like monoacylglycerols), structure-swelling lipids (phospholipids like phosphatidylcholine), and polymeric surfactants (PEGylated compounds). This composite approach maintains the thermodynamic stability and cubic phase structure necessary for particle stability while the phospholipids and PEGylated surfactants reduce toxicity by improving biocompatibility and reducing hemolysis, thus resolving the contradiction between stability and toxicity
Solution Approach 2:
The patent modifies the chemical composition parameters of the lipid system by incorporating specific ratios of structure-forming lipids (50-80%), structure-swelling lipids (10-40%), and polymeric surfactants (5-20%). By changing these compositional parameters, the system maintains stable cubic phase particle formation while reducing toxic effects through the inclusion of biocompatible phospholipids and PEGylated compounds, thereby resolving the toxicity-stability contradiction
2Ease of manufacture
If mechanical force or ultrasound is applied to form dispersions, then particle formation is improved, but particle size distribution broadens
Solution Approach 1:
The patent employs polymeric surfactants, particularly PEGylated compounds, as intermediary agents that adsorb at the particle-solvent interface and provide steric stabilization. These intermediaries prevent particle aggregation and control particle size during mechanical dispersion processes, allowing effective particle formation through ultrasound or shearing while maintaining narrow size distributions by preventing uncontrolled aggregation
Solution Approach 2:
The patent optimizes the concentration and molecular weight parameters of the polymeric surfactants to control particle size distribution. By adjusting the polymeric surfactant concentration (5-20%) and selecting appropriate molecular weights, the system achieves effective particle dispersion with narrow size distributions even when subjected to mechanical forces or ultrasound, resolving the contradiction between ease of manufacture and manufacturing precision
3Reliability
If lamellar or L3 surface phase is used on non-lamellar particles, then particle stability is improved, but active agent release control is reduced
Solution Approach 1:
The patent applies local quality differentiation by having the bulk particle interior maintain a non-lamellar cubic or hexagonal phase for structural stability and high internal surface area, while the surface phase can be tailored with different lipid compositions or coatings to control active agent release. This local differentiation allows the particle core to provide stability while the surface region provides controlled release functionality, resolving the contradiction between stability and release control
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 ternary amphiphilic composition achieves stable, non-toxic, and biocompatible colloidal dispersions with narrow particle size distributions, enhancing the delivery and stability of active agents, particularly suitable for intravenous administration and reducing the risk of side effects.
Implementation Method 1
a) at least 50% of at least one structure forming amphiphile... wherein the composition comprises non-lamellar particles or forms non-lamellar particles when contacted with an aqueous fluid
Implementation Method 2
The formation of non-lamellar regions in the amphiphile/water, amphiphile/oil and amphiphile/oil/water phase diagrams is a well known phenomenon. Such phases include liquid crystalline phases such as the cubic P, cubic D, cubic G and hexagonal phases
Implementation Method 3
c) 2 to 20% of at least one dispersion stabilising polymeric amphiphile... wherein the composition may be dispersed in a polar or non-polar solvent to form particles of a non-lamellar phase
Implementation Method 4
Because the amphiphile has both polar and apolar groups which cluster to form polar and apolar regions, it can effectively solubilise both polar and apolar compounds
Data Source
AI summary
The present invention provides a particulate composition including; a) at least 50% of at least one structure forming amphiphile, b) 0 to 40% of at least one structure swelling amphiphile, and c) 2 to 20% of at least one dispersion stabilizing polymeric amphiphile, where all parts are by weight relative to the sum of the weights of a+b+c and wherein the composition comprises non-lamellar particles or forms non-lamellar particles when contacted with an aqueous fluid. Where component b) is 0% then component a) comprises at least two structure forming amphiphiles. The invention also provides pharmaceutical compositions of the compositions and kits containing the compositions for establishing a pharmaceutical formulation of an active agent.