Nanonized Fenofibrate Suspension for Dissolution and Stability
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Solution Overview
Problem
Fenofibrate's poor water solubility and hydrophobic nature lead to limited absorption, requiring controlled dietary conditions for effective treatment of hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia, and existing methods like micronization and co-micronization have stability and amorphous form conversion issues.
Innovation Solution
A process for preparing an aqueous suspension of fenofibrate and fenofibric acid with a cellulose derivative as a solubilization adjuvant and surfactant, maintaining the crystalline form and achieving particle sizes below 250 nm, along with the addition of a phospholipid like soy lecithin for improved stability and absorption.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If fenofibrate is micronized or co-micronized to increase solubility, then dissolution speed improves, but particle stability deteriorates and amorphous form conversion occurs
Solution Approach 1:
The patent applies parameter changes by controlling particle size to a specific nanometric range (50-250 nm) and maintaining crystalline form through controlled processing conditions. This resolves the contradiction by finding an optimal parameter range that achieves fast dissolution while preventing amorphous conversion and maintaining stability.
Solution Approach 2:
The patent uses composite materials by combining nanonized fenofibrate with specific excipients including phospholipids (0.1-5% w/w), surfactants (0.1-2% w/w), and cellulose derivatives. This composite approach enhances particle stability and prevents amorphous form conversion while maintaining high dissolution speed.
2Reliability
If fenofibrate is nanonized to improve bioavailability, then absorption increases, but particle reagglomeration occurs
Solution Approach 1:
The patent introduces intermediary substances including phospholipids and surfactants that act as mediators between nanonized fenofibrate particles and the aqueous environment. These intermediaries prevent particle reagglomeration by providing steric and electrostatic repulsion, thereby maintaining particle dispersion stability while ensuring high bioavailability.
Solution Approach 2:
The patent employs phospholipids and surfactants that form flexible protective shells around nanonized fenofibrate particles. This shell formation prevents direct particle-particle contact and reagglomeration, maintaining stable dispersion in aqueous medium while preserving the high surface area-to-volume ratio needed for rapid dissolution and absorption.
3Reliability
If fenofibrate is taken after fatty meals to improve absorption, then bioavailability increases, but treatment compatibility deteriorates
Solution Approach 1:
The patent fundamentally changes the parameter of particle size from micrometer to nanometer scale, which alters the dissolution mechanism. This parameter change enables the drug to achieve rapid dissolution and absorption independent of dietary fat content, allowing flexible dosing timing and improving treatment compatibility while maintaining high bioavailability.
Solution Approach 2:
The patent extracts the dependency on dietary fat for absorption by nanonizing fenofibrate and incorporating it in a formulation that enables dissolution through mechanisms independent of bile salt micelles. This extraction of the food-effect dependency allows patients to take the medication at any time without dietary restrictions, improving treatment versatility.
4Speed
If particle size is reduced to increase surface area, then dissolution rate improves, but manufacturing complexity increases
Solution Approach 1:
The patent employs wet media milling, a hydraulic-based comminution process, to reduce fenofibrate particles to the nanometric range. This hydraulic approach, using media balls in an aqueous slurry, achieves consistent nanosization with controlled particle size distribution, balancing high dissolution rate with manageable manufacturing complexity.
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 process enhances bioavailability and stability of fenofibrate, eliminating the 'food effect' and allowing consistent absorption regardless of meal intake, with improved pharmacokinetic parameters and reduced particle size instability.
Implementation Method 1
a cellulose derivative as a solubilization adjuvant
Implementation Method 2
and surfactant
Implementation Method 3
along with the addition of a phospholipid like soy lecithin for improved stability and absorption
Implementation Method 4
liquid grinding making it possible to obtain nanonized fenofibrate
Implementation Method 5
The nanonization of fenofibrate further improves its dissolution profile
Data Source
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AI summary
The invention relates to a pharmaceutical formulation of nanonised fenofibrate, to a method for preparing same, and to the uses thereof.