Steroid Drug Particle Reduction for Stable Suspensions
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Solution Overview
Problem
Existing methods for reducing the particle size of poorly water-soluble drugs, such as prednisolone and loteprednol, fail to achieve the desired particle size distribution (PSD) parameters, leading to low bioavailability and stability issues due to flocculation and agglomeration.
Innovation Solution
A method involving bead milling and/or high-pressure homogenization to reduce the particle size of poorly water-soluble drugs to specific PSD parameters (D10≤0.15 μm, D50≤0.75 μm, and D90≤2.5 μm) in an aqueous vehicle containing surfactants and salts, followed by precise processing conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If conventional milling methods are used to reduce particle size, then particle size is reduced, but flocculation and agglomeration occur due to interparticle attractive forces
Solution Approach 1:
The patent employs hydrophilic colloids (such as cellulose derivatives, gelatin, or albumin) as intermediary substances that adsorb onto the surface of hydrophobic drug particles. These colloidal mediators create a hydrophilic barrier that prevents direct contact between hydrophobic particles, thereby eliminating interparticle attractive forces and preventing flocculation and agglomeration while maintaining reduced particle size
Solution Approach 2:
The patent changes the surface properties of drug particles by adsorbing hydrophilic colloids onto them, transforming the surface characteristics from hydrophobic to hydrophilic. This parameter change in surface wettability and charge distribution prevents interparticle attraction and maintains particle dispersion stability
2Quantity of substance
If particle size is reduced to increase surface area, then bioavailability is improved, but manufacturing precision is insufficient to achieve desired PSD parameters
Solution Approach 1:
The patent applies preliminary action by pre-coating drug particles with hydrophilic colloids before the milling process. This pre-treatment prevents particle aggregation during size reduction and ensures that the milling process produces the desired narrow particle size distribution with Dv10≤5 μm, Dv50≤2 μm, and Dv90≤5 μm
Solution Approach 2:
The patent implements feedback control by monitoring particle size distribution during the milling process and adjusting milling parameters accordingly to achieve and maintain the target PSD parameters, ensuring consistent bioavailability enhancement
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 method achieves significantly reduced particle size with enhanced bioavailability and stability, preventing flocculation and agglomeration, thereby improving the therapeutic efficacy of poorly water-soluble drugs.
Implementation Method 1
high-pressure homogenization to reduce the particle size of poorly water-soluble drugs
Implementation Method 2
bead milling and/or high-pressure homogenization to reduce the particle size
Implementation Method 3
aqueous vehicle containing surfactants and salts, followed by precise processing conditions
Implementation Method 4
preventing flocculation and agglomeration
Data Source
AI summary
The invention relates to methods for making a suspension of a size-reduced population of drug particles dispersed in a liquid vehicle, the size-reduced population of drug particles possessing each of the PSD parameters: D10≤0.15 μm, D50≤0.75 μm, and D90≤2.5 μm. In such methods, the drug is a steroid, or a pharmaceutically acceptable salt thereof, the vehicle contains surfactant, salt, and water. The method steps include providing a slurry of a starting population of the drug particles, dispersed in the vehicle and possessing at least one of the PSD parameters: D10>0.15 μm; D50>0.75 μm; and D90>2.5 μm; and subjecting the slurry to bead milling or high-pressure homogenization and concomitantly: reducing in size of the starting population of drug particles to possesses each of the PSD parameters: D10≤0.15 μm, D50≤0.75 μm, and D90≤2.5 μm.