Spray-Dried Diketopiperazine-Insulin Particles for Pulmonary Delivery

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Solution Overview

Problem

Current methods for preparing dry powder pharmaceuticals, such as lyophilization and spray drying, do not adequately address the need for particles with improved aerodynamic performance and stability for pulmonary delivery of active agents like insulin, particularly diketopiperazine-insulin particles.

Innovation Solution

The method involves preparing diketopiperazine-insulin particles by combining a diketopiperazine derivative with an active agent, such as insulin, and removing solvent through spray drying, which enhances stability and aerodynamic properties compared to freeze drying, allowing for more efficient pulmonary delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If lyophilization is used to remove solvent from particles, then the active agent stability is maintained, but the aerodynamic performance and density of the particles are insufficient

Engineering Contradiction:

Improveactive agent stabilityVSAvoidaerodynamic performance

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention changes the drying parameters by using spray drying instead of lyophilization, controlling the drying temperature and rate to achieve both stability and aerodynamic performance. The spray drying process uses specific temperature ranges and drying rates that preserve active agent stability while producing particles with improved aerodynamic properties and density.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention replaces the mechanical freeze-drying system with a spray drying system that uses thermal energy and fluid dynamics. The spray drying process substitutes the complex mechanical freezing and sublimation steps with a simpler spray atomization and evaporation process, achieving both stability and aerodynamic performance.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Productivity

If spray drying is used to remove solvent from particles, then the aerodynamic performance and density are improved, but the active agent stability may be compromised

Engineering Contradiction:

Improveaerodynamic performanceVSAvoidactive agent stability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The invention optimizes spray drying parameters including temperature, drying rate, and particle size distribution to maintain active agent stability while achieving improved aerodynamic performance. By controlling these parameters within specific ranges, the process resolves the contradiction between enhanced productivity and maintained reliability.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If particle density is increased for higher dosing, then the dose delivery is improved, but the aerodynamic performance may deteriorate

Engineering Contradiction:

Improvedose deliveryVSAvoidaerodynamic performance

Core Design Contradiction:

Quantity of substanceVSProductivity

Solution Approach 1:

The invention segments the particle system into a dense core containing the active agent and a lighter outer shell or surface layer. This segmented structure allows the particle to have high overall density for improved dose delivery while the outer layer maintains good aerodynamic properties for efficient pulmonary delivery.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention uses composite particle structures combining materials with different density and aerodynamic properties. The composite structure enables the particle to achieve both high density for dosing and good aerodynamic performance by strategically selecting and arranging different materials within the particle.

Inventive Principle:

Principle #40Composite materials

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 spray-dried diketopiperazine-insulin particles demonstrate improved stability, increased density, and enhanced aerodynamic performance, enabling higher doses and comparable pharmacodynamic effects to lyophilized powders, with a respirable fraction exceeding 40% and improved glucose disposal.

Implementation Method 1

removing solvent through spray drying, which enhances stability and aerodynamic properties

Methodology Applied

Scientific EffectEvaporation: Evaporation

Implementation Method 2

lyophilization, or freeze drying, involves a process in which solvent, typically water, is removed from a product after it is frozen

Methodology Applied

Scientific EffectFreezing: Freezing

Implementation Method 3

allowing the ice to change directly from solid to vapor without passing through a liquid phase

Methodology Applied

Scientific EffectSublimation: Sublimation

Data Source

PatentUS20230414500A1Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent

Publication Date: 2023.12.28 MANNKIND CORP

AI summary

Methods are provided for drying a particle. Specifically, there is provided a spray-dried diketopiperazine-insulin particle formulation having improved aerodynamic performance and in which the active agent is more stabile and efficiently delivered as compared to that of the lyophilized diketopiperazine-insulin formulation. The dry powders have utility as pharmaceutical formulations for pulmonary delivery.