Crystalline Inhalation Composite Particles for Low-Cohesion Delivery
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Solution Overview
Problem
Existing inhalation powder formulations face challenges with particle cohesion and agglomeration, leading to variable aerosolization and reduced delivery to deep airways, especially for high dosage formulations, and current methods like spray-drying and jet-milling produce amorphous products prone to instability and water sorption.
Innovation Solution
A pharmaceutical composition comprising crystalline composite particles of active pharmaceutical ingredients (API), sugars, and lipids, produced by co-milling, which enhances aerodynamic performance by minimizing interparticle interactions and cohesion, while maintaining stability and dissolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If particle size is reduced to target deep airways, then delivery to deep airways is improved, but particle cohesion and agglomeration increase
Solution Approach 1:
The patent introduces sugar and lipid particles as intermediary substances that coat the API particles. These intermediaries act as spacers that prevent direct contact between API particles, thereby reducing van der Waals forces and electrostatic interactions that cause cohesion and agglomeration. The sugar and lipid particles are dispersed throughout the formulation to maintain particle separation at the micro-scale.
Solution Approach 2:
The patent creates composite particles consisting of multiple components: API particles combined with sugar particles and lipid particles. This composite structure allows the formulation to maintain small particle size for deep airway delivery while the sugar and lipid components provide anti-adherent properties that prevent cohesion. The composite nature distributes different functions across different particle types within the same formulation.
2Manufacturing precision
If spray-drying or jet-milling is used to reduce particle size, then aerodynamic performance is improved, but amorphous products are produced that are prone to instability and water sorption
Solution Approach 1:
The patent changes the physical state parameter of the API from amorphous to crystalline form. By controlling the formulation and processing conditions, the API maintains its crystalline structure throughout the manufacturing process and storage. This crystalline state provides thermodynamic stability and resistance to water sorption, while the sugar and lipid components ensure the particle size and aerodynamic performance requirements are met.
3Quantity of substance
If high dosage formulations are used, then therapeutic efficacy is improved, but particle cohesion and agglomeration increase
Solution Approach 1:
The patent uses sugar and lipid particles as intermediary substances that scale with the dosage. In high dosage formulations, the same anti-adherent mechanism is applied, but with increased concentrations of sugar and lipid particles to maintain effective spacing between the larger quantity of API particles. This prevents cohesion even when the total mass of API is increased to achieve therapeutic efficacy.
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 composition achieves improved fine particle fraction, emitted dose, and stability, with reduced amorphization, and supports high dosage delivery via inhalation without using carriers, leveraging the biocompatibility and anti-adherent properties of sugars and lipids.
Implementation Method 1
The steps comprising: a. Blending the API and the excipient(s) to form a homogeneous powder; b. Reducing the particle size distribution of the blend
Implementation Method 2
leveraging the biocompatibility and anti-adherent properties of sugars and lipids
Implementation Method 3
which enhances aerodynamic performance by minimizing interparticle interactions and cohesion
Data Source
AI summary
The present invention describes a pharmaceutical composition comprising composite particles with a controlled aerodynamic particle size distribution, wherein the composite particles comprise one or more active pharmaceutical ingredients (API), at least one sugar and at least one lipid. A process for manufacturing the pharmaceutical composition comprises the steps of: a. Blending API and one or more excipients comprising at least one sugar or at least one lipid, or both at least one sugar and at least one lipid, into a homogeneous powder; b. Reducing the particle size distribution of the blend. The micronized pharmaceutical composition allows for the delivery of crystalline stable API with better aerodynamic properties than the micronized API alone, as well as improved downstream processing and stability properties.