Aggregate Particles for Inhalation via Controlled Crystallization
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Solution Overview
Problem
Conventional inhalation delivery systems face challenges in producing respirable particles with controlled crystallinity and stability, particularly when using multiple pharmaceutical agents, which can result in undesirable polymorphic forms and hygroscopicity, affecting the efficiency and safety of drug delivery.
Innovation Solution
The development of aggregate particles comprising nanoparticulate drug particles of umeclidinium bromide, vilanterol trifenatate, and fluticasone furoate, with a mass median aerodynamic diameter of less than 100 µm, using spray drying technology to maintain a pre-selected crystalline form and incorporate excipients like lactose or leucine, and magnesium stearate, which enhances stability and delivery efficiency without the need for surfactants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If spray drying is used to produce respirable particles, then particle size control is improved, but crystallinity control deteriorates resulting in amorphous particles with stability problems
Solution Approach 1:
The patent applies preliminary action by pre-forming crystalline drug particles through controlled crystallization before the spray drying process. This ensures that the desired crystalline structure is established prior to aerosolization, preventing transformation to amorphous forms during rapid drying. The method involves dissolving the drug in a solvent, controlling crystallization to form particles of specific size and crystal form, then suspending these pre-formed crystalline particles in a carrier solution for spray drying.
Solution Approach 2:
The patent employs parameter changes by carefully controlling solvent composition, temperature, and drying conditions to maintain crystallinity throughout the spray drying process. Specific parameters such as solvent type (aqueous or organic), drying temperature, and particle concentration are optimized to prevent crystalline-to-amorphous transformation while achieving respirable particle sizes. The method adjusts these parameters to balance particle size reduction with crystallinity preservation.
2Reliability
If multiple pharmaceutical agents are used in inhalation formulations, then therapeutic efficacy is improved, but physical and chemical stability deteriorates due to undesirable polymorphic forms and hygroscopicity
Solution Approach 1:
The patent applies composite materials by formulating multiple pharmaceutical agents together in a single inhalation composition with controlled crystallinity. The method involves dissolving multiple drugs (e.g., fluticasone propionate and salmeterol xinafoate) in a common solvent, controlling simultaneous crystallization to maintain desired crystal forms, and suspending the resulting composite particles in a carrier. This approach allows multiple therapeutics to be delivered together while maintaining individual drug stability and avoiding undesirable polymorphic transformations.
3Ease of manufacture
If conventional milling is used for particle size reduction, then manufacturing simplicity is improved, but delivery efficiency deteriorates due to inability to achieve desired aerodynamic size
Solution Approach 1:
The patent employs parameter changes by controlling particle size through crystallization parameters rather than mechanical milling. By adjusting solvent composition, temperature, cooling rate, and agitation during the crystallization process, the method directly produces particles with optimal aerodynamic properties for inhalation delivery. This approach replaces complex milling operations with a simpler crystallization process that inherently generates particles of the desired size range.
Solution Approach 2:
The patent substitutes mechanical particle size reduction (milling) with a chemical/physical crystallization process. Instead of using mechanical energy to grind particles to desired size, the method uses controlled crystallization from solution to directly form particles of optimal aerodynamic diameter. This replacement eliminates the need for subsequent milling steps while achieving superior delivery efficiency through better control of particle size distribution.
4Ease of operation
If amorphous particles are produced by spray drying, then aerosolization is improved, but chemical stability deteriorates and hygroscopicity increases
Solution Approach 1:
The patent applies preliminary action by establishing the desired crystalline structure before aerosolization occurs. The method involves controlled crystallization of the drug from solution to form particles with specific crystal forms, then suspending these pre-formed crystalline particles in a carrier solution for spray drying. This ensures that particles maintain their crystalline structure throughout aerosolization, avoiding the formation of amorphous particles that would exhibit poor stability and increased hygroscopicity.
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
This approach provides improved physical and chemical stability, increased delivery efficiency, and reduced variability in fine particle dose, ensuring targeted deposition and enhanced pharmacokinetic profiles for respiratory diseases like asthma and COPD, while simplifying the manufacturing process by eliminating the need for surfactant removal.
Implementation Method 1
spray drying technology to maintain a pre-selected crystalline form
Data Source
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AI summary
The present invention relates to aggregate particles comprising nanoparticulate drug particles. In particular, the present invention is directed to aggregate particles comprising nanoparticulate drug particles of umeclidinium bromide and optionally vilanterol trifenatate and/or fluticasone furoate. Aggregate particles of the present invention may further comprise nanoparticulate excipient particles and one or more binders. The invention also relates to powder compositions suitable for inhalation that comprise said aggregate particles, processes of producing said aggregate particles, and use of said powder compositions in the treatment of respiratory diseases, such as asthma and COPD.