Spray-Dried Core-Shell Particles for Dry Powder Inhaler Flow
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Solution Overview
Problem
Current dry powder inhalers for respiratory diseases face challenges with poor powder flow, fluidization, and dispersion properties of fine drug particles, leading to inconsistent lung targeting and high variability in drug delivery, especially when formulating fixed dose combinations of active ingredients with different physicochemical properties.
Innovation Solution
The development of spray-dried particles with a core of a crystalline active ingredient coated with an amorphous active ingredient dispersed in a hydrophobic excipient, which are phase-separated to improve aerodynamic particle size distribution and lung targeting, reducing inter-patient variability and flow rate dependence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If fine drug particles are micronized to achieve aerodynamic diameter between 1-5 μm for effective lung deposition, then lung delivery efficiency is improved, but powder flow, fluidization and dispersion properties deteriorate
Solution Approach 1:
The invention uses composite particles consisting of fine drug particles (1-5 μm) combined with larger carrier particles (50-200 μm). This composite structure allows the fine particles to maintain their lung-delivery capability while the larger carriers provide the necessary flow and dispersion properties. The carrier particles act as a matrix that holds the fine drug particles, preventing them from agglomerating while maintaining good powder handling characteristics.
Solution Approach 2:
The invention changes the particle size parameter by creating a bimodal distribution rather than using uniformly fine particles. The presence of larger carrier particles (50-200 μm) alongside fine drug particles (1-5 μm) fundamentally alters the powder's bulk properties, improving flowability and compressibility without compromising the aerodynamic diameter of the drug-containing particles that reach the lungs.
2Ease of operation
If controlled aggregation of undiluted drug is used to form pellets for improved flow properties, then powder flow and metering accuracy are improved, but powder dispersion and aerosol performance exhibit strong dependence on patient's inspiratory flow rate
Solution Approach 1:
The invention uses composite particles where fine drug particles are associated with larger carrier particles. This composite structure provides the flow properties needed for accurate metering while the specific design of the composite (with carriers 50-200 μm) ensures that dispersion occurs effectively across a range of inspiratory flow rates, reducing the strong dependence seen in pelletized formulations.
Solution Approach 2:
The invention applies different properties to different parts of the particle system: the fine drug particles (1-5 μm) are optimized for lung deposition, while the larger carrier particles (50-200 μm) are optimized for flow and dispersion. This local differentiation of particle functions allows the formulation to achieve both good metering and flow properties while maintaining reliable aerosol performance across varying inspiratory flow rates.
3Ease of operation
If binary ordered mixture of fine drug particles and coarse carrier particles is used, then powder flow properties are improved, but lung targeting decreases with high oropharyngeal deposition and high variability in lung dose
Solution Approach 1:
The invention uses composite particles where fine drug particles are specifically associated with carrier particles in a controlled manner. This composite structure improves flow properties while the specific size range of carriers (50-200 μm) and the association method ensure better lung targeting compared to simple binary mixtures, reducing oropharyngeal deposition and variability.
Solution Approach 2:
The invention optimizes the particle size parameters of both the drug particles (1-5 μm) and carrier particles (50-200 μm) to achieve a specific size relationship. This parameter optimization ensures that the carriers are large enough to provide good flow properties but not so large as to cause excessive oropharyngeal impaction, thereby improving lung targeting precision while maintaining manufacturability.
4Adaptability or versatility
If two or more active ingredients with different physicochemical properties are formulated in fixed dose combination, then therapeutic efficacy is improved, but formulation complexity and difficulty in achieving uniform blend increase
Solution Approach 1:
The invention uses composite particles where multiple active ingredients are incorporated into the fine particle phase (1-5 μm) that is associated with the carrier. This composite approach allows different drugs with different physicochemical properties to be delivered together in fixed ratios, simplifying the formulation process compared to creating separate formulations for each drug while maintaining therapeutic efficacy.
Solution Approach 2:
The invention merges multiple active ingredients into a single composite particle system where fine drug particles containing the active ingredients are associated with carrier particles. This merging approach simplifies the formulation of fixed-dose combinations by delivering multiple drugs together in one inhalation event, avoiding the complexity of coordinating multiple separate formulations while ensuring uniform dosing of all ingredients.
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 enhances lung delivery efficiency, reduces oropharyngeal and systemic deposition, and achieves improved dose consistency by controlling particle attributes such as size, morphology, and surface energy, leading to more effective targeting of aerosol to the lungs.
Implementation Method 1
spray-dried particles that contain a first active ingredient in substantially crystalline form, a second active ingredient in substantially amorphous form, and a pharmaceutically acceptable hydrophobic excipient, wherein the three materials are substantially phase separated in the spray-dried particles
Implementation Method 2
spray-dried particles that comprise a core of a first active ingredient in substantially crystalline form that is coated with a layer of a second active ingredient in substantially amorphous form that is dispersed in a pharmaceutically acceptable hydrophobic excipient
Data Source
AI summary
Dry powder formulations for inhalation comprising spray-dried particles and their use in the treatment of an obstructive or inflammatory airways disease. Each particle has a core of a first active ingredient in substantially crystalline form that is coated with a layer of a second active ingredient in substantially amorphous form that is dispersed in a pharmaceutically acceptable hydrophobic excipient. A process for preparing such formulations is also described.