Co-Suspension MDI Formulations for Multi-Agent Delivery
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Solution Overview
Problem
Current metered dose inhaler (MDI) formulations face challenges with aggregation and flocculation of active agents, leading to inconsistent dose delivery and mechanical failures, particularly with potent, low-dose medicaments, and require environmentally friendly propellants that maintain aerosol performance and stability.
Innovation Solution
The development of co-suspension compositions that stabilize two or more active agents, such as LAMA, LABA, and corticosteroids, using a suspension medium like hydrofluoroalkanes (HFAs) without surfactants, ensuring aerosol properties, particle size distribution, and delivered dose uniformity remain consistent with single-agent formulations, using suspending particles that associate with active agents to prevent separation and maintain stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If fine particulate active agents are suspended in propellant for MDI delivery, then aerosolization is enabled, but aggregation and flocculation occur rapidly leading to inconsistent dose delivery
Solution Approach 1:
The patent introduces surfactants as intermediary substances that coat the surfaces of fine particulate active agents in the suspension. These surfactants reduce surface tension and prevent direct particle-to-particle contact, thereby minimizing aggregation and flocculation while maintaining aerosolization capability. The surfactant layer acts as a protective mediator between the propellant and drug particles.
Solution Approach 2:
The patent modifies the physical and chemical parameters of the suspension system by adjusting surfactant concentration, particle size distribution, and propellant composition. These parameter changes optimize the balance between maintaining fine particle suspension stability and enabling effective aerosolization, preventing rapid aggregation while ensuring consistent dose delivery.
2Stability of the object's composition
If surfactants are used to stabilize suspension and prevent aggregation, then particle dispersion is improved, but surfactant solubility varies in non-CFC propellants reducing effectiveness
Solution Approach 1:
The patent selects surfactants with universal compatibility across multiple propellant types including HFA-134a, HFA-227, and PFCs. These surfactants possess amphiphilic structures that enable them to function effectively in both fluorinated and non-fluorinated propellant systems, providing consistent stabilization and aggregation prevention across different MDI formulations.
Solution Approach 2:
The patent employs composite surfactant systems combining multiple surfactant molecules with different hydrophobic and hydrophilic characteristics. This composite approach creates a more versatile stabilization system that adapts to varying propellant compositions, maintaining suspension stability and preventing aggregation across different propellant chemistries.
3Reliability
If CFC propellants are used for MDI formulations, then low toxicity and desirable vapor pressure are achieved, but negative environmental impact occurs
Solution Approach 1:
The patent transitions from CFC propellants to HFA and PFC alternatives by changing the chemical composition parameters while maintaining physical parameters such as vapor pressure and toxicity profile. This substitution eliminates ozone-depleting substances while preserving the essential aerosol generation performance through carefully selected alternative propellants with comparable physical properties.
Solution Approach 2:
The patent utilizes HFA and PFC propellants that create an inert, environmentally benign atmosphere within the MDI system. These propellants do not deplete ozone or contribute to greenhouse effects, providing an eco-friendly alternative that maintains the pressurized aerosol delivery function while eliminating harmful environmental impacts associated with traditional CFCs.
4Reliability
If multiple active agents are combined in single MDI formulation, then therapeutic efficacy is enhanced, but combination effects and pharmaceutical interactions may occur
Solution Approach 1:
The patent segments multiple active agents into separate suspension phases within the same MDI formulation, each maintained by its own surfactant stabilization system. This segmentation prevents direct chemical interactions between different drug molecules while allowing simultaneous aerosolization, thereby preserving formulation stability and avoiding unwanted pharmaceutical effects.
Solution Approach 2:
The patent introduces surfactants as intermediary substances that coat and isolate different active agent particles from each other in the suspension. These surfactant layers prevent direct contact and potential chemical reactions between multiple active agents, while still allowing each to be effectively delivered via aerosolization, thus maintaining both stability and enhanced 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 co-suspension compositions achieve significant increases in lung function measures, maintain aerosol performance, and ensure consistent delivery of both active agents, avoiding combination effects and pharmaceutical effects associated with multiple agents, while using environmentally friendly propellants without the need for cosolvents or adjuvants.
Implementation Method 1
MDIs use a relatively high vapor pressure propellant to expel aerosolized droplets containing an active agent into the respiratory tract when the MDI is activated
Implementation Method 2
The active agent to be delivered by a suspension MDI is typically provided as a fine particulate dispersed within a propellant or combination of two or more propellants
Implementation Method 3
Fine particles of active agent suspended in a propellant or propellant system tend to aggregate or flocculate rapidly
Implementation Method 4
Fine particles of active agent suspended in a propellant or propellant system tend to aggregate or flocculate rapidly
Implementation Method 5
surfactants are often used to coat the surfaces of the active agent in order to minimize or prevent the problem of aggregation and maintain a substantially uniform dispersion
Data Source
AI summary
Compositions, methods and systems are provided for pulmonary or nasal delivery of two or more active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.