R-152a MDI Composition for Stable Formoterol-Budesonide Delivery
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Solution Overview
Problem
Existing pharmaceutical compositions for metered dose inhalers (MDIs) face challenges with propellants like R-134a and R-227ea, which have high global warming potentials, poor drug solubility, stability issues, and nozzle blockage, and require refrigerated storage, especially for formoterol formulations with corticosteroids like budesonide.
Innovation Solution
A pharmaceutical composition using 1,1-difluoroethane (R-152a) as the propellant, with minimal water and oxygen content, along with formoterol fumarate dihydrate and budesonide, enhances chemical stability and avoids surfactants, ensuring stable delivery and reduced degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If R-134a or R-227ea propellants are used in MDI formulations, then the formulation can deliver drug to respiratory tract, but the global warming potential becomes too high
Solution Approach 1:
The patent changes the physical and chemical parameters of the propellant by selecting HFA-152a (1,1-difluoroethane) with specific properties: lower GWP (148) compared to R-134a (1430) and R-227ea (3220), appropriate boiling point (-24.7°C), and suitable vapour pressure to enable effective MDI operation while reducing environmental harm
Solution Approach 2:
The patent creates a composite pharmaceutical formulation combining HFA-152a propellant with specific drug compounds (formoterol and/or budesonide) and co-solvents, optimizing the interaction between components to achieve both environmental sustainability and therapeutic effectiveness
2Ease of manufacture
If R-134a or R-227ea propellants are used, then the formulation can be prepared, but poor drug solubility occurs leading to nozzle blockage
Solution Approach 1:
The patent optimizes formulation parameters including drug:propellant ratio, inclusion of co-solvents (ethanol, water), and pH adjustment to enhance drug solubility in HFA-152a, preventing precipitation and nozzle blockage during storage and actuation
Solution Approach 2:
The patent introduces co-solvents (ethanol and water) as intermediary substances that facilitate drug dissolution in the HFA-152a propellant, acting as mediators between the poorly soluble drug and the hydrofluoroalkane propellant to achieve homogeneous formulations
3Reliability
If formoterol and corticosteroid are formulated together, then enhanced therapeutic effect is achieved, but chemical stability deteriorates requiring refrigerated storage
Solution Approach 1:
The patent optimizes formulation parameters including drug concentrations, pH buffer systems, and co-solvent ratios to minimize chemical degradation reactions between formoterol and budesonide, achieving enhanced therapeutic effect while maintaining stability at ambient temperatures
Solution Approach 2:
The patent introduces buffer systems and co-solvents as intermediary substances that mediate the chemical interaction between formoterol and budesonide, reducing direct chemical degradation while maintaining therapeutic compatibility and efficacy
4Ease of operation
If conventional propellants are used, then formulation can be delivered, but refrigerated storage is required increasing complexity
Solution Approach 1:
The patent selects HFA-152a with optimized physical parameters (boiling point -24.7°C, vapour pressure 4.2 bar at 20°C) that enable effective MDI delivery while providing sufficient chemical stability to allow ambient temperature storage, eliminating refrigeration requirements and simplifying supply chain and patient storage
Data Source
Figure 1A~1B
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Figure 3A~3B
AI summary
A method of stabilising a pharmaceutical composition is described. The pharmaceutical composition comprises a propellant and at least one formoterol compound selected from formoterol, pharmaceutically acceptable salts of formoterol, solvates of formoterol, and solvates of pharmaceutically acceptable salts of formoterol which is dissolved or suspended in the propellant. The method comprises using a propellant comprising at least 90 weight % 1,1-difluoroethane (R-152a).