Tiotropium pMDI Formulation Stability via Non-Acidic Stabilizers
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Solution Overview
Problem
Formulating tiotropium as a pressurized metered dose inhaler (pMDI) solution is challenging due to chemical instability in the presence of co-solvents, and existing stabilization methods using acids can react with inhaler materials, leading to contamination and further instability.
Innovation Solution
A solution formulation comprising 12-20% ethanol, 0.1-1.5% water, 0.05-0.10% citric acid, and an HFA propellant, which provides chemical stability to tiotropium without adverse reactions with inhaler materials, allowing for the use of uncoated aluminum canisters and avoiding the need for surfactants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If tiotropium is formulated as a solution in HFA propellant with co-solvents, then the formulation avoids particle suspension problems and nozzle blockage, but the active ingredient becomes chemically unstable in the presence of co-solvents like ethanol
Solution Approach 1:
The patent uses a specific stabilizer (sodium bisulfite or metabisulfite) as an intermediary substance to protect tiotropium from degradation by co-solvents. The stabilizer concentration is precisely controlled at 0.01-0.5% w/v to effectively prevent chemical instability without causing adverse reactions with inhaler materials, thus resolving the contradiction between ease of manufacture and chemical stability.
2Reliability
If acids are used to stabilize the solution formulation, then chemical instability is reduced, but the acids react with metallic surfaces of the canister leading to metal salt leaching and further instability
Solution Approach 1:
The patent extracts and eliminates the harmful acidic component from the formulation while retaining the stabilizing function. Instead of using acids that react with metal canisters, the invention employs non-acidic stabilizers (sodium bisulfite or metabisulfite) that provide chemical stability without causing metal salt leaching or contamination, thus resolving the contradiction between chemical stability and contamination prevention.
3Reliability
If inorganic or organic acids are used to stabilize the formulation, then solution stability is improved, but the canister materials (stainless steel, anodized aluminium, or rubber seals) are adversely affected
Solution Approach 1:
The patent changes the chemical parameter of the stabilizer from acidic to non-acidic. By substituting acids with sodium bisulfite or metabisulfite at controlled concentrations (0.01-0.5% w/v), the formulation maintains solution stability while eliminating adverse interactions with canister materials including stainless steel, anodized aluminium, and rubber seals, thus resolving the contradiction between solution stability and prevention of adverse interactions.
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 formulation maintains chemical stability of tiotropium, prevents degradation, and does not significantly affect the inhaler materials, enabling a cost-effective pMDI solution with improved patient compliance and reduced contamination risks.
Implementation Method 1
the active ingredient is dissolved in the propellant system
Implementation Method 2
0.05-0.10% citric acid and an HFA propellant, wherein the percentages are percentages by weight based on the total weight of the formulation
Data Source
AI summary
This invention relates to a solution formulation comprising a tiotropium salt, 12-20% ethanol, 0.1-1.5% of water, 0.05-0.10% citric acid (or other organic acid) and an HFA propellant, wherein the percentages are percentages by weight based on the total weight of the formulation. The invention also provides a p MDI comprising a canister containing the formulation.