pMDI Formulation with HCl and EDTANa4 for LABA Stability
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Solution Overview
Problem
Existing pressurized metered dose inhaler (pMDI) formulations with LABA agents and corticosteroids face stability issues over extended periods, particularly when contained in aluminum cans, necessitating improved chemical stability to maintain consistent active ingredient delivery.
Innovation Solution
Incorporating a mixture of an acid, such as hydrochloric acid (HCl), and a chelating agent, like EDTANa4, into the formulation with a LABA agent and optionally a corticosteroid, stabilizes the formulation, enhancing its stability even in aluminum cans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a LABA agent and corticosteroid are formulated in a pMDI device with aluminum canister, then the formulation can be administered effectively, but the chemical stability of active ingredients deteriorates over extended periods
Solution Approach 1:
A chelating agent is introduced as an intermediary substance that binds to metal ions (Al³⁺ from the aluminum canister) to form stable complexes, preventing these metal ions from catalyzing the degradation of LABA agents and corticosteroids. This mediator approach effectively isolates the harmful interaction between the aluminum canister and the active ingredients, maintaining formulation stability throughout the product lifetime.
Solution Approach 2:
The patent modifies the chemical environment of the formulation by adjusting pH levels and adding stabilizing agents, thereby changing the parameters that govern chemical reactivity. By controlling the pH and introducing chelating agents, the formulation's resistance to degradation is enhanced, allowing stable storage in aluminum canisters over extended periods without significant loss of active ingredient integrity.
2Reliability
If stabilizing agents are added to improve chemical stability, then active ingredient degradation is reduced, but the formulation complexity increases
Solution Approach 1:
The patent extracts and addresses the specific destabilizing factor (metal ion catalysis) by selectively adding only the necessary chelating agent to bind these ions. Rather than adding multiple broad-spectrum stabilizers that would significantly complicate the formulation, the solution targets the specific mechanism of degradation, minimizing the increase in formulation complexity while achieving the desired stability improvement.
3Ease of manufacture
If the formulation is stored in an aluminum canister for extended periods, then manufacturing and device simplicity is maintained, but degradation products increase
Solution Approach 1:
The patent converts the potentially harmful interaction between aluminum canister material and active ingredients into a beneficial outcome by adding a chelating agent that selectively binds to aluminum ions. This approach allows the continued use of simple, inexpensive aluminum canisters while preventing them from generating degradation products, effectively transforming the canister from a source of instability into a stable delivery system.
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 inclusion of a mixture of HCl and EDTANa4 significantly improves the stability of LABA agents and corticosteroids in pMDI formulations, maintaining high residual active ingredient levels and ensuring consistent delivery over time.
Implementation Method 1
the inclusion of a mixture of an acid and a chelating agent in a formulation comprising a LABA agent, optionally in combination with a corticosteroids, substantially avoids the degradation of said active ingredients
Implementation Method 2
a pharmaceutical composition comprising formoterol fumarate in a solution of HFA propellant and a co-solvent, containing an amount of HCl such that the solution has an apparent pH between 3 and 3.5
Data Source
AI summary
The present invention generally relates to pharmaceutical composition comprising a LABA agent, optionally in combination with other active ingredients, a mixture of an acid and a chelating agent, a propellant and a co-solvent. The invention also provides a pharmaceutical composition for the treatment of respiratory diseases, such as asthma and COPD.