Metered Dose Inhaler Formulation With Maleic Acid for β2-Agonist Stability
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Solution Overview
Problem
Existing solution formulations for metered dose inhalers (MDIs) face challenges with the chemical instability of β2-agonists, particularly in the presence of co-solvents like ethanol, leading to degradation and loss of active substance content during shelf-life.
Innovation Solution
Incorporation of maleic acid as an organic acid in the pharmaceutical composition, along with a propellant and co-solvent, stabilizes β2-agonists by reducing hydrolytic and oxidative degradation, ensuring chemical stability and maintaining quality parameters.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional formulations (such as HFA 134a or HFA 125) are used in pressurized metered dose inhalers, then the inhaler can be manufactured and operated, but the formulations exhibit poor shelf-life stability and fail to meet ICH guidelines for pharmaceutical stability
Solution Approach 1:
The patent changes the physical-chemical parameters of the formulation by introducing co-solvents (alcohols, esters, or ethers) in combination with HFA propellants. This parameter change modifies the solvation environment, preventing drug degradation and maintaining formulation stability throughout the shelf life, thereby resolving the contradiction between reliability and composition stability.
Solution Approach 2:
The patent creates a composite formulation system combining HFA propellants with co-solvents (alcohols, esters, or ethers) and pharmaceutical active ingredients. This composite approach leverages the complementary properties of each component: HFA provides propellant function, co-solvents enhance stability, and the combination achieves both manufacturability and ICH-compliant shelf-life stability.
2Measurement precision
If the inhaler is designed to deliver a specific dose (e.g., 90 mcg albuterol sulfate), then the dosing precision is improved, but maintaining stability and preventing degradation becomes more difficult
Solution Approach 1:
The patent modifies the formulation parameters by adding co-solvents that create a more stable solvation environment for the pharmaceutical active ingredient. This allows precise dosing (e.g., 90 mcg albuterol sulfate) to be maintained throughout the shelf life without degradation, resolving the contradiction between dosing precision and drug stability.
3Ease of operation
If existing propellants (HFA 134a, HFA 125, propane, isobutane) are used, then the inhaler can function as a pressurized metered dose device, but none of these formulations meet ICH guidelines for pharmaceutical stability
Solution Approach 1:
The patent develops composite formulations that combine existing HFA propellants (which ensure inhaler functionality) with co-solvents (alcohols, esters, or ethers) that provide the stability required for ICH guideline compliance. This composite approach maintains ease of operation while achieving reliability.
Solution Approach 2:
The patent changes the formulation parameters by introducing co-solvents that modify the chemical environment, enabling the formulation to meet ICH stability guidelines while maintaining the propellant functionality of HFAs for proper inhaler operation.
Data Source
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AI summary
The present invention provides a stable pharmaceutical composition to be used with pressurized metered dose inhalers and comprises a β2 agonist, a propellant, a co-solvent, an organic acid(s) and optionally water. The invention further provides stable pharmaceutical composition comprising β2 agonist, an inhaled corticosteroid and/or a long acting muscarinic antagonist. The invention also provides pharmaceutical composition for the treatment or prophylaxis of asthma, chronic obstructive pulmonary disease (COPD), rhinitis or as adjunct therapy for cystic fibrosis, non-cystic fibrosis bronchiectasis, lung infections or pulmonary fibrosis.