Magnesium Stearate Stabilized Dry Powder Inhalation Formulation
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Solution Overview
Problem
Current PI3 kinase inhibitors for inhalation therapy face challenges in achieving stable and reproducible chemical and physical properties, particularly in dry powder formulations, which are essential for effective delivery of therapeutic compounds like the compound of formula (I) for treating inflammatory diseases such as COPD and asthma, due to susceptibility to oxidative degradation and hydrolytic cleavage.
Innovation Solution
Incorporating a particulate stabilizing agent, such as metal salts of stearic acid or stearyl fumarate, specifically magnesium stearate, alongside particulate lactose in the dry powder formulation to enhance the chemical and physical stability of the compound of formula (I), thereby protecting it from metal-catalyzed oxidative degradation and hydrolytic cleavage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If the compound of formula (I) is formulated in dry powder for inhalation, then it can be delivered effectively to treat inflammatory diseases, but it becomes susceptible to oxidative degradation and hydrolytic cleavage, compromising chemical stability
Solution Approach 1:
Magnesium stearate acts as an intermediary substance between the compound of formula (I) and the degrading environment. It forms a protective interface that prevents direct contact with oxidizing agents and water, thereby reducing oxidative degradation and hydrolytic cleavage while maintaining inhalation delivery capability
Solution Approach 2:
The formulation creates a microenvironment around the compound of formula (I) that is chemically inert to oxidation and hydrolysis. Magnesium stearate provides this protective atmosphere by forming a barrier layer that excludes reactive species and moisture, allowing the compound to remain stable during storage and administration
2Stability of the object's composition
If metal salts of stearic acid or stearyl fumarate are added to enhance chemical stability, then oxidative degradation and hydrolytic cleavage are reduced, but the formulation complexity increases
Solution Approach 1:
The invention optimizes the concentration of magnesium stearate within a specific range (0.1-10% w/w) to achieve effective stabilization without excessive complexity. This parameter optimization allows the formulation to maintain chemical stability while keeping the composition relatively simple and manageable
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 demonstrates improved chemical and physical stability, as evidenced by reduced degradation products and maintained peak characteristics, ensuring predictable and reproducible therapeutic efficacy when administered via inhalation.
Implementation Method 1
susceptibility to oxidative degradation and hydrolytic cleavage
Implementation Method 2
susceptibility to oxidative degradation and hydrolytic cleavage
Data Source
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AI summary
There is provided inter alia a dry powder pharmaceutical formulation for inhalation comprising: (i) 6-(2-((4-amino-3-(3-hydroxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl) methyl)-3- (2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N, N-bis(2-methoxyethyl)hex-5- ynamide or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof and solvates thereof in particulate form as active ingredient; (ii) particulate lactose as carrier; and (iii) a particulate stabilizing agent selected from metal salts of stearic acid such as magnesium stearate and metal salts of stearyl fumarate.