LPDE4-Selective PDE4 Inhibitor Formulation for pMDI Delivery
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Solution Overview
Problem
Current PDE4 inhibitors for treating respiratory diseases like asthma and COPD have undesirable side effects due to their action on central nervous system and gut PDE4, and existing second-generation inhibitors lack sufficient selectivity for the low-affinity form (LPDE4), which is less prone to these side effects.
Innovation Solution
A pharmaceutical formulation for pressurized metered dose inhalers (pMDIs) and nebulizers comprising a compound of general formula (I) as a PDE4 inhibitor, specifically using (-) enantiomers with a hydrofluoroalkane propellant or as a propellant-free solution, optimized for stability and delivery to target LPDE4 with reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If first-generation PDE4 inhibitors (rolipram, piclamilast) are used to treat respiratory diseases, then anti-inflammatory effects are achieved, but side effects such as nausea, gastric acid secretion and emesis occur due to action on central nervous system and gut PDE4
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures that confer selective affinity for LPDE4 over HPDE4. The compounds contain specific structural features (such as particular substituent patterns on the core structure) that enable them to preferentially bind to and inhibit LPDE4 in inflammatory cells while having minimal interaction with HPDE4 in the central nervous system and parietal cells, thereby achieving localized therapeutic action at the target site with reduced off-target effects
Solution Approach 2:
The patent employs parameter changes by systematically modifying molecular parameters of PDE4 inhibitors to optimize selectivity. By varying structural parameters such as substituent types, positions, and configurations on the benzoate residue, the patent achieves compounds with enhanced LPDE4 selectivity. The use of specific enantiomers ((-)-enantiomers) represents a parameter change in stereochemical configuration that improves both potency and selectivity for LPDE4
2Object-affected harmful factors
If second-generation PDE4 inhibitors (cilomilast, roflumilast) are used to improve selectivity for LPDE4, then some reduction in side effects is achieved, but sufficient selectivity towards LPDE4 is not provided
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters of PDE4 inhibitors to optimize selectivity. By varying structural parameters such as substituent types, positions, and configurations on the benzoate residue, the patent achieves compounds with enhanced LPDE4 selectivity. The use of specific enantiomers ((-)-enantiomers) represents a parameter change in stereochemical configuration that improves both potency and selectivity for LPDE4
Solution Approach 2:
The patent employs composite materials by combining multiple structural elements into a unified molecular architecture. The compounds integrate a core structure with specifically designed substituent groups (including sulphonamido substituents on the benzoate residue) that work synergistically to achieve high LPDE4 selectivity. This composite molecular design allows the compound to simultaneously maintain potency against LPDE4 while minimizing interaction with HPDE4
3Reliability
If PDE4 inhibitors are administered systemically to achieve therapeutic effects, then anti-inflammatory action is obtained, but the drug does not reach the site of action with sufficient concentration and systemic side effects occur
Solution Approach 1:
The patent applies the taking out principle by extracting the harmful systemic exposure component from the therapeutic effect. Through optimized inhalation formulation and LPDE4-selective compounds, the therapeutic anti-inflammatory action is concentrated at the respiratory site of action while systemic absorption and associated side effects are minimized or eliminated
Solution Approach 2:
The patent applies local quality by designing compounds with specific molecular structures that confer selective affinity for LPDE4 over HPDE4. The compounds contain specific structural features (such as particular substituent patterns on the core structure) that enable them to preferentially bind to and inhibit LPDE4 in inflammatory cells while having minimal interaction with HPDE4 in the central nervous system and parietal cells, thereby achieving localized therapeutic action at the target site with reduced off-target effects
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 provides a chemically and physically stable aerosol for effective inhalation, delivering a therapeutic dose with improved selectivity for LPDE4, reducing side effects and enhancing therapeutic benefit for respiratory diseases.
Implementation Method 1
pharmaceutical formulation to be administered by pressurized metered dose inhalers (pMDIs)
Data Source
AI summary
The invention relates to a pharmaceutical formulation to be administered by pressurized metered dose inhalers (pMDIs), comprising a compound of general formula (I). The invention also relates to the process for the preparation and to a pressurized metered dose inhaler filled with said pharmaceutical formulation.