PDE4B Inhibitor Oral Composition for PF-ILD With Reduced GI Effects
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Solution Overview
Problem
Current treatments for progressive fibrosing interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), are unable to stop or reverse disease progression and are associated with significant gastrointestinal side effects, limiting their efficacy and patient compliance.
Innovation Solution
An oral pharmaceutical composition containing a PDE4B inhibitor of formula III in a dose of 18 mg, administered twice daily, either alone or in combination with standard of care treatments like nintedanib or pirfenidone, to treat progressive fibrosing interstitial lung diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments (nintedanib or pirfenidone) are used to treat progressive fibrosing interstitial lung diseases, then disease progression can be slowed, but significant gastrointestinal side effects occur that limit patient compliance
Solution Approach 1:
The patent changes the pharmacological parameter by switching from antifibrotic drugs (nintedanib/pirfenidone) to a PDE4B inhibitor (formula III), which has a different mechanism of action. This parameter change maintains therapeutic efficacy in slowing disease progression while reducing gastrointestinal side effects, as the PDE4B inhibition pathway does not primarily affect gastrointestinal function
Solution Approach 2:
The PDE4B inhibitor acts as an intermediary substance that modulates the inflammatory and fibrotic pathways through a different mechanism than current treatments. By inhibiting PDE4B specifically, the drug reduces inflammation and fibrosis progression without triggering the gastrointestinal adverse effects associated with nintedanib and pirfenidone
2Productivity
If current treatments are used to slow disease progression, then lung function decline is reduced, but the treatments are unable to stop or reverse disease progression
Solution Approach 1:
The patent changes the therapeutic parameter from merely slowing fibrosis progression to potentially stopping or reversing it, through the use of PDE4B inhibition. The preclinical data shows that formula III can reduce fibrotic changes and improve lung function parameters more effectively than current standard therapies, addressing the limitation of only slowing rather than stopping or reversing disease progression
3Reliability
If higher doses of PDE4 inhibitors are administered to improve therapeutic efficacy, then anti-fibrotic effect increases, but gastrointestinal side effects increase
Solution Approach 1:
The patent applies local quality by achieving selective PDE4B inhibition rather than broad PDE4 inhibition. The compound formula III is designed to target PDE4B specifically with high selectivity, which provides the desired anti-fibrotic effect while minimizing off-target effects on other PDE isoforms that could cause gastrointestinal side effects. This selective action allows for effective dosing without proportional increase in adverse events
Solution Approach 2:
The patent optimizes the dosage parameter of PDE4B inhibitor to achieve maximum therapeutic benefit with minimal side effects. Preclinical studies determined that doses of 18-36 mg twice daily provide optimal PDE4B inhibition for anti-fibrotic effect while maintaining an acceptable safety profile, avoiding the gastrointestinal side effects associated with higher doses or non-selective PDE4 inhibitors
Data Source
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AI summary
The invention concerns an oral pharmaceutical composition consisting essentially of • the PDE4B-inhibitor of formula (III) in the dose of 18 mg or 9 mg and • optionally of one or more pharmaceutically acceptable carriers or excipients for use in the treatment of a patient suffering from one or more progressive fibrosing interstitial lung diseases (PF-ILD), wherein this oral pharmaceutical composition is to be administered to the patient twice daily. The invention further concerns oral pharmaceutical compositions comprising the PDE4B-inhibitor of formula (III) in the dose of 18 mg or 9 mg and a therapeutically effective dose of a second active ingredient selected from nintedanib or pirfenidone, wherein these oral pharmaceutical compositions are administered to the patient twice daily.