Inhalable sGC Activator Monohydrate for Pulmonary Hypertension
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Solution Overview
Problem
Current treatments for pulmonary hypertension, particularly those related to cardiopulmonary disorders, face limitations such as short duration of action, systemic side effects, and unselective vasodilation, which can lead to desaturation and reduced efficacy, especially in patients with chronic lung diseases.
Innovation Solution
The use of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in a stable, crystalline form, specifically as a monohydrate, for inhalation, which acts as a selective activator of soluble guanylate cyclase, providing prolonged bronchodilatory effects and reduced pulmonary vascular resistance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for pulmonary hypertension are used, then vasodilation effect is achieved, but systemic side effects occur and desaturation is reduced
Solution Approach 1:
The patent applies local quality by developing an inhalable sGC activator that selectively targets the pulmonary vasculature. The drug is delivered directly to the lungs via inhalation, creating a high local concentration at the target site while maintaining low systemic exposure. This selective pulmonary action provides effective vasodilation in the pulmonary circulation without causing the systemic side effects associated with oral medications.
2Reliability
If current treatments are administered, then pulmonary hypertension is treated, but duration of action is short requiring frequent dosing
Solution Approach 1:
The patent implements continuity of useful action by formulating the sGC activator as an inhalable composition that provides sustained pulmonary vasodilation. The inhalable formulation allows for continuous drug delivery to the pulmonary circulation, maintaining therapeutic effects over an extended period. This reduces the frequency of dosing compared to short-acting treatments while maintaining reliable treatment efficacy.
3Reliability
If unselective vasodilators are used, then pulmonary hypertension is treated, but desaturation occurs reducing efficacy
Solution Approach 1:
The patent applies local quality by using an inhalable sGC activator that selectively dilates pulmonary vessels without causing systemic vasodilation. The drug is deposited directly in the lungs where it acts on pulmonary arterial smooth muscle, producing localized vasodilation that improves pulmonary blood flow and oxygenation without the desaturation effects seen with unselective systemic vasodilators.
4Reliability
If inhalable formulation is used, then lung selectivity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent uses an intermediary approach by incorporating the sGC activator into an inhalable composition with suitable excipients and carriers. This formulation intermediary enables the drug to be delivered via inhalation, achieving high lung selectivity. The composition includes components that facilitate aerosolization and pulmonary deposition while maintaining drug stability, thereby managing the manufacturing complexity through a well-defined formulation 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
This approach offers a more effective and safer treatment option with prolonged duration of action, improved lung selectivity, and reduced systemic side effects, enhancing patient compliance and treatment efficacy for pulmonary hypertension, including forms associated with chronic lung diseases.
Implementation Method 1
acts as a selective activator of soluble guanylate cyclase, providing prolonged bronchodilatory effects and reduced pulmonary vascular resistance
Data Source
AI summary
The present invention relates to the use of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I), prefer-ably in form of one of its salts or solvates or hydrates, preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(triflu-oromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in form of monohydrate (I) of formula (I-M-I) or (5S)-{[2-(4-carboxyphenyl)ethyl] [2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid inform of mono hydrate (II) of formula (I-M-II), in the inhalative treatment of car-diopulmonary and pulmonary disorders, such as pulmonary arterial hypertension (P AH), chronic tromboembolic pulmonary hyperten-sion (CTEPH) and pulmonary hypertension (PH) associated with chronic lung disease (PH group 3) such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), char-acterized in that an inhalative dosage form comprising 240 to 4000 μg, preferably 480 to 2000 μg of (5 S)-{[2-(4-carboxyphenyl)ethyl] [2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6, 7,8-tetrahydroquinoline-2-carboxy lie acid of for-mula (I), preferably in form of one of its salts or solvates or hydrates, preferably in form of monohydrate I of formula (I-M-I) or (5 S)-{[2-(4-carboxyphenyl)ethyl] [2-(2-{[3-chloro-4′ (trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6, 7,8-tetrahydroquinoline-2-carboxy lie acid in form of mono hydrate (II) of formula (I-M-II), is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days, preferably at least 2 to 7 consecutive days, preferably for a period of at least 14 consecutive days, in particular from after onset of treatment for the whole course of the disease, wherein the inhalative dosage form preferably comprises the combination of the active ingredient and a pharmaceutically suitable excipient or carrier, while preferably the active ingredient and a pharmaceutically suitable excipient are filled in a hard capsule.