Crystalline Monohydrate Dry Powder Formulation for Lung-Selective Delivery
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Solution Overview
Problem
Current treatments for pulmonary hypertension, particularly in cardiopulmonary disorders like PAH and PH group 3, suffer from limited efficacy, systemic side effects, and inconvenient administration routes, with existing inhalable formulations 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 being unsuitable for dry powder inhalers due to amorphous form instability and lack of lung-selective delivery.
Innovation Solution
Development of a pharmaceutical dry powder formulation combining the compound with lactose carrier, specifically in the stable monohydrate form II, to ensure high fraction release and adequate distribution during inhalation, optimizing lung delivery and minimizing systemic side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the compound is formulated as amorphous form for inhalation, then the formulation can be made, but the formulation is unstable and cannot be stored properly
Solution Approach 1:
The patent changes the physical state parameter of the compound from amorphous to crystalline monohydrate form. This phase transition provides stability while maintaining inhalation suitability, as the crystalline monohydrate form is specifically identified as stable and suitable for dry powder inhaler formulations.
Solution Approach 2:
The patent utilizes phase transition by establishing that the compound exists in different solid forms (amorphous, crystalline monohydrate, crystalline dihydrate) and selects the crystalline monohydrate form for the formulation. This phase selection ensures stability and storage compatibility while maintaining the compound's pharmacological activity.
2Reliability
If systemic administration is used for pulmonary hypertension treatment, then the treatment can be effective, but serious side effects occur
Solution Approach 1:
The patent applies local quality by designing a lung-selective inhalation formulation that delivers the compound specifically to the lungs via dry powder inhalation. This localized delivery mechanism maintains treatment efficacy in the target organ (lungs) while minimizing systemic absorption and associated side effects.
Solution Approach 2:
The patent utilizes pneumatic principles through dry powder inhalation technology, where the formulation is delivered to the lungs through pneumatic mechanisms (inhalation breath). This allows direct deposition of the active compound in the respiratory tract, achieving local treatment without systemic circulation.
3Reliability
If frequent inhalation dosing is required for 24h coverage, then adequate treatment coverage is achieved, but patient compliance deteriorates
Solution Approach 1:
The patent applies dynamics by optimizing the formulation and dosing regimen to achieve a balance between treatment coverage and patient convenience. The crystalline monohydrate form provides stable pharmacokinetics that support once-daily dosing, making the treatment regimen adaptable to patient needs while maintaining 24-hour coverage.
Solution Approach 2:
The patent ensures continuity of useful action by formulating the compound in a stable crystalline monohydrate form that provides sustained release and prolonged action. This allows once-daily dosing while maintaining continuous treatment coverage throughout the 24-hour period, improving patient compliance.
Data Source
AI summary
The present invention relates to pharmaceutical dry powder formulations, comprising (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), preferably in form of one of its salts or solvates or hydrates, preferably (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 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 monohydrate (II) of formula (I-M-II) in combination with a lactose carrier, comprising lactose monohydrate as a mixture of coarse lactose and fine lactose, and to the process of manufacturing such pharmaceutical dry powder formulations and its application for use in the treatment of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (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).