Treatment of cardiopulmonary disorders
Inventors
BECKER-PELSTER, Eva Maria • Tinel, Hanna • Hahn, Michael • Lang, Dieter • Weimann, Gerrit • NAGELSCHMITZ, Johannes • Dietz, Lisa • SALEH, Soundos • Jung, David • Terebesi, Ildiko • MUNDRY, Tobias • RICHTER, Annett • Olenik, Britta • Keil, Birgit • Rösler, Bernd • Fey, Peter • Schirmer, Heiko • Becker, Guido • Bothe, Clemens • FABER, Helene • EGGER, Julian • Parry, Mark • Ward, David • VITRE, Cecile
Assignees
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Publication Number
US-12138256-B2
Publication Date
2024-11-12
Expiration Date
Abstract
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′-(trifluoromethyl)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 cardiopulmonary and pulmonary disorders, such as pulmonary arterial hypertension (P AH), chronic tromboembolic 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), characterized in that an inhalative dosage form comprising 240 to 4000 μg, preferably 480 to 2000 μg 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-carboxy lie acid of formula (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 (5S)-{[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.
Core Innovation
The invention relates to treating a cardiopulmonary disorder by administering a crystalline monohydrate compound 1. The crystalline monohydrate compound 1 is characterized by an X-ray powder diffraction reflection pattern measured at 25°C using monochromatic CuKα11 radiation, and the reflection pattern expressed as ±0.2° 2θ has at least one characteristic reflection selected from 6.9±0.2° 2θ, 7.2±0.2° 2θ, 7.3±0.2° 2θ, 12.8±0.2° 2θ, 15.2±0.2° 2θ, 16.0±0.2° 2θ, 23.0±0.2° 2θ, 25.8±0.2° 2θ, and 29.2±0.2° 2θ. The administration amount is about 240 μg to about 4000 μg.
The disclosed treatment framework includes administration by inhalation and administration twice daily for at least seven consecutive days. The cardiopulmonary disorder is narrowed to pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with chronic lung disease, designated as PH group 3. The disclosure also describes crystalline monohydrate compound 1, including monohydrate I and monohydrate II, defined and distinguished by X-ray powder diffraction and Raman spectra.
A key aspect of the invention is formulating the crystalline monohydrate compound as an inhalable dry powder using lactose. The lactose carrier includes coarse and fine lactose fractions, and the formulation defines particle-size distributions for the active and the coarse/fine lactose fractions, including X90 and X50 particle-size targets and defined component ratios. The formulation is described as stable to micronization and designed to provide aerosol performance metrics such as fine particle dose and fine particle fraction versus nominal dose.
Claims Coverage
The independent claim set centers on a method of treating a cardiopulmonary disorder by administering a crystalline monohydrate compound 1 defined by X-ray powder diffraction reflection criteria under specified measurement conditions, with a defined administration amount. Additional inventive features narrow the administration route, dosing frequency, treatment duration, disorder subtype, and reflection-angle combinations.
Crystalline monohydrate compound 1 defined by X-ray powder diffraction reflections
Treating a cardiopulmonary disorder using a crystalline monohydrate compound 1 in which, under specified CuKα11 monochromatic X-ray powder diffraction measurement conditions at 25°C, the X-ray powder diffraction reflection pattern expressed as ±0.2° 2θ has at least one of the listed characteristic reflections at 6.9, 7.2, 7.3, 12.8, 15.2, 16.0, 23.0, 25.8 and 29.2.
Dose amount for treating cardiopulmonary disorders
Administering about 240 μg to about 4000 μg of the crystalline monohydrate compound 1 to a subject for treating a cardiopulmonary disorder.
Inhalation administration of the defined crystalline monohydrate compound 1
Administering the crystalline monohydrate compound 1 by inhalation.
Specific dosing frequency and duration
Administering the crystalline monohydrate compound 1 twice daily for at least seven consecutive days.
Refined cardiopulmonary disorder selection
Treating a cardiopulmonary disorder selected from pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH) associated with chronic lung disease (PH group 3).
Additional X-ray powder diffraction reflection constraints
Defining the crystalline monohydrate form using additional or alternative characteristic X-ray powder diffraction reflection angles, including specific reflections at 12.8±0.2° 2θ and 29.2±0.2° 2θ.
The coverage centers on administering a crystalline monohydrate compound 1 whose identity is constrained by defined X-ray powder diffraction characteristic reflection 2θ values under specified measurement conditions, together with a defined administration dose range. Further claim coverage specifies inhalation administration, regimen constraints, narrows the target disorder to specified pulmonary hypertension subtypes, and further tightens the allowable diffraction reflection sets.
Stated Advantages
The crystalline monohydrate form is described as chemically stable.
The crystalline monohydrate is described as stable to micronization.
The formulation is designed for excellent aerosol performance, including fine particle dose, fine particle fraction, and delivered dose versus nominal dose.
Lung-selective reduction of pulmonary arterial pressure with minimal or no systemic blood pressure effects is supported by described comparative pharmacology.
Delayed onset and a duration of action of ≤4 h are described for inhaled dry powder and crystalline hydrate formulations in minipigs.
Attenuation of hypoxia-induced mPAP for approximately 16–17 h after inhalation is described in conscious hypoxia-challenged dogs.
Selectivity is supported by a unilateral ventilation/broncho-occlusion proxy for VQ mismatch with SaO2 desaturation.
Stable crystalline solid form suitable for dry powder inhalation.
Supports micronization and storage stability for inhalation.
Avoids systemic vasodilator side effects.
Lung-selective soluble guanylate cyclase activator approach aimed at cGMP signaling.
Reports minimal systemic blood pressure effects.
Reports prolonged reduction of PAP compared with comparators.
Documented Applications
Treating cardiopulmonary disorders including pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension associated with chronic lung disease (PH group 3), including COPD-PH and PH-IIP.
Administration as an inhalable dry powder, including administration by inhalation and capsule-based inhaler concepts.
In vivo and translational pharmacology evaluation of an inhaled sGC activator-type approach for pulmonary hypertension measures in PAH minipig models, including oxidative-stress/low-NO conditions and longer duration of action.
Comparison of inhaled efficacy versus standard-of-care drugs including bosentan, sildenafil, and riociguat, and evaluation of possible combination regimens.
Evaluation of dry powder formulations and crystalline hydrate forms, including sesquihydrate, monohydrate II, and semihydrate forms, in minipigs with dose-dependent, lung-selective PAP reduction.
Conscious hypoxia-challenged dog evaluation showing attenuation of hypoxia-induced mPAP after inhalation.
Selectivity evaluation using unilateral ventilation/broncho-occlusion proxy for VQ mismatch with SaO2 desaturation.
Bronchorelaxation study initiation in guinea pig/trachea rings and rat models.
Prophylactic allergen-induced asthma readouts in mice.
Early clinical pharmacology in healthy male subjects and phase I/1b patient studies using PVR/mPAP endpoints and cGMP target engagement.
Inhalative treatment of cardiopulmonary disorders, notably pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension in group 3 including PH-COPD and PH-IIP.
Dry powder inhalation capsules containing crystalline monohydrate forms of Compound 1.
Preclinical inhalation findings in PAH models.
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