WO2022074567A1

WO2022074567A1 - Pharmaceutical compositions comprising naphthyridinone derivatives and their use in the treatment of arrhythmia

Info

Publication number: WO2022074567A1
Application number: PCT/IB2021/059137
Authority: WO
Inventors: Eric Aubin; Narayan Babulal GAIKWAD; Carol GOALARD; Mohan RATHI; Bernd Ulrich Riebesehl; Harshalkumar TRIVEDI; Silvia TRUSCELLO
Original assignee: Novartis Ag
Priority date: 2020-10-06
Filing date: 2021-10-05
Publication date: 2022-04-14

Abstract

The disclosure provides pharmaceutical formulations comprising a GIRK1/4 channel blocker. The disclosure further provides methods of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor comprising administering to the subject in need of such treatment the pharmaceutical formulation comprising an effective amount of a GIRK1/4 channel blocker.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING NAPHTHYRIDINONE DERIVATIVES AND THEIR USE IN THE TREATMENT OF ARRHYTHMIA

PRIORITY

This application claims priority from Indian Patent Application No. 202011043519 filed October 6, 2020, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to pharmaceutical formulations comprising naphthyridinone derivatives of Formula I and methods for use thereof for inhibiting GIRK 1/4 channel and methods of treating diseases using same.

BACKGROUND

While most cardiac potassium channels contribute to repolarization in both atrial and ventricular tissues in humans, two - K_v1.5 and GIRK1/4 (i.e. G-protein regulated inwardly rectifying potassium channel 1/4) - are thought to be expressed solely in atria (Gaborit et al., 2007. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. The Journal of physiology 582, 675-693). This atrial-specific pattern of expression makes these particularly attractive targets for novel anti-arrhythmic therapies for AF, as they should not have the adverse ventricular effects of existing Class III drugs such as dofetilide.

Several lines of evidence point toward GIRK1/4 as a desirable anti-arrhythmia target for AF. In animals, vagal nerve stimulation promotes acetylcholine release from vagal afferents and an increase in KACII . This in turn shortens atrial (but not ventricular) action potential duration and effective refractory period and can induce AF via a re-entry mechanism (Hashimoto et al., 2006. Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation. Pharmacological research: the official journal of the Italian Pharmacological Society 54, 136-141). In atrial tissues from humans with persistent AF as well as from animals subjected to atrial rapid pacing (an accepted model for promoting electrical remodeling and susceptibility to AF), /KACH has been shown to be dysregulated. Specifically, the channel tends to be constitutively open, even in the absence of acetylcholine (Cha et al., 2006. Kir3 -based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 113, 1730-1737; Voigt et al., 2014. Constitutive activity of the acetylcholine-activated potassium current IK, A Ch in cardiomyocytes. Advances in pharmacology (San Diego, Calif) 70, 393-409). In these studies, it is observed in patients and animals that atrial APD/ERP is short. Naphthyridinone GIRK1/4 inhibitors have been disclosed in WO2018/073788.

Naphthyridinone GIRK1/4 inhibitors have limited aqueous solubility and limited stability in aqueous solutions for long term storage. Thus, the development of non-aqueous pharmaceutical formulations comprising GIRK1/4 blockers would be beneficial in the treatment of cardiac arrhythmias such as atrial fibrillation.

SUMMARY

The disclosure provides pharmaceutical formulations comprising a GIRK1/4 channel blocker. Provided herein are pharmaceutical formulations comprising (S)-8- chloro-l-(2,6-dichlorophenyl)-5-(2,3-dihydroxypropoxy)-2-(hydroxymethyl)-l,6- naphthyridin-4(lH)-one (Formula I):

The disclosure further provides methods of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor, in a subject in need thereof, comprising administering to the subject in need of such treatment the pharmaceutical formulation comprising an effective amount of a GIRK1/4 channel blocker. The disclosure further provides methods of treating or preventing cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension and/or sick sinus syndrome, in a subject in need thereof, comprising administering to a subject in need of such treatment the pharmaceutical formulation comprising an effective amount of a GIRK1/4 channel blocker.

In one aspect, provided herein is a pharmaceutical formulation comprising: a) a therapeutically effective amount of a compound of Formula (I),

b) propylene glycol; and c) ethanol.

In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 0.005% w/w to about 15% w/w of a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol.

In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 0.1 mg to about 500 mg of a compound of Formula (I),

In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 70 mg to about 90 mg of a compound of Formula (I),

b) about 75% w/w to about 80% w/w of propylene glycol; and c) about 15% w/w to about 25% w/w of ethanol.

In another aspect, provided herein is a method of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor, in a subject in need thereof, comprising administering to the subject in need of such treatment a pharmaceutical formulation comprising: a) a therapeutically effective amount of a compound of Formula (I)

In another aspect, provided herein is a pharmaceutical formulation comprising: a) a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol, for use in the treatment or prevention of a disease or disorder responsive to the inhibition of the GIRK receptor.

In another aspect, provided herein is a use of a pharmaceutical formulation comprising: a) a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol, for the manufacture of a medicament for treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor.

In a another aspect, provided herein is a method of making the pharmaceutical formulation comprising: a) mixing a therapeutically effective amount of a compound of Formula (I),

about 70% w/w to about 85% w/w of propylene glycol; and about 15% w/w to about 30% w/w of ethanol until a clear solution is obtained; and b) optionally filtering the mixture from step a).

BRIEF SUMMARY OF THE FIGURES FIG. 1. shows stability results based on chemical data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 2.

FIG. 2. shows stability results based on physical data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 3.

FIG. 3. shows stability results based on microbiological data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 4.

FIG. 4. shows stability results based on photostabilty and chemical data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 5.

FIG. 5. shows stability results based on photostabilty and physical data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 6.

FIG. 6. shows stability results based on freeze and thaw cycle test chemical data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 7.

FIG. 7. shows stability results based on freeze and thaw cycle test physical data of the compound of Formula (I) in the 80 mg/2 mL concentrate as summarized in Table 8.

DETAILED DESCRIPTION

The disclosure provides pharmaceutical formulations comprising GIRK1/4 channel blockers. In some embodiments, the compound of Formula (I) is an anhydrous free base. In some embodiments, the pharmaceutical formulations are suitable for injection.

The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. Various embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

Definitions

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. For purposes of interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.

It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “the pharmaceutical formulation” includes reference to one or more pharmaceutical formulations; and so forth.

The terms “comprise” or “comprises” or “comprising” and “including” are used herein in their open-ended and non-limiting sense unless otherwise noted and should be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The phrase “the compound of Formula (I)” refers to (S)-8-chloro-l-(2,6- dichlorophenyl)-5-(2,3-dihydroxypropoxy)-2-(hydroxymethyl)-l,6-naphthyridin-4(lH)- one having the following structure:

and its stereoisomers or mixture of stereoisomers, tautomers, polymorphs, co-crystals, or solvates thereof.

“Stereoisomer” or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure, which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.

If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures of desired enantiomeric excess (ee) or enantiomeric purity. Individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well- known in the art.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present disclosure can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, at least 97% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (.S')- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

“Enantiomers” means a pair of stereoisomers that are non-superimposable mirror images of each other.

“Diastereoisomers” or “diastereomers” mean optical isomers, which are not mirror images of each other.

“Racemic mixture” or “racemate” mean a mixture containing equal parts of individual enantiomers.

“Non-racemic mixture” means a mixture containing unequal parts of individual enantiomers.

Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.

“Solvate” means a complex of variable stoichiometry formed by a solute, for example, the compound of Formula (I) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solutionphase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

“Hydrate” means a solvate wherein the solvent molecule(s) is/are water.

As used herein, the term “pharmaceutical formulation” or “pharmaceutical composition” refers to a composition comprising one or more pharmaceutically active ingredients. In particular, a pharmaceutical formulation comprises a compound of Formula (I), together with at least one pharmaceutically acceptable carrier.

As used herein, the term “pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, adjuvants, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22^nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

The term “a therapeutically effective amount” of a compound of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by GIRK1/4 channel, or (ii) associated with GIRK1/4 channel activity, or (iii) characterized by activity (normal or abnormal) of GIRK1/4 channel; or (2) reduce or inhibit the activity of GIRK1/4 channel; or (3) reduce or inhibit the expression of GIRK1/4 channel. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present disclosure that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of GIRK1/4 channel; or at least partially reducing or inhibiting the expression of GIRK1/4 channel.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human. As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term “treat”, “treating" or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

“Administer”, “administering”, or “administration” means administering a pharmaceutical formulation comprising a disclosed compound to a subject.

Pharmaceutical Formulations

In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. Preferably, pharmaceutically acceptable carriers are sterile.

In addition, the pharmaceutical formulations of the present disclosure can be made up in a liquid form (including without limitation solutions, suspensions or emulsions). In some embodiments, the pharmaceutically acceptable carriers are solvents. In some embodiments, the pharmaceutically acceptable carriers are organic solvents or a mixture of organic solvents. In some embodiments, the formulation comprises propylene glycol. In some embodiments, the formulation comprises ethanol. In some embodiments, the formulation comprises a mixture of propylene glycol and ethanol.

In one aspect, the disclosure provides a pharmaceutical formulation comprising: a) a therapeutically effective amount of a compound of Formula (I),

b) propylene glycol; and c) ethanol.

In some embodiments, the pharmaceutical formulation comprises about 10% w/w to about 90% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 60% w/w to about 90% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 60% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 70% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 75% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 76% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 77% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 78% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 79% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 80% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 85% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 90% w/w of propylene glycol.

In some embodiments, the pharmaceutical formulation comprises about 5% w/w to about 95% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 5% w/w to about 40% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 5% w/w, about 7.5% w/w, about 9% w/w, 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, about 10% w/w, about 12.5% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 25% w/w, about 30% w/w, or about 40% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 10% w/w to about 40% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 15% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 16% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 17% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 18% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 19% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 20% w/w of ethanol.

In some embodiments, the pharmaceutical formulation comprises about 60% w/w to about 90% w/w of propylene glycol and about 10% w/w to about 40% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 70% w/w to about 85% w/w of propylene glycol and about 15% w/w to about 30% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 75% w/w to about 80% w/w of propylene glycol and about 15% w/w to about 25% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 75% w/w of propylene glycol and about 21% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 77% w/w of propylene glycol and about 19% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 80% w/w of propylene glycol and about 16% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 80% w/w of propylene glycol and about 20% w/w of ethanol.

In some embodiments of the pharmaceutical formulations disclosed herein, the compound of Formula (I) is at a concentration of about 0.005% w/w to about 15% w/w. In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 0.005% w/w to about 15% w/w of a compound of Formula (I)

Unless otherwise specified, the weight or dosage referred to herein for a particular compound (e.g., the compound of Formula (I)) of the disclosure is the weight or dosage of the compound itself, not that of a solvate thereof, which can be different to achieve the intended therapeutic effect. For example, the weight of a corresponding solvate of a compound suitable for the methods, compositions, or combinations disclosed herein may be calculated based on the ratio of the molecular weights of the solvate and compound itself.

In some embodiments of the pharmaceutical formulations disclosed herein, including the pharmaceutical formulation comprising: a) a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol, the compound of Formula (I) is at a concentration of about 0.005% w/w to about 10% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.005% w/w, about 0.01% w/w, about 0.015% w/w, about 0.02% w/w, about 0.025% w/w, about 0.03% w/w, about 0.035% w/w, about 0.04% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 1.0% w/w, about 1.5% w/w, about 2.0% w/w, about 2.5% w/w, about 3.0% w/w, about 3.5% w/w, about 4.0% w/w, about 4.5% w/w, about 5.0% w/w, about 6.0% w/w, about 7.0% w/w, about 8.0% w/w, about 9.0% w/w, or about 10.0% w/w of the formulation.

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol, the compound of Formula (I) is at a concentration of 0.005% w/w to about 5.0% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.005% w/w, about 0.01% w/w, about 0.015% w/w, about 0.02% w/w, about 0.025% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 1.0% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2.0% w/w, 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3.0% w/w, 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4.0% w/w, 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5.0% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of 0.005% w/w to about 2.25% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 2.0% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 4.0% w/w of the formulation.

In some embodiments of the pharmaceutical formulations disclosed herein, including the pharmaceutical formulation comprising: a) a compound of Formula (I),

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol, the amount of the compound of Formula (I) is about 0.1 mg to about 450 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, about 10.0 mg, about 10.5 mg, about 11.0 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 62 mg, about 64 mg, about 65 mg, about 66 mg, about 68 mg, about 70 mg, about 72 mg, about 74 mg, about 75 mg, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84 mg, about 85 mg, about 86 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 60 mg to about 100 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 75 mg to about 100 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 75 mg, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84 mg, about 85 mg, about 86 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, and about 100 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 0.5 mg to about 200 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 0.5 mg, about 1.0 mg, about 3.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. In some embodiments, the amount of the compound of Formula (I) is about 1.0 mg, about 3.0 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 110 mg, or about 150 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 1.0 mg. In some embodiments, the amount of the compound of Formula (I) is about 3.0 mg. In some embodiments, the amount of the compound of Formula (I) is about 10 mg. In some embodiments, the amount of the compound of Formula (I) is about 20 mg. In some embodiments, the amount of the compound of Formula (I) is about 30 mg. In some embodiments, the amount of the compound of Formula (I) is about 50 mg. In some embodiments, the amount of the compound of Formula (I) is about 60 mg. In some embodiments, the amount of the compound of Formula (I) is about 75 mg. In some embodiments, the amount of the compound of Formula (I) is about 85 mg. In some embodiments, the amount of the compound of Formula (I) is about 100 mg. In some embodiments, the amount of the compound of

Formula (I) is about 110 mg. In some embodiments, the amount of the compound of

Formula (I) is about 150 mg. In some embodiments, the amount of the compound of

Formula (I) is about 200 mg.

In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 0.5 mg to about 200 mg of a compound of Formula (I),

wherein the compound is at about 0.005% w/w to about 15% w/w of the formulation, b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol. In another aspect, provided herein is a pharmaceutical formulation comprising: a) about 0.5 mg to about 200 mg of a compound of Formula (I),

wherein the compound is at about 0.005% w/w to about 15% w/w of the formulation, b) about 75% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 25% w/w of ethanol.

In some embodiments of the pharmaceutical formulations disclosed herein, the propylene glycol and ethanol comprise < 10% w/w, < 5% w/w, < 2% w/w, < 1% w/w, < 0.5% w/w, < 0.1% w/w, or < 0.01% w/w of water. In some embodiments, the propylene glycol and ethanol comprise about 0.01% w/w to about 10% w/w of water. In some embodiments, the propylene glycol and ethanol comprises about 5% w/w, about 4% w/w, about 3% w/w, about 2% w/w, about 1% w/w, about 0.9% w/w, about 0.8% w/w, about 0.7% w/w, about 0.6% w/w, about 0.5% w/w, about 0.4% w/w, about 0.3% w/w, about 0.2% w/w, about 0.1% w/w, about 0.09% w/w, about 0.08% w/w, about 0.07% w/w, about 0.06% w/w, about 0.05% w/w, about 0.014 w/w, about 0.03% w/w, about 0.02% w/w, or about 0.01% w/w of water.

In some embodiments of the pharmaceutical formulations disclosed herein, the ethanol is anhydrous ethanol.

In some embodiments, provided herein is a pharmaceutical formulation A comprising: a) about 75 mg to about 100 mg of a compound of Formula (I),

In some embodiments, provided herein is a pharmaceutical formulation B comprising: a) about 80 mg of a compound of Formula (I),

b) about 77% w/w of propylene glycol; and c) about 19% w/w of ethanol.

In some embodiments, provided herein is a pharmaceutical formulation C comprising: a) about 96 mg of a compound of Formula (I),

b) about 77% w/w of propylene glycol; and c) about 19% w/w of ethanol.

In some embodiments of the pharmaceutical formulations, including the pharmaceutical formulations A, B, and C above, the volume of the formulation comprising the compound of Formula (I), propylene glycol, and ethanol is from about 0.1 mb to about 20 mL. In some embodiments, the volume of the formulation is about 0.1 mb, about 0.2 mb, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.5 mL, about 6 mL, about 7 mL, about 7.5 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL. In some embodiments, the volume of the formulation is from about 0.1 mL to about 10 mL. In some embodiments, the volume of the formulation is from about 1 mL to about 5 mL. In some embodiments, the volume of the formulation is about 2.4 mL. In some embodiments, the volume of the formulation is about 2.0 mL. As shown in the examples, the removal of water from the formulation improved the chemical stability of the compound of Formula (I) in solution. Accordingly, in some embodiments, the pharmaceutical formulations of the disclosure are anhydrous. Without being bound by any theory, water may facilitate the degradation of an active ingredient such as the compound of Formula (I).

Anhydrous pharmaceutical formulations and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients (e.g., anhydrous ethanol) and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

In some embodiments, the pharmaceutical formulations comprising the compound of Formula (I) are stable after long-term storage at 5 °C. Comparatively, the shelflife prediction for the same pharmaceutical formulations comprising the compound of Formula (I) supplemented with an equivalent amount of water is below 1 year. In some embodiments of the pharmaceutical formulations disclosed herein, the amount of the compound of Formula (I) in the formulation is at least 90% of the initial (at time zero) amount after about 6 months, after about 8 months, about 10 months, about 12 months, about 15 months, about 18 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, and about 60 months of storage at 5 °C. In some embodiments of the pharmaceutical formulations disclosed herein, the amount of the compound of Formula (I) in the formulation is at least 90% of the initial amount after about 6 months, after about 8 months, about 10 months, about 12 months, about 15 months, about 18 months, and about 24 months of storage at 5 °C.

The maximum solubility of the compound of Formula (I) in water is about 0.47 mg/mL. The maximum solubility of the compound of Formula (I) in aqueous 0.9% w/v sodium chloride solution is about 0.44 mg/mL. The maximum solubility of the compound of Formula (I) in propylene glycol is about 103 mg/mL. The maximum solubility of the compound of Formula (I) in ethanol is about 114 mg/mL. In some embodiments, the maximum solubility of the compound of Formula (I) in the pharmaceutical formulations disclosed herein is greater than about 100 mg/mL. In some embodiments, the maximum solubility of the compound of Formula (I) in a solution comprising about 70% w/w to about 85% w/w of propylene glycol and about 15% w/w to about 30% w/w of ethanol is about 104 mg/mL. In some embodiments, the maximum solubility of the compound of Formula (I) in a mixture of about 80% w/w propylene glycol and about 20% w/w ethanol is about 104 mg/mL. The use of propylene glycol and ethanol as solvents enables solubilizing the compound of Formula (I) at much higher concentrations than in aqueous based formulations. This results in small volumes of injection and total amounts of excipients remaining below the established permitted daily exposure.

Lyophilization is needed to remove water and avoid degradation in conventional formulations. An aqueous pharmaceutical formulation comprising the compound of Formula (I) was lyophilized. However, there was evidence of visible particles postreconstitution of the compound of Formula (I) from a lyophilized formulation using water for injection as a reconstitution vehicle.

Some of the advantages of the pharmaceutical formulations disclosed herein include low viscosity to enable an easy manufacturing process and clinical handling (e.g., reduced risk of inaccurate vial filling, short fdtration steps duration, easy compounding and homogenization, and good syringeability). Manufacturing of this liquid pharmaceutical formulations disclosed herein is much easier and cheaper than any lyophilisate formulation. In some embodiments, the pharmaceutical formulations disclosed herein are easy to manufacture.

In some embodiments of the pharmaceutical formulations disclosed herein, precipitation of the compound of Formula (I) is not observed. In some embodiments, the compound of Formula (I) does not precipitate from the solution comprising propylene glycol and ethanol. In some embodiments, the compound of Formula (I) does not precipitate from the solution comprising about 70% w/v to about 85% w/v of propylene glycol and about 15% w/v to about 30% w/v of ethanol.

Methods of Treatment

The compound of Formula (I) has GIRK1/4 channel modulating properties. The disclosure further provides methods of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor. In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor, in a subject in need thereof, comprising administering to the subject in need of such treatment a pharmaceutical formulation disclosed herein.

In some embodiments, the disclosure provides a pharmaceutical formulation disclosed herein for use as a medicament.

In some embodiments, the disclosure provides a pharmaceutical formulation disclosed herein for use in the treatment or prevention of a disease or disorder responsive to the inhibition of GIRK receptor.

In some embodiments, the disclosure provides for use of a pharmaceutical formulation disclosed herein for the manufacture of a medicament for treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor.

In some embodiments, provided herein is a method of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor, in a subject in need thereof, comprising administering to the subject in need of such treatment a pharmaceutical formulation comprising: a) about 0.005% w/w to about 15% w/w of a compound of Formula (I)

In some embodiments, provided herein is a method of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor, in a subject in need thereof, comprising administering to the subject in need of such treatment a pharmaceutical formulation comprising: a) about 0.1 mg to about 500 mg of a compound of Formula (I)

In another aspect, the disclosure provides a pharmaceutical formulation comprising: a) a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol for use as a medicament. In another aspect, the disclosure provides a pharmaceutical formulation comprising: a) a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol for use in the treatment or prevention of a disease or disorder responsive to the inhibition of GIRK receptor.

In another aspect, the disclosure provides for use of a pharmaceutical formulation comprising: a) a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; and c) about 15% w/w to about 30% w/w of ethanol for the manufacture of a medicament for treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor.

GIRK1/4 has been identified as a desirable anti -arrhythmia target for atrial fibrillation. Additionally, GIRK 1/4 blockers have been described as potentially useful in Sinoatrial/atrioventricular node dysfunction. GIRK1/4 channels mediate repolarization of the spontaneously depolarizing cells of the sinoatrial (SAN) and atrioventricular (AVN) nodes. Acetylcholine released from vagal nerve efferents binds to M2 muscarinic receptors present in these tissues, which in turn act upon GIRK1/4 channels to open them and permit potassium ion efflux from the cell. This repolarization (or hyperpolarization depending on the magnitude of efflux) determines the timing between spontaneous depolarizations, and hence heart rate and AV nodal conduction rate. Blockade of GIRK 1/4 channels is expected to oppose the negative chronotropic effects of acetylcholine, and this has been observed with the selective peptide GIRK1/4 blocker tertiapin (Drici et al., 2000. The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks. British Journal of Pharmacology 131, 569-577). In human diseases of pacemaking (e.g. sick sinus syndrome), the sinoatrial or atrioventricular nodes are dysfunctional, which can induce a variety of arrhythmias including bradycardia and asystoles. GIRK 1/4 blockade may be expected to ameliorate such arrhythmias. For example, in a recent study, genetic deletion of GIRK4 was shown to rescue the failure of cardiac impulse generation and conduction induced by heart-specific silencing of the so-called “funny current”, which mediates spontaneous depolarization in sinoatrial and atrioventricular tissue (Mesirca et al., 2014. Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nature Communications 5, 4664).

Furthermore, GIRK1/4 blockers have been described as potentially useful in primary hyperaldosteronism: Somatic and germline gain-of-fimction mutations in KCNJ5 (encoding GIRK4) have recently been implicated in primary aldosteronism, a condition that induces hypertension. These mutations alter the selectivity filter of the GIRK4 channel and permit sodium ion influx into certain adrenal cells. The resulting cellular depolarization permits calcium influx, which in turn enhances aldosterone production and secretion, and may also induce cellular proliferation to produce an aldosterone-secreting adenoma (Scholl and Litton, 2013. New insights into aldosterone-producing adenomas and hereditary aldosteronism: mutations in the K+ channel KCNJ5. Current opinion in nephrology and hypertension 22, 141-147). It is therefore possible that a selective GIRK4 blocker may prevent sodium ion influx, and its attendent promotion of aldosterone secretion in these patients.

In some embodiments of the methods and the uses disclosed herein, the disease or disorder responsive to the inhibition of the GIRK receptor is selected from the group consisting of cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension and sick sinus syndrome. In some embodiments of the methods and the uses disclosed herein, the disease or disorder responsive to the inhibition of the GIRK receptor is cardiac arrhythmia or atrial fibrillation. In some embodiments of the methods and the uses disclosed herein, the disease or disorder responsive to the inhibition of the GIRK receptor is atrial fibrillation.

In some embodiments of the methods and the uses disclosed herein, the compound of Formula (I) modulates heart rate and heart rate variability. In some embodiments, the compound of Formula (I) causes cardioversion. Without being bound by any theory, in some embodiments, the compound of Formula (I) may cause acute cardioversion of atrial fibrillation to sinus rhythm. Without being bound by any theory, in some embodiments, the compound of Formula (I) may cause prolongation of the atrial effective refractory period of atrial myocytes.

In some embodiments of the methods and the uses disclosed herein, the subject avoids the risks and discomfort of sedation and electrical shocks related to direct current cardioversion. The current methods of treatment can cause adverse ventricular effects, including but not limited to inducing ventricular arrhythmias and QTc prolongation.

The pharmaceutical formulations can be formulated for particular routes of administration such as oral administration, parenteral administration, intravenous administration, and rectal administration, etc. In some embodiments, the pharmaceutical formulations disclosed herein are formulated for parenteral administration. In some embodiments, the pharmaceutical formulations disclosed herein are formulated for injection. In some embodiments, the pharmaceutical formulations disclosed herein are formulated for intravenous administration. In some embodiments, the pharmaceutical formulations disclosed herein are formulations for intravenous injection.

In some embodiments of the methods and the uses disclosed herein, the pharmaceutical formulations disclosed herein are administered parenterally. In some embodiments, the pharmaceutical formulations disclosed herein are administered intravenously. In some embodiments, the pharmaceutical formulation is a concentrate solution for injection via intravenous infusion.

In some embodiments of the methods and the uses disclosed herein, the pharmaceutical formulations are diluted prior to administering the formulation to the subject in need thereof. In some embodiments, an aqueous solution is added to the formulation before intravenous administration. In some embodiments, an aqueous isotonic solution is added to the formulation before intravenous administration. In some embodiments, the aqueous isotonic solution is saline solution, glucose solution, Ringer’s solution, or Ringer’s lactate solution. In some embodiments, the aqueous isotonic solution is a 0.9% w/v sodium chloride solution, a 5% w/v glucose solution, Ringer’s solution, or Ringer’s lactate solution. In some embodiments, an aqueous solution comprising 0.9% w/v sodium chloride is added to the formulation before intravenous administration. An aqueous 0.9% w/v sodium chloride solution is also referred to as saline solution.

In some embodiments, the compound of Formula (I) does not precipitate at the contact interface with an aqueous isotonic solutions (e.g., saline) or plasma. In some embodiments, the pharmaceutical formulations become hazy upon dilution. Without being bound by any theory, the observed haziness is related to a liquid phase separation but no solid particle is formed, thereby preventing any safety risk for the patient. In some embodiments, the intravenous injection of the pharmaceutical formulations disclosed herein for the methods and the uses disclosed herein is not likely to induce red blood cells hemolysis in the patient.

In some embodiments of the pharmaceutical formulations disclosed herein, the pharmaceutical formulation is a concentrated solution for injection. In some embodiments, the pharmaceutical formulation is a concentrated solution for injection, which is diluted with an aqueous solution as indicated above before administration.

In another aspect, provided herein is an aqueous pharmaceutical formulation suitable for intravenous administration comprising: a) a compound of Formula (I),

b) propylene glycol; and c) ethanol, and d) optionally, an aqueous isotonic solution.

In some embodiments of the methods and the uses disclosed herein, aqueous 0.9% w/v of sodium chloride solution is added to the formulation prior to administering the formulation to the subject in need thereof. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol prior to administering the formulation to the subject in need thereof. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising about 0.1 mg to about 500 mg of the compound of Formula (I), about 70% w/w to about 85% w/w of propylene glycol, and about 15% w/w to about 30% w/w of ethanol prior to administering the formulation to the subject in need thereof.

In some embodiments of the methods and the uses disclosed herein, pharmaceutical formulation D comprises: a) about 0.1 mg to about 500 mg of a compound of Formula (I)

b) about 70% w/w to about 85% w/w of propylene glycol; c) about 15% w/w to about 30% w/w of ethanol; and d) an aqueous 0.9% w/v of sodium chloride solution added in a ratio of about 0.1:1 to about 1000: 1 by weight of component d) to components a) to c). In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 0.1:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14: 1, about 15:1, about 20: 1, about 30: 1, about 40: 1, about 50:1, about 100: 1, about 150:1, about 160:1, about 170:1, about 180:1, about 190:1, about 200:1, about 210:1, about 220: 1, about 230: 1, about 240: 1, about 250: 1, about 300: 1, about 400: 1, about 500:1, about 600:1, about 700:1, about 800:1, about 900:1, or about 1000:1. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 0.5: 1 to about 500: 1 by weight. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 0.5: 1 to about 2: 1. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 0.5: 1, about 0.6: 1, about 0.7: 1, about 0.8: 1, about 0.9: 1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, about 1.5: 1, or about 2: 1. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 1: 1.

In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 50: 1 to about 250: 1. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 50: 1, about 60: 1, about 70: 1, about 80: 1, about 90: 1, about 100: 1, about 110: 1, about 120: 1, about 130: 1, about 140: 1 about 150: 1, about 160: 1, about 170: 1, about 180: 1, about 190: 1, about 200: 1, about 210: l, about 220: 1, about 230: 1, about 240: 1 or about 250: 1. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 100: 1. In some embodiments, aqueous 0.9% w/v of sodium chloride solution is added to the formulation comprising a compound of Formula (I), propylene glycol, and ethanol in a ratio of about 200: 1.

In some embodiments of the methods and the uses disclosed herein, including of the aqueous pharmaceutical formulation D suitable for intravenous administration, the composition comprises about 30% w/w to about 50% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 30% w/w, about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about 39% w/w, about 40% w/w, about 41% w/w, about 42% w/w, about 43% w/w, about 44% w/w, about 45% w/w, or about 50% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 35% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 36% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 37% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 38% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 39% w/w of propylene glycol. In some embodiments, the pharmaceutical formulation comprises about 40% w/w of propylene glycol.

In some embodiments of the methods and the uses disclosed herein, including of the aqueous pharmaceutical formulation D suitable for intravenous administration, the composition comprises about 5% w/w to about 20% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 5% w/w, about 7.5% w/w, about 9% w/w, 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, about 10% w/w, about 12.5% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/w of ethanol.

In some embodiments of the methods and the uses disclosed herein, including of the aqueous pharmaceutical formulation D suitable for intravenous administration, the pharmaceutical formulation comprises about 30% w/w to about 50% w/w of propylene glycol and about 5% w/w to about 20% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 35% w/w to about 45% w/w of propylene glycol and about 5% w/w to about 15% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 35% w/w to about 40% w/w of propylene glycol and about 7.5% w/w to about 12.5% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 36% w/w of propylene glycol and about 12% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 38% w/w of propylene glycol and about 9.6% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 40% w/w of propylene glycol and about 8% w/w of ethanol. In some embodiments, the pharmaceutical formulation comprises about 40% w/w of propylene glycol and about 10% w/w of ethanol.

In another aspect of the methods and the uses disclosed herein, including of the aqueous pharmaceutical formulation D suitable for intravenous administration, the compound of Formula (I) is at a final concentration of about 0.005% w/w to about 15% w/w. In some embodiments, the compound of Formula (I) is at a concentration of about 0.005% w/w to about 10% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.005% w/w, about 0.01% w/w, about 0.015% w/w, about 0.02% w/w, about 0.025% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 1.0% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3.0% w/w, about 3.5% w/w, about 4.0% w/w, about 4.5% w/w, or about 5.0% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.005% w/w to about 2.25% w/w of the formulation.

In some embodiments of the methods and uses disclosed herein, including of the aqueous pharmaceutical formulation D suitable for intravenous administration, the compound of Formula (I) is at a final concentration of about 0.010% w/w to about 0.050% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.010% w/w, about 0.012% w/w, about 0.014% w/w, about 0.016% w/w, about 0.018% w/w, about 0.020% w/w, about 0.022% w/w, about 0.024% w/w, about 0.026% w/w, about 0.028% w/w, about 0.030% w/w, about 0.032% w/w, about 0.034% w/w, about 0.036% w/w, about 0.038% w/w, about 0.040% w/w, about 0.042% w/w, about 0.044% w/w, about 0.046% w/w, about 0.048% w/w, or about 0.050% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.020% w/w of the formulation. In some embodiments, the compound of Formula (I) is at a concentration of about 0.040% w/w of the formulation.

In some embodiments of the methods and the uses disclosed herein, including of the aqueous pharmaceutical formulation D suitable for intravenous administration, the amount of the compound of Formula (I) is about 0.1 mg to about 450 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, about 10.0 mg, about 10.5 mg, about 11.0 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 62 mg, about 64 mg, about 65 mg, about 66 mg, about 68 mg, about 70 mg, about 72 mg, about 74 mg, about 75 mg, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84 mg, about 85 mg, about 86 mg, about 88 mg, about 90 mg, about 92 mg, about 94 mg, about 95 mg, about 96 mg, about 98 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 60 mg to about 100 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 70 mg, about 72 mg, about 74 mg, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84 mg, about 86 mg, about 88 mg, or about 90 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 0.5 mg to about 200 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 0.5 mg, about 1.0 mg, about 3.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. In some embodiments, the amount of the compound of Formula (I) is about 1.0 mg, about 3.0 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 110 mg, or about 150 mg of the formulation. In some embodiments, the amount of the compound of Formula (I) is about 1.0 mg. In some embodiments, the amount of the compound of Formula (I) is about 3.0 mg. In some embodiments, the amount of the compound of Formula (I) is about 10 mg. In some embodiments, the amount of the compound of Formula (I) is about 20 mg. In some embodiments, the amount of the compound of Formula (I) is about 30 mg. In some embodiments, the amount of the compound of Formula (I) is about 50 mg. In some embodiments, the amount of the compound of Formula (I) is about 60 mg. In some embodiments, the amount of the compound of Formula (I) is about 75 mg. In some embodiments, the amount of the compound of Formula (I) is about 85 mg. In some embodiments, the amount of the compound of Formula (I) is about 100 mg. In some embodiments, the amount of the compound of Formula (I) is about 110 mg. In some embodiments, the amount of the compound of Formula (I) is about 150 mg. In some embodiments, the amount of the compound of Formula (I) is about 200 mg.

In some embodiments of the pharmaceutical formulations, the methods, and the uses disclosed herein, including pharmaceutical formulation D, the volume of the formulation for injection is about 0.5 mb to about 200 mb. In some embodiments, the volume of the formulation for injection is about 0.5 mb, about 0.6 mb, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2. 1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.5 mL, about 4 mL, about 4.5 mL, about 5 mL, about 5.5 mL, about 6 mL, about 7 mL, about 7.5 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 46 mL, about 47 mL, about 48 mL, about 49 mL, about 50 mL, about 51 mL, about 52 mL, about 53 mL, about 54 mb, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL, about 95 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150 mL, about 160 mL, about 170 mL, about 180 mL, about 190 mL, or about 200 mL. In some embodiments, the volume of the formulation for injection is about 0.5 mL to about 75 mL. In some embodiments, the volume of the formulation for injection is about 1 mL to about 60 mL. In some embodiments, the volume of the formulation for injection is about 1 mL, about 1.5 mL, about 2.5 mL, about 3.0 mL, about 3.75 mL, about 4.25 mL, about 5 mL, about 5.5 mL, about 7.5 mL, about 15 mL, or about 50 mL. In some embodiments, the volume of the formulation for injection is about 1.5 mL, about 5 mL, about 7.5 mL, about 15 mL, or about 50 mL.

In some embodiments of the methods and the uses of the pharmaceutical formulations disclosed herein, including pharmaceutical formulation D, the pharmaceutical formulation is a concentrate solution for injection via intravenous infusion. In some embodiments, the pharmaceutical formulation is injected over a period of time greater than about 1 minute. In some embodiments, the pharmaceutical formulation is injected over a period of time greater than about 5 minutes. In some embodiments, the pharmaceutical formulation is injected over a period of time greater than about 10 minutes. In some embodiments, the pharmaceutical formulation is injected over about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about 30 minutes. In some embodiments, the pharmaceutical formulation is injected over about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, or about 20 minutes. In some embodiments of the methods and the uses of the pharmaceutical formulations disclosed herein, including pharmaceutical formulation D, the pharmaceutical formulation is injected from a syringe. In some embodiments, the injection of the pharmaceutical formulation from a syringe is with a pump. In some of these embodiments, including pharmaceutical formulation D, the pharmaceutical formulation is injected at a flow rate of about 0.05 mL/min to about 15 mL/min. In some embodiments, the pharmaceutical formulation is injected at a flow rate of about 0.05 mL/min to about 10 mL/min. In some embodiments, the pharmaceutical formulation is injected at a flow rate of about 0.05 mL/min, about 0.06 mL/min, about 0.07 mL/min, about 0.08 mL/min, about 0.09 mL/min, about 0. 1 mL/min, about 0.11 mL/min, about 0.12 mL/min, about 0.13 mL/min, about 0.14 mL/min, about 0.15 mL/min, about 0.16 mL/min, about 0.17 mL/min, about 0.18 mL/min, about 0.19 mL/min, about 0.2 mL/min, about 0.21 mL/min, about 0.22 mL/min, about 0.23 mL/min, about 0.24 mL/min, about 0.25 mL/min, about 0.26 mL/min, about 0.27 mL/min, about 0.28 mL/min, about 0.29 mL/min, about 0.3 mL/min, about 0.31 mL/min, about 0.32 mL/min, about 0.33 mL/min, about 0.34 mL/min, about 0.35 mL/min, about 0.36 mL/min, about 0.37 mL/min, about 0.38 mL/min, about 0.39 mL/min, about 0.4 mL/min, about 0.41 mL/min, about 0.42 mL/min, about 0.43 mL/min, about 0.44 mL/min, about 0.45 mL/min, about 0.46 mL/min, about 0.47 mL/min, about 0.48 mL/min, about 0.49 mL/min, about 0.5 mL/min, about 0.51 mL/min, about 0.52 mL/min, about 0.53 mL/min, about 0.54 mL/min, about 0.55 mL/min, about 0.6 mL/min, about 0.65 mL/min, about 0.7 mL/min, about 0.75 mL/min, about 0.8 mL/min, about 0.85 mL/min, about 0.9 mL/min, about 0.95 mL/min, about 0.96 mL/min, about 0.97 mL/min, about 0.98 mL/min, about 0.99 mL/min, about 1.0 mL/min, about 1.01 mL/min, about 1.02 mL/min, about 1.03 mL/min, about 1.04 mL/min, about 1.05 mL/min, about 1.1 mL/min, about 1.2 mL/min, about 1.3 mL/min, about 1.4 mL/min, about 1.5 mL/min, about 2.0 mL/min, about 2.5 mL/min, about 3.0 mL/min, about 3.1 mL/min, about 3.2 mL/min, about 3.3 mL/min, about 3.4 mL/min, about 3.5 mL/min, about 4.0 mL/min, about 4.5 mL/min, about 5.0 mL/min, about 5.5 mL/min, about 6.0 mL/min, about 6.5 mL/min, about 7.0 mL/min, about 7.5 mL/min, about 8.0 mL/min, about 8.5 mL/min, about 9.0 mL/min, about 9.5 mL/min, and about 10.0 mL/min. In some embodiments, the pharmaceutical formulation is injected at a flow rate of about 0.05 mL/min to about 5 mL/min. In some embodiments, the pharmaceutical formulation is injected at a flow rate of about 0.07 mL/min, about 0.1 mL/min, about 0.17 mL/min, about 0.2 mL/min, about 0.25 mL/min, about 0.28 mL/min, about 0.33 mL/min, about 0.37 mL/min, about 0.50 mL/min, about 1.0 mL/min, or about 3.3 mL/min.

Preparation of Pharmaceutical Formulations

The pharmaceutical formulations provided herein may be manufactured by a process comprising mixing solvents and adding the compound of Formula (I) until the compound of Formula (I) is completely dissolved. In some embodiments, the compound of Formula (I) is amorphous before dissolution. In some embodiments, the compound of Formula (I) is a crystalline form before dissolution. In some embodiments, the compound of Formula (I) is a crystalline form of the hydrate before dissolution. In some embodiments, the crystalline form of the hydrate has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks chosen from 7.0 ± 0.2 °20, 14.1 ± 0.2 °20, 18.5 ± 0.2 °20, 24.7 ± 0.2 °20, 26.0 ± 0.2 °20 and 26.9 ± 0.2 °20, when measured using CuKa radiation with a wavelength of 1.5418 A and at a temperature of about 22 °C.

The pharmaceutical formulations can be subjected to conventional pharmaceutical operations such as sterilization and filtration.

In another aspect, provided herein is a method of making the pharmaceutical formulations disclosed herein, comprising: a) mixing a therapeutically effective amount of a compound of Formula (I),

The stability of the pharmaceutical formulations disclosed herein was evaluated at an accelerated condition (60 °C). However, significant degradation of the compound of Formula (I) was observed. The compound of Formula (I) was not stable at high temperature, and a terminal sterilization process could not be applied using a heat treatment.

In some embodiments of the methods of making the pharmaceutical formulations disclosed herein, the mixture from step a) is filtered. In some embodiments, the filter is sterile. In some embodiments, the filter is a polyvinylidene fluoride (PDVF) membrane.

In some embodiments of the methods of making the pharmaceutical formulations disclosed herein, the mixture from step a) is passed through an inline filter. In some embodiments, the method further comprises filling vials. In some embodiments, the method further comprises aseptically filling vials. In some embodiments, the vials are sterile. In some embodiments, the vials are glass and sterile. In some embodiments, the method further comprises closing the vials with stoppers. In some embodiments, the stoppers are sterile. In some embodiments, the stoppers are rubber and sterile. In some embodiments, the method further comprises sealing the closed vials. In some embodiments, the closed vials are sealed with crimp caps. EXAMPLES

The following examples are intended to illustrate the disclosure and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. List of abbreviations

ACN acetonitrile aq. aqueous cone. concentrated

EtOH ethanol g gram h(r) hour

L liter

LC/MS liquid chromatography-mass spectrometry mg milligram min minute mL milliliter pL microliter mmol millimole

N normal

PG propylene glycol pH -logioH⁺ concentration

Rt retention time

RP-HPLC reverse-phase high performance liquid chromatography temp. temperature

Liquid chromatography (LC) methods

Method-1: Assay and degradation products

Method-2: Assay by HPLC after dilution Both the above mentioned Method -1 and Method-2 have same chromatographic conditions as given below.

Principle: Reverse Phase HPLC method with UV-DAD detection.

Detection : HPLC system with gradient elution and UV detector, e.g., Agilent 1290 with UV detector or equivalent

Chromatographic conditions:

Column: Waters ACQUITY UPLC® BEH Cl 8, Length:

150 mm, internal diameter: 2.1 mm, 1.7 pm

Column temperature: 30 °C

Mobile phase (Eluents) : A: Water/Acetonitrile/TLA 95+5+0.05 (v+v+v)

B: Acetonitrile/Methanol/Water/TLA 90+5+5+0.05

(v+v+v+v)

Plow rate: 0.4 ml/min

Detection: 218 nm

Auto sampler temperature: 5 °C

Injection volume: 2 pl of the test (80 mg/2 mb) and reference solutions

Run time : 17 minutes

Gradient:

Time [min.] Phase A [%] Phase B [%] Curve

0 80 20 -

1.5 80 20

8.0 65 35 Linear

10.0 55 45 Linear

12.0 10 90 Linear

14.0 10 90 Linear

14.5 80 20 Linear

17.0 80 20

Method-3: Enantiomer by HPLC:

Principle: Normal phase HPLC method with UV detection Detection : HPLC system with gradient elution and UV detector, e.g., Agilent 1200 or equivalent

Chromatographic conditions:

Column: Daicel Chiralpak IA-3, Length: 150 mm, internal diameter: 4.6 mm, 3 pm

Column temperature: 40 °C

Mobile phase: Mixture of n-Hexane : Ethanol (55 :45, v/v), (Mobile phase preparation: Mix 550 mL of n-Hexane and 450 mL of Ethanol in a 1000 mL mobile phase bottle and degas)

Flow rate: 1.0 ml/min

Detection: 264 nm

Auto sampler temperature: 5 °C

Injection volume: 5 pl of the test (80 mg/2 mL) and reference solutions

Run time: 12 minutes

Example 1: Solution Formulation of the Compound of Formula (I)

Table 1 shows the components of the solution formulation for various doses of Formulation A (i.e., 4.02% by weight of the compound of Formula (I) calculated based on its free base relative to the total weight of the composition).

Table 1. Solution Formulation of the Compound of Formula (I)

Example 2: Manufacturing Process for Solution Formulation

Propylene glycol (PG) was added to a suitable vessel. Absolute ethanol was added, and the mixture was stirred for at least 15 min until homogenous. The compound of Formula (I) was slowly added as a powder while stirring to wet properly. The mixture was stirred for 60 min until the solution was clear and the compound of Formula (I) was completely dissolved. If needed, manual aid was provided, e.g., by stirring using a spatula or equivalent sterilized equipment, if the dissolution took more than 60 min. PG and ethanol were added to reach the appropriate final volume, and the mixture was stirred to form a homogenous solution.

The pharmaceutical formulation comprising the compound of Formula (I) was prepared as an 80 mg/2 mb concentrate solution for injection (i.e., liquid in a vial). The pharmaceutical formulation was a colorless to yellow homogenous solution passed through an inline filter into a 6 mb clear type I glass vial, closed with a sterile rubber stopper (13 mm), and crimped using an aluminum flip off cap (13 mm). The fill volume of the pharmaceutical formulation was set to 2.4 mb with a 0.4 mb (20%) overfill to assure the withdrawal of the nominal volume (i.e., 2.0 mb).

Example 3: Solubility and Stability Studies

The compound of Formula (I) had good solubility in organic solvents such as propylene glycol (102.88 mg/mL at 2-8 °C), ethanol (113.85 mg/mL at 2-8 °C), and polyethylene glycol (PEG) 300 (99.01 mg/mL at 2-8 °C). The maximum solubility of the compound of Formula (I) in water is about 0.47 mg/mL. The maximum solubility of the compound of Formula (I) in aqueous 0.9% w/v sodium chloride solution is about 0.44 mg/mL.

Clinical batches of the compound of Formula (I) 80 mg/2 mL concentrate solution for injection, which comprised propylene glycol and ethanol with a percent ratio of about 80:20 (w/w), showed satisfactory stability data at a long term condition 5°C/ ambient relative humidity (RH) up to 24 months and at an accelerated condition 25°C/ 60% RH up to 6 months. Additionally the clinical batch of the compound of Formula (I) also showed satisfactory stability data at accelerated conditions 30°C/75%RH and 40°C/75%RH up to 1 month. Impurity 1 increased slightly at 25°C/ 60% RH. The higher levels of impurities formed at higher temperature 30°C/75%RH and 40°C/75%RH were consistent with expectations as well. The physical appearance of the container did not change at any of the tested conditions. The physical appearance of the solution remained clear and free from visible foreign particles before and after dilution under all conditions tested.

The 24 months satisfactory stability data at a long term condition (5°C/ ambient RH, inverse) and 6 months satisfactory stability data at accelerated stability condition (25°C/60%RH, inverse) may support a shelf life of 36 months at the storage temperature 2°C to 8°C.

Significant changes were observed after exposure to light according to ICH Q1B conditions. However, the physical appearance of the solution remained colorless under the other tested conditions. Hence, the compound of Formula (I) 80 mg/2mL concentrate for solution for injection needs to be protected from light during storage and transportation.

The freeze and thaw cycles did not affect the compound of Formula (I) 80 mg/2mL concentrate for solution for injection.

Details on the stability tests are further detailed in Tables 2 - 8 (FIGs. 1 - 7) showing stability results of the compound of Formula (I) 80 mg/2 mb concentrate.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical formulation comprising: a) a therapeutically effective amount of a compound of Formula (I),

b) propylene glycol; and c) ethanol.

2. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation comprises about 60% w/w to about 90% w/w of propylene glycol.

3. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 60% w/w of propylene glycol.

4. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 70% w/w of propylene glycol.

5. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 75% w/w of propylene glycol. 50

6. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 80% w/w of propylene glycol.

7. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 85% w/w of propylene glycol.

8. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 90% w/w of propylene glycol.

9. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 60% w/w to about 90% w/w of propylene glycol and about 10% w/w to about 40% w/w of ethanol.

10. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 70% w/w to about 85% w/w of propylene glycol and about 15% w/w to about 30% w/w of ethanol.

11. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 75% w/w to about 80% w/w of propylene glycol and about 15% w/w to about 25% w/w of ethanol.

12. The pharmaceutical formulation according to any one of claim 1 or 2, wherein the pharmaceutical formulation comprises about 77% w/w of propylene glycol and about 19% w/w of ethanol.

13. The pharmaceutical formulation according to any one of the preceding claims, wherein the ethanol is anhydrous ethanol. 51

14. The pharmaceutical formulation according to any one of the preceding claims, wherein the compound of Formula (I) is at a concentration of about 0.005% w/w to about 15% w/w of the formulation.

15. The pharmaceutical formulation according to any one of the preceding claims, wherein the compound of Formula (I) is at a concentration of about 0.005% w/w, about 0.01% w/w, about 0.015% w/w, about 0.02% w/w, about 0.025% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 1.0% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3.0% w/w, about 3.5% w/w, about 4.0% w/w, about 4.5% w/w, or about 5.0% w/w of the formulation.

16. The pharmaceutical formulation according to any one of the preceding claims, wherein the volume of the formulation is from about 1 mb to about 5 mb.

17. The pharmaceutical formulation according to any one of the preceding claims, wherein an aqueous solution comprising 0.9% w/v of sodium chloride is added to the formulation before administration.

18. The pharmaceutical formulation according to claim 17 , wherein the volume of the formulation after addition of the sodium chloride solution is about 1 mb to about 60 mb.

19. The pharmaceutical formulation according to any one of the preceding claims, wherein the pharmaceutical formulation is for injection, preferably intravenous injection.

20. A pharmaceutical formulation comprising: a) about 0.005% w/w to about 15% w/w of a compound of Formula (I) 52

21. The pharmaceutical formulation according to claim 20, wherein the ethanol is anhydrous ethanol.

22. The pharmaceutical formulation according to any one of claims 20 or 21, wherein the compound of Formula (I) is at a concentration of 0.005% w/w to about 5.0% w/w of the formulation.

23. The pharmaceutical formulation according to any one of claims 20-22, wherein the compound of Formula (I) is at a concentration of about 0.005% w/w, about 0.01% w/w, about 0.015% w/w, about 0.02% w/w, about 0.025% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 1.0% w/w, about 1.5% w/w, about 2.0% w/w, about 2.5% w/w, about 3.0% w/w, about 3.5% w/w, about 4.0% w/w, about 4.5% w/w, or about 5.0% w/w of the formulation.

24. The pharmaceutical formulation according to any one of claims 20-23, wherein the volume of the formulation is from about 1 mb to about 5 mb.

25. The pharmaceutical formulation according to any one of claims 20-24, wherein an aqueous solution comprising 0.9% w/v of sodium chloride is added to the formulation before administration.

26. The pharmaceutical formulation according to claim 25, wherein the volume of the formulation after addition of the sodium chloride solution is about 1 mL to about 60 mb

27. The pharmaceutical formulation according to any one of claims 20-26, wherein the pharmaceutical formulation is for injection, preferably intravenous injection.

28. The pharmaceutical formulation according to claim 25 or 26, wherein the compound of Formula (I) is at a concentration of about 0.01% w/w to about 0.05% w/w of the formulation.

29. A pharmaceutical formulation comprising: a) about 0.1 mg to about 500 mg of a compound of Formula (I),

30. The pharmaceutical formulation according to claim 23, wherein the ethanol is anhydrous ethanol.

31. The pharmaceutical formulation according to any one of claims 29 or 30, wherein the compound of Formula (I) is about 0.5 mg to about 200 mg of the formulation.

32. The pharmaceutical formulation according to any one of claims 29-31, wherein the compound of Formula (I) is about 1.0 mg, about 3.0 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 110 mg, or about 150 mg of the formulation.

33. The pharmaceutical formulation according to any one of claims 29-32, wherein the volume of the formulation is from about 1 mb to about 5 mb.

34. The pharmaceutical formulation according to any one of claims 29-33, wherein an aqueous solution comprising 0.9% w/v of sodium chloride is added to the formulation before administration.

35. The pharmaceutical formulation according to claim 34, wherein the volume of the formulation after addition of the sodium chloride solution is about 1 mb to about 60 mb.

36. The pharmaceutical formulation according to any one of claims 29-35, wherein the pharmaceutical formulation is for injection.

37. The pharmaceutical formulation according to any one of claims 34-36, wherein the compound of Formula (I) is about 0.5 mg to about 200 mg of the formulation.

38. A pharmaceutical formulation comprising : 55 a) about 75 mg to about 100 mg of a compound of Formula (I),

39. The pharmaceutical formulation according to claim 38, wherein the volume of the formulation is from about 1 mb to about 5 mb.

40. The pharmaceutical formulation according to claims 38 or 39, wherein an aqueous solution comprising 0.9% w/v of sodium chloride is added to the formulation before administration.

41. The pharmaceutical formulation according to claim 40, wherein the volume of the formulation after addition of the sodium chloride solution is about 1 mb to about 60 mb.

42. The pharmaceutical formulation according to any one of claims 38 to 41, wherein the pharmaceutical formulation is for injection, preferably intravenous injection.

43. A method of treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor, in a subject in need thereof, comprising administering to the subject in need of such treatment a therapeutically effective amount of a pharmaceutical formulation according to any one of the preceding claims. 56

44. A method of treating or preventing a disease or disorder selected from the group consisting of cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension, and sick sinus syndrome, in a subject in need thereof, comprising administering to the subject in need of such treatment a therapeutically effective amount of a pharmaceutical formulation according to any one of claims 1-42.

45. A pharmaceutical formulation according to any one of claims 1-42 for use as a medicament.

46. A pharmaceutical formulation according to any one of claims 1-42 for use in the treatment or prevention of a disease or disorder responsive to the inhibition of GIRK receptor.

47. A pharmaceutical formulation according to any one of claims 1-42 for use in the treatment of cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension or sick sinus syndrome.

48. Use of a pharmaceutical formulation according to any one of claims 1-42 for the manufacture of a medicament for treating or preventing a disease or disorder responsive to the inhibition of the GIRK receptor.

49. Use of a pharmaceutical formulation according to any one of claims 1-42 for the manufacture of a medicament for treating or preventing a disease or disorder is selected from the group consisting of cardiac arrhythmia, atrial fibrillation, primary hyperaldosteronism, hypertension and sick sinus syndrome. 57

50. A method of making the pharmaceutical formulation of any one of claims 1-42, comprising: a) mixing a therapeutically effective amount of a compound of Formula (I),