Injectable dosage form of 2-[6-(4-cyclopropyl-4h-1,2,4-triazol-3-YL)-2-pyridyl]-5-morpholinocarbonyl-1-isoindolinone

Abstract

The present invention relates to an injectable form comprising: (i) At least 1.5 mg / mL of 2-[6-(4- cyclopropyl-4h-1,2,4-triazol-3-yl)-2-pyridyl]-5-morpholinocarbonyl-1-isoindolinone; (ii) a solvent selected from the group consisting of polyethylene glycol 300 (PEG300), polyethylene glycol 400 (PEG400), and mixtures thereof; and (iii) a co-solvent selected from the group consisting of PEG300, PEG400, propylene glycol, and mixtures thereof.

Description

[0001] INJECTABLE DOSAGE FORM OF 2-[6-(4-CYCLOPROPYL-4H-l,2,4-TRIAZOL-3-YL)-2- PYRIDYLJ-5-MORPHOLINOCARBONYL-1-ISOINDOLINONE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to injectable formulations of 2-[6-(4-cyclopropyl-4H-l,2,4-triazol- 3-yl)-2-pyridyl]-5-morpholinocarbonyl-l-isoindolinone and uses thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Compound 2-[6-(4-cyclopropyl-4H- 1 ,2,4-triazol-3 -y 1) -2 -pyridyl] -5 -morpholinocarbonyl- 1 - isoindolinone is of the following formula (I):

[0006] In all the present description, compound of formula (I) can also be named Compound A. Compound A has been disclosed in EP24305713.0 for its use in a method for treating sepsis. Compound A has a poor solubility and current stable formulations yield an API (active pharmaceutical ingredient) concentration of 0.5 mg / mL. Higher concentrations show precipitation after overnight storage (i.e. after about 8 hours).

[0007] There is thus a need to provide a stable injectable formulation to enable parenteral administration of Compound A at a concentration of at least 1.5 mg / mL.

[0008] SUMMARY OF THE INVENTION

[0009] The inventors have found a non-aqueous solvent system based on PEG 300, PEG 400 and / or propylene glycol, which enable to obtain a stable injectable formulation of Compound A at a concentration of about 2.6 mg / mL without precipitation. The formulation of the present invention is also compatible with saline for further dilution for intravenous infusion.

[0010] The injectable form of the invention has also an osmolality compatible with the route of administration. Osmolality of the injectable form of the invention administered intravenously within 24h is considered safe for the patient if within the range of 275 mOsmo / kg and 330 mOsmo / kg when diluted to the targeted concentration.

[0011] The present invention relates to novel injectable dosage form of 2-[6-(4-cyclopropyl-4H- 1,2,4- triazol-3-yl)-2 -pyridyl] -5 -morpholinocarbonyl- 1 -isoindolinone or of a pharmaceutically acceptable salt thereof. A first object of the invention relates to an injectable form comprising: i) Compound A of following formula (I): ii) A solvent selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), and mixtures thereof; and iii) A co-solvent selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), propylene glycol, and mixtures thereof.

[0012] A second object of the invention relates to a method for preparing an injectable form comprising Compound A of following formula (I): said method comprising the following steps: a) Preparing a solution comprising Compound A in a content of at least 1.5 mg / mL, a solvent (ii) and optionally a co-solvent (iii); and b) Centrifugating and / or filtrating to remove undissolved API, wherein solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), and mixtures thereof; and wherein co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), propylene glycol, and mixtures thereof.

[0013] The invention also relates to an injectable form comprising Compound A obtainable by the method of the invention.

[0014] Another object of the invention relates to a pharmaceutical composition comprising the injectable form of the invention or the injectable form obtainable by the method of the invention, and a dilution solvent, the dilution solvent being preferably selected from the group consisting of sterile water, saline solution (NaCl), a glucose solution at 2.5%, a glucose solution at 5%, sorbitol, mannitol, and mixtures thereof.

[0015] The invention also relates to an injectable form according to the invention or obtainable by the method of the invention, or the pharmaceutical composition of the invention, for use in a method for the treatment of Acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (also called acute decompensation) (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof.

[0016] The invention also relates to an injectable form according to the invention or obtainable by the method of the invention, or the pharmaceutical composition of the invention, for use in a method for the treatment of Acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, acute cirrhosis decompensation (AD), or acute liver decompensation in a subject in need thereof.

[0017] The invention also relates to an injectable form according to the invention or obtainable by the method of the invention, or the pharmaceutical composition of the invention, for use in a method for the treatment of sepsis, preferably of polymicrobial sepsis or sepsis-associated ACLF, in a subject in need thereof.

[0018] DETAILED DESCRIPTION OF THE INVENTION

[0019] Definitions

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0021] All percentages and ratios used herein, unless otherwise indicated, are by weight.

[0022] Any reference to a dose, amount or percentage of Compound A in this disclosure is based on the free base equivalent weight of Compound A. For example, 35 mg of Compound A refers to 35 mg of Compound A in the free base form or an equivalent amount of a salt of Compound A.

[0023] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0024] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0025] The term “injectable form” or ‘injectable dosage form” refers to dosage forms that are sterile and administrated to a subject by injection or intravenous infusion or implantation. The injectable dosage form of the invention can be parenterally administered to a subject, namely by intravenous, intramuscular, intradermal or subcutaneous administration.

[0026] The term "administering" refers to the act of delivering an injectable dosage form described herein into a subject by injection or parenteral administration. The term can also refer to the frequency (e.g., daily, weekly, monthly, etc.) of providing the injectable dosage form described herein to a patient. Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).

[0027] A "subject" or "patient" includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like). In one embodiment, the subject or patient is human. Patients described herein include patients having a disease or condition described herein. A patient can be described or referred to by the condition treated. For example, a patient having Acute on Chronic Liver Failure (ACLF) can be referred to herein as an ACLF patient. Likewise, a patient having Acute Liver Failure (ALF) can be referred to herein as an ALF patient. Likewise, a patient having sepsis can be referred to herein as a sepsis patient. A patient described herein can have a preexisting condition (e.g., a condition other than the disease or condition treated by the oral dosage form described herein that existed at the time of first administration). In one instance, the patient is an elderly / geriatric patient or a pregnant patient. In another instance, the patient is a pediatric patient.

[0028] "Treating", includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease or disorder.

[0029] "Treating" or "treatment" of a disease state includes: inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; or relieving the disease state, i.e. causing temporary or permanent regression of the disease state or its clinical symptoms.

[0030] "Preventing" the disease state includes causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state but does not yet experience or display symptoms of the disease state.

[0031] As used herein, the term "inhibiting" or "inhibition", as applied to a disease or condition, refers to any detectable positive effect on the development or progression of a disease or condition. Such a positive effect may include the delay or prevention of the onset of at least one symptom or sign of the disease or condition, alleviation or reversal of the symptom(s) or sign(s) and slowing or prevention of the further worsening of the symptom(s) or sign(s).

[0032] "Disease state" means any disease, disorder, condition, symptom, or indication.

[0033] The term "effective amount" as used herein refers to an amount of compound of formula (I) (Compound A), or of a pharmaceutically acceptable salt thereof, that produces an acute or chronic therapeutic effect upon appropriate dose administration. The effect includes the prevention, correction, inhibition, or reversal of the symptoms, signs and underlying pathology of a disease / condition and related complications to any detectable extent.

[0034] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0035] "Pharmacological effect" as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. In one embodiment, a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention, alleviation or reduction of primary indications in a treated subject. In another embodiment, a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention or reduction of primary indications in a treated subject.

[0036] "Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

[0037] A first object of the invention relates to an injectable form comprising: i) Compound A; ii) A solvent selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), and mixtures thereof; and iii) A co-solvent selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), propylene glycol, and mixtures thereof.

[0038] In the context of the invention, solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), and mixtures thereof. Preferably, solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 3350 Da (PEG300-PEG3350), and mixtures thereof. Preferably, solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), and mixtures thereof. More preferably, solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 400 Da (PEG300- PEG400), and mixtures thereof.

[0039] Preferably, solvent (ii) is selected from the group consisting of PEG300, PEG400, PEG600, PEG3350, PEG4000, and mixtures thereof. More preferably, solvent (ii) is selected from the group consisting of PEG300, PEG400, PEG600, and mixtures thereof. In a preferred embodiment, solvent (ii) is selected from the group consisting of polyethylene glycol 300 (PEG300), polyethylene glycol 400 (PEG400), and mixtures thereof.

[0040] In a preferred embodiment, solvent (ii) is PEG300.

[0041] In another embodiment, solvent (ii) is PEG400.

[0042] In another embodiment, solvent (ii) is a mixture of PEG 300 and PEG 400.

[0043] In the context of the invention, co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), benzyl benzoate, castor oil, cottonseed oil, N,N-dimethylacetamide, ethanol, glycerin, N-methyl-2 -pyrrolidone, peanut oil, poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil, vegetable oil, and mixtures thereof.

[0044] In a particular embodiment, co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), propylene glycol, and mixtures thereof. Preferably, co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 3350 Da (PEG300-PEG3350), propylene glycol, and mixtures thereof. Preferably, co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), propylene glycol, and mixtures thereof. More preferably, co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 400 Da (PEG300-PEG400), propylene glycol, and mixtures thereof.

[0045] Preferably, co-solvent (iii) is selected from the group consisting of PEG300, PEG400, PEG600, PEG3350, PEG4000, propylene glycol, and mixtures thereof. More preferably, co-solvent (iii) is selected from the group consisting of PEG300, PEG400, PEG600, propylene glycol, and mixtures thereof.

[0046] In a preferred embodiment, co-solvent (iii) is PEG400.

[0047] In another embodiment, co-solvent (iii) is PEG300.

[0048] In another embodiment, co-solvent (iii) is propylene glycol.

[0049] In another embodiment, co-solvent (iii) is a mixture of PEG 300 or PEG 400 with propylene glycol.

[0050] Typically, in the context of the invention, solvent (ii) and co-solvent (iii) are different.

[0051] In a particular embodiment, the invention relates to an injectable form comprising: i) Compound A ii) A solvent selected from the group consisting of PEG300, PEG400, and mixtures thereof; and iii) A co-solvent selected from the group consisting of PEG300, PEG400, propylene glycol, and mixtures thereof. In another particular embodiment, the invention relates to an injectable form comprising: i) Compound A ii) A solvent being PEG300; and iii) A co-solvent selected from the group consisting of PEG400, propylene glycol, and mixtures thereof.

[0052] In another particular embodiment, the invention relates to an injectable form comprising: i) Compound A ii) A solvent being PEG300; and iii) A co-solvent being propylene glycol.

[0053] In another particular embodiment, the invention relates to an injectable form comprising: i) Compound A ii) A solvent being PEG300; and iii) A co-solvent being a mixture of PEG400 and propylene glycol

[0054] In a preferred embodiment, the invention relates to an injectable form comprising: i) Compound A ii) A solvent being PEG300; and iii) A co-solvent being PEG400.

[0055] In the context of this embodiment, the weight ratio PEG300:PEG400 is preferably between about 0.2 and about 1, preferably between about 0.3 and about 1, preferably between about 0.4 and about 1, preferably between about 0.5 and about 1, preferably between about 0.5 and about 0.8, more preferably about 0.6.

[0056] In the context of the invention, the injectable form of the invention preferably comprises Compound A in a content of at least 1.5 mg / mL. In particular, the content of Compound A is at least 2 mg / mL, preferably at least 2.5 mg / mL, more preferably 2.6 mg / mL.

[0057] In a particular embodiment, the injectable form of the invention comprises Compound A in a content ranging from 1.5 mg / mL to 4 mg / mL, preferably from 1.5 mg / mL to 3.5 mg / mL, preferably from 1.5 mg / mL to 3 mg / mL, preferably from 2 mg / mL to 3 mg / mL, preferably from 2.4 mg / mL to 2.8 mg / mL, preferably from 2.5 mg / mL to 2.8 mg / mL. In particular, the content of Compound A in the injectable form of the invention is 2.6 mg / mL.

[0058] Compound A can be in the form of a pharmaceutically acceptable salt, particularly acid or base salts compatible with pharmaceutical use. Salts of Compound A include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.

[0059] Compound A can also be in the form of a pharmaceutically acceptable solvate.

[0060] Compound A can also be in the form of a radiolabeled compound or radioisotope compound.

[0061] In the context of the invention, the injectable form of the invention preferably has a density within the range of 1 g / L and 1.3 g / L, preferably within the range of 1.10 g / L and 1.20 g / L, more preferably 1.12 g / L. The density is measured according to the method known by the one skilled in the art at ambient temperature, i.e. between 18°C and 25°C.

[0062] In the context of the invention, the injectable form of the invention preferably has an osmolality within the range of 15 mOsmo / kg and 330 mOsmo / kg after dilution, in particular after 10-fold dilution, in particular in sterile water or saline solutions.

[0063] In the context of the invention, the injectable form of the invention preferably has a physiological pH. In particular, the injectable form of the invention preferably has a pH in the range between 7.35 to 7.45, with the average at 7.40. Typically, pH is measured according to the method known by the one skilled in the art at ambient temperature, i.e. between 18°C and 25°C.

[0064] In the context of the invention, the injectable form of the invention can further comprise pharmaceutically acceptable excipient adapted for administration by injection.

[0065] In particular, the injection form of the invention can further comprise one or more surfactants, in order to improve the stability. The surfactant can for example be selected in the group consisting of poloxamer (such as poloxamer 188), povidone (such as povidone K12), Kolliphor® HS 15, Kolliphor RH 40 Kolliphor® ELP, polysorbate (such as polysorbate 80), polyethoxylated sorbitan esters (ex MONTANOX™), sodium laurylsulfate (SLS), cetyltrimethyl ammonium bromide (CTAB), magnesium propionate, sodium caprylate and mixtures thereof.

[0066] In a particular embodiment, the injectable form of the invention can further comprise other pharmaceutically acceptable and nontoxic auxiliary agents, such as for example stabilizers, antioxidants, buffering agent, chelating agents, complexing agents, binders, colorant, preservatives, antimicrobial preservatives, emulsifiers, suspending agents, tonicity adjusters or viscosity modifiers.

[0067] The injectable form of the invention is preferably adapted for being administered by injection or infusion. In particular, the injectable form of the invention is adapted for intravenous administration, preferably by bolus injection. The obtained injectable form is also preferably compatible with sterile water or saline for further dilution, for example for intravenous infusion using an infusion bag. In particular, the injectable form of the invention is adapted for being administered with a syringe. Another object of the invention relates to a method for preparing an injectable form comprising Compound A, said method comprising the following steps: a) Preparing a solution comprising Compound A, a solvent (ii) and optionally a co-solvent (iii); and b) Centrifugating and / or fdtrating to remove undissolved API, wherein solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), and mixtures thereof; and wherein co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 4000 Da (PEG300-PEG4000), propylene glycol, and mixtures thereof.

[0068] In a particular embodiment, the method of the invention comprises the following steps: a) Preparing a solution comprising Compound A, a solvent (ii) and optionally a co-solvent (iii); and b) Centrifugating and / or fdtrating to remove undissolved API, wherein solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), and mixtures thereof; and wherein co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), propylene glycol, and mixtures thereof.

[0069] In another particular embodiment of the invention, solvent (ii) and co-solvent (iii) are as defined above in the specification.

[0070] In a particular embodiment, the solution prepared in step a) comprises Compound A in a content of at least 1.5 mg / mL. In particular, the content of Compound A is at least 2 mg / mL, preferably at least 2.5 mg / mL, more preferably 2.6 mg / mL.

[0071] In a particular embodiment, the solution prepared in step a) comprises Compound A in a content ranging from 1.5 mg / mL to 4 mg / mL, preferably from 1.5 mg / mL to 3.5 mg / mL, preferably from 1.5 mg / mL to 3 mg / mL, preferably from 2 mg / mL to 3 mg / mL, preferably from 2.4 mg / mL to 2.8 mg / mL, preferably from 2.5 mg / mL to 2.8 mg / mL. In particular, the content of Compound A in the solution prepared in step a) of the invention is 2.6 mg / mL.

[0072] Compound A can be in the form of a pharmaceutically acceptable salt, particularly acid or base salts compatible with pharmaceutical use. Salts of Compound A include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound. In a particular embodiment of the invention, the injectable form prepared by the method of the invention is as defined above in the specification.

[0073] In the context of the invention, step a) can be carried out by all methods known by the one skilled in the art. For example, Compound A, solvent (ii) and co-solvent (iii) can be mixed either additively or simultaneously, or Compound A can be mixed with solvent (ii) before adding co-solvent (iii), or solvent (ii) and co-solvent (iii) can be mixed before adding Compound A.

[0074] In a preferred embodiment, step a) is carried out at temperature from 10 to 50°C, preferably from ambient temperature to 40 °C. In particular, step a) is carried out at ambient temperature, namely from 18°C to 25°C. In another particular embodiment, step a) is carried out at a temperature from 30°C to 50°C, preferably from 35°C to 45°C.

[0075] Step a) can also be carried out by stirring the obtained mixture by methods known by the one skilled in the art, such as mechanically for example using a small magnetic stirrer. Preferably, the stirring can be carried out during at least one hour, preferably at least two hours, for example between 1 to 24 hours, such as from 2 to 24 hours, from 2 to 20 hours, from 2 to 15 hours, from 2 to 12 hours, or from 2 to 8 hours.

[0076] In the context of the invention, step b) can be carried out by all methods known by the one skilled in the art. Centrifugating and / or fdtrating can be swapped, centrifugation can be done first followed by filtration, or filtration can be done first followed by centrifugation. Step b) can also consist on centrifugation without filtration or filtration without centrifugation.

[0077] In a particular embodiment, the filtration of step b) can be carried out by means known by the one skilled in the art, such as with a filter membrane with a pore size ranging from 0.20 pm to 0.45 pm.

[0078] The method of the invention can further comprise a step of filing the obtained injectable form into a vial or a syringe, preferably a glass vial. Preferably, the vial has a fill volume of 75 mb at most.

[0079] The method of the invention can further comprise a step of sterilization of the obtained injectable form. The step of sterilization can be carried out by means known by the one skilled in the art such as by autoclaving.

[0080] The obtained injectable form is adapted for being administered by injection or infusion. In particular, the obtained injectable form is adapted for intravenous administration, preferably by bolus injection. The obtained injectable form is also preferably compatible with saline or sterile water for further dilution, for example for intravenous infusion. In particular, the obtained injectable form is adapted for being administered with a syringe.

[0081] Another object of the invention relates to an injectable form comprising Compound A obtainable by the method of the invention. In a particular embodiment of the invention, the injectable form obtainable by the method of the invention is as defined above in the specification. Another object of the invention relates to a pharmaceutical composition comprising the injectable form of the invention or the injectable form obtainable by the method of the invention, and a dilution solvent. In particular, the dilution solvent is selected from the group consisting of sterile water, saline solution (NaCl), a glucose solution at 2.5%, a glucose solution at 5%, sorbitol, mannitol, and mixtures thereof. Preferably, the dilution solvent is sterile water or saline solution (NaCl).

[0082] The pharmaceutical composition of the invention is adapted to administrate Compound A in a content of between 50 mg and 200 mg per dose, preferably 80 mg and 150 mg per dose, more preferably 100 mg / dose.

[0083] The pharmaceutical composition of the invention is adapted for being administered by injection or infusion. In particular, the obtained injectable form is adapted for intravenous administration, preferably by bolus injection.

[0084] Another object of the invention relates to the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for use in a method for the treatment of acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof, in particular of Acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, acute cirrhosis decompensation (AD) or acute liver decompensation in a subject in need thereof. In a particular embodiment of the invention, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is for use in a method for the treatment of Acute on Chronic Liver Failure (ACLF).

[0085] The invention further relates to a method for the treatment of ACLF in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject.

[0086] The invention further relates to a method for the treatment of acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof, in particular of acute liver failure (ALF), decompensated cirrhosis, acute cirrhosis decompensation (AD) or acute liver decompensation in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject. The invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof, in particular of acute liver failure (ALF), decompensated cirrhosis, acute cirrhosis decompensation (AD) or acute liver decompensation in a subject in need thereof, more particularly of ACLF, acute liver failure, decompensated cirrhosis, acute cirrhosis decompensation (AD) or acute liver decompensation, particularly ACLF.

[0087] In the context of the invention, ACLF is an abrupt and life-threatening worsening of clinical conditions in patients with advanced cirrhosis or with cirrhosis due to a chronic liver disease. Three major features characterize this syndrome: it generally occurs in the context of intense systemic inflammation, frequently develops in close temporal relationship with proinflammatory precipitating events (e.g., infections or alcoholic hepatitis), and is associated with single- or multiple-organ failure affecting minimal functioning of vital organs: liver, kidneys, brain, coagulation and / or cardiovascular functions and / or respiratory system. In other terms, ACLF is a multiorgan syndrome that generally develops in subjects with cirrhosis, in particular in subjects with decompensated cirrhosis, with at least one organ failure and with high short-term mortality rate. ACLF can develop in patients with chronic liver disease in response to sur-imposed precipitating factors.

[0088] In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is administered to a subject who has ACLF or is at risk of ACLF. In a particular embodiment, the subject suffers from a chronic liver disease with cirrhosis and is at risk of developing ACLF.

[0089] The term "ALF" describes a disorder characterized by an acute loss of liver function in the absence of pre-existing chronic liver disease. ALF has also been referred to as fulminant hepatic failure, acute hepatic necrosis, fulminant hepatic necrosis, and fulminant hepatitis. ALF is a rare and severe consequence of abrupt hepatocyte injury, and can evolve over days or weeks to a lethal outcome. A variety of insults to liver cells result in a consistent pattern of rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation. The absence of existing liver disease distinguishes ALF from liver failure due to end-stage chronic liver disease (decompensated cirrhosis, acute decompensation and acute-on-chronic liver failure).

[0090] The term "cirrhosis" as used herein, refers to a condition characterized by replacement of liver tissue by fibrosis and regenerative nodules which lead to loss of liver function up to decompensation. Ascites (fluid retention in the abdominal cavity) is the most common complication associated with cirrhosis decompensation. It is associated with a poor quality of life, increased risk of infection and poor long- term outcome. Other potentially life-threatening complications are hepatic encephalopathy and bleeding from esophageal varices. Cirrhosis decompensation has many possible clinical manifestations. These signs and symptoms may be either as a direct result of the failure of liver cells or secondary to the resultant portal hypertension. Effects of portal hypertension include splenomegaly, gastroesophageal varices, and portocollateral circulation as a result of formation of venous collateral veins between portal system and the periumbilical veins as a result of portal hypertension.

[0091] The term “compensated cirrhosis” or “compensated liver cirrhosis (CLC)” as used herein, is defined as cirrhosis with one or more decompensating events, such as ascites, variceal haemorrhage, or hepatic encephalopathy. Patients with CLC are largely asymptomatic with preserved hepatic function.

[0092] The term “decompensated cirrhosis” as used herein, means that the liver is extensively scarred and unable to function properly. Patients suffering from decompensated cirrhosis develop a variety of symptoms such as fatigue, loss of appetite, jaundice, weight loss, ascites and / or edema, hepatic encephalopathy and / or bleeding. Patients at early stages of decompensated cirrhosis are characterized by the presence of ascites with or without esophageal varices in a patient that has never bled. Patients at advanced stages of decompensated cirrhosis are characterized by more sever ascites alone or in association with bleeding, bacterial infections and / or hepatic encephalopathy. Complications associated with decompensated cirrhosis such as ascites, edema, bleeding problems, bone mass and bone density loss, hepatomegaly, menstrual irregularities in women and gynecomastia in men, impaired mental status, itching, kidney function failure and muscle wasting can be developed.

[0093] The term “recompensated cirrhosis” as used herein, refers to at least a partial regression of the structural and functional changes of cirrhosis after removal of the aetiology of cirrhosis. In particular, cirrhosis is considered recompensated cirrhosis when all the following criteria are met (see Baveno-VII consensus and J Clin Exp Hepatol. 2022 Aug 18; 13(2): 329-334. doi: 10.1016 / j.jceh.2022.08.002 . a) Resolution of clinical manifestations such as ascites (without the concurrent use of diuretics), hepatic encephalopathy (HE) (without the use of prophylactic medications), and absence of recurrent variceal bleeding for at least a duration of 12 months; b) Removal or suppression of primary aetiological cause of liver disease such as alcohol abstinence or effective viral suppression. c) Improvement in synthetic liver function such as serum albumin, International Normalized Ratio (INR), and bilirubin.

[0094] The term “acute decompensation” refers to an abrupt deterioration of liver function in patients with advanced chronic liver diseases, compensated cirrhosis or stable decompensated cirrhosis requiring immediate hospitalization. At hospital admission, patients with AD have multiple symptoms including, severe ascites, hepatic encephalopathy, variceal bleeding associated or not with sepsis and / or impaired renal function and / or coagulopathy and / or impaired cardiovascular function and / or impaired respiratory function. AD is a life-threatening condition with an overall mortality rate of 11% at 28-Days.

[0095] The term “chronic liver disease” is used herein to refer to liver diseases associated with a chronic liver injury regardless of the underlying cause. A chronic liver disease may result, for example, from alcohol abuse (alcoholic hepatitis), from viral infectious processes (e.g. viral hepatitis A, B, C, E), autoimmune processes (autoimmune hepatitis), non-alcoholic steatohepatitis (NASH), cancer or chronic exposure to mechanical or chemical injury to the liver. Chemical injury to the liver can be caused by a variety of substances, such as toxins, alcohol, carbon tetrachloride, trichloroethylene, iron or medications.

[0096] In a particular embodiment, the subject with decompensated cirrhosis, AD or ACLF, shows a high MELD score. The term "MELD score" or "Model for End-Stage Liver Disease" as used herein refers to a scoring system for assessing the severity of liver dysfunction. MELD uses the patient's values for serum bilirubin, serum creatinine and the international ratio for prothrombin time (INR) to predict survival. It is calculated according to the following formula:

[0097] MELD= 3.78 [Ln serum bilirubin (mg / dL)] + 11.2 [Ln INR] + 9.57 [Ln serum creatinine (mg / dL)] + 6.43 wherein, Ln means Napierian logarithm.

[0098] The term "high MELD score" as used herein, refers to a patient having a MELD score higher than 9, for example, at least 10, at least 15, at least 19, at least 20, at least 25, at least 29, at least 30, at least 35, at least 39, at least 40, at least 45 or more. In a particular embodiment, the present invention is applied to a subject having a MELD score higher than 20.

[0099] Another object of the invention relates to the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for use in a method for the treatment of sepsis, preferably of polymicrobial sepsis or sepsis-associated ACLF, in a subject in need thereof.

[0100] In the context of the invention, the term "sepsis" as used herein refers to a deleterious systemic inflammatory response to infection, formally defined as the presence of infection together with systemic manifestations of infection. The term sepsis as used herein encompasses sepsis, at any degree of severity, and complications thereof such, such as sepsis with multiple organ failure and septic shock.

[0101] In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is administered to a subject who suffers from or is at risk of sepsis with multiple organ failure. In another embodiment, the subject suffers from or is at risk of septic shock.

[0102] In another particular embodiment, the subject suffers from sepsis caused by one or more microbial species. In particular, the subject may suffer from sepsis caused by a bacterial, fungal or viral infection. In yet another embodiment, said sepsis is caused by a bacterial infection. In another particular embodiment, the subject suffers from or is at risk of sepsis with multiple organ failure.

[0103] In another particular embodiment, the subject suffers from or is at risk of septic shock.

[0104] In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is for use in a method for treating polymicrobial sepsis in a subject in need thereof.

[0105] In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is for use in a method for treating sepsis-associated ACLF in a subject in need thereof. In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is for use in a method for treating a sepsis caused by a bacterial infection in a subject in need thereof.

[0106] In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is for use in a method for treating sepsis with multiple organ failure.

[0107] In a particular embodiment, the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, is for use in a method for treating a septic shock.

[0108] The invention further relates to a method for the treatment of sepsis in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject.

[0109] In a particular embodiment, the invention further relates to a method for the treatment of polymicrobial sepsis in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject.

[0110] In a particular embodiment, the invention further relates to a method for the treatment of sepsis- associated ACLF in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject..

[0111] In a particular embodiment, the invention further relates to a method for the treatment of a sepsis caused by a bacterial infection in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject.

[0112] In a particular embodiment, the invention further relates to a method for the treatment of a sepsis with multiple organ failure in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject.

[0113] In a particular embodiment, the invention further relates to a method for the treatment of a septic shock in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of Compound A comprised in the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, to said subject.

[0114] The invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of sepsis.

[0115] In a particular embodiment, the invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of polymicrobial sepsis.

[0116] In a particular embodiment, the invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of sepsis-associated ACLF.

[0117] In a particular embodiment, the invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of sepsis caused by a bacterial infection.

[0118] In a particular embodiment, the invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of a sepsis with multiple organ failure.

[0119] In a particular embodiment, the invention further relates to the use of the injectable form of the invention, or the injectable form obtainable by the method of the invention, or the pharmaceutical composition of the invention, for the preparation of a medicament for the treatment of septic shock. In the context of the present invention, the compound of general formula (I) is administered to a subject, in a therapeutically effective amount. A "therapeutically effective amount" refers to an amount of the drug effective to achieve a desired therapeutic result. A therapeutically effective amount of a drug may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of drug to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of agent are outweighed by the therapeutically beneficial effects. The effective dosages and dosage regimens for drug depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of drug employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable dose of a composition of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above.

[0120] The frequency and / or dose relative to the administration can be adapted by one of ordinary skill in the art, in function of the patient, the pathology, the form of administration, etc. Typically, the compound of the invention can be administered at a dose comprised between 0.01 mg / day to 4000 mg / day, such as from 50 mg / day to 2000 mg / day, such as from 100 mg / day to 2000 mg / day; and particularly from 100 mg / day to 1000 mg / day. Administration can be performed daily or even several times per day, if necessary. In one embodiment, the compound is administered at least once a day, such as once a day, twice a day, or three times a day. In a particular embodiment, the compound of the invention is administered once or twice a day. In particular, oral administration may be performed once a day, during a meal, for example during breakfast, lunch or dinner, by taking a tablet comprising the compound of the invention.

[0121] Suitably, the course of treatment with the compound of the invention is for at least 1 week, in particular for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 24 weeks or more. In a particular embodiment, the course of treatment is for at least 1 month, at least 2 months or at least 3 months. In a particular embodiment, the course of treatment is for at least 1 year, or more depending on the condition of the subject being treated.

[0122] EXAMPLES

[0123] Example 1: preparation of Compound A according to the invention

[0124] Compound A of formula (I) can be synthetized following general procedures disclosed in WO2018 / 187506. Example 2: Effects of the formulation of the invention in comparison with other solvents

[0125] Several solvents have been tested to compare the solubility of Compound A and the stability of the prepared formulations.

[0126] Generalized procedure:

[0127] The following procedure is applicable for all batches with one single solvent or a combination of one solvent and one co-solvent, prepared in Example 2:

[0128] Solvent volume: 75 m ;

[0129] Target amount of API: 4 mg / mL total 300 mg;

[0130] Mixing the solvent (and the cosolvent where applicable) with API (=Compound A) and shaking for at least 20 hours a ambient temperature.

[0131] Centrifugating and / or filtrating to remove undissolved API.

[0132] The following second procedure could also be used for all batches with one solvent and one co-solvent prepared in Example 2:

[0133] Final batch size: 75 mb;

[0134] Mixing the solvent with API (Compound A) at target concentration of 5 mg / mL total 375 mg per batch (see Table 2 for solvent ratios used);

[0135] Shaking for at least 15 hours at ambient temperature;

[0136] Adding the co-solvent, see Table 2 for solvent ratios used;

[0137] Shaking for at least 2 hours at ambient temperature;

[0138] Centrifugating and / or filtrating to remove undissolved API.

[0139] Dilution samples:

[0140] Prepared bulk solutions were diluted lOx with saline solution and water. The dilutions are visually checked for precipitation of API.

[0141] Analysis overview:

[0142] All samples have been evaluated for the selected CQAs as described in Table 1 below:

[0143] Table 1: Analytical overview

[0144] Solvents preparation:

[0145] Table 2 shows the solvents or combinations of solvent used for these experiments. Table 2: Solvents

[0146] Batch preparation:

[0147] All solvents were tested fortheir maximum solubility of API. Based on the current knowledge 4 mg / mL API was expected to be above the maximum solubility, and would form a saturated solution for each solvent.

[0148] The target composition for all batches was: 75 g solvent* + 300 mg API, resulting in a concentration of The actual compositions of all batches are listed in Table 3.

[0149] Table 3 : Batches composition

[0150] API addition to the solvents:

[0151] After API addition to each of the solvents all batches resulted in a turbid suspension. Batch 0011 (85% ethanol) appears to be clear after API addition, but in this case the API sedimented fast to the bottom. After overnight dissolution all other batches remain turbid with little to no difference in appearance compared to the start of dissolution.

[0152] Samples for assay analysis

[0153] For each batch weighing 2x 8 mb of unfiltered bulk in two 15 mb tubes.

[0154] Centrifuging all tubes - For each 15 mb tube, transferring all supernatants to a 10 mb syringe with syringe filter attached.

[0155] Filtering the supernatant. Combining the filtrate of the two syringes per batch in one collection vial. Appearance after centrifugation:

[0156] The centrifugation and filtration steps resulted in samples that were clear and visually particle free. The prepared samples are analyzed for assay and used for dilution study.

[0157] Assay results

[0158] The filtered samples were analyzed for assay. The content of Compound A in the batches after filtration is measured by UV HPLC. See Table 4 for a result overview.

[0159] Table 4: Assay result of batches

[0160] Diluted samples: For each batch, 1 mb of filtered material was diluted with saline solution or sterile water (WFI).

[0161] The evaluation of the dilutions is done by checking directly after dilution, after 8 hours and a last check 24 hours after dilution. Dilutions are evaluated on the presence of precipitation.

[0162] Table 5 is a descriptive overview of the diluted samples. Table 5

[0163] Example 3: Effects on osmolality

[0164] To investigate the impact of the solvents on osmolality, samples are prepared for osmolality measurements. Three pure solvents and two dilutions of bulk formulations were measured. The pure solvents were:

[0165] • Propylene glycol

[0166] • PEG300

[0167] • Ethanol

[0168] The bulk formulations selected contained mixtures of the selected solvents:

[0169] • 003A: 75% Propylene glycol + 25% PEG300

[0170] • 003B: 50% Propylene glycol + 50% PEG300

[0171] • 005A: 40% w / w PEG300 + 60% w / w PEG400

[0172] • 005B: 44% w / w PEG300 + 56% w / w PEG400

[0173] • 005C: 49% w / w PEG300 + 51% w / w PEG400

[0174] • 005D: 40% w / w PEG300 + 57.5% w / w PEG400 + 2.5% w / w Propylene glycol

[0175] • 005E: 44% w / w PEG300 + 53.5% w / w PEG400 + 2.5% w / w Propylene glycol

[0176] • 005F: 50% w / w PEG300 + 47.5% w / w PEG400 + 2.5% w / w Propylene glycol

[0177] The estimated percentage of solvents after dilution was between 10% and 5%. Based on the obtained values shown in Table 6, it can be concluded that the osmolality of the diluted bulk batches could be higher than the assumed osmolality specification of 280 - 330 mOsmol / kg.

[0178] A 16x dilution of batch 003A to a concentration of 0. 19 mg / mL API was estimated to be approximately 500 mOsmol / kg using a linear correlation of the 10 times diluted sample.

[0179] Table 6: Osmolality samples

Claims

CLAIMS1. An injectable form comprising: i) Compound A of the following formula (I):ii) A solvent selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), and mixtures thereof; and iii) A co-solvent selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), propylene glycol, and mixtures thereof.

2. The injectable form according to claim 1, wherein the content of Compound A is at least 1.5 mg / mL.

3. The injectable form according to claim 1 or 2, wherein the content of Compound A is at least 2 mg / mL, preferably at least 2.5 mg / mL, more preferably 2.6 mg / mL.

4. The injectable form according to any one of claims 1 to 3, wherein solvent (ii) is selected from the group consisting of PEG300, PEG400, PEG600, and mixtures thereof, preferably PEG300, PEG400, and mixtures thereof, more preferably solvent (ii) is PEG300.

5. The injectable form according to any one of claims 1 to 4, wherein co-solvent (iii) is selected from the group consisting of PEG300, PEG400, PEG600, propylene glycol, and mixtures thereof, preferably PEG300, PEG400, propylene glycol, and mixtures thereof, more preferably PEG400, propylene glycol, or mixtures thereof, more preferably co-solvent (iii) is PEG400.

6. The injectable form according to any one of claims 1 to 5, wherein solvent (ii) is PEG300 and cosolvent (iii) is PEG400.

7. The injectable form according to claim 6, wherein the weight ratio PEG300:PEG400 is between about 0.2 and about 1, preferably between 0.5 and 1, preferably between 0.5 and 0.8, more preferably8. The injectable form according to any one of claims 1 to 7, having a density within the range of 1 g / L and 1.3 g / L, preferably within the range of 1.10 g / L and 1.20 g / L, more preferably 1.12 g / L.

9. The injectable form according to any one of claims 1 to 8, having an osmolality within the range of 275 mOsmo / kg and 330 mOsmo / kg after dilution.

10. A method for preparing an injectable form comprising Compound A of following formula (I):said method comprising the following steps: a) Preparing a solution comprising Compound A in a content of at least 1.5 mg / mL, a solvent (ii) and optionally a co-solvent (iii); and b) Centrifugating and / or filtrating to remove undissolved API, wherein solvent (ii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), and mixtures thereof; and wherein co-solvent (iii) is selected from the group consisting of polyethylene glycols having a molecular weight from 300 Da to 600 Da (PEG300-PEG600), propylene glycol, and mixtures thereof.

11. The method of claim 10, wherein the injectable form is as defined in any one of claims 1 to 9.

12. An injectable form comprising Compound A of following formula (I):obtainable by the method of claim 10 or 11.

13. A pharmaceutical composition comprising the injectable form according to any one of claims 1 to 9 or 12, and a dilution solvent, the dilution solvent being preferably selected from the group consisting of sterile water, saline solution (NaCl), a glucose solution at 2.5%, a glucose solution at 5%, sorbitol, mannitol, and mixtures thereof.

14. The injectable form according to any one of claims 1 to 9 or 12 or the pharmaceutical composition according to claim 13, for use in a method for the treatment of Acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof, in particular of Acute on Chronic Liver Failure (ACLF), acute liver failure, decompensated cirrhosis, acute cirrhosis decompensation, or acute liver decompensation in a subject in need thereof.

15. The injectable form according to any one of claims 1 to 9 or 12 or the pharmaceutical composition according to claim 13, for use in a method for the treatment of sepsis, preferably of polymicrobial sepsis, or sepsis-associated ACLF in a subject in need thereof.

16. A method for the treatment of Acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof, in particular of acute liver failure (ALF), decompensated cirrhosis, acute cirrhosis decompensation (AD) or acute liver decompensation in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form as defined in any one of claims 1 to 9 and 12, or the pharmaceutical composition as defined in claim 13, to said subject.

17. A method for the treatment of sepsis, preferably of polymicrobial sepsis, or sepsis-associated ACLF, in a subject in need thereof, said method comprising the administration by injection of a therapeutically effective amount of Compound A comprised in the injectable form as defined in any one of claims 1 to 9 and 12, or the pharmaceutical composition as defined in claim 13, to said subject.

18. Use of the injectable form as defined in any one of claims 1 to 9 and 12, or the pharmaceutical composition as defined in claim 13, for the preparation of a medicament for the treatment of acute on Chronic Liver Failure (ACLF), acute liver failure (ALF), compensated cirrhosis (also called compensated liver cirrhosis (CLC)), decompensated cirrhosis, acute cirrhosis decompensation (AD), recompensated cirrhosis, or acute liver decompensation in a subject in need thereof, in particular of acute liver failure (ALF), decompensated cirrhosis, acute cirrhosis decompensation (AD) or acute liver decompensation in a subject in need thereof.

19. Use of the injectable form as defined in any one of claims 1 to 9 and 12, or the pharmaceutical composition as defined in claim 13, for the preparation of a medicament for the treatment of sepsis, preferably of polymicrobial sepsis, or sepsis-associated ACLF, in a subject in need thereof.

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