EA047306B1 - COMPOSITION OF SYSTEMIC ACTION OF PYRIDINONE DERIVATIVE FOR TG2-ASSOCIATED DISEASES - Google Patents

Description

The invention relates to a systemic formulation, in particular an oral formulation for the prevention and/or treatment of TG2-related diseases such as fibrosis, in particular nephropathy, fibrotic liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) , idiopathic pulmonary fibrosis (IPF) and cystic fibrosis, and to its use in the prevention and/or treatment of fibrosis, in particular nephropathy, fibrotic liver diseases, including NAFLD and NASH, idiopathic pulmonary fibrosis and cystic fibrosis.

Furthermore, the present application also relates to the use of (S,E)-methyl-7-(1-(2-(2-ethylbutyl amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7 oxohept-2-enoate as a hepatoprotector, that is, as a hepatoprotective agent.

The present invention also relates to a pharmaceutical composition containing (S,E)methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-Shimidazole-5-carboxamido)-7-oxohept-2-enoate, for use as a hepatoprotective agent and for use in protecting the liver from liver toxicity, for improving liver function and/or repairing liver damage or prevention or treatment of liver disease or liver disorder, as evidenced by a decrease in serum levels of liver enzymes.

State of the art

Steatohepatitis is a type of fatty liver disease characterized by inflammation of the liver with simultaneous accumulation of fat in the hepatocytes. The simple deposition of fat in the liver is called steatosis, and together they mean fatty liver changes.

There are two main types of fatty liver disease: alcohol-related fatty liver disease and non-alcoholic fatty liver disease (NAFLD). Risk factors for NAFLD include diabetes, obesity, and metabolic syndrome. When inflammation is present, it is called alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH). Untreated steatohepatitis can cause fibrosis and subsequent cirrhosis, and NASH is now thought to be a common cause of unexplained cirrhosis.

Diabetic nephropathy is a kidney disease that develops due to diabetes mellitus (DM). Diabetes mellitus and type 2 diabetes mellitus (T2DM) are the most common cause of end-stage renal disease (ESRD). Diabetic nephropathy usually results in chronic and progressive degradation of kidney function, to the point where the patient must undergo dialysis or receive a transplant to survive. The initial stage of subtle morphological changes in the renal glomeruli is replaced by microalbuminuria. It is associated with a mild increase in blood pressure and an increase in the incidence of cardiovascular disease. This is followed by a continued increase in urinary protein excretion and determination of glomerular filtration rate. Diabetic nephropathy has many possible underlying pathophysiologic causes, including metabolic, protein glycosylation, hemodynamics, changes in glomerular blood flow/pressure, development of hypertension, and cytokine production; all of them are associated with the development of the extracellular matrix and increased vascular permeability, which leads to glomerular damage and proteinuria.

Huang et al (Kidney International 2009, 76, 383-394) describe a dipeptide derivative (NTU281) as an irreversible TG2 inhibitor. One of the disadvantages of this dipeptide derivative is that the dipeptide derivative must be administered locally to the kidney by an implanted osmotic pump. Systemic formulation of Johnson's dipeptide derivative is not permitted based on this indication because TG2 is ubiquitously expressed in almost all cell types and cellular compartments, is present on the cell surface and secretes into the extracellular matrix, and is present in various organs such that undesirable inhibitor effects may occur when administered. Non-target TG2s are most likely.

Huang et al describe an implanted osmotic pump containing the topical drug NTU281 (drug) in phosphate-buffered saline as a vehicle (50 mmol/L). Therefore, the osmotic pump must be implanted by surgery associated with anesthesia. Although anesthesia is commonly used in medicine, there is always a significant risk of complications, especially when treating vulnerable populations such as children and the elderly. Implanting an osmotic pump into the patient's body creates an additional risk for the patient, since electronic devices such as pumps are sensitive under physiological conditions and may, for example, burst, and are therefore not always reliable. Moreover, the pump must be maintained, which causes additional suffering for the patient. In addition, patient compliance can be significantly improved because the obstacle associated with surgery is eliminated. An implanted osmotic pump containing a topical dosage form cannot be used in humans.

Lauzier et al (Arthritis Research Therapy 2012, 14, R159) describe the effect of cystamine or an RNA derivative on TG2 inhibition by cystamine, a competitive TGase inhibitor, on invadopodia formation and cartilage destruction in arthritis. Cystamine is a disulfide containing two amino groups.

- 1 047306

Luciani et al (Nature Cell Biology 2010, 12, 863-875) describe the effects of cystamine and siRNA on lung inflammation in cystic fibrosis.

Luo et al (Journal of the American Heart Association, 2016, 1-12) disclose the effects of 1,3-dimethyl-2[(2-oxopropyl)thio]-imidazolium (R283) or the transglutaminase inhibitor halodihydroisoxazole derivative (KCC009) on inflammation with cystic fibrosis.

Olsen et al. (American Journal of Respiratory Cell and Molecular Biology 2014, 50, 737-747) reveal the influence of small electrophilic compounds, 2-cyano-3,12-dioxooleane-1,9-dien-28-oic acid and 15- deoxydelta-12,14-prostaglandin J2, on pulmonary fibrosis.

Sanchez-Lara et al (Veterinary Pathology 2015, Vol. 52(3) 513-523) describe the effects of 1,3dimethyl-2[(oxopropyl)-thio]imidazolium chloride (D003, Zedira), the non-selective TG inhibitor NTU281 or monoclonal antibody BB7 for chronic kidney disease.

In the pharmaceutical field, it remains a major challenge to establish the proper bioavailability of a drug under physiological conditions, particularly in the case of systemic therapy.

The purpose of the present invention is to create agents for the treatment of diabetic nephropathy and/or non-alcoholic steatohepatitis, exhibiting bioavailability and high antifibrotic effect along with low side effects.

Another object of the present invention is to provide a compound for use as a hepatoprotector, that is, a hepatoprotective agent, and for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating liver disease.

The object of the present invention is achieved by disclosing independent claims. Additional useful features, aspects and details of the invention will be apparent from the dependent claims, description, figures and examples of this application.

Brief description of the invention

The object of the present invention is achieved by a composition, preferably a systemic composition, containing (8,E)-me ^, til-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I), or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I). Here, the compound of formula (I) is also called compound 1 or Compound 1.

Surprisingly, it has been found that a compound of formula (I) can be used to reduce fibrosis, in particular fibrosis caused by diabetic nephropathy and non-alcoholic steatohepatitis. The compound contains a pyridinone moiety as the main structural element. Moreover, surprisingly, the compound of formula (I) can be used in the prevention and treatment of nephropathy, in particular diabetic nephropathy, liver fibrosis and cystic fibrosis, as a systemic drug, that is, the drug is distributed through the blood or lymphatic system throughout body. This is especially surprising due to the fact that TG2 is expressed ubiquitously in almost all cell types and cellular compartments, is present on the cell surface and secreted into the extracellular matrix, and is also present in various organs, and therefore suggests that off-target effects were would be the most likely. A study in NASH and mouse models confirms the antifibrotic effect on the liver and kidneys achieved by administration of a systemic preparation containing the compound of formula (I) (Example 2 and 3). Moreover, positive data from a bioavailability study in mice (Example 4) also confirm the bioavailability of compound (I) when administered systemically in vivo. Surprisingly, it was found that the bioavailability of compound (I) can be significantly increased in humans when using a systemic drug (Example 7).

In addition, the systemic formulation eliminates the use of devices such as an osmotic pump, such as those used by Johnson et al., and implantation of the said device can be completely avoided, and, therefore, the administration of the drug is objectively easier, more reliable, safer, and patient suffering can be significantly reduced. and objectively reduced. The composition in accordance with the invention can be introduced much more easily than the composition of the state of the art. In addition, the composition according to the invention exhibits a higher antifibrotic effect and, therefore, gives a better therapeutic result.

Diabetes is also often associated with NASH (non-alcoholic steatohepatitis), which is a common cause of unexplained cirrhosis of the liver. It is clear that concomitant treatment of NASH is often required

- 2 047306 and diabetic nephropathy. The systemic composition of the invention can be used to simultaneously target the liver (NASH) and kidneys (diabetic nephropathy). Similarly, cholestatic liver diseases such as PSC (primary sclerosing cholangitis) and PBC (primary biliary cholangitis) are fibrotic liver diseases that are often associated with cholemic nephropathy, a chronic and fibrotic inflammation of the kidneys caused by high exposure to endogenous bile acids. It is also possible to simultaneously treat the kidneys and preventive treatment of the liver, and vice versa. Thus, it is obvious that the systemic composition of the invention allows its use in a new clinical situation. Additionally, cystic fibrosis is often associated with diabetes. It can be seen that the systemic composition containing (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate exhibits the same antifibrotic effect in the liver and kidneys (example 5).

Description of the invention

The term systemic formulation refers to a pharmaceutical composition suitable for administration such that the drug or active agent is administered systemically throughout the body, for example, a circulatory system form of the drug so that the entire body is exposed. Administration may occur by enteral administration (absorption of the drug through the gastrointestinal tract) or parenteral administration (eg, pulmonary, nasal, injection, or infusion). Preferably, the term systemic formulation excludes an intravenous formulation.

The circulatory system, also called the cardiovascular system or vascular system, is the organ system in the body that allows blood to circulate and transport nutrients (such as amino acids and electrolytes), oxygen, carbon dioxide, hormones, and blood cells to and from blood cells , to provide nutrition and promote disease control, stabilize temperature and pH, and maintain homeostasis.

The circulatory system includes the lymphatic system, which circulates lymph. The passage of lymph, for example, takes much longer than the passage of blood. Therefore, the term systemic formulation refers to a formulation where the drug is distributed throughout the body, for example through the circulatory or lymphatic system throughout the body, for example after intravenous or intramuscular injection or after taking a tablet, that is, after enteral, in particular oral or parenteral administration.

The systemic formulations disclosed herein are preferably in the form of a tablet, coated tablet, capsule, powder or granule.

In contrast, a topical formulation is a formulation that is applied to the specific location on or in the body where it is intended to act. Local means place, locally, in a specific place, externally or limited to a specific area of the body. As a result, the risk of possible unwanted side effects in other areas of the body can be reduced. Most often, topical administration means application to a body surface, such as the skin or mucous membranes, to treat diseases using a wide range of drug classes including creams, foams, gels, lotions and ointments. Many topical medications are cutaneous, meaning they are applied directly to the skin. Topical medications may also be inhaled, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva or ear drops applied to the ear, medications applied to the surface of a tooth, or administering the drug using a pump, such as an osmotic pump.

Topical formulations include auricular, buccal, endobronchial, epicutaneous, inhalational, intraarticular, gluteus maximus, intracardiac, intradermal, intralumbar, intralymphatic, intramammary, intranasal, intraneuronal, intraocular, intraorbital, intraosseous, intrapericadial, intrapulmonary, intrathecal, intratracheal, intraurethral, intrauterine, intraventricular, intravesical, intravitreal, conjunctival, cutaneous, nasal, perineural, retrobulbar, subconjunctival, vaginal and ciliary formulations.

The term parenteral formulation as used herein refers to a formulation that is typically administered by injection or infusion and includes, but is not limited to, epidural, intraarterial, intravenous, intravasal, intravascular, intramuscular, intraperitoneal, intrapleural, subcutaneous, intradermal, and transdermal injection and infusion. Preferably, the parenteral drug is selected from the group consisting of or consisting of epidural, intravasal, intravascular, intramuscular, intraperitoneal, intrapleural, subcutaneous, intradermal and transdermal injection and infusion. Preferably, intra-arterial and intravenous formulations are excluded from parenteral formulations.

An enteral formulation, as used herein, refers to a formulation, typically a medicinal product, that is absorbed through the mouth (per os, orally, orally): tablets, dragees, capsules, juices, drops, etc. These drugs are absorbed into the blood in the gastrointestinal

- 3 047306 tract, then enter the liver through the portal vein system, and then into the bloodstream through the hepatic vein. The term as used herein refers to a formulation that is typically administered, without limitation, by enteral, intragastric, sublingual, oral (oral) and rectal routes. Preferably, the enteral formulation includes a formulation selected from the group consisting of or consisting of an enteral, intragastric, sublingual, oral (oral) and rectal formulation.

An oral formulation, as used in the invention, refers to a formulation that is a medicinal product that is absorbed through the mouth (per os, orally, orally): tablets, dragees, capsules, juices, drops, etc. These drugs are absorbed into the bloodstream in the gastrointestinal tract, then enter the liver through the portal vein system, and then into the bloodstream through the hepatic vein. The term as used herein refers to a formulation that is administered orally.

The systemic formulation may be in liquid or solid form, including solutions, oral drops, suspensions, emulsions, powders and granules such as effervescent granules, tablets such as uncoated tablets, coated tablets, effervescent tablets, soluble tablets, chewable tablets, oral lyophilisates, lozenges, lozenges, compressed lozenges, sublingual tablets, buccal tablets, granules, effervescent granules and capsules. For example, the systemic formulation may be a liquid formulation, including oral solutions, suspensions, emulsions, powders and granules for oral solutions and suspensions, oral drops, powder for oral drops, syrups, and powder and granules for syrups; or in solid form, including uncoated tablets, coated tablets, effervescent tablets, dissolvable tablets, chewable tablets, oral lyophilisates, lozenges, lozenges, compressed lozenges, sublingual tablets, buccal tablets, granules, effervescent granules and capsules. Uncoated and coated tablets and capsules, either hard or soft, are the preferred pharmaceutical formulations. Most preferably, the composition is a tablet or capsule. By way of example, mention may be made of aqueous or aqueous propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Preferably, the systemic formulation is a solid formulation, more preferably a solid enteral formulation, and most preferably a solid oral formulation.

Topical administration, as used in the invention, refers to the administration of a composition for topical use.

Systemic administration, as used in the invention, refers to the administration of a systemic action composition.

Topical availability, as used herein, refers to the release of a drug from its formulation, such as a formulation carrier or tablet, to the site where the drug must be absorbed by a specific tissue or organ for the drug to act at all.

Systemic availability, as used herein, refers to the proportion of a drug dose that reaches the systemic circulation unchanged after administration by a route other than intravenous administration. The term systemic availability also refers to the extent to which a drug or other substance is absorbed by a specific tissue or organ after administration. For example, a drug that is administered orally and that crosses the intestinal epithelial barrier is located in the intestinal tissue, and therefore it has systemic availability or, in other words, it is systemically available. Systemic availability and systemically available are synonymous with bioavailability or bioavailability. Therefore, locally administered compounds may also exhibit systemic availability.

The term drug level refers to the level of drug in the plasma, tissue or organ, and the phrase systemic availability at the target site refers to the same aspect.

As used herein, the term pharmaceutically acceptable salts refers to salts of certain ingredients that have the same activity as the unmodified compounds and that are neither biologically nor otherwise undesirable.

The pharmaceutically acceptable salt can be formed, for example, with organic and inorganic acids. Suitable acids include acetic acid, acetylsalicylic acid, organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid or glutamic acid, and organic tricarboxylic acid, such as citric acid or sodium hydrogen citrate, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzene sulfonic acid, bisulfic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentane propionic acid, digluconic acid acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphoric acid, glycine, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid

- 4 047306 slot, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthylsulfonic acid, naphthalic acid, nicotinic acid, nitrous acid, oxalic acid, pelargonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid, tosylic acid, undecenoic acid and amino acids of natural and synthetic origin. Preferably the acid is adipic acid.

Thus, a preferred embodiment of the present invention relates to the salt of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3- ylamino)-6-(1 methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I), and adipic acid.

Another preferred embodiment of the invention relates to a systemic formulation containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I), and adipic acid, or an enantiomer, solvate or hydrate of a salt of formula (I) and adipic acid.

As used herein, the term solvates refers to such forms of the compound, in particular (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, which form a complex due to coordination with solvent molecules.

As used herein, the term hydrates refers to such forms of the compound, in particular (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate, which form a complex due to coordination with water molecules.

As used in the invention, the term effective amount or therapeutically effective amount of an active agent, or a pharmaceutically active agent, or a drug, or an active pharmaceutical ingredient, which are synonyms, refers to the amount of an active agent, or a pharmaceutically active agent, or a drug, or an active pharmaceutical ingredient sufficient to produce a beneficial effect. Accordingly, these amounts are effective for the disease being treated, but low enough to avoid serious side effects. A therapeutically effective amount of the pharmaceutically active agent will produce significant symptomatic relief when administered repeatedly over time. The effective amount of the pharmaceutically active agent will vary depending on the particular condition or conditions being treated, the severity of the condition, the duration of treatment, the specific components of the composition used, and similar factors.

As used herein, the term active agent, pharmaceutically active agent, drug or active pharmaceutical ingredient, which are used interchangeably herein, refers to a compound having a therapeutic effect in a mammal, particularly a human.

As used herein, the term pharmaceutical composition refers to a composition that, when administered, exhibits a therapeutic effect in a mammal.

The systemic formulations of the invention described herein preferably contain (S,E)methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-shimidazole-5-carboxamido)-7-oxohept-2-enoate.

An embodiment of the present invention thus relates to the composition of a system

- 5 047306 action containing ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I).

In addition, the systemic formulation may be an enteral or parenteral formulation. An embodiment of the invention therefore relates to a systemic formulation containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, wherein the systemic formulation is in the form of an enteral or parenteral administration.

Preferably, the systemic formulation is in the form of an oral formulation. An oral formulation is a specific form of a formulation for enteral administration. Thus, a preferred embodiment of the invention relates to a systemic formulation containing (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, wherein the systemic formulation is in the form of an oral formulation .

In addition, ^3)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III α-imidazole-5-carboxamido)-7-oxohept-2-enoate can be administered in the form of its pharmaceutically active salts, solvate or hydrate, optionally using substantially non-toxic pharmaceutically acceptable excipients. Suitable dosage formulations are prepared in a known manner in a conventional solid or liquid carrier using pharmaceutically acceptable excipients.

Thus, the systemic composition of the invention may additionally contain an excipient. An embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1 ,2dihydropyridin-3-yl-amino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient.

After administration of the systemic composition, the administered dose of the drug should dissolve quickly and completely. Changes in gastric pH after oral administration must be regulated and dissolution of the administered dose of the formulation must be ensured. The higher the systemic availability (AUC) combined with mucosal release in the small intestine, the higher the expected pharmacological effect.

The excipient may be an acidifying agent. The term acidifier refers to a substance that, when dissolved in water, produces a pH level of less than 7.0. Thus, the systemic formulations of the invention may contain an acidifying agent. Acidulants include organic acids such as ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanedioic acid) or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate. Preferably the acidulant is adipic acid.

Preferred acidulants for systemic formulations disclosed herein are selected from the group consisting of ascorbic acid, organic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, glutamic acid, and organic tricarboxylic acids such as citric acid and sodium hydrogen citrate.

More preferred acidulants for systemic formulations disclosed herein are selected from the group consisting of adipic acid, fumaric acid, glutaric acid.

Thus, the systemic composition of the invention may contain an acidifying agent.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is an acidifying agent.

Another preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxo-ethyl)-2-oxo-1,2 -dihydro

- 6 047306 pyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one acidifier.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least at least one excipient is an acidifying agent, and wherein the at least one acidifying agent is selected from the group consisting of or consisting of an organic dicarboxylic acid and an organic tricarboxylic acid. Preferably, at least one acidulant is selected from the group consisting of an organic dicarboxylic acid and an organic tricarboxylic acid. More preferably, at least one acidulant is selected from the group consisting of or consisting of an organic dicarboxylic acid and an organic tricarboxylic acid. Even more preferably, at least one acidulant is selected from the group consisting of an organic dicarboxylic acid and an organic tricarboxylic acid.

Thus, a preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one acidifying agent wherein the at least one acidulant is selected from the group consisting of an organic dicarboxylic acid and an organic tricarboxylic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least at least one excipient is an acidulant, and wherein at least one acidulant is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid acid (hexanedioic acid) or glutamic acid. Preferably, at least one acidulant is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanedioic acid) or glutamic acid. More preferably, at least one acidulant is selected from the group containing or consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanedioic acid) or glutamic acid . Even more preferably, at least one acidulant is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanedioic acid) or glutamic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one acidifying agent, wherein at least At least one acidulant is selected from the group containing or consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanedioic acid) or glutamic acid.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate and at least one excipient or enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, wherein, at least one excipient is an acidifying agent, the acidifying agent being adipic acid, fumaric acid, glutaric acid.

A particularly preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, and at least one excipient or enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, where the at least one excipient is an acidulant, wherein the acidulant is adipic acid.

A particularly preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one

- 7 047306 acidifying agent, where at least one acidifying agent is adipic acid.

A particularly preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and adipic acid.

The drug solution is transferred to the small intestine after passing through the stomach. This passage, at least on an empty stomach, is associated with an increase in pH from approximately 2 to 6. The drug dose must remain in solution, that is, the drug must not precipitate. This effect can be achieved by adding a polymer sediment inhibitor. Thus, the polymer precipitation inhibitor inhibits the crystallization of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5-carboxamido)-7-oxohept2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and functions as a crystallization inhibitor.

Polymer sedimentation inhibitors are polymers capable of stabilizing the supersaturation stage of a drug, that is, they prevent the nucleation of drug molecules or the growth of initially formed drug particles, which is achieved by coating the surface of the drug particles, thereby preventing particle-particle interaction, or by increasing the viscosity of the suspension medium. The ability of sedimentation inhibitors to kinetically stabilize the supersaturated state of a drug is believed to result from intermolecular interactions between the drug and the polymer in solution (e.g., through hydrogen bonding or hydrophobic interactions), the ability of the polymer to sterically interfere with the crystallization process, or by increasing the viscosity of the suspension medium, and not by increasing the solubility of the drug, that is, by increasing the equilibrium solubility.

The saturation solubility of this compound is low at small intestinal pH (Example 10 and FIG. 11). The solution is stabilized by adding a polymeric sediment inhibitor, which can also act as a binder. When a drug is exposed to an aqueous environment, the polymeric sedimentation inhibitor slows down the precipitation or crystallization of the drug, preferably through complexation.

In addition, the polymer sedimentation inhibitor increases the viscosity of the medium, which further enhances the effect.

Thus, the systemic composition of the invention may also contain a polymeric deposition inhibitor. Therefore, the excipient may be a polymeric precipitation inhibitor.

The term polymeric precipitation inhibitor refers to a material that retards the precipitation or crystallization of a drug.

The polymer sediment inhibitor includes cellulose derivatives, starch derivatives, dextran/dextrin derivatives, polyether derivatives, polyvinyl derivatives, polyacrylic acid derivatives and polyamine derivatives, polysulfonic acid derivatives, and combinations thereof.

In some embodiments, the polymeric deposition inhibitor is selected from the group consisting of or consisting of:

cellulose derivatives including, but not limited to, microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC ), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose ( HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate);

starch derivatives, including, but not limited to, hydroxyethyl starch, hydroxypropyl starch (HPS) and pregelatinized starch;

dextran/dextrin derivatives, including, but not limited to, cyclodextran (i.e., cycloisomaltoheptaose (CI-7), cycloisomaltooctaose (CI-8), cycloisomaltoheptaose (CI-9)), hydroxypropyldextran, maltodextrin, a-/b-/', '-cyclodextrin. 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (HPeCD), β-cyclodextrin sulfobutyl ether sodium salt, methylated β-cyclodextrin, 2-hydroxypropyl-/-cyclodextrin;

polyether derivatives including, but not limited to, polyethylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO, poloxamer) such as poloxamer 188 and poloxamer 407;

- 8 047306 polyvinyl derivatives, including, but not limited to, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-co-polyvinyl acetate (PVPVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®);

polyacrylic acid derivatives including, but not limited to, poly(acrylic acid) (PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly( methacrylic acid/ethyl acrylate);

polyamine derivatives including, but not limited to, polyethylenimine (PEI), polyallylamine hydrochloride, polydiallyl-dimethylammonium chloride and poly(2-ethyl-2-oxazoline);

polysulfonic acid derivatives, including, but not limited to, polystyrene sulfonic acid (PSSA); and combinations of at least two of the above polymeric deposition inhibitors.

Preferably, the polymeric precipitation inhibitor is selected from the group containing or consisting of: microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose ( HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate), hydroxyethyl starch, (HPS) and pregelatinized starch, cyclodextran (i.e., cycloisomaltoheptaose (CI-7), cycloisomaltooctaose (CI-8), cycloisomaltonasose (CI-9)), hydroxypropyldextran, maltodextrin, α-/β-/γ-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin , 2-hydroxypropyl-β-cyclodextrin (HPeCD), β-cyclodextrin sulfobutyl ether sodium salt, methylated β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, polyethylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis( 2 aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEOPPO-PEO, poloxamer), such as poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone ( PVP), polyvinylpyrrolidone-co-polyvinyl acetate (PVPVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), poly(acrylic acid) (PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate ( PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly(methacrylic acid/ethyl acrylate), polyethylenimine (PEI), polyallylamine hydrochloride, polydiallyldimethylammonium chloride, poly(2-ethyl-2-oxazoline), polystyrene sulfonic acid (PSSA); and combinations of at least two of the above polymeric deposition inhibitors.

More preferably, the polymeric precipitation inhibitor is selected from the group containing or consisting of: microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L- hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC or hypromellose), carboxymethyl hydroxyethyl cellulose (CMHEC), sodium carboxymethyl hydroxyethyl cellulose (NaCMHEC), hydroxypropyl methyl cellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methyl cellulose acetate succinate (HPMCAS, hypromellose acetate succinate), ylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO, poloxamer), such as poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-co-polyvinyl acetate (PVPVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), poly(acrylic acid) ( PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly(methacrylic acid/ethyl acrylate), and combinations of at least two of the above polymers sedimentation inhibitors.

More preferably, a suitable polymeric deposition inhibitor includes L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol (PEG), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (poloxamer), polyvinyl alcohol (PVA) , polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), polyvinylcaprolactam-polyvinyl acetate-polyethylene graft copolymer

- 9 047306 glycol (Soluplus®) and/or sodium carboxymethylcellulose. Even more preferably, the polymeric deposition inhibitor is selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose and a cellulose derivative. More preferably, the polymeric deposition inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactampolyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, a cellulose derivative, or a combination of cellulose and a cellulose derivative.

Preferably, the cellulose is microcrystalline cellulose (MCC) and the cellulose derivative is selected from the group consisting of microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate cellulose trimellitate (CAT), methylcellulose (MC), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L- hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate).

Even more preferably, the polymeric deposition inhibitor is selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactampolyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose and hydroxypropylcellulose. Most preferably, the polymeric deposition inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropyl cellulose, hydroxypropyl cellulose, or a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose. The combination of L-hydroxypropylcellulose and hydroxypropylcellulose acts as a polymer sediment inhibitor and disintegrant so that the amount of disintegrant can be reduced.

The systemic formulations disclosed in the invention, and especially the systemic formulations for oral administration, most preferably contain polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose or a combination of L- hydroxypropylcellulose and hydroxypropylcellulose.

The systemic formulations disclosed herein, and especially the systemic formulations for oral administration, most preferably contain at least one acidifying agent and/or at least one polymeric deposition inhibitor.

The systemic formulations disclosed in the invention, and especially the systemic formulations for oral administration, most preferably contain adipic acid as an acidulant and L-hydroxypropylcellulose, hydroxypropylcellulose, polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) or a combination of Lhydroxypropylcellulose and hydroxypropylcellulose as a polymer sediment inhibitor.

An embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient wherein at least one excipient is a polymeric deposition inhibitor.

An embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one polymer precipitation inhibitor.

Preferably, the polymeric deposition inhibitor is selected from the group consisting of:

cellulose derivatives including, but not limited to, microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC ), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose ( HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethyl phthalate

- 10 047306 cellulose (HPMCP, hypromellose phthalate), hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate);

starch derivatives, including, but not limited to, hydroxyethyl starch, hydroxypropyl starch (HPS) and pregelatinized starch;

dextran/dextrin derivatives, including, but not limited to, cyclodextran (i.e., cycloisomaltoheptaose (CI-7), cycloisomaltooctaose (CI-8), cycloisomaltoheptaose (CI-9)), hydroxypropyldextran, maltodextrin, a-/b-/', '-cyclodextrin. 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (HPeCD), β-cyclodextrin sulfobutyl ether sodium salt, methylated β-cyclodextrin, 2-hydroxypropyl-/-cyclodextrin;

polyether derivatives including, but not limited to, polyethylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO, poloxamer) such as poloxamer 188 and poloxamer 407;

polyvinyl derivatives, including, but not limited to, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-co-polyvinyl acetate (PVPVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), derivatives polyacrylic acid, including, but not limited to, poly(acrylic acid) (PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly(methacrylic acid) acid/ethyl acrylate);

polyamine derivatives including, but not limited to, polyethylenimine (PEI), polyallylamine hydrochloride, polydiallyl-dimethylammonium chloride and poly(2-ethyl-2-oxazoline);

polysulfonic acid derivatives, including, but not limited to, polystyrene sulfonic acid (PSSA); and combinations of at least two of the above polymeric deposition inhibitors.

More preferably, the polymeric precipitation inhibitor is selected from the group containing or consisting of: microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L- hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC or hypromellose), carboxymethyl hydroxyethyl cellulose (CMHEC), sodium carboxymethyl hydroxyethyl cellulose (NaCMHEC), hydroxypropyl methyl cellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methyl cellulose acetate succinate (HPMCAS, hypromellose acetate succinate), ylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide) (PEO-PPO-PEO, poloxamer), such as poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-co-polyvinyl acetate (PVPVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), poly(acrylic acid) (PAA ), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly(methacrylic acid/ethyl acrylate), and combinations of at least two of the above polymeric inhibitors precipitation.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino )-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least wherein one excipient is a polymeric deposition inhibitor, and wherein the polymeric deposition inhibitor is selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and a cellulose derivative.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino )-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one polymeric precipitation inhibitor selected from the group , containing or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose and a cellulose derivative.

Preferably, the cellulose is microcrystalline cellulose (MCC), and the cellulose derivative is selected from the group consisting of microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, acetate

- 11 047306 cellulose butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC) ), hydroxypropylcellulose (HPC or hyprolose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropylmethylcellulose acetate succinate (HPMCAS , acetate -hypromellose succinate).

An embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient wherein at least one excipient is a polymeric sediment inhibitor, and wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose and/or hydroxypropylcellulose .

An embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one polymer a sedimentation inhibitor selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and polyvinyl alcohol (PVA), graft copolymer polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (Soluplus®), L-hydroxypropylcellulose and/or hydroxypropylcellulose.

The systemic composition of the invention may contain a binder. Thus, the excipient may be a binder. Binders are characterized as substances that bind or glue powders together and therefore serve as an adhesive in a formulation. In other words, a binder is a material that holds or attracts other materials together to form a single whole mechanically, chemically, through adhesion or cohesion. Suitable binders include sugar such as sucrose; polysaccharides such as xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes, and pregelatinized (modified) starches derived from wheat, corn, rice and potatoes, sodium starch glycolate; natural gums such as gum acacia, gelatin and tragacanth; seaweed derivatives such as alginic acid, sodium alginate and calcium ammonium alginate, cellulose or its derivatives such as hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone (crospovidone), in particular povidone K25 . Preferably the binder is a polymer, more preferably a gelling polymer, even more preferably the binder is cellulose or a cellulose derivative, even more preferably L-hydroxypropylcellulose and most preferably a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

Hydroxypropyl cellulose is a partially substituted poly(hydroxypropyl) cellulose ether. It may contain no more than 0.6% silica or other suitable anti-caking agent. Hydroxypropylcellulose is commercially available in several different grades that have different solution viscosities. The molecular weight is in the range of 50000-1250000. Hydroxypropylcellulose is partly O-(2hydroxypropylated) cellulose. It contains from 53.4 to 80.5% hydroxypropoxy groups relative to the dried substance. The average degree of polymerization lies in the range from 200 to 300. The molar degree of substitution is about 4.

Low-substituted hydroxypropylcellulose (L-HPC or LHPC) is a low-substituted poly(hydroxypropyl) cellulose ether. It is commercially available in several different grades that have different particle sizes and substitution levels.

Low-substituted hydroxypropylcellulose contains from 5 to 16% hydroxypropoxy groups relative to the dried substance. The molar degree of substitution is <1. In particular, low-substituted hydroxypropylcellulose is a low-substituted O-(2-hydroxypropylated) cellulose containing not less than 5.0% and not more than 16.0% hydroxypropoxy groups (

- 12 047306

OCH2CHOHCH3) in terms of the dried base.

Low-substituted hydroxypropylcellulose is a low-substituted O-(2hydroxypropylated) cellulose containing no less than 5.0% and no more than 16.0% hydroxypropoxy groups (-OCH ₂ CHOHCH ₃ ) based on the dried base.

Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG) graft copolymer (Soluplus®) has the following structural formula:

But

Povidone is a synonym for polyvinylpyrrolidone (PVP).

Polyvinylpyrrolidone consists of linear polymers of 1-ethenylpyrollidin-2-one. The different types of polyvinylpyrrolidone are characterized by the viscosity of their solutions, expressed by the K-value. Polyvinylpyrrolidone is in the form of white to yellowish powder or flakes and is easily soluble in water. The K value is a generally accepted classification in the plastics industry and is directly related to the average molar mass of the polymer. This makes it possible to indirectly deduce from the K value the degree of polymerization and, therefore, the chain length. Povidone K25, povidone K30, or povidone K90 are commercially available. Preferably, povidone K25 is used as a binder. The approximate average molecular weight of povidone K25 is 30,000 g/mol (Da) between 28,000 and 34,000 g/mol (Da).

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where at least one excipient is is a binder.

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder.

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where at least one excipient is is a binder, and wherein the binder is polyvinylpyrrolidone.

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one polyvinylpyrrolidone.

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where at least one excipient is is a binder, where the binder is polyvinylpyrrolidone and wherein the polyvinylpyrrolidone is povidone K25.

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and povidone K25.

- 13 047306

Moreover, the systemic composition of the invention may contain a binder and/or a polymeric deposition inhibitor.

A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient wherein the at least one excipient is selected from the group consisting of or consisting of a binder and a polymeric deposition inhibitor.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder and /or at least one polymeric deposition inhibitor.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is a binder and a polymeric deposition inhibitor. Preferably, at least one excipient simultaneously functions as a binder and as a polymeric deposition inhibitor. Thus, at least one excipient is a binder and a polymeric deposition inhibitor.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one compound, which is a binder and polymer sedimentation inhibitor.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one binder and, at least one polymeric sediment inhibitor.

Preferably, the binder is selected from the group consisting of or consisting of: a sugar such as sucrose; polysaccharides such as xanthan gum, guar gum, carrageenan; starches derived from wheat, corn, rice and potatoes, and pregelatinized (modified) starch derived from wheat, corn, rice and potatoes, sodium starch glycolate; natural gums such as gum acacia, gelatin and tragacanth; seaweed derivatives such as alginic acid, sodium alginate and calcium ammonium alginate; cellulose or its derivatives, such as hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose; and polyvinylpyrrolidone (crospovidone), in particular povidone K25; and the polymeric precipitation inhibitor is selected from the group containing or consisting of: microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate ( CAT), methyl cellulose (MC), methyl cellulose acetate phthalate, ethyl cellulose (EC), carboxymethyl cellulose (CMC), sodium carboxy methyl cellulose, carboxy methyl ethyl cellulose (CMEC), hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC or hyprolose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropylmethylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate), polyethylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis(2aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEOPPO-PEO , poloxamer), such as poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-copolyvinyl acetate (PVPVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), poly (acrylic acid) (PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly(methacrylic acid/ethyl acrylate), and combinations of at least at least the two aforementioned polymeric deposition inhibitors.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its

- 14 047306 enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is selected from the group consisting of or consisting of a binder and a polymeric precipitation inhibitor, and wherein the polymeric precipitation inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®), cellulose, a cellulose derivative, a combination of cellulose and a derivative, or a combination of cellulose derivatives.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder and/or, according to at least one polymeric sediment inhibitor, where the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®), cellulose, a cellulose derivative, a combination of cellulose and a derivative, or a combination of cellulose derivatives.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of a binder and a polymeric sediment inhibitor, and wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder and/or, according to at least one polymeric sediment inhibitor, where the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is selected from the group consisting of or consisting of a binder and a polymeric sediment inhibitor, wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose, and wherein the binder is L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, and/or polyvinylpyrrolidone.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one polymeric precipitation inhibitor, selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose and hydroxypropylcellulose, and at least one binder selected from the group of L-hydroxypropylcellulose, hydroxypropylcellulose and hydroxypropylcellulose and/or polyvinylpyrrolidone.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least at least one excipient is a binder and/or at least one excipient is a polymeric sediment inhibitor, and wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), a graft copolymer of polyvinyl caprolactam-polyvinyl acetate polyethylene glycol (Soluplus®), a cellulose derivative cellulose, a combination of cellulose and a derivative, or a combination of cellulose derivatives, and the binder is cellulose, a cellulose derivative, a combination of cellulose and a derivative, or a combination of cellulose derivatives

- 15 047306 and/or povidone K25.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder and/or, according to at least one polymeric sediment inhibitor, and wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinylacetate polyethylene glycol graft copolymer (Soluplus®), cellulose, a cellulose derivative, a combination of cellulose and a derivative, or a combination of cellulose derivatives, and the binder is cellulose, a cellulose derivative, a combination of cellulose and a derivative, or a combination of cellulose derivatives, and/or povidone K25.

Another preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein, at least one excipient is a binder and/or at least one excipient is a polymeric sediment inhibitor, wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), a graft copolymer of polyvinylcaprolactampolyvinyl acetate-polyethylene glycol (Soluplus®), L- hydroxypropylcellulose, hydroxypropylcellulose or a combination of L-hydroxypropylcellulose, and where the binder is L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose and/or povidone K25.

Another preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder and/ or at least one polymeric sediment inhibitor, wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose or a combination of L-hydroxypropylcellulose, and wherein the binder is L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose and/or povidone K25.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least at least one excipient is a binder and/or at least one excipient is a polymeric sediment inhibitor, wherein the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, where the binder is povidone K25.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one binder and/or, at least one polymeric sediment inhibitor, where the polymeric sediment inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, wherein the binder is povidone K25.

Positive data from a human pharmacokinetic study confirm the high bioavailability of compound (I). The high bioavailability in this context should be understood in comparison with animal studies that have been conducted previously.

Studies in the STAM and UUO mouse model demonstrate an antifibrotic effect in the liver and kidneys achieved by administration of a systemic drug containing a compound of formula (I). That is, the drug of formula (I), administered systemically, exhibits a high antifibrotic effect at the target site and, therefore, indicates systemic bioavailability. Thus, administration of an oral composition containing a drug of formula (I) shows a high antifibrotic effect at the target site, and therefore systemic availability (bioavailability) can be obtained, that is, the drug is absorbed into the target tissue.

The addition of an acidifier ensures complete dissolution of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)

- 16 047306

2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7 oxohept-2-enoate in the stomach, but pH in the small intestine increases from 2 to 6, and therefore the drug may precipitate before it can be absorbed by the small intestine. To ensure complete dissolution of the compound in the small intestine, the preparation according to the invention preferably contains an acidifying agent and/or a polymeric sedimentation inhibitor. Moreover, in Example 9 it can be seen that in humans only a dosage of 20 mg is sufficient to ensure effective plasma concentrations of the drug, and therefore systemic availability.

Pharmacokinetic studies show that (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1-methyl-III-imidazole-5-carboxamido)-7 oxohept-2-enoate is absorbed in the small intestine and a low dose of 20-50 mg is required to achieve a therapeutically effective drug concentration in humans (Example 7, Fig. 6). In addition, an antifibrotic effect can already be achieved with a human dose of 20 mg (Example 9 and Fig. 9).

Moreover, off-target effects could not be observed. As mentioned above, this is particularly surprising due to the fact that TG2 is ubiquitously expressed in almost all cell types and cellular compartments, present on the cell surface, secreted into the extracellular matrix, and present in a variety of organs, and therefore would be expected to that off-target effects are most likely.

Thus, the systemic composition of the invention may contain an acidifying agent and/or a polymeric sedimentation inhibitor. Preferably, the systemic composition contains an acidifier and a polymeric sediment inhibitor.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of a solvate, hydrate or pharmaceutically acceptable salt thereof and at least one excipient, wherein the at least one excipient is selected from the group consisting of or consisting of an acidifying agent and a polymer precipitation inhibitor.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyrigin- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent and at least one polymer sediment inhibitor.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt of at least one acidifying agent selected from adipic acid, fumaric acid and glutaric acid; and at least one polymeric precipitation inhibitor.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and at least one polymer sediment inhibitor.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least at least one excipient is selected from the group consisting of or consisting of an acidifier and a polymeric sediment inhibitor, and wherein the acidifying agent is selected from the group consisting of or consisting of adipic acid, fumaric acid and glutaric acid; and the polymeric deposition inhibitor is selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose and a cellulose derivative.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyrigin- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of an acidifier and a polymeric deposition inhibitor, and wherein the acidifying agent is adipic acid and the polymeric deposition inhibitor is selected from the group consisting of or consisting of polyvinyl alcohol (PVA), a polyvinyl caprolactam-polyvinyl acetate graft copolymer. polyethylene glycol (Soluplus®), cellulose and cellulose derivatives.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3

- 17 047306 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent and, according to at least one polymeric sediment inhibitor, wherein the acidifying agent is adipic acid, and the polymeric sediment inhibitor is selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose and a derivative cellulose.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent and, according to at least one polymeric sedimentation inhibitor selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactampolyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose and hydroxypropylcellulose.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and at least one a polymeric sediment inhibitor selected from the group consisting of or consisting of polyvinyl alcohol (PVA), polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose and hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of an acidifier and a polymeric sediment inhibitor, and wherein the acidulant is adipic acid and the polymeric sediment inhibitor is polyvinyl alcohol (PVA), a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one acidifying agent and/or, according to at least one polymeric precipitation inhibitor, wherein the acidulant is adipic acid and the polymeric precipitation inhibitor is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropyl cellulose, hydroxypropyl cellulose, or a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose .

Systemic composition containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-yl-amino)-6-( 1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, wherein the systemic composition also contains at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of an acidifier and a polymeric sediment inhibitor, the acidifying agent being selected from the group consisting of or consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid acid, fumaric acid, maleic acid, malic acid, adipic acid or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate.

Systemic composition containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 - methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, wherein the systemic composition further contains at least one excipient, wherein at least the one excipient is selected from the group consisting of or consisting of an acidifying agent and a binder, the acidifying agent being selected from the group consisting of or consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid , maleic acid, malic acid, adipic acid or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate, and wherein the binder is selected from the group consisting of a sugar such as sucrose; polysaccharides such as xanthan gum, guar gum, carrageenan; starches derived from wheat,

- 18 047306 corn, rice and potatoes, and pregelatinized starch obtained from wheat, corn, rice and potatoes, sodium starch glycolate; polyacrylic acids; natural gums such as gum acacia, gelatin and tragacanth; seaweed derivatives such as alginic acid, sodium alginate and calcium ammonium alginate, cellulose or a derivative thereof such as hydroxypropylcellulose, L-hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, or polyvinylpyrrolidone.

The systemic composition of the invention may contain an acidifier, a polymeric sedimentation inhibitor and/or a binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where the at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric precipitation inhibitor and a binder.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least one a polymer sedimentation inhibitor and at least one binder.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least , one polymeric sediment inhibitor and at least one binder, wherein the acidifying agent is adipic acid, the polymeric sediment inhibitor is polyvinyl alcohol (PVA), a graft copolymer of polyvinylcaprolactampolyvinyl acetate-polyethylene glycol (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L -hydroxypropylcellulose and hydroxypropylcellulose, and where the binder is polyvinylpyrrolidone.

The systemic composition of the invention may contain a disintegrant.

Thus, the excipient may be a baking powder. The term disintegrant refers to materials added to a composition to promote disintegration of the drug and release of the active pharmaceutical ingredient. Suitable disintegrants include starches, modified starches that are cold water soluble, such as sodium carboxymethyl starch; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose and cross-linked microcrystalline cellulose such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites and foaming compounds; effervescent compounds, such as combinations of citric acid, tartaric acid, sodium citrate, sodium dihydrogen citrate, monosodium citrate, sodium bicarbonate and/or potassium, which react in the presence of water to release carbon dioxide. Preferably the leavening agent is croscarmellose sodium.

Microcrystalline cellulose is purified, partially depolymerized cellulose that exists as a white, odorless, tasteless, crystalline powder composed of porous particles. It is produced by treating alpha cellulose, obtained in the form of pulp from fibrous plant material, with mineral acids. There are several different grades available commercially that differ in their production method, particle size, moisture content, flowability, and other physical properties. Grades with larger particle sizes generally provide better flow properties. Low-moisture grades are used with moisture-sensitive materials. Higher density grades have improved flowability.

The microcrystalline cellulose used here may have a nominal average particle size of 100 µm and a moisture content of <5.0%.

An embodiment of the invention thus relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1. 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where at least one excipient is a disintegrant.

An embodiment of the invention thus relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1. 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one baking powder.

The systemic composition according to the invention may contain an acidifier, a polymer inhibitor

- 19 047306 deposition torus, binder and/or disintegrant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where the at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sediment inhibitor, a binder and a disintegrant.

The systemic composition of the invention may contain a (lubricant)/glidant. The excipient may thus be a lubricant/glidant. (Lubricants)/glidants are materials that prevent caking, improve the flow characteristics of granulates so that the flow is smooth and uniform, and reduce friction between surfaces in direct contact to allow tablets, granulates, etc. to be released from the mold or mold. after pressing. Lubricants/glidants include sodium benzoate, metal stearate such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, high melting waxes, inorganic lubricants/glidants such as silica and talc, and others. )/glidants such as sodium oleate and polyethylene glycols. Preferably, the lubricant/glidant is talc or silica. Due to the fact that (lubricants)/glidants must be present on the surface of the granules, as well as between the granules and the equipment parts, they are usually added at the last stage before encapsulation or compression.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is a lubricant/glidant.

A preferred embodiment of the invention therefore relates to a systemic composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one (lubricant substance)/glidant.

The systemic composition of the invention may contain or consist of an acidifier, a polymeric sedimentation inhibitor, a binder and/or a lubricant/glidant.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sediment inhibitor, a binder and a lubricant/glidant.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sediment inhibitor, a binder and a lubricant/glidant.

The systemic composition of the invention may contain or consist of an acidifier, a polymeric sedimentation inhibitor, a binder, a disintegrant and/or a lubricant/glidant.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sediment inhibitor, a binder, a disintegrant and a lubricant/glidant.

In addition, the systemic composition of the invention may also contain diluents/fillers/binders, sweeteners, flavoring agents, buffering agents, antioxidants, emulsifiers, solubilizer/(wetting agent) and/or preservatives as excipients.

A suitable diluent/filler/binder is the substance that typically forms the largest portion of the composition or dosage form. Suitable diluent/filler/binder includes sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and cellulose such as microcrystalline cellulose; calcium hydrogen phosphate dihydrate and calcium sulfate. Preferably, the diluent/filler/binder is cellulose and/or mannitol. Most preferably, the diluent/filler/binder is microcrystalline cellulose and/or manganese

- 20 047306 nits. Preferably, the diluent/filler/binder is microcrystalline cellulose when the formulation is a tablet, and the diluent/filler/binder is mannitol when the formulation is a capsule.

The addition of mannitol further increases the porosity and therefore the wettability of the granules. A preferred embodiment of the invention therefore relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient wherein at least one excipient is a diluent/filler/binder.

The systemic composition of the invention may contain or consist of an acidulant, a polymeric sedimentation inhibitor, a binder, a disintegrant, a lubricant/glidant and/or a diluent/filler/binder.

An embodiment of the invention relates to a composition containing or consisting of (S,E)methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl-1Iimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least , one excipient is selected from the group consisting of or consisting of an acidulant, a polymeric sediment inhibitor, a binder, a disintegrant, a lubricant/glidant, and a diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least , one polymeric sediment inhibitor, at least one binder, at least one disintegrant, at least one lubricant/glidant and at least one diluent/filler/binder.

Preferred formulations are presented in a dosage form suitable for oral administration, such as tablets, for example, uncoated tablets, coated tablets, effervescent tablets, dissolvable tablets, chewable tablets, oral lyophilisates, lozenges, lozenges, compressed lozenges, sublingual tablets, buccal tablets, granules, effervescent granules and capsules. More preferably, the oral formulation is a tablet or capsule. Tablets, uncoated or coated, and capsules, hard or soft, are the most preferred pharmaceutical formulations.

An embodiment of the present invention relates to a systemic formulation containing N,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, wherein the systemic formulation is a tablet, capsule, powder or granule.

The systemic formulation of the invention may contain other ingredients, such as unavoidable impurities, capsule ingredients, including capsule colorants. The tablet may also contain coloring as another ingredient.

In addition, the term other ingredients also covers components used for the tablet coating.

The capsule shell may contain a dye. As used herein, the term dye includes pigments, such as white pigments. The dye can be, among other dyes, iron oxide, for example iron(III) oxide, iron(11,111) oxide or hydrated iron sesquioxide, or titanium dioxide.

Tablet means a compressed solid dosage form containing at least one active pharmaceutical ingredient with suitable excipients. The tablet can be made by compressing mixtures or granules obtained by wet granulation, dry granulation or compaction, which are known to the person skilled in the art.

The term capsule refers to a special container or shell, which consists of methylcellulose, polyvinyl alcohols or gelatins, or denatured gelatins, or starches, in which the active agents can be enclosed. Typically, hard shell capsules are prepared from hydroxypropyl methylcellulose or from mixtures of porcine bone and skin gelatins, which have relatively high gel strength. The capsule shell may contain small amounts of coloring agents, opacifiers, emollients and preservatives. Soft shell capsules contain gelatin as the base polymer, one or more emollients such as glycerin or sorbitol in higher quantities, and water. Typically, the amount of softening agent is 20-30% by weight of the capsule shell, the amount of gelatin is 40-45% by weight of the capsule shell, and the amount of water is 30-35% by weight of the capsule shell. After drying the capsule, the amount of water composition

- 21 047306 makes up 7-8 wt.% of the capsule shell.

The capsule shell may contain gelatin, hydroxypropyl methylcellulose (HMPC), polysaccharides such as starch, and carrageenan; and/or synthetic polymers such as polyvinyl alcohol copolymers. In addition, the capsule shell may contain a dye. As used herein, the term dye includes pigments, such as white pigments. The dye can be, along with other dyes, iron oxide, in particular iron oxide (I), iron oxide (I, I) or hydrated iron sesquioxide, titanium dioxide, natural dyes, azo and xanthan compounds. Moreover, the capsule shell may contain a preservative such as p-hydroxybenzoic acid esters or flavor enhancers such as ethyl vanillin. In addition, the capsule shell may contain a surfactant, for example sodium lauryl sulfate.

Formulation powders refer to powder mixtures containing active compounds and suitable excipients, which may be suspended in water or juice before use. Spherical granules are also called pellets or grains.

Granules refer to dry and hard grains. Each grain is an agglomerate of powder particles.

In this case, the drug particles are processed by the wrapping or embedding method, and the coating method applies to the dosage form itself. Tablets, dragee cores or capsules are coated with a coating layer containing excipients such as cellulose derivative, cellulose ethers such as hydroxypropyl methylcellulose (HMPC), synthetic polymers, shellac, corn protein, zein and other polysaccharides and anionic copolymers of methacrylic acid and methyl methacrylate. The coating may also contain colorants such as titanium dioxide, iron oxide, iron oxide or hydrated iron sesquioxide, lactose monohydrate and or carnauba wax. The capsule may also be coated.

Sustained release formulations are known in the art to provide a controlled rate of release of any one or more components or active components to optimize the therapeutic effect, ie, inhibitory activity and the like. Pharmacologically, the optimal concentration is guaranteed for a certain time exceeding the period of action of a single dose. Suitable sustained release dosage forms include multilayer tablets having layers with varying rates of disintegration, or controlled release polymer matrices impregnated with active ingredients, and are in the form of a tablet or capsule containing such impregnated or encapsulated porous polymer matrices. A sustained release drug prevents the compound from being released quickly. It is desirable that, after administration, a high concentration of the drug is rapidly released to the target site. Therefore, sustained release formulations are not preferred and should in fact be avoided for purposes of the present invention since preliminary results indicate that such formulations may not provide the required high drug concentrations of the present invention.

The systemic composition of the invention may be in the form of a capsule or tablet, that is, the active agent and excipient may be filled into a capsule. An embodiment of the invention is a systemic formulation containing or consisting of (8,B)-methyl-7-(1(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, wherein the systemic composition is in the form of a capsule or tablet.

A preferred embodiment of the invention is a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine3- ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least At least one excipient is selected from the group consisting of or consisting of an acidifier and a polymeric sediment inhibitor, the systemic composition being in the form of a capsule or tablet.

A preferred embodiment of the invention is a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine3- ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent and at least one polymeric sediment inhibitor, the systemic composition being in the form of a capsule or tablet.

Another preferred embodiment of the invention is a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where, at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sediment inhibitor and a binder, wherein the composition is systemic

- 22 047306 is in the form of a capsule or tablet.

Another preferred embodiment of the invention is a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least , one polymeric sedimentation inhibitor and at least one binder, wherein the systemic composition is in the form of a capsule or tablet.

Another preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where the at least one excipient is selected from the group containing or consisting of an acidulant, a polymeric sediment inhibitor, a binder, a disintegrant and a lubricant/glidant, the systemic composition being in the form of a capsule or tablet.

Another preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least at least one polymeric sedimentation inhibitor, at least one binder, at least one disintegrant and at least one lubricant/glidant, wherein the systemic composition is in the form of a capsule or tablet.

Another preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, where the at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sediment inhibitor, a disintegrant, a lubricant/glidant, and a diluent/excipient/binder, wherein the systemic formulation is in the form of a capsule or tablet.

Another preferred embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least , one polymeric sediment inhibitor, at least one binder, at least one disintegrant, at least one lubricant/glidant and at least one diluent/filler/binder, wherein the systemic composition is capsule or tablet form.

The preferred pharmaceutical preparation is for oral administration. Therefore, the preferred pharmaceutical preparations are a systemic formulation in the form of an enteral or parenteral preparation for oral administration. Therefore, especially capsules and tablets are the most preferred enteral or parenteral preparation for oral administration and especially those capsules and tablets which ensure rapid release of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2 -oxo-ethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate and thereby provide high drug concentrations. Thus, sustained release formulations are not suitable and in fact should not be used for the purposes of the present invention.

Moreover, oral pharmaceutical formulations containing adipic acid are preferred. More preferred are systemic formulations in the form of an enteral or parenteral preparation for oral administration containing adipic acid. Most preferred are capsules and tablets for oral administration containing (8,E)-methyl-7D1D2D2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III- imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and adipic acid.

In addition, a specific particle size distribution (PSD) and/or a specific particle size range (PSR) can be selected to further improve formulation performance.

Thus, an embodiment of the invention relates to a systemic formulation containing (B,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2- Dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate of formula (I):

- 23 047306

(I), or a solvate, hydrate or pharmaceutically acceptable salt of formula (I), wherein the particles are (8,E)-methyl7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imide zol-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm.

In addition, it is preferable that the particle size of (S,E)-methyl-7-(1-(2-(2-ethylbutylαamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxo hept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt is in the range of 0.1 to 100 μm, preferably in the range from 0.5 to 50 µm and more preferably in the range from 1.0 to 20 µm. Thus, the particle size range (PSR) (8,E)-methyl-7-(1(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt is from 0.1 to 100 µM, from 0.5 to 50 µM or from 1.0 to 20 µm. Preferably, the particle size of the drug of formula (I) is <10 μm.

Another preferred embodiment of the invention is a systemic formulation containing or consisting of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and L-hydroxypropylcellulose, where the particles are ^,E) -methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido) -7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm.

Thus, an embodiment of the invention relates to a systemic formulation containing N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I), wherein the particles are ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.95) <25 µm, with ^ ,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5 α-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt is preferably micronized.

Moreover, it is preferable that the particle size distribution be ^,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt was characterized by d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm, d(0.95) from 3 to 25 µm, more preferably d(0.1) from 0.2 to 3 µm, d(0.5) from 0.4 to 7.5 µm and d(0.95) from 2 to 15 µm and most preferably d(0.1) from 0.3 to 3 µm, d(0.5) from 0.5 to 5 µm and d(0.95) from 1 to 10 µm.

Particle size distribution is measured using laser diffraction (Malvern assay, sample dispersed in n-hexane and sorbitan monooleate). Thus, laser light is scattered depending on the particle size. From the diffraction pattern, which is a function of the angle-dependent scattered light intensity, the particle size can be calculated.

The parameter d(0,1) refers to the diameter at which 10% of the total volume of particles in the sample consists of particles with a diameter less than a specified value or range of values as analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate ). Therefore, d(0.1)=0.1 to 5 µm means that the upper limit of the particle size range, defining the smallest 10% of particles in the sample, is 0.1 to 5 µm. Therefore, 10% of the total particles have a particle size no larger than d(0.1), which in this case means that they have a maximum size of 0.1 to 5 μm.

Accordingly, the parameter d(0.5) refers to the diameter at which 50% of the total particle volume

- 24 047306 in the sample are particles with a diameter less than the specified value or range of values when analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate). Therefore, d(0.5)=0.3 to 10 µm means that the upper limit of the particle size range defining the smallest 50% of particles in the sample is 0.3 to 10 µm. Therefore, 50% of the total particles have a particle size no larger than d(0.5), which in this case means that they have a maximum size of 0.3 to 10 μm.

Accordingly, the parameter d(0.95) refers to the diameter at which 95% of the total volume of particles in the sample consists of particles with a diameter less than a specified value or range of values as analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate). Therefore, d(0.95)=3 to 25 µm means that the upper limit of the particle size range that defines the smallest 95% of particles in the sample is 3 to 25 µm. Therefore, 95% of the total particles have a particle size no larger than d(0.95), which in this case means that they have a maximum size of 3 to 25 μm.

Another embodiment of the present invention relates to a systemic formulation containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylami no)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and L-hydroxypropylcellulose, where the particles ( 8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1 methyl-III-imidazole -5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.95) <25 µm.

A preferred embodiment of the present invention relates to a systemic formulation containing (8,B)-methyl-7-(1-(2-(2-ethyl-butiamino)-2-oxoethyl)-2-oxo-1,2-dihydro- pyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, where particles (8, B) -methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido) -7-oxohept2-enoate have a particle size distribution defined as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 microns.

A more preferred embodiment of the invention is a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and L-hydroxypropylcellulose, where the particles (8 ,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5 -carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.1) from 0.1 to 5 μm, d(0.5) from 0.3 to 10 μm, and d( 0.95) from 3 to 25 µm.

An even more preferred embodiment of the invention is a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and L-hydroxypropylcellulose, where the particles (8 ,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5 -carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.1) from 0.2 to 3 μm, d(0.5) from 0.4 to 7.5 μm, and d(0.95) from 2 to 15 µm.

An even more preferred embodiment of the invention is a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, croscarmellose sodium and talc , where particles (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl- Sh-imidazole-5-carboxy samido)-7-oxohept-2-enoate have a particle size distribution, which is defined as d(0.1) from 0.1 to 5 μm, d(0.5) from 0.3 up to 10 µm and d(0.95) from 3 to 25 µm.

A particularly preferred embodiment of the invention is a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, Lhydroxypropylcellulose, croscarmellose sodium, talc , gelatin and titanium dioxide, where the particles are (8,B)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-( 1 -methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.1) from 0.1 to 5 μm, d(0. 5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm.

Another particularly preferred embodiment of the invention relates to a systemic composition containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its

- 25 047306 enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, povidone K25, croscarmellose sodium, microcrystalline cellulose and silicon dioxide, where the particles are (B,E)-methyl-7-(1-(2-(2 -ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution , which is defined as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm.

Thus, an embodiment of the invention relates to a systemic formulation containing (8,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2- Dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate of formula (I):

or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I), wherein the particles are (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm and a particle size distribution that is defined as d(0.95) <25 µm.

Thus, systemic formulations containing (B,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 are preferred -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, where (B,E)-methyl-7-(1-(2-( 2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, the solvate, hydrate or pharmaceutically acceptable salt is in the form of particles having a particle size distribution defined as d(0.95) <25 µm.

A preferred embodiment of the invention is a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine3- ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and Lhydroxypropylcellulose, where particles (B, E) -methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido) -7-oxohept-2-enoate have a particle size range of 0.1 to 100 μm and a particle size distribution defined as d(0.95) <25 μm.

A more preferred embodiment of the invention is a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, hydroxypropylcellulose, mannitol, croscarmellose sodium and talc, where particles (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm and a particle size distribution that is defined as d(0.95) < 25 microns.

A particularly preferred embodiment of the invention is a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, hydroxypropylcellulose, mannitol, croscarmellose sodium, talc, gelatin and titanium dioxide, where the particles are (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino) -6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm and a particle size distribution that is defined as d(0.95) <25 µm.

Another particularly preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, Lhydroxypropylcellulose, povidone K25, croscarmellose sodium , microcrystalline cellulose and silicon dioxide, where the particles are (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm and a particle size distribution defined as d(0.95) <25 µm.

- 26 047306

The systemic composition may contain ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 - methyl 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or enantiomer, solvate, hydrate or pharmaceutically acceptable salt in an amount of at least 0.01 mg, preferably at least 0.1 mg , more preferably at least 0.5 mg, even more preferably at least 1 mg, even more preferably at least 2 mg, even more preferably at least 3 mg, even more preferably, at least 4 mg, even more preferably at least 5 mg, even more preferably 0.01 to 1000 mg, even more preferably 0.05 to 900 mg, even more preferably 0.10 to 800 mg , even more preferably from 0.2 to 700 mg, even more preferably from 0.3 to 600 mg, even more preferably from 0.4 to 500 mg, even more preferably from 0.5 to 500 mg, even more preferably from 0 .6 to 450 mg, even more preferably from 0.7 to 400 mg, even more preferably from 0.8 to 375 mg, even more preferably from 0.9 to 350 mg, even more preferably from 1.0 to 300 mg, even more preferably from 1.25 to 300 mg, even more preferably from 1.5 to 275 mg, even more preferably from 1.75 to 250 mg, even more preferably from 2.0 to 225 mg, mg, even more preferably from 2.25 to 220 mg, even more preferably 2.5 to 220 mg, even more preferably 2.75 to 215 mg, even more preferably 3.0 to 210 mg, even more preferably 3.75 to 205 mg , even more preferably 4.0 to 205 mg, 4.5 to 200 mg, most preferably 5 to 200 mg per formulation.

The systemic composition may contain (S,E)-methyl-7-(1-(2-(2-ethylbutylαamino)-2-oxoethyl)2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or enantiomer, solvate, hydrate or pharmaceutically acceptable salt, solvate or hydrate in an amount of from 0.1 to 99% by weight, preferably from 0.2 up to 90 wt.%, more preferably from 0.3 to 85 wt.%, even more preferably from 0.4 to 80 wt.%, even more preferably from 0.5 to 75 wt.%, even more preferably from 0. 6 to 70 wt.%, even more preferably from 0.7 to 65 wt.%, even more preferably from 0.8 to 60 wt.%, even more preferably from 0.9 to 55 wt.%, even more preferably from 1 to 50 wt%, even more preferably 1 to 45 wt%, even more preferably 1.25 to 45 wt%, even more preferably 1.5 to 40 wt%, even more preferably 1, 75 to 35 wt%, even more preferably 2 to 34 wt%, even more preferably 2.25 to 33 wt%, even more preferably 2.5 to 32 wt% and most preferably 2.5 up to 31 wt.%, even more preferably from 2.5 to 30.5 wt.% and even more preferably from 2.6 to 30.3 wt.%, even more preferably from 3 to 30 wt.%, even more preferably from 3.5 to 29 wt.%, even more preferably from 4 to 28 wt.%, even more preferably from 4 to 27 wt.%, even more preferably from 4.5 to 27 wt.% and most preferably from 5 to 27 wt.% The abbreviation wt.% (weight percent) refers to the weight percent in the composition.

The amount of acidifier may range from 0.1 to 80% by weight, preferably from 0.5 to 77.5% by weight, more preferably from 1 to 75% by weight, more preferably from 1.5 to 72.5% by weight .%, more preferably from 2 to 70 wt.%, more preferably from 2.5 to 62.5 wt.%, more preferably from 3 to 57.5 wt.%, more preferably from 3.5 to 55 wt.% , even more preferably from 4 to 55 wt.%, even more preferably from 4.5 to 55 wt.%, even more preferably from 5 to 54 wt.%, even more preferably from 5.5 to 53 wt.%, even more preferably from 6 to 52 wt.%, even more preferably from 6.5 to 51 wt.%, even more preferably from 7 to 50 wt.%, even more preferably from 8 to 49 wt.%, even more preferably from 8 .5 to 49 wt.% and most preferably from 9 to 49 wt.%.

Moreover, the amount of acidifier may range from 1.00 to 500 mg, more preferably from 1.25 to 495 mg, even more preferably from 1.50 to 490 mg, even more preferably from 1.75 to 485 mg, further more preferably from 2.00 to 480 mg, even more preferably from 2.25 to 475 mg, even more preferably from 2.50 to 470 mg, even more preferably from 3.0 to 465 mg, even more preferably from 3.25 up to 460 mg, even more preferably from 3.5 to 455 mg, even more preferably from 3.75 to 450 mg, even more preferably from 4.00 to 445 mg, even more preferably from 4.25 to 440 mg, even more preferably from 4.5 to 435 mg, even more preferably from 4.75 to 430 mg, even more preferably from 5.0 to 425 mg, even more preferably from 5.25 to 420 mg, even more preferably from 5.5 to 415 mg, even more preferably 5.75 to 410 mg, even more preferably 6.0 to 410 mg, even more preferably 6.25 to 405 mg, even more preferably 6.5 to 400 mg, even more preferably from 6.75 to 395 mg, even more preferably from 7.0 to 390 mg, even more preferably from 7.5 to 390 mg, even more preferably from 7.75 to 385 mg, even more preferably from 8.0 to 380 mg, even more preferably from 8.5 to 375 mg, even more preferably from 9 to 370 mg, even more preferably from 9 to 365 mg, even more preferably from 9 to 360 mg, even more preferably from 9 to 350 mg, more more preferably 9 to 325 mg, even more preferably 9 to 300 mg, even more preferably 9 to 250 mg, even more preferably 9 to 200 mg and most preferably 9 to 180 mg.

In addition, the mass ratio of the acidifier relative to the mass of (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5-27 047306 carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 15 to 0.1 w/w, preferably from 14.5 to 0.2 w/w, more preferably from 14.0 to 0.3 w/w, even more preferably from 13.5 to 0.4 w/w, even more preferably from 13.0 to 0.5 wt./wt., even more preferably from 12.5 to 0.6 wt./wt., even more preferably from 12.0 to 0.7 wt./wt., more more preferably from 11.75 to 0.8 w/w, even more preferably from 11.5 to 0.9 w/w, even more preferably from 11.5 to 1.0 w/w, even more preferably from 11.5 to 1.1 wt./wt., even more preferably from 11.5 to 1.2 wt./wt., even more preferably from 11.5 to 1.3 wt./wt. , even more preferably from 11.5 to 1.4 wt./wt., even more preferably from 11.5 to 1.5 wt./wt., even more preferably from 11.5 to 1.6 wt./wt. ., even more preferably from 11.5 to 1.7 wt./wt. and most preferably from 11.5 to 1.8 wt./wt.

The amount of polymer precipitation inhibitor may vary from 0.1 to 40 wt%, preferably from 0.5 to 39 wt%, more preferably from 1 to 38 wt%, even more preferably from 1.25 to 38 wt%, even more preferably from 1.5 to 37% by weight, even more preferably from 1.75 to 36% by weight, even more preferably from 2 to 35% by weight, even more preferably from 1.5 to 34% by weight, even more preferably from 1.6 to 33 wt.%, even more preferably from 1.7 to 32 wt.%, even more preferably from 1.8 to 31 wt.%, even more preferably from 3.5 to 30 wt. %, even more preferably from 4 to 29 wt.%, even more preferably from 4.5 to 28.5 wt.%, most preferably from 5 to 28.5 wt.%.

Moreover, the amount of the polymeric precipitation inhibitor may range from 1 to 100 mg, preferably from 1.5 to 95 mg, more preferably from 2 to 92.5 mg, even more preferably from 2.5 to 90 mg, even more preferably from 3 to 87.5 mg, even more preferably from 3.5 to 85 mg, even more preferably from 4 to 82.5 mg, even more preferably from 4.5 to 80 mg, even more preferably from 5 to 77.5 mg, even more preferably from 5.5 to 75 mg, 6 to 72.5 mg, even more preferably from 6.5 to 70 mg, even more preferably from 7 to 65 mg, even more preferably from 7.5 to 62, 5 mg, even more preferably 8 to 60 mg, even more preferably 8.5 to 57.5 mg, even more preferably 9 to 55 mg, even more preferably 9.5 to 52.5 mg, even more preferably from 9.75 to 52.5 mg and most preferably from 10 to 50 mg.

In addition, the weight ratio of the polymer precipitation inhibitor relative to the weight of (S,E)methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3- yl-amino)-6-(1-methyl-Shimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0.05 to 10 wt./ wt., preferably from 0.06 to 9.5 wt./wt., more preferably from 0.07 to 9.00 wt./wt., even more preferably from 0.08 to 8.50 wt./wt. , even more preferably from 0.09 to 8.00 w/w, even more preferably from 0.1 to 7.5 w/w, even more preferably from 0.11 to 7.25 w/w ., even more preferably from 0.12 to 7 wt./wt., even more preferably from 0.13 to 6.75 wt./wt., even more preferably from 0.14 to 6.5 wt./wt. , even more preferably from 0.15 to 6.25 w/w, even more preferably from 0.16 to 6 w/w, even more preferably from 0.17 to 5.75 w/w, even more preferably from 0.18 to 5.5 wt./wt., even more preferably from 0.19 to 5.25 wt./wt. and most preferably from 0.20 to 5 wt./wt.

The amount of binder may vary from 0 to 40% by weight, preferably from 0 to 35% by weight, more preferably from 0 to 30% by weight, even more preferably from 0 to 25% by weight, even more preferably from 0 to 20% by weight .%, even more preferably from 0 to 15 wt.%, even more preferably from 0 to 12 wt.% and most preferably from 0 to 8.5 wt.%.

Moreover, the amount of binder may range from 1.00 to 100 mg, preferably from 1.50 to 95 mg, more preferably from 2.00 to 92.5 mg, even more preferably from 2.50 to 90 mg, further more preferably from 3.00 to 87.5 mg, even more preferably from 3.50 to 85 mg, even more preferably from 4.00 to 82.5 mg, even more preferably from 4.50 to 80 mg, even more preferably from 5.00 to 77.5 mg, even more preferably from 5.50 to 75 mg, from 6.00 to 72.5 mg, even more preferably from 6.50 to 70 mg, even more preferably from 7.00 to 65 mg, even more preferably 7.50 to 62.5 mg, even more preferably 8.00 to 60 mg, even more preferably 8.50 to 57.5 mg, even more preferably 9.00 to 55, 0 mg, even more preferably 9.50 to 52.5 mg, even more preferably 9.75 to 52.5 mg and most preferably 10 to 50 mg.

In addition, the mass ratio of the binder relative to the mass of (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-N-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0 to 10 w/w, preferably from 0 .05 to 9.5 w/w, more preferably from 0.06 to 9.00 w/w, even more preferably from 0.07 to 8.50 w/w, even more preferably from 0 .08 to 8.00 wt./wt., even more preferably from 0.09 to 7.5 wt./wt., even more preferably from 0.1 to 7.25 wt./wt., even more preferably from 0.11 to 7.00 w/w, even more preferably 0.12 to 6.75 w/w, even more preferably 0.13 to 6.50 w/w, even more preferably 0.14 to 6.25 w/w, even more preferably 0.15 to 6.00 w/w, even more preferably 0.16 to 5.75 w/w, even more preferably from 0.17 to

- 28 047306

5.50 w/w, even more preferably 0.18 to 5.25 w/w, even more preferably 0.19 to 5.5 w/w, even more preferably 0.20 up to 5 w/w, even more preferably from 0.20 to 4.5 w/w, even more preferably from 0.20 to 4 w/w, even more preferably from 0.20 to 3, 5 w/w, even more preferably 0.20 to 3 w/w, even more preferably 0.20 to 2.5 w/w. and even more preferably from 0.20 to 2 wt./wt.

The amount of disintegrant may vary from 0.1 to 40% by weight, preferably from 1 to 35% by weight, even more preferably from 2 to 30% by weight, even more preferably from 2.5 to 29% by weight, even more preferably from 3.0 to 28 wt.%, even more preferably from 3.5 to 27 wt.% and most preferably from 3.5 to 26.5 wt.%.

Moreover, the amount of disintegrant may vary from 0.1 to 150 mg, preferably from 0.50 to 145 mg, more preferably from 0.75 to 140 mg, even more preferably from 1.00 to 135 mg, even more preferably from 1 .25 to 130 mg, even more preferably from 1.50 to 125 mg, even more preferably from 1.75 to 120 mg, even more preferably from 2.00 to 115 mg, even more preferably from 2.25 to 110 mg, even more preferably from 2.50 to 105 mg, even more preferably from 2.75 to 100 mg, even more preferably from 3.00 to 95 mg, even more preferably from 3.25 to 90 mg, even more preferably from 3, 50 to 85 mg, even more preferably 3.75 to 80 mg, even more preferably 4.00 to 75 mg, even more preferably 4.25 to 70 mg, even more preferably 4.50 to 65 mg, even more preferably 4.75 to 60 mg, even more preferably 5.00 to 55 mg, even more preferably 5.50 to 50 mg, even more preferably 6.00 to 45 mg, even more preferably 6.50 to 42.5 mg, even more preferably 7.00 to 40 mg, even more preferably 7.50 to 40 mg, even more preferably 8.00 to 40 mg, even more preferably 8.50 to 40 mg, even more preferably 9.00 to 40 mg, even more preferably 9.50 to 40 mg and most preferably 10 to 40 mg.

In addition, the mass ratio of the disintegrant relative to the mass of (S,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0.05 to 12 w/w, preferably from 0.06 to 11.5 w/w, more preferably from 0.07 to 11 w/w, even more preferably from 0.08 to 10.5 w/w, even more preferably from 0 09 to 10 w/w, even more preferably 0.1 to 9.5 w/w, even more preferably 0.11 to 9 w/w, even more preferably 0.12 to 8.5 w/w, even more preferably 0.13 to 8 w/w, even more preferably 0.14 to 7.5 w/w, even more preferably 0.15 to 7 w/w, even more preferably 0.16 to 6.5 w/w, even more preferably 0.17 to 5.5 w/w, even more preferably 0.18 to 5 wt ./wt., even more preferably from 0.19 to 5 wt./wt. and most preferably 0.2 to 5 wt./wt.

The amount of lubricant/glidant may range from 0.1 to 10% by weight, more preferably from 0.25 to 9.5% by weight, even more preferably from 0.5 to 9% by weight, even more preferably from 0.75 to 8.5 wt%, even more preferably 1 to 8 wt%, even more preferably 1.25 to 7.5 wt%, even more preferably 1.5 to 7 wt% and even more preferably 1.5 to 6.5 wt.%.

Moreover, the amount of lubricant/glidant may range from 0.01 to 100 mg, preferably from 0.05 to 95 mg, more preferably from 0.1 to 90 mg, even more preferably from 0.3 to 85 mg, even more preferably from 0.4 to 80 mg, even more preferably from 0.5 to 0.6 mg, even more preferably from 0.7 to 70 mg, even more preferably from 0.8 to 65 mg, even more preferably from 0.9 to 60 mg, even more preferably from 1 to 55 mg, even more preferably from 1.1 to 50 mg, even more preferably from 1.2 to 45 mg, even more preferably from 1.3 to 40 mg, more more preferably 1.4 to 35 mg, even more preferably 1.5 to 30 mg, even more preferably 1.6 to 25 mg, even more preferably 1.7 to 20 mg, even more preferably 1.8 up to 20 mg, even more preferably 1.9 to 20 mg, even preferably 2 to 20 mg, even preferably 3 to 20 mg, even preferably 4 to 20 mg and most preferably 5 to 20 mg.

In addition, the mass ratio of lubricant/glidant relative to the mass of (S,E)methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3 -yl -amino)-6-(1-methyl-1Iimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0.05 to 2 wt/wt ., preferably from 0.06 to 1.8 wt./wt., more preferably from 0.07 to 1.6 wt./wt., from 0.08 to 1.4 wt./wt., even more preferably from 0.09 to 1.3 wt./wt. and most preferably from 0.1 to 1.2 wt./wt.

The amount of diluent/filler/binder in the composition may range from 0 to 50% by weight, preferably from 1 to 47.5% by weight, more preferably from 1.5 to 45% by weight, more preferably from 2 to 42, 5 wt.%, more preferably from 2.5 to 40 wt.%, more preferably from 3 to 38 wt.%, more preferably from 3.5 to 38 wt.%, more preferably from 4 to 38 wt.%, more preferably from 4.5 to 38 wt.% and even more preferably from 5 to 38 wt.%.

Moreover, the amount of diluent/filler/binder may range from 1 to 290

- 29 047306 mg, preferably from 2 to 280 mg, more preferably from 3 to 270 mg, even more preferably from 4 to 260 mg, even more preferably from 5 to 250 mg, even more preferably from 6 to 240 mg, even more preferably 7 to 230 mg, even more preferably 8 to 220 mg, even more preferably 9 to 210 mg, even more preferably 10 to 200 mg, even more preferably 11 to 190 mg, even more preferably 12 to 180 mg , even more preferably from 13 to 170 mg, even more preferably from 14 to 160 mg, even more preferably from 15 to 150 mg, even more preferably from 16 to 140 mg, even more preferably from 17 to 130 mg, even more preferably from 18 to 120 mg, even more preferably 19 to 110 mg, even more preferably 19 to 100 mg, even more preferably 20 to 90 mg, more preferably 21 to 80 mg, even more preferably 22 to 70 mg, even more preferably 23 to 60 mg, even more preferably 24 to 55 mg and most preferably 25 to 50 mg.

In addition, the weight ratio of diluent/filler/binder relative to the weight of (S,E)methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1Iimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0 to 20 wt./wt. , more preferably from 0.01 to 17.5 w/w, more preferably from 0.05 to 15 w/w, more preferably from 0.1 to 0.125 w/w, more preferably from 0. 15 to 10 w/w, more preferably 0.175 to 7.5 w/w, more preferably 0.2 to 6, more preferably 0.2 to 5.5, more preferably 0.2 to 5 w/w

The amount of other ingredients may range from 5 to 60% by weight, preferably from 6 to 57.5% by weight, more preferably from 7 to 55% by weight, even more preferably from 8 to 52.5% by weight, even more preferably from 9 to 51 wt.% and most preferably from 10 to 50 wt.% relative to the dosage form.

In addition, the amount of other ingredients may range from 50 to 200 mg, preferably from 55 to 190 mg, more preferably from 60 to 180 mg, even more preferably from 65 to 170 mg, even more preferably from 70 to 160 mg, more more preferably 75 to 150 mg, even more preferably 80 to 140 mg, even more preferably 90 to 130 mg, even more preferably 90 to 120 mg, even more preferably 90 to 110 mg and most preferably 90 to 100 mg.

In addition, the weight ratio of other ingredients relative to the weight of ^,E)-methyl-7-(1 -(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0 to 30 w/w, preferably from 0 .2 to 27.5 w/w, more preferably 0.3 to 25 w/w, even more preferably 0.35 to 22.5 w/w, even more preferably 0.4 up to 21 wt./wt. and most preferably from 0.45 to 20 wt./wt.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1I-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1I-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

An embodiment of the invention relates to a systemic formulation containing or consisting of M.E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 ylamino)-6-(1-methyl-1I-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 ylamino)-6-(1-methyl-1I-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 ylamino)-6-(1-methyl-1I-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4.5-55 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3ylamino)-6-(1-methyl-1I-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate,

- 30 047306 hydrate or pharmaceutically acceptable salt and 1-75 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyrigin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt. % acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4,5-55 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt. % acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt. % acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4,5-55 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt.% acidifier.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4,5 -55 wt.% acidifier.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4.5-55 wt.% adipic acid.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt. .% adipic acid.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt. .% adipic acid.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4,5 -55 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydro

- 31 047306 pyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt. % adipic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3- 75 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4, 5-55 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-75 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3-75 wt.% adipic acid.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 4.5-55 wt.% adipic acid.

An embodiment of the invention relates to a systemic formulation containing or consisting of (S^-megyl-?-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.1-40 wt.% polymeric precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2-35 wt.% polymeric precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3.5-30 wt.% polymeric precipitation inhibitor .

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0. 1-40 wt.% polymer sediment inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3, 5-35 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2- 30 wt.% polymer sediment inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0. 1-40 wt.% polymer sediment inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2- 35 wt.% polymer sediment inhibitor.

- 32 047306

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3, 5-30 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.1-40 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2-35 wt.% polymer sediment inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3.5-30 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (S^-methyl-?-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.1-40 wt.% L-hydroxypropylcellulose and/ or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2-35 wt.% L-hydroxypropylcellulose and/ or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3.5-30 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic composition containing or consisting of 0.1-80 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo -1,2-dihydropyridin-3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2- 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3, 5-30 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0. 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2- 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydro

- 33 047306 pyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3.5-30 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.1-40 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 3.5-30 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier and 0.1 -40 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier and 2-35 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier and 3.5 -30 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier and 0.1 -40 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier and 2-35 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier and 3.5 -30 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier and 0 ,1-40 wt.% polymer deposition inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier and 2 -35 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier and 3 .5-30 wt.% polymer

- 34 047306 sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier and 0.1-40 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier and 3.5-30 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier and 0.1-40 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier and 3.5-30 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier and 0.1-40 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier and 3.5-30 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier and 0.140 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier and 3.5-30 wt.% polymer sedimentation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or

- 35 047306 consisting of 0.1-45 wt.% (Hume'tyl-T-P-P-P-e'tylbutylamino^-oxoe'ti.tsO-oxo-t-dihydropyridin-3-ylamino) - 6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier and 0.1-40 wt. % polymer sediment inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier and 3.530 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier and 0.1-40 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier and 3.5-30 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier and 0.140 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier and 3.530 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier and 0.140 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier and 2-35 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier and 3.530 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its

- 36 047306 enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier and 0.1-40 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier and 235 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier and 3.5-30 wt.% polymer precipitation inhibitor.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 0. 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 2- 35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 3.5 -30.5 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid and 0.1 -40 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid and 2-35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid and 3.5 -30.5 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid and 0 ,1-40 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid and 2 -35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid and 3 .5-30.5 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

- 37 047306

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2

- 38 047306 digvdropyrvdin-3-ylamino)-6-(1-methyl-III-imvdazol-5-carboxamvdo)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt. % adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3 -75 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4 5-55 wt.% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4 .5-55 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt , 1-75 wt.% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt , 3-75 wt.% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt , 3-75 wt.% adipic acid and 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt , 3-75 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid and 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt , 4.5-55 wt.% adipic acid and 2-35

- 39 047306 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt.% polymer deposition inhibitor and 0-15 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 2-35 wt. .% polymer sediment inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 3.5- 30 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 0.1- 40 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 2-35 wt. .% polymer sediment inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 3.5 -30 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 0 ,1-40 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 2 -35 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 3 .5-30 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or

- 40 047306 consisting of 0.1-80 wt.% (S,E)-MeTM-7-(1-(2-(2^TM6yTMaMUHo)-2-OKCO3i^)-2-OKCO-1,2-gurugpopyridine -3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 2 -35 wt.% polymer deposition inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier, 3.530 wt.% polymer precipitation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its

- 41 047306 enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 2-35 wt.% polymer precipitation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier, 0.140 wt.% polymer precipitation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier, 3.530 wt.% polymer precipitation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier, 0.1-40 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier, 0.140 wt.% polymer precipitation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier, 2-35 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

- 42 047306

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier, 3.530 wt.% polymer precipitation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-me ^, tyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-15 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 0. 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 2- 35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 3, 5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 0, 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 2- 35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 3, 5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or

- 43 047306 consisting of 0.1-80 wt.% ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 2-35 wt. .% L-hydroxypropylcellulose and/or hydroxypropylcellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

- 44 047306

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid,

- 45 047306

2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-15 wt% binder, 0.1-35 wt% disintegrant and 0.1-10 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 3.5 -30 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic composition containing or consisting of

- 46 047306 (8,B)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 -methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 3.5-30 wt.% polymeric precipitation inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 0 ,1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 2 -35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 3.5 -30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% (lubricant)/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 0.140 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or

- 47 047306 consisting of 0.1-80 wt.% ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 3.530 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

A very preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% acidifier, 0.1-40 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its

- 48 047306 enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 2-35 wt.% polymer sedimentation inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1 -9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 3.530 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 0.1-40 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor and 0-12 wt.% binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier, 0.1-40 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier, 3.5-30 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% acidifier, 0.140 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% (lubricant)/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% acidifier, 3.530 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

- 49 047306

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-me ^, tyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohex'-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid , 0.1-40 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0-15 wt.% povidone K25, 0.1-35 wt.% croscarmellose sodium and 0.1-10 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 0, 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 2- 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 3, 5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 0, 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 2- 35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 3, 5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 2- 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 3, 5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydro

- 50 047306 pyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt. % adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or dioxide silicon.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or dioxide silicon.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid,

- 51 047306

2-35 wt.% L-hydroxypropyl cellulose and/or hydroxypropyl cellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose and 0-12 wt.% povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or dioxide silicon

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt% adipic acid, 0.1-40 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 2-35 wt% croscarmellose sodium and 1-9 wt% talc or dioxide silicon

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt% adipic acid, 2-35 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 235 wt% croscarmellose sodium and 1-9 wt% talc or silica.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid and 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt. % talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or

- 52 047306 consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 0 1-40 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 2-35 wt% croscarmellose sodium and 1-9 wt% talc or silica.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt% adipic acid, 2-35 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 235 wt% croscarmellose sodium and 1-9 wt% talc or silica.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% adipic acid, 2-35 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 2-35 wt% croscarmellose sodium and 1-9 wt% talc or dioxide silicon

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 3.5-30 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic composition containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt.% polymer sediment inhibitor, 0-15 wt.% binder, 0.1-35 wt.% disintegrant, 0.1-10 wt.% lubricant/glidant and 0-50 wt.% diluent/filler/ binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 050 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% (lubricant)/glidant and 0-50 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% (lubricant)/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharma

- 53 047306 ceutically acceptable salt, 1-75 wt.% acidifier, 3.5-30 wt.% polymer sedimentation inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant substance/glidant and 050 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 050 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% acidifier, 3.5 -30 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 050 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 0.1 -40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 2 -35 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 050 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% acidifier, 3.5 -30 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant, 2-35 wt.% disintegrant , 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% (lubricant)/glidant, 2-35 wt.% disintegrant , 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant, 2-35 wt.% disintegrant , 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2

- 54 047306 digvdropyrvdin-3-ylamino)-6-(1-methyl-III-imvdazol-5-carboxamvdo)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt. % acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/ filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 2-35 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/filler /binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 0.140 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent/filler /binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0.1-40 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 0.1-40 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 2-35

- 55 047306 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt.% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 0.140 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent/filler /binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt% acidifier, 3.530 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent/filler /binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% acidifier, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt. % diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt. % diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% acidifier, 3.5-30 wt.% polymeric sediment inhibitor, 0-12 wt.% binder and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt% acidifier, 0.1-40 wt% polymer sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt.% diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt% acidifier, 2-35 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% acidifier, 3.5-30 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% (lubricant)/glidant and 0-50 wt.% diluent/filler/binder.

- 56 047306

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% acidifier, 0.140 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% acidifier, 2-35 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant, 1-9 wt.% lubricant/glidant and 0-50 wt. % diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt% acidifier, 3.530 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant, 1-9 wt% lubricant/glidant and 0-50 wt% diluent /filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imdazole-5-carboxamndo)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 0, 1-40 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0-15 wt.% povidone K25, 0.1-35 wt.% croscarmellose sodium, 0.1-10 wt.% talc or silicon dioxide and 0-50 wt. % mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 0.1- 40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 2-35 wt. .% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt.% adipic acid, 3,5- 30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 0, 1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 2- 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt.% adipic acid, 3,5- 30.5 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% cr

- 57 047306 scarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 0.1-40 wt% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 2-35 wt% croscarmellose sodium, 1-9 wt% talc or silica and 0-50 wt% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 2-35 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 2-35 wt% croscarmellose sodium, 1-9 wt% talc or silica and 0-50 wt% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4.5-55 wt.% adipic acid, 3, 5-30.5 wt% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt% povidone K25, 2-35 wt% croscarmellose sodium, 1-9 wt% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropyl cellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt. .% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone

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K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 19 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropyl cellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt. .% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone

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K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-45 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0- 50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 75 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 235 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0- 50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3- 75 wt.% adipic acid,

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3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 2-35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt.% talc or dioxide silicon and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)- 2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4, 5-55 wt.% adipic acid, 3.5-30.5 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-12 wt.% povidone K25, 2-35 wt.% croscarmellose sodium, 1-9 wt. % talc or silicon dioxide and 0-50 wt.% mannitol and/or microcrystalline cellulose.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0-50 wt.% diluent/filler/binder, 0.1-40 wt.% polymer sediment inhibitor, 0-15 wt.% binder, 0.1-35 wt.% disintegrant and 0.1- 10 wt.% (lubricant)/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-75 wt .% acidifier, 0-50 wt.% diluent/filler/binder, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% (lubricant)/glidant.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-35 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0-50 wt.% diluent/filler/binder, 1-75 wt.% acidifier, 2-25 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant substance/glidant.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl) -2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0 -50 wt.% diluent/filler/binder, 1-75 wt.% acidifier, 2-25 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt. % lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 3-75 wt .% acidifier, 0-50 wt.% diluent/filler/binder, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-35 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0-50 wt.% diluent/filler/binder, 3-75 wt.% acidifier, 2-25 wt.% polymeric sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant substance/glidant.

A more preferred embodiment of the invention relates to a systemic composition containing or consisting of 2.5-30.5 wt.% ylamino)-6-(1-methyl-III-imvdazol-5-carboxamvdo)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0-50 wt.% diluent/filler/binder, 3-75 wt% acidifier, 2-25 wt% polymeric sediment inhibitor, 0-12 wt% binder, 2-35 wt% disintegrant and 1-9 wt% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 4,5- 55 wt.% acidifier, 0-50 wt.% diluent/filler/binder, 0.1-40 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt. .% lubricant/glidant.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-35 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0-50 wt.% diluent/filler/binder, 4.5-55 wt.% acidifier, 2-25 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt. % (lubricant)/glidant.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 2.5-30.5 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl) -2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0 -50 wt.% diluent/filler/binder, 4.5-55 wt.% acidifier, 2-25 wt.% polymer sediment inhibitor, 0-12 wt.% binder, 2-35 wt.% disintegrant and 1-9 wt.% lubricant/glidant.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0- 50 wt.% microcrystalline cellulose, 5-75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropyl cellulose, 0-15 wt.% povidone K25, 0.1-35 wt. % croscarmellose sodium and 0.1-9 wt.% talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-80% by weight (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0- 50 wt.% microcrystalline cellulose, 1-75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropyl cellulose, 0-15 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1-9 wt.% talc or silicon dioxide.

A more preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-35 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 0-50 wt.% microcrystalline cellulose, 1-75 wt.% adipic acid, 0.1-40 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-15 wt.% povidone K25, 2-35 wt.% croscarmellose sodium and 1 -9 wt.% talc or silicon dioxide.

If the Systemic Formulation is disclosed as a preparation consisting of ingredients in some quantity (weight percentage, weight ratio and/or absolute weight), the balance is made up of the other ingredients, that is, the balance is brought to 100% by weight by the other ingredients. Other ingredients are described above.

An embodiment of the invention relates to a systemic composition for use in the prevention and/or treatment of diseases disclosed in the invention, containing or consisting of at least 0.01 mg (S,E)-methyl-7-(1-(2- (2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg of adipic acid and 1-100 mg of Lhydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.01-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid and 1-100 mg L-hydroxypropylcellulose and/or hydroxypropylcellulose and up to 100 mg povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.01-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid, 1-100 mg L

- 62 047306 hydroxypropylcellulose and hydroxypropylcellulose and up to 100 mg povidone K25, 1-100 mg croscarmellose sodium and 1-50 mg talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.01-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-360 mg adipic acid, 10-40 mg Lhydroxypropylcellulose, 10-40 mg croscarmellose sodium and 1-20 mg talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of at least 0.1 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2- oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1- 500 mg adipic acid and 1-100 mg L-hydroxypropylcellulose.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid and 1-100 mg L-hydroxypropylcellulose and/or hydroxypropylcellulose and up to 100 mg povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid, 1-100 mg Lhydroxypropylcellulose and hydroxypropylcellulose and up to 100 mg povidone K25, 1-100 mg croscarmellose sodium and 1-50 mg talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.1-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-360 mg adipic acid, 10-40 mg Lhydroxypropylcellulose, 10-40 mg croscarmellose sodium and 1-20 mg talc or silicon dioxide.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 0.5-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid and 1-100 mg L-hydroxypropylcellulose and/or hydroxypropylcellulose and up to 100 mg povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.5-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid, 1-100 mg Lhydroxypropylcellulose and hydroxypropylcellulose and up to 100 mg povidone K25, 1-100 mg croscarmellose sodium and 1-50 mg talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 0.5-500 mg (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-360 mg adipic acid, 10-40 mg Lhydroxypropylcellulose, 10-40 mg croscarmellose sodium and 1-20 mg talc or silicon dioxide.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of 1-500 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, 2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg of adipic acid and 1 -100 mg L-hydroxypropylcellulose and/or hydroxypropylcellulose and up to 100 mg povidone K25.

An embodiment of the invention relates to a systemic formulation containing or consisting of 1-500 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1. 2-dihydropyridin3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-500 mg adipic acid, 1 -100 mg Lhydroxypropylcellulose and hydroxypropylcellulose and up to 100 mg povidone K25, 1-100 mg croscarmellose sodium and 1-50 mg talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of 1-500 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1. 2-dihydropyridin3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-360 mg adipic acid, 10 -40 mg Lhydroxypropylcellulose, 10-40 mg croscarmellose sodium and 1-20 mg talc or silicon dioxide.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3 -ylamino)-6-(1-methyl

- 63 047306

1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 1-15 wt./wt. acidifier, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 11.5-1.5 wt./wt. acidifier, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 11.5-1.8 wt./wt. acidifier, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.1-7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,B)methyl-7 -(1 -(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-1Nimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and 0.2-5 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,B)methyl-7 -(1 -(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-1Nimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier and 0.1-7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino) -6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier and 0.1-7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier and 0.1-7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing

- 64 047306 or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1 -methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier and 0.2-5 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,B)-methyl-7-(1 -(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3 ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier and 0.2-5 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6 -(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier and 0.2-5 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6 -(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. (lubricant)/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (3,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (3,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate,

- 65 047306 hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of the indicated compounds are calculated relative to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 w/w . acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. (lubricant)/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-2 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of the indicated compounds are calculated relative to the mass of (8,E)-me ^, til-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3 ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-2 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-2 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.1-1.5 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (B,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.1-1.5 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino) -6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3

- 66 047306 ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt. /wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder and 0.1-1.5 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino) -6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.2-5 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.5 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.2-5 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.2-5 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. acidifier, 0.1-7 wt./wt. polymer precipitation inhibitor, 0-5 wt./wt. binder, 0.1-7 wt./wt. baking powder, 0.05 to 2 wt./wt. (lubricant)/glidant, 0-5 wt./wt. diluent/filler/binder and 0-25 wt./wt. other ingredients, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 0-2 wt./wt. binder, 0.2-5 wt./wt. baking powder and 0.05-2 wt./wt. lubricant/glidant, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 0-2 wt./wt. binder, 0.2-5 wt./wt. baking powder, 0.05-2 wt./wt. lubricant/glidant and 0-5 wt./wt. diluent/filler/binder, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./wt. acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 0-2 wt./wt. binder, 0.2-5 wt./wt. baking powder, 0.05-2 wt./wt. (lubricant)/glidant, 0-5 wt./wt. diluent/filler/binder and 0-19.5 wt./wt. other ingredients, where w/w. (mass ratio) of these compounds is calculated relative to the mass of (S^-methyl-?-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

A particularly preferred embodiment of the invention relates to a systemic formulation containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./ wt. acidifier, 0.2-5 wt./wt. polymer precipitation inhibitor, 11.5-1.5 wt./wt. binder, 0.2-5 wt./wt. baking powder and 0.1-1.5 wt./wt. (lubricant)/glidant, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Another preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. adipic acid and 0.1-7 wt./wt. L-hydroxypropylcellulose and/or hydroxypropylcellulose, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Another particularly preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt./ wt. adipic acid and 0.2-5 wt./wt. L-hydroxypropylcellulose and/or hydroxypropylcellulose, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Another preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 1-15 wt./wt. adipic acid, 0.1-7 wt./wt. L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-2 wt./wt. Povidone K25, 0.2-5 w/w croscarmellose sodium and 0.05-2 wt./wt. talc or silicon dioxide, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (B,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Another particularly preferred embodiment of the invention relates to a systemic composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 11.5-1.8 wt ./wt. adipic acid, 0.2-5 wt./wt. L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0-1.5 wt./wt. Povidone K25, 0.2-5 w/w croscarmellose sodium and 0.1-1.2 wt./wt. talc or silicon dioxide, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (B,E)-methyl-7-(1 -(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 - ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Mass ratio of the acidifier relative to the mass of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 -methyl-1H-imidazole-5-carboxamido)-7-oxo hept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt is in the range of 11.5 to 1 w/w, and the weight ratio polymer sediment inhibitor relative

- 68 047306 but mass (S,E)-MeTn.i-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) 6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt is in the range from 0.2 to 5 wt./wt.

More preferred is the mass ratio of the acidifier relative to the mass of (S,E)methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-shimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt in the range from 11.5 to 1.8 wt./wt. and the mass ratio of the polymeric precipitation inhibitor relative to the mass of ^,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6 -(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt in the range from 0.2 to 5 wt./wt.

The weight ratio between the acidifier and the polymeric precipitation inhibitor may vary from 0.01 to 20 w/w, preferably from 0.02 to 15 w/w, more preferably from 0.03 to 12.5 w/w. , even more preferably from 0.04 to 10 wt./wt., even more preferably from 0.05 wt./wt., even more preferably from 0.06 to 9 wt./wt., even more preferably from 0. 07 to 8 wt./wt., even more preferably from 0.08 to 7 wt./wt., even more preferably from 0.09 to 6 wt./wt., even more preferably from 0.1 to 5 wt. /wt., even more preferably from 0.1 to 4.5 wt./wt., even more preferably from 0.1 to 4 wt./wt., even more preferably from 0.1 to 3.5 wt./ wt. and most preferably from 0.1 to 3 w/w, where the weight ratio is calculated relative to the weight of the acidifier in the formulation.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyrigin- 3ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, acidifier and polymeric precipitation inhibitor, where the mass ratio between the stabilizer solution and acidifier is in the range from 0.01 to 6 wt./wt., and where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of the acidifier.

Preferably, the preparation of the invention is not included in a pump that can be implanted. Administration by osmotic pump is not applicable to humans.

A preferred embodiment of the invention relates to a systemic formulation containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, acidifier and polymeric precipitation inhibitor, where the mass ratio between the solution stabilizer and acidifier is in the range from 0.05 to 3.5 wt./wt., and where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of the acidifier.

Preferably, the preparation of the invention is not included in a pump that can be implanted. Administration by osmotic pump is not applicable to humans.

Preferably, the maximum plasma or tissue concentration ( _Cmax value) is (8,E)-methyl-7-(1(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3- ylamino)-6-(1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt after administration is from 0.2 to 2000 ng/ml, where the value Cmax is measured in plasma samples using liquid chromatography coupled to mass spectrometry.

The inhibitory effect depends on the maximum concentration in plasma or tissue (Cmax value).

Another aspect of the invention relates to a preparation according to the invention for use as a medicament, preferably in a mammal and most preferably in a human.

A preferred embodiment of the invention relates to a systemic formulation for use in the prevention and/or treatment of diseases associated with TG2. Preferably, TG2-related diseases are selected from the group consisting of or including nephropathy, fibrotic liver diseases including NAFLD, NASH, cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH), cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation lung injury, bridging fibrosis, myocardial fibrosis, systemic sclerosis, collagen-induced arthritis (CIA), rheumatoid arthritis (RA), atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction, vascular stiffness, vascular calcification, fibroproliferative diseases, high blood pressure, glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid scar, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, IgA- nephropathy, massive progressive fibrosis, retroperitoneal fibrosis, systemic sclerosis and adhesive capsulitis, preferably in humans. Most preferably, TG2-related diseases are nephropathies, NASH, cystic fibrosis and diabetes-related fibrosis.

- 69 047306

A more preferred embodiment of the invention relates to a systemic formulation for use in prophylaxis and/or treatment, wherein the TG2-related disease is selected from the group consisting of nephropathy, fibrotic liver diseases including NAFLD, NASH, cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) and/or cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, myocardial fibrosis, systemic sclerosis, collagen-induced arthritis (CIA ), rheumatoid arthritis (RA), IgA nephropathy (IgA-N), vascular stiffness, vascular calcification, fibroproliferative diseases and high blood pressure, preferably in humans.

A preferred embodiment of the invention relates to a systemic formulation for use in the prevention and/or treatment of fibrosis, preferably in humans.

Thus, a further aspect of the invention relates to a compound of formula (I) for use in the prevention and/or treatment of fibrosis, preferably in humans.

Another aspect of the invention relates to a salt of a compound of formula (I) for use in the prevention and/or treatment of fibrosis, preferably in humans.

Another aspect of the invention relates to a salt of a compound of formula (I) and adipic acid for use in the prevention and/or treatment of fibrosis, preferably in humans.

Fibrosis is more preferably associated with fibrotic changes in the context of a diabetic condition. Thus, a particularly preferred embodiment of the invention relates to a preparation, preferably a systemic formulation, more preferably an enteral preparation and most preferably an oral preparation according to the invention for the prevention and/or treatment of diabetic nephropathy, diabetes-related non-alcoholic steatohepatitis and/or cystic fibrosis-related diabetes Thus, in a preferred embodiment of the invention, the TG2-related disease is selected from the group consisting of nephropathy, NASH and/or cystic fibrosis. In yet another preferred embodiment of the invention, the TG2-related disease includes diabetes-related fibrosis.

An embodiment of the invention relates to a preparation of the invention for use in the prevention and/or treatment of a disease selected from the group consisting of or consisting of nephropathy, NASH and/or cystic fibrosis.

Another aspect of the invention relates to a method for producing a drug according to the invention, comprising the step of:

A-1) obtaining (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Amount of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-III- imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt obtained in step A-1) above.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the step of:

A-1) obtaining from 1 to 500 g of (S,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the step of:

A-1) obtaining from 1 to 500 g of (S,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Another embodiment of the invention relates to a method for producing a drug according to the invention, comprising the step of:

A-1) obtaining from 0.1 to 80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt.

Obviously, the amount of the drug can also be replaced by another amount specified above.

In step A-2) at least one excipient described above is added. Preferably, the at least one excipient is a polymeric sedimentation inhibitor, preferably L-hydroxypropylcellulose, a disintegrant or a diluent/filler/binder.

Thus, an embodiment according to the invention relates to a method for producing a preparation according to the invention, comprising the steps of:

A-1) obtaining (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

- 70 047306

A-2) adding at least one excipient.

At stage A-2') (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-( 1-Methyl-N-imidazole-5-carboxamido)-7-oxohex'-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor, preferably Lhydroxypropylcellulose, and disintegrant, preferably croscarmellose sodium, are sieved dry condition, preferably separately.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in a dry state, preferably separately.

The amount of disintegrant, polymeric sediment inhibitor and disintegrant in step A-2') is indicated above.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining from 1 to 500 mg of (8,B)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 10 to 50 mg of a polymeric precipitation inhibitor and from 10 to 40 mg of a disintegrant in a dry state, preferably separately.

A preferred embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining from 1 to 500 mg of (8,B)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, 10 to 50 mg L-hydroxypropylcellulose and 10 to 40 mg croscarmellose sodium in dry form , preferably separately.

Another preferred embodiment of the invention relates to a method for producing the drug according to the invention, comprising the steps of:

A-1) obtaining from 0.1 to 80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 0.1 to 40 wt.% polymer precipitation inhibitor and from 2 to 15 wt. % baking powder in dry state, preferably separately.

Another more preferred embodiment of the invention relates to a method for producing the drug according to the invention, comprising the steps of:

A-1) obtaining from 0.1 to 80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 0.1 to 40 wt.% L-hydroxypropylcellulose and/or povidone K25 and from 2 to 15 wt.% croscarmellose sodium in a dry state, preferably separately.

Obviously, the amount of excipients and drug can also be replaced by another amount specified above.

In step A-3) a solvent may be added, which causes the particles to agglomerate and form a granular structure. Preferably the solvent is ethanol.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate,

- 71 047306 hydrate or pharmaceutically acceptable salt,

A-2) adding at least one excipient, and

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in a dry state, and

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure.

In step A-4), the granular mass may be wet sieved, preferably the granulated mass of step A-3).

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in the dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure, and

A-4) sifting the granular mass of stage A-3) in a wet state.

In step A-5), the granulated mass in the wet state is dried to obtain dry granules.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt,

A-2') sifting (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in the dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sieving the granular mass of stage A-3) in a wet state, and

A-5) drying the granular mass in a wet state.

In step B-1), an excipient, preferably adipic acid and/or talc, may be added to the dry granule and mixed, preferably in a dry mixer, to form a powder mixture.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

B-1) adding at least one excipient.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt,

A-2) adding at least one excipient, and

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

B-1) adding at least one excipient.

- 72 047306

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in the dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass while wet, and

B-1) adding to the dry granule at least one excipient such as an acidifier, preferably adipic acid, and/or a lubricant/glidant, preferably talc or silica.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining from 1 to 500 mg of (8,B)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 10 to 50 mg of a polymeric precipitation inhibitor and from 10 to 40 mg of a disintegrant in a dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass while wet, and

B-1) adding to the dry granule 10 to 360 mg of an acidifier and/or 1 to 20 mg of a lubricant/glidant, preferably talc or silica.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining from 0.1 to 80 wt.% (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 0.1 to 40 wt.% polymer precipitation inhibitor and from 2 to 15 wt. % baking powder in dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass while wet, and

B-1) adding to the dry granule from 5 to 75 wt.% acidifier and/or from 0.1 to 10 wt.% (lubricant)/glidant, preferably talc or silicon dioxide.

A preferred embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining from 1 to 500 mg of (8,B)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and from 10 to 50 mg of L-hydroxypropylcellulose and/or povidone K25 and from 10 to 40 mg of croscarmellose sodium is sifted dry, preferably separately,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass while wet, and

B-1) adding to the dry granule from 10 to 360 mg of adipic acid and from 1 to 20 mg of talc or silicon dioxide.

- 73 047306

Also, a more preferred embodiment of the invention relates to a method for obtaining a drug according to the invention, including the stages:

A-1) obtaining from 0.1 to 80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sieving (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and from 0.1 to 40 wt.% L-hydroxypropylcellulose and/or povidone K25 and 2 to 15 wt.% croscarmellose sodium is sifted dry, preferably separately,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass while wet, and

B-1) adding to the dry granule from 5 to 75 wt.% adipic acid and from 0.1 to 10 wt.% talc or silicon dioxide.

In step B-1'), the excipient, acidifier and/or (lubricant)/glidant may preferably be sieved, preferably separately if two excipients are sieved.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting ^3)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl -III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in the dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass in a wet state,

B-1') sifting an acidifier and a lubricant/glidant such as talc or silica, and

B-1) adding sieved acidifier and (lubricant)/glidant to the dry granulate.

A preferred embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining from 1 to 500 mg of (S,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting ^3)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl -III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 10 to 50 mg of a polymeric precipitation inhibitor and from 10 to 40 mg of a disintegrant in a dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass in a wet state,

B-1') sieving 10 to 360 mg of an acidifier and 1 to 20 mg of a lubricant/glidant such as talc or silica, and

B-1) adding sieved acidifier and (lubricant)/glidant to the dry granulate.

Another preferred embodiment of the invention relates to a method for producing the drug according to the invention, comprising the steps of:

A-1) obtaining from 0.1 to 80 wt.% (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting ^3)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl -III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, from 0.1 to 40 wt.% polymeric precipitation inhibitor and from 2 to 15 wt.% disintegrant in dry condition,

- 74 047306

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state,

A-5) drying the granular mass in a wet state,

B-1') sifting from 1 to 75 wt.% acidifier and from 0.1 to 10 wt.% (lubricant)/glidant, such as talc or silica, and

B-1) adding sieved acidifier and (lubricant)/glidant to the dry granulate.

In step C-1), the drug in different dosage forms can be prepared by filling the powder mixture of step B-1) into hard gelatin capsules or by compressing the powder mixture or granule into a tablet. The powder mixture or granules are already dosage forms. In step C-1) a solution suitable for parenteral administration, for example intravenous, can also be obtained if a solvent is added as an excipient in step B-1). A preparation for parenteral administration in solid form is also possible, which is used to prepare a solution before administration.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate,

B-1) adding excipient, and

C-1) receiving a systemic drug.

Thus, an embodiment of the invention relates to a method for producing a drug according to the invention, comprising the steps of:

A-1) obtaining (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1- methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and

A-2') sifting (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, polymeric precipitation inhibitor and disintegrant in the dry state,

A-3) adding a solvent, which leads to agglomeration of particles and the formation of a granular structure,

A-4) sifting the granular mass of stage A-3) in a wet state

A-5) drying the granular mass in a wet state,

B-1) adding adipic acid and talc to the dry granulate, and

C-1) obtaining a systemic drug by filling the powder mixture of step B-1) into a hard gelatin capsule or compressing the granule or powder mixture into a tablet.

Application of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxo-ethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl- Sh-imidazole-5-carboxamido)-7-oxohept-2-enoate as a hepatoprotector

The present application also relates to the use of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-III-imidazole-5-carboxamido)-7 oxohept-2-enoate, its enantiomer, solvate, hydrate or pharmaceutically acceptable salt as a hepatoprotector, that is, as a hepatoprotective agent.

The present invention also relates to a pharmaceutical composition containing (S,E)methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-Shimidazole-5-carboxamido)-7-oxohept-2-enoate, for use as a hepatoprotective agent and for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or prevention or treatment of liver disorder/disease, as evidenced by a decrease in serum levels of liver enzymes.

State of the art

The liver is not only involved in metabolism and detoxification, but is also involved in innate immune function and is therefore often exposed to harmful influences, potentially leading to physical damage. Interestingly, the liver has a unique ability to regenerate and fully recover after the most acute and unique situation. However, multiple conditions, including viral hepatitis, nonalcoholic fatty liver disease, long-term alcohol abuse, and chronic drug use, can cause permanent damage in which regenerative capacity eventually becomes dysfunctional, leading to liver scarring and cirrhosis. Despite ongoing therapeutic advances and advances in modern medicine, liver disease remains a public health problem worldwide.

The liver is the main organ involved in the biotransformation of foods and drugs. Liver diseases are a serious problem in the world. Hepatotoxicity most often manifests as liver dysfunction or damage due to excess

- 75 047306 drugs or xenobiotics. Hepatotoxicants are exogenous agents of clinical significance, which may include overdose of certain medicinal compounds, industrial chemicals, etc., which cause liver damage.

The exact mechanism of drug-induced liver injury remains largely unknown, but appears to involve two pathways: direct hepatotoxicity (type A or DILI-1 (drug-induced liver injury-1), an intrinsic or predictable response to a drug) and indirect hepatotoxicity ( type B or DILI-2 (drug-induced liver injury-2), an unpredictable or idiosyncratic reaction to a drug) or an adverse immune reaction.

Hepatotoxicity can lead to cytotoxic effects (necrosis, apoptosis), cholestasis, steatosis, fibrosis, cirrhosis, hepatitis and liver tumors. Symptoms associated with hepatotoxicity may include jaundice or icterus causing yellowing of the skin, eyes and severe abdominal pain, nausea or vomiting, weakness, severe fatigue, prolonged bleeding, skin rash, general itching, swelling of the feet and/or legs, abnormal and rapid weight gain in a short period of time, dark urine and light-colored stools. Elevated serum levels of various liver enzymes are considered a sign of hepatotoxicity.

Another object of the present invention is to provide a compound for use as a hepatoprotector, that is, a hepatoprotective agent, and for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating liver disorder/disease.

The object of the present invention is solved by specifying independent claims. Additional useful features, aspects and details of the invention will be apparent from the dependent claims, description, figures and examples of this application.

Brief description of the invention

The problem of the present invention is solved through the use of the compound (8,E)-methyl-7-(1 -(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I) as a hepatoprotector, that is, as a hepatoprotective agent.

In one embodiment, the invention provides a compound of formula (I) for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease.

In one embodiment, the invention provides a compound of formula (I) for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, wherein the compound reduces serum levels by at least at least one liver enzyme, preferably at least one liver enzyme selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP).

In one embodiment, the invention provides a compound of formula (I) for use in the prevention or treatment of a liver disorder/disease, wherein the liver disorder/disease is liver fibrosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) , cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) or liver inflammation.

In one embodiment, the invention provides a compound of formula (I) for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein hepatotoxicity, liver damage or liver disorder/disease caused by at least one hepatotoxicant, wherein preferably the at least one hepatotoxicant is selected from the group consisting of toxic chemicals, xenobiotics, anticancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, heavy metals, mycotoxin, galactosamine and lipopolysaccharides.

In one embodiment, the invention relates to a compound of formula (I) for use in the prevention or treatment of a liver disorder/disease, wherein the disorder

- 76 047306 liver disease/disease is liver fibrosis, in combination with one or more therapeutic agents.

In one embodiment, the invention provides a compound of formula (I) for use, the compound being administered orally.

Another aspect of the invention relates to a pharmaceutical composition containing the compound (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxo-ethyl)-2-oxo-1,2-dihydropyridin-3ylamino )-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use as a hepatoprotector.

Preferably, the pharmaceutical composition is useful for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease.

Preferably, the hepatotoxicity or liver damage, liver disorder/disease is caused by at least one hepatotoxicant, celiac disease or viral infection.

In particular, the at least one hepatotoxicant is selected from the group containing or consisting of toxic chemicals, xenobiotics, anticancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, heavy metals, mycotoxin, galactosamine and lipopolysaccharides ; celiac disease associated with a specific genetic phenotype (HLA DQ2/DQ8) and transglutaminase 2 (TG2)-stimulated pathobiology; and/or viral infection caused by hepatitis A, B, C viruses.

In one embodiment, the invention provides said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, wherein the compound reduces serum levels of at least , one liver enzyme, preferably at least one liver enzyme selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP).

In one embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the liver disorder/disease is liver fibrosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) or inflammation of the liver.

In one embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition further comprises at least one polymer sediment inhibitor.

Preferably, the at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and sodium carboxymethylcellulose.

In one embodiment, the invention relates to a pharmaceutical composition for use, wherein the pharmaceutical composition further comprises at least one acidulant and/or at least one binder.

In a preferred embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a disorder

- 77 047306 liver disease/disease, wherein at least one acidulant is selected from the group consisting of ascorbic acid, organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate.

In a preferred embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein at least one binder is selected from the group , consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes, pregelatinized (modified) starches derived from wheat, corn, rice and potatoes, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, K25 .

In one embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the (8,B)-methyl-7 particles -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3 ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)- 7-oxohept-2-enoate have a particle size distribution defined as d(0.95) <25 µm.

In some embodiments, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition is an oral preparation, wherein preferably The oral medication comes in the form of a tablet, capsule, powder, or granule.

In a preferred embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 1 to 15 wt. wt. acidifier, from 0.1 to 7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate.

In a preferred embodiment, the invention relates to a pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 0.1 to 45 wt. % (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl- Sh-imidazole-5-carboxy samido)-7-oxohept-2-enoate, from 3 to 75 wt.% acidifier, from 2 to 35 wt.% polymer sedimentation inhibitor, from 0 to 12 wt.% binder, from 2 to 35 wt.% disintegrant and 1 to 9 wt.% lubricant/glidant.

In a preferred embodiment, the invention relates to a pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 0.1 to 45 wt. % (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl- 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, 3 to 75 wt.% adipic acid, 2 to 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0 to 12 wt.% povidone K25 , from 2 to 35 wt.% croscarmellose sodium and from 1 to 9 wt.% talc or silicon dioxide.

In a preferred embodiment, the invention relates to a pharmaceutical composition for use in the prevention or treatment of a liver disorder/disease, wherein the liver disorder/disease is liver fibrosis.

Description of the invention

As used herein, the term pharmaceutically acceptable salts refers to salts of certain ingredients that have the same activity as the unmodified compounds and that are neither biologically nor otherwise undesirable.

The pharmaceutically acceptable salt may be formed, for example, with organic or inorganic acids. Suitable acids include acetic acid, acetylsalicylic acid, organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid,

- 78 047306 adipic acid or glutamic acid, and organic tricarboxylic acid such as citric acid or sodium hydrogen citrate, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzene-sulfonic acid, bisulfic acid, boric acid, butyric acid, camphoric acid , camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphoric acid, glycine, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid , hemisulfonic acid, heptanoic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthylsulfonic acid, naphthalic acid acid, nicotinic acid, nitrous acid, oxalic acid, pelargonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid, tosylic acid, undecenoic acid acid and amino acids of natural and synthetic origin. Preferably the acid is adipic acid, fumaric acid, glutaric acid, more preferably the acid is adipic acid.

Thus, a preferred pharmaceutically acceptable salt is (8,B)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) and adipic acid.

As used herein, the term solvates refers to such forms of the compound, in particular (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, which form a complex due to coordination with solvent molecules.

As used herein, the term hydrates refers to such forms of the compound, in particular (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-ylamino)-6-(1methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, which form a complex due to coordination with water molecules.

As used in the invention, the term effective amount or therapeutically effective amount of an active agent, or a pharmaceutically active agent, or a drug, or an active pharmaceutical ingredient, which are synonyms, refers to the amount of an active agent, or a pharmaceutically active agent, or a drug, or an active pharmaceutical ingredient sufficient to produce a beneficial effect. Accordingly, these amounts are effective for the disease being treated, but low enough to avoid serious side effects. A therapeutically effective amount of the pharmaceutically active agent will produce significant symptomatic relief when administered repeatedly over time. The effective amount of the pharmaceutically active agent will vary depending on the particular condition or conditions being treated, the severity of the condition, the duration of treatment, the specific components of the composition used, and similar factors.

As used herein, the term active agent, pharmaceutically active agent, drug or active pharmaceutical ingredient, which is used interchangeably herein, refers to a compound having a therapeutic effect in a mammal, particularly a human.

As used herein, the term treatment, therapy, or the like refers to a method of: (1) delaying the onset of a disease causing clinical symptoms; (2) inhibiting the disease, that is, stopping the development of clinical symptoms; and/or (3) alleviation of the disease, that is, causing regression of clinical symptoms or their severity.

As used herein, the term pharmaceutical composition refers to a composition that, when administered, exhibits a therapeutic effect in a mammal.

An oral formulation, as used in the invention, refers to a formulation that is a drug that is absorbed through the mouth (per os, orally, orally, tablets, pills, drops

- 79 047306 suls, juices, drops, etc.) These drugs are absorbed into the blood in the gastrointestinal tract, then enter the liver through the portal vein system, and then into the bloodstream through the hepatic vein. The term as used herein refers to a formulation that is administered orally.

Liver disorders in this case are caused mainly by hepatotoxicants. Hepatotoxicants include, but are not limited to, toxic chemicals (alcohols), xenobiotics (carbon tetrachloride, chlorinated hydrocarbons, isocyanates, pesticides such as insecticides, fungicides, herbicides, and detergents such as bile salts), anticancer agents (azathioprine, doxorubicin, cisplatin), immunosuppressants (cyclosporine), analgesics, anti-inflammatory drugs (paracetamol, thioacetamide), anti-tuberculosis drugs (isoniazid, rifampicin), biological drugs (bacillus Calmette-Guerin vaccine), radiation (gamma radiation), heavy metals (cadmium, arsenic) , mycotoxin (aflatoxin), galactosamine and lipopolysaccharides. Various risk factors for liver injury include concomitant liver disease, age, gender, alcoholism, diet, and genetic polymorphisms of cytochrome P ₄₅₀ enzymes.

The most commonly used parameters to assess hepatoprotective activity are morphological, for example, liver weight and volume; biochemical assessments such as measurement of transaminase activity, SGPT, SCOT, alkaline phosphatase, serum bilirubin, total serum protein, albumin, globulin and prothrombin index; functional parameters, sleep time under the influence of pentobarbitone and hexobarbitone; and finally, histopathological examination for the presence of necrosis, fatty degeneration and cirrhosis.

To screen for various liver-related diseases, several test items are collectively called liver function tests. Basic tests include the activity of serum levels of liver enzymes, including alanine transaminase (ALT) or serum glutamate pyruvate transaminase (SGPT), aspartate transaminase (AST) or serum glutamine oxaloacetic transaminase (SGOT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. In addition, total protein, albumin, LDH (lactic acid dehydrogenase), ammonia, etc. are sometimes tested.

Of AST (GOT) and ALT (GPT) are enzymes present in liver cells and when liver cells are damaged, they are preferentially released into the blood. Thus, blood levels of AST and ALT can be used as markers of liver damage. In the early stages of acute hepatocyte injury, AST, which is highly concentrated in hepatocytes, increases more than ALT, but after 24–48 hours and with chronic hepatocyte injury, levels of ALT, which has a longer half-life, are typically higher. In alcoholic hepatitis, AST increases even more.

Surprisingly, it has been shown that the compound of formula (I) can reduce the concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline phosphatase (ALP) in serum in a dose-dependent manner, as shown in table. 4 in Example 14. These results indicate that the compound of formula (I) has a protective effect on liver damage and has potential in the treatment of liver damage.

Celiac disease (celiac disease) is characterized by gluten-related pathobiology, which is driven by transglutaminase 2 (TG2). However, celiac disease or gluten intolerance is one of the most common gastrointestinal diseases. Celiac disease is characterized by chronic inflammation of the mucous membrane of the small intestine. In corresponding patients, the intestinal epithelium is consistently destroyed after ingestion of gluten-containing meals, resulting in decreased absorption of nutrients, which again has a huge impact on the corresponding patients and, for example, is associated with symptoms such as weight loss, anemia, diarrhea, nausea, loss appetite and fatigue.

The mechanisms underlying liver damage in celiac disease are poorly understood. However, elevated aminotransferase levels are a common finding in patients with celiac disease.

Oral in vivo treatment with compound 1 as an irreversible transglutaminase 2 (TG2) inhibitor at doses of 10, 50 and 100 mg in humans significantly reduces AST, ALT, total protein levels and inhibits cellular leakage of two enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) hepatocytes.

The efficacy and safety of a 6-week treatment with a compound of formula (I) in the form of a hard gelatin capsule described in Example 2 was studied in 160 adult patients with celiac disease (CeD). Patients who are in clinical and histological remission at the start of the study are administered 3 g of gluten per day and are randomized to receive placebo or one of 3 doses of the compound of formula (I), i.e., 10 mg, 50 mg or 100 mg. Every morning, after at least 6 hours of fasting, patients take the study drug orally, and 30 minutes before breakfast they eat one cookie containing 3 g of gluten. During the 6-week study, patients were required to follow a strict gluten-free diet.

Gluten challenge causes a moderate but statistically significant increase in ALA levels

- 80 047306 ninaminotransferase (ALT) from baseline to week 6 in the placebo group, but this increase, surprisingly, was not observed in any of the groups receiving the compound of formula (I) in the hard gelatin capsule described in Example 2. The difference in ALT between each drug group and placebo was statistically significant (P<0.01 for all comparisons), demonstrating a protective effect of the compound of formula (I) on the liver of gluten-exposed celiac disease patients. Alkaline phosphatase (ALP) levels also show a similar pattern (P<0.05). In the placebo group, values normalize after a gluten-free diet (GFD) at week 10 (Table). The finding that the compound of formula (I) inhibits liver damage, which is one of the gluten-induced extraintestinal manifestations in active celiac disease (CeD), as reflected by a modest increase in ALT and ALP, indicates that the compound has an overall hepatoprotective effect (see FIG. 12).

Administration of a compound of formula (I) to a mouse model of non-alcoholic steatohepatitis demonstrates a dose-dependent reduction in liver fibrosis (Example 3). Surprisingly, administration of the compound of formula (I) to STAM mice also resulted in a dose-dependent and significant reduction in liver inflammation, providing further evidence of its hepatoprotective effect.

Thus, an embodiment of the invention relates to the use of the compound (S,E)methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-Shimidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I) as a hepatoprotector, that is, as a hepatoprotective agent.

In one embodiment, the invention provides a compound of formula (I), its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a disorder/disease. liver.

In one embodiment, the invention provides a compound of formula (I), its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a disorder/disease. liver, wherein the compound reduces serum levels of at least one liver enzyme, preferably at least one liver enzyme selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP).

In one embodiment, the invention provides a compound of formula (I), its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a disorder/disease. liver, wherein the liver disorder/disease is liver fibrosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) ), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) or liver inflammation.

In one embodiment, the invention provides a compound of formula (I), its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a disorder/disease. liver, wherein the hepatotoxicity, liver damage or liver disorder/disease is caused by at least one hepatotoxicant, celiac disease or viral infection, wherein preferably the at least one hepatotoxicant is selected from the group consisting of or consisting of toxic chemicals, xenobiotics, anti-cancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, heavy metals, mycotoxin, galactosamine and lipopolysaccharides; celiac disease associated with a specific genetic phenotype (HLA DQ2/DQ8) and transglutaminase 2 (TG2)-stimulated pathobiology; and/or viral infection caused by hepatitis A, B, C viruses.

Preferably the toxic chemicals are alcohols; xenobiotics are carbon tetrachloride, chlorinated hydrocarbons, isocyanates, pesticides such as insecticides, fungicides, herbicides and detergents such as bile salts; anticancer agents are azathioprine, doxorubicin, cisplatin; the immunosuppressant is cyclosporine; anti-inflammatory drugs are paracetamol and thioacetamide; anti-tuberculosis drugs

- 81 047306 parasites are isoniazid and rifampicin; biological products are, for example, the Bacillus Calmette-Guerin vaccine; the radiation is preferably gamma radiation, the heavy metals being cadmium and arsenic; mycotoxin is aflatoxin, galactosamine and lipopolysaccharides.

Preferably, the invention relates to a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein hepatotoxicity, liver damage, or liver disorder/disease is caused by celiac disease, and celiac disease is associated with transglutaminase 2 (TG2).

In one embodiment, the invention provides a compound of formula (I), an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof for use as described above, wherein the compound is administered orally.

Pharmaceutical composition for use as a hepatoprotector

Another aspect of the invention relates to a pharmaceutical composition containing the compound (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3 ylamino) -6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use as a hepatoprotector.

Preferably, said pharmaceutical composition is useful for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease.

Preferably, the hepatotoxicity or liver damage, liver disorder/disease is caused by at least one hepatotoxicant, celiac disease or viral infection.

In particular, the at least one hepatotoxicant is selected from the group containing or consisting of toxic chemicals, xenobiotics, anticancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, heavy metals, mycotoxin, galactosamine and lipopolysaccharides .

In one embodiment, the invention relates to a pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the at least one hepatotoxicant is selected from the group consisting of or consisting of toxic chemicals, xenobiotics, anticancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, severe metals, mycotoxin, galactosamine and lipopolysaccharides, celiac disease associated with a specific genetic phenotype (HLA DQ2/DQ8), and transglutaminase 2 (TG2)-stimulated pathobiology; and/or viral infection caused by hepatitis A, B, C virus.

In one embodiment, the invention relates to the specified pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or prevention or treatment of a liver disorder/disease, wherein the compound reduces serum levels of at least one liver enzyme, preferably at least one liver enzyme selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ).

In one embodiment, the invention relates to the specified pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the liver disorder/disease is liver fibrosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis

- 82 047306 (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) or liver inflammation.

Preferably, the invention also relates to a pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or in the prevention or treatment liver disorders/diseases in combination with a gluten-free diet, where hepatotoxicity, liver damage, or liver disorder/disease is caused by celiac disease, and celiac disease is associated with transglutaminase 2 (TG2).

In one embodiment, the invention relates to the specified pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/restoring liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition further comprises at least one polymeric deposition inhibitor.

Preferably, the polymeric deposition inhibitor is selected from the group consisting of:

cellulose derivatives including, but not limited to, microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC ), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose ( HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate);

starch derivatives, including, but not limited to, hydroxyethyl starch, hydroxypropyl starch (HPS) and pregelatinized starch;

dextran/dextrin derivatives, including, but not limited to, cyclodextran (i.e., cycloisomaltoheptaose (CI-7), cycloisomaltooctaose (CI-8), cycloisomaltoheptaose (CI-9)), hydroxypropyldextran, maltodextrin, a-/b-/', '-cyclodextrin. 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (HPeCD), β-cyclodextrin sulfobutyl ether sodium salt, methylated β-cyclodextrin, 2-hydroxypropyl-/-cyclodextrin;

polyether derivatives including, but not limited to, polyethylene glycol (PEG), polyethylene oxide (PEO), polyether polyol, poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO, poloxamer) such as poloxamer 188 and poloxamer 407;

polyvinyl derivatives including, but not limited to, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-co-polyvinyl acetate (PVPVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®);

polyacrylic acid derivatives including, but not limited to, poly(acrylic acid) (PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly( methacrylic acid/ethyl acrylate);

polyamine derivatives including, but not limited to, polyethylenimine (PEI), polyallylamine hydrochloride, polydiallyl-dimethylammonium chloride and poly(2-ethyl-2-oxazoline);

polysulfonic acid derivatives, including, but not limited to, polystyrene sulfonic acid (PSSA); and combinations of at least two of the above polymeric deposition inhibitors.

More preferably, the polymeric precipitation inhibitor is selected from the group containing or consisting of: microcrystalline cellulose (MCC), cellulose acetate phthalate (CAP), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), methylcellulose (MC), methylcellulose acetate phthalate, ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, carboxymethylethylcellulose (CMEC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hyprolose), L-hydroxypropylcellulose, Hydroxypropyl methylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate), polyethylene glycol (PEG ), polyethylene oxide (PEO ), polyether polyol, poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)

- 83 047306 (PEO-PPO-PEO, poloxamer), such as poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-copolyvinyl acetate (PVPVA), polyvinylcaprolactam graft copolymer -polyvinyl acetate-polyethylene glycol (Soluplus®), poly(acrylic acid) (PAA), poly(acrylamide/acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid/methyl methacrylate), poly( methacrylic acid/ethyl acrylate), and combinations of at least two of the above polymeric deposition inhibitors.

Preferably, the at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and sodium carboxymethyl cellulose.

Thus, in one embodiment, the invention relates to the specified pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and /or in the prevention or treatment of a liver disorder/disease, wherein the pharmaceutical composition further contains at least one polymeric deposition inhibitor and at least one polymeric deposition inhibitor selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and sodium carboxymethylcellulose.

In addition, positive data from a human pharmacokinetic study confirm the high bioavailability of compound (I). The high bioavailability in this context should be understood in comparison with animal studies that have been conducted previously.

Studies in the STAM and UUO mouse model demonstrate an antifibrotic effect on the liver and kidneys achieved by administration of a systemic preparation containing a compound of formula (I). Therefore, the drug of formula (I) exhibits a high antifibrotic effect at the target site and thus indicates systemic bioavailability. That is, administration of an oral composition containing a drug of formula (I) exhibits a high antifibrotic effect at the target site, and thus systemic availability (bioavailability), that is, the drug is absorbed into the target tissue, can be obtained.

Surprisingly, administration of a compound of formula (I) to STAM mice not only resulted in a reduction in fibrosis, but also in a dose-dependent and significant reduction in liver inflammation, providing further evidence of its hepatoprotective effect.

The addition of an acidifier ensures complete dissolution of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 -methyl-III-imidazole-5-carboxamido)-7 oxohept-2-enoate in the stomach, but the pH in the small intestine rises from 2 to 6, and therefore the drug may precipitate before it can be absorbed by the small intestine . To ensure complete dissolution of the compound in the small intestine, the preparation according to the invention preferably contains an acidifying agent and/or a polymeric sedimentation inhibitor. Moreover, in Example 9 it can be seen that in humans, only a 20 mg dosage is sufficient to provide effective plasma drug concentrations, and therefore systemic availability.

Pharmacokinetic studies show that (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1-Methyl-III-imidazole-5-carboxamido)-7 oxohept-2-enoate is absorbed in the small intestine and a low dose of 20-50 mg is required to achieve a therapeutically effective drug concentration in humans (Example 7, Fig. 6). In addition, an antifibrotic effect can already be achieved with a human dose of 20 mg (Example 9 and Fig. 9).

Moreover, off-target effects could not be observed. As mentioned above, this is especially surprising due to the fact that TG2 is ubiquitously expressed in almost all cell types and cellular compartments, it is present on the cell surface, secreted into the extracellular matrix and is present in various organs, and therefore it can be assumed that off-target effects might be most likely.

In one embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition further comprises at least one acidified

- 84 047306 body and/or at least one binder.

Binders are substances that bind or “glue” powder particles together and make them cohesive by forming granules, thus acting as an adhesive in the formulation. Binders increase the cohesive strength already present in the diluent or bulking agent. Suitable binders include sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potato, pregelatinized (modified) starch derived from wheat, corn, rice and potato, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, povidone K 25 .

In one embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition further comprises at least one the acidulant and at least one acidulant is selected from the group consisting of ascorbic acid, organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate.

In one embodiment, the invention relates to the specified pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/restoring liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition further comprises at least one binder and the at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from from wheat, corn, rice and potatoes, pregelatinized (modified) starch derived from wheat, corn, rice and potatoes, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, alginate ammonium calcium, cellulose, cellulose derivatives, hydroxypropylcellulose, Lhydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, povidone K25.

In a preferred embodiment, the invention relates to said pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or prevention or treatment of liver disorder/disease, wherein the pharmaceutical composition further contains at least one polymeric deposition inhibitor and at least one acidifying agent, wherein:

at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose , methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and sodium carboxymethylcellulose; and at least one acidulant is selected from the group consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate.

In a preferred embodiment, the invention relates to said pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or prevention or treatment of liver disorder/disease, wherein the pharmaceutical composition further contains at least one polymeric deposition inhibitor and at least one binder, wherein:

at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose , hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl graft copolymer

- 85 047306 prolactam-polyvinyl acetate-polyethylene glycol (Soluplus®) and sodium carboxymethylcellulose; and at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes, pregelatinized (modified) starches derived from wheat, corn , rice and potatoes, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, povidone K25.

In a preferred embodiment, the invention relates to said pharmaceutical composition containing a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or prevention or treatment of a liver disorder/disease, where the pharmaceutical composition further contains at least one polymeric deposition inhibitor, at least one acidifier and at least one binder, wherein:

at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose , hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and sodium carboxymethylcellulose;

at least one acidulant is selected from the group consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, or glutamic acid acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate; and at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes, pregelatinized (modified) starches derived from wheat, corn , rice and potatoes, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, povidone K25.

Preferably, the invention relates to any of the above-described pharmaceutical compositions for use in protecting the liver from hepatotoxicity, improving liver function, protecting/restoring liver damage and/or in the prevention or treatment of a liver disorder/disease, wherein the pharmaceutical composition further contains diluents, disintegrants, lubricants, glidants and/or dyes.

Suitable diluents are substances that typically form the bulk of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn, rice and potato, and celluloses such as microcrystalline cellulose.

The term disintegrants refers to materials added to a composition to support the breakdown (disintegration) and release of pharmaceutically active drug ingredients. Suitable disintegrants include starches, cold water-soluble modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean gum, karaya gum, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as croscarmellose sodium, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.

Lubricants refer to a class of substances that are added to a dosage form to allow tablets, granules, etc. to be released from the mold by reducing friction or wear. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, high melting waxes and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine . Lubricants are usually added at the very last stage before pressing, since they must be present on the surface of the granules.

Glidants are materials that prevent the components of a pharmaceutical composition from caking and improve the flow characteristics of the granulate so that the resulting stream

- 86 047306 is smooth and uniform. Suitable glidants include silica and talc.

An embodiment of the invention thus relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, and at least , a single excipient, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, wherein at least one excipient is a disintegrant.

An embodiment of the invention thus relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one disintegrant, for Uses in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating liver disorder/disease.

The pharmaceutical composition of the invention may contain an acidulant, a polymeric sedimentation inhibitor, a binder and/or a disintegrant.

A variant of the invention relates to a pharmaceutical composition containing (8,E)-methyl-7-(1-(2(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof and at least one excipient, wherein at least one excipient is selected from a group containing or consisting of an acidulant, a polymeric sedimentation inhibitor, a binder and a disintegrant, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating liver disorder/disease.

The pharmaceutical composition of the invention may contain a lubricant/glidant. The excipient may therefore be a lubricant/glidant. (Lubricants)/glidants are materials that prevent caking, improve the flow characteristics of granulates so that the flow is smooth and uniform, and reduce friction between surfaces in direct contact to allow tablets, granulates, etc. to be released from the mold or mold. after pressing. Lubricants/glidants include sodium benzoate, metal stearate such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, high melting waxes, inorganic lubricants/glidants such as silica and talc, and others )/glidants such as sodium oleate and polyethylene glycols. Preferably, the lubricant/glidant is talc or silica. Due to the fact that (lubricants)/glidants must be present on the surface of the granules, as well as between the granules and the equipment parts, they are usually added at the last stage before encapsulation or compression.

A preferred embodiment of the invention therefore relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one ( lubricant)/glidant, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating liver disorder/disease.

A preferred embodiment of the invention relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric deposition inhibitor, a binder, and a lubricant/glidant, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treatment of a liver disorder/disease.

A preferred embodiment of the invention relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, wherein at least one excipient is selected from the group consisting of or consisting of an acidulant, a polymeric sediment inhibitor, a binder, a disintegrant, and a lubricant/glidant, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or in the prevention or treatment of liver disorder/disease.

In addition, the pharmaceutical composition of the invention as an excipient can also

- 87 047306 contain diluents/fillers/binders, sweeteners, flavoring agents, buffering agents, antioxidants, emulsifiers, solubilizer/wetting agent and/or preservatives.

A suitable diluent/filler/binder is the substance that forms the majority of the composition or dosage form. Suitable diluent/filler/binder includes sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and cellulose such as microcrystalline cellulose, calcium hydrogen phosphate dihydrate and calcium sulfate. The diluent/filler/binder is preferably cellulose and/or mannitol. Most preferably, the diluent/filler/binder is microcrystalline cellulose and/or mannitol. Preferably, the diluent/filler/binder is microcrystalline cellulose when the formulation is a tablet, and the diluent/filler/binder is mannitol when the formulation is a capsule.

The addition of mannitol further increases the porosity and therefore the wettability of the granules. A preferred embodiment of the invention therefore relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2 -dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient , for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, wherein at least one excipient is a diluent/filler/binder.

The pharmaceutical composition of the invention may contain or consist of an acidulant, a polymeric sedimentation inhibitor, a binder, a disintegrant, a lubricant/glidant and/or a diluent/filler/binder.

An embodiment of the invention relates to a pharmaceutical composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt and at least one excipient, for use in protection liver against hepatotoxicity, improving liver function, protecting/restoring liver damage and/or in preventing or treating a liver disorder/disease, wherein at least one excipient is selected from the group consisting of or consisting of an acidifier, a polymeric sedimentation inhibitor, a binder, a disintegrant , (lubricant)/glidant and diluent/filler/binder.

An embodiment of the invention relates to a systemic formulation containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, at least one acidifying agent, at least one polymeric sediment inhibitor, at least one binder, at least one disintegrant, at least one lubricant/glidant, and at least one diluent/excipient/binder, for use in protecting the liver from hepatotoxicity , improving liver function, protecting/repairing liver damage and/or in preventing or treating liver disorder/disease.

The preferred pharmaceutical composition is presented in a dosage form suitable for oral administration, such as tablets, for example, uncoated tablets, coated tablets, effervescent tablets, soluble tablets, chewable tablets, oral lyophilisates, lozenges, lozenges, compressed lozenges, sublingual tablets, buccal tablets, granules, effervescent granules and capsules. More preferably, the oral preparation is a tablet or capsule. Tablets, uncoated or coated, and capsules, hard or soft, are the most preferred pharmaceutical formulations.

In some embodiments, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition is an oral preparation, preferably oral the drug is a tablet, capsule, powder or granule.

The pharmaceutical composition for use according to the invention may also contain other capsule ingredients, such as capsule colorants. The tablet may also contain coloring as another ingredient.

In addition, the term other ingredients also covers components used for the tablet coating.

The capsule shell may contain a dye. As used herein, the term dye includes pigments, such as white pigments. The dye may be, among others, an iron oxide, in particular iron(I) oxide, iron oxide (IO) or hydrated jelly sesquioxide

- 88 047306 for or titanium dioxide.

Tablet means a compressed solid dosage form containing at least one active pharmaceutical ingredient with suitable excipients. The tablet can be made by compressing mixtures or granules obtained by wet granulation, dry granulation or compaction, which are known to the person skilled in the art.

The term capsule refers to a special container or shell consisting of methylcellulose, polyvinyl alcohols or gelatins, or denatured gelatins or starches, in which the active agents can be enclosed. Typically, hard-shell capsules are prepared from hydroxypropyl methylcellulose or from mixtures of porcine bone and skin gelatins, which have relatively high gel strength. The capsule shell may contain small amounts of coloring agents, opacifiers, emollients and preservatives. Soft shell capsules contain gelatin as the base polymer, one or more emollients such as glycerin or sorbitol in higher quantities, and water. Typically, the amount of softening agent is 20-30% by weight of the capsule shell, the amount of gelatin is 40-45% by weight of the capsule shell, and the amount of water is 30-35% by weight of the capsule shell. After drying the capsule, the amount of water is 7-8 wt.% of the capsule shell.

The capsule shell may contain gelatin, hydroxypropyl methylcellulose (HMPC), polysaccharides such as starch, and carrageenan; and/or synthetic polymers such as polyvinyl alcohol copolymers. In addition, the capsule shell may contain a dye. As used herein, the term colorant includes pigments, such as white pigments. The dye may be, among others, iron oxide, in particular iron(I) oxide, iron(I,I) oxide or hydrated iron sesquioxide, titanium dioxide, natural dyes, azo and xanthan compounds. Moreover, the capsule shell may contain a preservative such as phydroxybenzoic acid esters or flavor enhancers such as ethyl vanillin. In addition, the capsule shell may contain a surfactant, for example sodium lauryl sulfate.

Formulation powders refer to powder mixtures containing active compounds and suitable excipients, which may be suspended in water or juice before use. Spherical granules are also called pellets or grains.

Granules refer to dry and hard grains. Each grain is an agglomerate of powder particles.

In addition, to further improve the performance of the pharmaceutical composition, a specific particle size distribution (PSD) and/or particle size range (PSR) can be selected.

Thus, when using the pharmaceutical composition according to the invention, said pharmaceutical composition contains (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3- ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or solvate, hydrate or pharmaceutically acceptable salt of formula (I), wherein the particles are (S,E)methyl-7 -(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-shimidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 μm.

In addition, it is preferable that the particle size of (S,E)-methyl-7-(1-(2-(2-ethylbutylαamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7 oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt was in the range of 0.1 to 100 µm, preferably in the range of 0 .5 to 50 µm and more preferably in the range from 1.0 to 20 µm. Thus, the particle size range (PSR) (S,E)methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-Shimidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt is from 0.1 to 100 µM, from 0.5 to 50 µM or from 1.0 to 20 µm. Preferably, the particle size of the drug of formula (I) is <10 μm.

Another preferred embodiment of the invention is a pharmaceutical composition containing or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, and L-hydroxypropylcellulose, for use while protecting the liver from hepatotoxicity, improving

- 89 047306 liver function, protection/repair of liver damage and/or in the prevention or treatment of liver disorder/disease, wherein (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl) particles )-2-oxo1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range from 0.1 to 100 µm.

Thus, an embodiment of the invention relates to a pharmaceutical composition containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I), for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease wherein the particles ( 8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1 methyl-III -imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.95) <25 µm, with (8,B)-methyl-7-(1-(2 -(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof is preferably micronized.

Moreover, it is preferable that the particle size distribution of (8,B)-methyl-7-(1 -(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt has been characterized with d(0.1) from 0.1 to 5 μm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm, more preferably d(0.1) from 0.2 to 3 µm, d(0.5) from 0 .4 to 7.5 µm and d(0.95) from 2 to 15 µm, and most preferably d(0.1) from 0.3 to 3 µm, d(0.5) from 0.5 to 5 µm and d(0.95) from 1 to 10 µm.

Particle size distribution is measured using laser diffraction (Malvern assay, sample dispersed in n-hexane and sorbitan monooleate). Thus, laser light is scattered depending on the particle size. From the diffraction pattern, which is a function of the angle-dependent scattered light intensity, the particle size can be calculated.

The parameter d(0,1) refers to the diameter at which 10% of the total volume of particles in the sample consists of particles with a diameter less than a specified value or range of values as analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate ). Therefore, d(0.1)=0.1 to 5 µm means that the upper limit of the particle size range, defining the smallest 10% of particles in the sample, is 0.1 to 5 µm. Therefore, 10% of the total particles have a particle size no larger than d(0.1), which in this case means that they have a maximum size of 0.1 to 5 μm.

Accordingly, the parameter d(0.5) refers to the diameter at which 50% of the total volume of particles in the sample consists of particles with a diameter less than a specified value or range of values as analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate). Therefore, d(0.5)=0.3 to 10 µm means that the upper limit of the particle size range defining the smallest 50% of particles in the sample is 0.3 to 10 µm. Therefore, 50% of the total particles have a particle size no larger than d(0.5), which in this case means that they have a maximum size of 0.3 to 10 μm.

Accordingly, the parameter d(0.95) refers to the diameter at which 95% of the total volume of particles in the sample consists of particles with a diameter less than a specified value or range of values as analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate). Therefore, d(0.95)=3 to 25 µm means that the upper limit of the particle size range that defines the smallest 95% of particles in the sample is 3 to 25 µm. Therefore, 95% of the total particles have a particle size no larger than d(0.95), which in this case means that they have a maximum size of 3 to 25 μm.

Another embodiment of the present invention relates to a pharmaceutical composition containing or consisting of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, and L-hydroxypropylcellulose, for use in liver protection from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or in preventing or treating a liver disorder/disease where the (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2- oxoethyl)-2-oxo- 90 047306

1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.95 ) <25 µm.

A preferred embodiment of the present invention relates to a pharmaceutical composition containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, for use in protecting the liver from hepatotoxicity, improving liver function liver, protection/repair of liver damage and/or in the prevention or treatment of liver disorder/disease, wherein the (8,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5carboxamido)-7-oxohept-2-enoate have a particle size distribution that is defined as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm.

A more preferred embodiment of the invention is a pharmaceutical composition containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, and L-hydroxypropylcellulose, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or in preventing or treating liver disorder/disease, wherein (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)) particles -2-oxoethyl)-2-oxo1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution that is determined by as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm.

An even more preferred embodiment of the invention is a pharmaceutical composition containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid and L-hydroxypropylcellulose, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or in the prevention or treatment of liver disorder/disease, wherein (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl) )-2-oxo1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d (0.1) from 0.2 to 3 µm, d(0.5) from 0.4 to 7.5 µm and d(0.95) from 2 to 15 µm.

An even more preferred embodiment of the invention is a pharmaceutical composition containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, croscarmellose sodium and talc, for applications in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or in preventing or treating liver disorder/disease, wherein the (8,E)-methyl-7-(1-(2-(2ethylbutylamino)- 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5carboxamido)-7-oxohept-2-enoate have a particle size distribution that is defined as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm.

A particularly preferred embodiment of the invention is a pharmaceutical composition containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, croscarmellose sodium, talc, gelatin and titanium dioxide, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating liver disorder/disease, wherein the (8,E)-methyl-7-(1-(2 -(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm.

Another particularly preferred embodiment of the invention relates to a pharmaceutical composition containing or consisting of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine-3 -ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, povidone K25, croscarmellose sodium, microcrystalline cellulose and silica, for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating liver disorder/disease, wherein (8,E)-methyl-7-(1- (2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-5-carboxamido)-7-oxohept-2 -enoate have a particle size distribution defined as d(0.1) from 0.1 to 5 µm, d(0.5) from 0.3 to 10 µm and d(0.95) from 3 to 25 µm .

- 91 047306

Thus, an embodiment of the invention relates to a pharmaceutical composition containing or consisting of (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) or enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula! (I), where particles (8,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1 methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size range of 0.1 to 100 μm and a particle size distribution defined as d(0.95) <25 μm.

The pharmaceutical composition may contain (B,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl -1H-imidazole-5-carboxamido)-7-oxohept2-enoate or enantiomer, solvate, hydrate or pharmaceutically acceptable salt in an amount of from 0.1 to 99% by weight, preferably from 0.2 to 90% by weight, more preferably from 0.3 to 85 wt.%, even more preferably from 0.4 to 80 wt.%, even more preferably from 0.5 to 75 wt.%, even more preferably from 0.6 to 70 wt.%, even more preferably from 0.7 to 65 wt.%, even more preferably from 0.8 to 60 wt.%, even more preferably from 0.9 to 55 wt.%, even more preferably from 1 to 50 wt.%, even more preferably 1 to 45 wt%, even more preferably 1.25 to 45 wt%, even more preferably 1.5 to 40 wt%, even more preferably 1.75 to 35 wt%, even more preferably 2 to 34 wt%, even more preferably 2.25 to 33 wt%, even more preferably 2.5 to 32 wt% and most preferably 2.5 to 31 wt%, even more preferably from 2.5 to 30.5 wt.% and even more preferably from 2.6 to 30.3 wt.%, even more preferably from 3 to 30 wt.%, even more preferably from 3.5 to 29 wt. %, even more preferably from 4 to 28 wt.%, even more preferably from 4 to 27 wt.%, even more preferably from 4.5 to 27 wt.% and most preferably from 5 to 27 wt.% Reduction by wt.% (weight percent") refers to the weight percent in the pharmaceutical composition.

The pharmaceutical composition may also contain an amount of acidifier ranging from 0.1 to 80 wt%, preferably from 0.5 to 77.5 wt%, more preferably from 1 to 75 wt%, more preferably from 1.5 to 72 .5 wt.%, more preferably from 2 to 70 wt.%, more preferably from 2.5 to 62.5 wt.%, more preferably from 3 to 57.5 wt.%, more preferably from 3.5 to 55 wt.%, even more preferably from 4 to 55 wt.%, even more preferably from 4.5 to 55 wt.%, even more preferably from 5 to 54 wt.%, even more preferably from 5.5 to 53 wt.% %, even more preferably from 6 to 52 wt.%, even more preferably from 6.5 to 51 wt.%, even more preferably from 7 to 50 wt.%, even more preferably from 8 to 49 wt.%, even more preferably 8.5 to 49 wt%, and most preferably 9 to 49 wt%. The abbreviation wt% (weight percent) refers to the weight percent in the pharmaceutical composition.

The pharmaceutical composition may also contain an amount of polymeric precipitation inhibitor in the range of 0.1 to 40 wt%, preferably 0.5 to 39 wt%, more preferably 1 to 38 wt%, even more preferably 1.25 to 38 wt.%, even more preferably from 1.5 to 37 wt.%, even more preferably from 1.75 to 36 wt.%, even more preferably from 2 to 35 wt.%, even more preferably from 1.5 to 34 wt.%, even more preferably from 1.6 to 33 wt.%, even more preferably from 1.7 to 32 wt.%, even more preferably from 1.8 to 31 wt.%, even more preferably from 3. 5 to 30% by weight, even more preferably 4 to 29% by weight, even more preferably 4.5 to 28.5% by weight, most preferably 5 to 28.5% by weight.

The pharmaceutical composition may also contain an amount of binder ranging from 0 to 40% by weight, preferably from 0 to 35% by weight, more preferably from 0 to 30% by weight, even more preferably from 0 to 25% by weight, even more preferably from 0 to 20 wt.%, even more preferably from 0 to 15 wt.%, even more preferably from 0 to 12 wt.% and most preferably from 0 to 8.5 wt.%

The pharmaceutical composition may also contain an amount of disintegrant ranging from 0.1 to 40% by weight, preferably from 1 to 35% by weight, even more preferably from 2 to 30% by weight, even more preferably from 2.5 to 29% by weight. %, even more preferably from 3.0 to 28 wt.%, even more preferably from 3.5 to 27 wt.% and most preferably from 3.5 to 26.5 wt.%.

The pharmaceutical composition may also contain an amount of lubricant/glidant in the range of 0.1 to 10 wt%, more preferably 0.25 to 9.5 wt%, even more preferably 0.5 to 9 wt%. , even more preferably from 0.75 to 8.5 wt.%, even more preferably from 1 to 8 wt.%, even more preferably from 1.25 to 7.5 wt.%, even more preferably

- 92 047306 from 1.5 to 7% by weight and even more preferably from 1.5 to 6.5% by weight.

The pharmaceutical composition may also contain an amount of diluent/filler/binder ranging from 0 to 50 wt%, preferably from 1 to 47.5 wt%, more preferably from 1.5 to 45 wt%, more preferably from 2 to 42 .5 wt.%, more preferably from 2.5 to 40 wt.%, more preferably from 3 to 38 wt.%, more preferably from 3.5 to 38 wt.%, more preferably from 4 to 38 wt.%, more preferably from 4.5 to 38 wt.% and even more preferably from 5 to 38 wt.%.

The pharmaceutical composition may also contain amounts of other ingredients ranging from 5 to 60% by weight, preferably from 6 to 57.5% by weight, more preferably from 7 to 55% by weight, even more preferably from 8 to 52.5% by weight. , even more preferably from 9 to 51 wt.% and most preferably 10-50 wt.% relative to the dosage form.

In a preferred embodiment, the invention relates to a pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 0.1 to 45 wt. % (8,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl- Sh-imidazole-5carboxamido)-7-oxohept-2-enoate, from 3 to 75 wt.% acidifier, from 2 to 35 wt.% polymer precipitation inhibitor, from 0 to 12 wt.% binder, from 2 to 35 wt. % disintegrant and from 1 to 9 wt.% (lubricant)/glidant.

In a preferred embodiment, the invention relates to a pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 0.1 to 45 wt. % ^,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III -imidazole-5carboxamido)-7-oxohept-2-enoate, 3 to 75 wt.% adipic acid, 2 to 35 wt.% Lhydroxypropylcellulose and/or hydroxypropylcellulose, 0 to 12 wt.% povidone K25, from 2 to 35 wt.% croscarmellose sodium and from 1 to 9 wt.% talc or silicon dioxide.

In addition, in the pharmaceutical composition, the mass ratio of the acidifier relative to the mass of AE)-methyl-7 -(1 -(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 15 to 0.1 w/w, preferably from 14.5 to 0.2 w/w, more preferably from 14.0 to 0.3 w/w, even more preferably from 13.5 to 0.4 w/w, even more preferably from 13.0 to 0.5 w/w, even more preferably from 12.5 to 0.6 w/w, even more preferably from 12.0 to 0.7 w/w, even more preferably from 11.75 to 0.8 wt./wt., even more preferably from 11.5 to 0.9 wt./wt., even more preferably from 11.5 to 1.0 wt./wt., more more preferably from 11.5 to 1.1 wt./wt., even more preferably from 11.5 to 1.2 wt./wt., even more preferably from 11.5 to 1.3 wt./wt., more more preferably 11.5 to 1.4 w/w, even more preferably 11.5 to 1.5 w/w, even more preferably 11.5 to 1.6 w/w, even more preferably from 11.5 to 1.7 wt./wt. and most preferably from 11.5 to 1.8 wt./wt.

In addition, in the pharmaceutical composition, the mass ratio of the polymer precipitation inhibitor relative to the mass of AE)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)- 6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0.05 to 10 w/w, preferably from 0.06 to 9.5 w/w, more preferably from 0.07 to 9.00 w/w, even more preferably from 0.08 to 8.50 w/w, even more preferably from 0.09 to 8.00 wt./wt., even more preferably from 0.1 to 7.5 wt./wt., even more preferably from 0.11 to 7.25 wt./wt., more more preferably from 0.12 to 7 wt./wt., even more preferably from 0.13 to 6.75 wt./wt., even more preferably from 0.14 to 6.5 wt./wt., even more preferably 0.15 to 6.25 w/w, even more preferably 0.16 to 6 w/w, even more preferably 0.17 to 5.75 w/w, even more preferably from 0.18 to 5.5 wt./wt., even more preferably from 0.19 to 5.25 wt./wt., and most preferably from 0.20 to 5 wt./wt.

In addition, in the pharmaceutical composition, the mass ratio of the binder relative to the mass of ^,E)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0 to 10 w/w, preferably from 0.05 to 9.5 w/w, more preferably 0.06 to 9.00 w/w, even more preferably 0.07 to 8.50 w/w, even more preferably from 0.08 to 8.00 w/w, even more preferably 0.09 to 7.5 w/w, even more preferably 0.1 to 7.25 w/w, even more preferably from 0.11 to 7.00 w/w, even more preferably from 0.12 to 6.75 w/w, even more preferably from 0.13 to 6.50 w/w, even more preferably 0.14 to 6.25 w/w, even more preferably 0.15 to 6.00 w/w, even more preferably 0.16 to 5.75 w/w, even more preferably from

- 93 047306

0.17 to 5.50 w/w, even more preferably 0.18 to 5.25 w/w, even more preferably 0.19 to 5.5 w/w, even more preferably from 0.20 to 5 w/w, even more preferably from 0.20 to 4.5 w/w, even more preferably from 0.20 to 4 w/w, even more preferably from 0. 20 to 3.5 w/w, even more preferably 0.20 to 3 w/w, even more preferably 0.20 to 2.5 w/w, and even more preferably 0. 20 to 2 wt./wt.

In addition, in the pharmaceutical composition, the mass ratio of the disintegrant relative to the mass of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 - ylamino)-6-(1 methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0.05 to 12 w/w ., preferably from 0.06 to 11.5 wt./wt., more preferably from 0.07 to 11 wt./wt., even more preferably from 0.08 to 10.5 wt./wt., even more preferably from 0.09 to 10 w/w, even more preferably from 0.1 to 9.5 w/w, even more preferably from 0.11 to 9 w/w, even more preferably from 0 .12 to 8.5 wt./wt., even more preferably from 0.13 to 8 wt./wt., even more preferably from 0.14 to 7.5 wt./wt., even more preferably from 0. 15 to 7 w/w, even more preferably 0.16 to 6.5 w/w, even more preferably 0.17 to 5.5 w/w, even more preferably 0.18 to 5 wt./wt., even more preferably from 0.19 to 5 wt./wt. and most preferably from 0.2 to 5 wt./wt.

In addition, in the pharmaceutical composition, the weight ratio of (lubricant)/glidant relative to the weight of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0.05 to 2 w/w, preferably 0.06 to 1.8 w/w, more preferably 0.07 to 1.6 w/w, 0.08 to 1.4 w/w, even more preferably from 0.09 to 1.3 wt./wt. and most preferably from 0.1 to 1.2 wt./wt.

In addition, in the pharmaceutical composition, the weight ratio of the diluent/excipient/binder relative to the weight of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridine- 3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0 to 20 wt./ wt., more preferably from 0.01 to 17.5 wt./wt., more preferably from 0.05 to 15 wt./wt., more preferably from 0.1 to 0.125 wt./wt., more preferably from 0.15 to 10 w/w, more preferably 0.175 to 7.5 w/w, more preferably 0.2 to 6, more preferably 0.2 to 5.5, more preferably 0.2 up to 5 wt./wt.

In addition, in the pharmaceutical composition, the weight ratio of other ingredients relative to the weight of (8,B)-methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt may range from 0 to 30 wt./wt. , preferably from 0.2 to 27.5 w/w, more preferably from 0.3 to 25 w/w, even more preferably from 0.35 to 22.5 w/w, even more preferably from 0.4 to 21 wt./wt. and most preferably from 0.45 to 20 wt./wt.

In a preferred embodiment, the invention relates to said pharmaceutical composition for use in protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 1 to 15 wt. wt. acidifier, from 0.1 to 7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate.

Another aspect of the invention relates to the use of an effective amount of the compound (8,B)methyl-7 -(1 -(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino )-6-(1-methyl-1Nimidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I):

(I) its enantiomer, solvate, hydrate or pharmaceutically acceptable salt for the production of a pharmaceutical composition containing a compound of formula (I) as a hepatoprotector.

In one embodiment, the invention relates to the use of an effective amount of the compound (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3- ylamino)6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, or the said pharmaceutical composition in the manufacture

- 94 047306 medicinal product for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or in the prevention or treatment of liver disorder/disease.

The hepatotoxicity or liver disorder/disease is preferably caused by at least one hepatotoxicant, celiac disease or viral infection.

In particular, the at least one hepatotoxicant is selected from the group containing or consisting of toxic chemicals, xenobiotics, anticancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, heavy metals, mycotoxin, galactosamine and lipopolysaccharides , celiac disease associated with a specific genetic phenotype (HLA DQ2/DQ8), and transglutaminase 2 (TG2)-stimulated pathobiology; and/or viral infection caused by hepatitis A, B, C viruses.

In one embodiment, the invention relates to the use of an effective amount of a compound of formula (I), an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, or said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for the prevention or treatment of a liver disorder/disease, wherein the compound reduces serum levels of at least one liver enzyme, preferably at least one liver enzyme selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).

In one embodiment, the invention relates to the use of an effective amount of a compound of formula (I), an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-(1-methyl-III-imidazole-5-carboxamido)-7- oxohept-2enoate of formula (I), in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease, wherein the liver disorder/disease is liver fibrosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) or inflammation of the liver.

In one embodiment, the invention relates to the use of an effective amount of said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease, wherein the pharmaceutical composition further comprises, at least one polymeric sedimentation inhibitor.

Preferably, the at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and sodium carboxymethyl cellulose.

In one embodiment, the invention relates to the use of an effective amount of said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease. where the pharmaceutical composition additionally contains at least one acidulant and/or at least one binder.

Preferably, the at least one acidulant is selected from the group consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate.

Preferably, at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes, pregelatinized (modified) starches derived from wheat, corn, rice and potatoes, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose , sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, povidone K25.

- 95 047306

In one embodiment, the invention relates to the use of an effective amount of said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease wherein the particles (8,E )-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole-5 -carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.95) <25 µm.

In some embodiments, the invention relates to a pharmaceutical composition for use, wherein the pharmaceutical composition is an oral preparation, wherein preferably the oral preparation is a tablet, capsule, powder or granule.

In a preferred embodiment, the invention relates to the use of an effective amount of said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 1 up to 15 wt./wt. acidifier, from 0.1 to 7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of these compounds is calculated relative to the mass of N,E)-methyl-7 -(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)- 6-(1 methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate.

In a preferred embodiment, the invention relates to the use of an effective amount of said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 0 ,1 to 45 wt.% ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, from 3 to 75 wt.% acidifier, from 2 to 35 wt.% polymer precipitation inhibitor, from 0 to 12 wt.% binder, from 2 to 35 wt.% disintegrant and 1 to 9 wt.% (lubricant)/glidant.

In a preferred embodiment, the invention relates to the use of an effective amount of said pharmaceutical composition in the manufacture of a medicament for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or for preventing or treating a liver disorder/disease, wherein the pharmaceutical composition contains from 0 ,1 to 45 wt.% ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1 -methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, from 3 to 75 wt.% adipic acid, from 2 to 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, from 0 to 12 wt. .% povidone K25, from 2 to 35 wt.% croscarmellose sodium and from 1 to 9 wt.% talc or silicon dioxide.

Another aspect of the invention relates to a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of a compound I,E)-methyl-7-(1-( 2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methylIII-imidazole-5-carboxamido)-7-oxohept-2-enoate formula (I):

(I) its enantiomer, solvate, hydrate or pharmaceutically acceptable salt or pharmaceutical composition containing a compound of formula (I) as a hepatoprotector.

The hepatotoxicity or liver disorder/disease is preferably caused by at least one hepatotoxicant, celiac disease or viral infection.

The term subject as used herein means a mammal, preferably a human.

In particular, the at least one hepatotoxicant is selected from the group consisting of or consisting of toxic chemicals, xenobiotics, anticancer drugs, immunosuppressants, analgesics, anti-inflammatory drugs, anti-tuberculosis drugs, biologicals, radiation, heavy metals, mycotoxin, galactosamine and lipopolysaccharides ; celiac disease associated with a specific genetic phenotype (HLA DQ2/DQ8) and transglutaminase 2 (TG2)-stimulated pathobiology; and/or viral infection caused by hepatitis A, B, C viruses.

In one embodiment, the invention provides a method for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing

- 96 047306 ki or treatment of a liver disorder/disease comprising administering to a subject an effective amount of a compound of formula (I), an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof or said pharmaceutical composition, wherein the compound of formula (I) reduces serum levels by at least at least one liver enzyme, preferably at least one liver enzyme selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP).

In one embodiment, the invention provides a method for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or for preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of a compound of formula (I), its enantiomer, solvate, hydrate or pharmaceutically acceptable salt or said pharmaceutical composition containing a compound of formula (I), wherein the liver disorder/disease is liver fibrosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cirrhosis, cholestatic liver disease , such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), alcoholic steatohepatitis (ASH) or liver inflammation.

In one embodiment, the invention provides a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of said pharmaceutical composition containing a compound of formula (I), wherein the pharmaceutical composition further contains at least one polymeric deposition inhibitor.

Preferably, the at least one polymeric sediment inhibitor is selected from the group consisting of L-hydroxypropyl cellulose, hydroxypropyl cellulose, a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) , polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and sodium carboxymethylcellulose.

In one embodiment, the invention provides a method for protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or for preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of said pharmaceutical composition, wherein the pharmaceutical composition further comprises, at least one acidulant and/or at least one binder.

Preferably, the at least one acidulant is selected from the group consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, or glutamic acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate.

Preferably, at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes, pregelatinized (modified) starches derived from wheat, corn, rice and potatoes, sodium starch glycolate, natural gums, gum acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose , sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, povidone K25.

In one embodiment, the invention relates to a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of said pharmaceutical composition, wherein the particles (S,E)- methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imcdazol-5-carboxamido)- 7-oxohept2-enoate have a particle size distribution defined as d(0.95) <25 µm.

In some embodiments, the invention provides a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of said pharmaceutical composition, wherein the pharmaceutical composition is an oral preparation, wherein preferably the oral preparation is a tablet, capsule, powder or granule.

In a preferred embodiment, the invention relates to a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effect of

- 97 047306 active amount of the specified pharmaceutical composition, where the pharmaceutical composition contains from 1 to 15 wt./wt. acidifier, from 0.1 to 7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds is calculated relative to the mass of N,E)-methyl-7(1 -(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino) -6-(1-methyl-1H-imidazole5-carboxamido)-7-oxohept-2-enoate.

In a preferred embodiment, the invention relates to a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage, and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition contains from 0.1 to 45 wt.% ^,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate, 3 to 75 wt.% acidifier, 2 to 35 wt.% polymer precipitation inhibitor, 0 to 12 wt.% binder , from 2 to 35 wt.% disintegrant and from 1 to 9 wt.% (lubricant)/glidant.

In a preferred embodiment, the invention relates to a method of protecting the liver from hepatotoxicity, improving liver function, protecting/repairing liver damage and/or preventing or treating a liver disorder/disease, comprising administering to a subject an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition contains from 0.1 to 45 wt.% (S,E)methyl-7 -(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3 -ylamino)-6-( 1 -methyl-1Nimidazole-5-carboxamido)-7-oxohept-2-enoate, 3 to 75 wt.% adipic acid, 2 to 35 wt.% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0 to 12 wt.% povidone K25, from 2 to 35 wt.% croscarmellose sodium and from 1 to 9 wt.% talc or silicon dioxide.

Description of the figures

Fig. 1 shows ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl-III- imidazole-5-carboxamido)-7-oxohept-2-enoate (compound 1) in the UUO model.

Fig. Figure 2 shows immunohistochemical evidence of the complex N,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl -1H-imidazole-5carboxamido)-7-oxohept-2-enoate (compound 1) and TG2 in kidney tissue at different dosages.

Fig. 3 shows ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl-III- imidazole-5-carboxamido)-7-oxohept-2-enoate (compound 1) in the NASH model.

Fig. 4 shows the pharmacokinetics of N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III -imidazole-5-carboxamido)-7-oxohept-2-enoate in the C57BL/6 mouse.

Fig. Figure 5 shows the dose-activity relationship. For the STAM and UUO models, the antifibrotic effect is presented as a function of dose or as a function of exposure (Plasma Cmax or Plasma AUC).

Fig. 6 shows plasma profiles of the compound as well as human pharmacokinetic data obtained after multiple dosing according to Example 7.

Fig. 7 shows the correlation of human pharmacokinetic data with in vitro data for TG2 inhibition.

Fig. 8 shows the maximum plasma concentration (Cmax) achieved after administration of various doses of a compound of formula I in a formulation or as a single compound. To summarize data across species, doses are converted to human equivalent doses (HED) to account for differences in body surface area between species. Use generally accepted species-specific conversion factors as defined in the FDA guidance Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (release date 2005).

Fig. 9 shows the antifibrotic effects in animal models depending on the Cmax value as well as the AUC value. In addition, the Cmax value achieved in humans at dosages of 10, 20 and 50 mg of ^,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxo-ethyl)-2- oxo-1,2-dihydropyridin-3ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate.

Fig. 10 shows antifibrotic effects in animal models as a function of AUC value. In addition, the AUC values achieved in humans at dosages of 10, 20 and 50 mg of ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1, are presented. 2-dihydropyridin-3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate.

In fig. 11 shows the solubility at saturation of ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl -1H-imidazole-5-carboxamido)-7-oxohept2-enoate.

In fig. Figure 12 shows the study design of Case Study 14.

Examples

Example 1

Preparation of ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxo-ethyl)-2-oxo-1,2-dihydropyridin-3 ylamino)-6-(1-methyl- 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate (Compound of formula (I))

- 98 047306

Example 1.1. Preparation of 6-aminohept-2-enedicarboxylic acid derivatives (^)-1-tert-Butyl-5-methyl-2-(tert-butoxycarbonylamino)-pentanedioate

Molecular Formula: Ci ₅ H ₂₇ NO ₆

Molecular weight: 317.38

Dissolve 12.0 g Boc-Glu-OtBu (39.6 mmol) in 200 ml DMF. Under argon, 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq.) was added and the resulting suspension was stirred for 1 hour at RT. After this time, 2.47 ml of methyl iodide (39.6 mmol) was added and stirred at RT overnight. The solvent is removed in vacuo and the resulting residue is taken up in 400 ml of ethyl acetate. The undissolved solid was filtered off and the filtrate was washed with 75 ml of 10% citric acid, 10% NaHCO3 solution and brine respectively 3 times. After drying the organic phase over Na ₂ SO ₄ the solvent is removed in vacuo. The product is obtained as a yellow oil. The product can be used without further purification in the next reaction.

Yield: 13.4 g, >100%

ESI-MS: 340.2 [M+Na]+

^)-1-tert-Butyl-5-methyl-2-(bis(tert-butoxycarbonyl)amino)pentanedioate

Molecular Formula: C ₂₀ H ₃₅ NO ₈

Molecular weight: 417.49

Dissolve 13.4 g Boc-Glu(OMe)-OtBu (~39.6 mmol) in 30 ml acetonitrile and treat with 986 mg DMAP (70.91 mmol, 0.2 eq). Under a nitrogen atmosphere, add a solution of 17.6 g of di-tert-butyl bicarbonate (77.1 mmol, 2 eq.) in 100 ml of acetonitrile. After stirring overnight, the solvent is removed in vacuo and the resulting crude product is purified by chromatography on silica gel (column: 31 x 6.0 cm, petroleum ether/ethyl acetate 9:1)

Column chromatography: collect 250 ml fractions, product: fractions 6-13

TLC control: petroleum ether/ethyl acetate 8:2, Rf=0.70

Yield: 13.7 g, 32.8 mmol, 83%

ESI-MS: 440.3 [M+Na]+

^)-tert-Butyl-2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate

Molecular Formula: Ci ₉ H ₃₃ NO ₇

Molecular weight: 387.47

Dissolve 13.7 g of Boc ₂ -Glu(OMe)-OtBu (32.8 mmol) in 200 ml of absolute diethyl ether and cool to -78° C. under argon. At this temperature, 36.1 ml (36.1 mmol, 1.1 eq.) of diisobutylaluminum hydride solution (1 M in hexane) was slowly added dropwise. After addition, the solution is stirred for a further 15 min at -78°C before quenching the reaction mixture by adding 50 ml of water at the same temperature. With vigorous stirring, the mixture is heated to RT and the cloudy solution is filtered through celite. The filtrate is concentrated to dryness and the remaining water is removed by distillation with toluene. A slightly colored oil is obtained, which is used without further purification in the next reaction.

TLC control: petroleum ether/ethyl acetate 8:2, Rf=0.54

Yield: 13.3 g, >100% (purity 86.1%)

500-MHz- ^1H -NMR-(correlation) (DSMOO, δ ppm: 9.65 (s, 1H, H-4), 4.63 (dd, 1H, H-1, J _1/2a =4.8 Hz, J1/2b=9.85 Hz), 2.51-2.50 (m, 1H, H-3 _a ), 2.48-4.40 (m, 1H, H-3 _b ), 2.27-2.20 (m, 1H, H-2a), 1.98-1.91 (m, 1H,

- 99 047306

H-2 _b ), 1.44 (s, 18H, 6xCH ₃ (Boc)), 1.92 (s, 9H, 3xCH ₃ (O-tBu).

ESI-MS: 410.4 [M+Na]+ ^,E)-7-tert-Butyl-1-methyl-6-(bis(tert-butoxycarbonyl)-amino)hept-2-enedioate ο.. Λ) .

J g

O' 'D/Z,

Molecular Formula: C ₂₂ H ₃₇ NO ₈

Molecular weight: 443.53

Prepare 13.2 g of Boc ₂ -Glu(H)-OtBu (~32.8 mmol) in 20 ml of dried benzene and add a solution of 11.2 g of (methoxycarbonylmethylene)triphenylphosphorane (32.8 mmol) under an argon atmosphere at RT. After stirring overnight, the solvent was removed in vacuo and the resulting oily residue was purified by chromatography on silica gel (column: 39 x 6.0 cm, petroleum ether/ethyl acetate 9:1).

Column chromatography: collect 250 ml fractions, product: fractions 2-12

TLC control: petroleum ether/ethyl acetate 8:2, Rf=0.54

Yield: 12.0 g, 27.1 mmol, 83%

500-MHz- ¹ H-NMR-(correlation) (DMSD ₆ ), δ ppm: 6.66 (dt, 1H, H-4, J _4/3 =6.8 Hz, J _4/5 = 15.9 Hz), 5.64 (d, 1H, H-5, J _5/4 =15.9 Hz), 4.45-4.2 (m, 1H, H-1), 3.44 ( s, 3H, CH3-6), 2.01-1.95 (m, 2-H, H-3a, H-3 _b ), 1.951.86 (m, 1H, H-2a), 1.78- 1.67 (m, 1H, H-2b), 1.24 (s, 18H, 6xCH ₃ (Boc)).

ESI-MS: 466.3 [M+Na]+ (S,E)-2-(tert-Butoxycarbonylamino)-7-methoxy-7-oxohept-5-enoic acid (1a1)

Molecular Formula: C ₁₃ H ₂₁ NO ₆

Molecular weight: 287.31

Dissolve 7.0 g of (S,E)-7-tert-butyl-1-methyl-6-(bis(tert-butoxycarbonyl)αmino)hept-2-enedioate (15.8 mmol) in 40 ml of dichloromethane and add a solution of 70 ml of trifluoroacetic acid. Stir at RT for 4 hours. The solvent is removed in vacuo, and the green residue is dried in vacuo. The resulting oil is then used without purification. The pH is adjusted to approximately 7 by successive additions of DIPEA.

The oil is taken into 50 ml DMF and treated with 5.37 ml DIPEA. Add 4.08 g Boc-OSu (18.9 mmol, 1.2 eq.) and stir at RT overnight. The solvent is removed in vacuo, the residue is suspended in 130 ml of 5% KHSO4 solution. Extract with ethyl acetate (1x150 ml, 2x100 ml) and the collected organic phases are washed with brine (75 ml). After drying the organic phase over Na ₂ SO ₄ the solvent is removed in vacuo. The residue is purified by chromatography on silica gel (column: 13x6.0 cm, toluene/ethyl acetate 65:35, 0.5% acetic acid). A colorless oil is obtained.

Column chromatography: 200 ml fractions collected, product: fractions 2-5, first run 500 ml

TLC control: toluene/ethyl acetate 1:1, 0.5% acetic acid, Rf=0.35

Yield: 4.04 g, 14.1 mmol, 89% (purity 88.6%)

ESI-MS: 310.1 [M+Na]+

Example 1.2 Preparation of pyridinone derivatives

Benzyl-3-hydroxypyridin-3-ylcarbamate

Molecular Formula: C ₁₃ H ₁₂ N ₂ O ₃

Molecular weight: 244.25

Suspend 15 g of 2-hydroxynicotinic acid (108 mmol) in 180 ml of dried dioxane.

After adding 14.9 ml of triethylamine (108 mmol), the suspension becomes very clear. Adding

- 100 047306 Take 24 ml of diphenylphosphoryl azide (DPPA, 108 mmol) and the reaction solution is refluxed (130°C) under argon. As a result, gas evolution is observed. After 16 h, another 16.3 mL of TEA and 12.8 mL of benzyl alcohol (117 mmol, 1.1 eq.) are added successively and refluxed for another 24 h.

The solvent is removed in vacuo and the resulting brown residue is taken up in a mixture of 300 ml DCM and 300 ml brine. The pH is adjusted to approximately 1 with 1M HCl solution (about 22 ml), the phases are separated and the aqueous phase is then extracted twice with 200 ml of DCM. The collected organic phases are washed with 10% NaHCO ₃ solution (3x150 ml) and brine (1x150 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo. The resulting brown solid was recrystallized from 300 ml of methanol.

TLC control: DCM/MeOH 9:1, Rf=0.70

Yield: 16.2 g, 66.4 mmol, 62% (light brown, felt-like solid)

ESI-MS: 245.1 [M+H]+ tert-Butyl-2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetate

Molecular Formula: Ci ₉ H ₂₂ N ₂ O ₅

Molecular weight: 358.39

Suspend 16.2 g of benzyl-3-hydroxypyridin-3-ylcarbamate (66.4 mmol) in 900 ml of absolute THF, cool to 0°C under argon and add 2.92 g of NaH (60% in mineral oil, 73. 1 mmol, 1.1 eq.). To the resulting solution after the end of gas evolution (about 15 minutes), 13.7 ml of bromoacetic acid tert-butyl ester (89.7 mmol, 1.35 eq.) was added. Stir for 15 min at 0°C and then at RT overnight. The reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is taken up in 5 ml of ethyl acetate, treated with approximately 50 ml of diethyl ether and the resulting suspension is allowed to settle in the refrigerator overnight. The crystals are filtered and washed with a small amount of ether.

The filtrate is concentrated and purified by chromatography on silica gel (layer: 20x6 cm, eluent: petroleum ether/ethyl acetate 8/2)

Column chromatography: collect fractions of 250 ml, product: fractions 10-25

TLC control: petroleum ether/ethyl acetate 7/3, Rf=0.46

Yield: 19.3 g, 54.0 mmol, 81%

ESI-MS: 359.1 [M+H]+

2-(3-(Benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)-acetic acid

Molecular Formula: Ci ₅ Hi ₄ N ₂ O ₅

Molecular weight: 302.28

Dissolve 4.00 g of tert-butyl-2-(3-(benzyloxycarbonyl-amino)-2-oxopyridin-1(2H)-yl)acetate (11.2 mmol) in 50 ml of dichloromethane and treat with 50 ml of trifluoroacetic acid. Stir at RT for 3 hours before removing volatile components in vacuo. After drying under vacuum, a brown solid is obtained which is acceptable for subsequent use without purification.

Yield: 3.70 g, >100%

ESI-MS: 303.2 [M+H]+

Benzyl 1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylcarbamate

Molecular formula: C ₂ iH ₂₇ N ₃ O ₄

Molecular weight: 385.46

A mixture of 3.70 g 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetic acid (~11.2 mmol), 3.58 g TBTU (11.2 mmol) and 1.51 g HOBt (11.2 mmol) is dissolved in 60 ml DMF. The pH was adjusted to ~10 by adding 5.70 mL DIPEA (33.5 mmol, 3 eq.). 1.50 ml of 2ethylbutylamine (11.2 mmol) was added and the mixture was stirred at RT overnight. The solvent is removed in vacuo, the resulting residue is taken up in 300 ml of DCM and then washed with 10% citric acid (3x75 ml), saturated NaHCO ₃ solution (3x75 ml) and brine (75 ml). The organic phase is dried over Na2SO4, filtered and concentrated to dryness. A pale brown solid is obtained which

- 101 047306 is acceptable for subsequent processing without additional purification.

Yield: 5.22 g, >100%

ESI-MS: 386.3 [M+H]+

2-(3-Amino-2-oxopyridin-1 ^H-ylU^^-ethylbutyl^cetamide (2a)

Molecular Formula: C.’|3H2|N3O2

Molecular weight: 251.32

Dissolve 5.22 g of benzyl 1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylcarbamate (2.4 g, ~11.2 mmol) in a nitrogen atmosphere ) in 60 ml of methanol. To this solution add 500 mg Pd/C (10%) and stir under a hydrogen atmosphere at atmospheric pressure for 2.5 hours. The catalyst is filtered off on silica gel before removing the solvent in vacuo. A dark oil is obtained, which is acceptable for subsequent processing without additional purification.

Yield: 3.62 g, >100%

ESI-MS: 252.2 [M+H]+

Example 1.3 Preparation of (B,E)-methyl-6-(tert-butoxycarbonyl-amino)-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridine-3 - ylamino)-7-oxohept-2-enoate

Molecular formula: C ₂₆ H ₄₀ N ₄ O ₇ ;

Molecular weight: 520.62

Prepare a solution of 3.36 g of 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide (2a, ~10.4 mmol) in 20 ml of DMF. To this solution add a solution of 2.97 g of (8,E)-2-(tert-butoxycarbonylamino)-7-ethoxy-7-oxohept-5-enoic acid (1a1, 10.4 mmol), 3.93 g of HATU ( 10.4 mmol) and 3.52 ml DIPEA (20.7 mmol, 2 eq.) in 40 ml DMF. The pH is adjusted to approximately 7 by successive additions of DIPEA. The reaction mixture is stirred at 40°C for 2.5 hours and at RT overnight before removing the solvent in vacuo. The resulting brown residue is taken up in 250 ml of ethyl acetate, then washed with 10% citric acid (3x75 ml), saturated NaHCO ₃ solution (3x75 ml) and brine (75 ml). The organic phase is dried over Na ₂ SO ₄ and concentrated to dryness in vacuo. The residue is purified by chromatography on silica gel (layer: 13x6 cm, eluent toluene/acetone 7/3).

Column chromatography: first run 150 ml, collect 40 ml fractions, product: fractions 6-15

TLC control: DCM/MeOH 97:3, Rf=0.40

Yield: 3.34 g, 6.42 mmol, 62%

ESI-MS: 543.4 [M+Na]+ (B,E)-Methyl-7-(1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine- 3-ylamino)-6-(1 methyl-III-imidazole^-carboxamido^-oxogentd-enoate (Compound of formula (I))

Molecular formula: C ₂₆ H ₃₆ N ₆ O ₆ ;

Molecular weight: 528.60

Dissolve 3.14 g of (B.E)-methyl 6-(tert-butoxycarbonyl-amino)-7-(1-(2-(2-ethylbutylamino)-2oxoethyl)-2-oxo-1,2-dihydropyridine-3 -ylamino)-7-oxohept-2-enoate (3.1, 6.03 mmol) in a mixture of 25 ml dichloromethane and 35 ml TFA and stir for 3 hours at RT before removing volatiles in vacuo. The resulting brown oil was dried under high vacuum and dissolved in 10 ml DMF and 1.03 ml DIPEA (6.03 mmol) was added. To this solution were added 2.29 g of HATU (6.03 mmol) and 1.03 ml of DIPEA (6.03 mmol) in 30 ml of DMF. The pH is adjusted to approximately 7 by successive additions of DIPEA. Stir overnight at RT. The residue is taken up in 200 ml of ethyl acetate, then

- 102 047306 washed with 10% citric acid, saturated NaHCO ₃ solution and brine (75 ml each). The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo. The residue is purified by chromatography on silica gel (layer: 12x6 cm, eluent DCM/MeOH 97:3, after 2 liters 95:5).

Column chromatography: first run 1000 ml, collect 50 ml fractions, product: fractions 43-66

TLC control: DCM/MeOH 97:3, Rj=0.30

Yield: 1.42 g, 2.69 mmol, 45%

ESI-MS: 551.3 [M+Na]+ ¹ H-NMR (DMSOA, 500 MHz): δ ppm: 9.29 (s, 1H), 8.63 (d, 1H), 8, 21 (dd, 1H), 8.04 (t, 1H), 7.75 (d, 2H), 7.33 (dd, 1H), 6.93 (dt, 1H, J=15.63; 6, 93), 6.25 (t, 1H), 5.86 (d, 1H, J=15.69), 4.58 (s, 2H), 3.79 (s, 3H), 3.62 (s , 3H), 3.01 (t, 2H), 2.33 (m, 2H), 2.03 (m, 1H), 1.90 (m, 1H), 1.26 (m, 5H), 0 .83 (t, 6H).

Example 2

Study on the model of unilateral ureteral obstruction (UUO-model) in nephritic fibrosis

Antifibrotic effect in the kidneys (B,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1 α-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate (compound of formula (I)) was studied in the UUO model in the C57BL/6 mouse. In the UUO model, fibrosis is induced in one of the kidneys by ligating one ureter. The other kidney remains functional. The pathophysiology of the UUO model resembles chronic nephropathy in humans (chronic kidney disease, CKD).

Groups of 8 UUO mice are treated immediately after ureteral ligation for a two-week period with three different dosages of the indicated compound: 100, 300 and 1000 mg/kg body weight. The daily dose is administered orally as a suspension at intervals of 8 hours. In the control group, UUO mice are treated in the same way, but only with the methylcellulose vehicle. At the end of treatment, a histopathological examination of the kidney tissue is carried out, as well as a determination of the amount of hydroxyproline in the kidney. In addition, immunohistochemical localization of the complex (B,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 is performed -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate and TG2 via a specific antibody for (B,E)-methyl-7-(1(2-(2-ethylbutyl-amino)-2 -oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate.

Results: Treatment with (B,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-( 1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate leads to a significant, pronounced, dose-dependent decrease in the fibrous area of the kidney. The hydroxyproline content remains unchanged. Effect of (B,E)-methyl-7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl- 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate in the UUO model is shown in Fig. 1. The immunohistochemical localization of the complex of the compound of formula (I) and TG2 in kidney tissue at different dosages can be seen in FIG. 2.

Conclusion: The marked improvement in kidney histology compared to control indicates that the compound of formula (I) suppresses both fibrosis and fibrogenesis. The effects and underlying mechanism in the kidney are probably similar to the antifibrotic effects and mechanism in the liver.

Immunohistochemical localization of the complex of the compound of formula (I) and TG2 shows that (8,E)-methyl-7-(1-(2-(2-ethyl-butylamino)-2-oxoethyl)-2-oxo-1,2- Dihydropyridin-3-ylamino)-6-(1-methyl1H-imidazole-5-carboxamido)-7-oxohept-2-enoate reaches the target site and inhibits the target molecule.

Example 3

Study on a static animal model (STAM model) of non-alcoholic steatohepatitis

The antifibrotic effect of the compound of formula (I) in the liver was studied in the STAM model of non-alcoholic steatohepatitis. The model is based on the induction of chronic fibrotic inflammation of the liver through a combination of a chemical toxin (streptozotocin) and a fat-containing diet in the C57BL/6 mouse. The pathology is similar to that described for NASH in humans.

Groups of 8 STAM mice are treated over a two-week period with three different dosages of the indicated compound: 100, 300 and 1000 mg/kg body weight. The daily dose is administered orally as a suspension in two parts at intervals of 8 hours. In the control group, STAM mice are treated in the same way, but only with the methylcellulose carrier. At the end of treatment, a biochemical parameter in the plasma is measured, and after necropsy of the animals, a histopathological examination of the liver is performed, determination of liver fat content, as well as determination of the expression of a marker of inflammation and fibrosis.

Results: Treatment with a compound of formula (I) resulted in a significant, pronounced, dose-dependent improvement in liver histology. In more detail, the NAFLD Activity Score (NAS), as shown in FIG. 3, decreased in the medium and high dose group. The improvement in NAS is primarily due to a reduction in inflammation and hepatocyte bloating. In addition, a noticeable, dose-dependent reduction in the fibrotic area in the liver can be observed, which is significant

- 103 047306 in the medium and high dosage group. When compared with historical data, the reduction in fibrosis in the high-dose group occurred in the region of the drug telmisartan, which served as a positive control.

Conclusion: The antifibrotic effect of the compound of formula (I) is likely due to the inhibition of TG2 in the liver. As a result, cross-linking of collagen fibrils is prevented and fibrosis formation is reduced compared to untreated control animals. The reduction in inflammation and bloating is likely secondary to the antifibrotic effect. (8,B)-Methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazole -5carboxamido)-7-oxohept-2-enoate has no effect on liver fat content.

Example 4

Pharmacokinetics of the compound of formula (I) in the C57BL/6 mouse

The study serves to describe the pharmacokinetics of the compound of formula (I) in C57BL/6 mice. Dosing is similar to that in the STAM model (Example 3) or the UUO model (Example 2) to allow assessment of systemic exposure in these models and correlation of pharmacokinetic data with efficacy data.

Groups of 12 C57BL/6 mice are treated with three different dosages of the compound of formula (I) over a 7-day period: 100, 300 and 1000 mg/kg body weight. The daily dose is administered orally as a suspension in two parts at intervals of 8 hours. On the 7th day of treatment, three different blood samples are taken. The time points in the group are distributed so that the 24-hour profile covers 12 different time points (3 animals per time point).

Measurement of the compound of formula (I) in blood plasma is carried out using an approved HPLC-MS/MS method.

Conclusion: The plasma profile of the compound of formula (I) and the pharmacokinetic data obtained therefrom are presented in FIG. 4.

Example 5

Dose-activity relationship

The reduction in fibrotic area in the tissue compared to untreated control animals can be considered as an indicator of the antifibrotic effect of the compound of formula (I) in the STAM model as well as in the UUO model. For the STAM and UUO models, the antifibrotic effect as a function of dose or as a function of exposure ( _Cmax in plasma or AUC in plasma) is presented in Fig. 5.

Results: The results of the dose-activity study are presented in FIG. 5.

Conclusion: Although the tissue structure of the liver and kidney is different, and the pathogenesis of fibrotic changes in the STAM model and in the UUO model is fundamentally different, the compound of formula (I) exhibits the same antifibrotic effect in both models. The apparent nonlinear dose-activity relationship is likely due to saturation of absorption and systemic exposure following oral administration of the high dosage used here. When taking into account the antifibrotic effect depending on exposure in plasma, an almost linear correlation is obtained.

Example 6

Preparation of hard gelatin capsule

6.1 Preparation of A hard gelatin capsule

The acid granulate is produced by wet granulation using 96% ethanol as the granulating liquid. The compound of formula (I), L-hydroxypropylcellulose and croscarmellose sodium are sieved in dry form and then mixed. When ethanol is added, particles agglomerate and a granular structure forms. The granular mass is wet sieved, dried at 70°C and finally sieved again. In a dry mixer, sifted adipic acid, as well as talc, are added to the dry granulate and mixed. The powder mixture is then filled into a hard gelatin capsule.

6.2 Preparation of B hard gelatin capsule

For the preparation of a solid formulation for oral administration (8,B)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1-Methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate (15.0%) is mixed with polyvinyl alcohol (56.9%). The mixture is processed in a hot melt extruder to produce an extrudate. The extrudate is cooled and crushed. In a dry mixer, crospovidone (7.5%), L-hydroxypropylcellulose (7.2%) and fumaric acid (13.5%) are added to the ground extrudate and mixed. The powder mixture is then filled into a hard gelatin capsule.

6.3 Preparation of C hard gelatin capsule

Hydroxypropylcellulose (2.3%) is dissolved in isopropanol (96%) to obtain a granulating liquid. Mix (8,B)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl- 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate (38.8%), cellulose (microcrystalline; 7.8%), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (7.8%), croscarmellose sodium (7.8%) and adipic acid (34.9%). A granulating liquid is added to the powder mixture to obtain a granular mass. This mass is sieved in a damp

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Example 7

Pharmacokinetics of the compound of formula (I) in humans

Pharmacokinetics of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin3-ylamino)-6-(1-methyl-III- imidazole-5-carboxamido)-7-oxohept-2-enoate (compound of formula (I)) was studied in healthy volunteers. Topological groups of 18 subjects were each treated with a daily dose of 10, 20, 50 and 100 mg of the compound of formula (I), respectively, over a 7-day period. Determine the specified compound in blood plasma using a previously validated HPLC-MS/MS method.

Results: Compound plasma profiles as well as human pharmacokinetic data obtained after multiple dosing are presented in FIG. 6.

Conclusion: The drug concentration achieved with the drug increases in the dose range of 10-100 mg in proportion to the dose, and when normalized to body weight is noticeably higher than in animal studies where the drug is administered as a suspension.

The drug concentration achieved is compared with concentrations that result in vitro inhibition of TG2 enzyme activity (Fig. 7). Thus, TG2-catalyzed incorporation of dansylcadaverine into NN-dimethylcasein (DCC assay), indicating the cross-linking function of TG2, serves as a marker reaction. According to this correlation, half-maximal inhibition (IC50) of TG2 is achieved with a dose of 20 mg. A 50 mg dose of the newly developed formulation results in drug levels exceeding the already IC ₉₀ of enzyme inhibition. Inhibition of 90% at IC ₉₀ can be considered as the maximum pharmacodynamic effect.

Example 8

Comparison of drug pharmacokinetic data with pharmacokinetic data of a single compound

Pharmacokinetic data for humans ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl- 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate (compound of formula (I)), described in example 7, were prepared after administration in the hard gelatin capsule described in example 6.

To evaluate the effect of a drug, the pharmacokinetic data of the drug in the hard gelatin capsule are compared with the pharmacokinetic data obtained after administration of a simple compound without a dosage form. For regulatory and ethical reasons, single compound pharmacokinetic data have only been obtained in animals and not in humans.

Pharmacokinetic data for the pure compound are obtained from several studies in monkeys, pigs, rabbits, rats and mice. In all studies, the compound was administered orally after suspension in 0.5% (w/v) methylcellulose in water, pH 5±0.5. Blood samples are collected at different time points within 24 h of drug administration and quantified using a previously validated HPLC-MS/MS method.

In fig. 8 shows the maximum plasma concentration (Cmax) achieved after administration of various doses of a compound of formula I as a formulation or as a pure compound. To summarize data across species, doses are converted to human equivalent doses (HED) to account for differences in body surface area between species. Use generally accepted species-specific conversion factors as defined in the FDA guidance Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (release date 2005).

Comparison in Fig. 7 demonstrates over a wide dose range that the Cmax achieved after administration of the drug is more than 10 times higher than the Cmax achieved after administration of the pure compound. Although differences in Cmax may be partly attributable to species differences in pharmacokinetics, the large difference between data for humans and the closely related monkey suggests that formulation plays a major role in achieving high systemic exposure.

Example 9

Correlation of antifibrotic effect with human pharmacokinetics

Antifibrotic effect of ^,E)-methyl-7-(1 -(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2dihydropyridin-3-ylamino)-6-(1-methyl- 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate in an animal model suggests the potential use of this compound in fibrotic diseases of the liver or kidneys in humans. Comparison of systemic exposure (C _max s, AUC) XE)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6 -(1-methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate at a dose effective in animal studies with systemic exposure achieved in humans allows the potential effective dose range to be assessed.

Antifibrotic effects in animal models depending on the _Cmax value as well as the AUC value are presented in Fig. 9 and fig. 10. In addition, the Cmax or AUC has been shown to be achieved in humans at dosages of 10, 20 and 50 mg of the compound of formula (I).

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Conclusion: The relationship between fibrotic area and _Cmax value (Fig. 9) or AUC value (Fig. 10), respectively, confirms that the antifibrotic effect shown in the animal model can be achieved in humans as early as 20 mg dose. In humans, systemic exposure further increases linearly up to 100 mg. The nearly linear relationship of antifibrotic effect with systemic exposure suggests that at higher dosages in humans, a greater antifibrotic effect may be achieved than in the animal model.

Example 10

The saturation solubility of the compound of formula (I) is measured over the pH range from 1 to 6.8 using HPLC/UV.

The results are illustrated in Fig. eleven.

Results: It is clear that saturation solubility is much lower at pH=6.8 (small intestine) than at pH ~1.

Notably, bioavailability in the mouse model can be measured, although the solubility at saturation is much lower at pH=6.8 than at pH ~1.

Example 11

Preparation of a pharmaceutical composition in tablet form

11.1 Preparation A of pharmaceutical composition in tablet form

For the preparation of a solid formulation for oral administration (8,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1-Methyl-III-imidazole-5carboxamido)-7-oxohept-2-enoate (7.6%) is mixed with L-hydroxypropyl methylcellulose (18.3%), croscarmellose sodium (1.5%), povidone K25 (8. 4%) and cellulose (microcrystalline; 36.6%). The powder mixture is granulated with ethanol (96%). After wet sifting, the granules are dried. Adipic acid (13.7%), croscarmellose sodium (12.2%) and silicon dioxide (1.5%) are added to the granules to obtain the final mixture, which is compressed into tablets.

The tablet may then be coated with a film containing: lactose monohydrate, hydroxypropyl methylcellulose (E464; also known as hypromellose), titanium dioxide (E171), triacetin (E1518), yellow iron oxide (E172) and carnauba wax (E903).

11.2 Preparation of B pharmaceutical composition in tablet form

For the preparation of a solid formulation for oral administration (8,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1-Methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate (22.0%) is mixed with L-hydroxypropyl methylcellulose (10.6%), croscarmellose sodium (11.0%) and mannitol (11.0 %). The powder mixture is granulated with a solution of hydroxypropylcellulose (1.3%) in ethanol (96%). After wet sifting, the granules are dried. Glutaric acid (39.7%) and talc (4.4%) are added to the granules to obtain the final mixture, which is pressed into tablets.

11.3 Preparation of C pharmaceutical composition in tablet form

For the preparation of a solid formulation for oral administration (8,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1-Methyl-1H-imidazole-5carboxamido)-7-oxohept-2-enoate (15.4%) is mixed with polyvinyl alcohol (58.6%). The mixture is processed in a hot melt extruder to produce an extrudate. The product is cooled, crushed and mixed with croscarmellose sodium (6.2%), cellulose (microcrystalline; 6.2%), glutaric acid (12.4%), silica (0.6%) and talc (0.6% ), the final mixture is obtained, which is compressed into tablets.

The tablet may then be coated with a film containing: lactose monohydrate, hydroxypropyl methylcellulose (E464; also known as hypromellose), titanium dioxide (E171), triacetin (E1518), yellow iron oxide (E172) and carnauba wax (E903).

Example 12

Preparation of granules for capsules

12.1 Preparation of A granules for capsules

Add 50 mg L-hydroxypropylcellulose and 25 mg croscarmellose sodium to 10 mg (8,E)-methyl7-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-1H-imide zol-5-carboxamido)-7-oxohept-2-enoate. The compounds are sifted dry. 50 mg of ethanol is added to form a granular mass. This mass is sifted while wet and then dried. After drying, the mass is sifted again. 115 mg of adipic acid and 12 mg of talc are added to the dried granules in a dry mixer. The powder mixture is then filled into the capsule.

12.2 Preparation of B granules for capsules

Dissolve 24 mg of L-hydroxypropylcellulose in 22 ml of ethanol to obtain a granulating liquid. Mix 10 mg of (8,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1- methyl 1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, 3 mg L-hydroxypropylcellulose (low-substituted), 25 mg croscarmellose sodium and 25 mg mannitol. A granulating liquid is added to the powder mixture, resulting in a granular mass.

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This mass is sifted while wet and then dried. After drying, the mass is sifted again. In a dry mixer, 18 mg of adipic acid and 5 mg of talc are added to the dried granules. The powder mixture is then filled into the capsule.

12.3 Preparation of C granules for capsule

Dissolve hydroxypropylcellulose (1.3%) in ethanol (96%) to obtain a granulating liquid. Mix N,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III- imidazole-5-carboxamido)-7-oxohept-2-enoate (22.0%), L-hydroxypropyl cellulose (low substituted; 10.6%), croscarmellose sodium (11.0%) and mannitol (11.0%) . A granulating liquid is added to the powder mixture, resulting in a granular mass. This mass is sifted while wet and then dried. After drying, the mass is sifted again. In a dry mixer, adipic acid (39.7%) and talc (4.4%) are added to the dried granules. The powder mixture is then filled into the capsule.

Example 13

Micronization method ^,E)-Methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1methyl-1H- imidazole-5-carboxamido)-7-oxohept-2-enoate is micronized, with the particle size distribution preferably defined as d(0.1) from 0.1 to 5 μm, d(0.5) from 0.3 to 10 µm, d(0.95) from 3 to 25 µm, and the particle size range is from 0.1 to 100 µm.

Example 14

Data on the effectiveness and safety in vivo and the hepatoprotective effect of the pharmaceutical composition in the form of a capsule formulation

The efficacy and safety of 6 weeks of treatment with a compound of formula (I) in the hard gelatin capsule formulation described in Example 2 was studied in 160 adult patients with celiac disease (CeD). Patients who are in clinical and histological remission at the start of the study are challenged with 3 g of gluten per day and randomized to receive placebo or one of 3 doses of the compound of formula (I), i.e., 10, 50 or 100 mg. Every morning, after fasting for at least 6 hours, patients take the study medication orally, and then 30 minutes before breakfast eat one cookie containing 3 g of gluten. During the 6-week study, patients must follow a strict gluten-free diet (see Fig. 12).

The gluten challenge caused a modest but statistically significant increase in alanine aminotransferase (ALT) from baseline to week 6 in the placebo group, but this increase was surprisingly not observed in any of the groups receiving the compound of formula (I) in the form of a hard gelatin capsule. described in Example 2. The difference in ALT between each drug group and placebo was statistically significant (P<0.01 for all comparisons), confirming the protective effect of the compound of formula (I) on the liver of patients with celiac disease exposed to gluten . Alkaline phosphatase (ALP) levels also showed a similar pattern (P<0.05). In the placebo group, values normalize with a gluten-free diet at week 10 (Table 1). The finding that the compound of formula (I) inhibits liver injury, which is one of the gluten-induced extraintestinal manifestations of active celiac disease (CeD), as reflected by a modest increase in ALT and ALP (Ref. 3), indicates that the compound has a general hepatoprotective effect .

Mean (standard deviation) levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) from baseline to week 6 (safety sample, units: U/L)

10 mg (N=41) 50 mg (N=41) 100 mg (N=40) Placebo (N=38) ALT Baseline 20.5 (7.5) 21.4 (8.3) 26.3 (16.9) 23.8 (10.2) Week 6 20.0 (6.1) 22.2 (9.1) 23.7 (9.3) 28.6(11.8) Change from baseline -0.5 (8.1) 0.8 (7.2) -2.6 (13.4) 4.3(1.8) Difference relative to placebo -4.4 -3.8 -4.3 - P value 0.0019 0.0069 0.0022 - Week 10 (Control) 19.7 (5.9) 21.7 (10.2) 23.9(10.1) 23.9 (10.3) AST Baseline 22.5 (8.7) 22.6 (6.8) 260.8 (11.8) 23.9 (7.2) Week 6 22.5 (5.5) 23.6 (7.0) 26.5 (9.6) 26.3 (6.6) Change from baseline 0 (6.7) 1.0 (5.6) -0.4 (14.4) 2.1 (6.4)

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Difference relative to placebo -3.2 -2.2 0.3 - P value 0.0448 0.1423 0.8551 - Week 10 (Control) 20.6 (5.1) 21.9 (5.7) 24.3 (6.5) 24.1 (8.3) A.L.P. Baseline 60.0(18.3) 57.8 (15.0) 62.7(18.7) 63.6 (19.0) Week 6 59.3 (18.5) 57.3 (15.3) 62.3 (22.1) 67.0 (22.9) Change from baseline -L0 (5.4) -0.5 (5.7) -0.5 (8.4) 3.3 (7.8) Difference relative to placebo -2.6 -2.8 -2.8 -

Normal intervals for adult women/men: ALT, AST (10-35/10-50 units/l), ALP (35104/40-129 units/l)

Example 14 links:

. Korpimaki S, Kaukinen K, Collin R, et al. Gluten-sensitive hypertransaminasemia in celiac disease: an infrequent and often subclinical finding. The American journal of gastroenterology 2011; 106:1689-96.

Kahaly GJ, Frommer L, Schuppan D. Celiac disease and endocrine autoimmunity - the genetic link. Autoimmun Rev 2018;17:1169-75.

.Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet 2018;391:70-81.

Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut 2013;62:43-52.

. Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology 2009;137:1912-33.

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Claims (10)

CLAIM 1. Systemic composition containing ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2oxo-1,2-dihydropyridin-3-ylamino)-6-(1 -methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate of formula (I): (I) or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, at least one polymeric precipitation inhibitor and at least one acidifying agent, wherein the at least one polymeric precipitation inhibitor is selected from the group consisting of L-hydroxypropylcellulose, hydroxypropylcellulose , combinations of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylcaprolactam-polyvinyl acetate graft copolymer t-polyethylene glycol and sodium carboxymethylcellulose; and at least one acidulant is selected from the group consisting of ascorbic acid, an organic dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid or glutamic acid acid, and an organic tricarboxylic acid such as citric acid or sodium hydrogen citrate. 2. The systemic formulation according to claim 1, wherein the systemic formulation is an oral formulation. 3. The systemic composition according to claim 1 or 2, where the systemic composition additionally contains at least one binder. 4. The systemic composition according to claim 3, wherein at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potatoes , pregelatinized (modified) starch derived from wheat, corn, rice and potatoes, sodium starch glycolate, natural gums, acacia, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives , hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, povidone K25. 5. A systemic composition according to any one of claims 1-4, in which the particles are ^,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine -3-ylamino)-6-(1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate have a particle size distribution defined as d(0.95) <25 μm. 6. A systemic composition according to any one of claims 1 to 5, wherein the systemic composition is a tablet, coated tablet, capsule, powder or granule. 7. The systemic composition according to any one of claims 1 to 6, where the systemic composition contains from 1 to 15 wt./wt. acidifier, from 0.1 to 7 wt./wt. polymer precipitation inhibitor, where wt./wt. (mass ratio) of the indicated compounds are calculated relative to the mass of N,E)-methyl-7-(1-(2-(2ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6- (1-methyl-III-imidazole-5-carboxamido)-7-oxohept-2-enoate. 8. Systemic composition according to any one of claims 1 to 7, where the composition contains from 0.1 to 45 wt.%. (S,E)methyl-7-( 1 -(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-( 1 -methyl-shimide azole -5-carboxamido)-7-oxohept-2-enoate, 3 to 75 wt.% acidifier, 2 to 35 wt.% polymer precipitation inhibitor, 0 to 12 wt.% binder, 2 to 35 wt.% disintegrant and from 1 to 9 wt.% lubricant/glidant. 9. The systemic composition according to any one of claims 1 to 8, where the systemic composition contains from 0.1 to 45 wt.% ^,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2 -oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-III-imidazol-5-carboxamido)-7-oxohept-2-enoate, from 3 to 75 wt. % adipic acid, 2 to 35 wt% L-hydroxypropylcellulose and/or hydroxypropylcellulose, 0 to 12 wt% povidone K25, 2 to 35 wt% croscarmellose sodium and 1 to 9 wt% talc or silica . 10. Use of a systemic composition according to any one of claims 1 to 9 in the prevention and/or treatment of diseases associated with transglutaminase 2 (TG2). - 109 -